Patent Application
20060052396
The present invention relates to new compounds of formula I, as a free base or a pharmaceutically acceptable salt thereof, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. The present invention further relates the process for the preparation of compounds of formula I and to new intermediates prepared therein.
An object of the invention is to provide compounds of formula I for therapeutic use, especially compounds that are useful for the prevention and/or treatment of conditions associated-with glycogen synthgas kinase-3 (GSK3) in mammals including man. Particularly compounds of formula I exhibiting inhibition of GSK-3.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kin ase composed of two isoforms (α and β), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK3 on serine 9 residue and inactivates it.
Alzheimer's Disease (AD) Dementias, and Taupathies.
AD is characterized by cognitive decline, cholinergic dysfunction and neuronal death, neurofibrillary tangles and senile plaques consisting of amyloid-β deposits. The sequence of these events in AD is unclear, but believed to be related. Glycogen synthase kinase 3β(GSK3β) or Tau (τ) phosphorylating kinase selectively phosphorylates the microtubule associated protein τ in neurons at sites that are hyperphosphorylated in AD brains. Hyperphosphorylated protein τ has lower affinity for microtubules and accumulates as paired helical filaments, which are the main components that constitute neurofibrillary tangles and neuropil threads in AD brains. This results in depolymerization of microtubules, which leads to dying back of axons and neuritic dystrophy. Neurofibrillary tangles are consistently found in diseases such as AD, amyotrophic lateral sclerosis, parkinsonism-dementia of Gaum, corticobasal degeneration, dementia pugilistica and head trauma, Down's syndrome, postencephalatic parkinsonism, progressive supranuclear palsy, Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β to primary hippocampal cultures results in hyperphosphorylation of τ and a paired helical filaments-like state via induction of GSK3β activity, followed by disruption of axonal transport and neuronal death (Imahori and Uchida., J. Biochem 121:179-188, 1997). GSK3β preferentially labels neurofibrillary tangles and has been shown to be active in pre-tangle neurons in AD brains. GSK3 protein levels are also increased by 50% in brain tissue from AD patients. Furthermore, GSK3β phosphorylates pyruvate dehydrogenase, a key enzyme in the glycolytic pathway and prevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis of acetylcholine, a neurotransmitter with cognitive functions. Thus, GSK3β inhibition may have beneficial effects in progression as well as the cognitive deficits associated with Alzheimer's disease and other above-referred to diseases.
Chronic and Acute Neurodegenerative Diseases.
Growth factor mediated activation of the PI3K/Akt pathway has been shown to play a key role in neuronal survival. The activation-of this pathway results in GSK3β inhibition. Recent studies (Bhat et. al., PNAS 97:11074-11079 (2000)) indicate that GSK3β activity is increased in cellular and animal models of neurodegeneration such as cerebral ischemia or after growth factor deprivation. For example, the active site phosphorylation was increased in neurons vulnerable to apoptosis, a type of cell death commonly thought to occur in chronic and acute degenerative diseases such as Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia, ischemic stroke and head trauma. Lithium was neuroprotective in inhibiting apoptosis in cells and in the brain at doses that resulted in the inhibition of GSK3β. Thus GSK3β inhibitors could be useful in attenuating the course of neurodegenerative diseases.
Bipolar Disorders (BD)
Bipolar Disorders are characterised by manic episodes and depressive episodes. Lithium has been used to treat BD based on its mood stabilising effects. The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication. The recent discovery that lithium inhibits GSK3 at therapeutic concentrations has raised the possibility that this enzyme represents a key target of lithium's action in the brain (Stambolic et al., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459, 1996). Inhibition of GSK3β may therefore be of therapeutic relevance in the treatment of BD as well as in AD patients that have affective disorders.
Schizophrenia
GSK3 is involved in signal transduction cascades of multiple cellular processes, particularly during neural development. Kozlovsky et al (Am J Psychiatry 2000May;157(5):831-3) found that GSK3β levels were 41% lower in the schizophrenic patients than in comparison subjects. This study indicates that schizophrenia involves neurodevelopmental pathology and that abnormal GSK3 regulation could play a role in schizophrenia. Furthermore, reduced β-catenin levels have-been reported in patients exhibiting schizophrenia (Cotter et al. Neuroreport 9:1379-1383 (1998)),
Diabetes
Insulin stimulates glycogen synthesis in skeletal muscles via the dephosphorylation and thus activation of glycogen synthase. Under resting conditions, GSK3 phosphorylates and inactivates glycogen synthase via dephosphorylation. GSK3 is also over-expressed in muscles from Type II diabetic patients (Nikoulina et al., Diabetes 2000 February;49(2):263-71). Inhibition of GSK3 increases the activity of glycogen synthase thereby decreasing glucose levels by its conversion to glycogen. GSK3 inhibition may therefore be of therapeutic relevance in the treatment of Type I and Type II diabetes and diabetic neuropathy.
Hair Loss
GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector of the pathway for keratonin synthesis. β-catenin stabilisation may be lead to increase hair development. Mice. expressing a stabilised β-catenin by mutation of sites phosphorylated by GSK3 undergo a process resembling de novb hair morphogenesis (Gat et al., Cell 1998 Nov. 25;95 (5): 605-14)). The new follicles formed sebaceous glands and dermal papilla, normally established only in embryogenesis. Thus GSK3 inhibition may offer treatment for baldness.
Oral Contraceptives
Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54) reported that GSK3 is high in motile versus immotile sperm. Immunocytochemistry revealed that GSK3 is present in the flagellum and the anterior portion of the sperm head. These data suggest, that GSK3 could be a key element underlying motility initiation in the epididymis and regulation of mature sperm function. Inhibitors of GSK3 could be useful as contraceptives for males.
The object of the present invention is to provide compounds having a selective inhibiting effect at GSK3 as well as having a good bioavailability.
Accordingly, the present invention provides a compound of formula I
wherein:
The present invention further relates to a compound having the formula I
wherein:
One aspect of the invention relates to compounds of formula I, wherein:
A preferred embodiment of the invention relates to compounds of formula I, wherein Y is CONR5.
In one aspect of the invention P is phenyl, furan or thiophene or another 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S.
In another aspect of the invention preferably Q is pyridine.
In yet another aspect of the invention R is C0-6alkyl(SO2)NR1R2, (SO2)NR1R2 or OC1-6alkylNR1R2.
One aspect of the invention relates to compounds wherein R is in the 4 position.
The invention relates to the following compounds;
A further aspect of the invention relates to compounds
Another aspect of the invention relates to compounds
Listed below are definitions of various terms used in the specification and claims to describe the present invention.
In this specification the term “alkyl” includes both straight and branched chain alkyl groups. The term C1-6alkyl having 1 to 6 carbon atoms and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term C1-3alkyl having 1 to 3 carbon atoms and may be methyl, ethyl, n-propyl or i-propyl. The term C1-2alkyl having 1 to 2 carbon atoms and may be methyl or ethyl.
A similar convention applies to other radicals, for example “C0-6alkylaryl” includes 1-phenylethyl and. 2-phenylethyl.
In the case where a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group may be absent, i.e. there is a direct bond between the groups.
The term “cycloalkyl” refers to an optionally substituted, saturated cyclic hydrocarbon ring system. The term “C3-6cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or 0.20 cyclohexyl.
The term “alkenyl” refers to a straight or branched chain alkenyl group. The term C2-6alkenyl having 2 to 6 carbon atoms and one double bond, and may be vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl or hexenyl. The term C2-3alkenyl having 2 to 3 carbon atoms and one or two double bond, and may be vinyl, allyl, propenyl or i-propenyl.
The term “alkynyl” refers to a straight or branched chain alkenyl group C2-6alkynyl having 2 to 6 carbon atoms and one triple bond, and may be ethynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl or hexynyl. The term C2-3alkynyl having 2 to 3 carbon atoms and one triple bond, and may be ethynyl or propargyl.
The term “halo” refers to fluoro, chloro, bromo and iodo.
The term “aryl” refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. The “aryl” may be fused with a C5-7cycloalkyl ring to form a bicyclic hydrocarbon ring system. Examples and suitable values of the term “aryl” are phenyl, naphthyl, indanyl or tetralinyl.
The term “heteroaryl” and “5 or 6 membered heteroaromatic ring” containing one or more heteroatoms selected from N, O and S may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl.
The term “heterocycloalkyl” and “heterocyclic ring containing one or more heteroatoms selected from N, O or S may optionally contain a carbonyl function and is preferably a 5, 6 or 7 membered heterocyclic, ring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, 1-methyl-1′,4-diazepane, tetrahydropyranyl, thiomorpholinyl. In the case where the heterocyclic ring contains a heteroatom selected from S this includes optionally SO and SO2.
It is to be understood that when m is greater than one, R4 groups may be the same or different. Similarly, when m is greater, than one the R3 groups may be the same or different.
The term “hydrochloride” includes monohydrochloride, dihydrochloride, trihydrochloride and tetrahydrochloride salts.
A suitable pharmaceutically acceptable salt of the compound of the invention is, for example, an acid-addition salt, which is sufficiently basic, for example an inorganic or organic acid. In addition a suitable pharmaceutically acceptable salt-of the compounds of the invention which is sufficiently acidic is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base which affords a physiologically-acceptable cation.
Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
The invention relates to any and all tautomeric forms of the compounds of formula I.
The invention also relates to a compound of formula XI
wherein Y, X, Z, Q, R4, R5, R6, R7, R8, R9, A and m are defined as in formula I.
The invention further relates to a compound of formula XIII
wherein X, Z, P, R, R1, R2, R3, R6, R7, R8, R9, R10, R11, R12, A and n are defined as in formula I and R13 is hydrogen or C1-6alkyl.
One aspect of the invention relates to a compound of formula XV
wherein Y, Z, X, Q, R4, R5, R6, R7, R8, R9, A and m are defined as in formula I and R14 is diethylboronate, 1,3,2-dioxaborolane, 1,3,2-dioxaborinane or 1,3,2-benzodioxaborole.
Another aspect of the invention relates to a compound of formula XVI
wherein Y, Z, X, P, Q, R3, R4, R5, R6, R7, R8, R9, A, m and n are defined as in formula I and L is a leaving group.
A further aspect of the-invention relates to the following compounds, which may be used as intermediates for the preparation of a compound of formula I;
Another aspect of the present invention provides a process for preparing a compound of formula I as a free base or a pharmaceutically acceptable salt thereof. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis” T. W. Green, P. G. M. Wuts, Wiley-Interscience, New York, 1999.
Methods of Preparation of the Intermediates.
The process for the preparation of the intermediates, wherein Y, X, Z, P, Q, R1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, m and n are, unless specified otherwise, defined as in formula I, comprises of:
(i) halogenation of a compound of formula II wherein X and Z are N or CH, R13 is hydrogen, C1-6alkyl or when R13 is hydrogen in the form of a salt such as a sodium salt, to obtain a compound of formula III, may be carried out using a suitable halogenating reagent such as iodine, bromine, chlorine, halide salts such as ICI, BrCl or HOCl or other suitable halogenation reagents such as N-bromosuccinimide or phosphorous tribromide. The reaction may be catalysed by metals or acids such as Fe, Cu-salts, acetic acid or sulfuric acid or aided by oxidising agents such as nitric acid, hydrogen peroxide or sulfur trioxide. The reaction may be carried out in a suitable solvent such as water, acetic acid or chloroform at a temperature in the range of −700C to +100° C.
(ii) reacting a compound of formula V, wherein Q is a pyridine ring, R4 is hydrogen (when m=0), bromine or iodide, m is 1 and wherein at least one of Rx or Ry is a suitable protecting group CO2R8 to form a carbamate such as tert-butyl carbamate and the other of the Rx or Ry (in the case of one protecting group) is hydrogen, to obtain a compound of s5 formula IV, wherein Q is a pyridine ring, R4 is C1-6alkylNR6R7 and m is 1, may be carried out by,
a) a reaction with butyllithium in a suitable solvent such as tetrahydrofuran or hexane followed by the addition of a suitable reagent such as ethylene oxide followed by the activation of the formed alcohol by the formation of the mesylate or the tosylate with a suitable reagent such as methansulfonyl chloride or para-toluensulfonyl chloride in a suitable solvent such as methylene chloride or tetrahydrofuran with or without a suitable base such as potassium carbonate or a trialkyl amine such as triethyl amine and at a suitable reaction temperature range between 0° C. and +100° C., followed by the addition of the appropriate amine HNR6R7 at a reaction temperature range between 0° C. and +100° C.; or,
b) reacting a compond of formula VI, wherein Q is as defined above and wherein at least one of Rx or Ry is a suitable protecting group CO2R8, to form a carbamate such as tert-butyl carbamate and the other of the Rx or Ry (in the case of one protecting group) is hydrogen, with the appropriate amine HNR6R7 in the presence of a suitable reducing reagent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as methylene chloride, 1,2-dichloroethane and at a reaction temperature range between 0° C. and +80° c; or,
c) reacting a compound of formula V, wherein Q is a pyridine ring, R4 is bromine or iodide and m is 1,
in a palladium catalysed reaction using a suitable palladium reagent such as palladium tetrakistriphenylphosphine in the prescence of a copper(I) halide such as CuI and a suitable base such as potassium carbonate or a trialkyl amine such as triethyl amine, and a compound described in Scheme I. The reaction may be performed in a solvent such as dioxane, tetrahydrofaran, toluene or acetonitrile at temperatures between +25° C. and +100° C.
(iii) conversion of a compound of formula VIII, wherein Q is as defined above, to obtain a compound of formula VII, wherein Rx and Ry are hydrogen or at least one of Rx or Ry is a suitable protecting group CO2R8, to form a carbamate such as tert-butyl carbamate and the other of the Rx or Ry (in the case of one protecting group) is hydrogen, may be carried out by,
a) a reaction of a compound of formula VII with a suitable reagent such as diphenylphosphorylazide in tert-butanol and at a temperature interval between +25° C. and +100° C.; or,
b) by treatment of a compound of formula LX with a suitable tert-butyl carbamate formation reagent such as di-tert-butyl dicarbonate in a suitable solvent such as methylene chloride or chloroform and at a suitable temperature interval between 0° C. and +60° C.
(iv) hydrolysis of a compound of formula IV, to obtain a compound of formula X,
wherein Q is as defined above, R4 is C1akylNR6R7 and m is 1, may be carried out by treating a compound of formula IV under acidic conditions using suitable acids such as hydrochloric acid or trifluoroacetic acid neat or in an appropriate solvent such as methanol, acetonitrile, methylene chloride or tetrahydrofuran and at a temperature interval between 0° C. and +80° C.
(v) amidation of a compound of formula m, wherein X and Z are N or CH, R13 is C1-6alkyl to obtain a compound of formula XI, wherein Y is CONR5 may be carried out by treating a compound of formula III with the appropriate amine such as a compound of formula X or 3-aminopyridine. The reaction may be performed neat or using a suitable solvent such as N,N-dimethylformrnamide, methylene chloride or ethyl acetate at a temperature ranging from −25° C. to +150° C. The reaction may be aided by using a base such as potassium carbonate, trietylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene or an acid such as trimethylaluminum or p-toulenesulfonic acid.
(vi) amidation of a compound of formula III, wherein R1 is hydrogen, to obtain a compound of formula XI, wherein Y is CONR5 and R4 is a substituent that is not susceptible to certain coupling agents, may be performed by activation of a compound of formula II by treating the compound with coupling reagents such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate, 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, 1,1′-carbonyldiimidazole or. O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate or using an acyl halide reagent such as cyanuric chloride, oxalyl chloride, thionyl chloride or bromotrispyrrolidinophosphonium hexafluorophosphate, followed by treatment with the appropriate amine such as a compound of formula X or 3-aminopyridine.
(vii) amidation of a compound of formula II, wherein R13 is hydrogen or C1-6alkyl, to obtain a compound of formula XI, may be carried out by amidation conditions described in (v) and (vi) above to obtain a compound of formula X, wherein Y is CONR5 and R4 is a substituent that is not susceptible to certain coupling agents;
followed by,
halogenation of a compound of formula XII with a halogenating reagent as described in (i) above to obtain a compound of formula XI.
(viii) conversion of a compound of formula III to a compound of formula XIII, wherein X and Z are N or CH, R13 is C—-6alkyl and R3 P and n are as defined above, may be carried out by a de-halogen coupling with a suitable compound of formula XXIX.
The reaction may be carried out by coupling of a compound of formula III with an appropriate aryl boronic acid or a bomic ester of formula XXIX. The reaction may be carried out using a suitable palladium catalyst such as Pd(PPh3)4, Pd(dppf)Cl2 or Pd(OAc)2 together with a suitable ligand such as P(tert-butyl)3 or 2-(dicyclohexylphosphino)biphenyl or a nickel catalyst such as nickel on charcoal or Ni(dppe)Cl2 together with Zn and sodium triphenylphosphinetrimetasulfonate. A suitable base such as an alkyl amine e.g. triethyl amine, or potassium carbonate, sodium carbonate, sodium hydroxide or cesium fluoride may be used in the reaction, which is performed in a temperature range between +20° C. and +160° C. using an oil bath or a microwave oven in a suitable solvent or solvent mixture such as toluene, tetrahydrofuran, dimethoxyethane/water or N,N-dimethylformamide.
(ix) reaction of a compound of formula XIV, wherein X, Z and R13 is as defined above and R14 is as defind belove, to obtain a compound of formula XIII may be carried out by reacting a compound of formula XIV with a suitable aryl halide. The reaction may be carried out using a suitable palladium catalyst such as Pd(PPh3)4, Pd(dppf)Cl2 or Pd(OAc)2 together with a suitable ligand or a nickel catalyst such as nickel on charcoal or Ni(dppe)Cl2 together with Zn and sodium triphenylphosphinetrimetasulfonate. A suitable base such as an alkyl amine e.g. triethyl amine, or potassium carbonate, sodium hydroxide or cesium fluoride may be used in the reaction, which is performed in a temperature range between +20° C. and +120° C. in a suitable solvent such as toluene, tetrahydrofuran or N,N-dimethylformamide.
(x) conversion of a compound of formula XTII, wherein R13 is C1-6alkyl, to a compound of formula XIII, wherein R13 is hydrogen, may be carried out in a suitable solvent such as tetrahydrofuran or water or mixtures thereof in the presence of a suitable base such as potassium carbonate, sodium hydroxide or lithium hydroxide at a reaction temperature between +20° C. and +60° C.
(xi) borylation of a compound of formula III to a compound of formula XIV, wherein X and Z are N or CH and R14 may be a group outlined in Scheme II, R15 and R1are C1-6alkyl or C1-3alkyl fused together to form a 5 or 6 membered boron-oxygen-C2-3cycloalkyl and the alkyl, cycloalkyl, and the aryl moieties may be optionally substituted, may be carried out by a reaction with:
a) butyllithium or magnesium and a suitable boron compound-such as trimethyl borate or triisopropyl borate. The reaction may be performed in a suitable solvent such as tetrahydrofuran, hexane or methylene chloride in a temperature range between −78° C. and +20° C.; or,
b) a palladium catalyst such as palladium tetrakistriphenylphosphine, palladium diphenylphosphineferrocene dichloride or palladium acetate with or without a suitable ligand such as 2-(dicyclohexylphosphino)biphenyl, and a suitable boron species such as biscatecholatodiboron, bispinacolatodiboron or pinacolborane. A suitable base, which under the reaction conditions do not promote dimerisation of a compound of formula III, such as a tertiary amine such as trietylamine or diisopropylethylamine or potassium acetate may be used. The reaction may be performed in a solvent such as dioxane, toluene or acetonitrile at temperatures between 480° C. and +100° C.
(xii) borylation of a compound of formula XI to a compound of formula XV, wherein X and Z are N or CH, Y is CONR5, Q, R4 and m are as defined above and R14 is a group outlined in Scheme II, may be carried out by the reaction conditions described in (xi):
(xiii) amidation of a compound of formula XIV, wherein X and Z are N or CH, R13 is C1-6 alkyl and R14,Q, R4 and m are as defined above, to obtain a compound of formula XV, wherein Y is CONR5 and may be carried out by reacting a compound of formula XIV with a suitable amine such as a compound of formula X or 3-aminopyridine, under reaction conditions described in (v) and (vi).
(xiv) conversion of a compound of formula XI to a compound of formula XVI, wherein L is a leaving group such as outline d in Scheme III and Y is CONR5 and R3, R4, m and n are as defined above, may be carried out by a de-halogen coupling with a suitable aryl species using the conditions described in (viii). The suitable arylSO2-L species may be prepared by known methods described in the literature.
(xv) halogenating a compound of formula XVII, wherein R17 is bromine, NH2 or CH3(CO)NH and P, R3 and n are as defined above, to obtain a compound of formula XVII may be carried out by treatment of a compound of formula XVIII with a halogenation reagents such as thionyl chloride or oxalyl chloride. The reaction may be performed neat or in a suitable solvent such as tetrahydrofaran, dioxane, N,N-dimethylformamide or is methylene chloride at a temperature range between −20° C. and +60° C.;
(xvi) amidation of a compound of formula XVII, wherein R17 is bromine, NH2 or CH3(CO)NH, halo is fluorine, chlorine or bromine and P, R3 and n are as defined above, to obtain a compound of formula XIX, wherein R17 is bromine, NH2 or CH3(CO)NH and P, R1, R2, R3 and n are as defined above, may be carried out by reacting a compound of formula XVII with the suitable amine HNR1R2. The reaction may be performed in a suitable solvent such as tetrahydrofuran, dioxane, N,N-dimethylformamide or methylene chloride in a temperature range between 0° C. and +50° C.
(xvii) conversion of a compound of formula XX, wherein P, R3 and n are as defined above to obtain a compound of formula XIXa, wherein P, R1, R2, R3 and n are as defined above may be carried out by treating a compound of formula XX with a sulfonating reagent such as.chloro sulfonic acid followed by addition of a suitable amine, HNR1R2. The reaction may be performed neat or in an appropriate solvent such as tetrahydrofuran, methylene chloride and at a reaction temperature between 25° C. and reflux.
(xviii) transformation of a compound of formula XXI, wherein R17 is CH3(CO)NH, and R1, R2, R3, n and P are as defined above, to a compound of formula XXII may be carried out by the reaction with an acid such as hydrochloric acid or hydrobromic acid at a temperature range between +25° C. and +110° C.
(xix) conversion of a compound of formula XXII to obtain a compound of formula XXIII, wherein R1, R2, R3, n and P are as defined above, may be carried out by treatment of a compound of formula XXII with sodium nitrite and hydrobromic acid followed by the addition of bromide source such as CuBr in an appropriate solvent such as water at a temperature range between 0° C. and +5° C.
(xx) formation of an amide of formula XXIV, wherein R1, R2 R3, n and P are as defined above, may be carried out by treating a compound of formula XXV, wherein R13 is C1-6 alkyl, with the appropriate amine HNR1OR11. The reaction can be performed neat or using a suitable solvent such as N,N-dimethylformamide, methylene chloride or ethyl acetate at a temperature ranging from −25° C. to +150° C. The reaction may be aided by: using a base such as potassium carbonate, trietylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene or an acid such as trimethylaluminum or p-toulenesulfonic acid.
(xxi) amidation of a compound of formula XXV, wherein R13 is hydrogen and R3, n and P are as defined above to obtain a compound of formula XXV may be performed by activation of a compound of formula V by treating the compound with coupling reagents such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate, 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, 1,1′-carbonyldiimidazole or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or using an acyl halide reagent such as cyanuric chloride, oxalyl chloride, thionyl chloride or brbmotrispyrrolidinophosphonium hexafluorophosphate, followed by treatment with the appropriate amine HNR10R11. The reaction may be carried out in a suitable solvent such as N2N-dimethylformamide, acetonotrile or methylene chloride at a temperature ranging from −25° C. to +150 DC, with or without a suitable base such as an alkyl amine e.g. triethylamine, ethyl diisopropyl amine or N-methyl morpholine, or potassium carbonate or sodium hydroxide.
(xxii) bromination of a compound of formula XXVI to obtain a compound of formula XXIV, wherein R1, R2, R3, n and P are as defined above, may be carried out by treatment of a compound of formula XXVI with bromine with or without an appropriate base such as sodium acetate in a suitable solvent such as acetic acid.
