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HK1070066B - Hiv inhibiting pyrimidines derivatives - Google Patents

Hiv inhibiting pyrimidines derivatives Download PDF

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Publication number
HK1070066B
HK1070066B HK05102760.9A HK05102760A HK1070066B HK 1070066 B HK1070066 B HK 1070066B HK 05102760 A HK05102760 A HK 05102760A HK 1070066 B HK1070066 B HK 1070066B
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HK
Hong Kong
Prior art keywords
alkyl
group
formula
substituted
cyano
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HK05102760.9A
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Chinese (zh)
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HK1070066A1 (en
Inventor
Jérôme Emile Georges Guillemont
Patrice Palandjian
Marc René DE JONGE
Lucien Maria Henricus Koymans
Hendrik Maarten Vinkers
Frederik Frans Desiré DAEYAERT
Jan Heeres
Koen Jeanne Alfons Van Aken
Paulus Joannes Lewi
Paul Adriaan Jan Janssen
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詹森药业有限公司
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Priority claimed from PCT/EP2002/008953 external-priority patent/WO2003016306A1/en
Publication of HK1070066A1 publication Critical patent/HK1070066A1/en
Publication of HK1070066B publication Critical patent/HK1070066B/en

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Description

HIV inhibiting pyrimidine derivatives
The present invention relates to pyrimidine derivatives having HIV (human immunodeficiency virus) replication inhibiting properties. The invention further relates to a preparation method thereof and a pharmaceutical composition containing the same. The invention also relates to the use of the compounds for the preparation of a medicament for the prevention or treatment of HIV infection.
Compounds structurally related to the compounds of the present invention are disclosed in the prior art.
WO99/50250 and WO 00/27825 disclose aminopyrimidines having HIV replication inhibiting properties.
WO 97/19065 discloses substituted 2-anilinopyrimidines as protein kinase inhibitors.
WO 00/62778 relates to cyclic protein tyrosine kinase inhibitors.
WO 98/41512 describes substituted 2-anilinopyrimidines as inhibitors of protein kinases.
US 5,691,364 describes benzamidine derivatives and their use as anticoagulants.
WO 00/78731 describes 5-cyano-2-aminopyrimidine derivatives as KDR kinase or FGFr kinase inhibitors for the prevention and treatment of diseases associated with angiogenesis.
The compounds of the present invention differ from the compounds of the prior art in structure, pharmacological activity and/or pharmacological strength.
Surprisingly, it has been found that the compounds of the present invention have an enhanced ability to inhibit the replication of Human Immunodeficiency Virus (HIV), in particular that they have an improved ability to inhibit mutant strains, i.e. strains that are drug-resistant (drug-or multi-drug-resistant HIV strains) known in the art.
The present invention relates to compounds of the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein-a1＝a2-a3＝a4-represents a divalent radical of formula,
-CH＝CH-CH＝CH- (a-1)
-N＝CH-CH＝CH- (a-2)
-N＝CH-N＝CH- (a-3)
-N＝CH-CH＝N- (a-4)
-N＝N-CH＝CH- (a-5)
-b1＝b2-b3＝b4-represents a divalent radical of formula,
-CH＝CH-CH＝CH- (b-1)
-N＝CH-CH＝CH- (b-2)
-N＝CH-N＝CH- (b-3)
-N＝CH-CH＝N- (b-4)
-N＝N-CH＝CH- (b-5)
n is 0, 1, 2, 3 or 4; and when-a1＝a2-a3＝a4When-is (a-1), then n can also be 5;
m is 1, 2, 3 and when-b1＝b2-b3＝b4When-is (b-1), then m can also be 4;
R1represents hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy substituted C1-6An alkyl group; quilt C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
each R is2Independently represents hydroxy, halogen, optionally cyano or-C (═ O) R6Substituted C1-6Alkyl radical, C3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkynyl, C1-6Alkoxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino, polyhalomethyl, — polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6Or a group of the formula
Wherein each A1Independently N, CH or CR6(ii) a And is
A2Represents NH, O, S or NR6；
X1is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、C1-4Alkanediyl, -CHOH-, -S (═ O)P-、-X2-C1-4alkanediyl-or-C1-4alkanediyl-X2-；
X2represents-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-CHOH-、-S-、-S(＝O)P-；
R3Represents NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a Is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and is selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；
X3is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-S-、-S(＝O)P-、-X2-C1-4Alkanediyl-, -C1-4alkanediyl-X2a-、-C1-4alkanediyl-X2b-C1-4Alkanediyl, -C (═ N-OR)8)-C1-4Alkanediyl-;
wherein X2ais-NH-NH-, -N-, -O-, -C (O) -, -S (O)P-; and
wherein X2bis-NH-NH-, -N-, -C (O) -, -S (O)P-；
R4Represents halogen, hydroxy, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy, cyano, nitro, polyhaloC1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyl, formyl, amino, mono-or di (C)1-4Alkyl) amino or R7；
R5Is hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl or C1-6Alkylcarbonyloxy substituted C1-6Alkyl radical, C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
R6is C1-4Alkyl, amino, mono-or di (C)1-4Alkyl) amino or polyhaloC1-4An alkyl group;
R7denotes monocyclic, bicyclic or tricyclic saturated, partially saturated orAn aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each said carbocycle or heterocycle ring system optionally may be mono-, di-, tri-, tetra-or five independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8)、R7a、-X3-R7aOr R7a-C1-4Alkyl substituent substitution;
R7arepresents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems optionally may be substituted by one, two, three, four or five independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8) Substituted with the substituent(s);
R8is hydrogen, C1-4Alkyl, aryl or aryl C1-4An alkyl group;
R9and R10Each independently is hydrogen; a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R77Wherein each of C mentioned above1-6The alkyl groups optionally may each be independently selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s); or
R9And R10May together form a divalent or trivalent radical of the formula
-CH2-CH2-CH2-CH2- (d-1)
-CH2-CH2-CH2-CH2-CH2- (d-2)
-CH2-CH2-O-CH2-CH2- (d-3)
-CH2-CH2-S-CH2-CH2- (d-4)
-CH2-CH2-NR12-CH2-CH2- (d-5)
-CH2-CH＝CH-CH2- (d-6)
＝CH-CH＝CH-CH＝CH- (d-7)
R11Is cyano; optionally is covered with C1-4Alkoxy, cyano, amino, mono-or di (C)1-4Alkyl) amino or aminocarbonyl substituted C1-4An alkyl group; c1-4An alkylcarbonyl group; c1-4Alkoxycarbonyl, aminocarbonyl, mono-or di (C)1-4Alkyl) aminocarbonyl;
R12is hydrogen or C1-4An alkyl group;
R13and R14Each independently being C optionally substituted by cyano or aminocarbonyl1-6Alkyl, C optionally substituted by cyano or aminocarbonyl2-6Alkenyl, C optionally substituted by cyano or aminocarbonyl2-6An alkynyl group;
R15is C substituted by cyano or aminocarbonyl1-6An alkyl group;
R16is C optionally substituted by cyano or aminocarbonyl1-6Alkyl, or R7；
p represents 1 or 2;
aryl is phenyl or mono-, di-, tri-, tetra-or five are independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, R7or-X3-R7Phenyl substituted with the substituent(s) of (1).
C as a radical or part of a radical as used hereinbefore or hereinafter1-4Alkyl means a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; c as a radical or part of a radical1-6Alkyl means a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms as defined for C1-4Alkyl groups, and pentyl, hexyl, 2 methylbutyl, and the like; c as a radical or part of a radical2-6Alkyl means a straight or branched chain saturated hydrocarbon group having 2 to 6 carbon atoms such as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the like; c1-4Alkanediyl means a straight-chain or branched saturated divalent hydrocarbon radical having from 1 to 4 carbon atoms, such as methylene, 1, 2-ethanediyl or 1, 2-ethylene, 1, 3-propanediyl or 1, 3-ethanediylPropyl, 1, 4-butanediyl, 1, 4-butylene, or the like; c3-7Cycloalkyl is the generic name for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C2-6Alkenyl means a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms containing one double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; c2-6Alkynyl refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms containing one triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.; monocyclic, bicyclic or tricyclic saturated carbocycle represents a ring system consisting of 1, 2 or 3 rings, said ring system containing only carbon atoms and said ring system containing only single bonds; a monocyclic, bicyclic or tricyclic partially saturated carbocycle represents a ring system consisting of 1, 2 or 3 rings, said ring system containing only carbon atoms and containing at least one double bond, with the proviso that the ring system is not an aromatic ring system; monocyclic, bicyclic or tricyclic aromatic carbocycle represents an aromatic ring system consisting of 1, 2 or 3 rings, said ring system containing only carbon atoms; the term aromatic is well known to those skilled in the art and refers to a cyclic conjugated system with 4n +2 electrons, i.e. with 6, 10, 14 pi electrons (Hull's rule); monocyclic, bicyclic or tricyclic saturated heterocyclic ring represents a ring system consisting of 1, 2 or 3 rings and containing at least one heteroatom selected from O, N or S, which ring system contains only single bonds; monocyclic, bicyclic or tricyclic saturated heterocycles represent ring systems consisting of 1, 2 or 3 rings and containing at least one heteroatom selected from O, N or S and at least one double bond, with the proviso that the ring system is not an aromatic ring system; monocyclic, bicyclic or tricyclic aromatic heterocycles represent aromatic ring systems consisting of 1, 2 or 3 rings and containing at least one heteroatom selected from O, N or S.
Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [4, 2, 0] octyl, cyclononyl, cyclodecyl, decahydronaphthyl, tetradecahydroanthracenyl and the like.
Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [4, 2, 0] octenyl, cyclononenyl, cyclodecenyl, octahydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2, 3,4, 4a, 9, 9a, 10-octahydro-anthracenyl and the like.
Specific examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are phenyl, naphthyl, anthracenyl.
Specific examples of monocyclic, bicyclic or tricyclic saturated heterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadioxanyl, pyrazolidinyl, piperidinyl (piperidinyl), hexahydropyrimidyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl and the like.
Specific examples of the monocyclic, bicyclic or tricyclic saturated heterocyclic ring are pyrrolinyl, imidazolinyl, pyrazolinyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl (1, 3-benzodioxolyl), 2, 3-dihydro-1, 4-benzodioxinyl (2, 3-dihydro-1, 4-benzodioxolyl), indolinyl and the like.
Specific examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are azetidinyl, oxetanyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzooxadiazolyl, benzothiadiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, quinolizinyl, 2, 3-diazananyl, quinoxalinyl, quinazolinyl, pyridopyridyl, Pteridinyl, benzopyranyl, pyrrolopyridinyl, thienopyridinyl, furopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, isoxazolopyridinyl, oxazolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidyl, pyrazolopyrimidyl, imidazopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, isothiazolopyridazinyl, isothiazolopyridazolinyl, isoxazolopyridazinyl, isothiazolopyridazinyl, pyrazolopyridazinyl, and pyrazolopyridazinyl, Imidazopyridazinyl, oxadiazolyl, thiadiazolopyridyl, triazolopyridinyl, oxadiazolopyridazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolyl-pyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolyl-pyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazoloxazolooxazolyl, imidazothiazolyl, imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazodotriazinyl, thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
As used herein before, the term (═ O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, and a sulfonyl moiety when two of the terms are attached to a sulfur atom.
