Patent Application
20090264399
The present invention relates to novel compounds which are Janus Kinase 3 (JAK3) inhibitors, useful as a medicament, and to a pharmaceutical composition comprising the same.
JAK3 is a member of the Janus family of protein kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoetic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. XSCID patient populations have been identified with severely reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosuppression should result from blocking signaling through the JAK3 pathway. Animals studies have suggested that JAK3 not only plays a critical role in B- and T-lymphocyte maturation, but that JAK3 is constitutively required to maintain T-cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.
WO 2004/099205 discloses an JAK3 inhibitor represented by the following formula:
WO 2004/099204 discloses an JAK3 inhibitor represented by the following formula:
WO 99/65908, WO 99/65909, WO 01/42246, and WO 02/00661 disclose an JAK3 inhibitor represented by the following formula:
The present invention relates to a novel compound useful as a medicament, and to a pharmaceutical composition comprising the same. More particularly, the present invention relates to a compound having a potent inhibitory effect on the activity of Janus Kinase 3 (JAK3).
The inventors of the present invention have also found that JAK3 inhibitors, such as a compound of the formula (I) (hereinafter compound (I) or (I)), have a potent immunosuppressive effect and potent antitumor effect. Therefore, a JAK3 inhibitors such as compound (I) is useful as an active ingredient for a therapeutic or prophylactic agent for diseases or conditions caused by undesirable cytokine signal transduction, such as rejection reaction in organ transplantation, autoimmune diseases, asthma, atopic dermatitis, Alzheimer's disease, atherosclerosis, tumors, myelomas and leukemia, etc.
Accordingly, one object of the present invention is to provide a compound having biological activities for treating or preventing the diseases as stated above. And a further object of the present invention is to provide a pharmaceutical composition containing the compound (I) as an active ingredient. A yet further object of the present invention is to provide use of the JAK3 inhibitors, such as compound (I), for treating and preventing the diseases as stated above. A yet further object of the present invention is to provide a commercial package comprising the pharmaceutical composition containing the compound (I) and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating or preventing the diseases as stated above.
Thus, the present invention provides a compound having the following formula (I):
wherein
Another one of the preferred embodiments of the present invention can be represented by the compound (I), which is a compound having the following formula (Ia):
wherein
Another one of the preferred embodiments of the present invention can be represented by the compound (Ia), which is
Another one of the more preferred embodiments of the present invention can be represented by the compound (Ia), which is
Another one of the more preferred embodiments of the present invention can be represented by the compound (Ia), which is
Another one of the preferred embodiments of the present invention can be represented by the compound (I), which is a compound having the following formula (Ib):
wherein
Another one of the preferred embodiments of the present invention can be represented by the compound (Ib), wherein
Another one of the preferred embodiments of the present invention can be represented by the compound (Ib), wherein
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
Each of the terms “halogen” and “halo” includes fluorine, chlorine, bromine and iodine.
The term “heteroatom” includes nitrogen atom, oxygen atom and sulfur atom.
The term “lower” used in the description is intended to include 1 to 6 carbon atom(s) unless otherwise indicated.
Suitable “one or more” includes the number of 1 to 6, preferably 1 to 3.
The term “alkyl” includes a monovalent group of a straight or branched alkyl having 1 to 12 carbon atom(s) such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, neopentyl and the like.
Suitable “lower alkyl” includes straight or branched alkyl having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, etc.
The term “alkenyl” includes a monovalent group of a straight or branched alkyl having 2 to 12 carbon atom(s) such as ethenyl, propenyl, buthenyl, pentenyl, hexenyl, isopropenyl, neopenteyl and the like.
Suitable “lower alkyl” includes straight or branched alkyl having 2 to 6 carbon atom(s) such as methyl, ethenyl, allyl, propenyl, buthenyl, pentenyl, hexenyl, etc.
Suitable “cycloalkyl” includes cycloalkyl having 3 to 9 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc. Suitable “cycloalkyl” also includes cycloalkenyl having 3 to 9 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.
Suitable “cyclo(lower)alkyl” includes cycloalkyl or cycloalkenyl, each of which have 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl etc.
Suitable “lower alkoxy” includes straight or branched alkoxy having 1 to 6 carbon atom(s) such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc.
Suitable “halo(lower)alkyl” includes lower alkyl substituted with 1 to 3 halogen atom(s) such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, etc.
Suitable “lower alkenylene” includes straight or branched alkenylene having 2 to 6 carbon atom(s) such as vinylene, 1-methylvinylene, 2-methylvinylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 2-methyl-2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, etc.
Suitable “aryl” includes C6-C16 aryl such as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, azulenyl, etc.
Suitable “aryloxy” includes C6-C16 aryloxy such as phenoxy, naphthyloxy, anthryloxy, pyrenyloxy, phenanthryloxy, azulenyloxy, etc.
Suitable “aryl(lower)alkyl” includes phenyl(C1-C6)alkyl such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, etc., naphthyl(C1-C6)alkyl such as naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphtylhexyl, etc.
Suitable “aryl(lower)alkoxy” includes phenyl(C1-C6)alkoxy such as benzyloxy, phenethyloxy, phenylpropyloxy, phenylbutyloxy, phenylhexyloxy, etc., naphthyl(C1-C6)alkyloxy such as naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, naphthylpentyloxy, naphtylhexyloxy, etc.
Suitable “amino” includes unsubstituted amino, and amino mono- or di-substituted with substituent(s) selected from lower alkyl, lower alkanoyl and cycloalkyl such as N—(C1-C6 alkyl)amino (e.g., N-methylamino, N-ethylamino, N-propylamino, N-(n-butyl)amino, N-isobutylamino, N-(t-butyl)amino, etc.), N—(C1-C6 alkanoyl)amino (e.g., N-formylamino, N-acetylamino, N-propionylamino, N-butyrylamino, N-valerylamino, N-isovalerylamino, N-pivaloylamino, etc.), N—(C3-C6 cycloalkyl)amino (e.g., N-cyclopropylamino, N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, etc.), N,N-di(C1-C6 alkyl)amino (e.g., N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, etc.), etc.
The “acyl” as used herein includes, for example, alkanoyl [e.g., formyl, lower alkyl-carbonyl (e.g., acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, pivaloyl, 2,2-dimethylpropanoyl, hexanoyl and the like), heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl and the like];
alkoxycarbonyl [e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and the like) and the like];
lower alkyl-carbonyloxy(lower)alkylcarbonyl (e.g. acetyloxyacetyl, ethylcarbonyloxyacetyl and the like);
arylcarbonyl [e.g., C6-10 arylcarbonyl (e.g., benzoyl, toluoyl, naphthoyl, fluorenylcarbonyl and the like)];
arylalkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl and the like), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl and the like) and the like];
arylalkenoyl [e.g., aryl(C3-C6)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl and the like) and the like)];
naphthylalkenoyl [e.g., naphthyl(C3-C6)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, naphthylmethacryloyl, naphthylpentenoyl, naphthylhexenoyl and the like) and the like];
arylalkoxycarbonyl [e.g., aryl(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl and the like), fluorenyl(lower)alkoxycarbonyl (e.g., fluorenylmethyloxycarbonyl and the like) and the like];
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl and the like);
aryloxyalkanoyl [e.g., aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl and the like) and the like];
heterocyclic acyl (e.g., heterocyclic carbonyl and the like); heterocyclic alkanoyl [e.g., heterocyclic(lower)alkanoyl (e.g., heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclic hexanoyl and the like) and the like]; heterocyclic alkenoyl [e.g., heterocyclic(lower)alkenoyl (e.g., heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl and the like)];
carbamoyl;
alkylcarbamoyl [e.g., lower alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl and the like)];
alkoxycarbamoyl [e.g., lower alkoxycarbamoyl (e.g., methoxycarbamoyl, ethoxycarbamoyl and the like)] and the like;
arylcarbamoyl [e.g., C6-10-arylcarbamoyl (e.g., phenylcarbamoyl, naphthylcarbamoyl and the like) and the like];
arylthiocarbamoyl [e.g., C6-10 arylthiocarbamoyl (e.g., phenylthiocarbamoyl, naphthylthiocarbamoyl and the like) and the like];
alkylsulfonyl [e.g., lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and the like)];
alkoxysulfonyl [e.g., lower alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl and the like)] and the like;
arylsulfonyl (e.g., phenylsulfonyl and the like);
arylglyoxyloyl [e.g., C6-10 arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl and the like) and the like];
heterocyclic glyoxyloyl; and the like. Each of these acyl is optionally substituted by one or more suitable substituent(s).
Suitable “carbamoyl optionally mono- or di-substituted with lower alkyl(s)” includes carbamoyl; N-(lower)alkylcarbamoyl in which the alkyl portion is alkyl haying 1 to 6 carbon atom(s) such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert-butylcarbamoyl, N-pentylcarbamoyl, N-neopentylcarbamoyl, N-isopentylcarbamoyl, N-hexylcarbamoyl, etc.; N,N-di(lower)alkylcarbamoyl in which the alkyl portions are each alkyl having 1 to 6 carbon atom(s) such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, N,N-diisobutylcarbamoyl, N,N-di-tert-butylcarbamoyl, N,N-dipentylcarbamoyl, N,N-dineopentylcarbamoyl, N,N-diisopentylcarbamoyl, N,N-dihexylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-methyl-N-propylcarbamoyl, N-butyl-N-methylcarbamoyl, N-methyl-N-isobutylcarbamoyl, etc. Each of these carbamoyl is optionally substituted by one or more suitable substituent(s).
The “heteroaryl” includes groups having 5 to 14 ring atoms and π electrons shared in a cyclic array and containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur besides carbon atoms. Suitable “heteroaryl” includes such as thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, etc.
The “heteroaryl” and “(lower)alkyl” of the “heteroaryl(lower)alkyl” are similar to those exemplified for the “heteroaryl” and “(lower)alkyl” respectively. Suitable “heteroaryl(lower)alkyl” includes pyridylmethyl, pyridylethyl, quinolylmethyl, etc.
The “heterocycloalkyl” includes group having 4 to 14 ring atoms and containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur besides carbon atoms.
More suitable “heterocycloalkyl” includes group having 4 to 14 ring atoms and containing 1 to 3 nitrogen atom.
Most suitable “heterocycloalkyl” includes such as azetizinyl, pyrrolidinyl, piperazinyl, piperidinyl, homopiperazinyl, morpholinyl (e.g., morpholino etc.), thiomorpholinyl (e.g., thiomorpholino etc.), etc.
Suitable “heterocyclo(lower)alkyl” includes group having 4 to 7 ring atoms and 1 to 3 heteroatoms as above which is saturated.
More suitable “heterocyclo(lower)alkyl” includes group having 4 to 7 ring atoms and 1 to 3 nitrogen atoms as above which is saturated.
Most suitable “heterocyclo(lower)alkyl” includes group such as azetizinyl, pyrrolidinyl, piperazinyl, piperidinyl, homopiperazinyl, etc.
Suitable “n” of the “—(CH2)n-” for M is an integer of 0 to 4, preferably 0 or 1. The “—(CH2)n-” is optionally substituted with one or more suitable substituent(s) such as lower alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.), aryl(lower)alkyl (e.g. benzyl, etc.), etc. Furthermore, one or more methylenes (e.g., one methylene, etc.) may be replaced with suitable heteroatoms (e.g., oxygen atom, etc.).
Suitable examples of the “amino or hydroxyl protective group” include: acyl as described above; heterocyclic group (e.g., tetrahydropyranyl and the like); trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl (TBDMS), tri-tert-butylsilyl and the like), lower alkyldiarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl (TBDPS) and the like) and the like].
Suitable examples of the “carboxyl protective group” include: lower alkyl (e.g., methyl, ethyl, tert-butyl, benzyl and the like), alkenyloxycarbonyl (e.g., allyloxycarbonyl and the like);
aryl(lower)alkyl in which the aryl portion is optionally substituted with one or more suitable substituent(s) (e.g., benzyl, p-methoxybenzyl, (o or p)-nitrobenzyl, phenethyl, trityl, benzhydryl, bis(methoxyphenyl)methyl, m, p-dimethoxybenzyl, 4-hydroxy-3,5-di-t-butylbenzyl and the like);
[5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl (e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl and the like); and the like.
As substituent groups that can be used for the term “optionally substituted” or “which may be substituted”, those commonly used as substituent groups for each group can be used, and each group may have one or more substituent groups.
Suitable substituent in —R2 includes hydrogen, halogen, cyano, carboxy, carboxy or carbamoyl, etc.
As the substituent groups that can be used for “cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which may be substituted” in the definition of —R4 and —R6 the following groups (a) to (h) can be exemplified. Wherein, “RZ” is a lower alkyl which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, amino which may be substituted with one or two lower alkyls, aryl, heteroaryl and halogen.
(a) halogen;
(b) —OH, —ORZ, —O-aryl, —OCO—RZ, oxo(═O);
(c) —SH, —SRZ, —S-aryl, —SO—RZ, —SO-aryl, —SO2—RZ, —SO2-aryl, sulfamoyl which may be substituted with one or two RZ;
(d) amino which may be substituted with one or two RZ, —NHCO—RZ, —NHCO-aryl, —NHCO2—RZ, —NHCO2-aryl, —NHCONH2, —NHSO2—RZ, —NHSO2-aryl, —NHSO2NH2, nitro;
(e) —CHO, —CO—RZ, —CO2H, —CO2—RZ, carbamoyl which may be substituted with one or two RZ, cyano;
(f) aryl or cycloalkyl, each of which may be substituted with one or more groups selected from the group consisting of —OH, —O— (lower alkyl), amino which may be substituted with one or two lower alkyl, halogen and RZ.
(g) heterocycloalkyl or heteroaryl, each of which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, amino which may be substituted with one or two lower alkyl, halogen and RZ.
(h) C1-C6 alkyl which may be substituted with one or more groups selected from the substituent groups described in (a) to (g).
The compound (I) may be a salt, which is also encompassed in the scope of the present invention. For example, in case a basic group such as an amino group is present in a molecule, the salt is exemplified by an acid addition salt (e.g. salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid (e.g., [(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid or an enantiomer thereof, etc.), fumaric acid, maleic acid, mandelic acid, citric acid, salicylic acid, malonic acid, glutaric acid, succinic acid, etc.), etc., and in case an acidic group such as carboxyl group is present, the salt is exemplified by a basic salt (e.g. salt with a metal such as lithium, sodium, potassium, calcium, magnesium, aluminium, etc., a salt with amino acid such as lysine, etc.), etc.
In addition, solvates of the compound (I) such as hydrate, ethanolate, etc., are also encompassed in the scope of the present invention.
In case the compound (I) has stereoisomers, such isomers are also encompassed in the scope of the present invention. In addition to the processes as mentioned above, the compound (I) and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in a manner similar thereto. The starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto. The compound (I) and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto.
And, the thus-obtained compounds can be subjected to a process commonly used in the art such as alkylation, acylation, substitution, oxidation, reduction, hydrolysis, and the like to prepare some of the compounds of the general formula (I).
The following abbreviations are also used in the present specification: AcOH (acetic acid); DMSO (dimethylsulfoxide); MgSO4 (magnesium sulfate); Pd(OAc)2 (palladium acetate); CHCl3 (chloroform); EtOAc (ethyl acetate); DMI (1,3-dimethyl-2-imidazolidinone); HCl (hydrochloric acid); NMP (N-methyl-2-pyrrolidone); DMSO (dimethylsulfoxide); Zn (CN)2 (zinc cyanide); NaCN (sodium cyanide); WSCD (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); DCC (N,N′-dicyclohexylcarbodiimide); BopCl (Bis(2-oxo-3-oxazolidinyl)phosphinic chloride); NaOH (sodium hydroxide); LiOH (lithium hydroxide).
The compound and its pharmaceutically acceptable salt of the present invention can be prepared by various known synthesis methods, using characteristics based on its basic backbone or the kinds of substituent groups. The following describes representative preparation methods. And, according to the kinds of functional groups, it is advantageous in some cases in terms of preparation technique to substitute a functional group with a suitable protection group, i.e., a group that can be easily converted into the functional group, in the starting material or intermediate step. Then, if necessary, the protection group is removed to obtain a desired compound. Examples of the functional group include hydroxyl, carboxyl, amino group and the like, and examples of the protection group include those described in “Protective Groups in Organic Synthesis”, third edition, edited by Greene and Wuts. It is preferable to suitably use them depending on reaction conditions.
[wherein —Ri, —R4, —R5, —R6, -M-, —X— and —Y═ are as defined in the foregoing, —R3 is hydrogen and —Rb is carboxy moiety.]
The compound (Ia) can be prepared by reacting the (Ibb) with diphenylphosphoryl azide (DPPA) in the presence of a base such as triethylamine, pyridine and the like. As azide reagent, DPPA, sodium azide and the like are appropriate. Therefore it is necessary —R3 is hydrogen. Moreover, In case —R6 is not hydrogen, the object compound can be prepared by alkylation and the like by the (Ia). The reaction may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by tert-butanol, toluene and the like. The temperature of the reaction is not critical, and the reaction is usually carried out from ambient temperature to the boiling point of the solvent.
[wherein Lv: leaving group, —R1, —R2, —R3, —R4, —R5, -M-, —X— and —Y═ are as defined in the foregoing.]
In this process, substitution reaction can be applied to prepare the compound (Ib). Example of leaving group include halogen, alkanesulfonyl optionally substituted by one or more halogen, arylsulfonyl and the like. The compound (2a) can be reacted with a compound “R4MNHR3 (2b)” in a non-protic polar solvent such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like; an inert organic solvent such as halogenated hydrocarbon including dichloromethane, dichloroethane, chloroform and the like; ether including ether, tetrahydrofuran (THF), dioxane and the like; aromatic hydrocarbon including benzene, toluene, xylene and the like; or water, or a mixture thereof to prepare a compound (Ib). The reaction is preferably carried out at ambient temperature to reflux temperature of the used solvent.
In order to progress the reaction smoothly, it is advantageous in some cases to employ an excess amount of the compound (2b) or carry out the reaction in the presence of a base such as N-methylmorpholine, triethylamine, diethylisopropylamide, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine and the salt thereof and the like.
In addition this reaction can be also carried out in microwave reactor. And the reaction can be carried out with cesium carbonate under the existence of catalyst amount of palladium reagent.
[wherein Lv is leaving group; —R1, —R2, —R3, —R4, —R5, -M and —X— are as defined in the foregoing.]
In this process, compound (3b) can be prepared in accordance with the Process 2. In case —R1 is hydrogen and -M is bond, the compound (I) is prepared using a reagent such as trialkyl orthoformate in the presence of a acid catalyst such as hydrochloric acid, sulfuric acid and the like. It is preferable to carry out reduction of nitrogroup into amino group before this reaction. As reagent, reagent trialkyl orthocarbonate, alkylisothiocyanate, aryl aldehyde and the like are appropriate. The reaction may be carried out in a conventional solvent which does not adversely influence the reaction, which is exemplified by toluene and the like. The temperature of the reaction is not critical, and the reaction is usually carried out at ambient temperature to the boiling point of the solvent.
[wherein —R1, —R3, —R4, —R5, -M-, —X— and —Y═ are as defined above; —R2a is the same as above —R2 having protected carboxy, —R2b is the same as above, and —R2c is the same as above —R2 having —CONR8R9 moiety (wherein —R8 and —R9 are same or different cycloalkyl, aryl, or lower alkyl which is substituted with cyano)]
The compound (Ibb) is obtained by deprotecting the carboxy protective group of the compound (Iba). The reaction may be carried out by heating in the presence of water and a catalyst for ester hydrolysis and the like. Suitable catalysts for the ester hydrolysis includes, for example, bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. Optionally, one or more suitable solvent(s) for the deprotection is(are) used for this reaction. Such solvent includes such as methanol, ethanol, dioxane, etc. The temperature of the reaction is not critical, and the reaction is usually carried out from under cooling to heating.
The compound (Ibc) is obtained by reaction of the compound (Ibb) with “R8R9NH(4a)” in the presence of condensing reagents such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD. HCl) and the like. The reaction is, although it varies depending on the reactive derivatives or condensing agent, carried out in an inert solvent such as a halogenated hydrocarbon, aromatic hydrocarbon, ether, DMF, DMSO and the like, under cooling, cooling to ambient temperature, or ambient temperature to heating. In case 1 g is reacted in its acid halide form, to progress the reaction smoothly, it is advantageous in some cases to carry out the reaction in the presence of a base.
Intermediate is obtained according to the following processes or methods disclosed in the Preparations.
In the following Processes A, B, C, D and E, each of the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto.
[wherein —R1, —R2, —R3, —R4, —R5, —R8, —R9, —R2a, —R2b, —R2c, -M-, —X—, —Y═ and -Lv are as defined above, -Hal. is halogen, -Pg is protective group.]
In order to show the usefulness of the compound (I) of the invention, the pharmacological test result of the representative compound of the present invention is shown in the following.
The assay for JAK3 activity was performed basically according to the method as proposed by Okimoto et al, as follows.
Purified kinase domain (KD) of human JAK3 was purchased from Carna Bioscience Inc. (Kobe, Japan). 796-1124 (end) amino acids of human JAK3 [accession number #NM—000215] was expressed as N-terminal His-tagged protein (41 kDa) using the baculovirus expression system and purified by using Ni-NTA affinity chromatography.
Biotin-Lyn-Substrate-peptide and ATP were used as substrates. Assay buffer consisted of 15 mM Tris-HCl pH7.5, 0.01% Tween 20 and 2 mM DTT. For the standard assay, 20 μL of substrate solution (Assay buffer containing 627 nM Biotin-Lyn-Substrate-2, 20 μM ATP and 25 mM MgCl2), 10 μL of assay buffer containing test compound and 20 μL of enzyme solution were added to the plate and mixed well.
After 1 hour incubation at ambient temperature, the plate was washed 4 times with wash buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.02% Tween 20), and then blocking buffer (wash buffer containing 0.1% Bovine serum albumin) was added to the plate. After 30 minutes incubation at ambient temperature, blocking buffer was removed and HRP-PY-20 solution (HRP-PY-20 500 times diluted with blocking buffer) was added. After 30 minutes incubation at ambient temperature, the plate was washed 4 times and TMB substrate solution (Sigma) was added to the plate. After 4 minutes incubation at ambient temperature, 1 M H2SO4 was added to the plate to stop the reaction. Enzyme activity was measured as optical density at 450 nm.
The results of those tests are shown in the Table 1.
Among these Example compounds, some of preferred compounds IC50 values are exemplified as follows; 3.0 nM for Example 106, 3.0 nM for Example 112, 5.1 nM for Example 118.
The pharmaceutical composition of the present invention comprising JAK3 inhibitor such as the compound (I) is useful as a therapeutic or prophylactic agent for diseases or conditions caused by undesirable cytokine signal transduction, such as rejection reaction in organ transplantation, autoimmune diseases, asthma, atopic dermatitis, Alzheimer's disease, atherosclerosis, tumors, myelomas, and leukemia as exemplified below:
rejection reactions by transplantation of organs or tissues such as the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, islet, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc.; and graft-versus-host reactions following bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes and complications from diabetes, etc.
Furthermore, pharmaceutical preparations of the JAK3 inhibitor, such as the compound (I), are useful for the therapy or prophylaxis of the following diseases.
Inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases (e.g., psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous penphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, erythema, dermal eosinophilia, lupus erythematosus, acne, alopecia greata, etc.);
autoimmune diseases of the eye (e.g., keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's opthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine opthalmopathy, etc.);
reversible obstructive airways diseases [asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, etc.), particularly chronic or inveterate asthma (e.g., late asthma, airway hyper-responsiveness, etc.), bronchitis, etc.];
mucosal or vascular inflammations (e.g., gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel diseases, enteritis, necrotizing enterocolitis, intestinal damages associated with thermal burns, leukotriene B4-mediated diseases, etc.);
intestinal inflammations/allergies (e.g., coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, etc.);
food-related allergic diseases with symptomatic manifestation remote from the gastrointestinal tract (e.g., migrain, rhinitis, eczema, etc.);
autoimmune diseases and inflammatory conditions (e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g., arthritis deformans, etc.), polychondritis, etc.);
allergic conjunctivitis.
Therefore, the pharmaceutical composition of the present invention is useful for the therapy and prophylaxis of liver diseases [e.g., immunogenic diseases (e.g., chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis, sclerosing cholangitis, etc.), partial liver resection, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock, anoxia, etc.), hepatitis B, non-A non-B hepatitis, hepatocirrhosis, hepatic failure (e.g., fulminant hepatitis, late-onset hepatitis, “acute-on-chronic” liver failure (acute liver failure on chronic liver diseases, etc.), etc.), etc.].
Pharmaceutical preparations of the JAK3 inhibitor, such as the compound (I), either from alone or in combination with one or more additional agents which may include but are not limited to cyclosporin A, tacrolimus, sirolimus, everolimus, micophenolate (e.g. Cellcept®, Myfortic®, etc.), azathioprine, brequinar, leflunomide, sphingosine-1-phosphate receptor agonist (e.g. fingolimod, KRP-203, etc.), LEA-29Y, anti-IL-2 receptor antibody (e.g. daclizumab, etc.), anti-CD3 antibody (e.g. OKT3, etc.), Anti-T cell immunogloblin (e.g. AtGam, etc.) aspirin, CD28-B7 blocking molecules (e.g. Belatacept, Abatacept, etc.), CD40-CD154 blocking molecules (e.g. Anti-CD40, antibody, etc.), protein kinase C inhibitor (e.g. AEB-071, etc.), acetaminophen, ibuprofen, naproxen, piroxicam, and anti inflammatory steroid (e.g. prednisolone or dexamethasone) may be administrated as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice.
The pharmaceutical composition of the present invention can be used in the form of pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the JAK3 inhibitor, such as the compound (I), as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream, and any other form suitable for use.
The carriers those can be used for the present invention include water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations in a solid, semisolid, or liquid form. Furthermore, auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used.
For applying the composition to human, it is preferable to apply it by intravenous, intramuscular, topical or oral administration, or by a vascular stent impregnated with the compound (I). While the dosage of therapeutically effective amount of the JAK3 inhibitor, such as the compound (I), varies from and also depends upon the age and condition of each individual patient to be treated, in case an individual patient is to be treated; in the case of intravenous administration, a daily dose of 0.1-100 mg of the JAK3 inhibitor, such as the compound (I), per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1-100 mg of the JAK3 inhibitor, such as the compound of the formula (I)], per kg weight of human being, and in the case of oral administration, a daily dose or 0.5-50 mg of the JAK3 inhibitor, such as the compound (I), per kg weight of human being, is generally given for treatment.
During the preparation of the above-mentioned pharmaceutical administration forms, the compound (I) or a salt thereof can also be combined together with other immunosuppressive substances, for example rapamycin, mycophenolic acid, cyclosporin A, tacrolimus or brequinar sodium.
Hereinafter the reactions in each Preparations and Examples for preparing the compound (I) of the present invention are explained in more detail. The invention should not be restricted by the following Preparations and Examples in any way.
To the solution of 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine in 1,3-dimethyl-2-imidazolidinone was added Zn(CN)2 and tetrakis(triphenylphosphine)palladium(0) at ambient temperature. This was stirred at 140° C. for 1.5 hours. The reaction was cooled and was added water, extracted with EtOAc. The organic layer was washed with brine and was dried over MgSO4 and evaporated. Resultings were purified by silica gel column chromatography to afford 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as white powder.
1H-NMR (DMSO-d6) δ: 7.62-7.85 (4H, m), 8.17-8.22 (2H, m), 8.47 (1H, d, J=5.3 Hz), 9.13 (1H, s).
4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile was treated with 2M NaOH solution (4 ml) in tetrahydrofuran (8 ml) at ambient temperature for 1 hour. The reaction mixture was cooled and was added water. The aqueous layer was extracted with EtOAc. And the organic layer was washed with brine, dried over MgSO4 and concentrated. Resultings were purified by silica gel column chromatography to give 4-chloro-1H-pyrrolo[2,3-b]-pyridine-3-carbonitrile as colorless powder.