(xxiii) conversion of a compound of formula XXVIII, wherein R3, n and P are as defined above, to obtain a compound of formula XXVII, wherein R1, R2, R3, n, C1-6alkyl and P are as defined above, may be carried out by reacting a compound of formula XXVIII with a suitable alcohol, R1R2C1-6alkylOH in the presence of triphenylphosphine and an appropriate azidodicarboxylate such as diethyl azidodicarboxylate. The reaction may be performed in a suitable solvent such as tetrahydrofuran, toluene or methylene chloride and at a reaction temperature between 0° C. to 60° C.
(xxiv) conversion of a compounds of formula XXIII, XXIV and XXVII to obtain compounds of formula XXIX, wherein R14, R1, R2, R3, R10, R11, n, C1-6alkyl and P are as defined above, may be carried out by a borylation reaction described in (xi)
Methods of preparation of the End Products.
Another object of the invention are processes for the preparation of a compound of general formula I, wherein Y, X, Z, P, Q, R1, R2, R3,, R3, R5, R6, R7, R8, R9. R10, R11, R12, A, m and n are, unless specified otherwise, defined as in formula I, comprising of
A
de-halogen coupling, wherein R3 and R4 are substituents that are not susceptible to certain agents in the reaction, of a compound of formula XI with a suitable aryl species to give a compound of formula I:
Thus, the de-halogen coupling according to process A may be carried out by coupling of a compound of formula XI with:
Thus, the amidation according to process B may be carried out by treating a compound of formula XIII, wherein R13 is C1-C6alkyl, with the appropriate amine such as a compound of formula X or 3-aminopyridine. The reaction can be performed neat or using a suitable solvent such as N,N-dimethylformamide, methylene chloride or ethyl acetate at a temperature ranging from −25° C. to +150° C. The reaction may be aided by using a base such as potassium carbonate, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene or an acid such as trimethylaluminum or p-toulenesulfonic acid;
or,
the amidation of a compound of formula XIII, wherein R13 is hydrogen, may be performed by activation of a compound of formula XIII by treating the compound with coupling reagents such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride and 1-hydroxybenzotriazole hydrate, 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, 1,1′-carbonyldiimidazole or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or using an acyl halide reagent such as cyanuric chloride, oxalyl chloride, thionyl chloride or bromotrispyrrolidinophosphonium hexafluorophosphate followed by treatment with the appropriate amine such as a compound of formula X or 3-aminopyridine.
C
de-halogen coupling, wherein R3 and R4 are substituents that are not susceptible to certain agents in the reaction, of a compound of formula XV with an appropriate aryl species to give a compound of formula I,
wherein R14 IS
and R15 and R16 are C1-6alkyl or C1-3alkyl fused together to form a 5 or 6 membered boron oxygen-C2-C3cycloalkyl and the alkyl, cycloalkyl and the aryl moieties may be optionally substituted;
Thus, the de-halogen coupling according to process C may be carried out by using a suitable palladium catalyst such as Pd(PPh3)4, Pd(dppf)Cl2 or Pd(OAc)2 together with a suitable ligand such as P(tert-butyl)3 or 2-(dicyclohexylphosphino)biphenyl, or a nickel catalyst such as nickel on charcoal or Ni(dppe)Cl2 together with Zn and sodium triphenylphosphinetrimetasulfonate in the precense of a suitable aryl bromide, aryl iodide or aryl chloride. A suitable base such as an alkyl amine e.g. triethyl amine, or potassium carbonate, sodium hydroxide or cesium fluoride may be used in the reaction, which is performed in the temperature range between +20° C. and +120° C. in a suitable solvent such as toluene, tetrahydrofuran or N,N-dimethylform amide.
D
reaction of a compound of formula XVI, wherein L is a leaving group with an appropriate amine, to give a compound of formula Ia:
Thus, the reaction according to process D may be carried out by treating a compound of formula XVI with the appropriate amine HNR1R2, in a suitable solvent such as tetrahydrofuran, methanol or water at temperatures in the range of 0° C. and +80° C. with or without a suitable base such as an alkylamine such as triethyl amine, sodium hydroxide or potassium carbonate.
E
amidation, wherein R3 and R4 are substituents that are not susceptible to certain agents in the reaction, of a compound of formula Ib, with the appropriate amine to give a conpound of formula Ic:
Thus the amidation of a compound of formula I according to process E may be performed by activation of the carboxylic acid function in a compound of formula Ib, wherein R is COOH, by treating the compound with coupling reagents such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate, 1′,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate, 1,1′-carbonyldiimidazole or O-benzotriazol-1-yl-N,NN′,N′-tetramethyluronium hexafluorophosphate or using an acyl halide reagent such as cyanuric chloride, oxalyl chloride, thionyl chloride or bromotrispyrrolidinophosphonium hexafluorophosphate in a suitable solvent such as N,N-dimethylformamide, dioxane or tetrahydrofuran followed by treatment with the appropriate amine HNR10R11 and at a reaction temperature between 25° C. and 70° C.
The hydrochloric salt of compound of formula I may be obtained from a compound of formula I by treatment with hydrochloric acid at a temperature range between 0° C. and +25° C., in suitable solvent such as methylene chloride, tetrahydrofuran or methylene chloride/methanol mixture.
The following examples will now be illustrated by the following non-limiting examples.
General Methods
All starting materials are commercially available or earlier described in the literature. The 1H and 13C NMR spectra were recorded on Brucker 400 at 400 Mz and 0.100 MHz, respectively. The mass spectra were recorded utilising thermospray (Finnigan MAT SSQ 7000, buffer: 50 nM NH4OAc in CH3CN:H2O; 3:7), electron impact (Finnigan MAT SSQ 710) or electrospray (LC-MS; LC:Waters 2790, column XTerra MS C8 2.51 μm 2.1×30 mm, buffer gradient H2O+0.1% TFA:CH3CN+0.04% TFA, MS: micromass ZMD) ionisation techniques.
To 3-aminopyridine (10 g, 106 mmol) at 70° C. were added methyl 3-amino-6bromo-2-pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (645 μL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/ethanol, (9:1), as the eluent to give-750 mg (59% yield) of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.50 (br s, 1H), 8.82 (d, J=3 Hz, 1H), 8.43 (dd, J=5 and 1 Hz, 1H), 8.31 (s, 1H), 8.23 (ddd, J=8, 3 and 2 Hz, 1H), 7.34 (dd, J=8, 5 Hz, 1H); MS (TSP) m/z 294 (M++1).
A three necked round bottom flask equipped with a dripping funnel and a condenser was to charged with bispinacolatodiborone (508 mg, 20 mmol), Pd(dppf)Cl2:CH2Cl2; 1:1 (4.9 mg, 6 lmol) and potassium acetate (59.9 mg, 0.6 mmol). The system was evacuated and nitrogen atmosphere was introduced. N,N-dimethylformamide (SnL) was added and the mixture was stirred at 80° C. A solution of 4-bromo-(N,N-dimethyl)benzenesulfamide (52.8 mg, 0.2 mmol) in N,N-dimethylformamide (5 mL) was added to the reaction mixture is via the dripping funnel during 30 min. After 4 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1 M HCl (aq) and the layers were separated. To the organic layer was added 6.5 g silica gel and the mixture was concentrated to dryness. The residue was purified on a silica gel column using heptane/ethyl acetate, (5:1), as the eluent to give 31 mg (50% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) 7.95 (d, J=8 Hz, 2H), 7.74 (d,f=8 Hz, 2H), 2.67 (s, 6H), 1.34 (s, 12H).
The compound was prepared as described for Example 2 using 3-bromo-N,N-dimethylbenzenesulfonamide: yield 66. %; 3H NMR (CDCl3, 400 MHz) 8.20 (br s, 1H), 8.01 (br d, J=8 Hz, 1H), 7.87-7.84 (m, 1H), 7.54 (t, J=8 Hz, 1H), 2.72 (s, 6H), 1.13 (s, 12H).
The compound was prepared as described for Example 2 using 2-bromo-N,N-dimethylbenzenesulfonamide: yield 14%; MS (ES) m/z 312 (M++1).
2-Amino-5-bromonicotinic acid (0.25 g, 1.15 nmol), 3-aminopyridine (0.22 g, 2.3 mmol), diisopropylcarbodiimide (0.27 mL: 0.22 g, 1.74 mmol), 1-hydroxybenzotriazole hydrate (0.31 g, 2.3 mmol) and N-methylmorpholine (0.38 mL: 0.35 g, 3.8 mmol) were mixed in N,N-dimethylformamide (5 ml) and stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the remaining solid was purified on a silica gel column, using a gradient toluene 100% to ethyl acetate 100% as the eluent, to give 337 mg (52% yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ 6.93 (dd, J=6 Hz, 1H), 7.19 (d, J=2 Hz, 1H), 7.44(d, J=2 Hz, 1H), 7.55 (d, J=7 Hz, 1H), 7.64 (d, J=9 Hz, 1H), 8.20 (s, 1H), 10.30 (s, 1H); 13C NMR (DMS O-d6, 400 MHz) δ 103.84, 110.60, 127.21, 133.38, 135.45, 136.96, 138.31, 140.61, 151.18, 156.85, 165.63; MS (MS) m/z 293 and 295 (M++1).
The compound was prepared as described for Example 2 using 4-bromobenzenesulfonamide. After 4 h, 0.75 g silica gel was added to the reaction mixture and the solvent was removed in vacuo. The residue was purified on a silica gel column using heptane/ethyl acetate, (5:1->3:1), as the eluent to give the title compound (64% yield) as a yellow solid: mp 240-242 DC; 1H NMR (DMSO-d6, 400 MHz) 7.83 (s, 4H), 7.43 (s, 2H), 1.31 (s, 12H); 13C NMR (DMSO-d6, 100 MHz) 134.89, 124.95, 84.20, 24.70; EINS (70 eV) m/z 283 (M+).
Triisopropyl borate (2.35 mL, 10.2 mmol) was added to a cooled (−78° C.) solution of 4-bromo-N-[2-(dimethylamino)ethyl]benzenesulfonamide (0.626 g, 2.0 mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen atmosphere. The solution was treated with n-butyllithium (6.4 mL, 10.2 mmol) dropwise over 35 min. The resulting mixture was stirred at −78° C. for 3.5 h and at room temperature for another 16 h. Water (10 mL) was added, the mixture stirred for 30 min, and evaporated to dryness. The residue was pre-adsorbed onto silica and purified by column chromatography on silica using methylene chloride/methanol, (4:6), to methanol as the eluent to give 540 mg (88% yield) of the title compound as a white foam: 1H NMR (CD3OD, 400 MHz) δ 7.70 (d, J=8 Hz, 2H), 7.63 1o (d, J=8 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 2.36 (t, J=7 Hz, 2H), 2.16 (s, 6H); 13CNMR (CD3OD, 100 MHz) δ 137.7, 135.1, 126.2, 59.6, 45.7, 42.0; MS (TSP) m/z 273 (M++1).
The title compound was prepared as described for-Example 7 using 4-bromo-N-(3-morpholin-4ylpropyl)benzenesulfonamide: yield 54%; 1H NMR (CD3OD, 400 MHz) 5-7.70 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 3.65 (t, J=5 Hz, 4H), 2.89 (t, J=7 Hz, 2 H), 2.38 (m, 4H), 2.34 (m, 2H), 1.62 (m, 2H); 3C NMR (CD3OD, 100 Mz) δ 137.7, 135.0, 125.9, 67.8, 57.6, 54.8, 42.8, 27.1.
Triisopropylborate (0.64 mL, 2.8 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]4-methylpiperazine (0.602 g, 1.9 mmol) in anhydrous 2s tetrahydrofuran (7 mL) at −78° C. under nitrogen atmosphere followed by dropwise addition of n-butyllithium (1.4 nL, 2.2 mmol). The resulting mixture-was stirred at −78° C. for 2 h and at room temperature for another 16 h. Water (2.0 mL) was added, the mixture stirred for 30 min and evaporated to dryness. The residue was pre-adsorbed onto silica and purified by column chromatography using methylene chloride/methanol, (9:1 to 1:9), as the eluent. The product was recrystallized from water to give 311 mg (58% yield) of the title compound as white crystals: mp 215-218° C.; 1H NMR (DMSO-d6, 400 MHz) δ 10.89(br s, 1H), 8.47 (br s, 2H), 8.05 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 3.77 (m, 2H), 3.40 (m, 2H), 3.13 (m, 2H), 2.71 (s, 3H), 2.65 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) 133.7, 133.3, 124.7, 49.8, 41.6, 41.4; MS (TSP) m/z 285 (M++1).
N,N-Dimethylethylenediamine (0.55 mL, 5.0 mmol) was added to a stirred solution of 4-bromobenzenesulphonyl chloride (0.644 g, 2.5 mmol) in tetrahydrofuran (7.5 μL) and the resulting mixture was stirred at room temperature for 20 min. The solvent was evaporated and the resulting mixture dissolved in ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, and the solvent was evaporated to give the title compound as a white solid: yield: 99%; 1H NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H), 3.00 (t, J=6 Hz, 2H), 2.37 (t, J=6 Hz, 2H), 2.12 (s, 6H); 13C NMR (CDC3, 100 MHz) 140.6, 134.1, 130.5, 129.3, 58.7, 46.5,41.8.
The title compound was prepared as described for Example 10 using 3-morpholin-4-ylpropan-1-amine: yield: 87%; 1H NMR (CDCl3, 400 MHz) δ 7.73 (m, 2H), 7.67 (m; 2H), 7.19 (br s, 1H), 3.73 (t, J=4 Hz, 4H), 3.10 (m, 2H), 2.45 (m, 6H), 1.68 (quint, J=6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 139.7, 132.7, 128.9, 127, 67.3, 58.7, 53.9, 44.4, 24.2.
The following Examples 12-21 were synthesized as described for Example 10:
Starting material: 4-bromo-2,5-diflourobenzenesulfonyl chloride and 1-methylpiperazine, yield 97%: 1H NMR (CDCl3, 400 MHz) δ 7.60 (m, 1H), 7.48 (m, 1H), 3.27 (br s, 4H), 2.53 (br s, 4H), 2.33 (s, 3H); 3C N (CDCl3, 100 MHz) δ 156.4, 155.8, 155.7, 154.0, 153.9, 153.2, 126.1, 126.0, 125.9, 125.9, 122.8, 122.5, 118.4, 118.1, 115.5, 54.3, 45.9, 45.7.
Starting material: 4-bromo-2-ethylbenzenesulfonyl chloride and 1-methylpiperazine, yield 97%: 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, J=9 Hz, 1H), 7.53 (d, J=2 Hz, 1H), 7.45 (dd,J 8,2 Hz, 1H), 3.20 (t, J=5 Hz, 4H), 2.98 (q, J=8 Hz, 2H), 2.47 (t, J=5 Hz, 4H), 2.30 (s, 3H), 1.28 (t, J=8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 146.4, 134.3, 143.2, 132.0, 129.3, 128.1, 54.4, 46.0, 45.3, 26.2, 15.7.
Starting material: 0.4-bromo-2-(trifluoromethoxy)benzenesulfonyl chloride and 1-methylpiperazine, yield 96%: H N (CDCl3, 400 MHz) δ 7.84 (d, J=8 Hz, 1H), 7.55 (m, 2H), 3.27 (m, 4H), 2.50 (m, 4H), 2.32 (s, 3H); 3C NMR (CDCl3 100 MHz) δ 146.5, 146.5, 133.0, 130.1, 129.6, 128.4, 124.2, 124.2, 121.5, 118.9, 116.3, 54.5, 45.9, 45.7.
Starting material: 2-bromo4-fluorobenzenesulfonyl chloride and 1-methylpiperazine, yield 99%: 1H NMR (CDCl3, 400 MHz) δ 7.69 (m, 1H), 7.42 (m, 2H), 3.22 (m, 4H), 2.50 (m, 4H), 2.30 (s, 3H); N3CNMR (CDCl3, 100 MHz) δ 160.1, 157.5, 132.3, 128.7, 128.6, 128.2, 124.4, 124.3, 121.5, 121.0, 54.3,45.9, 45.7; MS (TSP) m/z 337 and 339 (M++1).
Starting material: 2-bromo-4-methylbenzenesulfonyl chloride and 1-methylpiperazine, yield 99%: 1H NMR (CD Cl3, 400 MHz) 87.74 (d, J=8 Hz, 1H), 7.46 (m, 2H), 3.20 (m, 4H), 2.59 (s, 3H), 2.47 (m, 4H), 2.30 (s, 3H); 13C N (CDCl3, 100 MHz) δ 140.2, 135.8, 134.8, 131.9, 129.5, 127.8, 54.4, 46.0, 45.2, 20.8; MS (TSP) m/z 333 and 335′ (M++1).
Starting material: 2-bromobenzenesulfonyl chloride and 1-methylpiperazine, yield 97%: H NMR (CDCl3, 400 MHz) δ 8.07 (dd, J=8, 2 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.43 (m, 2H), 3.39 (br s, 4H), 2.55 (br s, 4H), 2.35 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 137.6, 136.1, 133.9, 132.4, 127.7, 120.7, 54.5, 45.9, 45.5; MS (TSP) m/z 319 and 321 (M++1).
Starting material: 3-bromobenzenesulfonyl-chloride and 1-methylpiperazine, yield 86%:
H NMR (CDCl3, 400 MHz) δ 7.89 (m, 1H), 7.71 (m, 2H), 7.42 (r, 1H), 3.11 (br s, 4H), is 2.57 (br s, 4H), 2.33 (s, 3H); 13CNMR (CDCl3, 100 MHz) δ 137.4, 136.2, 130.8, 130.7, 126.5, 123.4,54.0,45.9, 45.7; MS (TSP) m/z 319 and 321 (M++1)
Starting material: 4-bromo-2-(trifluoromethoxy)benzenesulfonyl chloride and N,N-dimethylethylenediamine, yield 99%: 1H NMR (CDCl3, 400 MHz) δ 7.91 (d, J=9 Hz, 1H), 7.56 (m, 2H), 3.03 (m, 2H), 2.40 (m, 2H), 2.17 (s, 6H); 13C NMR (CDCl3, 100 MHz) “146.4, 132.3, 131.0, 129.8, 128.1, 123.1, 123.1, 121.6, 119.0, 57.3, 44.9, 40.4.
Starting material: 4-bromo-2-(trifluoromethoxy)benzenesulfonyl chloride and N,N-dimethyl-N′-ethylethylenediamine, yield 98%: 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J 9 Hz, 1H), 7.51 (m, 2H), 3.40 (t, J=7Hz,2H), 3.33 (q, J=7 Hz, 2H), 2.52 (t, J=7 Hz, 2H), 2.24 (s, 0.6H), 1.09 (t, J=7 Hz, 3H); 13cNMR(CDC3, 100 MHz) δ 146.3, 132.8, 132.1, 129.8, 127.9, 123.5, 123.5, 121.6, 119.0, 58.1, 45.5, 44.9, 43.2, 14.2.
Starting material: 4-bromo-2-(trifluoromethoxy)benzenesulfonyl chloride and ethylenediamine, yield 89%: 1H NMR (CD3OD, 400 MHz) δ 7.91 (m,n 1H), 7.71 (m, 2H), −2.98. (t, J=6 Hz, 2H), 2.67 (t, J=6 Hz, 2H); 13C NMR (CD3OD, 100 MHz) δ 147.6, 134.0, 133.3, 131.7, 128.8, 125.5, 123.1, 120.5, 46.6, 42.5.
4-Dimethylaminopyridine (0.025 g, 0.20 mmol) and di-tert-butyl dicarbonate (0.815 g, 3.73 mmol) was added to a stirred solution of N-(2-aminoethyl)-4-bromo-2-(trifluoromethoxy)benzenesulfonamide (0.644 g, 1.77 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at reflux-for 45 min. The solvent was evaporated and the crude product purified by column chromatography on silica using heptane/ethyl acetate, (3:1), to give 0.94 g (94% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.99 (m, 1H), 7.55 (m, 2H), 4.89 (br s, 1H), 3.94 (m, 2H), 3.44 (m, 2H), 1.43 (s, 9H), 1.31 (s, 9H).
A solution of methyl-(1-methylpyrrolidin-3-yl)amine (0.89 g, 7.8 mmol) in dioxane (5 mL) was added dropwise to a solution of 4bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in dioxane (5 mL) under vigorous stirring and cooling on ice-bath. The mixture was stirred 30 min, and then diluted with ethyl acetate (10 mL). The precipitated material was filtered off, washed with ethyl acetate (10 mL) and dried in vacuo. The solid was dissolved in water, alkalyzed with sodium hydroxide (2 M, aq) and extracted with ethyl acetate three times. The ethyl acetate phases were dried (Na2SO4) and evaporated in vacuo to afford 2.5 g (96% yield) of a clear oil: MS (ES) rr/z 333 and 335 (M++1).
The following Examples, 24-38, were synthesized as described for Example 23:
Starting material: 2-(dimethylamino)-1-methylethylamine: MS (ES) m/z 321 and 323 (M++1).
Starting material: 3-pyrrolidin-1-ylpropylamine: MS (ES) m/z 347 and 349 (M++1).
A solution of 1-N-acetylpiperazine (1 g, 7.8 mmol) and triethylamine (1 mL, 7.8 mmol) in dioxane (5 mL) was added dropwise to a solution of 4-bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in dioxane (5 XhL) under vigorous stirring and cooling with ice. The mixture was stirred 48 h. The filtrate was concentrated under reduced pressure to give 1.98 g (73% yield) of the title compound as an oil: MS (ES) m/z 347 and 349 (M++1).
Starting material: methyl-(1-methylpiperidin-4-yl)amine: MS (ES) m/z 347 and 349 (M++1).
Starting material: N,N,N′-trimethylpropane-1,3-diamine: MS (ES) m/z 335 and,337 (M++1).
Starting material: N′-ethyl-N,N-dimethylethane-1,2-diamine: MS (ES) m/z 335 and 337 (M++1).
Starting material: 3-(4-methylpiperazin-1-yl)propylamine: MS (ES) m/z 376 and 378
Starting material: 1-ethylpiperazine (diethyl ether was used instead of ethyl acetate): MS (ES) m/z 333 and 335 (M++I).
Starting material: 2-(pyrrolidin-1-yl)ethylamine: MS (ES) m/z 333 and 335 (M++1).
Starting material: 1-methyl-1,4-diazepane: MS (ES) rr/z 333 and 335 (M++1).
Starting material: 2-dimethylaminopropaneamine: MS (ES) m/z 321 and 323 (M++1).
Starting material: (1-ethylpyrrolidin-2-yl)methylamine: MS (ES) m/z 347 and 349 (M++1).
Starting material: N,N-diethylethane-1,2-diamine: MS (ES) m/z 335 and 337 (M++1).
Starting material: 2-pyridin-2-ylethylamine. The crude product was purified on a silica gel column using methanol/methylene chloride, (1:10), as the eluent: MS (ES) In/z 341 and 343 (M++1).
Starting material: N,N-methylpropane-1,3-diamine: MS (ES) m/z 321 and 323 (M++1).
A solution of dimethylpyrrolidin-3-ylamine (0.89 g, 7.8 mmol) in dioxane (5 mL) was added dropwise to a solution of 4-bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in dioxane (5 mL) under vigorous stirring and cooling on ice-bath. The mixture was stirred 30 min, and then diluted with diethyl ether (10 mL). The mixture was filtered and evaporation of the filtrate gave 2.6 g of a brown oil: MS (ES) m/z 333 and 335 (M++1).
The following Examples, 40-42, were synthesized as described for Example 39:
Starting material: morpholine. The title compound crystallized from the filtrate as long 0.25 needles: MS (ES) m/z 306 and 308 (M++1).
Starting material: isopropyl-(2-methoxyethyl)amine: MS (ES) m/z 336 and 338 (M++1).
Starting material: 2-methoxy-1-methylethylamine. The crude product was purified on a silica gel column using hexane/ethyl acetate, (4:1): MS (ES) m/z 308 and 310 (M++I).
A mixture of p-bromobensoic acid (1 g, 4.97 mmol) in thionyl chloride (10 mL) was refluxed for 10 inin and then cooled to room temperature and the thionyl chloride was evaporated in vacuo. The residue was dissolved in methylene chloride (10 mL) and the solution was cooled to 0° C. 2-Dimethylaminoethylamine (0.52 mL, 4.73 mmol) was added dropwise and the mixture was stirred at room temperature for 24 h. The mixture was acidified with 1 M HCl and washed with methylene chloride. The water phase was alkalized with 1 M NaOH (aq) and extracted with methylene chloride. The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo affording 1.07 g (84% yield) of the title compound as a white solid: mp 67-69° C.; 1H NMR (DMSOd6, 400 MHz) 8.06 (d, J=8 Hz, 2H), 7.98 (d, J=8 Hz, 2H), 3.67 (t, 2H), 2.80 (s, 6H), 2.49 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 165.2, 133.6, 131.3, 129.3, 124.9, 58.0, 45.2, 37.3; MS (EI) 7z/z 273 (M++1).