The term halogen is a generic term for fluorine, chlorine, bromine and iodine. In the foregoing and in the following use, polyhalomethyl as a group or part of a group is defined as methyl substituted by mono-or polyhalo, in particular methyl having one or more fluorine atoms, e.g., difluoromethyl or trifluoromethyl; polyhaloC as a group or part of a group1-4Alkyl or polyhalo C1-6Alkyl is defined as C substituted by mono-or polyhalogens1-4Alkyl or C1-6Alkyl groups, for example, groups defined in halomethyl, 1-difluoro-ethyl, and the like. When in polyhalomethyl, polyhaloC1-4Alkyl or polyhalo C1-6When more than one halogen atom is attached to an alkyl group in the definition of alkyl group, they may be the same or different.
At R7Or R7aThe meaning of the term heterocycle in the definition of (1) includes all possible heterocyclic isomers, for example, pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl.
If not otherwise stated, in R7Or R7aIn the definition of (a), a carbocyclic or heterocyclic ring may suitably be attached to the residue of the molecule of formula (I) by any ring carbon or heteroatom. Thus, for example, when the heterocycle is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, etc., or when the carbocycle is naphthyl, it can be 1-naphthyl, 2-naphthyl, etc.
When any variable (e.g., R)7、X2) When occurring more than one time in any constituent, each definition is independent.
Lines drawn from substituents into the interior of the ring system indicate that the bond may be attached to any suitable ring atom.
For therapeutic use, salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases can also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.
The pharmaceutically acceptable addition salts mentioned hereinbefore include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) may form. The latter can be conveniently obtained by treating the base form with a suitable acid, for example, an inorganic acid, e.g., hydrohalic acids, e.g., hydrochloric acid, hydrobromic acid, and the like; sulfuric acid; nitric acid; phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1, 2, 3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like. The salt form can in turn be converted to the free base form by treatment with a base.
The compounds of formula (I) containing an acid proton may be converted into the therapeutically active non-toxic metal or amine addition salt form by treatment with a suitable organic or inorganic base. Suitable salt forms of the bases include, for example, ammonium salts, alkali metal and alkaline earth metal salts, e.g., lithium, sodium, potassium, magnesium, calcium salts, and the like. Salts of organic bases, such as primary, secondary and tertiary aliphatic and aromatic amines, for example methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-N-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine (benzathine), N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, hydrabamine salts, and salts of amino acids, for example arginine, lysine and the like. The salt form can in turn be converted to the free acid form by treatment with an acid.
The term addition salts also includes the hydrates and solvent adducts which the compounds of formula (I) can form. Examples of these forms are hydrates, alcoholates and the like.
The term "quaternary ammonium" as used hereinbefore refers to quaternary ammonium salts of the compounds of formula (I) which may be formed by reaction of the basic nitrogen of the compound of formula (I) with a suitable quaternising agent, for example, an optionally substituted alkyl halide, aryl halide or aralkyl halide such as methyl iodide or benzyl iodide. Other reactants having good leaving groups may also be used, for example, alkyl triflates, alkyl mesylates, and alkyl p-toluenesulfonates. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloride, bromide, iodide, trifluoroacetate and acetate ions. The counter ion selected may be introduced using an ion exchange resin.
The N-oxide forms of the compounds of the invention include compounds of formula (I) in which one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
It will be appreciated that some of the compounds of formula (I) and the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof may contain one or more chiral centres and exist as stereochemically isomeric forms.
The term "stereochemically isomeric forms" as used hereinbefore refers to all the possible stereoisomers which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound refers to a mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as the individual isomers of each formula (I) and the N-oxides, salts, solvates or quats thereof being substantially free of, i.e. mixed with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Thus, when the compound of formula (I) is, for example, specific (E), this means that the compound is substantially free of the (Z) isomer. In particular, the stereocenter may have the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated groups may have either the cis-or trans-configuration. The double bond-containing compounds may have E (hetero) or Z (homo) -stereochemistry at the double bond. The terms cis, trans, R, S, E and Z are well known to those skilled in the art. The stereochemically isomeric forms of the compounds of formula (I) are obviously also intended to be embraced therein. The absolute stereochemical configuration of some compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines or metal complexes and intermediates used in their preparation have not been determined experimentally. In these cases, the first stereoisomer to be isolated is referred to as "a" and the second as "B", without further mention of its actual stereochemical configuration. However, when "a" and "B" have an enantiomeric relationship, the "a" and "B" stereoisomers can be clearly characterized, for example, in terms of their optical rotation. The absolute configuration of such compounds can be determined by one skilled in the art using methods known in the art, for example, X-ray diffraction. When "a" and "B" are a mixture of stereoisomers, they may be separated again, whereby the first of them is referred to as "a 1" and "B1" respectively, and the second is referred to as "a 2" and "B2" without further reference to their actual stereochemical configuration.
Some of the compounds of formula (I) may also exist in their tautomeric form. Although such forms are not explicitly indicated in the above formula, they are also included within the scope of the present invention.
The meaning of the compounds of the formula (I) also includes, wherever applicable hereinafter, the N-oxide forms thereof, the salts thereof, the quaternary amines thereof and the stereochemically isomeric forms thereof. Of most interest are those compounds of formula (I) which are stereochemically pure.
The substituents used in each of the foregoing and following paragraphs may each independently be selected from a range of multiple definitions, for example, for R9And R10All possible combinations are included which are chemically possible and which can form chemically stable molecules.
A particular group of compounds are those of formula (I) wherein R3Is substituted by at least one group selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of1-6An alkyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7And wherein two hydrogen atoms attached to the same carbon atom are substituted by C1-4C substituted by alkanediyl1-6An alkyl group; by hydroxy and a second group selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of1-6An alkyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of2-6An alkenyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；R4Is halogen, hydroxy, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy, cyano, nitro, polyhaloC1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyl, formyl, amino, mono-or di (C)1-4Alkyl) amino; r7Is monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems optionally may be substituted with one, two, three, four or five independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, R7a、-X3-R7aOr R7a-C1-4Alkyl substituent substitution; r7aIs a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems optionally may be substituted with one, two, three, four or five independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl; r9And R10Each independently is hydrogen; a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl or R7Wherein each of the above C1-6The alkyl groups may optionally be independently selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Is substituted with the substituent(s).
A group of interesting compounds are those of formula (I) wherein-a1＝a2-a3＝a4-represents a divalent group of formula-CH- (a-1).
Another group of compounds of interest are those of formula (I) having the formula,
An N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein-a1＝a2-a3＝a4-、-b1＝b2-b3＝b4-、R1、R2、R3、R4M, and X1As defined above; n' is 0, 1, 2 or 3 and when-a1＝a2-a3＝a4When-is (a-1), then n' may also be 4; r2’Is halogen, C1-6Alkyl, trihalomethyl, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group; provided that R is2’Located relative to NR1Para to the group.
Another group of compounds of interest are those of formula (I) having the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein,
-b1＝b2-b3＝b4-、R1、R2、R3、R4m, and X1As defined above;
n' is 0, 1, 2, 3 or 4;
R2’is halogen, C1-6Alkyl, trihalomethyl, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group;
yet another group of compounds of interest are those of formula (I) having the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein,
R1、R2、R3、R4and X1As defined above;
n' is 0, 1, 2, 3 or 4;
R2’is halogen, C1-6Alkyl, trihalomethyl, cyano, aminocarbonyl, C substituted by cyano or aminocarbonyl1-6An alkyl group.
Also particular compounds are those of formula (I), (I '), (I ") or (I'"), wherein one or any possible plurality of the following conditions are fulfilled:
a) m is 1, 2 or 3, particularly 2 or 3, more particularly m is 2 and the two R' s4The substituents being situated relative to X12-and 6-positions (ortho) of the group;
b) m is 1, 2 or 3 and R3Is located opposite to X14 position (para) of the group;
c)X1is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、C1-4Alkanediyl, -CHOH-, -S (═ O)P-、-X2-C1-4alkanediyl-or-C1-4alkanediyl-X2-；
d) Where applicable n' is 0;
e) wherein n is 1 and R is2The substituents being situated relative to NR1-the 4 position (ortho) of the linker;
f)R2is hydroxy, halogen, optionally substituted by hydroxy or-C (═ O) R6Substituted C1-6Alkyl radical, C3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups2-6Alkynyl, C1-6Alkoxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di (C)1-6Alkyl) amino, polyhalomethyl, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6Or a group of the formula
Wherein each A is1Independently N, CH or CR6(ii) a And
A2is NH, O, S or NR6；
g)R2’Is halogen, C1-6Alkyl, trihalomethyl, cyano, C substituted by cyano or aminocarbonyl1-6An alkyl group;
h)R2is cyano, aminocarbonyl or C substituted by cyano or aminocarbonyl1-6Alkyl, especially cyano;
i)R2’is cyano, aminocarbonyl or C substituted by aminocarbonyl1-6Alkyl, especially cyano.
Preferred embodiments include those compounds of formula (I), (I ') or (I'), wherein R is3Is NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a C substituted by cyano or aminocarbonyl2-6An alkyl group; by NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7(ii) a And R is9aRepresents a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein R is9aEach C in the definition1-6The alkyl groups optionally each independently may be selected from hydroxy, C1-6Alkoxy, hydroxy C1-6An alkoxy group; carboxy, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino; polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s); r9aMay also be reacted with R10Together form a divalent or trivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5), (d-6) or (d-7) as defined above.
A further interesting group of compounds are those of formula (I), (I ') or (I'), wherein R3Is NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a By NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7(ii) a And R is9aRepresents a hydroxyl group; c1-6Alkyl radical, C1-6An alkoxy group; c1-6Alkylcarbonyl group, C1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein R is9aEach C in the definition1-6The alkyl groups optionally each independently may be selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl radicalCyano, amino, imino, mono-or di (C)1-4Alkyl) amino; polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s); r9aMay also be reacted with R10Together form a divalent or trivalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5), (d-6) or (d-7) as defined above.
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3is-CH-N-NH-C (═ O) -R16(ii) a By NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is provided with one orA plurality of substituents are each independently selected from halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7(ii) a And R is9aAs defined above.
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3Is NHR13；NR13R14；-C(＝O)-R15(ii) a Is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7。
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3Is being NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7(ii) a And R is9aAs defined above.
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3To be one or more than one respectivelyIndependently selected from cyano, NR9R10Or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10Or R7C substituted by a substituent of2-6An alkenyl group; c substituted by cyano1-6Alkoxy radical C1-6An alkyl group; by hydroxy and is selected from cyano or R7C substituted with the second substituent of (1)1-6An alkyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3Is R7。
Yet another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3Represents C substituted by cyano1-6Alkyl, especially C, substituted by cyano2-6Alkyl, more particularly ethyl or propyl substituted by cyano; or C substituted by cyano2-6An alkenyl group. Preferably C substituted by cyano2-6An alkenyl group.
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3Is cyano and R7Substituted C1-6Alkyl, or by cyano and R7Substituted C2-6An alkenyl group.
Yet another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3Is as a quilt R7Substituted C1-6An alkyl group.
Yet another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is3is-C (═ N-O-R)8)-C1-4An alkyl group.
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is substituted hydroxy and is selected from cyano or R7Second taking ofSubstituted C1-6An alkyl group.
Yet another group of compounds of interest are those of formula (I), (I ') or (I'), wherein R is2Or R2’Is cyano or aminocarbonyl and R1Is hydrogen.
Another group of compounds of interest are those of formula (I), (I ') or (I'), wherein m is 2 or 3 and X1is-NR5、-O-、-C(＝O)-、-CH2-、-CHOH-、-S-、-S(＝O)P-, especially where X1is-NR5-or-O-.