1H-NMR (DMSO-d6) δ: 7.42 (1H, d, J=5.3 Hz), 8.34 (1H, d, J=5.3 Hz), 8.68 (1H, s, 13.20 (1H, br).
To a solution of 4-chloro-2-pyridinecarboxylic acid (5.95 g) in tert-butanol (89.25 mL) were added triethylamine (6.32 mL) and diphenylphosphoryl azide (8.95 mL). The mixture was stirred at 100° C. for overnight. To the solution was added water and the mixture was extracted with EtOAc and washed with water and brine. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized with EtOAc to give a white solid. The solid was dissolved in dioxane (50 mL). To the solution was added 4M HCl in dioxane (90 mL) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure to give 4-chloro-2-pyridinamine hydrochloride (3.02 g) as a white solid.
1H-NMR (DMSO-d6) δ: 6.95 (1H, dd, J=2.0, 6.9 Hz), 7.14 (1H, d, J=2.0 Hz), 8.02 (1H, d, J=6.9 Hz), 8.64 (2H, br).
MS (ESI): m/z 129 (M+H)+.
4-Chloro-2-pyridinamine hydrochloride (300 mg) was added portionwise to concentrated sulfuric acid (1.96 mL) at 4° C. To the mixture was added fuming nitric acid (0.1 mL) dropwise at 4° C. The mixture was stirred at ambient temperature for 3 hours. To the solution was added water and the mixture was extracted with EtOAc. The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane to give 4-chloro-3-nitro-2-pyridinamine (125 mg) as a yellow powder.
1H-NMR (DMSO-d6, δ): 6.87 (1H, d, J=5.0 Hz), 7.25 (2H, br), 8.12 (1H, d, J=5.0 Hz).
MS (ESI): m/z 174 (M+H)+.
In a microwave reaction vessel 4-chloro-3-nitro-2-pyridinamine (125 mg) and (3R,4R)-1-benzyl-N,4-dimethyl-3-piperidinamine (314 mg) were suspended in 2-propanol (6.25 mL). To the mixture was added N,N-diisopropylethylamine (0.63 mL). The vessel was sealed and reacted in the microwave reactor at 135° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-3-nitro-2,4-pyridinediamine (230 mg) as a yellow amorphous.
1H-NMR (DMSO-d6) δ: 0.92 (3H, d, J=6.9 Hz), 1.21-1.66 (2H, m), 1.96-2.17 (2H, m), 2.46-2.51 (1H, m), 2.57-2.71 (1H, m), 2.83-2.85 (1H, m), 3.48 (3H, s), 3.86 (2H, s), 3.86-3.88 (1H, m), 6.33 (2H, d, J=6.2 Hz), 6.81 (2H, br), 7.20-7.36 (5H, m), 7.67 (2H, d, J=6.2 Hz).
MS (ESI): m/z 356 (M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 5.
1H-NMR (DMSO-d6) δ: 0.94 (3H, d, J=6.8 Hz), 1.33 (3H, t, J=7.1 Hz), 1.81-1.84 (2H, m), 2.12-2.17 (1H, m), 2.25-2.47 (4H, m), 3.43-3.53 (2H, m), 4.26 (1H, m), 4.29 (2H, q, J=7.1 Hz), 6.58 (1H, d, J=3.5 Hz), 7.18 (1H, d, J=3.5 Hz), 7.22-7.27 (1H, m), 7.33 (4H, d, J=4.4 Hz), 8.56 (1H, s), 9.03-9.01 (1H, m), 11.66 (1H, brs).
MS (ESI+): m/z 393.
1H-NMR (DMSO-d6) δ: 1.18-1.50 (12H, m), 1.70-2.06 (4H, m), 3.23-4.12 (5H, m), 4.26 (2H, q, J=7.0 Hz), 6.70-6.79 and 7.01-7.10 (total 1H, each m), 7.13-7.22 (1H, m), 8.53 (1H, s), 8.74-8.89 (1H, m), 11.68 (1H, brs).
MS (ESI+): m/z 389.
To a solution of N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-3-nitro-2,4-pyridinediamine (230 mg) in ethanol (3.45 mL) and water (1.15 mL) were added iron powder (108 mg) and ammonium chloride (17 mg). The mixture was refluxed for 4 hours, then filtrated and extracted with 4:1 solution of chloroform and methanol. The extract was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:0:90:10) to give N4-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-2,3,4-pyridinetriamine (207 mg) as a pale brown powder.
1H-NMR (DMSO-d6) δ: 0.86 (3H, d, J=7.0 Hz), 1.52 (1H, m), 1.72 (1H, m), 2.12-2.32 (2H, m), 2.44 (3H, s), 2.66-2.73 (1H, m), 3.22-3.55 (4H, m), 4.58 (1H, m), 6.50 (1H, d, J=5.9 Hz), 7.24 (1H, d, J=5.9 Hz), 7.27-7.35 (5H, m).
MS (ESI): m/z 326 (M+H)+.
The following compound was obtained in a similar manner to that of preparation 8.
1H-NMR (DMSO-d6) δ: 0.87 (3H, d, J=7.1 Hz), 1.12-1.62 (8H, m), 2.14 (1H, m), 2.94 (3H, s), 2.77-2.83 (1H, m), 4.31 (1H, brs), 5.30 (1H, brs), 6.40 (1H, d, J=5.5 Hz), 7.28 (1H, d, J=5.5 Hz).
MS (ESI): m/z 235 (M+H)+.
In a microwave reaction vessel 4-chloro-3-nitro-2-pyridinamine (70 mg) and (1S,2R)-2-methylcyclohexanamine hydrochloride (66 mg) were suspended in 2-propanol (0.35 mL). To the mixture was added N,N-diisopropylethylamine (0.21 mL). The vessel was sealed and reacted in the microwave reactor at 130° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give N4-methyl-N4-[(1S,2R)-2-methylcyclohexyl]-3-nitro-2,4-pyridinediamine (75 mg) as a yellow amorphous.
1H-NMR (DMSO-d6) δ: 0.97 (3H, d, J=7.2 Hz), 1.36-1.83 (8H, m), 2.26 (1H, m), 2.65 (3H, s), 3.84-3.91 (1H, m), 6.42 (1H, d, J=6.1 Hz), 6.78 (2H, brs), 7.70 (1H, d, J=6.1 Hz).
MS (ESI): m/z 265 (M+H)+.
The following compounds were obtained in a similar manner to that of preparation 10.
1H-NMR (DMSO-d6) δ: 0.82-1.23 (3H, m), 1.31 (3H, t, J=7.1 Hz), 1.40-1.83 (4H, m), 1.09-2.21 (2H, m), 3.19-3.30 (2H, m), 3.88-3.99 (1H, m), 4.25 (2H, q, J=7.1 Hz), 4.46 (1H, t, J=5.4 Hz), 6.54 (1H, dd, J=1.9 Hz, 3.4 Hz), 7.19 (1H, t, J=2.9 Hz), 8.54 (1H, s), 8.77 (1H, d, J=7.9 Hz), 11.68 (1H, s).
MS (ESI): m/z 318.
1H-NMR (DMSO-d6) δ: 0.98-1.11 (1H, m), 1.32 (3H, t, J=7.1 Hz), 1.37-1.90 (8H, m), 3.21-3.30 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.43-4.49 (2H, m), 6.59-6.61 (1H, m), 7.15-7.18 (1H, m), 8.55 (1H, s), 9.15 (1H, d, J=8.0 Hz), 11.65 (1H, s).
MS (ESI): m/z 318.
1H-NMR (DMSO-d6) δ: 1.53-2.67 (9H, m), 4.48-4.56 (1H, m), 5.33 (2H, s), 6.67-6.76 (2H, m), 7.14-7.17 (1H, m), 7.25-7.30 (1H, m), 7.33-7.49 (5H, m), 8.59 (1H, s), 8.98 (1H, d, J=8.1 Hz), 11.66 (1H, s).
MS (ESI): m/z 393.
1H-NMR (DMSO-d6) δ: 1.44-2.34 (7H, m), 3.21-3.26 (1H, m), 4.20-4.28 (1H, m), 5.32 (2H, s), 6.64 (1H, d, J=3.4 Hz), 7.24-7.27 (1H, m), 7.33-7.49 (6H, m), 8.61 (1H, s), 8.82 (1H, d, J=7.9 Hz), 11.80 (1H, s).
MS (ESI): m/z 375.
1H-NMR (DMSO-d6) δ: 1.31-1.42 (2H, m), 1.55-1.68 (2H, m), 1.92-2.00 (2H, m), 2.11-2.17 (2H, m), 3.62 (3H, s), 3.94-4.02 (1H, m), 5.30 (2H, s), 6.58-6.61 (1H, m), 7.18-7.20 (1H, m), 7.33-7.48 (6H, m), 8.58 (1H, s), 8.73 (1H, d, J=8.0 Hz), 11.72 (1H, s).
MS (ESI): m/z 408.
1H-NMR (DMSO-d6) δ: 1.08 (3H, d, J=6.8 Hz), 1.31 (3H, t, J=7.1 Hz), 1.39 (9H, d, J=12.5 Hz), 2.23-2.38 (1H, m), 3.01-3.05 (1H, m), 3.16 (1H, dd, J=5.0, 11.2 Hz), 3.56 (1H, dd, J=7.1, 10.7 Hz), 3.80 (1H, dd, J=6.2, 11.2 Hz), 4.27 (2H, q, J=7.1 Hz), 4.32-4.40 (1H, m), 6.69 (1H, s), 7.24 (1H, s), 8.57 (1H, s), 8.84 (1H, m), 11.8 (1H, brs).
MS (ESI): m/z 389.
1H-NMR (DMSO-d6) δ: 1.09-2.00 (8H, m), 1.32 (3H, t, J=7.2 Hz), 2.72-2.85 (1H, m), 4.29 (2H, q, J=7.2 Hz), 4.78-4.85 (1H, m), 6.61-6.65 (1H, m), 7.19-7.24 (1H, m), 8.57 (1H, s), 9.29-9.35 (1H, m), 11.74 (1H, brs).
MS (ESI+): m/z 356.
To a solution 4-chloro-5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.04 g) in tetrahydrofuran (4.77 mL) was added dropwise tetra-n-butylammonium fluoride (0.372 mL, 1.0M in tetrahydrofuran) at ambient temperature. After stirred for 1 hour, the mixture was poured into brine (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layeres were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane/EtOAc=1/1) to give 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (520 mg) as a colorless solid.
1H-NMR (CDCl3) δ: 9.75 (1H, brs), 8.23 (1H, s), 7.42 (1H, d, J=3 Hz), 6.63 (1H, d, J=3 Hz).
MS (ESI): m/z 171 (M+H)+.
To a solution of a 2:1 mixture (589.8 mg) of 4-nitro-1H-pyrrolo-[2,3-b]pyridine 7-oxide and 3-nitro-1H-pyrrolo[2,3-b]pyridine-7-oxide in N,N-dimethylformamide (6 ml) was added dropwise methanesulfonyl chloride (0.68 ml) at 65° C. The reaction mixture was stirred at 65° C. for 2 hours. The reaction mixture was quenched with water (30 ml) under ice cooling, and neutralized (pH ˜6.5) with 20% NaOH solution. The resulting precipitates were collected by filtration, dried in vacuo at 40° C., and washed with EtOAc to give 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (172.8 mg) as a brown solid.
1H-NMR (DMSO-d6) δ: 7.5 (1H, d, J=5.1 Hz), 8.36 (1H, d, J=5.5 Hz), 8.92 (1H, s), 13.54 (1H, brs).
MS (ESI−): m/z 196 (M−H)−.
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo-[2,3-b]pyridine (1.22 g) in tetrahydrofuran (12.2 mL) was added 0.95M sec-butyl lithium in n-hexane (8.3 mL) dropwise at −78° C. The mixture was stirred at the same temperature for 1 hour. To the solution was added 4-methylbenzenesulfonyl cyanide (1.43 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (444 mg) as a white solid.
1H-NMR (DMSO-d6) δ: 1.06 (18H, d, J=7.5 Hz), 1.81-1.95 (3H, m), 6.88 (1H, d, J=3.5 Hz), 7.83 (1H, d, J=3.5 Hz), 8.71 (1H, s).
MS (ESI): m/z 356 (M+Na)+.
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (440 mg) in tetrahydrofuran (4.4 mL) was added 1M tetra-n-butylammonium fluoride (1.5 mL). The solution was stirred at ambient temperature for 0.5 hour. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with EtOAc and n-hexane to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (188 mg) as a white solid.
1H-NMR (DMSO-d6) δ: 6.71 (1H, d, J=3.5 Hz), 7.83 (1H, d, J=3.5 Hz), 8.67 (1H, s), 12.64 (1H, br).
MS (ESI): m/z 176.2 (M−H)−.
To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (100 mg) in ethanol (1 mL) was added 1M NaOH solution (0.89 mL) and the mixture was stirred at 50° C. for 2 hours. The mixture was cooled to 4° C. and acidified with 1M HCl and the precipitate was filtrated and washed with water to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (75 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 6.62-6.64 (1H, m), 7.67-7.70 (1H, m), 8.71 (1H, s), 12.35 (1H, brs).
MS (ESI): m/z 195 (M−H)−.
The following compounds were obtained in a similar manner to that of Preparation 22.
1H-NMR (DMSO-d6) δ: 0.97 (3H, d, J=6.8 Hz), 2.07-2.16 (1H, m), 2.32-2.46 (1H, m), 2.67-2.77 (2H, m), 2.87-2.97 (1H, m), 3.06-3.25 (2H, m), 4.29-4.41 (2H, m), 4.55-4.58 (1H, m), 6.90-6.93 (1H, m), 7.38-7.49 (4H, m), 7.65-7.70 (2H, m), 8.64 (1H, s), 10.10-10.13 (1H, m), 11.52 (1H, br), 12.63 (1H, br).
MS (ESI): m/z 365.
1H-NMR (DMSO-d6) δ: 1.28 and 1.40 (total 9H, each brs), 1.61-2.08 (4H, m), 3.00-4.12 (5H, m), 6.76-6.86 and 7.07-7.18 (total 1H, each m), 7.18-7.29 (1H, m), 8.53 (1H, s), 9.24-9.48 (1H, m), 11.92 (1H, brs), 13.03 (1H, br).
MS (ESI): m/z 361.
1H-NMR (DMSO-d6) δ: 0.91-1.25 (24H, m), 1.43-1.53 (1H, m), 1.70-1.84 (2H, m), 2.08-2.34 (2H, m), 3.48-3.59 (2H, m), 3.90-3.97 (1H, m), 3.52-3.54 (1H, m), 7.14 (1H, t, J=3.0 Hz), 7.52-7.54 (1H, m), 8.50 (1H, s), 8.95-9.01 (1H, m), 11.59 (1H, s), 12.32 (1H, br).
MS (ESI): m/z 446.
1H-NMR (DMSO-d6) δ: 0.69-1.94 (30H, m), 2.86-3.12 (2H, m), 4.38-4.45 (2H, m), 6.48-6.54 (1H, m), 7.04-7.09 (1H, m), 8.32 (1H, s), 8.50 (1H, s), 11.35 (1H, br).
MS (ESI): m/z 446.
1H-NMR (DMSO-d6) δ: 1.42-2.27 (8H, m), 3.20-3.26 (1H, m), 4.18-4.28 (1H, m), 6.64 (1H, dd, J=1.9 Hz, 3.4 Hz), 7.26 (1H, t, J=3.0 Hz), 8.54 (1H, s), 9.18-9.24 (1H, m), 11.78 (1H, s), 12.61 (1H, br).
MS (ESI): m/z 285.
1H-NMR (DMSO-d6) δ: 1.28-1.41 (2H, m), 1.55-1.68 (2H, m), 1.93-2.00 (2H, m), 2.10-2.17 (2H, m), 2.37-2.47 (1H, m), 3.62 (3H, s), 3.89-4.00 (1H, m), 6.57 (1H, dd, J=1.8 Hz, 3.6 Hz), 7.17 (1H, dd, J=2.5 Hz, 3.4 Hz), 3.51 (1H, s), 9.02 (1H, d, J=7.7 Hz), 11.63 (1H, s), 12.39 (1H, br).
MS (ESI): m/z 318.
1H-NMR (DMSO-d6) δ: 1.08 (3H, d, J=6.7 Hz), 1.39 (9H, d, J=11.7 Hz), 2.20-2.38 (1H, m), 3.01-3.19 (2H, m), 3.50-3.59 (1H, m), 3.75-3.82 (1H, m), 4.27-4.38 (1H, m), 6.67 (1H, s), 7.21 (1H, s), 8.52 (1H, s), 9.19 (1H, brs), 11.7 (1H, s).
MS (ESI): m/z 383 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.14-2.04 (8H, m), 2.71-2.83 (1H, m), 4.75-4.82 (1H, m), 6.58-6.62 (1H, m), 7.17-7.22 (1H, m), 8.53 (1H, s), 9.63 (1H, brs), 11.65 (1H, brs), 12.43 (1H, brs).
MS (ESI): m/z 356.
1H-NMR (DMSO-d6) δ: 1.59-2.54 (10H, m), 4.44-4.52 (1H, m), 6.65-6.69 (2H, m), 7.10-7.11 (1H, m), 7.26 (1H, s), 8.51 (1H, s), 9.52 (1H, br), 11.47 (1H, s).
MS (ESI): m/z 303.
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (840 mg) in N,N-dimethylformamide (8.4 mL) were added 1-hydroxybenzotriazole (808 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (929 mg). The mixture was stirred at 60° C. for 30 minutes. The solution was cooled to ambient temperature and added 28% ammonium hydroxide aqueous solution (1.2 mL). The mixture was stirred at ambient temperature for 1 hour. To the solution were added water and chloroform and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (90 mg) as a pale yellow powder.
1H-NMR (DMSO-d6) δ: 6.55-6.57 (1H, m), 7.63-7.66 (1H, m), 7.90 (2H, br), 8.29 (1H, s), 12.16 (1H, brs).
MS (ESI): m/z 218 (M+Na)+.
The following compound was obtained in a similar manner to that of Preparation 32.
1H-NMR (DMSO-d6) δ: 1.38 (9H, s), 1.40-1.66 (8H, m), 2.38-2.44 (1H, m), 3.58-3.66 (1H, m), 3.57-3.69 (2H, m), 7.05 (1H, br).
MS (ESI): m/z 243.
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]-pyridine (15 g) in tetrahydrofuran (150 mL) was added 1M sec-butyllithium in tetrahydrofuran (97 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 1 hour. To the mixture was added ethyl chloroformate (9.29 mL) and the mixture was stirred at −78° C. for 0.5 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The extract was wash with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (120 mL) and to the solution was added 1M tetra-n-butylammonium fluoride in tetrahydrofuran (56 mL). The mixture was stirred at ambient temperature for 1 hour and then extracted with EtOAc. The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was with diisopropyl ether to give ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate.
1H-NMR (DMSO-d6) δ: 1.36 (3H, t, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 6.64-6.67 (1H, m), 7.70-7.73 (1H, m), 8.71 (1H, s), 12.41 (1H, br).
MS (ESI): m/z 223 (M−Na)−.
A mixture of 4-chloro-5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (250 mg), N-methylcyclohexanamine (306 μl), Pd(OAc)2 (17 mg), sodium tert-butoxide (176 mg), 2-dicyclohexylphosphino-2′,4′, 6′-tri-1-propyl-1,1′-biphenyl (73 mg) and 1,4-dioxane (2.5 mL) was evacuated and backfield with N2 three times, then degassed with N2 for 10 minutes. The mixture was heated at 100° C. for 2.5 hours. After cooling to ambient temperature, the reaction mixture was concentrated. Purification of the crude product by column chromatography (silica gel, n-hexane:EtOAc=1:50) afforded N-cyclohexyl-5-fluoro-N-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (53 mg) as a colorless solid.
MS (ESI): m/z 404 (M+H)+.
To a solution of cis-3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (500 mg) in tetrahydrofuran (5 ml) was added triethylamine (344 μl) and isobutyl chloroformate (320 μl) under stirring at 0° C. After stirring at 0° C. for 1 hour, sodium borohydride (233 mg) was added, and methanol (5 ml) was added dropwise under stirring at 0° C. After stirring at 0° C. for 1 hour, 10% aqueous potassium hydrogen sulfate (10 ml) was added and neutralized with saturated aqueous sodium hydrogencarbonate. and extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with n-hexane:EtOAc=70:30 to 40:60 to give tert-butyl[cis-3-(hydroxymethyl)cyclohexyl]carbamate (311 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.64-0.79 (2H, m), 0.97-1.26 (2H, m), 1.37 (9H, s), 1.58-1.63 (4H, m), 3.11-3.24 (4H, m), 4.38 (1H, t, J=5.4 Hz), 6.7 (1H, d, J=8.2 Hz).
MS (ESI+): m/z 230.
The following compound was obtained in a similar manner to that of Preparation 36.
1H-NMR (DMSO-d6) δ: 1.06-1.54 (8H, m), 1.38 (9H, s), 1.67-1.75 (1H, m), 3.20-3.29 (2H, m), 3.52-3.60 (1H, m), 4.36 (1H, t, J=5.2 Hz), 6.67 (1H, d, J=7.8 Hz).
MS (ESI): m/z 230.
To a suspension of sodium hydride (60% in oil) (15 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (84 μl). After stirring at ambient temperature for 5 minutes, cis-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (100 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by praparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (500 μl), and 1M NaOH solution (352 μl) was added, then stirred at 100° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (352 μl) and pH 4 buffer (10 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[cis-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (2H)-yl)cyclohexyl]acrylic acid (21 mg) as a yellow powder.
1H-NMR (DMSO-d6) δ: 1.22-2.56 (9H, m), 4.44-4.55 (1H, m), 5.75 (1H, dd, J=1.4 Hz, 15.8 Hz), 6.60-6.62 (1H, m), 6.84 (1H, dd, J=6.5 Hz, 15.8 Hz), 7.44 (1H, t, J=3.0 Hz), 7.92 (1H, s), 10.91 (1H, s), 11.60 (1H, s), 12.19 (1H, br).
MS (ESI+): m/z 327.
To a solution of tert-butyl[trans-3-carbamoylcyclohexyl]-carbamate (180 mg) in N,N-dimethylformamide (2 ml) was added 2,4,6-trichloro-1,3,5-triazine (76 mg) under stirring at 0° C. After stirring at ambient temperature for 2 hours, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane:EtOAc=80:20-50:50 to give tert-butyl[trans-3-cyanocyclohexyl]carbamate (125 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.14-1.91 (8H, m), 1.38 (9H, s), 3.16-3.22 (1H, m), 3.42-3.53 (1H, m), 6.89 (1H, d, J=7.2 Hz).
MS (ESI): m/z 266 (M+H+MeCN)+.
The following compound was obtained in a similar manner to that of Example 245.
1H-NMR (DMSO-d6, δ): 1.29-2.08 (8H, m), 2.73-2.83 (1H, m), 3.58-3.67 (1H, m), 8.44 (3H, brs).
MS (ESI): m/z 168.
[α]D24=−14.1 (c 1.05, methanol)
To a solution of ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3.8 g) in N,N-dimethylformamide (76 mL) was added 60% sodium hydride (580 mg) at 4° C. The mixture was stirred at the same temperature for 1 hour. To the mixture was added [2-(chloromethoxy)ethyl](trimethyl)silane (2.55 mL) and the solution was stirred at ambient temperature for 1 hour. To the solution was added water and EtOAc. The mixture was extracted with EtOAc and washed with brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:3 to 1:1) to give ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5.4 g) as a pale yellow oil.
1H-NMR (DMSO-d6) δ: −0.09 (9H, s), 0.80 (2H, t, J=8.0 Hz), 0.91 (3H, d, J=6.9 Hz), 1.32 (3H, t, J=7.0 Hz), 1.36-1.47 (4H, m), 1.60-1.65 (3H, m), 1.78 (1H, m), 1.98 (1H, m), 3.50 (2H, t, J=8.0 Hz), 4.27 (1H, m), 4.30 (2H, q, J=7.0 Hz), 5.53 (2H, s), 6.69 (1H, d, J=3.7 Hz), 7.36 (1H, d, J=3.7 Hz), 8.60 (1H, s), 9.07 (1H, d, J=9.0 Hz).
MS (ESI+): m/z 432.2.
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride (13 mg) at 4° C. The mixture was stirred at the same temperature for 0.5 hour. To the mixture was added 4-(bromomethyl)benzonitrile (73 mg) and the solution was stirred at ambient temperature for 1 hour. To the solution was added water and EtOAc. The mixture was extracted with EtOAc and washed with brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:3 to 1:1) to give 4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (117 mg) as a white amorphous.
1H-NMR (DMSO-d6) δ: −0.13 (9H, s), 0.75-0.80 (2H, m), 0.94 (3H, d, J=7.1 Hz), 1.45-1.51 (2H, m), 1.64-1.68 (1H, m), 1.84-1.91 (3H, m), 2.34-2.36 (1H, m), 2.49-2.52 (1H, m), 2.93-3.01 (1H, m), 3.47 (2H, t, J=8.1 Hz), 4.50-4.54 (1H, m), 5.21-5.22 (2H, m), 5.59 (2H, s), 6.63 (1H, d, J=3.7 Hz), 7.48 (2H, d, J=8.3 Hz), 7.67 (1H, d, J=3.7 Hz), 7.81 (2H, d, J=8.3 Hz), 8.06 (1H, s).
MS (ESI): m/z 516.
The following compounds were obtained in a similar manner to that of Preparation 42.
1H-NMR (DMSO-d6, δ): −0.12 (9H, s), 0.76-0.80 (2H, m), 0.93 (3H, d, J=7.1 Hz), 1.43-1.52 (2H, m), 1.63-1.68 (1H, m), 1.81-1.91 (3H, m), 2.31-2.36 (1H, m), 2.73 (1H, m), 2.89 (1H, m), 2.93-3.03 (1H, m), 3.45-3.50 (2H, m), 4.49-4.54 (1H, m), 5.11-5.21 (1H, m), 5.59 (2H, s), 6.62 (1H, d, J=3.7 Hz), 7.33-7.36 (1H, m), 7.66 (1H, d, J=3.7 Hz), 7.69-7.72 (1H, m), 8.15 (1H, s), 8.47 (1H, dd, J=1.6, 4.8 Hz), 8.61 (1H, d, J=1.7 Hz).
MS (ESI+): m/z 492.
1H-NMR (DMSO-d6, δ): 0.96 (3H, d, J=7.1 Hz), 1.41-1.55 (3H, m), 1.64-1.70 (1H, m), 1.80-1.92 (3H, m), 2.33-2.39 (1H, m), 2.94-3.06 (1H, m), 4.49-4.54 (1H, m), 5.00-5.11 (4H, m), 6.51-6.53 (1H, m), 6.88-6.91 (2H, m), 6.96-6.98 (1H, m), 7.21-7.39 (6H, m), 7.46-7.48 (1H, m), 7.97 (1H, s), 11.65 (1H, brs)
MS (ESI+): m/z 467.
1H-NMR (DMSO-d6, δ): 0.96 (3H, d, J=7.1 Hz), 1.42-1.56 (3H, m), 1.64-1.71 (1H, m), 1.82-1.93 (3H, m), 2.33-2.40 (1H, m), 2.95-3.05 (1H, m), 4.50-4.56 (1H, m), 5.21-5.31 (2H, m), 6.53 (1H, d, J=3.5 Hz), 7.48 (1H, d, J=3.5 Hz), 7.65 (1H, dd, J=7.9 Hz), 7.77 (1H, d, J=7.9 Hz), 8.07 (1H, s), 8.12-8.15 (1H, m), 8.19-8.20 (1H, m), 11.69 (1H, brs).