The title compound was prepared as described for Example 43 using N1,N1,N2-trinethylethane-1,2-diamine. Purification on a silica gel column using chloroformimethanol, (95:5), as the eluent gave 0.98 g (72% yield) of the, title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.48 (d, J=8 Hz, 2H), 7.23 (d, J=9 Hz, 2 25s H), 3.59 (br s, 1H), 3.27 (br's, 1H), 3.03 (s, 1H), 2.94 (s, 2H), 2.52 (br s, 1H), 2.35 (br S, 1H), 2.26 (s, 3H), 2.04 (s, 3H); 130 NMR (CDCl3, 100 MHz) δ 170.1, 135.3, 131.4, 128.6, 123.5, 57.2, 56.4, 49.3, 45.6; MS (EI) m/z 285 (M++1).
To solution of 4-(acetylamino)-3-fluorobenzenesulfonylfluoride (0.566 g, 2.4 mmol) in dry tetrahydrofuran (5 mL) was added N-meth piperazine (0.25 mL, 2.3 mmol) and triethylamine (0.52 mL, 3.6 mmol) at room temperature. The mixture was stirred at room temperature for 5 days and then heated to 60° C. for 2 days. The mixture was cooled to room temperature and a precipitation was formed. The precipitation was filtered and washed with cold methylene chloride and dried in vacuo to give 0.724 g (95% yield) of the title compound as a white solid: 1H NMR (CD3CN, 400 MHz) δ 8.45 (m, 2H), 7.48 (m, 2H), 2.96 (t, J=5 Hz, 4H), 2.38 (t, J=5 Hz, 2H), 2.17 (s, 3H), 2.16 (s, 3H); 13C NMR (CD3CN, 100 MHz) δ 170.5, 153.9, 151.4, 132.4, 131.4, 131.4, 125.4, 122.5, 118.3, 15.8, 115.5,54.8, 47.0, 45.9, 24.6; MS (ESP) m/z 316 (M++1).
A suspension of 2-aminotoluene-5-sulfonic acid (10.1 g, 54 mmol) in thionyl chloride (80 mL) and N3N-dimethylformanride (0.5 mL) was refluxed for, 28 h to give a dark solution. The solvent was evaporated and the resulting residue was suspended in tetrahydrofuran/methylene chloride (100:50 mL). 1-Methylpiperazine (25 mL, 225 mmol) was added carefully, and the resulting mixture was stirred at room temperature for 45 min. The solvent was evaporated and the crude product was purified by column chromatography using methylene chloride/methanol, (9:1), as the eluent to give 6.34 g (44% yield) of the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 2H), 6.66 (m, 1H), 4.07 (s, 2H), 3.06 (br s, 4H), 2.58 (br s, 4H), 2.33 (s, 3H), 2.15 (s, 31); 13C NMR (CDCl3, 100 MHz) δ 149.6, 130.6, 128.1, 123.3, 122.0, 114.2, 54.3, 45.9, 45.8, 17.7.
A solution of sodium nitrite (0.385 g, 5.58 mmol) in water (2 mL) was added dropwise to a stirred solution of 2-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]aniline (1.2 g, 4.45 mmol) in HBr (aq. conc. 17 mL) andwater (10 mL) at 5° C. The resulting mixture was stirred at 5° C. for 30 min and a solution of CuBr (0.332 g, 2.31 mmol) in HBr (aq. conc. 12 mL) was added. The resulting mixture was stirred at 5° C. for 20 min, and at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and ice was added carefully to give an orange precipitate. The crystals were collected, washed with water and purified by column chromatography on silica using methylene chloride methanol, (9:1), as the eluent to give 0.62 g (42. % yield) of the title compound as white crystals; 1H NMR (CDCl3, 400 MHz) δ 7.68 (d, J=8 Hz, 1H), 7.58 (d, J=2 Hz, 1H), 7.40 (dd, J=8, 2 Hz, 1H), 3.10 (br s, 4H), 2.61 (br s, 4H), 2.46 (s, 3H), 2.33 (s, 3H); 13CNMR (CDCl3, 100 MHz) δ 139.8, 134.6, 134.0, 130.8, 129.7, 126.6, 53.8, 45.5, 45.4, 23.3; MS (TSP) 333 and 335 (M++1).
N-[2-Fluoro-4-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide (0.724 g, 2.3 mmol) in HCl (30 mL, 18% in water) was heated at 110° C. for 30 min. The solution was cooled to 0-C and aqueous NaOH (conc. 46%) was added dropwise until the solution reached pH 5 and a precipitate was formed. The mixture was stirred at room temperature for 20 min then the precipitate was filtered and washed with cold water to give 0.484 g (75% yield) of the title compound as a off-white solid: 1H NMR (CD3CN, 400 MHz) δ 7.31 (m, 2H), 6.89 (m, 1H), 4.91 (br s, 2H), 3.01 (br s, 4H), 2.56 (br s, 2H), 2.29(s, 3H); 3CNMR (CD3CN, 100 MHz) δ 150.5, 148, 140.6, 140.5, 125.1, 125.0, 121.9, 121.9, 117.0, 115.1, 115.0, 114.7, 114.5, 53.1, 45.0, 43.9; MS (ESP) m/z 272 and 274 (M++1).
To a solution of 2-fluoro-4-[(4-methyl-1-piperazinyl)sulfonyl]benzenamine (0.430 g, 1.57 mmol) in HBr (5 mL, 46%.in water) was added sodium nitrite (0.13 g, 1.89 mmol), in water (2 mL), dropwise at 0-5° C. After 30 min of stirring at 0-5° C., CuBr (75 mg, 0.52 25-mmol) in HBr (1 mL, 46% in water) was-added dropwise and the resulting mixture was stirred at 70° C. for 1 h. Cold water and ice was added and the solution was alkalyzed with saturated NaCO3 (aq) and a precipitate was formed. The water mixture was partitioned between water and methylene chloride. The water phase was extracted with methylene chloride (3 times), the combined organic phases were dried (MgSO4) and evaporated in, vacuo. The product was purified by column chromatography using methylene chloride/methanol, (95:5), as the eluent to give 0.256 g (48% yield) of the title compound as a beige colored solid: 1H NMR (CD3CN, 400 MHz) δ 7.86 (m, 1H), 7.57 (m, 1H), 7.47 (m, 1H), 2.99 (t, J=5 Hz, 4H) 2.38 (t, J.=5 Hz, 4H), 2.18 (s, 3H); 13C NMR (CD3CN, 100 MHz) 159.8, 157.3, 136.9, 136.9, 134.4, 124.4, 124.4, 117.0, 115.6, 115.4, 114.1, 113.9, 53.4, 45.7, 44.5; MS (ESP) m/z 339 (M++1).
Chlorosulfonic acid (6.5 mL, 96 mmol) was added to 2-(trifluoromethyl)aniline (5.0 mL, 40 mmol) under stirring to give a solid that was slowly dissolved upon heating. The mixture was heated at 60° C. for 2 h, allowed to cool to room temperature and was poured over ice to give a white solid. The solid was filtered off, dissolved in tetrahydrofuran (30 mL) and 1-methylpiperazine (4.5 mL, 41 mmol) was added. The resulting mixture was stirred at room temperature for 20 min, and the solvent was evaporated to give the crude product. Purification by column chromatography on silica using methylene chloride/methanol, (9:1), as the eluent gave 0.414 g (3% yield) of the title compound as white crystals: 1H NMR (CDCl3, 400 MHz5) δ 7.79 (m, 1H), 7.62 (m, 1H), 6.78 (d, J=9 Hz, I H), 4.68 (br s, 2H), 3.04 (r s, 4H), 2.52 (br s, 4H), 2.30 (s, 3H).
The title compound was prepared as described for Example 47 using 4-[(4-methylpiperazin--yl)sulfonyl]-2-(trifluoromethyl)aniline: yield 32%; 1H NMR (CDCl3, 400 MHz) δ 8.02 (d, J=2 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.74 (dd, J=8, 2 Hz, 1H), 3.13 (br s, 4H), 2.57 (br s, 4H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 136.1, 135.6, 131.6, 126.9, 123.4, 120.7, 53.7,45.2,45.1; MS (ES) 387 and 389 (M++1).
2-Bromo-4-fluoro-1-methylbenzene (1.5 g, 7.9 mmol) was cooled to 0° C. and chlorosulfonic acid (1.85 g, 15.9 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature after 10 min and stirring was continued for 30 min. The reaction mixture was then warmed to 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature and slowly added to an ice/water mixture. The precipitate was dissolved in a methylene chloride/tetrahydrofuran mixture, (10:1, 60 mL), and washed with a saturated sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate. Filtration and removal of the solvent in vacuo yielded 1.3 g of the crude sulfonchloride that was dissolved in tetrahydrofuran (20 mL) and cooled to 0° C. N-Methylpiperazine (2 mL) was added and stirring was continued for 30 min at room temperature. A saturate aqueous sodium hydrogencarbonate solution (20 n L) was added and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate. Filtration and removal of the solvent in vacuo gave a residue which was purified-by chromatography on silica gel using a gradient ethyl acetate to ethyl “acetate/methanol, (1:1), as the eluent to give 1.09 g (39% yield) of the title compound: 1H NMR (DMSOd6, 400 MHz) δ 7.86 (d, J=10 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 3.04 (m, 4H), 2.38 (s, 3H), 2.34 (m, 4H), 2.14 (s, 3H); MS (ES) m/z 352 (M++1).
The title compound was prepared as described for Example 52 using 2-bromo-1,4-dimethylbenzene, yield 32%: 1H NMR (DMSO-d6, 400 MHz) δ 7.71 (s, 2H), 3.02 (m, 4 H), 2.48 (s, 3H), 2.37 (s, 3H), 2.32 (m, 4H), 2.14 (s, 3H).
Piperidine (3.0 g, 35.2 mmol) was added to a solution of 4-bromo-benzenesulfonyl chloride 4.5 g, 17.6 mmol) in methylene chloride (10 mL) at 0° C. The mixture was stirred for 2 h, NaOH (aq) (1 M, 5 mL) was added and stirring was continued for 10 min. The organic phase was separated and diluted with methylene chloride (40 mL), washed with HCl (aq) (1 M, 10 mL) and water. The organic phase was dried (sodium sulfate) and the solvent was evaporated to give 5.1 g (96% yield) of the title compound as a white solid: 13C NMR. (solvent, 100 MHz) δ 35.33, 132.16, 129.05, 127.48, 46.82, 25.04, 23.34; MS (E-S) m/z 304 and 306 (M++1). The following Examples, 55-57, were synthesized as described for Example 54: Example 55 1-[(4-Bromophenyl)sulfonyl]pyrrolidine
Starting materials: pyrrolidine and 4-bromobenzenesulfonyl chloride. Yield 98% as a white solid: 13C NMR (solvent, 100 MHz) δ 135.93, 132.17, 128.84, 127.39,47.84,25.13; MS (ES) m/z 290 and 292 (M++1).
1-[(4-Bromo-2,5-difluorophenyl)sulfonyl]piperidine
Starting materials: piperidine and 4-bromo-2,5-difluorobenzenesulfonyl. Yield 96% as a white solid: MS (ES) m/z 340 and 342 (M++1).
Starting materials: pyrrolidine and 4-bromo-2,5-difluorobenzenesulfonyl chloride, yield 97%: MS (ES).m/z 326 and 328 (M++1).
4-Dimethylaminopyridine (16 mg, 0.13 mmol) and di-tert-butyl dicarbonate (0.317 g, 1.45 mmol) was added to a stirred solution of 1-[(4-bromophenyl)sulfonyl]piperazine (0.40 g, 1.31 mmol) in tetrahydrofuran (12 mL) and the resulting mixture was stirred at room temperature for 30 min. The solvent was evaporated and the crude product purified by chromatography on silica gel using heptanelethyl acetate, (2:1), as the eluent to give 0.506 g (95% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.70 (m, 2H), 7.61 (m, 2H), 3.52 (t, J=5 Hz, 4H), 2.98 (t, J=5 Hz, 4H), 1.42 (s, 9H); 13CNMR (CDCl3, 100 MHz) δ 154.3, 134.7, 132.7, 129.4, 128.4, 80.7, 46.0, 28.5.
4-Bromobenzoic acid (3.0 g, 14.9 mmol) was dissolved in refluxing thionyl chloride (35 mL) and the solution was heated under reflux for 1 h and then cooled to room temperature. The solvent was evaporated, co-evaporated with toluene (3×40 mL), and the resulting solid was dried in vacuo. The solid was dissolved in methylene chloride (118 mL), cooled on ice-bath, and 1-methylpiperazine (1.5 mL, 13.6 mmol) was added dropwise to give a solid. Methylene chloride/K2CO3 (saturated, aq.) was added and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated to give 3.86 g (91% yield) of the title compound: 1H NMR (DMSQ-d6, 300 MHz) δ 7.64 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 3.59 (m, 4H), 2.34 (m, 4 H), 2.21 (s, 3H); MS (ES) 283 and 285 (M++1).
A mixture of p-bromophenol (0.5 g, 2.89 mmol), 1-methyl-3-pyrrolidionol(0.38 ml, 3.47 mmol) and triphenylphosphine (0.91 g, 3.47 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) and cooled to 0° C. Diethyl azodicarboxylate (0.55 ml, 3.47 mmol) was added dropwise and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the residue partioned between water and ethyl acetate. The organic phase was washed twice with water, dried (MgSO4) and the solvent was evaporated. The product was purified by column chromatography on silica using methylene chloride/methanol, (98:2), as the eluent to give the title compound as a clear oil which crystallized on standing, yield 77%: 1H NMR (IMSO-d6, 400 MHz) δ 7.36 (d, J=9 Hz, 2H), 6.80 (d, J=9 Hz, 2H), 4.83 (m, 1H), 2.73 (m, 1H), 2,64 (m, 1H), 2.59 (m, 1H), 2.34 (m, 2H), 2.25 (s, 3H), 1.73 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 165.6, 132.1, 117.3, 111.7, 76.9, 61.6, 54.5, 41.6, 32.2; MS (ESP) nmz 258 (M++1).
Diethyl azodicarboxylate (1.72 mL, 10.9 mmol) was added dropwise to a cooled (0° C.) solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2.10 g, 9.1 mmol; described in: Xue, C. B. Bioorg. Med. Chem. 1997, 5, 693.), 4-bromopbenol (1.58 g, 9.1 mmo]), and triphenylphosphine (3.10 g, 11.9 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at room-temperature for 23 h and the solvent was evaporated. Purification by chromatography on silica using methylene chloride/methanol/triethylamine, (95:5:0.1), as the eluent gave 0.50 g (14% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 7.43 (m, 2H), 6.92 (m, 2H), 4.06 (t, J=6 Hz, 2H), 3.30 (t, J=5 Hz, 4H), 2.69 (t, J=6 Hz, 2H), 2.42 (t, J=5 Hz, 4H), 1.39 (s, 9H).
The following Examples, 62-65, were synthesized as described for Example 61:
Starting material: 4-bromo-2,5-difluorophenol, yield 62%: 1H NMR (DMSO-d6, 300 MHz) δ 7.67 (dd, J=11, 7 Hz, 1H), 7.38 (dd, J=10, 8 Hz, 1H), 4.18 (t, J=6 Hz, 2H), 3.30 (m, 4-H), 2.73 (t, J=6 Hz, 2H), 2.43 (m, 4H), 1.39 (s, 9H); MS (ES) 421 and 423 (M++1).
Starting material: 4-bromo-2,5-difluorophenol and 4-(2-hydroxyethyl)morpholine, yield 55%: 1H NMR (DMSO-d6, 300 MHz) S.7.68 (dd, J=11, 7 Hz, 1H), 7.39 (dd, J.=11, 8 Hz, 1H), 4.18 (t, J=6 Hz, 2H), 3.56 (t,J=5 Hz, 2H), 2.70 (t, J=6 Hz, 2H), 2.46 (t, J=5 Hz, 4H), 1.18 (m, 2H).
Starting material: 2-(4-methylpiperazin-1-yl)ethanol (described in: Ide, W. S. et al, J. Am. Chem. Soc. 1954, 76, 1122) and 4-bromo-3,5-dimethylphenol, yield 64%: 1H NMR (DMSO-d6, 300 MHz) δ 6.80 (s. 2H), 4.02 (t, J=6 Hz, 2H), 2.65 (t, J=6 Hz, 2H), 2.46 (m, 4H), 2.31 (m, 10H), 2.14 (m,+3H).
Starting material: 2-(4-methylpiperazin-1-yl)ethanol (described in: Ide, W. S. et al, J. Am. Chem. Soc. 1954, 76,1122) and 4-bromo-3-methylphenol, yield 83%: 1H NMR (DMSO-d6, 300 MHz)37.42(d, J=9 Hz, 1H), 6.97 (d, J=3 Hz, 1H), 6.72 (dd, =9,3 Hz, 1H), 4.03 (t, J=6 Hz, 2H), 2.65 (t, J=6 Hz, 2H), 2.46 (m, 4H), 2.29 (m, 7H), 2.14 (s, 3H); MS (ES) 313 and 315 (M++1).
A solution of 4-bromo-2,5-difluorophenol (0.36 g, 1.7 mmol), 1-(2-chloroetbyl)pyrrolidine hydrochloride (0.38 g, 2.2 mmol), and potassium carbonate (0.86 g, 6.2 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 16 h. The solution was cooled to room temperature, water was added and the aqueous-phase was extracted with methylene chloride. The combined organic phases were evaporated, co-evaporated with toluene (4×30 mL), and the resulting solid was dried under vacuum to give 0.51 g (97% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 7.68 (dd, J=11, 7 Hz, 1H), 7.37 (dd, J=10, 8 Hz, 1H), 4.15 (t, J=6 Hz, 2H), 2.79 (t, J=6-Hz, 2H), 2.50 (m, 4H), 1.67 (m, 4H).
5-Bromothiophene-2-sulfonyl chloride (1 g, 3.8 mmol) was dissolved in tetrahydrofuran (20 mL) and the solution was cooled to 0° C. Dimethylamine (8 mL, 2 M in ethanol, 16 mmol) was added and stirring was continued for 20 min. The reaction mixture was allowed to warm to room temperature and water (20 mL) and ethyl acetate (40 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate. Filtration and removal of the solvent in vacuo gave a residue which was purified by column chromatography on silica using a gradient heptane/ethyl acetate (100:0->0: 100)-to give 1 g (97% yield) of the title compound as a solid: 1H NMR (CDCl3, 400 MHz) δ 7.31 (d, J=4 Hz, 1H), 7.15 (d, J=4 Hz, 1H), 2.77 (s, 6H); MS (ES) m/z 270 and 272 (M++1).
1-(2-Furoyl)piperazine (2 g, 1.1 mmol) and sodium acetate (1.8 g, 22 mmol) were dissolved in acetic acid (40 mL, 0.7 mmol). Bromine was added dropwise and the solution was stirred for 12 h. The solution was poured on ice (300 mL) and the aqueous solution was neutralized with solid sodium carbonate. The aqueous solution was extracted with chloroform and the combined organic layers were dried over magnesium sulfate. Filtration and removal of solvent in vacuo-gave a residue, which was dissolved in tetrahydrofuran (10 mL). Di-tert-butyldicarbonate (2.6 g, 12 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using a gradient ethyl acetate/heptane (1:100->0:100) as the eluent to give 263 mg (7% yield) of the title compound as a white solid: 1H NMR (DMSO-d6, 400 MIz) δ 6.82 (m, 1H), 6.24 (m, 1H), 3.61 (m, 4H), 3.34 (m, 4H), 1.31 (s, 9H); MS (ES) m/z 359 and 361 (M++1).
The following Examples 69-71 were synthesized as described for Example 7:
Starting material: 1-[(4-bromo-2-ethylphenyl)sulfonyl)4-methylpiperazine, yield 55%: 1HNMR (CD3OD, 400 MHz) δ 7.78 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J=8 Hz, 1H), 3.22 (m, 4H), 3.01 (q, J=8 Hz, 2H), 2.66 (m, 4H), 2.40 (s, 3H), 1.27 (t, J=8 Hz, 3H); 13C NMP (CD3OD, 100 MHz) δ 144.3, 138.1, 136.1, 132.3, 130.1, 55.2, 45.8, 45.6, 27.6, 16.9.
Starting material:1-{[4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl}-4-methylpiperazine, yield 61%: 1HNMR (CD3OD, 400 MHz) δ 7.73 (d, J=8 Hz, 1H), 7.62 (m, 2H), 3.19 (m, 4H), 2.47 (m, 4. H), 2.26 (s, 3H); 3C NMR (CD3OD, 100 MHz) δ 146.6, 132.7,130.7; 126.7, 126.3, 125.8, 123.3, 120.7, 55.4, 46.7, 46.0; MS (TSP) n-z 369 (M++1).
Starting material: tert-butyl 4-[(4-bromophenyl)sulfonyl]piperazine-1-carboxylate, yield 94%: 1H NMR (CD3OD, 400 MHz) δ 7.93 (m, 2H), 7.14 (m, 2H), 3.49 (br s, 4H), 2.95 (br s, 4H), 1.40 (s, 9H); 13CNMR (CD3OD, 400 MHz) δ 156.1, 135.6, 81.9, 47.3, 28.6.
n-Butyllitium (13 mL, 22.1 mmol) was added dropwise over 30 min to a cooled (−78° C.) solution of 1-[(4-bromo-2,5-difluorophenyl)sulfonylpiperidine (2.5 g, 7.35 mmol) and triisopropyl borate (4.5 g, 22.1 μmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen atmosphere. The reaction mixture was stirred for 12 h while the temperature was allowed to reach room temperature. HCl (aq) (5 mL, 2 M) was added and stirring was continued for 30 min. Additional methylene chloride (100 mL) was added and the organic phase was washed with HCl (aq) (20 mL, 2 M). The organic phase was dried (sodium sulfate) and evaporated. The remaining residue was purified by reversed phase chromatography (C-18) using a gradient water/acetonitrile to give 1.2 g (53% yield) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 7.41 (dd, J=10, 5 Hz, 1H), 7.37 (dd, J 4, 4 Hz, 1H), 3.12 (m, 4H), 1.58 (m, 4H), 1,47 (m, 2H); MS (ES) m/z 306 (M++1)
The following Examples, 73-76, were synthesized as described for Example 72:
Starting material: 1-[(4bromo-2,5-difluorophenyl)sulfonyl]pyrrolidine. Yield 48% 1H NMR (CD3OD/CDCl3, (1:1), 400 MHz) δ 6.68 (d, J=8 Hz, 1H), 6.23 (dd, J=2, 2 Hz, I H), 2.50 (m, 4H), 1.31 (m, 4H); MS (ES) m/z 292 (M++1).
Starting material: 1-[(4-bromophenyl)sulfonyl]pyrrolidine. Purification on a silica gel column using a gradient of methylene chloride to methylene chloride/ethanol, (1:1), gave the title compound as a white solid, yield 70%: 13C NMR (CDCl3/CD3OD (1:1), 100 MHz) δ 136.79, 133.50, 125.4s, 47.19, 24.30; MS (ES) “/z 256 (M++1).
Starting material: 1-[(4-bromophenyl)sulfonyl]piperidine, Yield 78% asia white solid: 3C NMR (CDCl31CD3OD (1:1), 100 MHz) δ 136.35,133.56,125.84, 46.39, 24.87, 24.52, 22.76; MS (ES).m/z 270 (M++1).
Starting material: 4-bromo-N,N-dimethylbenzenesulfonamide. Purification by chromatography on a silica gel column using a gradient methylene chloride to methylene chloride/methanol, (2:1), as the eluent gave the title compound, yield 60%: MS (ES) m/z 230 (M++1).