Yet another group of compounds of interest are those of formula (I), (I '), (I ") or (I'"), wherein one or more, preferably all, of the following conditions are fulfilled:
a) n is at least 1, in particular 1; or n' is 0;
b)R2or R2’Is cyano;
c) m is 1, 2 or 3;
d)R4is C1-6Alkyl, especially methyl; a nitro group; an amino group; halogen; c1-6Alkoxy or R7；
e)R3Is R7、NR13R14、-C(＝O)R15、-CH＝N-NH-C(＝O)R16、-C(＝O)NHR13、-C(＝O)NR13R14、-C(＝N-OR8)-C1-4Alkyl, C substituted by cyano1-6Alkyl, C twice substituted by cyano1-6Alkyl radical, by NR9R10Substituted C1-6Alkyl, C substituted by hydroxy and cyano1-6Alkyl, by hydroxy and R7Substituted C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, C substituted by cyano1-6Alkoxy radical C1-6Alkyl radical, by R7Substituted C2-6Alkenyl, C substituted by cyano2-6Alkenyl, by cyano-bisSubstituted by less than one carbon atom2-6Alkenyl, by cyano and R7Substituted C2-6Alkenyl, by cyano and-C (═ O) -C1-6Alkyl substituted C2-6Alkenyl, C substituted by cyano and halogen2-6Alkenyl, by-C (═ O) -NR9R10Substituted C2-6Alkenyl, C substituted by halogen2-6Alkenyl, C twice substituted by halogen2-6Alkenyl or by NR9R10Substituted C2-6An alkenyl group;
f)X3is-C (═ O) -, -CH2-C (═ O) -, OR-C (═ N-OR)8)-C1-4Alkanediyl-;
g)X1is NH or O;
h)R1is hydrogen or C1-4An alkyl group.
Preferred compounds of formula (I), (I '), (I ") or (I'") are compound 1, 25, 84, 133, 152, 179, 233, 239, 247, 248 (see tables 3,4 and 5), the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof.
In general, the compounds of formula (I) can be prepared by reacting a compound of formula (I) wherein W is1An intermediate of formula (II) which is a suitable leaving group such as halogen, triflate, tosylate, mesylate, etc., is reacted with an intermediate of formula (III). The reaction can be carried out at elevated temperatures.
In addition, the above reaction may be carried out in the presence of a suitable solvent such as acetonitrile; alcohols such as ethanol, 2-propanol-hydrochloric acid; n, N-dimethylformamide; n, N-dimethylacetamide, 1-methyl-2-pyrrolidone; 1, 4-dioxane and propylene glycol monomethyl ether. Preferred solvents are 2-propanol, 6N HCl in 2-propanol or acetonitrile, especially acetonitrile. Optionally, sodium hydride may also be present.
In this and the following preparation processes, the reaction product can be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art, for example, extraction, crystallization, distillation, trituration and chromatography.
A compound of formula (I) wherein R3R being an aromatic ring system representing a mono-, bi-or tricyclic ring7R is a hydrogen atom3With R7’And the compound is represented by the formula (I-a), wherein W2Represents a suitable leaving group, e.g. halogen, hydroxy, triflate, tosylate, thiomethyl, mesyl, trifluoromethylsulfonyl and the like, of formula (IV) wherein R isaRepresents a boronic acid group or a tri (C)1-4Alkyl) stannyl, such as tributylstannane, with an intermediate of formula (V) in the presence of a suitable catalyst, such as tetrakis (triphenylphosphine) palladium, a suitable salt, such as sodium carbonate, potassium carbonate and Cs2CO3And a suitable solvent, e.g. dioxane, dimethyl ether, toluene or an alcohol/water mixture such as MeOH/H2The reaction is carried out in the presence of O. RaIt may also represent a halogen such as bromine, in which case the reaction is carried out in the presence of 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis (1, 3, 2-dioxaborolane).
A compound of formula (I) wherein R3Is R representing a monocyclic, bicyclic or tricyclic saturated ring system7R is a hydrogen atom3With R7”And the compound is represented by formula (I-b), and can be prepared by reacting an intermediate of formula (IV) with an intermediate of formula (VI).
A compound of formula (I) wherein R3RepresentsC substituted by cyano1-6Alkyl radical, the R3With C1-6alkyl-CN and the compound is represented by formula (I-c), wherein W3Intermediates of formula (VII) which represent a suitable leaving group, e.g. a halogen such as chlorine, are prepared by reaction with a suitable cyanate, e.g. sodium cyanide or potassium cyanide, in the presence of a suitable solvent, e.g. N, N-dimethylformamide or dimethylsulfoxide.
A compound of formula (I) wherein R3Is represented by R7Substituted C1-6An alkyl group; NR (nitrogen to noise ratio)9R10Or optionally CN, R7Or NR9R10Substituted C1-6An alkoxy group; the R is3With C1-6alkyl-Q represents, wherein Q represents R7；NR9R10Or optionally CN, R7Or NR9R10Substituted C1-5An alkoxy group; and which are represented by formula (I-d) may be prepared by reacting an intermediate of formula (VII) with an intermediate of formula (VIII), optionally in the presence of a suitable salt such as potassium carbonate, potassium cyanide, potassium iodide and a suitable solvent such as acetonitrile.
A compound of formula (I) wherein R3Is represented by-C (═ N-O-R)8)-C1-4Alkyl, which is represented by formula (I-e), may be prepared by reacting an intermediate of formula (IX) with an intermediate of formula (X) in the presence of a suitable solvent, for example an alcohol such as ethanol.
A compound of formula (I) wherein R3Represents CRc’＝CRc-CN, wherein RcRepresents hydrogen or C1-4Alkyl and Rc’Represents hydrogen, C1-4Alkyl or R7Provided that CR isc’＝CRcRestricted to C only2-6Alkenyl radicals, which are represented by the formula (I-f), can be prepared by reacting an intermediate of the formula (XI) with a phosphorus ylide precursor, where R isbRepresents for example (phenyl)3P+-Cl-Or (CH)3CH2-O) P (═ O) -Wittig or Horner-Emmons reagents of formula (XII) in the presence of a suitable salt such as potassium tert-butoxide and a suitable solvent such as tetrahydrofuran.
Compounds of formula (I-f-1) and (I-f-2) as described below can be prepared by reacting a compound of formula (I-f-1) and (I-f-2) wherein W is5An intermediate of formula (XXXIX) representing a suitable leaving group, or a suitable addition salt thereof, is prepared by reaction with acrylonitrile or acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent.
Suitable leaving groups in the above reaction are for example halogen, triflate, toluene sulfonic acid, methane sulfonic acid and the like. Preferably W5Is halogen, more specifically iodine or bromine.
The palladium (Pd) catalyst may be a homogeneous Pd catalyst such as Pd (OAc)2、PdCl2、Pd(PPh3)4、Pd(PPh3)2Cl2Palladium bis (dibenzylideneacetone), palladium thiomethylphenylglutaramide metal ring compounds (pa11adium thiomethylphenylglutaramide metal ring), or the like, or heterogeneous Pd catalysts such as palladium on carbon, palladium on metal oxide, palladium on zeolite.
Preferably, the palladium catalyst is a heterogeneous catalyst, more preferably palladium on carbon (Pd/C). Pd/C is a recyclable catalyst that is stable and relatively inexpensive. It can be easily separated (filtered) from the reaction mixture, thus reducing the risk of Pd remaining in the final product. The use of Pd/C also avoids the need for expensive, toxic and product-contaminating ligands, such as phosphine ligands.
Suitable bases in the above reaction are, for example, sodium acetate, potassium acetate, N-diethylethylamine, sodium bicarbonate, sodium hydroxide and the like.
Suitable solvents in the above reaction are, for example, acetonitrile, N-dimethylacetamide, ionic liquids such as [ bmim [ ]]PF6N, N-dimethylformamide, water, tetrahydrofuran, dimethylsulfoxide, 1-methyl-2-pyrrolidone, and the like.
A compound of formula (I) wherein R3Represents CRc＝CRc”-CN, wherein RcAs defined above and Rc”Represents NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7The compound is represented by formula (I-g) and can be prepared by reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII) in the presence of a suitable solvent such as an alcohol and an alcoholate, e.g. methanol and sodium ethoxide.
A compound of formula (I) wherein R3Represents CH ═ C (CN) -CH2CN, represented by formula (I-h), which can be prepared by reacting an intermediate of formula (XI-b) with 2-butenedionitrile in the presence of tributylphosphine and a suitable solvent, such as tetrahydrofuran.
A compound of formula (I) wherein R3Represents CH ═ C (CN)2The compounds are represented by formula (I-h') and can be prepared by reacting an intermediate of formula (XI-b) with malononitrile in the presence of a suitable base such as piperidine and a suitable solvent such as an alcohol, e.g. ethanol and the like.
A compound of formula (I) wherein R3represents-CHOH-CH2-CN, represented by formula (I-I), obtainable by reacting an intermediate of formula (XI-b) with CH3-CN is prepared by reaction in the presence of a suitable proton-abstracting agent, such as butyllithium, and a suitable proton-abstracting agent substrate, such as N- (1-methylethyl) -2-propylamine, and in the presence of a suitable solvent, such as tetrahydrofuran.
A compound of formula (I) wherein R3Represents CRc’＝CRc-halogen, wherein RcRepresents hydrogen or C1-4Alkyl and Rc’Represents hydrogen, C1-4Alkyl or R7Provided that CR isc’＝CRcRestricted to C only2-6Alkenyl radicals, represented by the formula (I-j), obtainable by reacting an intermediate of the formula (XI) with R, wherein R is a phosphorus ylide precursor, where appropriatebRepresents for example (phenyl)3P+-Cl-Or (CH)3CH2-O)2P (═ O) -wittig or Horner-Emmons reagents of formula (XII') are prepared by reaction in the presence of n-BuLi and a suitable solvent, such as tetrahydrofuran.
A compound of formula (I) wherein R3Represents CRc＝CRc”-halogen, wherein RcAs defined above and Rc”’Represents CN, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7The compound is represented by formula (I-k), and can be prepared by reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII-a) in a Horner-Emmons reagent such as (CH)3CH2-O)2P (═ O) -Cl, nBuLi, 1, 1, 1-trimethyl-N- (trimethylsilyl) -silylamine and a suitable solvent such as tetrahydrofuran.
A compound of formula (I) wherein R3Represents CH ═ C (Br)2The compound is represented by the formula (I-1) and can be prepared by reacting an intermediate of the formula (XVIII) with CBr4In the presence of a suitable catalyst salt such as (CuCl)2And a suitable base such as NH3And in the presence of a suitable solvent such as dimethyl sulfoxide.
Compounds of formula (I-m) can be prepared by reacting an intermediate of formula (XIV) with (Cl)2C ═ S is prepared by reaction in the presence of a suitable solvent, such as dioxane.
The compounds of formula (I-n) may be prepared by reacting an intermediate of formula (XV) with an intermediate of formula (XVI) in the presence of a suitable solvent, for example an alcohol or alcoholate, such as ethanol or sodium methylate.
A compound of formula (I) wherein R3Is represented by-C (═ O) NR9R10C substituted and optionally further substituted by cyano2-6Alkenyl, which is represented by the formula (I-o), wherein C2-6Alkenyl' represents C optionally substituted by cyano2-6Alkenyl radicals obtainable by reacting an intermediate of the formula (XXIX) with an intermediate of the formula (XXX) in the presence of hydroxybenzotriazole and ethyldimethylaminopropylcarbodiimide (ethylmethylene imine) and a suitable solvent, for example dichloromethane or tetrahydrofuran, and optionally in the presence of a suitable base, for example N, N-diethylethylamine, NH4OH and the like.