MS (ESI+): m/z 406.
To a solution of 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3.9 g) and triethylamine (5.11 mL) in dioxane (39 mL) was added diphenylphosphoryl azide (5.0 mL) and the mixture was stirred at 120° C. for 3 hours. To the mixture were added EtOAc and water. The organic layer was separated and extracted with EtOAc. The extract was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:4 to 1:2) to give 1-[(1S,2R)-2-methylcyclohexyl]-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (3.33 g) as a white powder.
1H-NMR (DMSO-d6, δ): −0.09 (9H, s), 0.80 (2H, t, J=8.1 Hz), 0.94 (3H, d, J=7.1 Hz), 1.46-1.82 (7H, m), 2.30-2.33 (1H, m), 2.88-2.98 (1H, m), 3.50 (2H, t, J=8.1 Hz), 4.41-4.45 (1H, m), 5.60 (2H, s), 6.58 (1H, d, J=3.6 Hz), 7.62 (1H, d, J=3.6 Hz), 7.95 (1H, s), 10.81 (1H, brs).
MS (ESI+): m/z 401.
To a solution of tert-butyl[cis-3-(hydroxymethyl)cyclohexyl]carbamate (311 mg) in EtOAc (3.1 ml) was added 4M HCl in EtOAc which was stirred at ambient temperature for 1 hour. Resulting precipitates were collected by filtration and washed with diisopropyl ether to give [cis-3-aminocyclohexyl]methanol hydrochloride (236 mg) as a white powder.
1H-NMR (DMSO-d6, δ): 0.66-1.34 (3H, m), 1.56-2.03 (7H, m), 2.91-3.40 (1H, m), 3.78-3.98 (2H, m), 7.99 (3H, br).
MS (ESI): m/z 130.
The following compounds were obtained in a similar manner to that of Preparation 47.
1H-NMR (DMSO-d6, δ): 1.15-1.28 (1H, m), 1.43-1.72 (6H, m), 1.99-2.09 (4H, m), 3.87-3.96 (2H, m), 3.89 (3H, br).
MS (ESI): m/z 130.
1H-NMR (DMSO-d6, δ): 1.33-1.62 (5H, m), 1.68-1.82 (2H, m), 1.95-2.02 (1H, m), 2.55-2.61 (1H, m), 3.36-3.45 (1H, m), 6.84 (1H, br), 7.28 (1H, br), 7.94 (3H, br).
MS (ESI): m/z 143.
1H-NMR (DMSO-d6, δ): 1.30-2.15 (8H, m), 3.11-3.18 (1H, m), 3.34-3.38 (1H, m), 8.07 (3H, br).
MS (ESI): m/z 125.
1H-NMR (DMSO-d6, δ): 1.07 (3H, d, J=6.5 Hz), 2.97-3.04 (2H, m), 3.60-3.80 (2H, m), 5.01-5.08 (1H, m), 7.08 (1H, s), 7.65 (1H, s), 8.15 (1H, s), 9.23 (1H, b rs), 9.64 (1H, brs), 11.8 (1H, s), 12.4 (1H, s).
MS (ESI): m/z 258.
1H-NMR (DMSO-d6, δ): 1.68-2.15 (4H, m), 3.06-3.21 (1H, m), 3.25-3.39 (1H, m), 3.73-3.89 (1H, m), 4.37-4.58 (2H, m), 7.12-7.19 (1H, m), 7.63-7.71 (1H, m), 8.17 (1H, s), 9.04-9.22 (1H, m), 9.69-9.85 (1H, m), 11.77 (1H, s), 12.47 (1H, s).
MS (ESI): m/z 258.
To a solution of ethyl 4-{[cis-3-(hydroxymethyl)cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (125 mg) in N,N-dimethylformamide (1.25 ml) were added imidazole (40 mg) and chloro(triisopropyl)silane (125 μl). The mixture was stirred at ambient temperature for 18 hours. To the mixture were added water and EtOAc. The mixture was extracted with EtOAc and washed with saturated aqueous sodium hydrogencarbonate and brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform:methanol=100:1-95:5 to give ethyl 4-{[cis-3-{[(triisopropylsilyl)oxy]methyl}cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (170 mg) as a brown oil.
1H-NMR (DMSO-d6) δ: 0.72-1.11 (24H, m), 1.32 (3H, t, J=7.1 Hz), 1.39-1.99 (7H, m), 2.91-3.38 (1H, m), 4.27 (2H, q, J=7.1 Hz), 4.46-4.51 (1H, m), 6.58-6.60 (1H, m), 7.15 (1H, t, J=2.8 Hz), 8.54 (1H, s), 9.14 (1H, d, J=8.2 Hz), 11.61 (1H, s).
MS (ESI): m/z 474.
The following compound was obtained in a similar manner to that of Preparation 53.
1H-NMR (DMSO-d6) δ: 0.86-1.13 (24H, m), 1.32 (3H, t, J=7.1 Hz), 1.39-1.98 (6H, m), 2.86-3.38 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.45-4.51 (1H, m), 6.6 (1H, dd, J=1.7 Hz, 3.5 Hz), 7.15 (1H, t, J=2.9 Hz), 8.54 (1H, s), 9.14 (1H, d, J=8.2 Hz), 11.60 (1H, s).
MS (ESI): m/z 474.
To a solution of 4-{[cis-3-{[(triisopropylsilyl)oxy]methyl}-cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.06 g) in dioxane (28 ml) was added triethylamine (1.33 ml) and diphenylphosphoryl azide (2.86 ml). After stirring at 120° C. for 4 hours, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane:EtOAc=60:40-35:65 to give 1-[cis-3-{[(triisopropylsilyl)oxy]methyl}cyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (970 mg) as a yellow powder.
1H-NMR (DMSO-d6) δ: 0.92-1.26 (24H, m), 1.45-1.58 (1H, m), 1.72-2.24 (7H, m), 3.6 (2H, d, J=5.0 Hz), 4.40-4.51 (1H, m), 6.57-6.60 (1H, m), 7.42 (1H, t, J=3.0 Hz), 7.93 (1H, s), 10.90 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 443.
The following compound was obtained in a similar manner to that of Preparation 55.
1H-NMR (DMSO-d6) δ: 1.04 and 1.34 (total 9H, each s), 1.66-2.07 (4H, m), 3.17-3.42 (2H, m), 3.83-3.97 (1H, m), 3.97-4.16 (1H, m), 4.16-4.37 (1H, m), 6.54-6.61 and 7.04-7.11 (total 1H, each m), 7.37-7.48 (1H, m), 7.90 (1H, s), 10.88 (1H, brs), 11.50 (1H, s).
MS (ESI): m/z 358.
To a solution of 1-[trans-3-(hydroxymethyl)cyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (180 mg) in dichloroethane (2 ml) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (293 mg) at 4° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture were added chloroform, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium thiosulfate. The organic layer was separated and extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform:methanol=100:0-85:15 to give trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg).
1H-NMR (DMSO-d6) δ: 0.71-1.35 (3H, m), 1.45-1.86 (2H, m), 2.16-2.98 (3H, m), 3.55-3.62 (1H, m), 4.36-4.68 (1H, m), 6.6 (1H, dd, J=1.9 Hz, 3.5 Hz), 7.46 (1H, t, J=3.1 Hz), 7.92 (1H, s), 9.75 (1H, s), 10.89 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 285.
The following compounds were obtained in a similar manner to that of Preparation 57.
1H-NMR (DMSO-d6) δ: 0.80-3.17 (7H, m), 4.24-4.56 (2H, m), 6.55-6.63 (2H, m), 7.44 (1H, t, J=3.1 Hz), 7.92-7.93 (1H, m), 9.62 (1H, s), 10.92 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 285.
To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-Carboxylic acid (343 mg) in N,N-dimethylformamide (4 ml) was added phenylmethanol (375 μl) 4-dimethylaminopyridine (428 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (676 mg). After stirring at ambient temperature for 3 days, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform to give benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (200 mg) as a yellow powder.
1H-NMR (DMSO-d6) δ: 5.40 (2H, s), 6.6 (1H, d, J=1.8 Hz), 7.35-7.39 (3H, m), 7.41-7.45 (2H, m), 7.71 (1H, d, J=3.5 Hz), 8.75 (1H, s), 12.42 (1H, br).
MS (ESI): m/z 297.
To a solution of benzyl 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (36 mg) in dioxane (7 ml) and methanol (7 ml) was added 10% Pd—C (50% wet) (10 mg) and stirred at ambient temperature for 3 hours under hydrogen atmosphere. After filtration the filtrate was evaporated in vacuo to give 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (28 mg).
1H-NMR (DMSO-d6) δ: 1.59-2.54 (10H, m), 4.44-4.52 (1H, m), 6.65-6.69 (2H, m), 7.10-7.11 (1H, m), 7.26 (1H, s), 8.51 (1H, s), 9.52 (1H, br), 11.47 (1H, s).
MS (ESI+): m/z 305.
To a 1,2-dichloroethane solution of 2-(trifluoromethyl)cyclohexanone (10.0 g) and [(1S)-1-phenylethyl]amine (7.29 g) was added NaBH(OAc)3 (25.51 g) at ambient temperature. After stirring for 2 days at ambient temperature, 150 mL of saturated aqueous sodium hydrogencarbonate was added. After extraction with EtOAc, combined organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel column chromatography (n-hexane:EtOAc=8:1 to 2:1) to give (1R,2S)—N-[(1R)-1-phenylethyl]-2-(trifluoromethyl)cyclohexanamine (7.83 g) as a white solid.
1H-NMR (DMSO-d6) δ: 1.15-2.39 (13H, m), 2.93-2.99 (1H, m), 3.69-3.80 (1H, m), 7.15-7.40 (5H, m).
MS (ESI+): m/z 272.
To a solution of (1R,2S)—N-[(1R)-1-phenylethyl]-2-(trifluoromethyl)cyclohexanamine (3.53 g) and 13 mL of HCl (2M ethanol solution) in 35 mL of ethanol was added Pd(OH)2 (2.78 g) under N2. H2 gas was purged and stirred for 2 days under 4 atm at 60° C. Pd(OH)2 was filtered off through a pad of Celite. Solvent was removed under reduced pressure. (1R,2S)-2-(Trifluoromethyl)cyclohexanamine hydrochloride (2.37 g) was obtained as a white solid.
1H-NMR (DMSO-d6) δ: 1.29-2.08 (8H, m), 2.73-2.83 (1H, m), 3.58-3.67 (1H, m), 8.44 (3H, brs).
MS (ESI+): m/z 168.
[α]D24=−14.1 (c 1.05, methanol).
The following compounds were obtained in a similar manner to that of Example 274.
1H-NMR (DMSO-d6) δ: 3.46-3.58 (2H, m), 3.77-3.96 (2H, m), 4.20-4.38 (2H, m), 6.36-6.60 (1H, m), 7.30-7.36 (2H, m), 8.24-8.30 (2H, m).
1H-NMR (CDCl3) δ: 3.46-3.58 (2H, m), 3.77-3.96 (2H, m), 4.20-4.38 (2H, m), 6.36-6.60 (1H, m), 7.30-7.36 (2H, m), 8.24-8.30 (2H, m).
1H-NMR (CDCl3) δ: 1.89-2.08 (4H, m), 2.91-3.00 (1H, m), 3.52-3.95 (4H, m), 7.30 (2H, d, J=8.9 Hz), 8.26 (2H, d, J=8.9 Hz).
1H-NMR (DMSO-d6) δ: 3.83-3.92 (1H, m), 4.14-4.53 (4H, m), 7.43-7.48 (2H, m), 8.26-8.32 (2H, m).
1H-NMR (DMSO-d6) δ: 1.35-1.49 (2H, m), 1.74-1.85 (2H, m), 3.14-3.23 (1H, m), 3.69-3.92 (3H, m), 4.82 (1H, d, J=4.0 Hz), 7.40-7.46 (2H, m), 8.24-8.30 (2H, m).
1H-NMR (DMSO-d6) δ: 4.01 (2H, t, J=12.8 Hz), 4.13 (2H, t, J=12.8 Hz), 7.32-7.37 (2H, m), 8.26-8.31 (2H, m).
1H-NMR (DMSO-d6) δ: 2.90 (3H, s), 3.39-3.49 (2H, m), 3.66-4.23 (4H, m), 7.48 (2H, d, J=9.2 Hz), 8.29 (2H, d, J=9.2 Hz).
In a microwave reaction vessel ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (15 mg) and (1S,2R)-2-methylcyclohexanamine hydrochloride (65.5 mg) were suspended in n-butanol (0.075 mL). To the mixture was added N,N-diisopropylethylamine (0.093 mL). The vessel was sealed and reacted in the microwave reactor at 160° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give ethyl 4-{methyl[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (5 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.0 Hz), 1.18-1.79 (8H, m), 1.30 (3H, t, J=7.0 Hz), 2.12 (1H, m), 2.95 (3H, s), 3.84-3.89 (1H, m), 4.27 (2H, q, J=7.0 Hz), 6.54-6.56 (1H, m), 7.28-7.34 (1H, m), 8.24 (1H, s), 11.69 (1H, brs).
MS (ESI): m/z 316 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 1.
1H-NMR (DMSO-d6) δ: 1.32 (3H, t, J=7.1 Hz), 1.33-1.77 (8H, m), 1.99-2.08 (2H, m), 3.95-4.08 (1H, m), 4.26 (2H, q, J=7.1 Hz), 6.55 (1H, d, J=3.5 Hz), 7.18 (1H, d, J=3.5 Hz), 8.54 (1H, s), 8.84-8.88 (1H, m), 11.67 (1H, brs)
MS (ESI): m/z 288 (M+H)+.
1H-NMR (DMSO-d6, δ): 0.91 (3H, d, J=6.9 Hz), 1.32 (3H, t, J=7.1 Hz), 1.35-2.16 (9H, m), 4.23-4.34 (3H, m), 6.59 (1H, d, J=3.5 Hz), 7.17 (1H, d, J=3.5 Hz), 8.68 (1H, s), 9.02-9.06 (1H, m), 11.66 (1H, br).
MS (ESI): m/z 302 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.02-1.76 (10H, m), 2.91 (3H, s), 3.52-3.63 (1H, m), 6.48-6.49 (1H, m), 7.28-7.31 (1H, m), 8.07 (2H, br), 8.21 (1H, s), 11.56 (1H, br s).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.02 (3H, d, J=7.2 Hz), 1.07-2.16 (9H, m), 3.25 (3H, s), 4.25-4.35 (1H, m), 6.50-6.55 (1H, m), 7.17-7.21 (1H, m), 8.18 (1H, s), 11.98 (1H, m).
MS (ESI): m/z 269 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.52-1.68 (6H, m), 1.96-2.02 (2H, m), 4.41-4.44 (1H, m), 6.55-6.61 (1H, m), 7.09-7.12 (1H, m), 8.61 (1H, s), 9.64-9.67 (1H, m), 11.43 (1H, brs).
MS (ESI): m/z 245 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.95-1.26 (5H, m), 1.60-1.84 (6H, m), 3.45 (2H, dd, J=6.0, 12.0 Hz), 6.54-6.60 (1H, m), 7.08-7.10 (1H, m), 8.34 (1H, s), 9.61-9.66 (1H, m), 11.43 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.64 (10H, m), 6.56-6.59 (1H, m), 7.28-7.31 (2H, m), 7.89 (1H, m), 8.18 (1H, s), 11.56 (1H, br).
MS (ESI): m/z 245 (M+H)+.
1H-NMR (DMSO-d6) δ: 4.87 (2H, d, J=5.9 Hz), 6.53-6.58 (2H, m), 7.25-7.39 (5H, m), 7.91 (2H, m), 8.40 (1H, s), 9.88 (1H, m), 11.45 (1H, m).
MS (ESI): m/z 267 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.02-1.75 (8H, m), 1.38 (9H, s), 3.66-3.84 (1H, m), 6.56 (1H, d, J=3.5 Hz), 7.15 (1H, m), 7.65 (1H, d, J=3.5 Hz), 8.37 (1H, s), 9.76-9.81 (1H, m), 11.47 (1H, brs).
MS (ESI): m/z 360 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.30-1.55 (4H, m), 1.38 (3H, t, J=7.1 Hz), 1.86 (2H, m), 2.09 (2H, m), 3.54-3.63 (1H, m), 3.73 (1H, br), 4.07 (1H, m), 4.33 (2H, q, J=7.1 Hz), 6.76-6.78 (1H, m), 7.35-7.37 (1H, m), 8.60 (1H, s), 9.36-9.40 (1H, m), 12.43 (1H, brs).
MS (ESI): m/z 304.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.81 (3H, t, J=7.1 Hz), 1.21-1.39 (8H, m), 1.53-1.72 (5H, m), 1.86-1.94 (1H, m), 4.36 (2H, q, J=7.1 Hz), 4.47-4.51 (1H, m), 6.84-6.86 (1H, m), 7.34-7.36 (1H, m), 8.61 (1H, s), 9.67-9.72 (1H, m), 12.44 (1H, brs).
MS (ESI): m/z 316.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.34 (3H, t, J=7.0 Hz), 1.37-1.88 (8H, m), 1.88-1.91 (1H, m), 3.33 (2H, d, J=7.2 Hz), 3.35 (1H, br), 4.32 (2H, q, J=7.0 Hz), 4.55-4.58 (1H, m), 6.69-6.71 (1H, m), 7.24-7.25 (1H, m), 8.58 (1H, s), 9.37-9.42 (1H, m), 11.96 (1H, brs).
MS (ESI): m/z 318.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.14-2.15 (9H, m), 3.30 (2H, d, J=7.2 Hz), 3.98-4.08 (1H, m), 6.81-6.82 (1H, m), 7.31-7.34 (1H, m), 7.69 (1H, br), 8.38 (1H, br), 8.53 (1H, s), 10.98-11.02 (1H, m), 12.51 (1H, brs).
MS (ESI): m/z 289.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.90 (3H, d, J=7.0 Hz), 1.41-1.82 (8H, m), 2.15 (1H, m), 4.29-4.34 (1H, m), 6.07-6.12 (1H, m), 6.78-6.80 (1H, m), 7.24-7.26 (1H, m), 8.08 (1H, s), 11.81 (1H, brs).
MS (ESI): m/z 255.2 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.25-1.42 (3H, m), 1.48-1.76 (5H, m), 1.96-2.06 (2H, m), 4.03-4.15 (1H, m), 6.94 (1H, s), 7.27 (2H, t, J=9.0 Hz), 7.92 (2H, dd, J=9.0, 5.0 Hz), 8.37 (1H, s), 9.71 (1H, d, J=8.0 Hz), 12.00 (1H, s).
MS (ESI): m/z 253 (M+H)+.
mp>280° C.
1H-NMR (DMSO-d6) δ: 1.42-1.50 (2H, m), 2.09-2.11 (2H, m), 3.17 (2H, d, J=5.4 Hz), 3.42-3.47 (2H, m), 4.21-4.24 (2H, m), 4.31-4.33 (1H, m), 6.63-6.34 (1H, m), 6.99 (1H, d, J=4.5 Hz), 6.90-7.10 (1H, brs), 7.17-7.18 (1H, m), 7.70-7.90 (1H, m), 7.85 (1H, dd, J=1.2, 4.5 Hz), 8.38 (1H, s), 8.49 (1H, d, J=1.2 Hz), 9.75 (1H, d, J=4.0 Hz), 11.51 (1H, brs).
MS (ESI): m/z 362 (M+H)+.
MS (ESI): m/z 247 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.87-0.92 (3H, m), 0.97-1.81 (8H, m), 2.02-2.12 (1H, m), 3.82-3.92 (0.4H, m), 4.33-4.39 (0.6H, m), 6.47-6.55 (1H, m), 6.83-7.11 (1H, m), 7.10-7.16 (1H, m), 7.58-7.94 (1H, m), 8.35 (0.4H, s), 8.36 (0.6H, s), 9.60 (0.4H, d, J=7.6 Hz), 10.01 (0.6H, d, J=8.4 Hz), 11.49 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.90 (3H, d, J=6.8 Hz), 1.34-1.91 (9H, m), 4.16-4.21 (1H, m), 6.50-6.54 (1H, m), 6.84-7.08 (1H, br), 7.09-7.12 (1H, m), 7.60-7.91 (1H, br), 8.35 (1H, s), 9.91 (1H, d, J=8.4 Hz), 11.45 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.46-1.71 (10H, m), 1.89-2.10 (2H, m), 4.07-4.23 (1H, m), 6.52 (1H, dd, J=3.5, 1.7 Hz), 7.11 (1H, dd, J=2.9, 2.9 Hz), 6.8-7.8 (2H, br s), 8.31 (1H, s), 9.67 (1H, d, J=8.1 Hz), 11.43 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.34-1.92 (8H, m), 2.66-2.78 (1H, m), 4.70-4.77 (1H, m), 6.53-6.56 (1H, m), 6.89-7.10 (1H, br), 7.13-7.16 (1H, m), 7.71-7.92 (1H, br), 8.38 (1H, s), 10.22 (1H, d, J=8.8 Hz), 11.50 (1H, brs).
MS (ESI): m/z 327.2 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.95 (3H, s), 1.01 (3H, s), 1.30-1.95 (8H, m), 3.68-3.84 (1H, m), 6.57 (1H, d, J=3.5 Hz), 7.17 (1H, d, J=3.5 Hz), 7.20-8.95 (2H, brs), 8.37 (1H, s), 10.11 (1H, d, J=8.7 Hz), 11.76 (1H, s).
MS (ESI): m/z 287 (M+H)+.
MS (ESI): m/z 303 (M+H)+.
1H-NMR (DMSO-d6) δ: 4.95 (2H, d, J=5.2 Hz), 6.82 (1H, dd, J=1.7, 3.4 Hz), 6.92-7.30 (3H, m), 7.45-7.69 (2H, m), 8.39 (1H, s), 9.69 (1H, t, J=5.2 Hz), 11.58 (1H, brs).
MS (ESI): m/z 321 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.04-1.85 (14H, m), 3.94-4.04 (1H, m), 6.49-6.54 (1H, m), 6.93 (1H, brs), 7.08-7.12 (1H, m), 7.61-7.93 (2H, m), 8.34 (1H, s), 9.68 (1H, d, J=8.7 Hz).
MS (ESI): m/z 287 (M+H)+.
1H-NMR (DMSO-d6) δ: 12.8 (1H, br), 9.75 (1H, d, J=9.4 Hz), 8.44 (1H, s), 8.02 (1H, s), 7.82 (1H, br), 7.02 (1H, br), 5.20-5.27 (1H, m), 1.28-1.99 (9H, m), 0.87 (3H, d, J=6.9 Hz).
MS (ESI): m/z 274 (M+H)+.
MS (ESI): m/z 247 (M+H)+.
MS (ESI): m/z 247 (M+H)+.
MS (ESI): m/z 247 (M+H)+.
MS (ESI): m/z 281 (M+H)+.
MS (ESI): m/z 289 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.91-0.97 (6H, m), 2.1-2.2 (1H, m), 3.47-3.50 (1H, m), 3.51-3.63 (1H, m), 3.91-3.93 (1H, m), 4.79-4.82 (1H, m), 6.60 (1H, bs), 6.9 (1H, bs), 7.09-7.10 (1H, m), 7.7 (1H, bs), 8.34 (1H, s), 9.64 (1H, d, J=8.4 Hz), 11.42 (1H, bs).
MS (ESI): m/z 263 (M+H)+.
MS (ESI): m/z 331 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.94 (3H, d, J=5.6 Hz), 1.34-1.43 (1H, m), 1.55-1.75 (3H, m), 1.83-1.93 (1H, m), 1.98-2.07 (1H, m), 2.15-2.26 (1H, m), 4.34-4.41 (1H, m), 6.58-6.61 (1H, m), 6.80-7.05 (1H, br), 7.08-7.12 (1H, m), 7.58-7.87 (1H, br), 8.35 (1H, s), 9.76 (1H, d, J=8.0 Hz), 11.42 (1H, brs).
MS (ESI): m/z 259.3 (M+H)+.
MS (ESI): m/z 297 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.88-0.94 (3H, m), 1.11-2.11 (9H, m), 3.76-3.86 (0.38H, m), 4.21-4.29 (0.62H, m), 6.46-6.53 (1H, m), 6.85-7.06 (1H, m), 7.09-7.14 (1H, m), 7.59-7.85 (1H, m), 8.34 (0.38H, s), 8.36 (0.62H, s), 9.55 (0.38H, d, J=8.0 Hz), 9.97 (0.62H, d, J=8.0 Hz), 11.43 (1H, brs).
MS (ESI): m/z 273.2 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.17-1.66 (11H, m), 3.59 (2H, d, J=12.2 Hz), 6.71 (1H, d, J=1.7 Hz), 6.99 (1H, brs), 7.11 (1H, d, J=1.7 Hz), 7.75 (1H, brs), 8.34 (1H, s), 9.76 (1H, t, J=2.1 Hz), 11.6 (1H, brs).
MS (ESI): m/z 289 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.58-1.67 (1H, m), 1.96-2.07 (2H, m), 2.11-2.25 (2H, m), 2.44-2.53 (1H, m), 4.18-4.26 (1H, m), 5.62-5.68 (1H, m), 5.71-5.77 (1H, m), 6.47-6.50 (1H, m), 6.86-7.06 (1H, br), 7.11-7.15 (1H, m), 7.65-7.85 (1H, br), 8.35 (1H, s), 9.72 (1H, d, J=8.0 Hz), 11.46 (1H, brs).
MS (ESI): m/z 257.2 (M+H)+.
MS (ESI): m/z 289 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.35-1.77 (7H, m), 1.90-1.98 (1H, m), 3.29 (3H, s), 3.49-3.53 (1H, m), 4.07-4.15 (1H, m), 6.47-6.49 (1H, m), 6.79-7.06 (1H, br), 7.09-7.14 (1H, m), 7.55-7.80 (1H, br), 8.33 (1H, s), 9.82 (1H, d, J=8.4 Hz), 11.43 (1H, brs).
MS (ESI): m/z 311.2 (M+Na)+.
MS (ESI): m/z 310 (M+H)+.
MS (ESI): m/z 283 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.53-1.65 (2H, m), 1.98-2.19 (6H, m), 4.18-4.28 (1H, m), 6.68 (1H, d, J=3.0 Hz), 7.14 (1H, brs), 7.20 (1H, d, J=3.0 Hz), 7.88 (1H, brs), 8.39 (1H, s), 9.92 (1H, d, J=8.1 Hz), 11.70 (1H, s).
MS (ESI): m/z 295 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.52 (3H, d, J=6.6 Hz), 5.25-5.40 (1H, m), 6.43 (1H, dd, J=1.6, 3.6 Hz), 6.99 (1H, dd, J=2.2, 3.6 Hz), 7.14-7.98 (7H, m), 8.39 (1H, s), 10.07 (1H, d, J=8.0 Hz), 11.39 (1H, brs).
MS (ESI): m/z 281 (M+H)+.
MS (ESI): m/z 360 (M+H)+.
1H-NMR (DMSO-d6) δ: 3.60-3.67 (1H, m), 3.74-3.81 (1H, m), 5.09 (1H, t, J=2.6 Hz), 5.19-5.25 (1H, m), 6.38 (1H, dd, J=0.9, 1.7 Hz), 6.96 (1H, dd, J=1.3, 1.7 Hz), 7.01 (1H, brs), 7.17-7.22 (1H, m), 7.23 (2H, t, J=3.8 Hz), 7.39 (2H, d, J=3.8 Hz), 7.80 (1H, brs), 8.37 (1H, s), 10.15 (1H, d, J=4.0 Hz), 11.35 (1H, b rs).
MS (ESI): m/z 297 (M+H)+.
1H-NMR (DMSO-d6) δ: 4.93 (2H, d, J=6.3 Hz), 6.49 (1H, d, J=3.5 Hz), 7.03-8.08 (6H, m), 8.42 (1H, s), 10.07 (1H, t, J=6.3 Hz), 11.69 (1H, brs).