To a solution of 4-bromo-N-methyl-N-(1-methylpyrroidin-3-yl)benzenesulfonamide (333 mg, 1 mmol) and triisopropyl borate (1146 ul, 5 mmol) in tetrahydrofuran (7 ML) was added n-butyllithitim (2 mL, 2.5 M solution in hexaney slowly at −78° C. The mixture was stirred at −78° C. for 16 h and then heated to room temperature. 2 mL of water was added, and the mixture was stirred for another 30 min. A two-phase system has formed, where the light phase was discarded. 1 g of celite was added to the aqueous phase and the solvent was removed by evaporation. Chromnatography on silica using a gradient of methylen chloride (d00%) to methanol (100%) followed by methanol (100%) to methanol/water, (1:1), afforded 300 mg of the title compound after removal of the solvents: MS (ES) m/z 299, (M++1)
The following Examples 78-80 were synthesized as described for Example 77:
Starting material: 1-acetyl-4-[(4-bromophenyl)sulfonyl]piperazine: MS (ES) m/z 313 (M++1).
Starting mlaterial: 4-bromo-N-[2-(dimethylamino)ethyl]-N-ethylbenzenesulfonamide: MS (ES) m/z 301 (M++1).
Starting material: 1-[(4-bromophenyl)sulfonyl]-NN-dimethylpyrrolidin-3-amine: MS (ES) m/z 299 (M++1).
To a solution of 4-bromo-N-[2-(dimetbylamino)-1-methylethyl)benzenesulfonamide (286 mg, 1 mmol) and triisopropyl borate (1146 uL, 5 mmol) in tetrahydrofuran (7 mL) was added n-buthyl lithium (2 mL, 2.5 M solution in hexane) slowly at −78° C. The mixture was stirred at −78° C. for 16 h and then heated to room temperature. Water (2 mL) was added, and the mixture was stirred for another 30 min. A two-phase system has formed, where the light phase was discarded. Celite (1 g) was added to the aqueous phase and the solvent was removed by evaporation. The celite was packed in a reservoir on top of 5 g of C-18 silica, and eluted with 40 mL of water followed by evaporation in vacuo: MS (ES) mnz 287 (M++I).
The following Examples 82-96 were synthesized as described for Example 81:
Starting material: 4-bromo-N-(3-pyrrolidin-1-ylpropyl)benzenesulfonamide: MS (ES) m/z 313 (M++1).
Starting material: 4-bromo-N-methyl-N-(1-methylpiperidin-4-yl)benzenresulfonamide: MS (ES) m/z 313 (M++1).
Starting material: 4-bromo-N-[3-(dimethylamino)propyl]-N-methylbenzenesulfonamide: MS (ES) m/z 301 (M++1).
Starting material: 4-[(4bromophenyl)sulfonyl]morpholine: MS (ES) m/z 342 (M++1).
Starting material: 4-bromo-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide: MS (ES) m/z 342 (M++1).
Starting material: 1-[(4-bromophenyl)sulfonyl]4-ethylpiperazine: MS (ES) m/z 299 (M++1).
Starting material: 4-bromo-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide: MS (ES) m/z 299 (M++1).
Starting material: 1-[(4-bromophenyl)sulfonyl]-4-methyl-1,4-diazepane: MS (ES) m/z 299
Starting material: 4-bromo-N-[2-(dimethylamino)propyl]benzenesulfonamide: MS (ES) m/z 287 (M++1).
Starting material: 4-bromo-N-isopropyl-N-(2-methoxyethyl)benzenesulfonamide: MS (ES) m/z302 (M++1).
Starting material: 4-bromo-N-[(1-ethylpyrrolidin-2-yl)methyl]benzenesulfonamide: MS (ES) m/z 313 (M++1).
Starting material: 4-bromo-N-[2-(diethylamino)ethyl]benzenesulfonamide: MS (ES) m/z 301 (M++1).
Starting material: 4-bromo-N-(2-pyridin-2-ylethyl)benzenesulfonamide: MS (ES) m/z 307
Starting material: 4-bromo-N-(2-methoxy-1-methylethyl)benzenesulfonamide: MS (ES) m/z 274 (M++1).
Starting material: 4-bromo-N-[3-(dimethylamino)propyl]benzenesulfonamide: MS (ES) m/z 287 (M++1).
tert-Butyl 4-formylpyridin-3-y]carbamate (0.10 g, 0.45 mmol) and dimethyl ammonium hydrochloride was mixed in-methylene chloride (2 mL) and stirred for 30 min; Sodium triacetoxyborohydride (0.19 g, 0.90 mmol)+was added and the resulting mixture was stirred for 1 h. The crude product mixture was pre-adsorbed onto silica and purified by chromatography on silica gel using gradient heptane to he ptane/ethyl acetate, (1:1), as the eluent to give 53 mg (47% yield) of the title compound as a oil: MS (ES) m/z 252 (M++1).
Trifluoroacetic acid, 50% in methylene chloride (10 mL), was added to tert-butyl 4-[(dimethylamino)methyl)pyridin-3-ylcarbamate (0.20 g, 0.796 mmol). The reaction mixture was stirred for 2 h. The solvent was evaporated and the crude product was dissolved in water (5 mL) and freeze-dried to give 0.115 g (95% yield) of the title compound as a brown oil: 1H NMR (CDCl3, 400 MHz) δ 7.85 (s, 1H), 7.67 (d, J=5 Hz, 1H), 6.93 (d, J=5 Hz, 1H), 3.33 (s, 2H), 2.12 (s, 6H); MS (ES) m/z 152 (M++I).
tert-Butyl 4-(pyrrolidin-1-ylmethyl)pyridin-3-ylcarbamate (1 g, 3.6 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (3 mL, 39 mmol) was added and stirring was continued for 30 min. The solvent was removed in vacuo and ethyl acetate (5 mL) were added and removed in vacuo. This procedure was repeated 3 times. The residue, was dissolved in methanol (50 mL) and DOWEX-OH was added until the m-ethanolic solution was basic. Filtration and removal of the solvent in vacuo gave the title 0.57 g (90% yield) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 7.92 (s, 1H), 7.75 (d, J=5 Hz, 1H), 7.05 (d, J=5 Hz, 1H), 3.61 (s, 2H), 2.49 (m, 4H), 1.79 (m, 4H); MS (ES) m/z 178 (M++1).
The following Examples, 100-101, were synthesized as described for Example 99:
Starting material: tert-butyl 4-(2-pyrrolidin-1-ylethyl)pyridin-3 ylcarbamate, yield 80%: 1H NMR (CD3OD, 400 MHz) δ 7.95 (s, 1H), 7.75 (d, J=5 Hz, 1H), 7.04 (d, J=5 Hz, I—H), 2.75 (m, 4H), 2.66 (m, 4H), 1.86 (m, 4H); MS (FS) n7/z 192 (M++1).
Starting material: tert-butyl 4-(3-pyrrolidin-1-ylpropyl)pyridin-3-ylcarbamate, yield 80%: 1H NMR (CD3OD, 400 MHz)δ 7.91 (s, 1H), 7.72 (d, J=6 Hz, 1H), 7.02 (d, J=5 Hz, 1-H, 2.59-2.49 (m, 8H), 1.87-1.79 (m, 6H); MS (ES) m/z 206 (M++1).
Tert-Butyl 4-formylpyridin-3-ylcarbamate (1.03 g, 4.64 mmol; described in: Venuti, M. C. et al. J. Med. Cliem. 1988, 31, 2136-2145) was dissolved in 11,2-dichloroethane (20 mL) under nitrogen atmosphere. Pyrrolidine (0.41 mL, 4.9 mmol) and acetic acid (0.27 mL) 4.72 mmol) were added and the reaction mixture was stirred for 1 h. Sodium-triacetoxyborobydride (1.27 g, 6 mmol) was added and stirring was continued for 10 h. Sodium hydroxide solution (1 M, 5 ml, 5 mmol) was Added and the layers were separated. The aqueous layer wasp extracted with methylene chloride and the combined organic layers were dried over sodium sulfate. Filtration and removal of the solvent in vacuo yielded a residue. Purification on a silica gel column using a radient methylene chloride/methanol, (100:2) to (100:10), as the eluent gave 900 mg (70% yield) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 9.83 (s, 1H), 9.21 (s, 1H), 8.16 (d, J=5 Hz, 1H), 6.96 (d, J=5 Hz, 1H), 3.66 (s, 2H), 2.49 (m, 4H), 1.81 (m, 4H), 1.52 (s, 9H); MS (ES) m/z 278
tert-Butyl 4-(2-hydroxyethyl)pyridin-3-ylcarbamate (1 g, 4.2 mmol) was dissolved in methylene chloride (40 mL) under inert gas atmosphere and cooled to 0° C. Methanesulfonyl chloride (0.48 mL, 6.3 mmol) and triethylamine (1.8 mL, 12.6 mmol) were added and stirring was continued for 1.5 h. Pyrrolidine (1.76 mL, 21 mmol) was added and the reaction mixture was stirred for 12 h at room temperature. Saturated aqueous sodium chloride solution (5 mL) was added and the organic layer was separated and dried over sodium sulfate. Filtration and removal of the solvent in vacuo yielded a residue, which was purified by chromatography on silica gel using ethyl acetate/heptane, (1:8->1:1), as the eluent to give 730 mg (60% yield) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 9.09 (br s, 1H), 8.18 (d, J=5 Hz, 1H), 6.96 (d, J=5 Hz, 1H), 2.76 (m, 4H), 2.66 (m, 4H), 1.89 (m, 4H), 1.54 (s, 9H); MS (ES) m/z 292 (M++1).
Tert-Butyl pyridin-3-ylcarbamate (2 g, 10.3 mmol, described in Kelly, T. A., McNiel, D. W., Tetrahedron Lett. 1994, 35, 9003-9006) was dissolved under inert gas atmosphere in tetrahydrofuran (60 mL) and the solution was cooled to −78° C. Tert-butyl lithium (14 mL, 1.7 M in pentane) was added dropwise and stirring was continued for 3 h. Ethylene oxide (1 mL, 20 mmol) was added dropwise and the reaction was allowed to warm up to room temperature. Saturated ammonium chloride solution was added (5 mL). The organic layer was separated and dried over magnesium sulfate. Filtrationand.removal of the solvent in vacuo yielded a residue which was purified by column chromatography on silica gel using heptane/ethyl acetate, (10:1->0:100), as the eluent to give 1.7 g (70% yield) of the title compound as a white solid: 1H NMR (CD3OD, 400 MHz) δ 8.66 (s, 1H), 8.22 (d, J=5 Hz, 1H), 7.33 (d, J=5 Hz, 1H), 3.83 (t, J=6 Hz, 2H), 2.89 (t, J=7 Hz, 2H), 1.54 (s 9H); MS (ES) m/z 239 (M++1).
tert-Butyl 4-(3-pyrrolidin-1-ylprop-1-ynyl)pyridin-3-ylcarbamate (1.23 g, 4 mmol) was dissolved in 20 mL methanol. Palladium (10%) on charcoal (40 mg) was added and the reaction mixture was shaken for 12 h under hydrogen pressure (40 psi). The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo to give 1.2 g (97% yield) of title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 10.17 (br s, 1H), 8.91 (br s, 1H), 8.22 (d, J=5 Hz, 1H), 7.03 (d, J=5 Hz, 1H), 2.70 (t, J=6 Hz, 2<H), 2.52 (m, 4H), 2.20 (t, J=6 Hz, 2H), 1.89 (m, 4H), 86 (,2H), 1.53 (s, 9H);MS(ES) m/z 306 (M++1).
tert-Butyl 4-(3-hydroxyprop-1-ynyl)pyridin-3-ylcarbamate (1.1 g, 4.4 mmol) was dissolved under inert-gas atmosphere in methylene chloride (40 mL) and cooled to 0° C. Methanesulfonyl chloride (0.51 mL, 6.6 mmbl) and triethylamine,(1.9 mL, 13.2 mmol) were added and stirring was continued for 1.5 h. Pyrrolidine (1.9 mL, 22 mmol) was added and the reaction mixture was stirred for 12 h at room temnperature. Saturated aqueous sodium chloride solution (5 mL) was added and the organic layer was separated and dried over sodium sulfate. Filtration and removal of the solvent in vacuo yielded a residue, which was purified by chromatography on silica gel using a gradient ethyl acetate/heptane, (1:8), to ethyl acetate/methanol, (1:1), as the eluent to give 1.25 g (94% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) S 9.36 (s, 1H), 8.22 (d, J=5 Hz, 1H), 7.21 (dd, J=5, 1 Hz, 1H), 7.07 (br s, 1H), 3.73 (s, 2H), 2.70 (m, 4H), 1.86 (m, 4H), 1.53 (s, 9H); MS (ES) m/z 302 (M++1).
The title compound was prepared as described for Example 106 using tert-butyl 5-(3-hydroxyprop-1-ynyl)pyridin-3-ylcarbamate, yield 82%: 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.31 (s, 1H), 6.71 (s, 1H), 2.88 (m, 4H), 1.92 (m, 4H), 1.51 (s, 9H); MS (ES) m/z 302 (M++1).
tert-Butyl 4-iodopyridin-3-ylcarbamate (0.32 g, 1.0 mmol; described in: Crous, R. et al, Heterocycles, 1999, 51, 721-726), Pd(PPh3)4 (58 mg, 0.05 mmol), copper(1) iodide (19 mg, 0.1 Imnol), potassium carbonate (0.45 g, 3.0 mmol), 1-dimethylamino-2-propyne (0.323 ML, 3.0 mmol) were mixed with anhydrous tetrahydrofuran (3 mL) in a sealed reaction tube. All air was evacuated and tube was flushed with nitrogen for 5 min. The reaction mixture was heated to 55° C. over night. The mixture was filtered through Celite. Silica gel was added and the solvent was evaporated. Purification by chromatography on silica gel using a gradient, heptane to heptane/ethyl acetate, (2:1), as the eluent gave 188 mg (73% yield) of the title compound as oil: 1H NMR (CDCl3, 400 MHz) δ 9.49 (s, 1H), 8.38 (d, J=5 Hz), 7.37 (d, J=5 Hz, 1H), 3.77 (s, 2H), 2.55 (s, 6H), 1.67 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 174.48, 151.88, 142.79, 140.17, 135.54, 125.00, 118.78, 81.54, 48.15, 43.64, 28.18, 21.25; MS (ES) ni/z 276 (M++1).
tert-Butyl 4-[3-(dimethylamino)prop-1-ynyl]pyridin-3-ylcarbamate (0.31 g, 1.13 mmol) and palladium (1O %)on charcoal (10 mg) was mixed with methanol (25 mL). The reaction mixture was shaken under hydrogen atrnosphere (2 bar) for 3 h. The product mixture was filtered through Celite and the solvent was evaporated. The remaining oil was dissolved in trifluoroacetic acid (50% in methylen chloride, 10 mL) and stirred for 2 h. Evaporation of the solvent followed by purification by reversed phase chromatography (C-18), gradient water/acetonitrile and freeze-drying gave 0.202 g (99% yield) of the title compound: MS (ES) z 180 (M++1).
The title compound was prepared as described for Example 109 using tert-butyl 5-(3-pyrrolidin-1-ylprop-1-ynyl)pyridin-3-ylcarbamate. The solvent was evaporated and the crude residue was dissolved in methanol and basic ion exchange resin (Dowex OI) was added until the solution was basic. Filtering and evaporation of the solvent gave the title compound as a brown syrup, yield 99%: MS (ES) nVz 206 (MG+4).
tert-Butyl 4-iodopyridin-3-ylcarbamate (2.07 g, 6.5 mmol; described in: Crous, R. et al, Heterocycles, 1999, 51, 721-726), prop-2-yn-1-ol (0.45 mL, 7.7 mmol), copper(I) iodide (120 mg, 0.63 mmol), triethylamine (3 mL, 21.4 mmol) and Pd(PPh3)4 (80Mg, 0.07 mmol) were dissolved under inert gas atmosphere in tetrahydrofuran (40 mL). The reaction mixture was stirred for 12 h at 50° C. Water (10 mL) and saturated aqueous sodium chloride solution (40 mL) were added. The organic layer was separated and dried over magnesium sulfate. Filtration and removal of solvent in vacuo yielded a residue which was purified by chromatography on silica gel using a gradient heptanelethyl acetate, (1:10), to ethyl acetate/methanol, (1:1), as the eluent to give 1.3 g (81% yield) of the title compound as a solid: 1H NMR (CDCl3, 400 MH) δ 9.39 (s, 1H), 8.21 (d, J=5 Hz, 1H), 7.22 (d, J=5 Hz, 1H), 7.05 (s, 1H), 4.59 (s, 2H), 1.53 (s, 9H).
tert-Butyl 5-bromopyridin-3-ylcarbamate (4.0 g-14.3 mmol), propargylalcohol (1.6 g, 29 mmol), potassium carbonate (4.05 g, 29 mmol), copper(I)iodide (0.279 g, 1.423 mmol) and Pd(PPh3)4 (0.85 g 0.73 mmol) were mixed in tetrahydrofuran (25 mL) and heated to 65° C. over night. Evaporation of the solvent and absorption on silica gel followed by chromatography on a silica gel column using heptane to heptane/ethyl acetate, (1:1), gradient gave 1.0 g (28% yield) of the title compound, 1H NMR (CD3OD, 400 MHz) δ 8.41 (d, J=2 Hz, 1H) 8.08 (s, 1H), 7.91 (s, 1H), 4.32 (s, 2H), 1.42 (s, 9H)I; 3C (CD3OD, 100 MHz) 8154.71, 145.81, 139.69, 137.95, 128,94, 121.67, 92.66,81.74, 81.61, 51.06, 28.55; MS (ES) m/z 249 (M++1)
tert-Butyl 5-[3-(dimethylamino)prop-1-ynyl]pyridin-3-ylcarbamate The title compound was prepared as described for Example 112 using tert-butyl 5-bromopyridin-3-ylcarbamate and 1-dimethylamino-2-propyne, yield 91% as brown solid: 13C NMR (CDCl3, 100 MHz) δ 152.52, 146.37, 138.87, 134.90, 127.98, 120.15, 87.15, 82.44,47.97,43.61, 28.23. MS (ES) m/z 276 (M++1).
5-Bromonicotinic acid (10 g, 49.5 mmol), diphenylphosphorylazide (11.2 mL, 52 mmol) and triethylaminue (7.25 mL, 52 mmol) were mixed in'tert-butylalcohol (50 mL). The reaction mixture was stirred for 12 h at 60° C. and the solvent was evaporated in vacuo. The remaining crude product was diluted with methylene chloride (500 mL) and washed with HCl (aq) (100 mL, 0.2 M), water (100 mL), sat NaHCO3 (aq) (100 mL) and water (100 IrSL). The organic phase was evaporated and purification by chromatography on a silica gel column using a gradient heptane to heptane/ethyl acetate, (2:1), gave 11 g (81% yield)of the title compound: 13C NMR (CDCl3, 100 MHz) δ 152.97, 144.33, 137.67, 137.36, 128.78, 121.40, 82.18, 28.67; MS (ES) m/z 273 and 275 (M++1).
tert-Butyl 5-[3-(dimethylamino)prop-1-ynyl]pyridin-3-ylcarbamate (0.310 g, 1.126 mmol) and palladium (10%) on charcoal (10 mg) were mixed with methanol (25 mL) in a reaction bottle. Vacuum nitrogen cycle 3 times was performed to remove the air. The reaction mixture was shaken under hydrogen atmosphere (2 bar) for 1.5 h. The product mixture was filtered through celite and the solvent was evaporated. Chromatography on silica gel using methylene chloride to methylene chloride/ethanol, (2:1), as the eluent gave 1.8 g (89% yield) of the title compound: MS (ES) m/z 280 (M++I).
Trifluoroacetic acid, 50% in methylene chloride (10 mL), was added to a solution of tert-butyl 5-[3-(dimethylamino)propyl]pyridin-3-ylcarbamate (1.0 g, 3.58 mmol) and stirred for 2 h. Evaporation of the solvent followed by addition of methanol and treatment with DOWEX (8) OH gave after filtration and evaporation 0.60 g (94% yield) the title compound: 1H NMR (CD3OD 400 MHz) δ 7.63 (m, 2H), 7.71 (m, 1H), 7.32 (m, 1H), 3.04(m11,2H) 2.91 (m, 2H), 2.63 (m, 6H), 2.50 (t, J=8 Hz, 2H); 3CNMR (CD3OD, 100 MHz) δ 149.88, 142.37, 129.41, 128.74, 125.12, 57.93, 43.43, 30.14, 26.21; MS (ES) m/z 180 (M++1).
Triethylaluminium (8.7 mL, 17.4 mmol) was added dropwise to a solution of methyl-2-amino-5-bromobenzoate (2 g, 8.69 mmol) and 3-arinopyridine (0.82 g, 8.69 mmol) in methylene chloride (20 mL) at roorn temperature (N2-atm). The mixture-was refluxed for 5 days and ice and water was added in portions. The organic solution was washed, twice, with water, dried (MgSO4) and evaporated in vacuo to give 0.143 g (6% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.26 (s, 1H), 8.85 (d, J=2 Hz, 1H), 8.29 (dd, J=4, 1 Hz, 1H), 8.09 (m, 1H), 7.81 (d, J=2 Hz, 1H), 7.35 (m, 2H), 6.74 (d, J=9 Hz, 1H), 6.54 (br s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 166.8, 20-149.2, 144.5, 135.6, 134.9, 130.7, 127.6, 123.4, 118.6, 115.8, 105.0; MS (ES) m/z 292 and 294 (M++1).
2-Amino-5-broinonicotinic acid (60 mg, 0.28 mmol), 4-(pyrrolidin-1-ylmethyl)pyridin-3-amine (60 mg, 0.34 mmol), 2-(1H-benzotriazol 1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (133 mg, 0.41 mmol), 1-hydroxybenzotriazole hydrate (56 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) were suspended in acetonitrile (8 mL) and stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue was separated between methylene chloride arid saturated aqueous sodium hydrogen carbonate solution and the organic layer was dried over sodium sulfate. Filtration and removal of solvent in vacuo gave the crude product which was purified by chromatography on silica gel using a gradient ethyl acetate/heptane, (1:1) to (10:1), as the eluent to give 96 mg (93% yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.69 (s, 1H), 9.26 (s, 1H), 8.28 (d, J5=Hz, 1H), 8.24 (d, J=3 Hz, 1H), 7.95 (d,J 3 Hz, 1H), 7.34 (brs, 2H), 7.32 (d, J=4 Hz, 1H), 3.83 (s, 2H), 2.53 (m, 4H), 1.79 (m, 4H); MS (ES) m/z 376 and 378 (M++1).
3-Amino-6-6-bromopyrazine-2-carboxylic acid (148 mg, 0.68 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 2798-2800), 4-(pyrrolidin-1-ylmethyl)pyridin-3-amine (100 mg, 0.56 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (288 mg, 0.89 mmol), 1-hydroxybenzotriazole hydrate (118 mg, 0.87 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) were suspended in acetonitrile (8 mL) and stirred under inert gas atmosphere at room temperature for 12 h. The solvent was removed in vacuo and the residue was separated between methylene chloride and saturated aqueous sodium hydrogen carbonate solution and the organic layer was dried over sodium sulfate. Filtration and removal of solvent in vacuo gave the crude product, which was purified by chromatography on silica gel using a gradient ethyl acetate/heptane, (1:1) to (4:1), as an eluent to give 210 mg (98% yield).of the title compound as a light brown solid: 1H NMR (DMSO-d6,400 MHz) δ 11.97 (s, 1H), 9.41 (s, 11H), 8.46 (s, 1H), 8.30 (d, J=5 Hz, 1 H), 7.84 (br s, 2H), 7.34 (d, J=5 Hz, 1H), 3.77 (s, 2H), 2.57 (m, 4H), 1.84 (m, 4H).
The following Examples, 120-121, were synthesized as described for Example 119:
Starting material: 4-(2-pyrrolidin-1-ylethyl)pyridin-3-amine. Purification by chromatography on silica gel using a gradient ethyl acetatelmethanol, (10:1), to ethyl acetatelmethanol/triethyl amine, (4:1:0.05), as the eluent gave the title compound as a brown oil, yield 91%: 1H NMR (DMSO-d6, 400 MHz) 610.51 (br s, 1H), 8.68 (s, 1H), 8.43, s (1H), 8.33 (d, J=5 Hz, 1H), 7.72 (br s, 2H), 7.35 (d, J=5 Hz, 1H), 2.77 (m, 2H), 2.67 (m, 2H), 2.49 (m, 4H), 1.63 (m, 4H).