A compound of formula (I) wherein R3represents-C (═ O) NR13R14or-C (═ O) NR13The compounds are represented by the formulae (I-p-1) and (I-p-2) and can be prepared by reacting an intermediate of formula (XXXI) with an intermediate of formula (XXXII-1) or (XXXII-2) in the presence of hydroxybenzotriazole and ethyldimethylaminopropyl carbodiimide and a suitable solvent such as dichloromethane or tetrahydrofuran, and optionally in the presence of a suitable base such as N, N-diethylethylamine.
A compound of formula (I) wherein R3Represents CH-N-NH-C (═ O) -R16The compound is represented by formula (I-q) and can be prepared by reacting an intermediate of formula (XI-b) with an intermediate of formula (XXXIII) in a suitable solvent such as dichloromethaneAnd an alcohol such as methanol, ethanol, etc.
A compound of formula (I) wherein R3Represents N (CH)3)2The compounds are represented by the formula (I-r) and can be prepared by reacting the compound in the presence of a suitable catalyst such as a suitable acid, e.g., acetic acid, etc., palladium on charcoal, raney nickel, and in the presence of a suitable reducing agent such as sodium cyanoborohydride or H2And a suitable solvent such as acetonitrile, by reductively methylating the intermediate of formula (XXXIV) with formaldehyde.
A compound of formula (I) wherein R3Represents pyrrolyl, which is represented by formula (I-s) and may be prepared by reacting an intermediate of formula (XXXIV) with 2, 5-dimethoxytetrahydrofuran in the presence of a suitable acid, for example acetic acid.
A compound of formula (I) wherein R3Represents CH ═ CH-R7The compounds are represented by formula (I-t) and may be prepared by reacting an intermediate of formula (XXXV) (Ph represents phenyl) with an intermediate of formula (XXXVI) in the presence of nBuLi and a suitable solvent, for example tetrahydrofuran.
The compounds of formula (I) may be further prepared by interconverting compounds of formula (I) according to group conversion reactions known in the art.
The compounds of formula (I) may be converted to the corresponding N-oxide form according to methods known in the art for converting a trivalent nitrogen into its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting materials of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as, for example, benzoxybenzoic acid (benzacarboperoxoic acid) or haloperoxybenzoic acids such as 3-chloro-perbenzoic acid, peroxy alkanoic acids such as peroxyacetic acid, alkyl hydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of these solvents.
For example, wherein R3Compounds of formula (I) including a cyano group may be converted to R wherein R is3A compound of formula (I) comprising an aminocarbonyl group. Wherein R is3Compounds of formula (I) including a cyano group may also be further converted to R wherein R is by reaction with sodium azide in the presence of ammonium chloride and N, N-dimethylacetamide3Compounds of formula (I) including tetrazolyl groups.
Wherein R is3Compounds of formula (I) including an aminocarbonyl group can be converted to R wherein R is3A compound of formula (I) comprising a cyano group. The dehydration may be carried out according to methods well known to those skilled in the art, for example in a "synthetic organic conversion reaction. The functional group preparation guide "(" Comprehensive Organic transformations. A guide to functional group precursors "), Richard C.Larock, John Wiley and Sons, Inc, 1999, P1983-1985, which is incorporated herein by reference. Various suitable reagents are listed in this reference, such as SOCl2、HOSO2NH2、ClSO2NCO、MeO2CNSO2NEt3、PhSO2Cl、TsCl、P2O5、(Ph3PO3SCF3)O3SCF3Polyphosphate esters, (EtO)2POP(OEt)2、(EtO)3PI22-chloro-1, 3, 2-dioxaphospholane, 2, 2, 2-trichloro-2, 2-dihydro-1, 3, 2-dioxaphospholane, POCl3、PPh3、P(NCl2)3、P(NEt2)3、COCl2、NaCl·AlCl3、ClCOCOCl、ClCO2Me、Cl3CCOCl、(CF3CO)2O、Cl3CN＝CCl22, 4, 6-trichloro-1, 3, 5-triazine, NaCl AlCl3、HN(SiMe2)3、N(SiMe2)4、LiAlH4And the like. All reagents listed in this publication are incorporated herein by reference. Wherein R is3Comprising C2-6Alkenyl compounds of formula (I) may be prepared by reaction with a suitable reducing agent such as H2Conversion to R therein by reduction in the presence of a suitable catalyst such as palladium on charcoal and a suitable solvent such as an alcohol such as methanol3Comprising C1-6Alkyl compounds of formula (I).
Wherein R is3Represents CH (OH) -R16The compound of formula (I) can be converted to R wherein R is3Represents C (═ O) -R16A compound of formula (I).
Wherein R is3Represents C (═ O) -CH2-R16aWherein R is16aCompounds of formula (I) representing cyano or aminocarbonyl groups obtainable by reaction with POCl3Is reacted to convert into wherein R3Represents C (Cl) ═ CH-R16aA compound of formula (I).
Wherein R is3Compounds of the formula (I) which represent a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring which is substituted by formyl can be prepared by reaction with NH2OR8In the presence of a suitable base, e.g. sodium hydroxide, and a suitable solvent, e.g. an alcohol such as ethanol and the likeIs converted into wherein R3Is represented by CH (═ N-O-R8) Substituted monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring. Wherein R is3Compounds of formula (I) representing a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring substituted by CH (═ N-O-R8) may be converted to compounds of formula (I) in which R is a carbon atom, by reaction with a carbodiimide in the presence of a suitable solvent, for example tetrahydrofuran3Represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring substituted by CN.
Wherein R is4Compounds of formula (I) representing nitro groups may be reacted with a suitable reducing agent such as H2A suitable catalyst such as raney nickel and conversion in the presence of a suitable solvent such as an alcohol such as methanol to wherein R4A compound of formula (I) representing an amino group.
Wherein R is1Compounds of formula (I) which are hydrogen may be reacted with a suitable alkylating agent such as iodo-C1-6Conversion of alkyl groups to R wherein R is carried out in the presence of a suitable base such as sodium hydride and a suitable solvent such as tetrahydrofuran1Is represented by C1-6Alkyl compounds of formula (I).
Some of the compounds of formula (I) and some of the intermediates of the present invention may contain asymmetric carbon atoms. Pure stereochemical isomers of the compounds and the intermediates can be prepared by applying methods known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatographic techniques such as reverse-phase chromatography, liquid chromatography, and the like. Enantiomers can be prepared from a racemic mixture by first converting the racemic mixture to a mixture of diastereomeric salts or compounds with an appropriate resolving agent, such as a chiral acid; the diastereomeric salt or mixture of compounds is then physically separated by methods such as selective crystallization or chromatographic techniques such as liquid chromatography; and finally converting the separated diastereoisomeric salt or compound into its corresponding enantiomer. If the reactions taking place are carried out in a stereospecific manner, pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials.
Another method for separating the enantiomers of the compounds of formula (I) and intermediates includes liquid chromatography, particularly with a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and are commercially available or can be prepared according to methods known in the art, or some of the compounds of formula (I) or the intermediates can be prepared according to the methods described in WO99/50250 and WO 00/27825.
Intermediates of formula (II) can be prepared by introducing an intermediate of formula (XVII) with a leaving group of formula (XIX) introducing agent such as POCl3Is prepared by carrying out a reaction in which W1Represents a leaving group and R represents the remainder of the leaving group introducing agent.
An intermediate of formula (III) wherein X1Represents NH, which is represented by (III-a), and can be obtained from an intermediate of formula (XX) in ZnCl2And in the presence of a suitable solvent, for example an alcohol such as ethanol.
Intermediates of formula (III' -a) can be prepared from intermediates of formula (XX) (wherein R is3Represents C substituted by CN2-6Alkenyl, the intermediate being represented by (XX-a) in ZnCl2And suitably C1-4alkyl-OH, e.g. ethanol.
Intermediates of the formulae (III-b-1) and (III-b-2) below can be prepared by reacting an intermediate of the formula (XLI) or a suitable acid addition salt thereof (wherein W is6Representing a suitable leaving group) with acrylonitrile or propyleneamine in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent.
Suitable leaving groups in the above reaction are for example halogen, triflate, tosylate, mesylate and the like. Preferably W6Is a halogen, more preferably iodine or bromine.
The palladium (Pd) catalyst may be a homogeneous Pd catalyst, e.g. Pd (OAc)2、PdCl2、Pd(PPh3)4、Pd(PPh3)2Cl2Palladium bis (dibenzylideneacetone), palladium thiomethylphenylglutaramide metal ring compounds (pa11adium thiomethylphenylglutamide 11 acid), or the like, or a heterogeneous Pd catalyst such as palladium on carbon, palladium on metal oxide, palladium on zeolite.
Preferably, the palladium catalyst is a heterogeneous catalyst, more preferably palladium on carbon (Pd/C). Pd/C is a recyclable catalyst, which is stable and relatively inexpensive, which can be easily separated (filtered) from the reaction mixture, thereby reducing the risk of residual Pd in the final product. The use of Pd/C also avoids the need for expensive, toxic and product-contaminating ligands, such as phosphine ligands.
Suitable bases in the above reaction are, for example, sodium acetate, potassium acetate, N-diethylethylamine, sodium bicarbonate, sodium hydroxide and the like.
Suitable solvents in the above reaction are, for example, acetonitrile, N-dimethylacetamide, ionic liquids such as [ bmim [ ]]PF6N, N-dimethylformamide, water, tetrahydrofuran, dimethyl sulfoxide and 1-methylAnd 2-pyrrolidone.
The intermediate of formula (III-b-2) can be converted to an intermediate of formula (III-b-1) in the presence of a suitable dehydrating reagent. The dehydration may be carried out according to methods well known to those skilled in the art, for example in a "synthetic organic conversion reaction. The functional group preparation guide "(" comprehensive organic transformations. A. guide to functional group preparations "), Richard C.Larock, John Wiley and Sons, Inc, 1999, P1983-1985, which is incorporated herein by reference. Various suitable reagents are listed in the references, e.g. SOCl2、HOSO2NH2、ClSO2NCO、MeO2CNSO2NEt3、PhSO2Cl、TsCl、P2O5、(Ph3PO3SCF3)O3SCF3Polyphosphate esters, (EtO)2POP(OEt)2、(EtO)3PI22-chloro-1, 3, 2-dioxaphospholane, 2, 2, 2-trichloro-2, 2-dihydro-1, 3, 2-dioxaphospholane, POCl3、PPh3、P(NCl2)3、P(NEt2)3、COCl2、NaCl·AlCl3、ClCOCOCl、ClCO2Me、Cl3CCOCl、(CF3CO)2O、Cl3CN＝CCl22, 4, 6-trichloro-1, 3, 5-triazine, NaCl AlCl3、HN(SiMe2)3、N(SiMe2)4、LiAlH4And the like. All reagents listed in the publications are incorporated herein by reference.
An intermediate of formula (XX) wherein R3Represents CRc’＝CRc-CN and RcAnd Rc’As defined above, said intermediates are represented by formula (XX-b), and can be prepared from intermediates of formula (XXI) by the above-described reaction for preparing compounds of formula (I-f).