MS (ESI): m/z 303 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.46-1.48 (2H, m), 2.05 (2H, m), 3.26-3.33 (2H, m), 4.05-4.08 (2H, m), 4.26 (1H, m), 6.61-6.63 (2H, m), 6.87 (1H, d, J=4.4 Hz), 6.90-7.10 (1H, brs), 7.15-7.16 (1H, m), 7.50-7.54 (1H, m), 8.11-8.12 (1H, m), 8.37 (1H, s), 9.74 (1H, d, J=4.0 Hz), 11.49 (1H, s).
1H-NMR (DMSO-d6) δ: 11.7 (1H, s), 8.89 (1H, d, J=9.0 Hz), 8.54 (1H, s), 7.16 (1H, s), 6.66 (1H, s), 4.85-4.89 (1H, m), 4.26 (2H, q, J=7.0 Hz), 3.98-4.01 (1H, m), 3.53-3.63 (2H, m), 2.05-2.10 (1H, m), 1.32 (3H, t, J=7.0 Hz), 0.98 (3H, d, J=6.9 Hz), 0.96 (3H, d, J=6.9 Hz).
MS (ESI): m/z 292 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.6 (1H, s), 8.91 (1H, d, J=8.2 Hz), 8.54 (1H, s), 7.17 (1H, d, J=3.5 Hz), 6.64 (1H, d, J=3.5 Hz), 5.02 (1H, br), 4.26 (2H, q, J=6.9 Hz), 4.20-4.25 (1H, m), 3.48-3.62 (2H, m), 1.32 (3H, t, J=6.9 Hz), 1.27 (3H, d).
MS (ESI): m/z 264 (M+H)+.
MS (ESI): m/z 374 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.04-1.85 (14H, m), 3.94-4.04 (1H, m), 6.49-6.54 (1H, m), 6.93 (1H, brs), 7.08-7.12 (1H, m), 7.61-7.93 (2H, m), 8.34 (1H, s), 9.68 (1H, d, J=8.7 Hz).
MS (ESI): m/z 287 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.5 (1H, s), 9.69 (1H, d, J=8.9 Hz), 8.36 (1H, s), 7.80-7.90 (1H, br), 7.12 (1H, s), 6.85-7.10 (1H, br), 6.55 (1H, s), 4.03-4.06 (1H, m), 3.45-3.53 (2H, m), 3.27 (3H, s), 2.00-2.04 (1H, m), 0.97 (3H, d, J=6.8 Hz, 0.93 (3H, d, J=6.8 Hz).
MS (ESI): m/z 277 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.4 (1H, brs), 9.64 (1H, d, J=8.8 Hz), 8.34 (1H, s), 7.70 (1H, br), 7.10 (1H, s), 6.98 (1H, br), 6.60 (1H, s), 4.80-4.83 (1H, m), 3.90-3.95 (1H, m), 3.50-3.62 (2H, m), 2.05-2.13 (1H, m), 0.96 (3H, d, J=6.9 Hz) 0.92 (3H, d, J=6.9 Hz).
MS (ESI): m/z 263 (M+H)+.
MS (ESI): m/z 277 (M+H)+.
MS (ESI): m/z 335 (M+H)+.
1H-NMR (DMSO-d6) δ: 3.64 (1H, dd, J=2.8, 5.4 Hz), 3.79 (1H, dd, J=2.1, 5.4 Hz), 5.21-5.27 (1H, in), 6.42 (1H, d, J=1.4 Hz), 6.98-7.02 (1H, m), 7.13 (2H, brs), 7.20 (1H, t, J=3.6 Hz), 7.31 (2H, dd, J=3.6, 3.6 Hz), 7.39 (2H, d, J=3.6 Hz), 7.89 (1H, brs), 8.74 (1H, s), 10.30 (1H, d, J=4.0 Hz), 11.53 (1H, s).
MS (ESI): m/z 297 (M+H)+.
MS (ESI): m/z 219 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.28-1.83 (8H, m), 3.90 (1H, brs), 4.06-4.23 (1H, m), 5.08 (1H, brs), 6.76 (1H, d, J=2.4 Hz), 7.32 (1H, dd, J=2.4, 2.8 Hz), 7.59 (1H, b rs), 8.30 (1H, brs), 8.49 (1H, s), 10.73 (1H, d, J=8.1 Hz), 12.57 (1H, brs).
MS (ESI): m/z 275 (M+H)+.
MS (ESI): m/z 297 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.36-1.58 (2H, m), 1.93-2.08 (2H, m), 3.47-3.63 (2H, m), 3.78-3.92 (2H, m), 4.07-4.26 (1H, m), 6.56 (1H, brs), 7.14 (1H, dd, J=2.8, 2.8 Hz), 6.92-8.07 (2H, brm), 8.37 (1H, s), 9.72 (1H, d, J=8.0 Hz), 11.48 (1H, brs).
MS (ESI): m/z 261 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.7 (1H, s), 8.89 (1H, d, J=9.0 Hz), 8.54 (1H, s), 7.16 (1H, s), 6.66 (1H, s), 4.85-4.89 (1H, m), 4.26 (2H, q, J=7.0 Hz), 3.98-4.01 (1H, m), 3.53-3.63 (2H, m), 2.05-2.10 (1H, m), 1.32 (3H, t, J=7.0 Hz), 0.98 (3H, d, J=6.9 Hz), 0.96 (3H, d, J=6.9 Hz).
MS (ESI): m/z 292 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.52 (3H, d, J=6.5 Hz), 5.29-5.46 (2H, m), 6.47 (1H, d, J=3.5 Hz), 6.57 (1H, dd, J=3.5 Hz), 7.05 (1H, d, J=3.5 Hz), 7.14 (2H, t, J=8.9 Hz), 7.38-7.48 (2H, m), 7.60-7.68 (1H, m), 7.91 (1H, brs), 8.42 (1H, s), 10.23 (1H, d, J=7.8 Hz), 11.64 (1H, brs).
MS (ESI): m/z 299 (M+H)+.
MS (ESI): m/z 274 (M+H)+.
MS (ESI): m/z 281 (M+H)+.
MS (ESI): m/z 288 (M+H)+.
MS (ESI): m/z 305 (M+H)+.
MS (ESI): m/z 277 (M+H)+.
MS (ESI): m/z 268 (M+H)+.
MS (ESI): m/z 268 (M+H)+.
MS (ESI): m/z 417 (M+H)+.
MS (ESI): m/z 311 (M+H)+.
MS (ESI): m/z 335 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.03 (3H, t, J=7.2 Hz), 1.50-1.98 (4H, m), 2.05-2.31 (2H, m), 2.60-2.73 (1H, m), 2.75-2.93 (1H, m), 3.05-3.16 (1H, m), 3.51-3.79 (2H, m), 6.63-6.78 (1H, m), 7.05-7.11 (1H, m), 6.49-7.91 (2H, brs), 8.32 (1H, s), 9.47-9.57 (1H, m), 11.42 (1H, brs).
MS (ESI): m/z 288 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.53-1.82 (4H, m), 2.25-2.69 (4H, m), 4.11 (1H, brs), 6. 41 (1H, s), 6.55 (1H, s), 6.80-7.41 (7H, m), 7.60-8.00 (1H, brs), 8.32 (1H, s), 9.75 (1H, d, J=4.0 Hz), 11.39 (1H, s).
MS (ESI): m/z 350 (M+H)+.
MS (ESI): m/z 269 (M+H)+.
MS (ESI): m/z 303 (M+H)+.
MS (ESI): m/z 297 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.7 (1H, s), 9.04 (1H, d, J=8.4 Hz), 8.57 (1H, s), 7.19-7.35 (6H, m), 6.68 (1H, s), 4.51-4.45 (1H, m), 4.38-4.41 (1H, m), 4.27 (2H, q, J=7.0 Hz), 3.62-3.78 (2H, m), 2.82-2.92 (1H, m), 2.28-2.32 (1H, m), 1.68-2.08 (6H, m), 1.33 (3H, t, J=7.0 Hz).
MS (ESI): m/z 394 (M+H)+.
MS (ESI): m/z 335 (M+H)+.
MS (ESI): m/z 271 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.87 (3H, d, J=6.8 Hz), 1.37 (3H, t, J=7.2 Hz), 1.52-4.43 (12H, m), 6.62 (1H, dd, J=2.0, 3.6 Hz), 7.09 (1H, dd, J=2.8, 3.6 Hz), 7.13-7.35 (5H, m), 8.56 (1H, s), 9.33 (1H, d, J=9.6 Hz), 11.59 (1H, s).
MS (ESI): m/z 393 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.72-1.78 (13H, m), 3.17 (1H, d, J=5.2 Hz), 3.58-3.70 (1H, m), 4.01-4.18 (1H, m), 4.87 (1H, t, J=5.2 Hz), 6.57-6.63 (1H, m), 7.09-7.15 (1H, m), 6.59-8.04 (2H, brd), 8.33 (1H, s), 9.48 (1H, d, J=8.3 Hz), 11.4 (1H, brs).
MS (ESI): m/z 317 (M+H)+.
MS (ESI): m/z 302 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.84-4.53 (9H, m), 6.72-6.78 (1H, m), 7.13-7.34 (2H, m), 7.91 (1H, brs), 8.42 (1H, s), 9.91 (1H, d, J=16.8 Hz), 11.70 (1H, brs).
MS (ESI): m/z 309 (M+H)+.
MS (ESI): m/z 268 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.84-1.89 (2H, m), 2.31-2.41 (2H, m), 3.21-3.28 (2H, m), 4.64-4.69 (2H, m), 4.75-4.83 (1H, m), 6.29 (1H, br), 7.09 (1H, d, J=9.1 Hz), 7.33 (1H, m), 7.90 (1H, d, J=2.3 Hz), 7.92-7.93 (1H, m), 8.55 (1H, d, J=2.2 Hz), 10.93 (1H, brs), 11.58 (1H, brs).
MS (ESI): m/z 360.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 4.91 (2H, d, J=5.8 Hz), 6.48 (1H, d, J=2.6 Hz), 7.02-7.98 (7H, m), 8.40 (1H, s), 9.85 (1H, t, J=5.8 Hz), 11.49 (1H, brs).
MS (ESI): m/z 285 (M+H)+.
MS (ESI): m/z 303 (M+H)+.
MS (ESI): m/z 305 (M+H)+.
MS (ESI): m/z 295 (M+H)+.
MS (ESI): m/z 327 (M+H)+.
MS (ESI): m/z 325 (M+H)+.
MS (ESI): m/z 282 (M+H)+.
To a solution of ethyl 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]-pyridine-5-carboxylate (7 mg) in ethanol was added 1M NaOH solution and the mixture was stirred at 90° C. for 18 hours The mixture was cooled to 4° C. and acidified with 1M HCl and extracted with a 4:1 solution of chloroform and methanol. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (6.3 mg) as a white solid.
1H-NMR (DMSO-d6) δ: 1.24-2.06 (10H, m), 4.06-4.12 (1H, m), 6.71-6.74 (1H, m), 7.31-7.34 (1H, m), 8.58 (1H, s), 9.68-9.72 (1H, m), 12.22 (1H, brs), 13.52 (1H, br).
MS (ESI): m/z 260 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 96.
1H-NMR (DMSO-d6) δ: 0.93 (3H, d, J=6.9 Hz), 1.23-2.01 (9H, m), 4.38-4.40 (1H, m), 6.88-6.89 (1H, m), 7.37-7.40 (1H, m), 8.64 (1H, s), 10.20-10.24 (1H, m), 12.76 (1H, brs), 13.80 (1H, br).
MS (ESI): m/z 274 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.35-1.56 (4H, m), 1.86 (2H, m), 2.09 (2H, m), 3.56 (2H, m), 4.09 (1H, m), 6.80-6.82 (1H, m), 7.38-7.40 (1H, m), 8.59 (1H, s), 9.86-9.90 (1H, m), 12.66 (1H, brs), 13.93 (1H, br).
MS (ESI): m/z 276.2 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.80 (3H, t, J=7.2 Hz), 1.21-1.93 (11H, m), 4.44-4.48 (1H, m), 6.81-6.83 (1H, m), 7.31-7.33 (1H, m), 8.58 (1H, s), 9.96-10.00 (1H, m, 12.37 (1H, brs).
MS (ESI): m/z 288.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.23-1.94 (9H, m), 3.31-3.35 (3H, m), 4.51 (1H, m), 6.64-6.65 (1H, m), 7.19-7.20 (1H, m), 8.53 (1H, s), 9.55 (1H, m), 11.81 (1H, brs).
MS (ESI): m/z 290.4 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.53-1.66 (2H, m), 1.79-1.87 (2H, m), 2.05-2.13 (2H, m), 2.24-2.46 (3H, m), 2.33-2.44 (1H, m), 6.64 (1H, dd, J=1.8 Hz, 3.4 Hz), 7.44 (1H, t, J=3.0 Hz), 7.92 (1H, s), 10.91 (1H, s), 11.60 (1H, s), 12.18 (1H, br).
MS (ESI+): m/z 301.
1H-NMR (DMSO-d6) δ: 0.90 (3H, d, J=6.9 Hz), 1.30-2.00 (9H, m), 3.72 (3H, s), 4.23 (1H, m), 6.59 (1H, d, J=3.6 Hz), 7.22 (1H, d, J=3.6 Hz), 8.56 (1H, s), 9.29 (1H, m), 12.40 (1H, brs).
MS (API-ES): m/z 288.3 (M+H)+, 286.3 (M−H)−.
1H-NMR (DMSO-d6) δ: 1.68-1.79 (2H, m), 1.91-2.02 (4H, m), 2.11-2.02 (2H, m), 4.86-4.97 (1H, m), 6.53 (1H, dd, J=1.9, 3.5 Hz), 7.42-7.45 (1H, m), 7.92 (1H, s), 10.89 (1H, s), 11.58 (1H, s).
MS (ESI): m/z 243 (M+H)+.
To a solution of 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (5.0 mg) in N,N-dimethylformamide (0.1 mL) were added 1-hydroxybenzotriazole (3.9 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 mg). The mixture was stirred at 60° C. for 30 minutes. To the solution was added ammonium chloride and the mixture was stirred at ambient temperature for 18 hours. To the solution were added water and chloroform and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtrated and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (3 mg) as a white powder.
1H-NMR (DMSO-d6, δ): 1.14-2.01 (10H, m), 3.91-4.01 (1H, m), 6.48-6.54 (1H, m), 7.10-7.13 (1H, m), 7.70 (2H, br), 8.34 (1H, s), 9.64-9.68 (1H, m), 11.43 (1H, brs).
MS (ESI): m/z 259 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 104.
1H-NMR (DMSO-d6) δ: 1.29-2.82 (9H, m), 4.72-4.78 (1H, m), 6.54-6.62 (1H, m), 6.95-8.02 (3H, m), 8.28-8.40 (1H, m), 10.33-12.17 (2H, m).
MS (ESI): m/z 327 (M+H)+.
The following compounds were obtained in a similar manner to that of Preparation 32.
1H-NMR (DMSO-d6) δ: 0.90 (3H, d, J=6.8 Hz), 1.23-1.91 (9H, m), 4.16-4.18 (1H, m), 6.51-6.52 (1H, m), 7.08-7.11 (1H, m), 7.37 (2H, br), 8.36 (1H, s), 9.85-9.90 (1H, m), 11.43 (1H, br).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.23-1.48 (4H, m), 1.82-1.87 (2H, m), 2.02-2.07 (2H, m), 3.50 (1H, m), 3.88 (1H, m), 4.62 (1H, m), 6.53-6.56 (1H, m), 7.17-7.18 (2H, m), 7.83 (1H, m), 8.37 (1H, s), 9.77-9.81 (1H, m), 11.67 (1H, brs).
MS (ESI): m/z 275 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.78 (3H, t, J=7.2 Hz), 1.21-1.68 (10H, m), 1.82-1.89 (1H, m), 4.29-4.32 (1H, m), 6.51-6.53 (1H, m), 7.00 (1H, br), 7.08-7.11 (1H, m), 7.67 (1H, br), 8.35 (1H, s), 9.87-9.92 (1H, m), 11.43 (1H, brs).
MS (ESI): m/z 287.4 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.34-1.91 (9H, m), 3.29-3.38 (1H, m), 4.37-4.43 (2H, m), 6.51-6.55 (1H, m), 7.02 (1H, br), 7.07-7.10 (1H, m), 7.68 (1H, br), 8.35 (1H, s), 9.88-9.92 (1H, m), 11.41 (1H, brs).
MS (ESI): m/z 289.3 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.58-1.91 (4H, m), 2.22-3.05 (7H, m), 4.21-4.63 (1H, m), 6.00-6.05 (1H, m), 6.47-6.58 (1H, m), 6.84-7.00 (1H, m), 7.41-7.45 (1H, m), 7.91-7.94 (1H, m), 10.91 (1H, s), 11.62 (1H, s).
MS (ESI): m/z 326.
1H-NMR (DMSO-d6) δ: 0.91-1.31 (2H, m), 1.41-2.45 (4H, m), 2.79-3.19 (3H, m), 4.45-4.57 (1H, m), 5.75-5.90 (1H, m), 6.52-6.68 (2H, m), 6.90 (1H, s), 7.34 (1H, s), 7.45 (1H, d, J=3.3 Hz), 7.93 (1H, s), 10.95 (1H, s), 11.64 (1H, s).
MS (ESI): m/z 326.
Diphenyl azidophosphate (0.083 mL) was added to 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (56 mg) and triethylamine (0.075 mL) in tert-butanol (1.5 mL) and the mixture was stirred at 100° C. for 4 hours. tert-butanol was removed under reduced pressure, then chloroform and water were added, and the organic layer was separated, washed with brine, and dried over MgSO4. After removal of MgSO4 and solvent, the residue was purified by column chromatography on silica gel with chloroform and methanol (98:2 to 90:10) to give 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (53 mg) as a white solid.
1H-NMR (DMSO-d6) δ: 0.94 (3H, d, J=7.1 Hz), 1.46-1.90 (7H, m), 2.30-2.34 (1H, m), 2.85-3.03 (1H, m), 4.44-4.47 (1H, m), 6.47-6.49 (1H, m), 7.41-7.45 (1H, m), 7.89 (1H, s), 10.72 (1H, brs), 11.57 (1H, brs).
MS (ESI): m/z 271.3 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 112.
1H-NMR (DMSO-d6) δ: 0.93 (3H, dd, J=6.4, 6.4 Hz), 1.43 (9H, d, J=22 Hz), 2.92-3.08 (2H, m), 3.66-4.06 (3H, m), 4.81-4.84 (1H, m), 6.49 (1H, brs), 7.46 (1H, s), 7.96 (1H, s), 11.02 (1H, brs), 11.6 (1H, s).
MS (ESI): m/z 358.
1H-NMR (DMSO-d6) δ: 1.04 (3H, d, J=7.2 Hz), 1.76-1.81 (1H, m), 2.08-2.15 (1H, m), 2.21-2.28 (1H, m), 2.37-2.42 (1H, m), 2.73-2.77 (1H, m), 2.98-3.02 (1H, m), 3.22-3.31 (1H, m), 3.46 (1H, d, J=13.4 Hz), 3.57 (1H, d, J=13.4 Hz), 4.39-4.44 (1H, m), 6.42-6.44 (1H, m), 7.23-7.28 (1H, m), 7.34-7.36 (4H, m), 7.42-7.44 (1H, m), 7.89 (1H, s), 10.75 (1H, brs), 11.57 (1H, brs).
MS (ESI+): m/z 362.
1H-NMR (DMSO-d6) δ: 1.50-3.0 (9H, m), 4.79-4.87 (1H, m), 6.58-6.62 (1H, m), 7.42-7.47 (1H, m), 7.89 (1H, s), 10.77 (1H, brs), 11.60 (1H, brs).
MS (ESI+): m/z 325.
1H-NMR (DMSO-d6) δ: 1.60-1.76 (2H, m), 1.84-2.09 (4H, m), 2.24-2.59 (2H, m), 3.47-3.53 (1H, m), 4.55-4.66 (1H, m), 6.56 (1H, dd, J=1.9 Hz, 3.5 Hz), 7.48 (1H, t, J=3.0 Hz), 7.93 (1H, s), 10.95 (1H, s), 11.66 (1H, s).
MS (ESI+): m/z 283.
1H-NMR (DMSO-d6) δ: 1.55-1.69 (2H, m), 1.80-1.88 (2H, m), 2.06-2.12 (2H, m), 2.25-2.39 (2H, m), 2.50-2.61 (1H, m), 3.33 (3H, s), 4.34-4.44 (1H, m), 6.65 (1H, dd, J=1.8 Hz, 3.4 Hz), 7.43 (1H, t, J=3.1 Hz), 7.92 (1H, s), 10.90 (1H, s), 11.59 (1H, s).
MS (ESI+): m/z 315.
1H-NMR (DMSO-d6) δ: 0.71 (3H, t, J=7.4 Hz), 1.35-1.99 (8H, m), 2.86-2.89 (1H, m), 3.49 (2H, m), 4.55-4.56 (1H, m), 6.71-6.72 (1H, m), 7.60-7.62 (1H, m), 8.08 (1H, s), 11.35 (1H, brs), 12.26 (1H, brs).
MS (ESI): m/z 285 (M−HCl+H)+.
1H-NMR (DMSO-d6) δ: 1.48-1.67 (3H, m), 1.86-2.10 (4H, m), 2.69-2.99 (2H, m), 4.79-4.87 (1H, m), 6.59-6.62 (1H, m), 7.44-7.46 (1H, m), 7.89 (1H, s), 10.78 (1H, s), 11.61 (1H, brs).
MS (ESI): m/z 325 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.96 (1.5H, d, J=6.4 Hz), 1.14 (1.5H, d, J=7.2 Hz), 1.44-2.54 (9H, m), 4.37-4.66 (1H, m), 6.55-6.58 (1H, m), 7.44-7.46 (1H, m), 7.91-7.92 (1H, m), 10.88 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 274 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.55-1.86 (12H, m), 2.28-2.41 (2H, m), 4.61-4.77 (1H, m), 6.48-6.51 (1H, m), 7.44 (1H, t, J=2.9 Hz), 7.92 (1H, s), 10.88 (1H, s), 11.58 (1H, s).
MS (ESI): m/z 285 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.52-2.37 (12H, m), 4.47-4.61 (1H, m), 6.52-6.58 (1H, m), 7.41-7.47 (1H, m), 7.92 (1H, s), 10.86 (1H, brs), 11.58 (1H, brs).
MS (ESI): m/z 271 (M+H)+.
1H-NMR (DMSO-d6) δ: 5.36 (2H, s), 6.58 (1H, dd, J=2.0, 5.2 Hz), 7.13 (1H, ddt, J=2.0, 3.6, 9.6 Hz), 7.39 (1H, dd, J=2.4, 3.6 Hz), 7.47 (1H, ddd, J=5.2, 9.6, 20.0 Hz), 8.32 (1H, s), 10.96 (1H, brs), 11.56 (1H, brs).
MS (ESI): m/z 319 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.47-2.22 (8H, m), 2.75-2.82 (1H, m), 3.63-3.72 (1H, m), 4.24-4.30 (1H, m), 4.45-4.51 (1H, m), 6.48-6.49 (1H, m), 7.42-7.45 (1H, m), 7.90 (1H, s), 10.75 (1H, brs), 11.57 (1H, brs).
MS (ESI): m/z 287.2 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.06-4.65 (13H, m), 6.61-6.79 (1H, m), 7.41-7.50 (1H, m), 7.94 (1H, s), 11.01 (1H, brs), 11.64 (1H, s).
MS (ESI): m/z 351 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.96 (1.5H, d, J=6.4 Hz), 1.12 (1.5H, d, J=7.2 Hz), 1.16-1.24 (1H, m), 1.53-2.06 (6H, m), 2.22-2.51 (1H, m), 3.30-3.37 (1H, m), 4.27-4.41 (1H, m), 6.58-6.62 (1H, m), 7.43-7.47 (1H, m), 7.91-7.92 (1H, m), 10.87-10.89 (1H, m), 11.61 (1H, s).
MS (ESI): m/z 271 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.87 (6H, t, J=7.3 Hz), 1.30-1.37 (4H, m), 1.81-1.90 (1H, m), 3.88 (2H, d, J=7.7 Hz), 6.48 (1H, dd, J=1.8 Hz, 3.7 Hz), 7.43 (1H, t, J=3.1 Hz), 7.93 (1H, s), 10.88 (1H, s), 11.57 (1H, s).
MS (ESI): m/z 259 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.39-1.66 (5H, m), 1.82-1.90 (1H, m), 2.06-2.13 (1H, m), 2.77-2.89 (1H, m), 3.03 (3H, s), 3.57-3.61 (1H, m), 4.45-4.51 (1H, m), 6.67-6.71 (1H, m), 7.36-7.38 (1H, m), 7.91 (1H, s), 10.86 (1H, brs), 11.45 (1H, brs).
MS (ESI): m/z 287.2 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.26-1.54 (3H, m), 1.65-1.96 (5H, m), 2.14-2.31 (2H, m), 4.31-4.43 (1H, m), 6.60 (1H, m), 7.45 (1H, t, J=3.0 Hz), 7.92 (1H, s), 10.88 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 257 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.05-1.15 (5H, m), 1.58-1.86 (6H, m), 3.82 (2H, d, J=7.2 Hz), 6.51-6.53 (1H, m), 7.42 (1H, t, J=2.9 Hz), 7.92 (1H, s), 10.86 (1H, s), 11.56 (1H, s).
MS (ESI): m/z 271 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.84 (3H, s), 1.09 (3H, s), 1.31-1.93 (7H, m), 2.82-3.08 (1H, m), 4.08-4.22 (1H, m), 6.64-6.70 (1H, m), 7.37-7.43 (1H, m), 7.89 (1H, s), 10.77 (1H, brs), 11.56 (1H, brs).
MS (ESI): m/z 285 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.77-2.21 (14H, m), 4.23 (1H, m), 7.42 (1H, brs), 7.93 (1H, brs), 8.32 (1H, s), 10.88 (1H, brs), 11.58 (1H, s).
MS (ESI): m/z 285 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.73-2.22 (14H, m), 4.16-4.36 (1H, m), 6.45-6.65 (1H, m), 7.40-7.49 (1H, m), 7.94 (1H, s), 10.91 (1H, brs), 11.64 (1H, brs).
MS (ESI): m/z 285 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.71 (3H, d, J=7.2 Hz), 1.50-2.42 (6H, m), 2.73-2.83 (1H, M), 4.89-4.98 (1H, m), 6.62-6.66 (1H, m), 7.39-7.43 (1H, m), 7.89 (1H, s), 10.80 (1H, brs), 11.55 (1H, brs).
MS (ESI): m/z 257 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.67 (3H, d, J=6.0 Hz), 1.08 (3H, d, J=6.6 Hz), 1.52 (3H, d, J=7.0 Hz), 2.37-2.48 (1H, m), 4.13-4.23 (1H, m), 6.54 (1H, br, s), 7.42 (1H, t, J=3.0 Hz), 7.93 (1H, s), 10.87 (1H, s), 11.58 (1H, s).
MS (ESI): m/z 245 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.76 (3H, t, J=7.3 Hz), 1.78 (6H, s), 2.13 (2H, q, J=7.3 Hz), 6.49 (1H, dd, J=1.9 Hz, 3.6 Hz), 7.45 (1H, t, J=3.1 Hz), 7.91 (1H, s), 10.78 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 245 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.67 (3H, d, J=5.3 Hz), 1.09 (3H, d, J=6.7 Hz), 1.53 (3H, d, J=6.8 Hz), 2.38-2.43 (1H, m), 4.14-4.22 (1H, m), 6.54 (1H, br, s), 7.42 (1H, t, J=3.0 Hz), 7.93 (1H, s), 10.87 (1H, s), 11.58 (1H, s).