Starting material: 4-[(dimethylamino)methyl]pyridin-3-amine. Purification by chromatography on silica using a gradient ethyl acetate/heptane, (4:1), to ethyl acetate/methanol, (2:1), as an eluent gave the title compound as a yellow solid, yield 70%: 1H NMR (CD3OD, 400 MHz) δ 9.53 (s, 1H), 8.26 (s, 1H), 8.20 (d, J=5 Hz, 1H), 7.26 (d, J=5 Hz, 1H), 3.62 (s, 2H), 2.36 (s, 6H); MS (ES) m/z 351 and 353 (M++1).
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.81 g, 4.2 mmol) and 1-hydroxybenzotriazole (0.57 g, 4.2 mmol) were added to a mixture of 5-(3-dimethylamino-propyl)pyrdin-3-ylamine (0.345 g, 1.93 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (0.546 g, 2.5 mmol, described in Ellingson, R. C., Henry, R. L., J. Am. Chem. Soc. 1949, 71, 2798-2800) in N,N-dimethylformamide (2 mL) at 0° C. The mixture was stirred for 30 min. Precipitation was almost immediate, filtering the precipitate and washing with diisopropyl ether gave 0.402 g (55% yield) of the title compound: 1H NMR (CDCl3/CD3OD (1:1), 400 MHz) δ 8.75 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 3.12 (m, 4H), 2.81 (s, 6H), 2.70 (dd, J=8, 8 Hz, 2H), 2.01 (m, 4H); MS (ES) m/z 379 and 381(M+1).
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.81 g, 4.2 mmol) and 1-hydroxybenzotriazole (0.57 g, 4.2 mmol) were added to a mixture of 5-(3-pyrrolidin-1-yl-propyl)pyridin-3-ylamine (0.3 g, 1.46 mmol), 3-amino-6-bromropyrazine-2-carboxylic acid (0.382 g, 1.76 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chen. Soc. 1949, 2798-2800) in N,N-dimethylformamide (2 mL) at 0 IC. The mixture was stirred for 1 h. The solvent was evaporated and the crude product was purified by chromatography on a silica gel column using a gradient methylene chloride to methylene chloride/methanol, (2:1), to give 0.456 g, (77% yield) of the title compound: 1H NMR (CDCl3/CD3OD (1:1), 400 MHz)68.85 (d, J=2 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J=2 Hz, 1H), 8.20 (dd, J=2, 2 Hz, 1H), 2.91 (m, 4H), 2.84 (m, 2H), 2.80 (m, 2H), 2.04 (m, 2H), 1.98 (m, 4H); 13C NMR (CDCl3/CD3OD (1:1),400 MHz) δ 163.52, 153.98, 149.13, 143.65, 138.60, 136.79, 134.34, 127.35, 124.09, 121.63, 54.49, 53.27, 29.47, 28.01, 22.29; MS (ES) niz 405 and 407 (M++1).
3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (0.40 g, 1.72 mmol), 4-(—N1N-1S dimethylsulfonamide)phenylboronic acid (0.474 g, 2.07 mmol) and Pd(dppf)Cl2 (63 mg, 86.2 μmol) were mixed in toluene/ethanol, (1: 1, 2 mL), and Na2CO3 (2 M (aq), 0.40 mL). Nitrogen gas was bubbled through the reaction mixture for 5 min and the mixture was heated to 80° C. for 16 h. Silica gel was added and the solvent was evaporated. The residue was purified by chromatography on a silica gel column using a gradient, heptane to heptane/ethyl acetate, (2:1), as the eluent to give 0.40 g (69% yield) as a yellow solid: 1H NMR (CD3OD, 400 MHz) 8.64 (s, 1H), 7.86 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 3.73 (s, 3H), 2.45 (s, 6H); MS (ES) m/z337 (M++1).
Methyl 3-amino-6-{4-[(dimethylamino)sulfonyl]phenyl}pyrazine-2-carboxylate (0.25 g, 0.74 mmol) and lithium hydroxide (0.20 g, 8.35 mmol) were mixed in tetrahydrofuran/water, (10:1, 50 mL), and stirred for 2 h. The solvent was evaporated and the residue was dissolved in water and washed with chloroform. The phases were separated and the water-phase was acidified with.HCl (aq) (2 M). Extraction with chloroform/diethyl ether, (20:1), gave after evaporation 0.21 g, (87% yield) the title compound as a yellow solid: MS (ES) m/z 323 (M++1).
tert-Butllitium (13.3 mL, 22.7 mmol) was added dropwise to a cooled (−78° C.) solution of 3-(tert-butoxycarbonylamino)pyridine (2.0 g, 10.3 mmol; described in: Kelly, T. A., McNell, D. W. Tetrahedron Lett. 1994, 35, 9003-9006) in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 3 h. N-Formylpiperidine-(1.4: mL, 12.4 mmol) was added dropwise to the cooled reaction mixture and stirring was continued for 1 h. Water (5 mL) was added and the mixture was stirred for min. The crude reaction-mixture was pre adsorbed onto silica and purified by chromatography on silica gel using a gradient heptane to heptane/ethyl acetate, (2:1), to give 1.83 g (80% yield) of the title compound as a yellowish solid: 1H NMR (CDCl3, 400 MHz) δ 9.92 (s, 1H), 9.81 (s, 1H), 9.74 (s, 1H), 8.44 (d, J=5 Hz, 1H), 7.45 (d, J.=6 Hz, 1H), 1.48 (s, 9H); 13C NMR (CDCl3, 100 MHz) 142.87, 141.87, 135.29, 125.93, 124.45, 81.64, 28.03; MS (ES) m/z 195 (M++1).
Methyl 3-amino-6-[4-(pyrrolidin-1-ylsulfonyl)phenyl]pyrazine-2-carboxylate (1.0 g, 2.76 mmol) and lithium hydroxide (1.0 g 24 mmol) were mixed in tetrahydrofuran/water, (9:1, mL) and stirred at room temperature over night for 18 h. The reaction mixture was evaporated and the crude product was purified by reversed phase chromatography (C-18) using water/acetonitrile gradient to give 0.85 g (88% yield) of the title compound in: MS (ES) m/z 349 (M++1).
4-(Pyrrolidylsulfonamide)phenylboronic acid (0.33 g, 1.29 mmol), methyl 3-amino-6-bromopyrazine-2-carboxylate (0.25 g, 1.08 mmol), K3PO3 (1.1 mL, 3 M, 3.2 mmol), and Pd(dppf)Cl2 (0.044 g, 54 mmol) were suspended in ethylene glycol dimethyl ether/water (1.5:0.5 mL) and heated in a microwave oven at 160° C. for 10 min. The reaction was repeated 3×. The combined product mixtures were evaporated with silica gel and the crude product was purified by chromatography on silica gel using a heptan/ethylacetate gradient to give 0.96 g (82% yield) of the title compound: MS (ES) m/z 363 (M++1).
End Compounds
3-Amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (0.25 g, 0.85 mmol), 4-(pyrrolidin-1-ylsulfonyl)phenylboronic acid (0.26 g, 1.02 mmol), Pd(dppf)Cl2 (35 mg, 42-0o pmol) and sodium carbonate (2 M, 1.5 mL, 3.0 mmol) were mixed with dimethoxyethane in a schlenk tube and nitrogen gas was flushed through the reaction tube mixture for 5 min. The mixture was heated to reflux for 1 h. Silica gel was added and the solvent was evaporated. The residue was purified by chromatography on a silica gel column, using a gradient heptane to heptane/ethyl acetate, (2:1), as the eluent to give 0.335 g (93% yield) as a yellow solid: MS (ES) m/z 425 (M++1).
The title compound was prepared as described for Example 129 using 4-(piperidin-1-ylsulfonyl)phenylboronic acid, yield 99%: MS (ES) m/z 439 (M++1).
The following Examples, 131-133, were synthesized as described for Example 237
Starting material: 3-ethyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenylboronic acid. The crude product was purified by column chromatography on silica using methylene chloride/methanol, (95:5), as the eluent, yield 62%: 1H NM (CDCl3) δ 9.88 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.45 (s, 1H), 8.30 (m, 1H), 8.01 (m, 1H), 7.88 (s, 1H), 7.82 (m, 1H), 7.38 (m, 1H), 3.33 (br s, 4H), 3.12 (m, 2H), 2.62 (br s, 4H), 2.39 (s, 3H), 1.38 (m, 3H); 13CNMR (CDCl3) δ 164.4, 154.8, 145.9, 145.8, 145.4, 141.7, 140.5, 138.8, 135.0, 134.3, 131.4, 128.3, 127.1, 124.5, 124.0, 123.3, 54.3, 45.7, 45.0, 26.6, 16.1; MS (TSP) m/z 482 (M++1).
Starting material: 4-[(4-methylpiperazin-1-yl)sulfonyl]-3-(trifluoromethoxy)phenylboronic acid. The-crude product was purified by column chromatography on silica using methylen chloride/methanol, (95:5), yield 70%: 1H NMR (CDCl3) δ 9.79 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.45 (m, 1H), 8.27 (d, J=8 Hz, 1H), 8.09 (d, J=8 Hz, 1H), 7.97 (s, 1H), 7.89 (d, J=8 Hz, 1H), 7.38 (dd, J=8,5-Hz, 1H), 3.41 (br s, 4H), 2.64 (br s, 4H), 2.41 (s, 3H); MS (TSP) m/z 538 (M++1).
tert-Butyl 4-[(4-{5-amino-6-[(pyridin-3-ylamino)carbonyl]pyrazin-2-yl}phenyl)sulfonyl]piperazine-1-carboxylate
Starting material: 4-([4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}phenylboronic acid. The crude product was purified by column chromatography on silica using methylen chloride/methanol, (95:5), yield 60%: 1H NMR (CDCl3) δ 9.85 (s, 1H), 8.86 (s, 1H); 8.76 (s, 1H), 8.45 (d, J=S Hz, 1H), 8.30 (d, J=8Hz, 1H), 8.07 (d, J=8 Hz, 2H), 7.89 (d, J=8 Hz, 2H), 7.38 (dd, J=5, 8 Hz, 1H), 3.54 (br s, 4H), 3.04 (br s, 4H), 1.40 (s, 9H); 13CNMR (CDCl3) δ 164.4, 154.9, 154.3, 145.9, 145.8, 141.7, 140.5, 138.5, 135.5, 134.2, 128.8, 127.4, 126.4, 124.6, 124.0, 80.7, 46.1, 28.5; MS (TSP) m/z 540 (M++1)
4-piperidin-1-ylsulfonyl)phenylboronic acid (0.49 g, 0.55 mmol), 3-amino-6-bromo-N-{5-[3-(dimethylamino)propyl pyridin-3-yl}pyrazine-2-carboxamide (0.175 g, 0.46 mmol), Na2CO3 (0.147 g, 1.38 mmol), and Pd(dppf)Cl2 (0.019 g, 23 lmol) were suspended in ethylene glycol dimethyl ether/water, (3:1 mL) and heated in a microwave oven at 160° C. for 10 min. The product mixture-was filtered through celite, diluted with methylene chloride (25 mL), washed with sodium hydroxide (aq, 1 M) and water. The organic phase was dried (Na2SO4) and evaporated to give 0.197 g, (82% yield) of the title compound: MS (ES) m/z 524 (M++1).
The title-compound was prepared as described for Example 134 using 4-(pyrr lidin-1-ylsulfonyl)phenylboronic acid, yield 73%: MS (ES) nz/z 510 (M+1).
3-Amino-6-{4-[(dimethylamino)sulfonyl]phenyl}pyrazine-2-carboxylic acid (71 mg, 0.22 mmol), 4[(dimethylamino)methyl]pyridin-3-amine (40 mg, 0.265 mmol) and bromo-tripyrrolidinophosphoniumhexafluorophosphat (0.154 g, 0.33 mmol) were mixed in N,N-dimethylformamide (2 mL) and stirred for 5 min. N1N-Diisopropylethylamine (90-1 ml, 0.66 mmol) was added and the reaction mixture was stiired for 15 h, The solvent was evaporated and the crude residue was dissolved in HCl (1 M aq, 2 mL) and applied on a reversed phase chromatography column (XTerra C8 19×300 mm) and eluted with a water/acetonitrile gradient. Freeze-drying gave 42 mg (42% yield) of the title compound as a yellow solid: MS (ES) ?ni/z 456 (M++1).
The title compound was prepared as described for Example 136 using 3-amino-6(4-[(dimethylamino)sulfonyl]phenyl)pyrazine-2-carboxylic acid and 4-(3-dimethylaminopropyl)pyridin-3-amine. The title compound was purified on a.reversed phase column (Xerra C8 19×300 mm) and eluted with a water/acetonitrile gradient to give 25 mg (7% yield) as a yellow solid: 1H NMR (CD3OD, 400 MHz) δ 8.79 (s, 1H), 8.78 (d, J=10 Hz), 8.25 (m, 1H), 8.23 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H) 7.33 (d, J=5 Hz, 1H), 2.73 (t, J=8, 8 Hz, 2H), 2.60 (s, 6H), 2.54 (t, J=8 Hz), 2.28 (s, 6H), 1.85 (m, 2H); MS (ES) m/z 484 (M++1).
A mixture of 4-((methyl(1-methylpyrrolidin-3-yl)amino)sulfonyl)phenylboronic acid (298 mg, 1 mmol), 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (294 mg; 1 mmol) and Pd(dppf)Cl2×CH2Cl2 (42 mg, 0.05 mmol) in toluene (10 mL), ethanol (2 mL) and saturated aqueous sodium carbonate solution (2 mL) was stirred at 80° C. for 16 h. The mixture was cooled to room temperature, and precipitated material was filtered off, dissolved in aqueous HCl (1 M, 5 mL), alkalyzed with aqueous NaOH (2 M) and extracted with methylene chloride. The organic phase is washed with water, dried (Na2SO4), evaporated to dryness and chromatographed on silica using methylene chloride/mnethanol, (10:1), as the eluent to give 0.103 mg (22% yield) of the title compound: MS (ES) 448 (M++1).
The following Examples 139-152 were synthesized as described for Example 138:
Starting material: 4-((methyl-(1-methylpiperidin-4-yl)amino)sulfonyl)phenylboronic acid, yield 4%: MS (ES) 482 (M++1).
Starting material: 4-(((dimethylamino)propyl)(methyl)amino)sulfonyl)phenylboronic acid, yield 20%.The compound was dissolved in 1 M HCl(q, evaporated and freeze dried: MS (ES) 470 (M++I).
Starting material: 4-((3-dimethylamino)pyrrolidin-1-yl)sulfonyl)phenylboronic acid, yield 22%: MS (ES) 468 (M++1).
Starting material: 4-(morpholin4-ylsulfonyl)phenylboronic acid. Purification on a silica gel column using methylene chloride/methanol, (100:1), as the eluent gave the title compound, yield 18%: MS (ES) 441 (M++1).
Starting material: 4-(((3-(4-methylpiperazin-1-yl)propyl)amino)sulfonyl)phenylboronic acid, yield 27%. The compound was dissolved in 1 M HCl, evaporated and freeze dried: MS (ES) 511 (M++I).
Starting material: 4((4-ethylpiperazin-1-yl)sulfonyl)phenylboronic acid, yield 62%: MS (ES) 468 (M++1).
Starting material: 4((2-pyrrolidin-1-ylethyl)amino)sulfonyl)phenylboronic acid, yield 30%. The compound was dissolved in 1 M HCl(.q, evaporated and freeze dried: MS (ES) 468 (M++1).
Starting material: 4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenylboronic acid, yield 5%. The compound was dissolved in 1 M HCl(q), evaporated and freeze dried: MS (ES) 468(M++1).
Starting material: 4-(((2-dimethylamino)jpropyl)amino)sulfonyl)phenylboronic acid, yield 26%: MS (ES) 456 (M++1). The base was dissolved in methylene chloride/methanol, (9/1), and HCl in diethyl ether (2 M) was added to acidic pH. The formed precipetate was filtered and dried in vacuo to give the title compound, yield 90% (from the base). 1H NMR (DMSO-d6) δ 11.09, (s, 1H), 9.36 (d, J=2 Hz, 1H), 9.09 (s, 1H), 8.84 (d, J=9 Hz, 1H), 8.66 (m, 1H), 8.51 (d, J=9 Hz, 2H), 8.28 (t, J=6 Hz, 1H), 7.99 (dd, J=9, 6 Hz, 1H), 7.94 (d, J=9 Hz, 2H), 3.37 (m, 1H), 3.19 (m, 1H), 2.97 (m, 1H), 2.72 (d, J=Hz, 3 H), 2.66 (d, J=5 Hz, 3H), 1.22 (d, J=5 Hz, 3H).
Starting material 4-((isopropyl-(2-methoxyethyl)amino)sulfonyl)phenylboronic acid, yield 43%. The compound was dissolved in 1 M HCl (aq), evaporated and freeze dried; MS (ES) 471 (M++1).
Starting material: 4-((((1-ethylpyrrolidin-2-yl)amino)-sulfonyl)phenylboronic acid, yield 8%. The compound was dissolved in 1 M HCl(aq) evaporated and freeze dried: MS (ES) 482 (M++1).
Starting material: 4-(((2-diethylamino)ethyl)amino)sulfonyl)phenylboronic acid, yield 81%. The compound was dissolved in 1 M HCl(,q), evaporated and freeze dried: 1H NMR (D2O, 400 MHz) δ 8.90 (s, 1H), 8.25 (m, 2H), 8.08 (s, 1H), 7.66 (m, 1H), 7.56 (d, 2H), 7.31 (d, 2H), 3.07 (m, 9H), 1.11 (t, 6H); MS (ES) 470 (M++1).
Starting material: 0.4-(((2-pyridin-2-ylethyl) amino)sulfonyl)phenylboronic acid. Purification on a silica gel column using methylene chloride/methanol, (50:1), as the eluent gave the title compound, yield 12%: MS (ES) 476 (M++1).
Starting material: 4-(((2-methoxy-1-methylethyl)amino)sulfonyl)phenylboronic acid. Purification on a silica gel column using methylene chloride/methanol, (50:1), as the eluent gave the title compound, yield 80%. The compound was dissolved in 1 M HCl(aq), evaporated and freeze dried: 1H NMR (D2O, 400 MHz) □ 9.40 (s, 1H), 8.73 (d, 1H), 8.66(s, 1H), 8.45 (d, 1H), 8.12 (d, 2H), 7.95 (dd, 1H), 7.75 (d, 2H), 3.25-3.30 (m, 1H), 3.04-3.14 (m, 2H), 3.06 (s, 3H), 0.84 (d, 3H); MS (ES) 443 (M++1).
To a mixture of 4-(((2-dimethylamino)-1-methylethyl)amino)sulfonyl)phenylboronic acid (286 mg, 1 mmol), 3-amino-6-bromo-N-3-ylpyrazine-2-carboxamide (235 mg, 0.8 mmol) and Pd(dppf)Cl2×CH2Cl2 (42 mg, 0.05 mmol) was added tetrahydrofuran (3 mL) and a saturated aqueous sodium carbonate solution (1 mL) in a microwave vial. The mixture was subjected to microwave irradiation for 15 min at 160° C. The mixture was cooled to room temperature, and precipitated material was filtered off, dissolved in 1 M aqueous HCl (5mL), alkalyzed with aqueous NaOH and extracted with methylene chloride. The organic phase was washed with water, dried (Na2SO4), evaporated to dryness and chromatographed on silica using methylene chloride/methanol, (10:1), as the eluent to give 67 mg (15% yield) the title compound: MS (ES) 456 (M++1).
The following Examples 154-157 were synthesized as described for Example 153:
Starting material: 4-((3-pyrrolidin-1-ylpropyl)amino)sulfonyl)phenylboronic acid, yield 5%: 1H NMR (CDCl3, 400 M 8z) δ9.85 (s, 1H), 8.82 (s, 1H), 8.73 (s, 1H), 8.41 (d, 1H), 8.26 (m, 1H), 8.01 (d, 2H), 7.95 (d, 2H), 7.34 (dd, 1H), 3.11 (t, 2H), 2.62 (t, 2H), 2.57 (m, 4H), 1.82 (m, 4H), 1.71 (t, 2H); MS (ES) 482 (M++1).
Starting material: 4-((4-acetylpiperazin-1-yl)sulfony)phenylboronic acid, yield 2%:MS (ES) 482 (M++1).
Starting material: 4-(((2-dimethylamino)ethyl)(ethyl)amino)sulfonyl)-phenylboronic acid.
The compound was precipitated as the hydrochloride salt, yield 26%: 1H NMR. (D2O, 400 MHz) δ8.92 (s, 0.1H), 8.27 (m, 2H), 8.07 (s, 1H), 7.69 (m, 1H), 7.57 (d, 2H), 7.32 (d, 2H), 3.28,(m, 2H), 3.18 (m, 2H), 2.97 (m, 2H), 2.77 (s, 6H), 0.75 (t, 3H); MS (ES) 470 (M+1+).
Starting material: 4-(((3-dimethylamino)propyl)amino)sulfonyl)phenylboronic acid, yield 22%: 1H NMR (D2O, 400 MHz) δ 8.95 (s, 1H), 8.29 (m, 2H), 8.12 (s, 1H), 7.71 (m, 1H), 7.58 (d, 2H), 7.32 (d, 2H), 3.04 (t, 2H), 2.80 (t, 2H), 2.73 (s, 6H), 1.76 (m, 2H). The compound was dissolved in 1 M HCl(aq), evaporated and freeze dried: MS (ES) 456 (M++1).
4-[(4-Methylpiperazin-1-yl)sulfonyl]phenylboronic acid (117 mg, 0.41 mmol), 2-amino-5-bromo-N-[4-(pyrrolidin-1-ylmethyl)pyridin-3-yl]nicotinamide (54 mg, 0.14 mmol), sodium carbonate (50 mg, 0.47 mmol), Pd(dppf)Cl2×CH2Cl2 (28 mg, 0.04 mmol) were suspended in ethylene glycol dimethyl ether/water (2.5:0.6 mL) and heated in a microwave oven at −160° C. for 10 min. Silica was added and the solvent was evaporated. Purification by column chromatography using ethyl acetate to ethyl acetate/methanol, (10:1), as the eluent gave a product which was further purified by reversed phase chromatography (column: XTerra C8 19×300 mm, gradient: water/acetonitrile/ammonium acetate). After removal of the solvent, the residue was dissolved in methylene chloride and the organic layer was washed with aqueous saturated sodium hydrogen carbonate solution and subsequently dried over sodium sulfate. Filtration and removal of solvent in vacuo gave 65 mg (8-7% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 11.76 (br s, 1 H), 9.57 (s, 1H), 8.41 (d, J=2 Hz, 1H), 8.28 (d, J=5 Hz, 1H), 7.86 (d, J=2 Hz, 1H), 7.79 (d,J 9 Hz, 2H), 7.62 (d,J=9 Hz, 2H), 7.06 (d, J=5 Hz, 1H), 6.88 (brs, 2H), 3.74 (br s, 2H), 3.04 (m, 4H), 2.47 (m, 8H), 2.25 (s, 3H), 1.51 (m, 4H); 3C NMR (CDCl3, 100 MHz) δ 165.7; 159.3; 151.0; 145.1; 142.7; 142.6; 135.5; 134.8; 134.5; 134.0; 128.7; 126.7; 124.2; 123.6; 110.4; 59.1; 54.2; 53.9; 46.1; 45.9; 23.6; MS (ES) 7m/z 536
Triethyl amine (33.2 mg, 0.255 mmol) in N,N-dimethylformamide (0.1 mL) was added to a solution of 4-(5-amino-6-[(pyridin-3-ylamino)carbonyl]pyrazin-2-yl)6enzoic acid (52.9 mg, 0.15 mmol) and O-(benzotriazol-7-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.18 mmol) in N,N-dimethylformamide (8.5 mL). N″-Ethyl-N,N-dimethylethane-1,2-diamine (17.4 mg, 0.15 mmol) in N,N-dimetbylformamide (0.33 mL) was added and the mixture was shaken at room temperature for 24 h. Most of the solvent was removed and the crude reaction mixture was dissolved in dimethyl sulfoxide (1 mL) and purified by chromatography with acetonitrile/water (5:95 increasing to 0.95:5 for 12 minutes, XTerra C8-column 19×100 mm). The product was further purified by a second chromatography with acetonitrile/water (10:90 increasing to 60:10 in 13 minutes, XTerra C8S-column 19×300 mm) to give 8 mg (12% yield) of the title compound: MS (ES) m/z 434
The following Examples, 160-175, were synthesized as described for Example 159:
Starting material: N,N,N′-trimethylpropane-1,3-diamine, yield 25%: MS (ES) m/z 434 (M+1+1)
Starting material: N,N,-dimethyl-1,3-propanediamine, yield 5%: MS (ES) m/z 420 (M++1).