Intermediates of formula (XXI) can be prepared by reaction with a suitable oxidizing agent such as KMnO4Suitable solvents, for example methylene chloride and tris [2- (2-methoxyethoxy) ethyl]By oxidation of an intermediate of formula (XXII) in the presence of an amine.
An intermediate of formula (XXI), wherein Rc’The intermediate is represented by formula (XXI-a) for hydrogen, and may also be prepared by reacting an intermediate of formula (XXIII) wherein W4 represents a suitable leaving group, for example a halogen such as bromine, with N, N-dimethylformamide in the presence of nBuLi and a suitable solvent, for example tetrahydrofuran.
An intermediate of formula (XXII), wherein Rc’Represents C1-4 alkyl, which is represented by formula (XXII-a), and can be prepared by reacting an intermediate of formula (XXIII) with an intermediate of formula (XXIV) in the presence of nBuLi and a suitable solvent such as tetrahydrofuran.
Intermediates of formula (XI) can be prepared by reacting an intermediate of formula (XXV) with an intermediate of formula (II), optionally in the presence of a suitable base, such as 1-methyl-pyrrolidin-2-one, or a suitable acid, such as hydrochloric acid.
Intermediates of formula (XV) can be prepared by reacting an intermediate of formula (XXVI) with an intermediate of formula (II) in the presence of a suitable base such as 1-methyl-pyrrolidin-2-one and sodium hydride and a suitable solvent such as dioxane.
Intermediates of formula (VII) can be prepared by introducing an intermediate of formula (XXVII) with a leaving group introducing agent of formula (XIX'), e.g. SOCl2In the presence of a suitable solvent such as dichloromethane.
An intermediate of formula (XXVII) wherein C1-6Alkyl represents CH2The intermediate is represented by formula (XXVII-a), and can be prepared by a suitable reducing agent such as LiAlH4By reduction of an intermediate of formula (XV) or (XXXI) in the presence of a suitable solvent, for example tetrahydrofuran.
Intermediates of formula (XXVII-a) may be converted to intermediates of formula (XXXI) by reaction with jones reagent in the presence of a suitable solvent such as acetone.
Intermediates of formula (XI-b) can be prepared by reacting in a suitable oxidizing agent, e.g., MnO2And oxidizing the intermediate of formula (XXVII-a) in the presence of a suitable solvent such as dichloromethane, N-dimethylformamide.
Intermediates of formula (XIV) can be prepared by reacting an intermediate of formula (XV) with H2N-NH2In the presence of a suitable solvent, for example an alcohol such as ethanol and the like.
Intermediates of formula (IX) and (XI-a) can be prepared in a suitable reducing agent such as NaBH4、LiAlH4Or BuLi and a suitable solvent such as tetrahydrofuran or alcohols such as methanol, ethanol, etc. to intermediates of formula (XXVII '-a) and (XXVII' -b).
Intermediates of formula (XI-b) can be prepared by reaction with C1-4The alkyl-iodides are converted to intermediates of formula (XXVII' -a) by reaction in the presence of Mg and a suitable solvent such as diethyl ether and tetrahydrofuran.
Intermediates of formula (XVIII) can be prepared by reacting an intermediate of formula (XI-b) with H2N-NH2In the presence of a suitable solvent, for example an alcohol such as ethanol and the like.
Intermediates of formula (XXIX) or (XXXI) are prepared by reacting a compound of formula (XXIX) or (XXXI) wherein C2-6Alkenyl' represents C optionally substituted by cyano2-6An alkenyl group of formula (XXXVII), or by hydrolysis of an intermediate of formula (XV) in the presence of a suitable aqueous acid such as 2N hydrochloric acid and the like and in the presence of a suitable solvent such as an alcohol, e.g. isopropanol and the like.
An intermediate of formula (XXXVII), wherein C2-6Alkenyl represents CH ═ CH, the intermediate is represented by formula (XXXVII-a), which can be obtained by reacting an intermediate of formula (XI-b) with a precursor which can be considered to be a suitable phosphorus ylide compound, wherein R isbRepresents for example (phenyl)3P+-Cl-Or (CH)3CH2-O)2P (═ O) -wittig or Horner-Emmons reagents of formula (XII ") are prepared by reaction in the presence of a suitable solvent such as tetrahydrofuran.
An intermediate of formula (XXXVII), wherein C2-6Alkenyl' is-CH ═ c (cn) -, which is represented by formula (XXXVII-b), can be prepared by reacting an intermediate of formula (XI-b) with NC-CH2-C(＝O)O-C1-6Alkyl groups are prepared by reaction in the presence of a suitable base, for example piperidine, and a suitable solvent, for example an alcohol such as ethanol.
Intermediates of formula (XXXIV) can be prepared by reacting an intermediate of formula (XXXVIII) in H2And a suitable catalyst such as palladium on carbon or raney nickel, and a suitable solvent such as an alcohol, e.g. methanol or the like.
Intermediates of formula (XXXV) may be prepared by reacting an intermediate of formula (VII-a) in the presence of triphenylphosphine and a suitable solvent, for example acetonitrile.
Intermediates of formula (XXXIX) can be prepared by reacting an intermediate of formula (XL) with W wherein5And W1As defined above, by reaction of an intermediate of formula (II-a).
The compounds of formula (I) prepared in the above preparation processes may be synthesized in the form of a mixture of stereoisomers, in particular a racemic mixture of enantiomers, which may be separated from each other according to art-known resolution methods. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. The diastereoisomers are subsequently separated by selective or fractional crystallization, from which the enantiomers are freed by means of a base. Another method for separating enantiomers of compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
If the reaction taking place proceeds stereospecifically, the pure stereochemically isomeric forms may also be prepared from the corresponding pure stereochemically isomeric forms of the appropriate starting materials. Preferably, if a particular stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These processes can advantageously use enantiomerically pure starting materials.
It will be appreciated by those skilled in the art that functional groups of intermediate compounds may need to be protected by protecting groups in the above-described processes.
Functional groups to be protected include hydroxyl, amino and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl)) Benzyl and tetrahydropyranyl. Suitable amino protecting groups include t-butyloxycarbonyl or benzyloxycarbonyl. Suitable carboxylic acid protecting groups include C1-6Alkyl or benzyl esters.
The protection and deprotection of the functional groups may occur before or after the reaction step.
The use of protecting groups is well described in "protecting groups in organic chemistry", ed by J W F McOmie, Plenum Press (1973), and "protecting groups in organic Synthesis", second edition, T W Greene and P G M Wutz, Wiley Interscience (1991).
The invention also relates to novel compounds of formula (VII), (XXVII), (XXIX) and (XXXVII) which are useful as intermediates in the synthesis of compounds of formula (I) and which also exhibit HIV replication inhibiting activity.
In particular, the invention also relates to compounds of the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined above for compounds of formula (I), and W3Represents a suitable leaving group such as, for example, halogen, e.g., chlorine, and the like.
The invention also relates to compounds of the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined above for compounds of formula (I).
The invention also relates to compounds of the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined above for the compounds of formula (I), and C2-6Alkenyl' represents C optionally substituted by cyano2-6An alkenyl group.
The invention also relates to compounds of the formula,
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined above for the compounds of formula (I), and C2-6Alkenyl' represents C optionally substituted by cyano2-6An alkenyl group.
The following compounds of formula (III-b) are involved in the synthesis of compounds of formula (I).
The invention therefore also relates to compounds of the formula (III-b),
N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein R4And X1As defined above for the compounds of formula (I).
Preferred compounds of the formula (III-b) are those in which X1A compound representing NH. More preferred compounds of formula (III-b) are those wherein X1Represents NH and C2-6Alkenyl represents CH ═ CH compounds. The most preferred compounds of formula (III-b) are those of formula (III-b-1) described above.
The compounds of formulae (I), (I'), (VII), (XXVII), (XXIX) and (XXXVII) according to the invention show antiretroviral properties (reverse transcriptase inhibiting properties), in particular against Human Immunodeficiency Virus (HIV), which are the causative agents of acquired immunodeficiency syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys or alters their normal functions, particularly the coordination of the immune system. As a result, the number of T-4 cells in the infected patient gradually decreases and the expression becomes abnormal. Thus, individuals whose immune defense system is unable to fight infections and tumors and who are infected with HIV often die as a result of accidental infections such as pneumonia, or as a result of cancer. Other conditions that accompany HIV infection include thrombocytopenia, kaposi's sarcoma and central nervous system infections characterized by progressive demyelination, resulting in dementia and symptoms such as progressive dysphonia, dyskinesia and disorientation. Further complicating HIV infection is peripheral neuropathy, Progressive Generalized Lymphadenopathy (PGL), and AIDS-related complex (ARC).
The compounds of the present invention also show activity against drug resistant HIV strain(s), particularly drug resistant HIV-1 strain, more particularly the compounds of the present invention show activity against HIV strain(s), especially HIV-1 strain(s), which have acquired resistance to one or more non-nucleotide reverse transcriptase inhibitors known in the art. Non-nucleotide reverse transcriptase inhibitors known in the art are non-nucleotide reverse transcriptase inhibitors other than the compounds of the present invention, in particular commercially available non-nucleotide reverse transcriptase inhibitors. And the compounds of the invention have little or no binding affinity for human alpha-1 acid glycoprotein; the human alpha-1 acid glycoprotein does not or only weakly affect the anti-HIV activity of the compounds of the present invention.
Due to their antiretroviral properties, in particular their anti-HIV-1 activity, the compounds of formula (I), their N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, are useful in the treatment of individuals infected by HIV and in the prevention of these infections. In general, the compounds of the invention are useful in the treatment of warm-blooded animals infected with viruses whose presence is dependent on or mediated by an enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, particularly conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), Progressive Generalized Lymphadenopathy (PGL), and chronic central nervous system diseases caused by retroviruses, such as HIV-mediated dementia and multiple sclerosis.
Thus, the compounds of the invention or any subgroup thereof may be used as medicaments against the above conditions. The use as a medicament or method of treatment comprises administering to an HIV-infected subject an effective amount to combat HIV and other pathogenic retroviruses, particularly HIV-1 related conditions. In particular, the compounds of formula (I) can be used for the preparation of a medicament for the treatment or prevention of HIV infection.
In view of the use of the compounds of formula (I), there is provided a method of treating warm-blooded animals including humans suffering from viral infections, especially HIV infections, or a method of preventing warm-blooded animals including humans from suffering from viral infections, especially HIV infections. Said method comprises the administration, preferably oral administration, of an effective amount of a compound of formula (I), an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a possible stereochemically isomeric form thereof, to warm-blooded animals including humans.
The invention also provides a composition for treating viral infections comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
The compounds of the invention or any subgroup thereof may be formulated into various pharmaceutical formulations for administration purposes. All compositions which are generally intended for systemic administration can be cited as suitable compositions. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. Desirably, these pharmaceutical compositions may be in unit dosage form suitable for administration, particularly by injection, orally, rectally, transdermally, or parenterally. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, for oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions, with water, glycols, oils, alcohols and the like; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients may also be included, for example to enhance solubility. For example, injectable solutions may be prepared in which the carrier comprises a physiological saline solution, a glucose solution or a mixture of physiological saline and glucose solution. Suspensions for injection may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid preparations which are convertible into the desired liquid preparation shortly after administration. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in minor proportions, which additives do not produce a significant deleterious effect on the skin. The additives may be conveniently administered to the skin and/or may aid in the preparation of the desired composition. These compositions may be administered in various ways, for example as a transdermal patch, as a patch (spoton), as an ointment. The compounds of the present invention may also be administered by inhalation or insufflation using methods and formulations used in the art for administration by this means. Thus, in general, the compounds of the present invention may be administered to the lungs in the form of solutions, suspensions or dry powders. Any system developed for the delivery of solutions, suspensions or dry powders by oral or nasal inhalation or insufflation is suitable for the administration of the compounds of the invention.