MS (ESI): m/z 245 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.91-2.22 (4H, m), 2.93-3.10 (2H, m), 5.21-5.25 (1H, m), 5.77 (1H, dd, J=5.5 Hz, 11 Hz), 6.74-6.78 (1H, m), 6.94-6.99 (1H, m), 7.07-7.18 (2H, m), 7.24-7.28 (1H, m), 7.97 (1H, s), 11.11 (1H, s), 11.41 (1H, s).
MS (ESI): m/z 305 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.88 (3H, d, J=7.1 Hz), 5.81 (1H, s), 5.90 (1H, q, J=7.1 Hz), 7.21-7.28 (2H, m), 7.31-7.37 (4H, m), 7.96 (1H, s), 11.05 (1H, s), 11.47 (1H, s).
MS (ESI): m/z 279 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.71 (2H, dd, J=4.4, 12.8 Hz), 2.44-2.55 (2H, m), 3.51-3.59 (2H, m), 4.04 (2H, dd, J=4.4, 11.6 Hz), 4.60-4.69 (1H, m), 6.64 (1H, dd, J=2.0, 3.6 Hz), 7.46-7.48 (1H, m), 7.94 (1H, s), 10.94 (1H, s), 11.62 (1H, s).
MS (ESI): m/z 259 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.88 (3H, d, J=7.2 Hz), 5.81 (1H, s), 5.88 (1H, q, J=7.2 Hz), 7.21-7.28 (2H, m), 7.31-7.37 (4H, m), 7.96 (1H, s), 11.05 (1H, s), 11.48 (1H, s).
MS (ESI): m/z 279 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.38-1.48 (2H, m), 1.74-1.77 (2H, m), 1.97-2.00 (2H, m), 2.26-2.36 (2H, m), 3.63 (1H, m), 4.33-4.39 (1H, m), 4.73 (1H, d, J=4.1 Hz), 6.56-6.57 (1H, m), 7.43-7.45 (1H, m), 7.91 (1H, s), 10.89 (1H, brs), 11.60 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.82-2.59 (8H, m), 4.59-4.70 (1H, m), 6.59-6.69 (1H, m), 7.49-7.69 (1H, m), 7.94 (1H, s), 10.95 (1H, brs), 11.62 (1H, brs).
MS (ESI): m/z 293 (M+H)+.
1H-NMR (DMSO-d6) δ: 5.23 (2H, s), 6.39 (1H, dd, J=1.8, 3.4 Hz), 7.21-7.34 (6H, m), 7.96 (1H, s), 11.03 (1H, s), 11.52 (1H, s).
MS (ESI): m/z 265 (M+H)+.
1H-NMR (DMSO-d6) δ: 5.27 (2H, brs), 6.38-6.45 (1H, m), 6.97-7.39 (4H, m), 7.98 (1H, s), 11.11 (1H, brs), 11.58 (1H, brs).
MS (ESI): m/z 301 (M+H)+.
1H-NMR (DMSO-d6) δ: 5.30 (2H, s), 6.08 (1H, dd, J=1.8, 3.4 Hz), 7.00 (1H, dd, J=1.2, 7.6 Hz), 7.27 (1H, dt, J=1.6, 7.2 Hz), 7.30-7.33 (1H, m), 7.39-7.48 (2H, m), 8.32 (1H, s), 11.12 (1H, s), 11.56 (1H, s).
MS (ESI): m/z 349 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.27 (3H, t, J=7.2 Hz), 1.73-2.14 (4H, m), 3.04-3.18 (2H, m), 3.55-3.81 (3H, m), 4.34-4.50 (2H, m), 6.66-6.70 (1H, m), 7.48-7.50 (1H, m), 7.98 (1H, s), 11.18 (1H, brs), 11.69 (1H, brs).
MS (ESI): m/z 286 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.40-1.51 (3H, m), 1.64-1.71 (1H, m), 1.81-1.97 (3H, m), 2.33-2.38 (1H, m), 2.82-2.91 (1H, m), 3.08 (3H, s), 3.40-3.45 (1H, m), 3.55-3.60 (1H, m), 4.46-4.50 (1H, m), 6.48-6.50 (1H, m), 7.42-7.44 (1H, m), 7.89 (1H, s), 10.72 (1H, brs), 11.58 (1H, brs).
MS (ESI): m/z 301 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.93-1.02 (2H, m), 1.10-1.20 (2H, m), 3.05-3.15 (1H, m), 6.66-6.70 (1H, m), 7.39-7.43 (1H, m), 7.88 (1H, s), 10.74 (1H, s), 11.52 (1H, s).
MS (ESI): m/z 237 (M+Na)+.
1H-NMR (DMSO-d6) δ: 11.9 (1H, br), 11.3 (1H, s), 8.06 (1H, s), 7.09-7.39 (5H, m), 6.03 (1H, s), 5.54-5.58 (1H, m), 3.34-3.53 (4H, m).
MS (ESI): m/z 313 (M+Na)+.
1H-NMR (DMSO-d6) δ: 11.6 (1H, br), 11.9 (1H, br), 7.92 (1H, br), 7.40 (1H, s), 6.62-6.66 (1H, m), 3.60-4.42 (3H, m), 3.14 (3H, s), 2.38-2.42 (1H, m), 1.15 (3H, br), 0.70 (3H, br).
MS (ESI): m/z 275 (M+H)+.
1H-NMR (DMSO-d6) δ: 3.03 (2H, d, J=7.6 Hz), 4.22 (2H, d, J=7.6 Hz), 6.58 (1H, d d, J=1.8, 3.4 Hz), 7.16-7.29 (5H, m), 7.43-7.45 (1H, m), 7.92 (1H, s), 10.85 (1H, s), 11.57 (1H, s).
MS (ESI): m/z 279 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.90-2.21 (4H, m), 2.92-3.12 (2H, m), 5.23 (1H, s), 5.77 (1H, dd, J=5.6 Hz, 11.4 Hz), 6.75-6.77 (1H, m), 6.93-7.00 (1H, m), 7.09-7.18 (2H, m), 7.24-7.28 (1H, m), 7.97 (1H, s), 11.10 (1H, s), 11.41 (1H, s).
MS (ESI): m/z 305 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.94 (3H, d, J=7.2 Hz), 1.36-1.90 (7H, m), 2.30-2.37 (1H, m), 2.88-3.01 (1H, m), 4.40-4.45 (1H, m), 6.47-6.49 (1H, m), 7.41-7.44 (1H, m), 7.89 (1H, s), 10.72 (1H, brs), 11.57 (1H, brs).
MS (ESI): m/z 293 (M+Na)+.
To a mixture of rel-N′-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N4-methyl-2,3,4-pyridinetriamine (110 mg) in triethyl orthoformate (2.25 mL) was added concentrated HCl (0.044 mL). The mixture was stirred at ambient temperature overnight. The precipitate was filtrated and washed with diisopropyl ether to give rel-N-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (133 mg) as a off-white powder.
1H-NMR (DMSO-d6) δ: 1.04 (3H, d, J=6.1 Hz), 1.66-1.73 (1H, m), 2.31 (1H, m), 2.50 (3H, s), 3.17-3.66 (5H, m), 3.87 (1H, m), 4.40 (2H, m), 6.74 (1H, d, J=7.1 Hz), 7.44-7.48 (4H, m), 7.64-7.66 (2H, m), 8.16 (1H, d, J=7.1 Hz), 8.45 (1H, m).
MS (ESI): m/z 336 (M−HCl+H)+.
The following compounds were obtained in a similar manner to that of Example 155.
1H-NMR (DMSO-d6) δ: 0.94 (3H, d, J=7.3 Hz), 1.41-1.99 (8H, m), 2.32 (1H, m), 3.05 (3H, s), 5.23-5.32 (1H, m), 6.25 (1H, d, J=5.9 Hz), 7.87 (1H, d, J=5.9 Hz), 8.01 (1H, s), 12.57 (1H, brs).
MS (ESI): m/z 245 (M+H)+.
1H-NMR (DMSO-d6) δ: 12.8 (1H, brs), 9.45 (1H, d, J=8.4 Hz), 8.43 (1H, s), 8.05 (1H, s), 7.82 (1H, br), 7.05 (1H, br), 4.82-4.90 (1H, m), 1.24-1.97 (10H, m).
MS (ESI): m/z 260 (M+H)+.
1H-NMR (DMSO-d6) δ: 13.0 (1H, br), 11.1 (1H, br), 8.33 (1H, s), 7.99 (1H, s), 5.13-5.16 (1H, m), 2.98-3.10 (2H, m), 1.15-2.30 (7H, m).
MS (ESI): m/z 348 (M+Na)+.
1H-NMR (DMSO-d6) δ: 12.3 (1H, br), 10.8 (1H, s), 7.71 (1H, s), 4.60-4.63 (1H, m), 4.51 (2H, q, J=7.0 Hz), 3.21-3.25 (1H, m), 2.23-2.32 (1H, m), 1.30-1.99 (10H, m), 0.95 (3H, d, J=7.2 Hz).
MS (ESI): m/z 316 (M+H)+.
1H-NMR (DMSO-d6) δ: 12.6 (1H, br), 10.9 (1H, br), 7.86 (1H, s), 4.68-4.73 (1H, m), 2.5 (3H, s), 2.25-2.31 (1H, m), 1.23-1.91 (8H, m), 0.93 (3H, d, J=7.2 Hz).
MS (ESI): m/z 286 (M+H)+.
1H-NMR (DMSO-d6) δ: 13.4 (1H, br), 11.2 (1H, br), 8.24 (2H, d, J=7.3 Hz), 7.99 (1H, s), 7.49-7.59 (3H, m), 4.78-4.83 (1H, m), 1.23-2.39 (9H, m), 1.01 (3H, d, J=7.2 Hz).
MS (ESI): m/z 370 (M+Na)+.
1H-NMR (DMSO-d6) δ: 14.5 (1H, brs), 11.3 (1H, s), 8.14 (1H, s), 4.76-4.80 (1H, m), 3.17-3.33 (1H, m), 2.33 (1H, m), 1.38-1.92 (7H, m), 0.94 (3H, d).
MS (ESI): m/z 340 (M+H)+.
In a microwave reaction vessel, to a solution of rel-N-[(3R,4R)-1-benzyl-4-methyl-3-piperidinyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (130 mg) in ethanol (1.3 mL) were added 1,4-cyclohexadiene (1.5 mL) and palladium hydroxide on carbon (130 mg). The vessel was sealed and reacted in the microwave reactor at 110° C. for 0.5 hour. The reaction mixture was cooled to ambient temperature and filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was washed with diisopropyl ether to give N-methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-3H-imidazo[4,5-b]pyridin-7-aminedihydrochloride (48 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.11 (3H, d, J=7.2 Hz), 1.63-1.70 (1H, m), 2.15 (1H, m), 2.89-3.67 (8H, m), 5.74 (1H, m), 6.75 (1H, d, J=7.0H, z), 8.14 (1H, d, J=7.0 Hz), 8.32 (1H, s), 8.42 (1H, m), 9.05-9.62 (2H, m), 14.19 (1H, br).
MS (ESI): m/z 246 (M−2HCl+H)+.
To a solution of N-methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (40 mg) in N,N-dimethylformamide (0.6 mL) were added cyanoacetic acid (16 mg), 1-hydroxybenzotriazole (25.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.033 mL). The mixture was stirred at ambient temperature overnight, then extracted with EtOAc and washed with brine. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 3-{(3R,4R)-3-[3H-imidazo[4,5-b]pyridin-7-yl(methyl)amino]-4-methyl-1-piperidinyl}-3-oxopropanenitrile (25 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.0 Hz), 1.57 (1H, m), 1.79 (1H, m), 2.40 (2H, m), 3.01 (3H, s), 3.38 (1H, m), 3.65-3.93 (2H, m), 4.12 (2H, m), 5.59-5.63 (1H, m), 7.90-7.93 (1H, m), 8.03-8.05 (1H, m), 8.32 (1H, s), 12.67 (1H, brs).
MS (ESI): m/z 313 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 164.
1H-NMR (DMSO-d6) δ: 1.23-2.15 (8H, m), 3.86-4.31 (3H, m), 6.61-6.66 (1H, m), 7.15-7.19 (2H, m), 7.96 (1H, m), 8.38 (1H, s), 9.67-9.82 (1H, m), 11.54 (1H, m),
MS (ESI): m/z 327 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.00 (3H, m, J=7.2 Hz), 1.39-4.62 (17H, m), 6.47 (1H, brs), 7.43 (1H, brs), 7.91 (1H, s), 10.81-10.88 (1H, m), 11.58-11.63 (1H, m).
MS (ESI): m/z 384.
1H-NMR (DMSO-d6) δ: 1.05-1.14 (3H, m), 1.65-4.94 (16H, m), 6.48-6.52 (1H, m), 7.25-7.46 (2H, m), 7.92 (1H, s), 10.84 (1H, brs), 11.64 (1H, brs).
MS (ESI): m/z 468.
1H-NMR (DMSO-d6) δ: 1.01 (3H, d, J=7.1 Hz), 1.76-1.84 (1H, m), 2.00-2.16 (1H, m), 3.40-3.60 (1H, m), 3.82-4.16 (1H, m), 4.24-4.64 (3H, m), 6.58-6.62 (1H, m), 7.04-7.16 (1H, m), 7.37-7.47 (2H, m), 7.72 (1H, d, J=4.3 Hz), 7.91 (1H, s), 10.86 (1H, s), 11.62 (1H, s).
MS (ESI+): m/z 382.
1H-NMR (DMSO-d6) δ: 1.01 (3H, d, J=7.1 Hz), 1.55 (6H, s), 1.66-2.10 (2H, m), 3.40-4.83 (6H, m), 6.52-6.55 (1H, m), 7.42-7.44 (1H, m), 7.88 (1H, s), 10.88 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 367.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.78-1.88 (1H, m), 1.97-2.14 (1H, m), 3.40-3.64 (1H, m), 3.88-4.03 (1H, m), 4.24-4.37 (1H, m), 4.42-4.64 (3H, m), 6.58-6.64 (1H, m), 7.04-7.18 (1H, m), 7.24-7.38 (1H, m), 7.41-7.46 (1H, m), 7.91 (1H, s), 10.85 (1H, s), 11.60 (1H, s).
MS (ESI+): m/z 416.
1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=7.0 Hz), 1.66-4.66 (14H, m), 6.62 (1H, s), 7.38-8.00 (6H, m), 10.85 (1H, s), 11.62 (1H, s).
MS (ESI): m/z 459.
1H-NMR (DMSO-d6) δ: 1.55-1.70 (2H, m), 1.81-1.98 (4H, m), 2.13-2.46 (3H, m), 4.16 (2H, d, J=5.6 Hz), 4.34-4.44 (1H, m), 6.61-6.63 (1H, m), 7.46 (1H, t, J=3.0 Hz), 7.92 (1H, s), 8.61 (1H, s), 10.90 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 339.
1H-NMR (DMSO-d6) δ: 1.01 (3H, d, J=6.8 Hz), 1.63-4.60 (18H, m), 6.37-6.48 (1H, m), 7.41-7.47 (1H, m), 7.89-7.94 (1H, m), 10.86 (1H, brs), 11.63 (1H, brs
MS (ESI): m/z 399.
1H-NMR (DMSO-d6) δ: 0.99-1.05 (3H, m), 1.66-4.76 (8H, m), 5.54-5.90 (2H, m), 6.52-6.58 (1H, m), 7.45-7.48 (1H, m), 7.90-7.94 (1H, m), 9.24-9.31 (1H, m), 10.85-10.96 (1H, m), 11.58-11.67 (1H, m).
MS (ESI): m/z 404 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.03 (3H, d, J=7.2 Hz), 1.4-4.8 (12H, m), 6.57 (1H, d, J=1.5 Hz), 6.55-7.44 (1H, m), 7.91 (1H, s), 10.87 (1H, brs), 11.61 (1H, s).
MS (ESI+): m/z 365.
1H-NMR (DMSO-d6) δ: 1.56-1.70 (2H, m), 1.80-1.94 (4H, m), 2.30-2.45 (2H, m), 2.81-2.92 (2H, m), 3.20 (3H, s), 4.41 (2H, s), 6.69-6.72 (1H, m), 7.44 (1H, t, J=2.9 Hz), 7.92 (1H, s), 10.50 (1H, s), 11.59 (1H, s).
MS (ESI+): m/z 353.
1H-NMR (DMSO-d6) δ: 1.46-1.48 (2H, m), 2.05 (2H, m), 3.26-3.33 (2H, m), 4.05-4.08 (2H, m), 4.26 (1H, m), 6.61-6.63 (2H, m), 6.87 (1H, d, J=4.4 Hz), 6.90-7.10 (1H, brs), 7.15-7.16 (1H, m), 7.50-7.54 (1H, m), 8.11-8.12 (1H, m), 8.37 (1H, s), 9.74 (1H, d, J=4.0 Hz), 11.49 (1H, s).
MS (ESI): m/z 327 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.15-3.91 (7H, m), 4.02 and 4.11 (total 2H, each m), 4.27-4.58 (2H, m), 6.60-6.65 and 6.74-6.80 (total 1H, each m), 7.42-7.49 (1H, m), 7.93 and 7.94 (total 1H, each s), 10.99 (1H, brs), 11.61 and 11.65 (total 1H, each s).
MS (ESI): m/z 325 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.72-2.56 (6H, m), 3.41-4.27 (6H, m), 4.47-4.59 (1H, m), 6.39-6.60 (1H, m), 7.41-7.45 (1H, m), 7.91-7.92 (1H, m), 10.91 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 339 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.46-2.38 (6H, m), 3.32-3.52 (7H, m), 6.58-6.60 (1H, m), 7.44-7.47 (1H, m), 7.90-7.95 (1H, m), 10.93-11.01 (1H, m), 11.58-11.63 (1H, m).
MS (ESI): m/z 339 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.83-1.97 (4H, m), 2.32-2.33 (1H, m), 2.62-2.67 (1H, m), 3.15-3.20 (1H, m), 3.72-3.87 (1H, m), 4.34 (1H, m), 4.45-4.50 (2H, m), 6.61-6.62 (1H, m), 7.43-7.46 (1H, m), 8.19 (1H, s), 10.98 (1H, brs), 11.60-11.65 (1H, m).
MS (ESI): m/z 347.2 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.14-1.18 (4H, m), 1.81-1.84 (2H, m), 2.43-2.45 (1H, m), 2.88 (1H, m), 4.08-4.28 (2H, m), 4.65-4.67 (1H, m), 6.58-6.59 (1H, m), 7.44-7.46 (1H, m), 7.93 (1H, s), 10.93 (1H, brs), 11.61 (1H, brs).
MS (ESI): m/z 347.2 (M+Na)+.
1H-NMR (DMSO-d6) δ: 2.26-2.46 (1H, m), 2.62-2.79 (1H, m), 3.50-3.74 (1H, m), 3.83-4.27 (1H, m), 5.31-5.48 (1H, m), 6.54-6.66 (1H, m), 7.52-7.59 (1H, m), 8.04 (1H, s), 11.10 and 11.12 (total 1H, each s), 11.74 (1H, s).
MS (ESI): m/z 333 (M+Na)+.
1H-NMR (DMSO-d6) δ: 3.80-3.97 (2H, m), 4.36-4.54 (2H, m), 4.56-4.76 (2H, m), 5.48-5.60 (1H, m), 6.57-6.63 (1H, m), 7.46-7.52 (1H, m), 7.96 (1H, s), 11.10 (1H, brs) 11.67 (1H, s).
MS (ESI): m/z 319 (M+Na)+.
1H-NMR (DMSO-d6) δ: 2.24-3.11 (2H, m), 3.43-4.15 (6H, m), 5.25-5.33 (1H, m), 6.47-6.54 (1H, m), 7.45-7.48 (1H, m), 7.95 (1H, s), 11.02-11.04 (1H, m), 11.66 (1H, s).
MS (ESI): m/z 311 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.90-0.96 (3H, m), 1.33-1.67 (2H, m), 2.04-2.15 (1H, m), 2.80-3.18 (2H, m), 3.34-3.40 (1H, m), 3.60-3.67 (1H, m), 3.84-4.09 (1H, m), 4.19-4.37 (2H, m), 6.56-6.64 (1H, m), 6.79-7.19 (2H, m), 7.71-7.92 (1H, br), 8.36-8.42 (1H, m), 9.84-9.90 (1H, m), 11.47-11.57 (1H, m).
MS (ESI): m/z 341.4 (M+H)+.
To a solution of 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (25 mg) in N,N-dimethylformamide (0.375 mL) were added 1-hydroxybenzotriazole (19.5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22.5 mg) and methylamine hydrochloride (9.8 mg). The mixture was stirred at 55° C. for 1 hour. To the solution were added water and EtOAc and the mixture was extracted with EtOAc. The extract was washed with water, dried over MgSO4, filtrated and evaporated The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-(cyclohexylamino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (5 mg), as a pale yellow powder.
1H-NMR (DMSO-d6) δ: 1.15-2.01 (10H, m), 2.73 (3H, d, J=4.4 Hz), 3.91-3.95 (1H, m), 6.47-6.50 (1H, m), 7.11-7.14 (1H, m), 8.17-8.20 (1H, m), 8.27 (1H, s), 9.38-9.42 (1H, m), 11.42 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 187.
1H-NMR (DMSO-d6) δ: 0.49-0.66 (2H, m), 0.80-1.00 (2H, m), 2.90-3.09 (1H, m), 6.90-7.02 (1H, m), 7.03 (1H, br), 7.04-7.18 (1H, m), 7.73 (1H, br), 8.35 (1H, s), 9.58 (1H, d, J=2.1 Hz), 11.45 (1H, s).
MS (ESI): m/z 217 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.96 (3*1/2H, d, J=7.2 Hz), 0.97 (3*1/2H, d, J=7.2 Hz), 1.63-4.65 (10H, m), 6.51-6.55 (1H, m), 7.43 (1*1/2H, dd, J=2.4, 3.6 Hz), 7.46 (1*1/2H, dd, J=2.4, 3.6 Hz), 7.906 (1*1/2H, s), 7.911 (1*1/2H, s), 10.86 (1H, brs), 11.57 (1*1/2H, brs), 11.62 (1*1/2H, brs).
MS (ESI): m/z 339 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.23-1.97 (10H, m), 2.97 (6H, s), 3.72 (1H, m), 6.48-6.54 (2H, m), 7.15-7.17 (1H, m), 7.78 (1H, s), 11.40 (1H, brs).
MS (ESI): m/z 287 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.05-2.01 (20H, m), 3.91 (1H, m), 3.95 (1H, m), 6.48-6.49 (1H, m), 7.11-7.13 (1H, m), 7.96 (1H, d, J=7.7 Hz), 8.31 (1H, s), 9.32 (1H, d, J=8.0 Hz), 11.44 (1H, brs).
MS (ESI): m/z 341 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.02-2.04 (10H, m), 4.00 (1H, m), 6.59-6.60 (1H, m), 7.04-7.44 (4H, m), 7.68 (2H, d, J=7.9 Hz), 8.50 (1H, s), 9.13-9.17 (1H, m), 10.13 (1H, brs), 11.77 (1H, brs).
MS (ESI): m/z 335 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.02-2.04 (10H, m), 2.76 (2H, t, J=6.4 Hz), 3.41-3.50 (2H, m), 3.94-3.97 (1H, m), 6.49-6.51 (1H, m), 7.13-7.16 (1H, m), 8.32 (1H, s), 8.54-8.60 (1H, m), 9.28-9.32 (1H, m), 11.50 (1H, br).
MS (ESI): m/z 312 (M+H)+.
To a solution of tert-butyl(3R)-3-{[5-(aminocarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]amino}-1-piperidinecarboxylate (125 mg) in dioxane (1.25 mL) was added 4M HCl in dioxane (1 ml) and the solution was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated to give 4-[(3R)-3-piperidinylamino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride (112 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.52-2.16 (8H, m), 4.56 (1H, m), 6.55-6.56 (1H, m), 7.63-7.65 (1H, m), 8.49 (3H, m), 8.59 (1H, s), 10.65-10.69 (1H, m), 12.72 (1H, br s).
MS (ESI): m/z 260 (M+H)+.
To a solution of 4-[(3R)-3-piperidinylamino]-1H-pyrrolo[2,3-b]-pyridine-5-carboxamide hydrochloride (50 mg) in dichloromethane (1.0 mL) were added triethylamine (0.014 mL) and methanesulfonyl chloride (0.094 mL) at 4° C. The mixture was stirred at ambient temperature for 5 hours. To the mixture was added water and chloroform and the organic layer was extracted with chloroform. The extract was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol to give 4-{[(3R)-1-(methylsulfonyl)-3-piperidinyl]-amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (7 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.02-1.24 (2H, m), 1.47-2.03 (4H, m), 2.87 (3H, s), 2.88-3.09 (2H, m), 4.14-4.22 (1H, m), 6.55-6.57 (1H, m), 7.17-7.89 (2H, br), 7.63-7.66 (1H, m), 8.29 (1H, s), 11.52 (1H, m), 12.17 (1H, m).
MS (ESI): m/z 360 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 195.
1H-NMR (DMSO-d6) δ: 1.71-2.07 (4H, m), 2.93 (3H, s), 3.23-3.44 (2H, m), 3.94-4.19 (3H, m), 6.85-6.92 (1H, m), 7.41-7.48 (1H, m), 7.92 (1H, s), 10.96 (1H, s), 11.56 (1H, s).
ESI-MS(+) m/z; 336 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.54-1.98 (4H, m), 2.87 (3H, s), 2.87-2.99 (2H, m), 3.25-3.32 (1H, m), 3.64-3.66 (1H, m), 4.16 (1H, m), 6.53 (1H, m), 6.90-7.15 (1H, brs), 7.16-7.17 (1H, m), 7.70-7.90 (1H, brs), 8.38 (1H, s), 9.77 (1H, d, J=3.6 Hz), 11.52 (1H, 1).
MS (ESI): m/z 338 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.99 (1H, m), 2.30-2.35 (1H, m), 3.16-3.48 (3H, m), 3.32 (3H, s), 3.61-3.65 (1H, m), 4.75 (1H, m), 6.58-6.59 (1H, m), 6.90-7.10 (1H, brs), 7.18-7.20 (1H, m), 7.70-8.00 (1H, brs), 8.40 (1H, s), 9.85 (1H, d, J=4.0 Hz), 11.57 (1H, s).
MS (ESI): m/z 346 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.97-1.99 (1H, m), 2.28-2.38 (1H, m), 3.22-3.49 (3H, m), 3.37 (3H, s), 3.61-3.65 (1H, m), 4.75 (1H, brs), 6.58-6.59 (1H, m), 7.00-7.20 (1H, brs), 7.18-7.19 (1H, m), 7.70-8.00 (1H, brs), 8.41 (1H, s), 8.86 (1H, d, J=4.0 Hz), 11.58 (1H, s).
MS (ESI): m/z 346 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.51-1.58 (2H, m), 2.09-2.11 (2H, m), 3.07-3.12 (2H, m), 3.46-3.49 (2H, m), 4.11 (1H, m), 6.57-6.58 (1H, m), 6.90-7.10 (1H, brs), 7.15-7.17 (1H, m), 7.64-7.95 (1H, brs), 8.61 (1H, s), 9.73 (1H, d, J=4.0 Hz), 11.51 (1H, s).
1H-NMR (DMSO-d6) δ: 1.69-1.85 (1H, m), 1.90-2.03 (2H, m), 2.39-2.56 (1H, m), 2.86 (1H, dd, J=11.3, 11.3 Hz), 2.94 (3H, s), 3.42 (1H, dd, J=11.3, 11.3 Hz), 3.61-3.77 (2H, m), 4.46-4.59 (1H, m), 6.59-6.64 (1H, m), 7.44-7.50 (1H, m), 7.94 (1H, s), 11.00 (1H, brs), 11.66 (1H, s).