Starting material: 2-pyrrolidin-1-yl-ethylamine, yield 29%: MS (ES) m/z 432 (M++1).
Starting material: 3-pyrrolidin-1-yl-propylamine, yield 14%: MS (ES) m/z: 446 (M++1).
Starting material: 1-methyl-[1,4]diazepane, yield 18%: MS (S) m/z 432 (M++1).
Starting material: methyl-(1-methylpyrrolidin-3-yl)amine, yield 36%: MS (ES) m/z 432 (M++1).
Starting material: N,N-dimethylethylenediamine1 yield: MS (ES) m/z 406 (M+I).
Starting material: N1,N1-dimethylpropane-1,2-diamine, yield 39%: MS (ES) m/z 420 (M++1).
Starting material: dimethylpyrrolidin-3-ylamine, yield 41%: MS (ES) m/z 432 (M++I).
Starting material: 2-(aminomethyl)-1-ethylpyrrolidine, yield 7%: MS (ES) m/z 446 (M++1)”
Starting material: 3-(4-methyl-piperazin-1-yl)-propylamine, yield 23%: MS (ES) m/z 476
Starting material: methyl-(1-methylpiperidin-4-yl)amine, Yield 27%: MS (ES) m/z 446
Starting material: 2-piperidin-1-ylethylamine, yield 5%: MS (ES) m/z 446 (M++1).
Starting material: 1-ethylpiperidin-3-ylamine, yield 8%: MS ( ) m/z 446 (M++1).
Starting material: 2-(1-methylpyrrolidin-2-yl)ethylamine yield 30%: MS (ES) mni/z 446
Starting material: 4-pyrrolidin-1-ylpiperidine, yield 38%: MS (ES) m/z 472 (M++1).
4-[(4-Methyl-1-piperazine-1-yl)sulfonyl)phenylboronic acid (0.06 g, 0.20 mmol), 2-amino-5-bromo-N-(3-pyridinyl)benzamide (0.155 g, 0.54 mmol), Na2CO3 (0.065 g, 0.62 mmol), and Pd(dppf)Cl2 (4 mg, 0.006 mmol) were suspended in ethylene glycol dimethyl ether/water (2.6:0.6 mL) and heated in a microwave oven at 160° C. for 10 min. Silica was added and the solvent was evaporated. Purification by column chromatography using methylene chloride/methanol, (95:5), as the eluent gave 58 mg (63% yield) of the title compound: 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 8.86 (d, J=5 Hz, 1H), 8.30 (m, 1H), 8.12 (m, 1H), 8.06 (d, J=2 Hz, 1H), 7.94 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.68(dd, J=9, 2 Hz, 1H), 7.39 (dd, J=8,4 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 6.70 (brs, 2H), −2.89 (m, 4H), 2.35 (m, 4H), 2.13 (s, 3H); 13C NMR (DMSO-d6) δ 156.4, 144.5, 144.4, 142.3, 135.7, 131.8, 131.0, 128.2, 127.7, 127.7, 123.1, 124.3, 123.5, 117.1, 114.5,53.5, 45.8, 45.3; MS (ESP) nVz 452 (M+1).
Triisopropylborate (1.95 mL, 8.4 mmol) was added to a solution of 1-[(4-bromo-2,5-difluorophenyl)sulfonyl]0.4-methylpiperazine (1.0 g, 2.8 mmol) in anhydrous tetrahydrofuran (15 mL) at −78 aC under an atmosphere of nitrogen followed by dropwise addition of n-butyllithium (5.0 mL, 8.0 mmol) over 30 min. The resulting mixture was stirred at −78° C. for 2 h, HC (3 M aq, 4.7 mL, 14.1 mmol) was added, and the reaction mixture was allowed to warn to room-temperature. Sodium carbonate (3 g, 28.3 mmol) was added followed by the addition of 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (0.585 g, 1.99 mmol) and Pd(dppf)Cl2 (80 mg, 0.10 mmol). The resulting mixture was heated at 70° C. for 16 h. Silica was added, the solvent was evaporated and the crude mixture was purified by column chromatography using methylene chloride/methanol, (95:5), to give 0.55:g (57% yield) of the base as a pale yellow solid: H. NMR (DMSO-d6) δ 10.63 (s, 1H), 8.94 (s, 1H), 8.81 (s, 1H), 8.57 (m, 1H), 8.38 (m, 1 H), 8.17 (m, 1H), 8.03 (br s, 2H), 7.71 (m, 1H), 7.44 (m, 1H), 3.13(br s, 4H), 2.38 (br s, 4H), 2.15 (s, 3H); MS (TSP) m/z 491 (M++1) HCl in diethyl ether (1 M, 0.81 mL) was added to a solution of the base (0.096 g, 0.21 mmol) in methylene chloride/methanol, (0.95:0.05, 8 mL). The yellow precipitate was filtered off, washed with diethyl ether and dried in vacuo to give 102 mg (99% yield) of the title compound as a yellow solid: 1H (D2O) δ 9.37 (d, J=2 Hz, 1H), 8.73 (s, 1H), 8.63 (m, 1H), 8.56 (d, J=6 Hz, 1H), 8.08 (dd, J=1.1, 6 Hz, 1H)802 (dd,J9,6 Hz, 1H), 7.73 (dd, J=10, 6 Hz, 1H), 4.05 (m, 2H), 3.63 (m, 2H), 3.27 (m, 2H), 3.16 (m, 2H), 2.93 (s, 3H); MS (TSP) m/z 491 I(M++1).
The following Examples, 178-206, were synthesized as described for Example 177:
Starting material: 1-[(4-bromo-2-fluoropheny])sulfonyl]4methylpiperazine. Yield: 49% o of the base: 1H NMR (CDCl3) δ9.88 (s, 1H), 8.83 (s, 1H), 8.70 (s, 1H), 8.36 (m, 1H), 8.26 (m, 1H), 7.90 (m, 1H), 7.79 (m, 2H), 7.37 (m, 1H), 3.36 (br s, 4H), 2.76 (s, 3H), 2.62 (br s, 4H); Ms (TSP) m/z 472 (M++1). Hydrochloride, yield 93%: 1H NMR (D2O) δ 9.40 (d, J=2 Hz, 1H), 8.68 (s, 1H), 8.63 (m, 1H), 8.53 (m, 1H), 8.03 (m, 1H), 7.95 (dd, J=12, 1 Hz, 1H), 7.89 (dd, J=8, 3 Hz, I H), 7.80 (m, 1H), 3.96 (m, 2H), 3.55 (m, 2H), 3.20 (m, 2H), 3.04 (m, 2H), 2.86 (s, 3H); MS (TSP) m/z 472 (M++1).
-3-Amino-6-{3-methyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-N-pyridin-3-ylpyrazine-2-carboxamide hydrochloride
Starting material: 1-[(4-bromo-2-methylphenyl)sulfonyl)4methylpiperazine. Yield 62% as the base: 1H NMR (CDCl3) δ 9.86,(s, 1H), 8.85 (s, 1H), 8.74 (s, 1H), 8.45 (d, J=5 Hz, 1H), 8.30 (dd, J=8, I.Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.82 (s, 1H), 7.37 (dd, J 8, 5 Hz, 1H), 3.34 (br s, 4H), 2.74 (s, 3H), 2.62 (br s, 4. H), 2.39 (s, 3 H); 13C NMR (CDCl3) 8164.4, 154.8, 146.0, 145.8, 141.9, 140.3, 139.1, 138.7, 135.4, 134.2, 131.4, 130.0, 127.3, 124.6, 124.0, 123.4, 54.3, 45.8, 45.0, 21.4; MS (TSP) mn/z 468 (M++1). Hydrochloride, yield 99%: 1H NMR (D2O) δ 9.32 (d, J=2 Hz, 1H), 8.56 (m, 2H), 8.49(s, 1H), 8.02 (dd, =8, 6 Hz, 1H), 7.75 (m, 2H), 7.66 (d, J=8 Hz, 1H), 3.84 (m, 2H), 3.58 (m, 2H), 3.14 (m, 4H), 2.90 (s, 3H), 2.44 (s, 3H); 13C NMR (D2O) δ 164.9, 153.9, 145.3, 139.7, 139.2, 137.5, 137.1, 137.0, 133.3, 132.6, 131.0, 129.4, 128.0, 123.6, 123.1, 53.1, 43.3, 42.6, 20.3; MS (TSP) m/z 468 (M++1).
Starting material: 1-[(2-bromophenyl)sulfonyl]-4-methylpiperazine. Yield 29% of the base: 1H NMR (CDCl3) δ 10.43 (s, 1H), 8.94 (s, 1H), 8.47 (m, 1H), 8.35 (m, 2H), 7.98 (m, 1-H), 7.69 (m, 1H), 7.60 (m, 2H), 7.29 (m, 1H), 3.27 (br s, 4H), 2.40 (br s, 4H), 2.28 (s, 3 H); 3C NMR (CDCl3) δ 164.7, 154.1, 146.6, 145.3, 141.8, 140.1, 137.9, 136.9,135.1, 133.0, 132.0, 129.6, 129.1, 126.7, 124.1, 123.8, 54.5, 45-9, 45.3; MS (TSP) m/z 454 (M++1) Hydrochloride, yield 99%: 1H NMR (D2O) δ 9.36 (s, 1H), 8.51 (m, 3H), 7.99 (m, 2H), 7.85 (m, 1H), 7.72 (m, 2H), 3.73 (,2H), 3.51 (m, 2H), 3.15 (m, 2H), 3.02 (m, 2H), 2.88 (s, 3H); 13C NMR (D2O) δ 165.4, 154.1, 147.6, 139.6, 137.9, 137.3, 136.3, 136.1, 135.3, 134.7, 132.9, 132.8, 130.3, 129.9, 128.0, 123.2, 53.3, 43.3, 42.7; MS (TSP) mn/z 454
Starting material: 1-[(3-bromophenyl)sulfonyl]-4-methylpiperazine. Yield 63% as the base:
1H NMR (CDCl3) δ 9.85 (s, 1H), 8.82 (d, J=8 Hz, 1H), 8.71 (s, 1H), 8.43 (d, J=4 Hz, 1H), 8.28 (m, 1H), 8.22 (s, 1H), 8.12 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.69 (t, J=8 Hz, 1H), 7.35 (m, 1H), 3.26 (ir s, 4H), 2.72 (br s, 4H), 2.42 (s, 3H); 3C NMR (CDCl3) δ 164.4, 154.7, 145.8, 145.5, 141.7, 13.8.7, 137.4, 136.5, 134.3, 130.2, 130.1, 127.8, 127.3, 124.9, 124.5, 124.0, 54.1,45.9, 45.7; MS (TSP) m/z 454 (M++1).
Hydrochloride, yield 84%; 1H NMR (D20) δ 9.33 (d, i=2 Hz, 1H), 8.62 (s, 1H), 8.55 (m, 2H), 8.23 (m, 1H), 8.16 (s, 1H), 8.03 (m, 1H), 7.67 (m, 2H), 3.93 (m, 2H), 3.58 (m, 2H), 3.23 (m, 2H), 2.87 (s. 3H), 2.83 (m, 2H); 13 C NMR (D2O) 6165.2, 154.1, 145.3, 137.7, 137.6, 137.2, 137.0, 136.8, 135.1, 132.8, 131.1, 131.0, 128.0, 127.7, 124.0, 123.8, 53.0, 43.5,43.2; MS (TSP) m/z 454 (M++1).:
Starting material: 1-[(4-bromo-3-methylphenyl)sulfonyl]-4-methylpiperazine. Yield 74% as the base: 1H NMR (CDCl3) δ 9.76 (s, 1H), 8.80 (s, 1H), 8.39 (s, 2H), 8.23 (d, J=8 Hz, 1H), 7.67 (m, 2H), 7.55 (d, J=8 Hz, 1H), 7.31 (m, 1H), 3.16 (br s, 4H), 2.64 (br s, 4-30H), 0.48 (s, 3H), 2.37 (br s, 3H); 13C NMR (CDCl3) δ 164.2, 154.1, 147.5, 145.6, 141.5, 140.8, 140.5, 137.6, 134.7, 134.1, 130.1, 126.9, 125.7, 124.1, 123.6, 53.8, 45.6, 45.3, 20.8. Hydrochloride, yield 95%: 1H NMR (DzO) δ 9.42 (d, J=2 Hz, 1H), 8.61 (m, 1H), 8.56 (m, 1. H), 8.43 (s, 1H), 8.03 (dd, J=8, 6 Hz, 1H), 7.78 (d, J=8 Hz, 2H), 3.96 (m, 2H), 3.61 (m, 2H), 3.26 (m, 2H), 2.91 (s,3H), 2.86 (m, 2H), 2.47 (s, 3H); 3C NMR (D20) 165.7, 153.9, 147.8, 141.6, 140.5, 139.0, 137.9, 137.4, 137.0, 133.8, 133.2, 131.0, 130.1, 128.0, 125.6, 43.9, 43.1, 20.2; MS (TSP) m/z 468 (M++1).
Starting material: 4-bromo-N-[2-(dimethylamino)ethyl]-2-(trifluoromethoxy)benzene-sulfonamide. Yield 56% as the base: 1H NMR (DMSO-d6) δ 10.67 (s, 1H), 9.07 (s, 1H), 8.95 (d, J=2 Hz, 1H), 8.42 (m, H), 8.35 (m, 2H), 8.20 (m, IH), 7.99 (d, J=8 Hz, I H), 7.93 (br s, 2H), 7.79 (br s, 1H), 7.45 (m,1H),2.99 (t,J-=7 Hz, 2H), 2.28 (t, J=7 Hz, 2H), 2.07 (s, 6H); 13C NMR (DMSO-d6) δ 164.8.154.9, 145.8, 145.6,145.5, 145.1, 142.8, 141.7, 135.3, 134.6, 132.6, 130.3, 128.2, 124.3, 24.1, 123.5, 121.3, 118.7, 118.3, 58.2,44.9; MS (TSP) nz/z 526 (M+11). Hydrochloride, yield 99%: 1H NMR (D2O) δ 9.84 (br s, 1H), 8.64 (s, 1H), 8.56 (d, J=6 Hz, 1H), 8.45 (m, 1H), 7.99 (m 2H), 7.94 (m, 1H), 7.87 (d, J=8 Hz, 1H), 3.33 (s, 4H), 2.95 (s, 6H; 13C N (D2O) δ 162.9, 152.4, 144.5, 143.7, 140.3, 135.6, 135.4, 134.2, 134.0, 130.9, 129.7, 127.2, 125.9, 122.0, 121.4, 119.7, 115.3, 54.8, 41.3, 35.9; MS (TSP) m/z 526 (M++1).
3-Amino-6-[4-{[[2-(dimethylamino)ethyl](ethyl)amino]sulfonyl}-3-(trifluoromethoxy)phenyl]-N-pyridin-3-ylpyrazine-2-carboxamidehydrochloride
Starting material: 4-bromo-N-[2-(dimethylamino)ethyl]-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide. Yield 87% as the base: 1H NMR (CDCl3) δ 9.79 (s, 1H), 8.82 (d, J=2 Hz, 1H), 8.76 (s, 1H), 8.44 (m, 1H), 8.25 (m, 1H), 8.16 (d, J=8 Hz, 1H), 7.96 (m, 1H), 7.87 (dd, J=8, 1 Hz, 1H), 7.37 (dd, J=85 Hz, 1H), 3.55 (m, 2 H), 3.40 (q, J=7 Hz, 2H), 2.72 (m, 2H), 2.39(S.6H)z 1.15 (t, J=:7 HZ,3H); 13C NMR (CDCl3) δ 164.0, 155.1, 146.8, 146.0, 145.6, 142.0, 141.6, 137.0, 134.1, 132;7, 132.1, 126.9, 124.7, 124.5, 124.0, 122.9, 121.9, 119.3, 117.0, 58.0, 45.2, 44.6, 43.5, 14.4; MS (TSP) m/z 554 (M++1). Hydrochloride, yield 91%: 1H NMR (D2O) δ 9.42 (d, J=2 Hz, 1H), 8.63 (s, 1H), 8.60 (d, J=6 Hz, H), 8.50 (m, 1H), 8.06 (m, 1H), 7.95 (m, 2H), 7.89 (d, J=8 Hz, 1H), 3.74 (t, J=6 Hz, 2H), 3.42 (t, J=6 Hz, 2H), 3.33 (q, J=7 Hz, 2H), 2.98 (s, 6H), 0.97 (t, J=7 Hz, 3H); i3C NMR (D2O) δ 162.7, 152.1, 144.0, 143.4, 140.0, 135.3, 134.9, 134.4, 133.6, 130.3, 130.1, 127.1, 125.8, 121.7, 121.2, 114.8, 53.5,41.3, 41.1, 11.3, 10.2; MS (TSP)m/z 554 (M++1).
Starting material: tert-butyl 2-(([4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl}-(tert-butoxycarbonyl)armino)ethylcarbamate. The product was used in the next step without further analysis.
Starting material:1-[([4-bromo-3-(trifluoromethyl)pbenyl]sulfonyl} lmethylpiperazine.
Purification on a reversed phase column (XTerra C8 19x300 mm) using a water/acetonitrile gradient as the eluent gave the base in 3% yield: 1H NMR (CDCl3) δ 9.79 (br s, 1H), 8.81 (br s, 1H), 8.44 (s, 1H), 8.41 (m, 1H), 8.21 (m, 2H), 8.03 (dd, J=8, 2 Hz, 1H), 7.74 (m, H), 7.32 (dd, J=8, 5 Hz, 1H), 3.19 (m, 4H), 2.63 (m, 4H), 2.37 (br s, 3H); MS (TSP) m/z 522 (M++1). Hydrochloride, yield 99%: 1H NMR (D20, 400 MHz) δ 9.18 (br S, 1H), 8.47 (m, 2H), 8.41 (m, 1H), 8.28 (m, 1H), 8.17 (m, 1H), 7.94 (d, J=8 Hz, 1H), 7.88 (m, 1H), 4.04 (m, 2H), 3.64 (m, 2H), 3.49 (m, 1H), 3.30 (m, 2H), 3.12 (m, 1H), 2.92 (s, 3H); MS (TSP) m/z 522.0 (M++1).
Starting material: N-[2-(4-bromophenoxy)ethyl]-N,N-dimethylami.ne (described in Ruenitz, P., et al, J. Med. Chem. 1982, 25, 1056-1060). Yield 19% of the base: 1H NMR (DMSO-d6) δ 10.56 (s, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 8.34 (d, J=3 Hz, 1H), 8.21 (m, 1H), 8.17 (d, J=9 Hz, 21H), 7.58 (br s, 21H), 7.42 (dd, J=8, 4 Hz, 1H), 7.03 (d, J=9 Hz, 2H), 4.11 (t, J=6 Hz, 2H), 2.64 (t, J=6 Hz 2H), 2.22 (s, 6H); 3CNMR (DMSO-d6) δ 165.3, 158.8, 153.9, 145.0, 144.4, 143.0, 138.9, 134.7, 128.4, 127.2, 123.5, 123.0, 115.7, 114.6, 65.8, 57.7, 45.6; MS (EI) m/z 379 (M++1). Hydrochloride: yield 45%.
3-Amino-6-[4-[2-(4-morpholinyl)ethoxy]phenyl]-N-(3-pyridinyl)-2-pyrazinecarboxamide hydrochloride
Starting material: 4-[2-(4-bromophenoxy)ethyl]morpholine (described in Lednicer, D., et al, J. Med. Chem. 1965, 8, 52-57). Yield 20% of the base: 1H NMR (DMSO-d6) δ 10.55 (s, 1H), 8.99 (br s, 1H), 8.88 (s, 1H), 8.4 (m, 1H), 8.22 (d, J=8 Hz, 2H) 8.12 (d, J=9 Hz, 2H), 7.56 (br s, 21H), 7.51 (d, J=9 Hz, 1H), 7.41 (dd, J=8, 5 Hz, 1H), 4.16 (t, J=0.6 Hz, 2H), 4.08 (t, J=6 Hz, 1H), 3.58 (in, 6H), 2.72 (m, 3H); 13C NMR (DMSO-d6) δ 165.2, 158.7, 157.5, 153.8, 144.9, 144.3, 143.0, 138.8, 132.3, 128.3, 127.1, 123.4, 123.0, 114.8, 114.6, 66.1, 65.3, 56.9, 53.6; MS (EI) m/z 421 (M++I). Hydrochloride: yield 46%.
Starting material: 4-bromo-N-[2-(dimethylamino)ethyl]-N-methylbenzamide. Yield 20% of the base: 1H NMR (CDCl3) δ 10.59 (s, 1H), 8.98 (s, 2H), 8.36 (dd, J=4, 1 Hz, 1H), 8.30 (d, J=8 Hz, 2H), 8.21 (m, 1H), 7.73 (br s, 2H), 7.49 (d, J=9 Hz, 2H), 7.42 (dd, J=8, 4 Hz, 1H), 3.32 (br s, 4H), 2.96 (br s, 3H), 2.23 (br s, 3H), 1.99 (br s, 3H); 13C NMR (CDCl3) δ 139.4, 154.2, 145.5, 145.3, 141.5, 134.1, 127.0, 125.5, 124.0, 123.8, 109.5, 76.7, 58.4, 50.8, 45.5, 29.7, 22.7, 18.4; MS (ED m/z 420 (M++1). Hydrochloride, yield 28%: 1H NMR (D20) δ 9.34 (s, 1H), 9.33 (s, 1H), 8.65 (s, 1H), 8.58 (d, J=0.9 Hz, 1H), 8.50 (d, J=6 Hz, 1H), 7.99 (d, J=8 Hz, 2H), 7.52 (d, J=8 Hz, 2H), 3.92 (t, J=6 Hz, 2H), 3.48 (t, J=7 Hz, 2H), 3.06 (s, 3H), 3.00 (s, 6H).
Starting material: 1-[2-(4-bromophenoxy)ethylj4-methylpiperazine (described in Ide, et al., J. Am. Chem. Soc., 1954, 76, 1122-1125). Yield 66% of the base: 1H NMR (DMSO-d6) 10.54 (s, 1H), 8.97 (d, J=2 Hz, 1H), 8.88 (s, 1H), 8.34 (dd, J=5, 2 Hz, 1H), 8.21 (m, 11H), 8.16 (d,J-9 Hz, 2H), 7.56 brs, 2H), 7.42 (dd, J=8, 5 Hz, 1H), 7.03 (d, J=9 Hz, 2H), 4.14 (t, J=6 Hz, 2H), 2.72 (t, J=6 Hz, 2H), 2.57 (brs, 8H), 2.31 (s, 3H); MS (ES) m/z 434 (M++1). Hydrochloride, yield 92%: 1H NMR (D2O) δ 9.4 (s, 1H), 8.66 (s 1H), 8.63 (d, J=9 Hz, 1H), 8.55 (d, J=6 Hz, 1H), 8.05 (dd, J=8, 6 Hz, 1H), 7.94 (d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, H), 7.13 (d, J=9 Hz, 2H), 4.43 (t, J=S Hz 2H), 3.62 (br s, 10H), 3.0 (s, 3H); 13C NMR (D2) δ 166.2, 158.8, 154.0, 145.4, 140.8, 138.3, 137.6, 137.4, 133.8, 129.7, 128.4, 128.0, 124.0, 115.9, 62.9, 56.7, 51.2, 50.2, 43.9.
Starting material: 4-bromo-N-(2-morpholin-4-ylethyl)benzamide described in Rafli, H., et al., Life Sci. 1996, 58, 1159-1170, yield 1% as the base: 1H NMR (DMSO-d6) δ 10.61 (s, 2H), 9.02 (s, 1H), 8.96 (d, J=2 Hz, 1H), 8.49 (m, 1H), 8.34 (d, J=9 Hz, 2H), 8.20 (m, 1H), 7.94 (d, =9 Hz, 2H), 7.78 (br s, 2H), 7.44 (dd, J=8, 4 Hz, 1H), 3.57 (t, J=5 Hz, 4H), 3.40 (m, 4H), 2.42 (m, 4H); MS (ES) m/z 448 (M++1).