To increase the solubility of the compound of formula (I), suitable ingredients such as cyclodextrins may be included in the composition. Suitable cyclodextrins are alpha-, beta-, gamma-cyclodextrins or ethers and mixed ethers thereof, wherein one or more of the hydroxyl groups in the cyclodextrin anhydroglucose unit are replaced by C1-6Alkyl, especially methyl, ethyl or isopropyl, substitution, e.g. randomly methylated β -CD; by hydroxy radicals C1-6Alkyl, in particular hydroxyethyl, hydroxy-propyl or hydroxybutyl; by carboxyl group C1-6Alkyl, especially carboxymethyl and carboxy-ethyl; quilt C1-6Alkylcarbonyl, in particular acetyl. Of particular note as ligands and/or solubilizers are β -CD, randomly alkylated β -CD, 2, 6-dimethyl- β -CD, 2-hydroxyethyl- β -CD, 2-hydroxypropyl- β -CD, and (2-carboxymethoxy) propyl- β -CD, and in particular 2-hydroxypropyl- β -CD (2-HP- β -CD).
The term mixed ether refers to cyclodextrin derivatives in which at least 2 of the cyclodextrin hydroxyl groups are etherified with different groups, such as hydroxy-propyl and hydroxy-ethyl.
The average molar degree of substitution (m.s.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average degree of substitution (d.s.) refers to the average number of substituted hydroxyl groups per anhydroglucose unit. The m.s. and d.s. values can be determined by various analytical techniques such as Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for a given cyclodextrin derivative. Preferably, the m.s. is in the range of 0.125 to 10 and the d.s. is in the range of 0.125 to 3 as determined by mass spectrometry.
Other suitable compositions for oral or enteral administration include particles consisting of a solid dispersion comprising a compound of formula (I) and one or more suitable pharmaceutically acceptable water-soluble polymers.
The term "solid dispersion" is hereinafter defined as a solid (as opposed to liquid or gaseous) system comprising at least two components, including a compound of formula (I) and a water-soluble polymer, wherein one component is dispersed more or less uniformly throughout the other component or components (when additional pharmaceutically acceptable formulation agents are included, typically as known in the art, e.g., plasticizers, preservatives, etc.). When the dispersion of the components is such that the system is chemically and physically homogeneous or homogeneous throughout or consists of a single phase as defined in thermodynamics, such a solid dispersion is referred to as a "solid solution". Solid solutions are preferably physical systems (physical systems) because the components thereof are generally readily bioavailable by the organism to which they are administered. This advantage can probably be explained by the ease with which the solid solution forms a liquid solution when contacted with a liquid medium such as gastrointestinal fluids. The ease of dissolution can be attributed, at least in part, to the fact that less energy is required to dissolve the components in the solid solution than is required to dissolve the components in the crystalline or microcrystalline solid phase.
The term "solid dispersion" also includes dispersions that are less uniform throughout than a solid solution. Such dispersions are not chemically and physically uniform throughout or include more than one phase. For example, the term "solid dispersion" also relates to a system containing domains or small domains, wherein amorphous, microcrystalline or crystalline compound of formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer or both are dispersed approximately equally in another phase comprising water-soluble polymer or compound of formula (I), or in a solid solution comprising compound of formula (I) and water-soluble polymer. The domains are regions of the solid dispersion having some particular physical characteristics, are small in size, and are evenly and randomly distributed throughout the solid dispersion.
Various techniques for preparing solid dispersions have been proposed including melt-extrusion, spray-drying and solution-evaporation.
The dissolution-evaporation method comprises the following steps:
a) dissolving a compound of formula (I) and a water-soluble polymer in a suitable solvent, optionally at elevated temperature;
b) heating the solution obtained in step a), optionally under vacuum, until the solvent is evaporated. It is also possible to pour the solution onto a large surface to form a film and to evaporate the solvent therefrom.
In the spray-drying technique, the two components may also be dissolved in a suitable solvent, the resulting solution then being sprayed from the spray dryer nozzle and the solvent then being evaporated from the resulting droplets at elevated temperature.
A preferred technique for preparing the solid dispersion is a melt extrusion process comprising the steps of:
a) mixing a compound of formula (I) with a suitable water-soluble polymer,
b) optionally mixing an additive with the resulting mixture,
c) the resulting mixture is heated and mixed until a homogeneous melt is obtained,
d) extruding the resulting melt from one or more nozzles; and
e) the melt is cooled until it solidifies.
The terms "melting (melt)" and "melting (fusing)" are to be understood in a broad sense. These terms refer not only to the transition from a solid to a liquid state, but also to the transition to a glassy or rubbery state, and in which it is possible for one component of the mixture to be embedded in another component in a nearly uniform manner. In certain cases, one component will melt and the other component(s) will dissolve in the melt, thereby forming a solution that upon cooling can form a solid solution with advantageous dissolution characteristics.
After the preparation of the solid dispersion described above, the resulting product may optionally be milled and sieved.
The solid dispersion product may be milled or ground to particles having a particle size of less than 600 μm, preferably less than 400 μm, most preferably less than 125 μm.
The granules prepared as above may then be formulated into pharmaceutical dosage forms such as tablets and capsules by conventional techniques.
It will be appreciated that the skilled person will be able to optimise the parameters of the above described solid dispersion preparation techniques, such as the most suitable solvent, operating temperature, type of apparatus used, spray-drying rate, melt-extruder throughput rate.
The water-soluble polymer in the particles is a polymer having an apparent viscosity of 1 to 5000 mPa.S, more preferably 1 to 700 mPa.S, most preferably 1 to 100 mPa.S, when dissolved in an aqueous solution at a concentration of 2% (W/V) at 20 ℃. For example, suitable water-soluble polymers include alkyl celluloses, hydroxyalkyl alkyl celluloses, carboxyalkyl celluloses, alkali metal salts of carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters, starches, pectins, chitin derivatives, di-, oligo-and polysaccharides such as trehalose, alginic acid or alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar and xanthan gums, polyacrylic acids and salts thereof, polymethacrylic acids and salts thereof, methacrylic acid copolymers, polyvinyl alcohols, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate, combinations of polyvinyl alcohols and polyvinylpyrrolidone, polyalkylene oxides, and copolymers of ethylene oxide and propylene oxide. A preferred water-soluble polymer is hydroxypropyl methylcellulose.
In the preparation of the above-described particles, one or more cyclodextrins may also be used as water-soluble polymers, as disclosed in WO 97/18839. The cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more specifically alpha, beta or gamma cyclodextrins or pharmaceutically acceptable derivatives thereof.
Substituted cyclodextrins that can be used to prepare the above particles include polyethers described in U.S. Pat. No. 3,459,731. Cyclodextrins further substituted by C wherein one or more of the cyclodextrin hydroxy groups is replaced by a hydrogen1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl, or C1-6Alkoxy carboxyl group C1-6Alkyl-substituted ethers or mixtures of these ethers. In particular such substituted cyclodextrins are those wherein one or more of the cyclodextrin hydroxy groups are hydrogenated with C1-3Alkyl, hydroxy C2-4Alkyl or carboxyl C1-2Alkyl-substituted or more particularly methyl-, ethyl-, hydroxyethyl-, hydroxypropyl-, hydroxybutyl-, carboxymethyl-or carboxyethyl-substituted ethers.
Particularly useful are beta-cyclodextrin ethers such as, by way of example, the dimethyl-beta-cyclodextrins and polyethers such as hydroxypropyl beta-cyclodextrin and hydroxyethyl beta-cyclodextrin disclosed by m. Such alkyl ethers may be methyl ethers having a degree of substitution of about 0.125 to 3, for example about 0.3 to 2. Such hydroxypropyl cyclodextrins can be formed, for example, by the interaction of beta-cyclodextrin and propylene oxide, and can have an MS value of about 0.125 to 10, for example about 0.3 to 3.
Another type of substituted cyclodextrin is thiobutyl cyclodextrin.
The proportion of the compound of formula (I) relative to the water-soluble polymer may vary within a wide range. For example, ratios of 1/100 to 100/1 may be used. The ratio of formula (I) to cyclodextrin advantageously ranges from about 1/10 to 10/1. More beneficial ratios range from about 1/5 to 5/1.
It is more suitable to formulate the compound of formula (I) into a nanoparticulate dosage form having adsorbed on the surface an amount of surface modifier sufficient to maintain the effective average particle size at less than 1000 nm. Useful surface modifying agents are believed to be physically attached to the surface of the compound of formula (I) but not chemically bonded to the compound. Suitable surface modifying agents may preferably be selected from known organic and inorganic pharmaceutically acceptable excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifying agents include nonionic and anionic surfactants.
A further advantageous way of formulating the compound of formula (I) relates to a pharmaceutical composition according to which the compound of formula (I) is incorporated in a hydrophilic polymer and the mixture is applied as a coating on a plurality of pellets, thereby obtaining a composition which can be conveniently manufactured and which is suitable for the preparation of oral pharmaceutical dosage forms.
The pellet comprises a central circular or spherical core, a coating of a hydrophilic polymer with a compound of formula (I) and optionally a seal coat.
There are a wide variety of materials suitable for the pellet core, provided that the material is pharmaceutically acceptable and has the appropriate size and hardness. Examples of such materials are polymers, inorganic substances, organic substances and saccharides and derivatives thereof.
It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required formulation carrier. Examples of such unit dosage forms are tablets (including scored and coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
The effective daily amount can be determined by those skilled in the treatment of HIV infection based on the test results provided herein. It is generally considered that an effective daily amount is from 0.01mg/kg to 50mg/kg body weight, more preferably from 0.1mg/kg to 10mg/kg body weight. The desired dose may suitably be administered in two, three, four or more divided doses at appropriate intervals throughout the day. The divided doses may be formulated in unit dosage forms, for example each containing from 1 to 1000mg, especially from 5 to 200mg, of the active ingredient.
The exact dosage and frequency of administration will depend upon the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, and other medications that the individual may be receiving, as will be appreciated by those skilled in the art. Furthermore, it will be apparent that the effective daily amount may be reduced or increased based on the response of the subject being treated and/or as assessed by the physician prescribing the compounds of the instant invention. The effective daily amounts described above are therefore only instructive and do not limit the scope or application of the invention to any degree.
The compounds of formula (I) may be used alone or in combination with other therapeutic agents such as antiviral agents, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They may also be used alone or in combination with other prophylactic agents to prevent viral infections. The compounds may be used in vaccines and methods for the sustained protection of individuals against viral infection. The compounds may be applied to such vaccines, either alone or together with other compounds of the invention or with other antiviral agents, in the same manner as conventional uses of reverse transcriptase inhibitors in vaccines. Thus, the present compounds may be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines and administered in prophylactically effective doses to continuously protect individuals from HIV infection.