MS (ESI): m/z 358 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.77-2.04 (4H, m), 2.39-2.53 (3H, m), 2.95 (3H, s), 3.28-3.59 (3H, m), 4.57-4.65 (1H, m), 6.66-6.69 (1H, m), 7.43-7.45 (1H, m), 7.92 (1H, s), 10.91 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 350 (M+H)+.
1H-NMR (DMSO-d6) δ: 2.22-2.36 (1H, m), 2.46-2.63 (1H, m), 3.03 (3H, s), 3.38-3.50 (1H, m), 3.61-3.80 (3H, m), 5.29-5.43 (1H, m), 6.66-6.72 (1H, m), 7.46-7.52 (1H, m), 7.96 (1H, s), 11.03 (1H, brs), 11.65 (1H, s).
MS (ESI): m/z 322 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.55-2.00 (5H, m), 2.27-3.85 (5H, m), 2.93 (3H, s), 4.56-4.70 (1H, m), 6.56-6.58 (1H, m), 7.44-7.46 (1H, m), 7.92 (1H, s), 10.96 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 350 (M+H)+.
1H-NMR (DMSO-d6) δ: 2.27-2.35 (1H, m), 2.46-2.68 (2H, m), 3.04 (3H, s), 3.37-3.79 (3H, m), 5.40 (1H, t, J=8.6 Hz), 6.80-6.83 (1H, m), 7.57 (1H, t, J=3.0 Hz), 8.04 (1H, s), 11.27 (1H, s), 11.90 (1H, s).
MS (ESI): m/z 322 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.23 (1H, m), 1.79 (1H, m), 1.95-1.98 (4H, m), 2.85-2.88 (1H, m), 2.94 (3H, s), 3.65-3.73 (1H, m), 4.50-4.54 (1H, m), 6.55-6.67 (1H, m), 7.49-7.51 (1H, m), 7.97 (1H, s), 11.12 (1H, brs), 11.78 (1H, brs).
MS (ESI): m/z 336.1 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.87-1.91 (2H, m), 2.95 (3H, s), 2.99-3.20 (4H, m), 3.73-3.76 (2H, m), 4.53-4.59 (1H, m), 6.65-6.66 (1H, m), 7.47-7.49 (1H, m), 7.94 (1H, s), 10.96 (1H, brs), 11.63 (1H, brs).
MS (ESI): m/z 358.1 (M+Na)+.
4-Chloro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (70 mg), (1S,2R)-2-methylcyclohexanamine hydrochloride (108.5 mg), N,N-diisopropylethylamine (0.126 ml) and 1,3-dimethyl-2-imidazolidinone (0.35 ml) were combined and irradiated microwave at 16° C. for 1 hour. After cooled to ambient temperature, the mixture was diluted in EtOAc. The organic solution was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative NH2 silica gel column chromatography with 5% methanol in chloroform to give 2-(4-fluorophenyl)-4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (13.7 mg) as an off-white solid.
1H-NMR (DMSO d6) δ: 0.92 (3H, d, J=7.0 Hz) 1.22-2.03 (9H, m), 4.34 (1H, m) 7.00 (1H, s), 7.26 (2H, t, J=9.0 Hz), 7.93 (2H, dd, J=9.0, 5.5 Hz), 8.38 (1H, s), 9.93 (1H, d, J=8.5 Hz), 11.98 (1H, brs).
MS (ESI): m/z 367 (M+H)+.
mp.>280° C.
To a 1:1 mixture (100 mg) of 7-chloro-1H-imidazo[4,5-b]pyridine and 5-chloro-1H-imidazo[4,5-b]pyridine was added N-methylcyclohexanamine (500 ul), and irradiated microwave at 200° C. for 2 hours. The reaction mixture was diluted with chloroform, washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography over NH-silica gel with a chloroform/EtOAc (100:1-100:5) as eluant to give N-cyclohexyl-N-methyl-1H-imidazo[4,5-b]pyridin-7-amine (54.8 mg) as a white solid.
1H-NMR (DMSO-d6) δ: 1.03-1.87 (10H, m), 2.99 (3H, s), 5.17-5.41 (1H, m), 6.27 (1H, d, J=5.9 Hz), 7.87 (1H, d, J=5.9 Hz), 8.03 (1H, s), 12.54 (1H, b.s).
MS (ESI): m/z 231 (M+H)+.
To a suspension of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (57 mg) in 2-propanol (180 μl) were added N-methylcyclohexanamine (154 μl) and N,N-diisopropylethylamine (50 μl), and irradiated microwave at 120° C. for 15 minutes. The reaction mixture was purified by flash column chromatography over silica gel with a EtOAc/methanol (100:0-60:40) as eluant. then by preparative silica gel thin-layer chromatography with EtOAc as eluant to give a solid. The solid was washed with diisopropyl ether to give N-cyclohexyl-N-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (7.9 mg) as a yellow solid.
1H-NMR (DMSO-d6) δ: 0.98-1.17 (3H, m), 1.42-1.62 (5H, m), 1.64-1.8 (2H, m), 2.77 (3H, s), 3.14-3.25 (1H, m), 6.7 (1H, d, J=5.5 Hz), 8.06 (1H, d, J=5.8 Hz), 8.47 (1H, s), 12.8 (1H, brs).
MS (ESI): m/z 275 (M+H)+, 297 (M+Na)+.
4-Chloro-1H-pyrrolo[2,3-b]pyridine (224 mg) and N-methylcyclohexanamine hydrochloride (1.1 g) was combined and stirred at 180° C. for 5 hours under nitrogen atmosphere. After cooled, the reaction mixture was dissolved in chloroform (20 ml), washed with saturated aqueous sodium hydrogencarbonate (10 ml) and brine, dried over MgSO4, and evaporated in vacuo to give crude red oil. The residue was purified by flash column chromatography over NH-silica gel with a EtOAc as eluant. The fractions containing the object compound were combined, and evaporated under reduced pressure. The residue was washed with ether to give N-cyclohexyl-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (49.8 mg) as a pale yellow solid.
1H-NMR (DMSO-d6) δ: 1.06-1.22 (1H, m), 1.29-1.44 (2H, m), 1.54-1.69 (3H, m), 1.69-1.87 (4H, m), 2.92 (3H, s), 3.91-4.02 (1H, m), 6.19 (1H, d, J=5.8 Hz), 6.4 (1H, d, J=3.7 Hz), 7.13 (1H, d, J=3.6 Hz), 7.82 (1H, d, J=5.5 Hz), 11.25 (1H, s).
MS (ESI): m/z 230 (M+H)+.
To the suspension of 4′-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile in n-butanol was added N-methylcyclohexanamine. This was irradiated microwave at 170° C. for 1.5 hours. After the reaction mixture was cooled to ambient temperature, to the mixture was added water and dichloromethane. And layers were separated. The organic layer was washed with brine, dried over MgSO4, and was concentrated. Resultings were purified by prep TLC. (EtOAc was used as an eluent) to give 4-[cyclohexyl(methyl)amino]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as colourless powder.
1H-NMR (DMSO-d6) δ: 1.10-1.27 (3H, m), 1.52-1.57 (3H, m), 1.73 (4H, m), 2.79 (3H, s), 3.70 (1H, t, J=11.6 Hz), 6.65 (1H, d, J=5.5 Hz), 8.11 (1H, d, J=5.5 Hz), 8.43 (1H, s), 12.59 (1H, br).
The following compound was obtained in a similar manner to that of Example 212.
1H-NMR (DMSO-d6) δ: 0.93 (3H, d, J=7.1 Hz), 1.35-2.10 (9H, m), 2.91 (3H, s), 3.79 (1H, m), 6.82 (1H, d, J=2.7 Hz), 7.97 (1H, d, J=2.7 Hz), 8.28 (1H, s).
To a solution N-cyclohexyl-5-fluoro-N-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (50 mL) in tetrahydrofuran (0.7 mL) was added tetra-n-butylammonium fluoride (0.372 mL, 1.0M in tetrahydrofuran) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours, then another 3 equivalent of tetra-n-butylammonium fluoride (0.372 mL) was added. The mixture was heated at 50° C. for 2 hours, at reflux for 6 hours. After cooling to ambient temperature, the mixture was concentrated. The residue was purified by column chromatography (gradient elution, n-hexane to 1:1 n-hexane/EtOAc) to give N-cyclohexyl-5-fluoro-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (10 mg) as a pale yellow solid.
1H-NMR (DMSO-d6) δ: 11.4 (1H, s), 7.91 (1H, d, J=6.1 Hz), 7.28 (1H, dd, J=3.4, 2.8 Hz), 6.45 (1H, dd, J=3.4, 1.8 Hz), 3.55-3.51 (1H, m), 3.01 (3H, d, J=3.0 Hz), 1.81-1.74 (4H, m), 1.70-1.55 (3H, m), 1.31-1.23 (2H, m), 1.15-1.09 (1H, m).
MS: m/z 248 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 214.
1H-NMR (DMSO-d6) δ: 1.47-2.41 (9H, m), 3.56-3.62 (2H, m), 4.47-4.56 (1H, m), 4.58 (1H, t, J=5.1 Hz), 6.57-6.58 (1H, m), 7.44 (1H, t, J=3.0 Hz), 7.91 (1H, s), 10.87 (1H, s), 11.59 (1H, s).
MS (ESI+): m/z 287.
1H-NMR (DMSO-d6) δ: 1.00-2.26 (10H, m), 3.21-3.37 (2H, m), 4.36-4.47 (1H, m), 6.58 (1H, s), 7.44 (1H, t, J=3.0 Hz), 7.92 (1H, s), 10.88 (1H, s), 11.59 (1H, s).
MS (ESI): m/z 287.
1H-NMR (DMSO-d6) δ: 0.96 (3H, d, J=7.1 Hz), 1.42-1.49 (3H, m), 1.65-1.68 (1H, m), 1.81-1.91 (3H, m), 2.35-2.37 (1H, m), 2.99-3.02 (1H, m), 4.48-4.54 (1H, m), 5.03-5.15 (2H, m), 6.51-6.52 (1H, m), 7.24-7.33 (5H, m), 7.45-7.47 (1H, m), 7.97.
MS (ESI): m/z 361 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.5 (1H, s), 10.8 (1H, s), 7.91 (1H, s), 7.41 (1H, s), 6.54 (1H, s), 4.91-4.94 (1H, m), 4.92-4.65 (1H, m), 3.94-3.97 (1H, m), 3.71-3.75 (1H, m), 1.46 (3H, d, J=7.0 Hz).
MS (ESI): m/z 233 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.5 (1H, brs), 10.8 (1H, brs), 7.9 (1H, s), 7.39 (1H, s), 6.38-6.61 (1H, m), 4.68-4.81 (1H, m), 3.80-4.20 (3H, m), 2.32-2.40 (1H, m), 1.05-1.07 (1H, br), 0.64-0.72 (1H, br).
MS (ESI): m/z 261 (M+H)+.
1H-NMR (DMSO-d6) δ: 11.5 (1H, brs), 10.8 (1H, brs), 7.9 (1H, s), 7.39 (1H, s), 6.38-6.61 (1H, m), 4.68-4.81 (1H, m), 3.80-4.20 (3H, m), 2.32-2.40 (1H, m), 1.05-1.07 (1H, br), 0.64-0.72 (1H, br).
MS (ESI): m/z 261 (M+H)+.
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (100 mg) and (1S,2R)—N,2-dimethylcyclohexanamine hydrochloride (288 mg) in DMI (1 mL) was heated in the microwave reactor (210° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (chloroform:methanol=10:1) gave 5-fluoro-N-methyl-N-[(1S,2R)-2-methylcyclohexyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.
1H-NMR (CDCl3) δ: 9.02 (1H, brs), 7.97 (1H, d, J=6.4 Hz), 7.16 (1H, d, J=3.7 Hz), 6.61 (1H, d, J=3.7 Hz), 3.93-3.87 (1H, m), 3.18 (3H, s), 2.34-2.21 (2H, m), 1.84-1.20 (7H, m), 1.04 (3H, d, J=7.2 Hz).
MS (ESI): m/z 262 (M+H)+.
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and cyclohexylamine (87 mg) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 4 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave N-cyclohexyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.
1H-NMR (CDCl3) δ: 9.90 (1H, br), 7.95 (1H, d, J=4.4 Hz), 7.14 (1H, d, J=3.4 Hz), 6.50 (1H, d, J=3.4 Hz), 4.46 (1H, br), 3.90-3.80 (1H, m), 2.2-1.2 (10H, m).
MS (ESI): m/z 234 (M+H)+.
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and piperidine (50 mg) in 1-butanol (0.4 mL) was heated in the microwave reactor (120° C., 0.5 hour, 180° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (10 mL) two times and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 5-fluoro-4-(1-piperidinyl)-1H-pyrrolo[2,3-b]pyridine (10 mg) as a white solid.
1H-NMR (CDCl3) δ: 10.2 (1H, br), 8.01 (1H, d, J=6.0 Hz), 7.18 (1H, d, J=3.5 Hz), 6.56 (1H, d, J=3.5 Hz), 3.60-3.40 (4H, m), 1.90-1.65 (6H, m).
MS (ESI): m/z 220 (M+H)+.
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg), 3-piperidinecarboxamide (45 mg) and N,N-diisopropylethylamine (30 μL) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-piperidinecarboxamide (5 mg) as a pale brown solid.
1H-NMR (DMSO-d6) δ: 11.5 (1H, s), 7.96 (1H, d, J=5.7 Hz), 7.38 (1H, s), 7.33 (1H, d, J=3.0 Hz), 6.87 (1H, s), 6.49 (1H, d, J=3.0 Hz), 3.82-3.70 (2H, m), 3.21-3.06 (2H, m), 2.52-2.44 (1H, m), 1.94-1.52 (4H, m).
MS (ESI): m/z 263 (M+H)+.
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (60 mg), (1S,2R)-2-methylcyclohexanamine hydrochloride (105 mg) and N,N-diisopropylethylamine (123 μL) in NMP (0.3 mL) was heated in the microwave reactor (200° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification of the product by column chromatography (silica gel, gradient elution, 1:1 EtOAc/n-hexane to EtOAc) provided 5-fluoro-N-[(1S,2R)-2-methylcyclohexyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (30 mg) as a tan solid.
1H-NMR (CDCl3) δ: 10.5 (1H, br), 7.97 (1H, d, J=4.6 Hz), 7.15 (1H, d, J=3.6 Hz), 6.51 (1H, d, J=3.6 Hz), 4.65-4.55 (1H, m), 4.18-4.12 (1H, m), 2.20-2.09 (2H, m), 1.80-1.40 (7H, m), 0.98 (3H, d, J=7.0 Hz).
MS (ESI): m/z 248 (M+H)+.
To a solution of rel-1-[(3R,4S)-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (20 mg) in 1,3-dimethyl-2-imidazolidinone (0.5 mL) were added 6-chloronicotinonitrile (20 mg) and triethylamine (41 μl), The mixture was stirred at 160° C. for 2 hours. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give rel-6-[(3R,4S)-3-methyl-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinyl]nicotinonitrile (13 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.81 (3H, d, J=7.1 Hz), 1.93-1.98 (1H, m), 2.38-2.44 (1H, m), 3.13-3.24 (2H, m), 3.51-3.56 (1H, m), 4.45-4.52 (1H, m), 4.63-4.69 (1H, m), 4.77-4.83 (1H, m), 6.65-6.66 (1H, m), 7.02 (1H, d, J=9.2 Hz), 7.45-7.47 (1H, m), 7.83 (1H, dd, J=2.4, 9.1 Hz), 7.91 (1H, s), 8.47 (1H, d, J=2.3 Hz), 10.80 (1H, brs), 11.60 (1H, brs).
MS (ESI+): m/z 374.
The following compounds were obtained in a similar manner to that of Example 226.
1H-NMR (DMSO-d6) δ: 1.62-1.78 (1H, m), 1.88-2.05 (2H, m), 2.51-2.70 (1H, m), 3.03-3.17 (1H, m), 3.67-3.79 (1H, m), 4.37-4.74 (3H, m), 6.53-6.61 (1H, m), 7.05 (1H, d, J=9.2 Hz), 7.40-7.46 (1H, m), 7.86 (1H, dd, J=9.2, 2.3 Hz), 7.95 (1H, s), 8.48 (1H, d, J=2.3 Hz), 11.00 (1H, s), 11.63 (1H, s).
MS (ESI): m/z 360 (M+H)+.
1H-NMR (DMSO-d6) δ: 2.31-2.48 (1H, m), 2.61-2.78 (1H, m), 3.54-3.69 (1H, m), 3.81-4.18 (3H, m), 5.39-5.55 (1H, m), 6.37-6.46 (1H, m), 6.59-6.75 (1H, m), 7.40-7.46 (1H, m), 7.87 (1H, dd, J=8.9, 2.2 Hz), 7.97 (1H, s), 8.47-8.58 (1H, m), 11.05 (1H, brs), 11.64 (1H, s).
MS (ESI): m/z 346 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.68-1.84 (1H, m), 1.87-2.04 (2H, m), 2.43-2.62 (1H, m), 2.99-3.11 (1H, m), 3.63-3.75 (1H, m), 4.03-4.18 (2H, m), 4.42-4.55 (1H, m), 6.48-6.57 (1H, m), 7.09 (2H, d, J=9.0 Hz), 7.40-7.47 (1H, m), 7.57 (2H, d, J=9.0 Hz), 7.95 (1H, s), 11.00 (1H, s), 11.63 (1H, s).
MS (ESI): m/z 359 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.74-2.30 (4H, m), 3.23-3.49 (1H, m), 3.51-3.67 (1H, m), 3.93-4.09 (1H, m), 4.15-4.35 (1H, m), 4.57-4.87 (1H, m), 6.48-6.80 (1H, m), 7.11-7.43 (1H, m), 7.45-7.50 (1H, m), 7.83 (1H, dd, J=8.9, 2.3 Hz), 7.91 (1H, s), 8.51 (1H, d, J=2.3 Hz), 10.95 (1H, brs), 11.52 (1H, brs).
MS (ESI): m/z 360 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.61-1.80 (1H, m), 1.87-2.06 (2H, m), 2.52-2.69 (1H, m), 3.00-3.15 (1H, m), 3.63-3.79 (1H, m), 4.38-4.59 (2H, m), 4.59-4.73 (1H, m), 6.53-6.62 (1H, m), 7.07 (1H, d, J=9.2 Hz), 7.40-7.48 (1H, m), 7.80 (1H, dd, J=9.2, 2.4 Hz), 7.95 (1H, s), 8.38-8.43 (1H, m), 11.01 (1H, s), 11.64 (1H, s).
MS (ESI): m/z 425 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.70-1.89 (1H, m), 1.89-2.09 (2H, m), 2.39-2.65 (1H, m), 3.14-3.31 (1H, m), 3.73-3.89 (1H, m), 4.25-4.45 (2H, m), 4.58-4.74 (1H, m), 6.59-6.69 (1H, m), 6.96 (1H, dd, J=7.6, 4.8 Hz), 7.41-7.50 (1H, m), 7.95 (1H, s), 8.10 (1H, dd, J=7.6, 1.8 Hz), 8.41 (1H, dd, J=4.8, 1.8 Hz), 10.99 (1H, s), 11.63 (1H, s).
MS (ESI): m/z; 382 (M+Na)+.
1H-NMR (DMSO-d6) δ: 2.32-2.74 (3H, m), 3.57-3.66 (1H, m), 3.87-4.07 (3H, m), 5.40-5.51 (1H, m), 6.40-6.42 (1H, m), 6.62-6.69 (1H, m), 7.87 (1H, dd, J=2.1 Hz, 8.9 Hz), 7.97 (1H, s), 8.52 (1H, s), 11.03 (1H, s), 11.63 (1H, s).
MS (ESI+): m/z 346.
1H-NMR (DMSO-d6) δ: 1.67-1.82 (1H, m), 1.92-2.07 (2H, m), 253-2.70 (1H, m), 3.12-3.25 (1H, m), 3.76-3.90 (1H, m), 4.40-4.53 (1H, m), 4.57-4.72 (1H, m), 4.72-4.87 (1H, m), 6.57-6.64 (1H, m), 7.07 (1H, d, J=9.6 Hz), 7.40-7.46 (1H, m), 7.95 (1H, s), 8.23 (1H, dd, J=9.6, 2.9 Hz), 8.96 (1H, d, J=2.9 Hz), 11.02 (1H, brs), 11.63 (1H, s).
MS (ESI+): m/z 380 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.67-1.83 (1H, m), 1.88-2.05 (2H, m), 2.46-2.63 (1H, m), 3.12-3.24 (1H, m), 3.59-3.70 (1H, m), 3.75-3.86 (1H, m), 3.95-4.05 (1H, m), 4.57-4.68 (1H, m), 6.61-6.67 (1H, m), 6.97 (1H, dd, J=8.1, 4.6 Hz), 7.44-7.49 (1H, m), 7.95 (1H, s), 8.29 (1H, dd, J=8.1, 1.7 Hz), 8.42 (1H, dd, J=4.6, 1.7 Hz), 11.00 (1H, s), 11.65 (1H, s).
MS (ESI): m/z 380 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.62-1.78 (1H, m), 1.85-2.03 (2H, m), 2.44-2.63 (1H, m), 2.93-3.05 (1H, m), 3.55-3.67 (1H, m), 4.30-4.53 (3H, m), 6.50-6.58 (1H, m), 6.98 (1H, d, J=9.2 Hz), 7.40-7.46 (1H, m), 7.60 (1H, dd, J=9.2, 2.6 Hz), 7.95 (1H, s), 8.09 (1H, d, J=2.6 Hz), 10.99 (1H, s), 11.63 (1H, s).
MS (ESI): m/z 369, 371 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.25-1.41 (1H, m), 1.77-2.14 (4H, m), 2.32-2.62 (1H, m), 3.46-4.68 (5H, m), 6.52 (1H, s), 6.87 (1H, d, J=9.2 Hz), 7.46 (1H, t, J=3.0 Hz), 7.85-7.89 (1H, m), 7.95 (1H, s), 8.47 (1H, s), 10.99 (1H, s), 11.64 (1H, s).
MS (ESI): m/z 374.
1H-NMR (DMSO-d6) δ: 1.71-2.65 (8H, m), 3.64-4.15 (3H, m), 4.37-4.59 (1H, m), 6.07-7.28 (1H, m), 6.88 (1H, d, J=9.0 Hz), 7.27 (1H, s), 7.87-7.90 (2H, m), 10.89 (1H, s), 11.56 (1H, s).
MS (ESI): m/z 374.
1H-NMR (DMSO-d6) δ: 1.69-1.85 (1H, m), 1.92-2.09 (2H, m), 2.56-2.72 (1H, m), 3.15-3.27 (1H, m), 3.83-3.96 (1H, m), 4.45-4.57 (1H, m), 4.88-5.04 (2H, m), 6.64-6.70 (1H, m), 7.41-7.46 (1H, m), 7.95 (1H, s), 9.09 (1H, s), 9.17 (1H, s), 11.03 (1H, brs), 11.64 (1H, s).
MS (ESI): m/z 381 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.06 (3H, d, J==7.2 Hz), 1.73-4.68 (8H, m), 6.41-6.44 (1H, m), 7.03 (1H, dd, J=0.8, 9.2 Hz), 7.38-7.40 (1H, m), 7.81 (1H, dd, J=2.4, 9.2 Hz), 7.92 (1H, s), 8.45 (1H, dd, J=0.8, 2.4 Hz), 10.87 (1H, brs), 11.59 (1H, brs).
MS (ESI+): m/z 374.
[α]D25+196.5 (c 0.43, CHCl3)
1H-NMR (DMSO-d6) δ: 1.06 (3H, d, J=8.0 Hz), 1.75-4.81 (8H, m), 6.46-6.49 (1H, m), 7.05 (1H, d, J=9.6 Hz), 7.37-7.41 (1H, m), 7.92 (1H, s), 8.18 (1H, dd, J=2.8, 9.6 Hz), 8.94 (1H, d, J=2.8 Hz), 10.87 (1H, brs), 11.59 (1H, brs).
MS (ESI+): m/z 394.
1H-NMR (DMSO-d6) δ: 1.02 (3H, d, J=7.2 Hz), 1.85-4.79 (8H, m), 6.54-6.56 (1H, m), 7.41-7.44 (1H, m), 7.92 (1H, s), 8.00 (1H, s), 10.89 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 380.
1H-NMR (DMSO-d6) δ: 1.14 (3H, d, J=7.2 Hz), 1.77-4.71 (8H, m), 6.48-6.52 (1H, m), 7.40-7.45 (1H, m), 7.92 (1H, s), 7.95 (1H, s), 10.89 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 380.
1H-NMR (DMSO-d6) δ: 1.06 (3H, d, J=6.8 Hz), 1.79-2.56 (3H, m), 3.47-4.76 (5H, m), 6.47-6.52 (1H, m), 7.38-7.41 (1H, m), 7.45 (1H, d, J=9.6 Hz), 7.83 (1H, d, J=9.6 Hz), 7.92 (1H, s), 10.87 (1H, brs), 11.59 (1H, brs).
MS (ESI+): m/z 375.
To a solution of rel-1-[(3R,4S)-1-benzyl-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (125 mg) in ethanol (6.25 mL) was added palladium hydroxide (200 mg). The mixture was stirred under hydrogen gas at 45° C. for 2 hours. The catalyst was filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure to give rel-1-[(3R,4S)-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (93 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.72-1.77 (1H, m), 2.17-2.22 (1H, m), 2.65-2.71 (1H, m), 2.89-2.92 (1H, m), 3.00-3.18 (3H, m), 4.11 (1H, br), 4.50-4.55 (1H, m), 6.52-6.54 (1H, m), 7.43-7.44 (1H, m), 7.90 (1H, s), 10.75 (1H, brs), 11.57 (1H, brs).
MS (ESI+): m/z 272.
The following compound was obtained in a similar manner to that of Example 245.
1H-NMR (DMSO-d6) δ: 0.96 (3H, d, J=7.1 Hz), 1.40-1.56 (3H, m), 1.65-1.70 (1H, m), 1.81-1.92 (3H, m), 2.33-2.39 (1H, m), 2.95-3.05 (1H, m), 4.49-4.54 (1H, m), 4.94-5.05 (2H, m), 6.52-6.53 (1H, m), 6.62-6.67 (2H, m), 6.74 (1H, d, J=7.7 Hz), 7.09-7.13 (1H, m), 7.45-7.47 (1H, m), 7.94 (1H, s), 9.40 (1H, brs), 11.65 (1H, brs).
MS (ESI): m/z 377.
To a solution of rel-4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (50 mg) in dioxane (0.5 mL) was added 4M hydrogen chloride in dioxane (1 mL) and the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate aqueous solution and brine, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL). To the mixture were added 1M NaOH solution (0.29 mL) and 1,2-ethanediamine (0.2 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was extracted with chloroform. The extract was washed with water, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give rel-4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (36 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.95 (3H, d, J=7.1 Hz), 1.42-1.54 (3H, m), 1.65-1.69 (1H, m), 1.81-1.91 (3H, m), 2.34-2.39 (1H, m), 2.94-3.02 (1H, m), 4.49-4.54 (1H, m), 5.19-5.20 (2H, m), 6.52-6.54 (1H, m), 7.46-7.49 (3H, m), 7.82 (2H, d, J=8.3 Hz), 8.32 (1H, s), 11.68 (1H, brs).
MS (ESI+): m/z 386.
The following compound(s) was(were) obtained in a similar manner to that of Example 247.