Starting material: 3-(4-bromophenoxy)-1-methylpyrrolidine. Yield 79% of the base: 1H NMR (DMSO-d6) δ 10.54 (s, 1H), 8.97 (d, J=2 Hz, 1H), 8.87 (s, 1H), 8.34 (dd, J=5, 2 Hz, 1H), 3.21 (m, 1H), 8.15 (d, J=9 Hz, 2H), 7.56 (br s, 2H), 7.42 (dd, J=8, 5 Hz, 1H), 6.96 (d, J=9 Hz, 2H), 4.93 (m, 1H), 2.79 (m, 1H), 2.66 (m, 2H), 2.35 (m, 2H), 2.26 (s, 3H), 1.78 (m, 1H); 3C NMR (DMSO-d6) δ 165.2, 157.6, 153.8, 144.9, 144.3, 142.9, 138.8, 134.6, 128.2, 127.2, 123.4, 123.0, 115.2, 76.7, 61.7, 54.6, 41.6, 32.4; MS (ES) m/z 391 (M++1). Hydrochloride, yield 96%: 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 9.42 (d, f=2 Hz, 1H), 8.96 (m, 2H), 8.69 (d, J=5 Hz, 1H), 8.22 (m, 2H), 8.08 (dd, J=9, 6 Hz, 1H), 7.08 (d, J=9 Hz, 2H), 5.25 (m, 1H), 3.97 (m, 1H), 3.65 (m, 2H), 3.17 (m, 2:H), 2.85 (m, 3H), 2.29 (m, 1H).
Starting material: 1-[(4-bromo-3-fluorophenyl)sulfonyl]-4-methylpiperazine. Yield 36% of the base: MS (ES) m/z 472 (M++1).
Hydrochloride, yield 28%: 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.96 (m, 1H), 8.78 (d, J=2 Hz, 1H), 8.53 (t, J=8 Hz, 1H), 8.35 (dd,J 4,2 Hz, 1H), 8.2 (m, 1H), 7.92 (brs, 2H), 7.68 (m, 2H), 7.42 (m, 1H), 2.97 (m, 4H), 2.37 (m, 4H), 2.14 (s, 3H); 3C NMR (DMSO-d6) S 164.6, 160.2, 157.7, 154.4, 147.9, 145.0, 142.8, 135.8, 134.4, 132.8, 131.5, 128.3, 128.2, 124.8, 124.8, 123.6, 115.3, 53.4, 45.7, 45.2.
Starting material: 1-[(4-bromo-2-fluoro-5-methylphenylsulfonyl]4-methylpiperazine Purification by chromatography on silica gel using a gradient of ethyl acetatelheptane, (1:100), to ethyl acetate/methanol, (10:1), followed by formation of the hydrochloric salt in 3 ML of a methylene chloride/methanol mixture (v/v=3: 1) by the addition of 5 mL of hydrochlorid acid in diethyl ether (1 M) gave after washing with diethyl ether and drying 92 mg (48% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 9.41 (d, J=3 Hz, 1H), 8.62 (m, 1H), 8.56 (m, 1H), 8.39 (s, 1H), 8.04 (dd, J=9, 6 Hz, 1H), 7.72 (d, J=7 Hz, 1H), 7.53 (d, J=11 Hz, 1H), 4.00 (m, 2H), 3.62 (m, 2H), 3.24 (m, 2H), 3.10 (m, 2Hz 2.92 (s, 3H), 2.40 (s, 3H); MS (ES) m/z 486 (M++1).
Starting material: 1-[(4-bromo-2,5-dimethylphenyl)sulfonyl]-4-methylpiperazine. Purification by chromatography on silica gel using a gradient of ethyl acetate/heptane, (1:100), to ethyl acetate/methanol, (10:1), followed by formation of the hydrochloric salt in 3 mL of a methylene chloride/methanol mixture (v/v-=3: 1) by the addition of 5 mL of hydrochlorid acid in diethyl ether (1 M) gave after washing with diethyl ether and drying 90 mg (48% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 9.40 (m, 1H), 8.59 (m, 1H), 8.55 (m, 1H), 8.36 (s, 1H), 8.03 (ddd, J=9, 6, 1 Hz, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 3.90 (d, J=12 Hz, 2H), 3.60 (d, J=1 Hz, 2H), 3′.18 (quint, J=13 Hz, 4H), 2.93 (s, 3H), 2.52 (s, 3H), 2.38 (s, 3H); MS (ES) m/z 482 (M++1).
Starting material: 1-[2-(4-bromophenoxy)ethyl]piperidine (described in: Stauffer, S. R. et al, Bioorg. Med. Chem. 2001, 9, 151-162): 1H NMR (DMSO-d6, 300 MHz) δ 10.56 (s, 1H), 8.98 (d, J=2 Hz, 1H), 8.88 (s, 1H), 8.36 (dd, J=5, 1 Hz, 1H), 8.22 (m, 1H), 8.17 (d, J=9 Hz, 2H), 7.57 (brs, 2H), 7.43 (dd, J=8, 5 Hz, 1H), 7.04 (d, J=9 Hz, 2H), 4.13 (t, J=6 Hz, 2H), 2.67 (t, J=6 Hz, 2H), 2.44 (m, 4H), 1.50 (m, 4H)) 1.39 (m, 2H). Hydrochloride, yield 28%: 1H NMR (DMSO-d6, 300 MHz) δ 11.18 (s, 1H), 10.91 (m, 1H), 9.50 (d, J=2 Hz, 1H), 9.07 (s, 1H), 9.00 (d, J=9 Hz, 1H), 8.78 (d, J=5 Hz, 1H), 8.35 (d, J=9 Hz, 2H), 8.15 (dd, J=9, 6 Hz, 1H), 7.23 (d, J=9 Hz, 2H), 4.64 (r, 2H) 3.60 (m, 4H), 3.11 (m, 2H), 1,93 (m, 4H), 1.26 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 165.7, 157.9, 153.9, 145.1, 138.9, 137.9, 136.5, 136.0, 133.2, 128.8, 127.4, 127.3, 122.1, 114.8, 62.5, 54.6, 52.6,22.2, 21.2; MS (ES) 419 (M++1)
Starting material: 1-[2-(4-bromophenoxy)ethylpyrrolidine (described in Penning, T. D. et al, J. Med. Chem. 2000, 43, 721-735). Hydrochloride: 1HNMR (DMSO-d6, 390 MHz) δ 11.26 (br s, 1H), 1.10 (s, 1H), 9.41 (d, J.=2 Hz, 1H), 8.95 (s, —H), 8.93 (d, J=7 Hz, 1 H), 8.68 (d, J=5 Hz, 1H), 8.23 (d, J=9 Hz, 2H), 8.07 (dd, J=9, 6 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 4.44 (m, 2H), 3.58 (m, 4H), 3.12 (m, 2H), 1.94 (m, 4H); MS (ES) 405(M++1).
Starting materials: tert-butyl 4-[2-(4bromophenoxy)ethyl]piperazine-1-carboxylate, yield 70% as the base: 1H NMR (DMSO-d6, 300 MHz) δ 11.66 (s, 1H), 10.09 (d, J=2 Hz, 1H), 9.99 (s, 1H), 9.46 (m, 1H), 9.32 (m, 1H), 9.28 (d, J=0.9 Hz, 2H), 8.68 (s, 2H), 8.54 (dd, J=8, 5 Hz, 1H), 8.16 (d, J=9 Hz, 2,H), 5.26 (t, J=6 Hz, 2H), 4.42 (m, 4H), 3.85 (t, J=6 Hz, 2H), 3.57 (m, 4H), 2.50 (s, 9H); MS (ES).520 (M++1).
Starting material: 1-(4-bromobenzoyl)-4-methylpiperazine. Hydrochloride, yield 26%: 1H NMR (DMSO-d6, 300 MHz) δ 11.41 (br s, 1H), 11.11 (s, 1H), 9.40 (s, 1H), 9.06 (s, 1H), 8.90 (d, J=9 Hz, H), 8.69 (d, J=5 Hz, 1H), 8.38 (d, J=8 Hz, 2H), 8.06 (dd, J=9, 6 Hz, 1H), 7.59 (d, J=8 Hz, 2H), 3.39 (m, 4H), 3.13 (m, 2H), 2.77 (s, 3H), 2.50 (m,2 H); MS (ES) 418 (M++1).
Starting material: tert-butyl 4-[2-(4-bromo-2,5-difluorophenoxy)ethyl]piperazine-1-carboxylate, yield 22% as the base: 1H NMR (DMSO-d6, 300 MHz) δ 10.57 (s, 1H), 8.95(d, J=2 Hz, 1H), 8,69 (d, J=2 Hz, 1H), 8.37 (dd, J=5, 1 Hz, 1H), 8.29 (dd, J=13, 8 Hz, 1 H), 8.17 (dd, J8, 1 Hz, 1H), 7.75 (s, 2H), 7.44 (dd, J8, 5 Hz, 1H), 7.35 (dd, J=13,7 Hz, 1H), 4.25 (t, J=6 Hz, 2H), 2.75 (t, J=6 Hz, 2H), 3.31 (m, 4H), 2.46 (m, 4H), 1.39 (s, 9H).
Starting material: 4-[2-(4-bromo-2,5-difluorophenoxy)ethyl]morpholine. Hydrochloride, yield 63%: 1H NMR (DMSO-d6, 300 MHz) δ 11.07 (s, 1H), 9.37 (d, J=2Hz, 1H), 8.86 (d, J=9 Hz, 1H), 8.70 (s, 1H), 8.68 (m, 1H), 8.33 (dd, J=12, 7 Hz, 1H), 8.02 (dd, J=8, 5 Hz, 1H), 7.77 (br s, 2H), 7.36 (dd, J=13, 7 Hz, 1H), 4.66 (m, 2H), 3.96 (m, 4H), 3.63 (m, 2H), 3.50 (m, 2H), 3.27 (m, 2H).
Starting material: 1-[2-(4-bromo-2,5-difluorophenoxy)ethyl]pyrrolidine, yield 31%: 1H NMR (DMSO-d6,300 MHz) δ 10.88 (s, 1H), 10.74 (br s, 1H), 9.21 (d, J=2 Hz, 1H), 8.74 (d, J=2 Hz, 1H), 8.58 (m, 2H), 8.34 (dd, J=12, 7 Hz, 1H), 7.81 (dd, J=8, 5 Hz, 2 H), 7.41 (dd, J=13, 7 Hz, 1H), 4.54 (m, 2H), 3.64 (m, 4H), 3.13 (m, 2H), 2.04 (m, 2H), −1.90 (m, 2H); MS (ES)441(M++1).
Starting material: 1-[2-(4-bromo-3,5-dimethylphenoxy)ethyl]-4-methylpiperazine. Hydrochloride, yield 7%: 1H NMR (DMSO-d6, 300 MHz) δ 10.46 (s, 1H), 9.3.1 (s, 1H), 8.93 (d, J=2 Hz, 1H), 8.30 (m 1H), 8.21 (m, 2H), 762 (brs, 2H), 7.38 (m, 1H), 6.76 1 (s, H), 4.12 (m, 2H), 2.79 (m, 10H), 2.50 (s, 3H), 2.09 (s, 6H); MS (ES) 462 (M++1).
Starting material:1-[2-(4-bromo-3-methylphenoxy)ethyl]4-methylpiperazine. Hydrochloride, yield 23%: 1H NMR (DMSO-d6, 300 MHz) δ 11.10 (s, 1H), 9.38 (d, J=2 Hz, 1H), 8.89 (d, J=9 Hz, 1H), 8.67 (d, J=5 Hz, 1H), 8.49 (s, 1H), 8.04 (dd, J9, 5 Hz, 1H), 7.52 (d, J=0.8 Hz, 2H), 7.01 (d,1H), 6.97 (m, 1H), 4.52 (m, 2H), 3.81 (m, 10H), 2.84 (s, 3H), 2.41 (s, 3H); MS (ES) 448 (M++1).
Starting material: 5-bromo-N,N-dimethylthiophene-2-sulfonamide. Purification by chromatography on silica gel using a gradient of ethyl acetate/heptane, (1:100), to ethyl acetate/methanol (1:1), gave 80 mg (28% yield) of the title compound as the base: 1H NMR (DMSO-d6, 400 MHz). 10.47 (s, 1H), 8.98 (m, 2H), 8.39 (m, 1H), 8.18 (m, 1H), 7.97 (m, 1H), 7.91 (m, 2H), 7.68 (m, 1H), 7.46 (m, 1H), 2.72 (s, 6H) 13CNMR (DMSO-d6, 100 MHz) 6164.4, 154.5, 147.6, 145.1, 144.5, 143.1, 133.7, 133.4, 133.2, 128.6, 123.9, 123.6, 123.4, 37.7; MS (ES) m/z 405.24 (M++).
Starting material: tert-butyl 4-(5-bromo-2-furoyl)piperazine-1-carboxylate. Purification by chromatography on silica gel using a gradient of ethyl acetate/heptane, (1:100), to ethyl acetate/methanol, (10:1), gave the title compound as the base, yield33%: 1H NMR (CD3OD, 400 MHz) δ9.02 (m, 1H), 8.74 (s, 1H), 8.33 (m, 2H), 7.48 (dd, J=8, 5 Hz, 1 H), 7.31 (d, J=4 Hz, 1H) 7.20 (d, J=4 Hz, 1H), 3.87 (m, 4H), 3.58 (m, 4H), 1.48 (s, 9H); MS (ES) m/z 494. (M++1).
4-[(4-Methylpiperazin-1-yl)sulfonyl]phenylboronic acid (157 mg, 0.55 mmol), 2-amino-5-bromo-N-pyridin-3-ylnicotinamide (54 mg, 0.18 mmol), sodium carbonate (58 mg, 0.54 nmol), Pd(dppf)Cl2×CH2Cl2 (7 mg, 0.01 mmol) were suspended in ethylene glycol dimethyl ether/water (2.5:0.6 mL) and heated in a microwave oven at 160° C. for 10 min. Silica was added and the solvent was evaporated. Purification by chromatography on a silica gel column using ethyl acetate to ethyl acetate/methanol, (10:1), as the eluent gave a product which was-further purified by reversed phase chromatography (water/acetonitrile/ammonium acetate gradient, column: XTerra C8 19x300 mm). After removal of the solvent, the residue was dissolved in methylene chloride. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and subsequently dried over sodium sulfate. Filtration and removal of solvent in vacuo gave an oil which was dissolved in 3 mL methylene chloride/methanol mixture (v/v=3:1).
Hydrochloric acid (5 mL, 1 M in diethyl ether) were added and the precipitate was washed with diethyl ether and dried in vacuo to give 50 mg (53% yield) of the title compound: 1H NMR (D2O, 400M{z) δ 9.35 (d, J,=2 Hz, 1H), 8.82 (d; J=2 Hz, 1H), 8.64 (ddd, J=9, 2, 1 Hz, 1H), 8.57 (m, 1H), 8.43 (d, J=2 Hz, 1H), 8.04 (m, 1H), 7.89 (m, 4H), 3.92 (d, J=14 Hz, 2H), 3.57 (d, J=13 Hz, 2H), 3.21 (m, 2H), 2.86 (s, 3H), 2.82 (m, 2H); 13C NMR (D2O, 100 MHz) δ 163.2, 151.1, 140.6, 137.9, 137.7, 135.7, 135.5, 135.4, 131.7, 131.6, 126.7, 125.7, 125.5, 121.6, 112.9, 50.7, 41.2, 40.9; MS (ES) m/z 453 (M++1).
The following Examples, 208-213, were synthesized as described for Example 207:
Starting material: 4-[(4-methylpiperazin-1-yl)sulfonyl]phenylboronic acid and 3-amino-6-bromo-N-[4-(pyrrolidin-1-ylmethyl)pyridin-3-yl]pyrazine-2-carboxamide. Purification by chromatography on a silica gel column using ethyl acetate to ethyl acetate/methanol, (1:1), as the eluent followed by formation of the hydrochloric salt in 3 mL of a methylene chloride/methanol mixture (v/v=3: 1) by the addition of hydrochloride acid in diethyl ether (5 mL, 1 M) gave after washing with diethyl ether and drying 70 mg (23% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 9.01 (s, 1H), 8.79 (d, J=6 Hz, 1H), 8.75 (m, 1H), 8.15 (m, 3H), 7.83 (d, J=9 Hz, 2H), 4.68 (s, 2H), 3.90 (d, J=14 Hz, 2H), 3.56 (d, J=12 Hz, 2H), 3.39 (br m, 4H), 3.20 (t, J=12 Hz, 2H), 2.85 (s, 3H), 2.79 (m, 2H); 2.03 (br s, 4H); 13CNMR (D2O, 100 MHz) δ 166.9, 154.5, 146.0, 143.8, 143.4, 142.7, 141.1, 138.4, 135.1, 133.6, 128.6, 127.8, 126.9, 124.4, 55.5, 53.1, 52.9, 43.5,43.1, 22.9; MS (ES) m/z 537 (M++1).
Starting materials: 2,5-difluoro-4-(pyrrolidin-1-ylsulfonyl)phenylboronic acid and 3amino-6-bromo-N-[4-(2-pyrrolidin-1-ylethyl)pyridin-3-yl]pyrazine-2-carboxamide.
Purification by chromatography on a silica gel column using ethyl acetate/heptane, (10:1), to ethyl acetate/methanol, (1:1), as the eluent, followed by formation of the hydrochloric salt in 3 mL of a methylene chloride/methanol mixture (v/v=3:1) by the addition of hydrochloride acid in diethyl ether (5 mL,1 M) gave after washing with diethyl ether and drying 40 mg (35% yield) of the title coripound: 1H NMR (D20, 400 MHz) δ 9.04 (s, 1H), 8.78 (d, J=2 Hz, 1H), 8.61 (d, J=5 Hz, 1H), 8.02 (dd, J=10, 6 Hz, 1H), 7.89 (d, J=6 Hz, 1H), 7.75 (dd, J=10, Hz, 1H), 3.59 (br m, 4H), 3.36 (m, 6H), 3.04 (m, 2H), 2.00(m, 2-H), 1.90 (m, 2H), 1.82 (mi, 4H); MS (ES) m/z 558 (M+t1).
Starting materials: 2,5-difluoro-4-(pyrrolidin-1-ylsulfonyl)phenylboronic acid and 3-amino-6-bromo-N-[5-(3-pyrrolidin-1-ylpropyl)pyridin-3-ylpyrazine-2-carboxamide. The product mixture was filtered through C-8 reversed phase gel, using acetonitrile. The solvent was evaporated and the crude product was purified by reversed phase chromatography (column: XTerra C8 19x300 mm) using a water/acetonitrile gradient to give 21 mg, (20% yield).of the base. The base was dissolved in methylene chloride/methanol, (89:1, 5.0 mL) and cooled to, 0° C. HCl in diethyl ether (5 mL, 1 M) was added dropwise and the mixture was stirred for 30 min at 0’0 C. The precipitate was collected by filtration and washed with diethyl ether and dried to give 15 mg (12% yield) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 9.42 (d, J=2 Hz, 1H),8.77 (d, J=2 Hz, 1H), 8.53 (s, 1H), 8.26 (dd, J=11, 6 Hz, 1H), 7.65 (dd, J=10, 5 Hz, 1H), 3.61 (m, 2H), 3.30 (in, 4H), 3.03 (m, 2H), 2.93 (dd, J=8, 8 Hz, 2H), 2.10 (m, 4H), 1.96 (m, 2H), 1.79 (m, 4H); MS (ES) m/z 572 (Mt++).
Starting material: 2,5-difluoro-4-(piperidin-1-ylsulfonyl)phenylboronic acid, yield 15%: 1H NMR (CD3OD, 400 MHz) δ 9.41 (m, 1H), 8.75 (m, 2H), 8.53 (s, 1H), 8.25 (dd, J=11, 8Hz, 1H), 7.58 (dd, J=10, 6 Hz, 1H), 3.60 (m, 2H), 3.37 (t, J=7 Hz, 2H) 3.10 (m, 4H), 3.01 (m, 2H), 2.93 (m, 2H) 2.12 (m, 2H), 2.06 (m, 2H), 1.54 (m, 4H), 1.43 (m, 2H), −20 1.06 (m, 2H); MS (ES) m/z 586 (M++1).
Starting materials: 4(piperidin-1-ylsulfonyl)phenylboronic acid. Purification by reversed phase chromatography (C18, water/acetonitrile gradient) gave after precipitation the title compound, 26%.yield: 1H NMR (CD3OD, 400 MHz) δ 9.42 (s, 1H), 8.80 (s, 2H), 8.50 (s, 1 H),8.29 (d, J=8 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 3.61 (m, 2H), 3.23 (m, 2H), 3.02 (m, 2H), 2.89 (m, 6H), 2.14 (m, 2H), 2.06 (m, 21H), 1.95 (m, 2H), 1.52 (m, 4H), 1.32(m, 2H); MS (ES) m/z 550 (M++i).
Starting materials: 4-(pyrrolidin-1-ylsulfonyl)phenylboronic acid, yield 23%: 1H NMR (CD3OD, 400 MHz) δ 9.43 (s, 1H), 8.84 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.34 (d, J=8 Hz, 2H), 7.87 (d,J 8 Hz, 2H), 3.67 (m, 2H), 3.29 (m, 2H), 3.21 (m, 4H), 3.08 (m, 2H), 2.97 (dd, J=8, 8, 0.2H), 2.15 (m, 4H), 2.00 (m, 2H), 1.70 (m, 4H); MS (ES) m,z 536 (M++1).
3-Amino-6-[4-(pyrrolidin-1-ylsulfonyl)phenyl]pyrazine-2-carboxylic acid (66 mg, 0.19-mmol), 4-(2-pyrrolidin-1-ylethyl)pyridin-3-amine (30 mg, 0.16 mmol), 2-(1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluroniumtetrafluoroborate (91 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (35 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) were suspended under inert gas atmosphere in acetonitrile (8 mL) and stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue was separated between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate. Filtration and removal of the solvent in vacuo gave a crude product, which was purified by chromatography on silica gel using a gradient ethyl acetate/heptane, (4:1); to ethyl acetate/methanol, (1:2), as the eluent. The product was dissolved in 3 in L of a methylene chloride/methanol mixture (v/v=3:1) and of hydrochloride acid in diethyl ether (51 M) was added. The precipitate was washed with diethyl ether and dried in vacuo to give 15 mg (15% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 9.12 (s, 1H), 8.80 (s, 1H), 8.62 (d, J=6Hz, 1H), 8.20 (d, J=9 Hz, 2H), 7.95 (m, 3H), 3.54 (m, 4H), 3.38 (m, 2H), 3.26 (m, 4H), 2.97 (m, 2-H), 1.87 (m, 2H), 1.81 (m, 2H), 1.70 (m, 4H); MS (ES) mnz 522 (M++1).
The following Examples 215-216, were synthesized as described for Example 214: Example 215
Starting material: 4-(3-pyrrolidin-1-ylpropyl)pyridin-3-amine, yield 1:1 M D2O, 5400 MHz) δ 9.25 (s, 1. H), 8.82 (s, 1H), 8.60 (d, J=6 Hz, 1H),8.20 (d, J=9 Hz, 2H)) 8.00 (d, J=6 Hz, 1H), 7.96 (d, J=9 Hz, 2H), 3.46 (m, 2H), 3.27 (m, 4H), 3.19 (t, J=8 Hz, 2H), 3.07 (t, J=8 Hz, 2H), 2.79 (m, 2H), 2.11 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.71 (m, 4H); MS (ES) m/z 536 (M++I).