Anti-retroviral compounds in combination with the compounds of formula (I) may also be used as medicaments. The invention therefore also relates to a product containing (a) a compound of formula (I), and (b) another antiretroviral compound, for simultaneous, separate or sequential use as a combined preparation for anti-HIV therapy. The different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier. The other antiretroviral compound may be a known antiretroviral compound such as suramin, pentamidine, thymopentin, castanospermineAmines, dextran (dextran sulfate), sodium phosphoformate (trisodium phosphoformate); nucleoside reverse transcriptase inhibitors such as azidothymidine (3 '-azido-3' -deoxythymidine, AZT), didanosine (2 ', 3' -dideoxyinosine; ddI), zalcitabine (deoxycytidine, ddC) or lamivudine (2 '-3' -dideoxy-3 '-thiacytidine, 3TC), stavudine (2', 3 '-didehydro-3' -deoxythymidine, d4T), abacavir, and the like; non-nucleoside reverse transcriptase inhibitors such as nevirapine (11-cyclopropyl-5, 11-dihydro-4-methyl-6H-bipyridino [3, 2-b:2 ', 3' -e)][1，4]Diaza derivatives-6-ketone), efavirenz, delavirdine, TMC-120, TMC-125, etc.; phosphonate reverse transcriptase inhibitors such as tenofovir and the like; TIBO (tetrahydro-imidazo [4, 5, 1-jk)][1，4]-benzodiazepines-2(1H) -ketones and thiones) such as (S) -8-chloro-4, 5,6, 7-tetrahydro-5-methyl-6 (3-methyl-2-butenyl) -imidazo [4, 5, 1-jk][1，4]Benzodiazepine-2(1H) -thione; alpha-APA (alpha-anilinophenylacetamides) compounds such as alpha- [ (2-nitrophenyl) amino]-2, 6-dichlorobenzene-acetamide, and the like; inhibitors of the trans-activator protein, such as TAT-inhibitors, e.g., RO-5-3335, or REV inhibitors, and the like. Protease inhibitors such as indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, amprenavir, TMC-126, BMS-232632, VX-175, etc.; fusion inhibitors such as T-20, T-1249 and the like; CXCR4 receptor antagonists such as AMD-3100 and the like; inhibitors of viral integrase; nucleotide-like reverse transcriptase inhibitors such as tenofovir and the like; ribonucleotide reductase inhibitors such as hydroxyurea and the like.
The therapeutic effect of the compounds of the present invention may be enhanced by administering them with other antiviral agents directed against different events in the viral life cycle. Combination therapy as described above exerts a synergistic effect in inhibiting HIV replication in that the components of the composition act at different sites of HIV replication. Such a combination may reduce the dose of a given conventional antiretroviral agent when it is desired to achieve the desired therapeutic or prophylactic effect as compared to a monotherapy administered agent. Such a combination may reduce or eliminate the side effects of conventional single antiretroviral therapy without affecting the antiviral activity of the drug. This combination reduces the potential for resistance to a single drug while minimizing concomitant toxicity. These combinations may also increase the efficacy of traditional drugs without increasing concomitant toxicity.
The compounds of the invention may also be administered in combination with immunomodulators, such as levamisole, brepirimidine, anti-human interferon-alpha antibodies, interferon-alpha, interleukin 2, methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone, and the like; antibiotics such as pentamidine isethionate and the like; cholinergic agents such as tacrine, rivastigmine, donepezil, galantamine, and the like; NMDA channel blockers, e.g., memantine, that prevent or combat infection and diseases or disease symptoms associated with HIV infection, such as AIDS, and ARC, e.g., dementia. A compound of formula (I) may also be combined with another compound of formula (I).
Although the present invention focuses on the use of the present compounds for the prevention or treatment of HIV infection, the present compounds may also be used as inhibitors of other viruses, depending on acting on similar reverse transcriptins in events that are essential to their life cycle.
The following examples will illustrate the present invention in detail.
Experimental part
Hereinafter, "DMF" refers to N, N-dimethylformamide, "DIPE" refers to diisopropyl ether, "THF" refers to tetrahydrofuran, "DMA" refers to N, N-dimethylacetamide, "DMSO" refers to dimethyl sulfoxide, "DME" refers to methyl ether, "EtOAc" refers to ethyl acetate, "EDCI" refers to N' - (ethylidenecarbamimidoyl) -N, N-dimethyl-1, 3-propanediamine.
A. Preparation of intermediate compounds
Example A1
a) Preparation of intermediate 1
In N2nBuLi (0.012mol) was added dropwise to a mixture of N' - (4-bromo-2, 6-dimethylphenyl) -N, N-dimethylimidocarboxamide (methanimidamide) (0.0078mol) in THF (20ml) at-70 ℃ in a stream. The mixture was stirred at-30 ℃ for 30 minutes and then cooled to-70 ℃. A mixture of DMF (0.078mol) in THF (30ml) was then added dropwise. The mixture was stirred at-70 ℃ for 2 hours, then warmed to 0 ℃, poured out into water and extracted with ethyl acetate. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. Yield: 1.8g of intermediate 1.
b) Preparation of intermediate 2
In N2A mixture of diethyl (cyanomethyl) phosphonate (0.0037mol) in THF (10ml) was cooled to 5 ℃ in the stream. Potassium tert-butoxide (0.0037mol) was added portionwise. The mixture was stirred at 5 ℃ for 30 minutes and then at room temperature for 30 minutes. A mixture of intermediate 1(0.0024mol) in THF (10ml) was added. The mixture was stirred at room temperature for 1 hour and then poured off to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. Yield: 0.82g (100%) of intermediate 2.
c) Preparation of intermediate 3 and intermediate 22
Intermediate 3 intermediate 22
Intermediate 2(0.059mol) in ethanol (150ml) and ZnCl2(0.299mol) the mixture is stirred under reflux for 24 hours and then poured off to K2CO3In solution (10% in water) with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (9g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.8g (6%) of intermediate 22. The filtrate was concentrated and recrystallized from DIPE to give 6g of intermediate 3.
In addition, intermediate 3 can also be prepared as follows:
to 159g of 4-iodo-2, 6-dimethyl-aniline solution, 63.8g of sodium acetate were added. The reaction mixture was taken under nitrogen and 7g of wet palladium on charcoal (Pd/C10%) and 64.4ml of acrylonitrile were added. The reaction mixture was heated to 130 ℃ and stirred overnight. After cooling to room temperature, 0.51 l of toluene and 0.5 l of N, N-dimethylacetamide were added. The reaction mixture was filtered through Dicalite and the filtrate was washed with 0.5 l of toluene. Water (6 l) was added to the mixture and stirred for 30 minutes. And (5) layering. To the aqueous phase 1 l of toluene was added and the mixture was stirred for 30 minutes. The layers were separated again, and the separated organic layer was collected and the solvent was distilled to give 123g of intermediate 3.
Intermediate 3 was converted to its hydrochloride salt as follows:
to 123g of intermediate 3 mixture in 630ml of ethanol was added 1.25 l of diisopropyl ether. The reaction mixture was placed under a nitrogen atmosphere. The mixture was heated to 60 ℃ and stirred for 30 minutes. 120ml of a 6N solution of hydrochloric acid in 2-propanol were added and the mixture was stirred for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and the residue was washed with 100ml of 2-propanol. The residue was dried at 50 ℃ under reduced pressure. Yield: 103g (77%) of intermediate 3 hydrochloride (1: 1).
Intermediate 3(E) was prepared as follows:
x) preparation of intermediate 3a (E)
Intermediate 3a (E)
In 10ml of dry acetonitrile, 2.00g (10.0mol) of 4-bromo-2, 6-dimethylaniline, 1.07g (1.5eq) of acrylamide, 224mg (0.1eq) of Pd (OAc) were dissolved2609mg (0.2eq) of tris (2-tolyl) phosphine and 1.52g N, N-diethylethylamine. With N2The mixture was purged for 20 minutes and stirred at 70 ℃ overnight. The mixture was diluted with 150ml dichloromethane and saturated NaHCO3Washed with aqueous solution and dried (saturated NaCl, Na)2SO4) And filtered. The solvent was distilled off, and the residue was stirred in diisopropyl ether and then filtered. Yield: 1.51g (79.5%) of intermediate 3a (E).
y) preparation of intermediate 3(E)
Intermediate 3(E)
Adding POCl3(3ml) cooled to 0 ℃ and 500mg (2.63mmol) of intermediate 3a (E) added. After 30 minutes, the cooling bath was removed and the mixture was stirred at 20 ℃ overnight. The mixture was added dropwise to 150ml of diisopropyl ether with vigorous stirring. The precipitate was filtered and washed with isopropyl ether. The residue was added to 100ml ethyl acetate/100 ml saturated NaHCO3Aqueous solution and stirring. The ethyl acetate layer was separated and dried (saturated NaCl, Na)2SO4) And filtered. The solvent is distilled. Yield: 380mg (84%) of intermediate 3 (E).
d) Preparation of intermediate 4
H is to be2SO4A mixture of 4-bromo-2, 6-dimethylaniline (0.024mol) in (30ml) was stirred at-5 ℃. Slow addition of KNO3(0.024 mol). The mixture was stirred at-5 ℃ for 30 minutes and poured out to H2O and extracted with ethyl acetate. By H2The organic layer was washed with O, separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (0.058g, 95%) was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate; 70/30; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 4.1g of intermediate 4.
Example A1A
Preparation of intermediate 28
1-chloro-pyrrolidine-2, 5-dione (0.032mol) was added to CH at 60 deg.C34-amino-3-methyl-benzoic acid Ethyl ester [ CAS 40800-65-5 ] in CN (50ml)](0.029mol) in a mixture. The mixture was stirred and slowly refluxed. Adding K2CO310 percent. By CH2Cl2The mixture is extracted. The organic layer was distilled. The residue (6.6g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 5.2g intermediate 28 (84%).
Example A2
4- [ (1, 4-dihydro-4-oxo-2-pyrimidinyl) amino group in POCl3(90ml)]The benzonitrile (0.12mol) mixture was stirred under argon at reflux for 20 min. The reaction mixture was poured slowly into 750ml of ice/water and the solid isolated by filtration. The solid was suspended in 500ml of water and the pH of the suspension was adjusted to neutrality by addition of 20% NaOH solution. Again using CH2Cl2The solid is isolated by extraction, suspended in 200ml of 2-propanone and 1000ml of CH are added2Cl2. The mixture was heated until all solids dissolved. Cooling to the chamberAfter warming, the aqueous layer was separated and the organic layer was dried. During the removal of the drying agent by filtration, a white solid was formed in the filtrate. The filtrate was further cooled in a freezer and then filtered to obtain 21.38g (77.2%) [4- [ (4-chloro-2-pyrimidinyl) amino group]Benzonitrile (intermediate 5).