1H-NMR (DMSO-d6) δ: 0.94 (3H, d, J=7.1 Hz), 1.41-1.57 (3H, m), 1.63-1.70 (1H, m), 1.80-1.92 (3H, m), 2.32-2.39 (1H, m), 2.93-3.05 (1H, m), 5.09-5.20 (2H, m), 6.52 (1H, d, J=2.9 Hz), 7.36 (1H, dd, J=4.8, 7.8 Hz), 7.46-7.49 (1H, m), 7.70 (1H, d, J=7.9 Hz), 8.08 (1H, s), 8.32 (1H, s), 8.47 (1H, dd, J=1.5, 4.8 Hz), 8.61 (1H, d, J=1.8 Hz), 11.68 (1H, brs).
MS (ESI+): m/z 362.
To a solution of rel-1-[(1S,2R)-2-Methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (20 mg) in N,N-dimethylformamide (0.5 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (33 μl) and 1-bromo-2-methoxyethane (21 μl). The mixture was stirred at ambient temperature for 2 hours, then 60° C. for 22 hours. To the mixture was added water. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give pale yellow solid, which was triturated and washed with diisopropyl ether to give rel-3-(2-methoxyethyl)-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (4 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.04 (3H, d, J=6.0 Hz), 1.41-1.53 (3H, m), 1.62-1.66 (1H, m), 1.78-1.91 (3H, m), 2.30-2.37 (1H, m), 2.91-3.00 (1H, m), 3.22 (3H, s), 3.60-3.63 (2H, m), 4.01-4.05 (2H, m), 4.45-4.50 (1H, m), 6.50-6.51 (1H, m), 5.47-7.46 (1H, m), 8.12 (1H, s), 11.62 (1H, brs).
MS (ESI+): m/z 329.
The following compounds were obtained in a similar manner to that of Example 249.
1H-NMR (DMSO-d6) δ: 0.96 (3H, d, J=7.1 Hz), 1.44-1.55 (3H, m), 1.64-1.70 (1H, m), 1.82-1.92 (3H, m), 2.32-2.41 (1H, m), 2.93-3.03 (1H, m), 4.50-4.56 (1H, m), 5.15 (2H, d, J=3.3 Hz), 6.54 (1H, d, J=3.2 Hz), 7.24 (2H, d, J=5.7 Hz), 7.48-7.49 (1H, m), 7.97 (1H, s), 8.50-8.52 (2H, m), 11.69 (1H, brs).
MS (ESI+): m/z 362.
1H-NMR (DMSO-d6) δ: 0.95 (3H, d, J=7.1 Hz), 1.41-1.55 (3H, m), 1.64-1.70 (1H, m), 1.81-1.91 (3H, m), 2.33-2.41 (1H, m), 29.3-3.03 (1H, m), 4.49-4.55 (1H, m), 5.18 (2H, s), 6.52-6.54 (1H, m), 7.18 (1H, d, J=7.8 Hz), 7.26-7.29 (1H, m), 7.46-7.49 (1H, m), 7.75 (1H, ddd, J=1.8, 7.6 Hz), 7.92 (1H, s), 8.49 (1H, d, J=4.1 Hz), 11.64 (1H, brs).
MS (ESI+): m/z 362.
1H-NMR (DMSO-d6) δ: 0.96 (3H, d, J=7.1 Hz), 1.43-1.55 (3H, m), 1.64-1.68 (1H, m), 1.85-1.92 (3H, m), 2.33-2.38 (1H, m), 2.94-3.03 (1H, m), 3.71 (3H, s), 4.56-4.62 (1H, m), 5.05-5.16 (2H, m), 6.73-6.74 (1H, m), 6.83-6.90 (2H, m), 6.92-6.93 (1H, m), 7.23-7.27 (1H, m), 7.61-7.63 (1H, m), 8.23 (1H, s), 12.29 (1H, brs).
MS (ESI+): m/z 391.
1H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.2 Hz), 1.41-1.57 (3H, m), 1.65-1.71 (1H, m), 1.81-1.93 (3H, m), 2.35-2.41 (1H, m), 2.62 (3H, s), 2.96-3.07 (1H, m), 4.50-4.56 (1H, m), 28-5.28 (2H, m), 6.52-6.54 (1H, m), 7.39 (1H, d, J=8.5 Hz), 7.46-7.48 (1H, m), 7.63 (1H, dd, J=8.6, 2.0 Hz), 7.84-7.89 (2H, m), 8.03 (1H, s), 8.48 (1H, d, J=8.4 Hz), 11.66 (1H, brs).
MS (ESI+): m/z 426.
1H-NMR (DMSO-d6) δ: 0.93 (3H, d, J=7.1 Hz), 1.41-1.54 (3H, m), 1.63-1.69 (1H, m), 1.79-1.91 (3H, m), 2.33-2.36 (4H, m), 2.91-3.01 (1H, m), 4.47-4.52 (1H, m), 5.12 (2H, s), 6.08 (1H, d, J=0.8 Hz), 6.52-6.53 (1H, m), 7.47-7.49 (1H, m), 8.01 (1H, s), 11.69 (1H, brs).
MS (ESI+): m/z 366.
1H-NMR (DMSO-d6) δ: 0.95 (3H, d, J=7.1 Hz), 1.43-1.56 (3H, m), 1.64-1.70 (1H, m), 1.82-1.91 (3H, m), 2.37-2.42 (1H, m), 2.90-3.01 (1H, m), 4.51-4.56 (1H, m), 5.54-5.58 (2H, m), 6.56-6.57 (1H, m), 7.42-7.45 (1H, m), 7.50-7.52 (1H, m), 8.17 (1H, s), 8.19 (1H, dd, J=1.4, 8.2 Hz), 8.50 (1H, dd, J=1.4, 4.8 Hz), 11.71 (1H, brs).
MS (ESI): m/z 425.
1H-NMR (DMSO-d6) δ: 0.96 (3H, d, J=7.0 Hz) 1.42-1.57 (3H, m), 1.63-1.70 (1H, m), 1.80-1.92 (3H, m), 2.31-2.41 (1H, m), 2.94-3.06 (1H, m), 4.48-4.54 (1H, m), 5.18 (2H, s), 6.51-6.53 (1H, m), 6.82-6.86 (1H, m), 7.17-7.22 (1H, m), 7.45-7.49 (2H, m), 7.77 (1H, s), 8.07 (1H, s), 8.45-8.48 (1H, m), 11.64 (1H, brs).
MS (ESI+): m/z 401.
1H-NMR (DMSO-d6) δ: 0.92, 0.93 (3H, d, J=7.2 Hz), 1.46-1.69 (6H, m) 1.79-1.90 (3H, m), 2.90-2.97 (1H, m), 3.23-3.28 (1H, m), 4.08-4.20 (2H, m), 4.46-4.52 (1H, m), 4.90-4.95 (1H, m), 6.51-6.53 (1H, m), 7.47-7.53 (2H, m), 8.16, 8.17 (1H, s), 11.67 (1H, brs).
MS (ESI+): m/z 392.
To a solution of 1-phenylpiperazine (0.0356 mL) in AcOH (0.9 mL) was added paraformaldehyde (7.8 mg), and stirred at ambient temperature for 5 minutes. To the mixture was added rel-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (45 mg), and stirred at 80° C. for 2.5 hours. To the mixture was added 1-phenylpiperazine (0.0102 mL) and paraformaldehyde (2.2 mg), and stirred at 80° C. for 40 minutes. ACOH was removed in vacuo, and the residue was diluted with tetrahydrofuran, then basified with saturated aqueous sodium hydrogencarbonate. The mixture was extracted with EtOAc, washed with 10% NaCl solution, and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give rel-1-[(1S,2R)-2-methylcyclohexyl]-8-[(4-phenyl-1-piperazinyl)methyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (first product) (10.4 mg) as a white powder and 1-[(1S,2R)-2-methylcyclohexyl]-8-[(4-{4-[(4-phenyl-1-piperazinyl)methyl]phenyl}-1-piperazinyl)methyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (second product) (13.7 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.88 (3H, d, J=7.1 Hz), 1.26-1.56 (3H, m), 1.67-1.94 (4H, m), 2.16-2.28 (1H, m), 2.29-2.60 (4H, m), 3.02-3.17 (5H, m), 3.38 (1H, d, J=12.8 Hz), 3.95 (1H, d, J=12.8 Hz), 5.20-5.28 (1H, m), 6.75 (1H, t, J=7.2 Hz), 6.89 (2H, d, J=8.6 Hz), 7.18 (2H, dd, J=8.6, 7.2 Hz), 7.39 (1H, d, J=2.6 Hz), 7.88 (1H, s), 10.77 (1H, s), 11.52 (1H, d, J=2.6 Hz).
MS (ESI): m/z 467 (M+Na)+.
1H-NMR (DMSO-d6) δ: 0.89 (3H, d, J=7.1 Hz), 1.23-3.48 (28H, m), 3.95 (1H, d, J=12.8 Hz), 5.20-5.28 (1H, m), 6.75 (1H, t, J=7.2 Hz), 6.83-6.93 (4H, m), 7.10-7.22 (4H, m), 7.39 (1H, d, J=2.7 Hz), 7.88 (1H, s), 10.78 (1H, s), 11.52 (1H, d, J=2.7 Hz).
MS (ESI): m/z 619 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 258.
1H-NMR (DMSO-d6) δ: 0.89 (3H, d, J=7.1 Hz), 1.23-3.48 (28H, m), 3.95 (1H, d, J=12.8 Hz), 5.20-5.28 (1H, m), 6.75 (1H, t, J=7.2 Hz), 6.83-6.93 (4H, m), 7.10-7.22 (4H, m), 7.39 (1H, d, J=2.7 Hz), 7.88 (1H, s), 10.78 (1H, s), 11.52 (1H, d, J=2.7 Hz).
MS (ESI): m/z 619 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.89 (3H, d, J=7.1 Hz), 1.27-3.40 (19H, m), 3.90 (1H, d, J=12.7 Hz), 5.21-5.30 (1H, m), 7.12-7.32 (5H, m), 7.35 (1H, d, J=2.5 Hz), 7.88 (1H, s), 10.78 (1H, s), 11.48 (1H, d, J=2.5 Hz).
MS (ESI): m/z 444 (M+H)+.
1H-NMR (DMSO-d6) δ: 0.89 (3H, d, J=7.2 Hz), 1.24-1.55 (3H, m), 1.66-1.96 (4H, m), 2.16-2.56 (5H, m), 3.05-3.19 (1H, m), 3.37 (1H, d, J=12.7 Hz), 3.54-3.68 (4H, m), 3.94 (1H, d, J=12.7 Hz), 5.17-5.25 (1H, m), 6.90 (1H, d, J=9.1 Hz), 7.37 (1H, d, J=2.3 Hz), 7.84 (1H, dd, J=9.1, 2.3 Hz), 7.89 (1H, s), 8.47 (1H, d, J=2.3 Hz), 10.79 (1H, brs), 11.53 (1H, d, J=2.3 Hz).
MS (ESI): m/z 493 (M+Na)+.
1H-NMR (DMSO-d6) δ: 0.86 (3H, d, J=7.2 Hz), 1.24-1.58 (3H, m), 1.58-1.97 (4H, m), 2.16-2.76 (9H, m), 3.03-3.19 (1H, m), 3.28-3.43 (1H, m), 3.51-3.72 (8H, m), 3.93 (1H, d, J=11.4 Hz), 4.73 (2H, s), 5.21-5.31 (1H, m), 6.82-6.96 (2H, m), 7.42 (1H, d, J=2.6 Hz), 7.75-7.88 (2H, m), 8.26 (1H, s), 8.40-8.50 (2H, m), 11.65 (1H, d, J=2.6 Hz).
MS (ESI): m/z 693 (M+Na)+.
1H-NMR (DMSO-d6) δ: 0.90 (3H, d, J=7.1 Hz), 1.26-1.56 (3H, m), 1; 67-1.97 (4H, m), 2.16-2.63 (5H, m), 3.05-3.20 (1H, m), 3.41 (1H, d, J=12.8 Hz), 3.45-3.64 (4H, m), 3.94 (1H, d, J=12.8 Hz), 5.18-5.26 (1H, m), 6.93 (1H, dd, J=7.6, 4.8 Hz), 7.40 (1H, d, J=2.5 Hz), 7.88 (1H, s), 8.06 (1H, dd, J=7.6, 1.9 Hz), 8.40 (1H, dd, J=4.8, 1.9 Hz), 10.78 (1H, s), 11.53 (1H, d, J=2.5 Hz).
MS (ESI): m/z 493 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.10 (3H, d, J=7.0 Hz), 0.90-3.41 (21H, m), 3.83 (1H, d, J=13.0 Hz), 5.14-5.24 (1H, m), 7.09-7.32 (6H, m), 7.86 (1H, s), 10.76 (1H, s), 11.44 (1H, d, J=2.2 Hz).
MS (ESI): m/z 458 (M+H)+.
To a suspension of 1-[(3R)-3-piperidinyl]-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one dihydrochloride (20 mg) in 1,3-dimethyl-2-imidazolidinone (1 ml) was added triethylamine (51 μl) and isocyanato(trimethyl)silane (24 μl) which was stirred at 110° C. for 1 hour. The solvent was evaporated and purified by column chromatography on Hi-Flash™ (NH2)*(YAMAZEN CORPORATION) eluting with chloroform:methanol=100:0-85:15 to give (3R)-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinecarboxamide (12 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.50-1.98 (3H, m), 2.30-2.83 (3H, m), 3.40-3.46 (1H, m), 3.95-5.45 (3H, m), 6.06 (1H, s), 6.59-6.61 (1H, m), 7.44 (1H, t, J=3.0 Hz), 7.93 (1H, s), 10.96 (1H, s), 11.62 (1H, s).
MS (ESI): m/z 301.
To a suspension of diethylcyano phosphonate (11 mg) in tetrahydrofuran (0.5 ml) was added potassium tert-butoxide (7 mg) at 0° C. and the mixture was stirred at ambient temperature for 30 minutes. A solution of trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (10 mg) in tetrahydrofuran (0.5 ml) was added at 0° C. and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with dichloromethane:methanol=10:1 to give (2E)-3-[trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylonitrile (3 mg) as a brown powder.
1H-NMR (DMSO-d6) δ: 1.14-3.41 (10H, m), 4.41-4.63 (1H, m), 5.78-5.89 (1H, m), 6.54-6.65 (1H, m), 7.19-7.33 (1H, m), 7.91-7.98 (1H, m), 10.94 (1H, s), 11.65 (1H, s).
MS (ESI+): m/z 308.
To a solution of rel-1-[(1S,2R)-2-methylcyclohexyl]-3-(3-nitrobenzyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (150 mg) in a mixed solution of ethanol (1.5 mL) and water (0.45 mL) were added iron powder (62 mg) and ammonium chloride (10 mg). The solution was refluxed for 3 hours. After cooling to ambient temperature, the precipitate was filtered through a pad of Celite. After concentration under reduced pressure, the residue was extracted with chloroform and washed with water and dried over MgSO4. Concentration under reduced pressure to give 3-(3-aminobenzyl)-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]-pyridin-2(1H)-one (139 mg) as a white powder.
1H-NMR (5-DMSO) δ: 0.96 (3H, d,=7.1 Hz), 1.42-1.53 (3H, m), 1.65-1.70 (1H, m), 1.80-1.93 (3H, m), 2.33-2.40 (1H, m), 2.95-3.05 (1H, m), 4.48-4.53 (1H, m), 4.86-4.96 (2H, m), 5.06 (2H, brs), 6.41-6.47 (3H, m), 6.51-6.53 (1H, m), 6.94 (1H, dd, J=7.7 Hz), 7.45-7.47 (1H, m), 7.90 (1H, s), 11.64 (1H, brs).
MS (ESI+): m/z 376.
The following compound was obtained in a similar manner to that of Example 267.
1H-NMR (DMSO-d6) δ: 12.4 (1H, br), 9.61 (1H, d, J=9.5 Hz), 8.35 (1H, s), 7.80 (1H, br), 7.02 (1H, br), 5.20-5.25 (1H, m), 2.40 (3H, s), 1.16-1.80 (9H, m), 0.83 (3H, d, J=6.8 Hz).
MS (ESI): m/z 288 (M+H)+.
To the mixture of rel-1-[(3R,4R)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one-(100 mg) and 2,4-dichloropyrimidine (82 mg) in ethanol (2 mL), triethylamine (75 mg) was added at ambient temperature. Then After the mixture was stirred at ambient temperature for 17 hours, water (10 mL) was added. The resulting precipitate was collected, to afford rel-1-[(3R,4R)-1-(2-chloro-4-pyrimidinyl)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (65 mg) as yellow powder. From NMR, it was found that the obtained powder was mixture of regioisomer (4:1).
1H-NMR (DMSO-d6) δ: 1.04 (3H, d,=7.1 Hz), 1.70-1.82 (1H, m), 1.96-2.13 (1H, m), 3.25-3.54 (2H, m), 4.37-4.80 (4H, m), 6.53 (1H, s), 6.93 (1H, d, J=6.3 Hz), 7.39-7.42 (1H, m), 7.92 (1H, s), 8.03 (1H, d, J=6.1 Hz), 10.89 (1H, s), 11.60 (1H, s).
MS (ESI): m/z 384.
The following compounds were obtained in a similar manner to that of Example 269.
1H-NMR (DMSO-d6) δ: 1.04 (3H, d, J=6.2 Hz), 3.09-3.27 (2H, m), 3.90-4.20 (3H, m), 5.00-5.03 (1H, m), 6.43 (1H, brs), 6.65 (1H, brs), 7.42 (1H, s), 7.87 (1H, d, J=8.7 Hz), 7.99 (1H, s), 8.52 (1H, s), 11.1 (1H, brs), 11.7 (1H, s).
MS (ESI+): m/z 360.
1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=6.4 Hz), 3.01-3.19 (1H, m), 3.55-3.60 (1H, m), 4.03-4.09 (1H, m), 4.21-4.30 (1H, m), 4.54-4.60 (1H, m), 4.87-4.94 (1H, m), 6.58 (1H, brs), 7.43 (1H, s), 7.97 (1H, s), 8.15 (1H, s), 8.52 (1H, s), 11.1 (1H, brs), 11.6 (1H, s).
MS (ESI+): m/z 394.
1H-NMR (DMSO-d6) δ: 0.95 (3H, d, J=7.1 Hz), 1.61-1.68 (1H, m), 2.01-2.18 (1H, m), 2.30-2.47 (2H, m), 2.61-2.70 (1H, m), 2.83-2.95 (1H, m), 3.53-3.67 (1H, m), 3.77 (2H, s), 4.55-4.65 (1H, m), 6.43-6.48 (1H, m), 7.43-7.47 (1H, m), 7.58-7.65 (1H, m), 7.80-7.86 (1H, m), 7.88 (1H, s), 8.06-8.15 (1H, m), 8.20 (1H, s), 10.78 (1H, s), 11.61 (1H, s).
MS (ESI+): m/z 329.
To a solution of rel-1-[(3R,4R)-1-(2-chloro-4-pyrimidinyl)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]-pyridin-2(1H)-one (60 mg) and sodium cyanide (38 mg) in DMSO (1 mL), 1,4-diazabicyclo[2.2.2]octane (5 mg) was added at ambient temperature. The temperature was raised to 80° C. and stirred for 7 hours. After cooling down to ambient temperature, water (15 mL) was added to the mixture and resulting precipitate was collected by filtration. The filtrate was purified by pre-packed column (chloroform:methanol=95:1 to 80:20) to afford rel-4-[(3R,4R)-4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinyl]-2-pyrimidinecarbonitrile (41 mg) as white powder.
1H-NMR (DMSO-d6) δ: 1.03 (3H, d, J=7.2 Hz), 1.74-1.88 (1H, m), 1.96-2.08 (1H, m), 3.36-3.51 (1H, m), 3.72-4.80 (5H, m), 6.52-6.56 (1H, m), 7.20 (1H, d, J=6.5 Hz), 7.39-7.42 (1H, m), 7.92 (1H, s), 8.20-8.24 (1H, m), 10.88 (1H, s), 11.59 (1H, s).
MS (ESI+): m/z 375.
To the suspension of 3,3-difluoropyrrolidine hydrochloride (574 mg) and pyridine (949 mg) in dichloroethane (20 mL), 4-nitrophenylchloroformate (806 mg) was added at ambient temperature and stirred for 1 hour before quenching by water. Organic layer was separated and water layer was extracted with EtOAc. Combined organic layer was washed with brine, dried with MgSO4, filtered, and evaporated to give a residue, which was purified with pre-packed column (n-hexane:EtOAc=9:1 to 5:1) to affored desired 4-nitrophenyl 3,3-difluoropyrrolidine-1-carboxylate (937 mg) as white powder. The suspension of 1-[(3R,4R)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (80 mg), 4-nitrophenyl 3,3-difluoropyrrolidine-1-carboxylate (120 mg) and diisopropylethylamine (95 mg) in NMP (1 mL) was heated at 120° C. for 30 minutes under the irradiation of microwave. To the resulting solution water was added and it was extracted with chloroform. The combined organic layer was washed with brine, dried with MgSO4, filtered and evaporated to give a residue, which was purified by pre-packed column (chloroform:methanol=99:1 to 9:1), to afforded rel-1-{(3R,4R)-1-[(3,3-difluoropyrrolidin-1-yl)carbonyl]-4-methylpiperidin-3-yl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (62.5 mg) as white powder.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.64-1.72 (1H, m), 1.94-2.08 (1H, m), 2.26-2.39 (2H, m), 2.40-2.48 (1H, m), 3.08-3.20 (1H, m), 3.40-3.84 (6H, m), 4.20-4.30 (1H, m), 4.50-4.58 (1H, m), 6.45-6.50 (1H, m), 7.41-7.47 (1H, m), 7.91 (1H, s), 10.84 (1H, s), 11.61 (1H, s).
MS (ESI+): m/z 405.
The following compounds were obtained in a similar manner to that of Example 274.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.62-2.51 (3H, m), 2.76 (6H, s), 3.05-4.60 (5H, m), 6.42-6.46 (1H, m), 7.42-7.46 (1H, m), 7.91 (1H, s), 10.83 (1H, brs), 11.61 (1H, brs).
MS (ESI): m/z 343.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.62-3.53 (13H, m), 3.74-3.80 (1H, m), 4.16-4.25 (1H, m), 4.52-4.59 (1H, m), 6.42-6.46 (1H, m), 7.42-7.46 (1H, m), 7.91 (1H, s), 10.83 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 369.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.39-4.59 (18H, m), 6.42-6.45 (1H, m), 7.43-7.45 (1H, m), 7.91 (1H, s), 10.82 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 383.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.64-1.72 (1H, m), 2.40-2.50 (1H, m), 1.96-2.08 (1H, m), 3.10-3.45 (6H, m), 3.66-3.82 (3H, m), 4.23-4.34 (1H, m), 4.48-4.60 (1H, m), 6.47 (1H, d, J=2.0 Hz), 7.42-7.45 (1H, m), 7.91 (1H, s), 7.94 (1H, s), 10.84 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 398.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.03 (6H, t, J=6.8 Hz), 1.65-2.53 (3H, m), 3.05-3.66 (7H, m), 4.16-4.25 (1H, m), 4.54-4.60 (1H, m), 6.39-6.43 (1H, m), 7.42-7.47 (1H, m), 7.91 (1H, s), 10.83 (1H, brs), 11.62 (1H, brs).
MS (ESI+): m/z 371.
1H-NMR (DMSO-d6) δ: 0.97 (3H, d, J=7.2 Hz), 1.63-2.53 (3H, m), 3.09-3.19 (1H, m), 3.45-4.49 (9H, m), 6.47-6.51 (1H, m), 7.41-7.45 (1H, m), 7.91 (1H, s), 10.84 (1H, brs), 11.60 (1H, brs).
MS (ESI−): m/z 378.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.17 (6H, d, J=6.8 Hz), 1.20 (6H, d, J=6.4 Hz), 1.67-2.52 (3H, m), 3.03-3.66 (5H, m), 4.09-4.17 (1H, m), 4.61-4.68 (1H, m), 6.36-6.39 (1H, m), 7.43-7.46 (1H, m), 7.91 (1H, s), 10.80 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 399.
1H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.2 Hz), 1.65-2.03 (2H, m), 2.15 (3H, s), 2.23-2.48 (5H, m), 3.09-3.23 (5H, m), 3.29-4.59 (4H, m), 6.42-6.45 (1H, m), 7.42-7.46 (1H, m), 7.91 (1H, s), 10.83 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 398.
1H-NMR (DMSO-d6) δ: 0.99 (3H, m), 1.65-4.58 (16H, m), 6.43-6.45 (1H, m), 7.43-7.45 (1H, m), 7.91 (1H, s), 10.83 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 385.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.65-2.53 (3H, m), 2.87 (3H, s), 3.17-3.81 (3H, m), 4.12 (2H, s), 4.27-4.59 (2H, m), 6.48-6.52 (1H, m), 7.44-7.48 (1H, m), 7.93 (1H, s), 10.91 (1H, brs), 11.68 (1H, brs).
MS (ESI): m/z 390 (M+Na)+.
1H-NMR (DMSO-d6) δ: 1.02 (3H, d, J=7.2 Hz), 1.81-4.79 (18H, m), 6.53-6.57 (1H, m), 7.41-7.45 (1H, m), 7.92 (1H, s), 10.87 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 387.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.58-2.04 (6H, m), 2.40-2.51 (1H, m), 2.97-3.40 (6H, m), 3.55-3.73 (2H, m), 4.20-4.27 (1H, m), 4.49-4.57 (1H, m), 6.43-6.46 (1H, m), 7.42-7.46 (1H, m), 7.91 (1H, s), 10.82 (1H, s), 11.61 (1H, s).
MS (ESI+): m/z 408.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.19-4.57 (17H, m), 4.65 (1H, d, J=4.4 Hz), 6.41-6.45 (1H, m), 7.42-7.46 (1H, m), 7.91 (1H, s), 10.82 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 399.
1H-NMR (DMSO-d6) δ: 0.97-1.04 (3H, m), 1.60-4.76 (15H, m), 6.42-6.50 (1H, m), 7.41-7.47 (1H, m), 7.90-7.93 (1H, m), 10.85 (1H, s), 11.57-11.64 (1H, m).
MS (ESI+): m/z 394.
1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=7.1 Hz), 1.22-2.00 (10H, m), 2.39-2.50 (1H, m), 2.82-3.00 (1H, m), 3.60-4.41 (5H, m), 6.34 (1H, d, J=6.9 Hz), 6.37-6.40 (1H, m), 7.41-7.45 (1H, m), 7.91 (1H, s), 10.85 (1H, s), 11.61 (1H, s).
MS (ESI+): m/z 383.
1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=7.1 Hz), 1.52-1.64 (1H, m), 1.83-1.97 (1H, m), 2.40-2.47 (1H, m), 2.56 (3H, d, J=4.2 Hz), 2.94-3.03 (1H, m), 3.80-3.86 (1H, m), 4.05-4.12 (1H, m), 4.17-4.26 (1H, m), 4.30-4.39 (1H, m), 6.38-6.42 (1H, m), 6.48-6.56 (1H, m), 7.41-7.44 (1H, m), 7.91 (1H, s), 10.84 (1H, s), 11.60 (1H, s).
MS (ESI+): m/z 329.
1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=7.2 Hz), 1.60-3.13 (4H, m), 3.79-4.42 (6H, m), 6.42-6.46 (1H, m), 7.29-7.35 (1H, m), 7.42-7.44 (1H, m), 7.92 (1H, s), 10.86 (1H, brs), 11.61 (1H, brs).
MS (ESI+): m/z 354.
1H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.2 Hz), 1.66-2.53 (3H, m), 3.16-4.60 (9H, m), 6.51-6.53 (1H, m), 7.42-7.46 (1H, m), 7.91 (1H, s), 10.84 (1H, brs), 11.60 (1H, brs).
MS (ESI+): m/z 441.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.64-1.73 (1H, m), 2.00 (3H, s), 1.87-3.77 (13H, m), 4.21-4.31 (1H, m), 4.51-4.59 (1H, m), 6.42-6.48 (1H, m), 7.42-7.48 (1H, m), 7.91 (1H, s), 10.83 (1H, s), 11.61 (1H, s).