Starting material: 4-(pyrrolidin-1-ylmethyl)pyridin-3-amine. Purification by chromatography on silica gel using a gradients ethyl acetate/heptane, (4:1), to ethyl acetate/methanol, (2:1), as the eluent, followed by formation of the hydrochloric salt in 3 of a methylene chloride/methanol mixture (v/v 3: 1) by the addition of hydrochloride acid in diethyl ether (5 mL, 1 M) gave, after washing with diethyl ether and drying, 50 mg (34% yield) of the tide compound: 1H NMR (D2O, 400 MHz) δ 8.78 (m, 1H), 8.68 (m, 1H), 8.66 (s, 1H), 8.04 (d, J=9 Hz, 2H), 7.91 (d J=5 Hz, 1H), 7.71 (d, J=9 Hz, 2H), 4.56 (s, 2H), 3.3 8 br s, 4H), 3,11 (t, J66 Hz, 4H), 2.01 (ni, 4H), 1.61 (m, 4H); MS (ES) m/z 508 M+)
4(Pyrrolidin-1-ylsulfonyl)phenylborornc acid (174 mg, 0.68 mmol), 3-amino-6-bromo-N-(4-[(dimethylamino)methylpyridin-3-yl)pyrazine-2-carboxamide (220 mg, 0.62 mmol), sodium carbonate (181 mg in 0.9 Ti water, 1.71 mmol), Pd(dppf)Cl2×CH2Cl2 (40 mg, 0.05 mmol) were dissolved under inert gas atmosphere in tetrahydrofuran (10 Ti) and the reaction mi xture was heated to 50° C. and stirred for 2 h. Lithium chloride (100 mg, 2.3 mmol).and Pd(PPh3)4 (20 mg, 0.01 mmol) and Pd(dppf)Cl2xCH Cl2 (30 nmg, 0.04 mmol) were added and stirring at 50° C. was continued for 10 h. Saturated aqueous sodium chloride solution (5 mL) and ethyl acetate (15 mL) and tetrahydrofuran (20 mL) were added. The layers were separated and the organic layer was dried over magnesium sulfate. Filtration and removal of solvent in vacuo gave a residue, which was purified by column chromatography on silica gel using a gradient of ethyl acetate/heptane, (1:1), to ethyl acetate/methanol, (11), as eluent. The product was dissolved in 3 mL of a methylene chloride/methanol mixture (v/v=3:1) and of hydrochloride acid in diethyl ether (5 mL, 1 M) was added. The precipitate was washed with diethyl ether and dried in vacuo'to give 35-mg (10% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 9.10 (m, 1H), 8.85 (m, 1H), 8.66 (m, 1H), 8.24 (m, 1H), 8.00 (m, 2H), 7.72 (m, 2H, 4.66 (s, 2H), 3.14 (s, 4 H), 2.92 (m, 6 H), 1.61 (m, 4H); ° C. NMR (D2O, 100 MHz) δ 166.7, 154.2, 145.4, 144.1, 142.5, 141.5, 140.0, 138.4, 136.1, 134.5, 128.9, 128.3, 126.5, 124.4, 55.7, 48.7, 43.8, 25,1; MS (ES) m/z 482 (M++1).
The title compound was prepared as described for Example 217 using 4(piperidin-1-ylsulfonyl)phenylborbnic acid, yield 14%: 1H NMR (D2O, 400 5 Hz) δ 9.03 (s, 1H), 8.80-(m, J=6 Hz),8.69 (s, 1H), 8.17 (m, 1H), 8.06 (d,J 7 Hz, 2H), 7.69(d, J=7 Hz, 2H), 4.62 (s, 2H), 2.91 (s, 6H), 2.88. (s, 4H), 1.50 (m, 4H), 1.32, (m, 2H); MS (ES) m/z 496
The following Examples, 219-225, were synthesized as described for Example 240:
Starting material: 3-amino-6-{3-ethyl-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-N-pyridin-3-ylpyrazine-2-carboxamide, yield 99%: 1H NMR (D2O)O 9.34 (d, J=2 Hz, 1H), 8.60 (s, 1 H), 8.56(d, J=0.6 Hz, 1H), 8.51 (m, 1H), 8.01 (dd, J=9; 6 Hz, 1H), 7.91 (s, 1H), 7.84 (dd, J 8, 2 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 3.87 (m, 2H), 3.59 (m, 2H), 3.16 (m, 4H), 2.91 (s, 3H), 2.89 (q, J=8 Hz, 2H); 1.26 (t, J=8 Hz, 3Hj
Starting material: 3-amino-6-[4-[(4-methylpiperazin-1-yl)sulfbnyl]-3-(trifluoromethoxy)phenyl]-N-pyridin-3-ylpyrazine-2-carboxamide: yield 96%: 1H NMR (D2O) δ 9.34 (s, 1H), 8.66 (s, 1H), 8.56 (d, J=5 Hz, 1H), 8.44 (d, J=9 Hz, 1H), 7.98 (m, 3H), 7.87 (d, J=9 Hz, 1H), 3.98 (m, 2H), 3.60 (m, 2H), 3.19 (m, 4H), 2.91 (s, 3H); “C NMR (D2O) δ 165.0, 154.6, 146.6, 145.8, 142.7, 137.9, 137.4, 136.0,135.9, 133.3, 132.6, 127.9, 127.7, 124.2, 123.6, 117.5, 53.3, 43.29, 43.1; MS.(TSP) m/z 538 (M?+1)
Starting material: 3-amino-6-(4-{[(2-aminoethyl)amino]sulfonyl}-3-(trifluoromethoxy)phenyl]-N-pyridin-3-ylpyrazine-2-carboxamide, yield 95%: 1H NMR (D20, 400 MHz 5 9.33 (d, J=2 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J=5 Hz, 1H), 8.44 (m, 1H), 8.00 (m, 2H), 7.96 (m, 1H), 7.91 (m, 1H), 3.25 (m, 2H), 3.15 (m, 2H); MS (TSP) m/z 498 (M*+1).
Starting material: 4-amino-4′-[(4-methylpiperazin-1-yl)sulfonyl]-N-pyridin-3-yl-1,1′-biphenyl-3-carboxamide, yield 62%: 1H NMR (D2O, 400 MHz) δ 9.26 (s, 1H), 8.50 (m, 2H), 7.96 (m, 1H), 7.84 (m, 1H), 7.78 (d, J=8 Hz, 2H), 7.71 (d, J=9 Hz, 2H), 7.64 (m, 1H), 6.98 (d, J=9 Hz, 1H), 3.86 (d, J=14 Hz, 2H), 3.55 (d, J=13 Hz, 2H), 3.18 (m, 2H), 2.83 (s, 3H), 2.75 (m, 2H); 13C NMR (D20) δ 145.0, 144.95, 138.5, 137.3, 136.7, 133.1, 132.6, 131.9, 130.1, 128.6, 127.9, 127.8, 127.4, 120.7, 118.0, 52.9, 43.5, 43.1.
Starting material: 2-amino-5-(4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl)-N-[4-(pyrrolidin-1-ylmethyl)pyridin-3-yl)nicotinamide, yield 85%: 1H NMR (D2O, 400 MHz) 8-9.04 (d, J=2 Hz, 1H), 8.90 (s, 1H), 8.78 (d, J=6 Hz, 1H), 8.51 (d, J=2 Hz, 1H); 8.04 (d, J=6 Hz, 1H), 7.99 (m, 4H), 4.68 (s, 2H), 3.98 (m 2H), 3.61 (m, 2H), 3.26 (br m, 6H), 2.90 (s, 0.3H), 2.89 (br m, 2H), 2.10 (m, 4H); MS (ES) m/z 536 (MW+1).
Starting material: 3-amino-N-pyridin-3-yl-6-[4-(pyrrolidin-1-ylsulfonyl)phenyl)pyrazine-2-carboxamide, yield 97%: 13C NMR (CD3OD, 100 MHz) δ 166.72, 156.06, 147.03, 141.26, 139.74, 139.30, 138.16, 137.43, 137.14, 134.08, 129.17, 128.20, 127.48, 127.48, 124.58, 26.22; MS (ES) nz/z 425 (M++1).
Starting material: 3-amino-6-[4-(piperidin-1-ylsulfonyl)phenyl]-N-pyridin-3-ylpyrazine-2-carboxamide, yield 95%: 1H NMR (CD3OD, 400 MHz) δ 9.54 (m, 1H), 8.84 (m, 2H), 8.56 (d, J=9 Hz, 1H), 8.31 (dJ=8 Hz, 2H), 8.9 (d, J=8, 6 Hz, 1H), 7,82 (dJ=8 Hz, 2H), 2.97 (t, J=6 Hz, 4H), 1.59 (m, 4H), 1.40 (m, 2H);MS (ES) m/z 439 (M++1).
A solution of tert-butyl 4[(4-(5-amino-6-[(pyridin-3-ylamino)carbonyl)pyrazin-2-yl)phenyl)sulfonyl]piperazine-1-carboxylate (0.3 g, 0.56 mmol) in methanolimethylen chloride (10:2 mL) was heated at 60° C. for 6 h. The solvent was evaporated. The resulting residue was dissolved in methanol/water, (2:1), filtered, and the solvent evaporated to give 0,28 g (98% yield) of the title compound: 1H NMR (D20, 400 MHz) δ 8.31 (d, J=2 Hz, 1H), 8.58 (s, 1H) 8.53 (m, 1H), 8.50 (m, 1H), 8.05 (d, J=8 Hz, 2H), 7.97 (dd, J=9, 6 Hz, 1H), 7.67 (d, J=8 Hz, 2H), 3.26 (br s, 8H); 3C NMR (D2O, 100 MHz) δ 165.1, 154.1, 145.5, 140.3, 137.6, 137.4, 137.1, 137.0, 133.5, 132.7, 128.5, 128.0, 126.4, 123.9, 43.1, 43.1; MS (ES) m/z 440.20 (M++1).
HCl in diethyl ether (1.0 M, 25-mmol) was added to a solution of tert-butyl 2-([(4-(5-amino-6-[(pyridin-3-ylamino)carbonyl]pyrazin-2-yl}phenyl)sulfonyl]-(tert-butoxycarbonyl)amino)ethylcarbamate in methanol (40 mL). The resulting mixture was stirred under reflux for 38 h. The solvent was evaporated and a mixture of saturated aqueous sodium carbonate and methylene chloride was added. The organic phase was washed with water, dried over-MgSO4, and the solvent was evaporated. Purification by column chromatography using methylene chloride/methanol, (7:3), gave 0.26 g (62% yield) of the title compound as a brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.67 (s,
HCl (4.2mL, 1.0 M in diethyl ether) was added dropwise to a cooled (0° C.) solution of tert-butyl 4-[2-(4-(5-amino-6-[(pyridin-3-ylamino)carbonyl]pyrazin-2-yl)phenoxy)ethyl]piperazine-1-carboxylate (0.300 g, 0.58 mmol) in methanol (35 mL). The solution was stirred at room temperature for 92 h. The solvent was evaporated and resulting solid was dissolved in refluxing methanol (160 mL). HCl (4.0 mL 0.7 M in diethyl ether) was added and the resulting mixture was heated at reflux for 2 h. The solvent was evaporated and the residue was dried under vacuum to give 0.25 g (88% yield) of the title compound: 1HNMR (DMSO-d6, 300 MHz) δ 11.09 (s, 1H), 10;00 (br s, 2H), 9.41 (d, J=2 Hz, 1H), 8.95 (s, 1H), 8.93 (m,I 1H), 8.68 (d, J=5 Hz, 1H), 8.23 (d, =9 Hz, 2H), 8.06 (dd, J 9, 6 Hz, 1H), 0.12 (d J 9 Hz, 2H), 4.51 (m, 2H), 3.57 (m, 10H); MS (ES) m/z 420 (M++1).
The title compound was prepared as described for Example 228 using tert-butyl 4-[2-(4-0.15-amino-6-[(pyridin-3-ylamino)carbonyllpyrazin-2-yl)-2,5-difluorophenoxy)ethyl]piperazine-1-carboxylate. Heating at 60° C. for 1 h was enough to complete the reaction, yield 91%: 1H NMR (DMSO-d6, 300 MHz) δ 10.99 (s, 0.1H), 9.79 (br s, 2H), 9.29 (s, 1H), 8.74 (s, 1H), 8.73 (m, 1H), 8.62 (d, J.=5 Hz, 1H), 8.33 (dd, J=12, 7 Hz, 1H), 7.92 (dd, J 8, 5 Hz, 1H), 7.80 (br s, 1H), 7.40 (dd, J=13, 7 Hz, 1H), −4.61 (m, 2H), 3.66 (m, 2H), 3.58 (m, 4H), 3.49 (m, 4H).
tert-Butyl 4-(5-(5-amino-6-[(pyridin-3-ylamino)carbony1)pyrazin-2-yl)-2-furoyl)piperazine-1-carboxylate (97 mg, 0.2 mmol) was dissolved in methanol (2 mL) and methylene chloride (2 nL). Hydrochloric acid (1 mL, 1 M in diethyl ether) was added and the reaction mixture was heated for 3 h at reflux. The solvent was removed in vacuo'and the residue was washed with meth ene chloride/methanol 3 mL, 1) to give 40 mg (43% yield) of the title compound as a yellow solid: 1H NMR (D2O, 400 MHz) δ 9.35 (m, 1H), 8.63 (ddd, J=9, 2, 1 Hz, 1H), 8.53 (m, 1H), 8.45 (s, 1H), 8.01 (m, 1H), 7.08 (d, J=4 Hz, 1H), 7.00 (d, J=4 Hz, 1H), 4.05 (br s, 4H), 3.38 (m, 4H), 13C NMR (D2O, 100 MHz) δ 165.2, 160.3, 153.9, 152.8, 144.7, 144.6, 137.8, 137.2, 136.8, 133.0, 131.7, 127.9, 123.7, 120.0, 109.2, 43.3; MS (ES) m/z 394 (M++1).
Pd(PPh3)4 (1.05 g, 0.91 mmol) was added to a to a solution of 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (2.0 g, 6.8 mmol), 4-carboxyphenylboronic acid (1.12 g, 6.7mmol), and sodium carbonate (2.88 g, 27.2 mmol) in tetrahydrofuran/water, (1:1, 240 mL), and the resulting mixture was heated at 75° C. for 16 days. The solvent was evaporated and the residue dissolved in water. The aqueous phase was extracted with ethyl acetate and then neutralized (pH 7) using HCl (10% aq). The formed crystals were filtered off and dried in vacuo to give 1.7 g (77% yield) of the title compound: MS (ES) m/z 336 (M++1).
In a round bottom flask fitted with a condenser, a mixture3-amino-6-bromo-N-pyndin-3-ylpyrazine-2-carboxamide (23 mg, 78 μmol), N″-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzenesulfonamide (24 mg, 78 mmol) and Pd(dppf)Cl2×CH2Cl2 (3.2 mg, 3.9 μmol) in toluene (2 mL), ethanol (0.2 mL) and Na2CO3 solution (2 M, 0.2 mL) was stirred at 80° C. over night. Silica gel (0.5 g) was added to the reaction mixture and the mixture was concentrated to dryness. The residue was purified on a silica gel column using heptane/ethyl acetate, (1:1), as the eluent to give 30 mg (96% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 10.62 (s, 1H), 9.05 (s, 1H), 8.98 (d, J=2 Hz, 1H), 8.52-8.50 (m, 2H), 8.37 (dd, J=5, 1 Hz, 1H), 8.22 (ddd, J=8, 2 and 2 Hz, 1H), 7.85 (br s, 2H), 7.83-7.81 (m, 2H), 7.45 (dd, J=8, 5 Hz, 1H), 2.65 (s, 6H); MS (ES)/Z 399
The compound was prepared as described for Example 233 using N,N-dimethy1-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide: yield 24%; mp 234.5-238.0° C.; 1H NMR (DMSO-d6, 400 MHz) δ 10.65 (s, 1H), 9.03,(s, 1H), 8.96 (d, J=2 Hz, 1H), 8.64-8.61 (m, 1H), 8.37-8.36 (m, 2H), 8.21 (ddd, J=8, 2 and 3 Hz, 1H), 7.80 (br s, 2H), 7.78-7.75 (m, 2H), 7.44 (dd, J=8, 5 Hz, 1H), 2.68 (s, 6H); MS (ES) m/z 399 (M++1).
Tbe compound was prepared as described for Example 233 using N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide: yield: 60%; mp 221.5-223.0° C.; 1H NMR (DMSO-d6, 400 MHz) δ 10.56 (s, 1H), 8.90 (d, J=2 Hz, 1H), 8.52 (s, 1H), 8.32 (dd, J=5, 1 Hz, 1H), 8.19 (ddd, J=8, 2 and 2 Hz, 1H)I 7.87 (d, =8 Hz, 1H), 7.79-7.78 (m, 2H), 7.75 (br s, 2H), 7.70 (dq, J=12 and 4 Hz, 1-H), 7.41 (dd, J 8,5 Hz, 1H), 2.75 (s, 6H); 13C NMR (MSO-d6, 100 MHz) δ 164.90, 154.14, 141.59, 144.90, 141.74, 139.05, 137.08, 136.46, 134.82, 132.73, 132.69, 129.16, 128.39, 127.08, 123.74, 122.26, 37.13; MS (ES) m/z 399 (M++1).
The compound was prepared as described for Example 233 using 4-(4,4,5,5-tetramethyl-0.1,3,2-dioxaborolan-2-yl)benzenesulfonamide: yield 40%; 1H NMR (DMSO-d6, 400 MHz) 3 10.61 (br s, 1H), 9.03 (s, 1H), 8.98 (d, J=2 Hz, 1H), 8.44 (d, J=9 Hz, 2H), 8.37 (dd, J=5, 1Hz, 1H), 8.21 (ddd, J=8,2 and 2 Hz, 1H), 7.90 (d, J=8 Hz, 2H), 7.82 (brs, 2H), 7.44 (dd, J=8, 5 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) 3 165.06, 154.70, 145.52, 145.22, 143.46, 143.27, 138.86, 137.03, 134.63, 128.73, 126.06, 126.01, 123.85, 123.56; MS (ES),7/z 370.97 (M++1).
2-Amino-5-bromo-N-pyridin-3-ylnicotinamide (0.10 g, 0.34 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (0.13 g, 0.41 mmol) and Pd(dppf)Cl2XCH2Cl2 (12.4 mg, 17.2 lmol) were mixed in toluene/ethanol, (1: 1, 2 mL), and saturated Na2CO3 (aq) solution (6.20 mL). Nitrogen gas was bubbled through the reaction mixture for 5 min and the mixture was heated for 16 h. Silica gel was added and the solvent was evaporated. The residue was purified on a silica gel column, using a gradient heptane 100% to ethyl acetate 100% as the eluent, to give 95 nmg (79% yield). Additional purification using reversed phase chromatography (C18, water/acetonitrile gradient) gave 36 mg (26% yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ 2.70 (s, 6H), 7.87 (d, J=9 Hz, 2H), 7.93 (dd, 6 Hz, 1H), 8.13 (d, J=9 Hz, 2H), 8.62(d, J=6 Hz I H),8.67 (d, J=9 Hz, 1H), 8.71 (d, J=2 Hz, 1H), 8.87 (s, 1H), 9.28 (s, 1H), 11.60 (s, 1H); MS (ES) m/z 398 (M++1).
The title compound was prepared as described for Example 233 using 4-([(3-morpholin-4-ylpropyl)amino]sulfonyl}phenylboronic acid: yield 86%: mp 219-227° C. (decomnp.); 1H NM (DMSO-d6, 400 MHz) δ 10.61 (s, 1H), 9.03 (s, 1H), 8.99 (m, 1H), 8.47 (d, =8-Hz, 2H), 8.38 (d, J=4 Hz, 1H),8.22 (m, 1H), 7.86 (d, =J8 Hz, 4H), 7.69 (t, J=6 Hz, I H), 7.45 (dd,3J 8, S Hz, 1H), 3.50 (t, J=4 Hz, 4H), 2.80 (q, J=7 Hz. 2H), 2.22 (m, 6H), 1.52 (quint, J=7 Hz, 2H); 13C NMR.(DMSO-d6, 100 MHz) 3 165.0, 154.7, 145.5, 145.2, 143.2, 139.6, 139.3, 136.8, 134.6, 128.6, 126.9, 126.2, 123.8, 123,5, 66.2, 55.3, 53.2, 40.8, 25.9; MS (ES) m/z 498 (M+++1).
The title compound was prepared as described for Example 233 using 4-[(4-methylpiperazin-1-yl)sulfonyl]phenylboronic acid: yield: 79%; mp decomposes 220-2296C; 1H NMR (DMSO-d6, 400 MHz) δ 9.85 (br s, 1H), 8.88 (br s, 1H), 8.75 (s, 1H), 8.45 (d, J=4 Hz, 1H), 5.30 (m, 1H), 8.07 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 7.37 (dd, J=8, 5 Hz, 1H), 3.37 (m, 4H), 2.92 (m, 4H), 2.56 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) 56172.1, 162.6, 153.7, 153.6, 149.6, 146.2, 142.9, 142.0, 136.4, 135.0, 134.4, so 132.5, 131.7, 61.5, 52.6; MS (TSP) m/z 454 (M++1).
HCl in diethyl ether (1 M, 0.81 mL) was added to a solution of 3-amino-6-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-N-pyridin-3-ylpyrazine-2-carboxamide (0.096 g, 0.21 mmol) in of methylene chloride/methanol, (0.95:0.05, 8 mL). The yellow precipitate was filtered off, washed with diethyl ether and dried under vacuo to give the title compound as a yellow solid: mp 217-223° C. (decomp.).
Pharmaceutical Formulations
According to one aspect of the present invention there is provided a pharmaceutical formulation comprising a compound of formula I, as a free base or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.
The composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment, patch or cream or for rectal administration as a suppository.
In general the above compositions may be prepared in a conventional manner using conventional excipients, pharmaceutical diluents or inert carriers. Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
The following illustrate representative pharmaceutical dosage forms containing a compound of formula I, as a free base or a pharmaceutically acceptable salt thereof, (hereafter compound X), for therapeutic or preventive use in mammals:
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
Medical Use
Surprisingly, it has been found that the compounds defined in the present invention, as a free base or a pharmaceutically acceptable salt thereof, are well suited for inhibiting glycogen-synthase kinase-3 (GSK3). Accordingly, the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 activity, i.e. the compounds may be used to produce an inhibitory effect of OSK3 in mammals, including man in need of such prevention and/or treatment.
GSK3; is highly expressed in the central and peripheral nervous system and in other tissues. Thus, it is expected that a the compounds of the invention are well suited for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 in the central and peripheral nervous system. In particular, such compounds of the invention are expected to be suitable for prevention and/or treatment of conditions associated with especially, dementia, Alzheimer's Disease, Parkinson's Disease, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Gaum, HIV dementia, diseases with associated neurofibrillar tangle pathologies, amyotrophic lateral sclerosis, corticobasal degeneration, dementia pugilistica, Down syndrome, Huntington's Disease, ppstencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disorders, affective disorders, depression, schizophrenia, cognitive disorders, Type I and Type I diabetes and diabetic neuropathy, hair loss and contraceptive medication.
The dose required for the therapeutic or preventive treatment of a particular disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
The present invention relates also to the use of a compound of formula I as defined hereinbefore, in the manufacture of a medicament for the prevention and/or treatment of conditions associated with GSK3.
In the context of the present specification, the term “therapy” includes treatment as well as prevention, unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.
The invention also provides a method of treatment and/or prevention of conditions associated with,GSK3, in a patient suffering from, or at risk of, said condition, which comprises administering to the patient an effective amount of a compound of formula I, as hereinbefore defined.
Non-Medical Use
In addition to their use in therapeutic medicine, the compounds of formula I as a free base or a pharmaceutically acceptable salt thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for thei evaluation of the effects of inhibitors of GSK3 related activity in laboratory animals such as cat, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
Pharmacology
Determination OfATP competition in Scintillation Proximity GSK3,8Assay.
GSK3β Scintillation Proximity Assay.
The competition experiments were carried out in duplicate with 10 different concentrations of the inhibitors in clear-bottom microtiter plates (Wallac, Finland). A biotinylated peptide substrate, Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO3H2)-Pro-Gln-Leu (AstraZeneca, Lund), was added at a final concentration of 1 μM in an assay buffer containing 1 mU recombinant human GSK30 (Dundee University, UK), 12 mM morpholinepropanesutlfonic acid (MOPS), pH 7.0, 0.3 mrM EDTA, 0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5. % glycerol and 0.5 μg BSA/25 μl. The reaction was initiated by the addition of 0.04 μCi [γ-33P]ATP (Amersham, UK) and unlabelled ATP at a final concentration of 1 MM and assay volume of 25 μl. After incubation for 20 minutes at room temperature, each reaction was terminated by the addition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.11% Triton X-100 and 0.25 mg streptavidin coated Scintillation Proximity Assay (SPA) beads (Amersham, UK). After 6 hours the radioactivity was determined in a liquid scintillation counter (1450 MicroBeta Trilux, Wallac). The inhibition curves were analysed by non-linear regression using GraphPad Prism, USA. The KF value of ATP for GSK30, used to calculate the inhibition constants (Ki) of the various compounds, was 20 μM.
The following abbreviations have been used:
Typical Ki values for the compounds of the present invention are in the range of about 0.25 0.001 to about 10,000 nM, preferably about 0.001 to about 1000 nM, particularly preferred about 0.001 nM to about 300 nM.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0102439-7 | Jul 2001 | SE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/SE02/01339 | 7/3/2002 | WO | 12/22/2003 |