MS (ESI+): m/z 426.
1H-NMR (DMSO-d6) δ: 0.96-1.02 (3H, m), 1.60-4.72 (15H, m), 6.41-6.48 (1H, m), 7.40-7.44 (1H, m), 7.83-7.88 (1H, m), 10.85 (1H, s), 11.50-11.63 (1H, m).
MS (ESI+): m/z 394.
1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=7.2 Hz), 1.62-1.78 (1H, m), 1.87-2.10 (1H, m), 2.40-3.80 (12H, m), 4.20-4.32 (1H, m), 4.50-4.60 (1H, m), 6.42-6.47 (1H, m), 7.41-7.48 (1H, m), 7.91 (1H, s), 8.02 (1H, s), 10.82 (1H, s), 11.61 (1H, s).
MS (ESI+): m/z 412.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.65-2.48 (3H, m), 2.83 (3H, s), 3.15-4.58 (11H, m), 6.46-6.49 (1H, m), 7.42-7.45 (1H, m), 7.91 (1H, s), 10.83 (1H, brs), 11.60 (1H, brs).
MS (ESI+): m/z 412.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.0 Hz), 1.27-1.32 (3H, m), 1.63-3.80 (10H, m), 4.05-4.61 (3H, m), 6.40-6.48 (1H, m), 7.40-7.46 (1H, m), 7.77-7.95 (2H, m), 10.83 (1H, s), 11.61 (1H, brs).
MS (ESI+): m/z 412.
1H-NMR (DMSO-d6) δ: 0.98 (3H, d, J=7.1 Hz), 1.32-1.47 (2H, m), 1.64-3.73 (17H, m), 4.18-4.30 (1H, m), 4.50-4.59 (1H, m), 6.41-6.47 (1H, m), 7.41-7.46 (1H, m), 7.91 (1H, s), 10.79 (1H, s), 11.58 (1H, brs).
MS(+): m/z 452.
To a suspension of 1-[(3R)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one dihydrochloride (30 mg) and 1-hydroxybenzotriazole (18.4 mg) in N,N-dimethylformamide (0.72 mL) was added triethylamine (0.028 mL), 2-thiophenecarboxylic acid (15.1 mg), and WSCD.HCl (70 mg, 0.365 mmol). After stirring for 9 hours at ambient temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogencarbonate, water (×3), and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 1-[(3R)-1-(2-thienylcarbonyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (24.0 mg) as a white crystals.
1H-NMR (DMSO-d6) δ: 1.68-2.07 (3H, m), 2.44-2.66 (1H, m), 3.05-3.44 (1H, m), 3.63-3.90 (1H, m), 4.23-4.59 (3H, m), 6.66-6.73 (1H, m), 7.05-7.16 (1H, m), 7.40-7.52 (2H, m), 7.71-7.79 (1H, m), 7.94 (1H, s), 11.00 (1H, br), 11.64 (1H, s).
MS (ESI): m/z 368 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 299.
1H-NMR (DMSO-d6) δ: 1.59-2.06 (3H, m), 2.31-4.69 (6H, m), 5.53-5.81 (2H, m), 6.58-6.67 and 6.76-6.84 (total 1H, each m), 7.43-7.52 (1H, m), 7.94 and 7.95 (total 1H, each s), 9.29 and 9.33 (total 1H, each s), 10.99 (1H, brs), 11.64 (1H, brs).
MS (ESI): m/z 368 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.62-2.06 (3H, m), 2.41-3.55 (6H, m), 3.59-4.04 (1H, m), 4.46-4.70 (2H, m), 6.69-6.86 (1H, m), 7.42-7.56 (1H, m), 7.87 and 7.96 (total 1H, each s), 10.96 (1H, br), 11.59 and 11.66 (total 1H, each s).
MS (ESI): m/z 384 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.56-2.12 (3H, m), 2.31-4.09 (6H, m), 4.26-4.59 (2H, m), 4.77-4.98 (1H, m), 6.56-6.64 and 6.72-6.81 (total 1H, each m), 7.41-7.52 (1H, m), 7.94 (1H, s), 8.15 (1H, brs), 11.00 (1H, br), 11.63 and 11.66 (total 1H, each s).
MS (ESI): m/z 387 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.64-2.07 (4H, m) 3.33-3.47 (1H, m) 3.47-3.59 (1H, m), 3.84-4.05 (3H, m), 4.14-4.25 (1H, m), 4.38-4.48 (1H, m), 7.27-7.32 (1H, m), 7.43-7.50 (1H, m), 7.93 (1H, s), 10.96 (1H, brs), 11.55 (1H, s).
MS (ESI): m/z 325 (M+H)+.
To a solution of 1-[(3R)-1-(5-nitro-2-pyridinyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (19.3 mg) in ethanol (3 mL), tetrahydrofuran (1 mL), and water (0.15 mL) was added 10% Pd—C (50% wet, 10 mg) and ammonium formate (32 mg). After stirring for 50 minutes at 75° C., catalyst was removed by filtration, and solvent was also removed under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous sodium hydrogencarbonate, and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1 to 8:1) to give 1-[(3R)-1-(5-amino-2-pyridinyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (8.5 mg) as a pale brown crystals.
1H-NMR (DMSO-d6) δ: 1.64-1.82 (1H, m), 1.82-2.01 (2H, m), 2.41-2.57 (1H, m), 2.72-2.87 (1H, m), 3.29-3.47 (1H, m), 3.99-4.21 (2H, m), 4.47-4.64 (1H, m), 4.58 (2H, s), 6.51-6.59 (1H, m), 6.72 (1H, d, J=8.9 Hz), 6.92 (1H, dd, J=8.9, 2.7 Hz), 7.40-7.46 (1H, m), 7.58 (1H, d, J=2.7 Hz), 7.94 (1H, s), 10.97 (1H, s), 11.62 (1H, s).
ESI-MS(+) m/z: 350 (M+H)+.
The following compounds were obtained in a similar manner to that of Example 304.
1H-NMR (DMSO-d6) δ: 1.83-2.04 (3H, m), 2.38-2.58 (1H, m), 2.61-2.74 (1H, m), 3.26-3.41 (1H, m), 3.44-3.54 (1H, m), 3.57-3.69 (1H, m), 4.77-4.89 (1H, m), 4.89 (2H, s), 6.71-6.77 (1H, m), 6.80 (1H, dd, J=7.7, 4.7 Hz), 6.96 (1H, dd, J=7.7, 1.6 Hz), 7.43-7.50 (1H, m), 7.54 (1H, dd, J=4.7, 1.6 Hz), 7.93 (1H, s), 10.93 (1H, s), 11.61 (1H, s).
MS (ESI): m/z 350 (M+H)+.
1H-NMR (DMSO-d6) δ: 1.04 (3H, d, J=7.2 Hz), 1.60-4.62 (10H, m), 6.28-6.32 (1H, m), 6.73 (1H, d, J=9.2 Hz), 6.92 (1H, dd, J=2.8, 9.2 Hz), 7.38-7.41 (1H, m), 7.58 (1H, d, J=2.8 Hz), 7.91 (1H, s), 10.83 (1H, brs), 11.59 (1H, brs).
MS (ESI+): m/z 364.
To a suspension of ethyl 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (75 mg) in dioxane (1.5 ml) and water (1.5 ml) was added LiOH (27 mg) which was stirred at 60° C. for overnight. After cooling to the ambient temperature, 1M HCl (1.14 ml) was added to the reaction mixture, and the solvent was evaporated. The residue was dissolved in dioxane (1.5 ml) and diphenylphospholyl azide (74 μl) and triethylamine (1 ml) was added. After stirring at 120° C. for 4 hours, the reaction mixture was cooled to ambient temperature. The mixture was poured into water, extracted with EtOAc, washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with dichloromethane:methanol=10:1 to give trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarboxamide (5 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.48-2.80 (9H, m), 4.94-5.56 (1H, m), 6.77 (1H, br), 6.86 (1H, s), 7.35 (1H, br), 7.40 (1H, t, J=3.0 Hz), 7.89 (1H, s), 10.79 (1H, s), 11.53 (1H, s).
MS (ESI+): m/z 300.
To a suspension of sodium hydride (60% in oil) (7 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (53 μl). After stirring at ambient temperature for 5 minutes, trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (250 μl), and 1M NaOH solution (176 μl) was added, then stirred at 110° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (176 μl) and pH 4 buffer (5 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylic acid (11.0 mg) as a brown powder.
1H-NMR (DMSO-d6) δ: 0.97-1.11 (1H, m), 1.52-1.94 (4H, m), 2.17-2.31 (1H, m), 2.44-2.60 (2H, m), 2.93-3.00 (1H, m), 4.45-4.55 (1H, m), 5.93 (1H, dd, J=10.9 Hz, 15.9 Hz), 6.46-6.56 (1H, m), 7.06 (1H, dd, J=5.3 Hz, 15.9 Hz), 7.43 (1H, t, J=3.0 Hz), 7.93 (1H, s), 10.92 (1H, s), 11.62 (1H, s), 12.28 (1H, br).
MS (ESI+): m/z 327.
To a solution of rel-1-[(3R,4R)-4-methylpiperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (80 mg), dioxane (1.6 mL) and 4M saturated aqueous sodium hydrogencarbonate (2.4 mL) was added dimethylsulfamoyl chloride (51 mg) at ambient temperature. The mixture was stirred for 2 hours then chloroform (8 mL) was added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give rel-(3R,4R)—N,N,4-trimethyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidine-1-sulfonamide (41 mg) as a colorless solid.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.2 Hz), 1.70-2.53 (3H, m), 2.77 (6H, s) 3.13-3.22 (1H, m), 3.41-3.73 (2H, m), 4.32-4.41 (1H, m), 4.53-4.60 (1H, m), 6.44-6.47 (1H, m), 7.44-7.47 (1H, m), 7.91 (1H, s), 10.87 (1H, s), 11.63 (1H, brs).
MS (ESI+): m/z 379.
To a solution of rel-4-chloro-N-{6-[(3R,4R)—4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]pyridin-3-yl}butanamide (72 mg) and tetrahydrofuran (2.2 mL) was added potassium 2-methylpropan-2-olate (138 mg) at ambient temperature. The mixture was stirred for 0.5 hour then chloroform (10 mL) and H2O (4 mL) were added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to give rel-1-{(3R,4R)-4-methyl-1-[5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]piperidin-3-yl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (66 mg) as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.07 (3H, d, J=7.2 Hz), 1.65-2.53 (6H, m), 3.13-3.24 (1H, m), 3.73-3.79 (2H, m), 4.02-4.57 (5H, m), 6.29-6.32 (1H, m), 6.96 (1H, d, J=9.2 Hz), 7.36-7.40 (1H, m), 7.88 (1H, dd, J=2.4, 9.2 Hz), 7.92 (1H, s), 8.26 (1H, d, J=2.4 Hz), 10.86 (1H, brs), 11.59 (1H, brs).
MS (ESI+): m/z 432.
To a solution of {1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}acetonitrile (25 mg) in dichloromethane (1 mL) was added boron trifluoride etherate (35.7 μl) dropwise at 4° C. The mixture was stirred at ambient temperature for 0.5 hour. To the mixture was added 5.5M sodium acetate aqueous solution (0.207 mL) and the mixture was stirred at 80° C. for 4 hours. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on NH silica gel with EtOAc and n-hexane (50:50 to 95:5) to give {1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}acetonitrile (4 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.92 (3H, d, J=7.1 Hz), 1.41-1.53 (3H, m), 1.64-1.67 (1H, m), 1.80-1.90 (3H, m), 2.33-2.35 (1H, m), 2.91-2.94 (1H, m), 4.47-4.53 (1H, m), 5.16 (2H, s), 6.55 (1H, d, J=3.2 Hz), 7.53 (1H, d, J=3.2 Hz), 8.26 (1H, s, 11.78 (1H, brs).
MS (ESI): m/z 332 (M+Na)+.
The following compounds were obtained in a similar manner to that of Example 311.
1H-NMR (DMSO-d6) δ: 1.07-1.88 (10H, m), 2.89 (3H, s), 3.37-3.51 (1H, m), 6.55 (1H, s), 7.63 (1H, d, J=2.7 Hz), 8.27 (1H, s).
MS (ESI): m/z 388 (M+H)+.
1H-NMR (DMSO-d6) δ: 3.18 (3H, s), 4.81 (2H, s), 6.21 (1H, d, J=5.6 Hz), 6.40 (1H, d, J=3.6 Hz), 7.08 (1H, d, J=3.6 Hz), 7.19-7.39 (5H, m), 7.83 (1H, d, J=5.6 Hz), 11.28 (1H, brs).
MS (ESI): m/z 238 (M+H)+.
To a solution of 3-methyl-1-[(1S,2R)-2-methylcyclohexyl]-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (40 mg) in water (2 mL) was added trifluoroacetic acid (2 mL) and the mixture was stirred 110° C. for 3 hours. The mixture was extracted with chloroform. The extract was washed with saturated aqueous sodium hydrogencarbonate and water, dried over MgSO4, filtrated and evaporated to give a white solid. The solid was dissolved with tetrahydrofuran (2 mL) and saturated potassium carbonate aqueous solution (2 mL) was added. The mixture was stirred for 1 hour. To the mixture was added 1,2-ethanediamine (0.5 mL) and the mixture was stirred for 1 hour. The mixture was extracted with chloroform. The extract was washed with water, dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 95:5) to give 3-methyl-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (25 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.93 (3H, d, J=7.1 Hz), 1.47-1.87 (7H, m), 2.32-2.33 (1H, m), 2.94-2.98 (1H, m), 3.36 (3H, s), 4.44-4.49 (1H, m), 6.51 (1H, d, J=3.5 Hz), 7.46 (1H, d, J=3.5 Hz), 8.07 (1H, s), 11.63 (1H, brs).
MS (ESI): m/z 285 (M+H)+.
To a solution of ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (50 mg) in tetrahydrofuran (1 mL) was added lithium aluminum hydride (21 mg) at 4° C. The reaction mixture was stirred at the same temperature for an hour, at ambient temperature for an hour, and at 60° C. for 2 hours. After cooled to ambient temperature, to the mixture was added water (0.021 ml), 15% NaOH solution (0.021 ml), water (0.063 ml) one after another. The precipitate was filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with chloroform:methanol=8:1 to give (4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (15.6 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.93 (3H, d, J=7.0 Hz), 1.28-2.04 (9H, m), 4.14 (1H, m), 4.55 (2H, d, J=4.8 Hz), 5.26 (1H, m), 6.03 (1H, d, J=8.9 Hz), 6.45 (1H, d, J=3.4 Hz), 7.12 (1H, d, J=3.4 Hz), 7.67 (1H, s), 11.17 (1H, brs).
MS (API): m/z 260 (M+H)+.
To a mixture of 6,7-diamino-1-[(1S,2R)-2-methylcyclohexyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (147 mg) in toluene-ethanol (1 mL-0.5 mL) was added methyl isothiocyanate (43 μL). The resulting solution was heated for 80° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was added drop wise water. The mixture was extracted with EtOAc (2×15 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4. Removal of the solvent preceded the crude thiocarbamate which was used in the next step with out purification. To a solution of above carbamate in toluene (1 mL) was added WSCD HCl (162 mg) at ambient temperature. The mixture was heated at 110° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (20 mL), and washed with saturated aqueous sodium hydrogencarbonate (20 mL) and brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel chloroform:methanol=90:10) to give 2-(methylamino)-8-[(1S,2R)-2-methylcyclohexyl]-6,8-dihydrodiimidazo[4,5-b:4′,5′-d]pyridin-7(3H)-one (10 mg) as a pale yellow solid.
1H-NMR (DMSO-d6) δ: 11.4 (1H, s), 10.6 (1H, s), 7.50 (1H, s), 6.56-6.58 (1H, m), 4.60-4.63 (1H, m), 2.86 (3H, d, J=4.9 Hz), 2.27 (1H, t, J=6.8 Hz), 1.20-2.21 (8H, m), 0.94 (3H, d, J=7.2 Hz).
MS (ESI): m/z 301 (M+H)+.
To a solution of pyrrolidine (0.0184 mL) in ACOH (0.6 mL) was added paraformaldehyde (7.8 mg), and stirred at ambient temperature for 5 minutes. To the mixture was added 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (30 mg), and stirred at 85° C. for 8 hours, then stirred at ambient temperature for 14 hours. AcOH was removed in vacuo, and the residue was diluted with tetrahydrofuran, then basified with saturated aqueous sodium hydrogencarbonate. The mixture was extracted with EtOAc, washed with 10% NaCl solution, and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1 to 10:1) to give 1-[(1S,2R)-2-methylcyclohexyl]-8-(1-pyrrolidinylmethyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (32.7 mg) as a pale yellow amorphous solid.
1H-NMR (DMSO-d6) δ: 0.92 (3H, d, J=7.1 Hz), 1.19-1.94 (12H, m), 2.14-2.33 (4H, m), 3.04-3.19 (1H, m), 3.30 (1H, d, J=12.6 Hz), 4.05 (1H, d, J=12.6 Hz), 5.23-5.33 (1H, m), 7.32-7.36 (1H, m), 7.86 (1H, s), 10.74 (1H, s), 11.41 (1H, b rs).
MS (ESI): m/z 354 (M+H)+.
To a solution of ethyl 1-[(1S,2R)-2-methoxycyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (10 mg) in acetonitrile (0.38 mL) was added iodo(trimethyl)silane (0.025 mL) at 5° C. and the mixture was stirred at ambient temperature for 2 hours and further stirred at 60° C. for 2 hours. The mixture was cooled to 4° C. To the mixture were added saturated disodium thiosulfate aqueous solution and saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative Thin layer chromatography (chloroform:methanol=10:1) to give 1-[(1S,2R)-2-hydroxycyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (14.1 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 1.39-1.91 (7H, m), 2.58-2.73 (1H, m), 4.17 (1H, brs), 4.35-4.44 (1H, m), 5.59 (1H, brs), 6.66 (1H, m), 7.36-7.45 (1H, m), 7.94 (1H, s), 11.06 (1H, brs), 11.56 (1H, brs).
MS (ESI): m/z 273 (M+H)+.
To a solution of rel-(1R,2S)-2-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarboxamide (14 mg) in N,N-dimethylformamide (140 μl) was added 2,4,6-trichloro-1,3,5-triazine (8.63 mg) at 0° C. The reaction mixture was stirred at ambient temperature overnight. The solution was diluted with water and extracted with EtOAc/tetrahydrofuran. The organic layer was dried over MgSO4 and concentrated in vacuo. The residual solid was washed with diisopropylethylether to give rel-(1R,2S)-2-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbo-nitrile (3 mg) as a pale brown solid.
1H-NMR (DMSO-d6) δ: 0.44-0.60 (2H, m), 0.69-0.78 (1H, m), 1.91-2.16 (4H, m), 2.97-3.06 (1H, m), 3.50-3.52 (1H, m), 4.45-4.52 (1H, m), 6.55 (1H, dd, J=1.8 Hz, 3.0 Hz), 7.46 (1H, dd, J=2.9 Hz, 3.2 Hz), 7.93 (1H, s), 10.86 (1H, s), 11.64 (1H, s).
MS (ESI): m/z 282 (M+H)+.
A mixture of 6,7-diamino-1-[(1S,2R)-2-methylcyclohexyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (40 mg), orthoformic acid triethyl ester (1 mL) and HCl (20 uL) was stirred at ambient temperature for an hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH2 silica gel, chloroform:methanol=95:5) to give 8-[(1S,2R)-2-methylcyclohexyl]-6,8-dihydrodiimidazo[4,5-b:4′,5′-d]pyridin-7(3H)-one (21 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 12.9 (1H, br), 11.1 (1H, br), 8.32 (1H, s), 8.00 (1H, s) 4.69-4.75 (1H, m), 2.30-2.32 (1H, m), 1.38-1.99 (8H, m), 0.94 (3H, d, J=7.3H z).
MS (ESI): m/z 294 (M+Na)+.
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (30 mg, 0.111 mmol) in N,N-dimethylformamide (0.6 mL) was added N,N-dimethylmethyleneiminium iodide (26.7 mg), and stirred at 85° C. for 1.5 hours. To the mixture was added Eschenmoser's salt (12.3 mg), and stirred at 80° C. for 30 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogencarbonate, 10% NaCl solution (×5), and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1 to 10:1) to give 8-[(dimethylamino)methyl]-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (11.6 mg) as a pale yellow amorphous solid.
1H-NMR (DMSO-d6) δ: 0.88 (3H, d, J=7.1 Hz), 1.27-2.26 (8H, m), 2.10 (6H, s), 3.00-3.20 (2H, m), 3.83 (1H, d, J=12.7 Hz), 5.11-5.23 (1H, m), 7.30-7.35 (1H, m), 7.87 (1H, s), 10.75 (1H, s), 11.45 (1H, s).
MS (ESI): m/z 328 (M+H)+.
A mixture of 7-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridine-6-carboxamide (46 mg), 6-chloronicotinonitrile (37 mg) and N,N-diisopropylethylamine (46 uL) in NMP (0.5 mL) was heated in the microwave reactor (90° C., 10 minutes). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (20 mL) and half-saturated aqueous sodium hydrogencarbonate (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the product by column chromatography (silica gel, gradient elution, chloroform:methanol=20:1 to 10:1) provided (7 mg) 7-{[1-(5-cyano-2-pyridinyl)-4-piperidinyl]amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide as a white solid.
1H-NMR (DMSO-d6) δ: 12.8 (1H, br), 9.50 (1H, d, J=8.5 Hz), 8.48 (1H, d, J=2.4 Hz), 8.45 (1H, s), 8.10 (1H, s), 7.85 (1H, br), 7.82 (1H, dd, J=2.4, 9.0 Hz), 7.05 (1H, br), 6.98 (1H, d, J=9.0 Hz), 5.05-5.12 (1H, m), 4.29-4.32 (2H, m), 3.25-3.28 (2H, m), 2.11-2.18 (2H, m), 1.40-1.43 (2H, m).
MS (ESI): m/z 363 (M+Na)+.
The following compound was obtained in a similar manner to that of Example 322.
1H-NMR (DMSO-d6) δ: 1.06 (3H, d, J=7.2 Hz), 1.74-1.82 (1H, m), 1.97-2.07 (1H, m), 3.28-3.43 (1H, m), 4.20-4.70 (5H, m), 6.40-6.44 (1H, m), 7.03 (1H, d, J=9.2 Hz), 7.37-7.41 (1H, m), 7.81 (1H, dd, J=2.0, 9.2 Hz), 7.92 (1H, s), 8.32 (1H, brs), 10.86 (1H, s), 11.59 (1H, s).
MS (ESI): m/z 374 (M+H)+.
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (1 mL) was added N-bromosuccinimide (66 mg). The mixture was stirred at ambient temperature for 2 hours. To the mixture were added chloroform and water. The mixture was extracted with chloroform. The extract was washed saturated aqueous sodium hydrogencarbonate and brine, dried over MgSO4 and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in a small-amount of methanol and to the solution was added EtOAc. The precipitate was filtrated and washed with EtOAc to give 8-bromo-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (12 mg) as a white powder.
1H-NMR (DMSO-d6) δ: 0.99 (3H, d, J=7.1 Hz), 1.35-1.99 (7H, m), 2.36 (1H, m), 2.89-3.15 (1H, m), 5.18-5.26 (1H, m), 7.67 (1H, d, J=2.8 Hz), 7.95 (1H, s), 10.95 (1H, brs), 12.07 (1H, brs).
MS (ESI): m/z 371,373 (M+Na)+.
A mixture of cyclobutanamine (6.4 mg), ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.030M solution in 1-methyl-2-pirrolidone, 1.00 mL), and N,N-diisopropylethylamine (0.016 mL) was heated at 150° C. for 6 days. The reaction mixture was cooled to ambient temperature, then solvent was removed in vacuo. To the residue was added 1,4-dioxane (1 mL) and LiOH (0.090M solution in water, 1.00 mL). The mixture was heated at 100° C. for 24 hours and it was cooled to ambient temperature, and the solvent was removed in vacuo. To the residue was added 1,4-dioxane (1 mL), N,N-dimethylformamide (0.5 mL), N,N-diisopropylethylamine (0.016 mL), and diphenylphosphoryl azide (0.090M solution in 1,4-dioxane, 1.00 mL). The mixture was heated at 100° C. for 24 hours and it was cooled to ambient temperature, and the solvent was removed in vacuo. To the residue was added chloroform (2 mL), and 1M NaOH solution (1 mL) and was mixed with Bortex Mixer. The organic phase was separated with 1PS Filter Tube (from Whatman) and evaporated. Purification by preparative high performance liquid chromatography gave 1-cyclobutyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.3 mg).
The following compounds (Example 330-Example 406) were obtained in a similar manner to that of Example 325.
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo[4,5-d]-pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in N,N-dimethylformamide, 1.00 mL), 1-hydroxybenzotriazole (4.1 mg, 0.030 mmol), 3-but-enoic acid (0.50M solution in NMP, 0.080 mL), and PS-Carbodiimide (Argonaut technologies, 50 mg) was agitated at ambient temperature for 16 hours. PS-Trisamine (Argonaut technologies, 50 mg), PS-Isocyanate (50 mg) was added and the reaction agitated at ambient temperature for a further 2 hours and filtered. The filtrate was concentrated to yield 1-(1-but-3-enoylpiperidin-3-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (9.7 mg).
The following compounds (Example 407-Example 515) were obtained in a similar manner to that of Example 326.
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in pyridine, 1.00 mL), thiophene-2-sulfonyl chloride (7.3 mg) was heated at 90° C. for 16 hours. The reaction mixture was concentrated and redissolved in N,N-dimethylformamide. PS-Trisamine (50 mg), PS-Isocyanate (50 mg) was added and the mixture agitated at ambient temperature for 6 hours then filtered. The filtrate was concentrated in vacuo and purification by preparative high performance liquid chromatography gave 1-[1-(2-thienylsulfonyl)piperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.3 mg).
The following compounds (Example 516-Example 540) were obtained in a similar manner to that of Example 327.
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo[4,5-d]-pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in NMP, 1.00 mL), ethyl bromoacetate (6.7 mg), K2CO3 (8.3 mg), potassium iodide (0.3 mg) was heated at 90° C. for 16 hours. Chloroform (4 mL) and water (2 mL) was added and was mixed with Bortex Mixer. The organic phase was separated with 1PS Filter Tube (from Whatman) and evaporated. Purification by preparative high performance liquid chromatography gave ethyl[3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]acetate (2.8 mg).
The following compounds (Example 541-Example 557) were obtained in a similar manner to that of Example 328.
A mixture of 1-(2-methylcyclohexyl)-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in N,N-dimethylformamide, 1.00 mL), 3-bromopropyl phenyl ether (12.9 mg), 1,8-diazabicyclo[4,3,0]non-5-ene (0.013 mL), was heated at 60° C. for 16 hours. The solvent was removed in vacuo and purification by preparative high performance liquid chromatography gave 1-(2-methylcyclohexyl)-3-(3-phenoxypropyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (2.6 mg).
The following compounds (Example 558-Example 666) were obtained in a similar manner to that of Example 329.
As mentioned above, the present invention can provide a novel compounds having a potent inhibitory effect on the activity of Janus Kinase 3 (JAK3), and a pharmaceutical composition comprising the same. The compound is useful as an active ingredient of an immunosuppressant and an antitumor agent, and as an active ingredient of a therapeutic or prophylactic agent for diseases or conditions caused by undesirable cytokine signal transduction, such as rejection reaction in organ transplantation, autoimmune diseases, asthma, atopic dermatitis, Alzheimer's disease, atherosclerosis, tumor, myeloma and leukemia, etc.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2005-378858 | Dec 2005 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2006/314326 | 7/13/2006 | WO | 00 | 1/11/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60698928 | Jul 2005 | US |