Example A3
a) Preparation of intermediate 6
In N2To a mixture of N' - (4-bromo-2, 6-dimethylphenyl) -N, N-dimethyliminocarboxamidine (0.0157mol) in THF (50ml) was added dropwise nBuLi (0.024mol) in the stream at-70 ℃. The mixture was stirred at-30 ℃ for 30 minutes and then cooled to-70 ℃. A solution of 2-methylpropionaldehyde (0.055mol) in THF (50ml) was added. The mixture was stirred at-70 ℃ for 2 hours, then warmed to 0 ℃ and poured out to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (6.7g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 90/5/0.5; 15-40 μm). Two fractions were collected and the solvent was distilled. Fraction 1: yield: 1.5g intermediate 6 (38%).
b) Preparation of intermediate 7
Reacting tris [2- (2-methoxyethoxy) ethyl group at room temperature]Ammonia (0.0193mol) was added to CH2Cl2(20ml) of intermediate 6(0.0048 mol). The KMnO is added in portions4(0.0193 mol). The mixture was stirred at room temperature overnight, then filtered through celite and washed with CH2Cl2And (6) washing. By K2CO310% washing of the organic layerSeparating, drying (MgSO)4) The solvent was filtered and distilled. Yield: 1.2g (100%) of intermediate 7.
c) Preparation of intermediate 8
Intermediate 7(0.0043mol) in ethanol (20ml) and ZnCl2(0.017mol) the mixture is stirred at reflux overnight and poured off to H2In O with CH2Cl2/CH3And (5) OH extraction. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. Yield: 0.94g (82%) of intermediate 8.
d-1) preparation of intermediate 9
A mixture of intermediate 8(0.0049mol) and intermediate 5(0.0025mol) was stirred at 150 ℃ for 2 hours and with K2CO310％/CH2Cl2/CH3And (5) OH extraction. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (1.3g) was crystallized from DIPE. The precipitate was filtered off and dried. The mother liquor layer was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 98.5/1.5; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.21g of intermediate 9.
d-2) preparation of intermediate 29
A mixture of intermediate 28(0.023mol) and intermediate 5 (prepared according to A2) (0.025mol) in 3N HCl (10ml) was stirred at 105 deg.C, then warmed to room temperature and filtered. The precipitate was washed with DIPE and dried. Yield: 8.4g intermediate 29 (96%)
d-3) preparation of intermediate 30
Ethyl 4-amino-3-chlorobenzoate [ CAS82765-44-4 ] in 1-methyl-pyrrolidin-2-one (40ml)](0.02mol) and intermediate 5 (prepared according to A2) (0.0243mol) were stirred at 180 ℃ for 2 hours and then poured off to H2In O and extracted three times with EtOAc (80 ml). The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (10g) was subjected to silica gel column chromatography (eluent: CH)2Cl2100, respectively; 15-30 μm). Two fractions were collected and the solvent was distilled. Yield: 1.7g of fraction 1 and 1g of fraction 2. Fraction 2 was extracted with diethyl ether. The precipitate was filtered and dried. Yield: 0.95g of intermediate 30 (12%).
e-1) preparation of intermediate 17
In N2In-stream NaBH4(0.0001mol) was added portionwise to a mixture of intermediate 9(0.0001mol) in ethanol (7ml) at 5 ℃. The mixture was stirred at 5 ℃ for 1 hour, poured out into ice and washed with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue was crystallized from DIPE (0.1 g). The precipitate was filtered and dried. 0.044g of intermediate 17 was obtained.
e-2) preparation of intermediate 32
In N2BuLi 1.6M (0.009mol) was added to a stream at-78 ℃ in THF (25ml)(intermediate 31) (prepared according to A4 a) (0.0029 mol). The mixture was stirred at-78 ℃ for 10 minutes, then warmed to room temperature and stirred for 3 hours. Addition of H2And O. By CH2Cl2The mixture is extracted. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (1.28g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 98/2/0.1; 15-40 μm). Three fractions were collected and the solvent was distilled. Yield: 0.189g fraction 1, 0.14g fraction 2 and 0.5g fraction 3 (48%). Fraction 3 was subjected to kromasil column chromatography (eluent: CH)2Cl2EtOAc 80/20; 10 μm) was purified. Two fractions (F1, F2) were collected and the solvent was distilled. Yield: 0.25g F1 (24%) and 0.1g F2. F1 was crystallized from diethyl ether. The precipitate was filtered and dried. Yield: 0.21g of intermediate 32 (20%).
e-3) preparation of intermediate 34
A solution of methyl magnesium iodide (1.0M in ether) (0.6ml) was added to THF (3ml)Intermediate 33 (prepared according to A5. a) (0.0006mol) in solution. The mixture was filtered through celite. Addition of H2And O. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.05g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 96/4; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.015g of intermediate 34 (7.2%).
Example A4
a) Preparation of intermediate 10
In N2A mixture of ethyl 3, 5-dimethyl-4-hydroxybenzoate (0.0025mol) in 1, 4-dioxane (2.5ml) was stirred at room temperature in a stream. Sodium hydride (0.0033mol) was added. The mixture was stirred for 2 minutes. Intermediate 5(0.0028mol) was added. The mixture was stirred for 10 minutes. 1-methyl-2-pyrrolidone (2.5ml) was added. The mixture was stirred at 150 ℃ for 12 hours and poured out to H2In O with CH2Cl2/CH3And (5) OH extraction. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (1.7g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 92/8; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.7g of intermediate 10 (70%).
b-1) preparation of intermediate 11
In N2A solution of intermediate 10(0.0005mol) in THF (5ml) was added dropwise to LiAlH in THF (5ml) in a stream at 0 deg.C4(0.001mol) in a suspension. The mixture was stirred at 0 ℃ for 1 hour and poured off to H2O (0.5 ml). Adding CH2Cl2. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue was chromatographed on a kromasil column (eluent: CH)2Cl2100 to CH2Cl2/CH3OH 99/1; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue was crystallized from diethyl ether (0.1 g). The precipitate was filtered and dried. Yield: 0.043g intermediate 11 (24%).
b-2) preparation of intermediate 37
In N2In-stream LiAlH4(0.0196mol, 0.75g) were added portionwise to a mixture of intermediate 29 (prepared according to A3 d-2) (0.0098mol) in THF (100ml) at 5 ℃. The mixture was stirred at room temperature overnight. Poured out into EtOAc and then H2O and filtered through celite. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. Yield: 3.4 g. The fraction was subjected to kromasil column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 97/3/0.1; 15-40 μm). The pure fractions were collected and the solvent was distilled. The fraction was purified using DIPE/CH3And (4) crystallizing CN. The precipitate was filtered and dried. Yield: 0.03g of intermediate 37.
c) Preparation of intermediate 12
Will CH2Cl2The mixture of intermediate 11(0.0043mol) in (50ml) was stirred at 0 ℃. Dropwise addition of SOCl2(0.0206 mol). The mixture was poured out to ice water/K2CO3In (1). The mixture was stirred at room temperature for 5 minutes. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. Yield: 1.5g intermediate 12 (98%).
d) Preparation of intermediate 55
Jones reagent (0.0084mol) was added to a mixture of intermediate 19 (see Table 1) (prepared as in A4 b-1) (0.0028mol) in acetone (50 ml). The mixture was stirred at room temperature for 2 hours and then poured off to H2In O with NaHCO3Alkalizing. The precipitate was filtered and dried. Yield: 1.39 g. The residue (0.1g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 85/15/1 then CH3OH 100) purification. The pure fraction was crystallized from isopropanol/DIPE. Yield: 0.071g of intermediate 55.
Example A5
a) Preparation of intermediate 13
Will CH2Cl2Intermediate 19 (see Table 1) (prepared according to A4. b-1) (0.0037mol) and MnO in (100ml)2(0.0185mol) was stirred at room temperature overnight and then filtered through celite. The filtrate was distilled. Yield: 1.3g of intermediate 13.
b) Preparation of intermediate 21
Intermediate 13 (prepared according to A5. a) (0.0029mol) in EtOH (10ml) and H2N-NH2·H2The O (0.0058mol) mixture was stirred at room temperature overnight and the solvent was distilled off until it was evaporated to dryness. Yield: 0.53g of intermediate 21.
Example A6
Preparation of intermediate 14
Hydrazine (0.0077mol) was added to EtOH (10ml)(prepared according to A3. d-1) (0.0005 mol). The mixture was stirred and refluxed overnight. Hydrazine (0.028mol) was added. The mixture was stirred and refluxed overnight. Yield: 0.28g of intermediate 14.
Example A7
a) Preparation of intermediate 23
Intermediate 35 in 3N HCl (60ml) and iPrOH (15ml)(prepared according to A3. d-1) (0.0056mol) the mixture was stirred overnight at reflux. The precipitate was filtered, washed with H2O, extracted with DIPE and dried. Yield: 2.3g of intermediate 23 (100%).
b) Preparation of intermediate 56
A mixture of intermediate 10 (prepared according to A4. a) (0.0012mol) in 3N HCl (26ml) and iPrOH (4ml) was stirred at reflux for 12 h. The solvent was distilled until dry. With (CH)3)2The residue was extracted with CO. The solvent is distilled. The residue was extracted with diethyl ether. The precipitate was filtered and dried. Yield: 0.4g (78.5%). The fraction was stirred at 60 ℃ for 20 minutes. Yield: 0.19 g. The fraction is treated with H2Crystallizing the O/2-acetone. The precipitate was filtered and dried. Yield: 0.12g of intermediate 56 (26%).
Example A8
a) Preparation of intermediate 24
Intermediate 31 (prepared according to A4. a) (0.0005mol) and ethyl (triphenylphosphoranylidene) acetate [ CAS 1099-45-2 ] in THF (5ml)](0.0006mol) the mixture was stirred at 80 ℃ for 48 hours and poured off to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (0.4g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.08g (33%). This fraction was treated with DIPE/CH3And (4) crystallizing CN. The precipitate was filtered and dried. Yield: intermediate 24 (33%).
b) Preparation of intermediate 25
Piperidine (0.0011mol) was added at room temperature over 30 minutes. Intermediate 31 (prepared according to A4. a) (0.0005mol) was added. The mixture was stirred at room temperature for 1 hour and poured out to H2In O with CH2Cl2And (4) extracting. The precipitate was filtered and dried. The residue (0.2g) was replaced with CH3CN/DIPE crystal. The precipitate was filtered and dried. Yield: 0.048 intermediate 25 (19%) (mp.222 ℃ C.).
Example A9
Preparation of intermediate 26
Adding methanol (30ml)Prepared according to A3. d-1) (0.0011mol) and Pd/C (0.2g) were hydrogenated at 1 bar pressure at room temperature for 2 hours and then filtered through celite. By CH3OH washes the diatomaceous earth. The filtrate was distilled until dry. The residue (0.3g) was taken up in 2-propanone/CH3OH/Ether crystallization. The precipitate was filtered and dried. Yield: 0.07g of fraction 1. Fraction 1 was subjected to kromasil column chromatography (eluent: CH)2Cl2/CH3OH 99.5/0.5; 5 μm) was purified. Three fractions 9F1, F2, F3) were collected and the solvent was distilled. Yield: 0.0516gF1, 0.1g F2 and 0.15g F3. F1 was extracted with diethyl ether. Will be provided withThe precipitate was filtered and dried. Yield: 0.028g of intermediate 26 (8%) (mp.272 ℃ C.).
Example A10
Preparation of intermediate 27
Will CH3In CN (10ml)(prepared according to A4. c) (0.0005mol) and triphenylphosphine (0.0005mol) were stirred under reflux for a weekend period. The solvent was distilled until dry. The residue was extracted with diethyl ether. The precipitate was filtered and dried. Yield: 0.34g intermediate 27 (94%).
Example A11
Preparation of intermediate 58
A mixture of 4-bromo-2, 6-dimethylaniline (0.013mol) and intermediate 5(0.013mol) was stirred at 150 ℃ for 1 hour. The mixture was poured into 10% K2CO3By using CH in combination with the aqueous solution of2Cl2MeOH (95/5) extraction. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue was crystallized from diisopropyl ether. The precipitate was filtered and dried. Yield: 2.3g (45%). The mother liquor layer was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH-NH4OH 98.5/1.5; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.90g (17%). The overall yield of intermediate 5 was: 3.2g (62%).
Intermediate 59 was prepared similarly.
Intermediate 59
Tables 1 and 2 list the intermediates involved in the preparation of the compounds of the present invention.
TABLE 1
Intermediate number Example No. 2 X R R R Physical data
49 A3e-1 O -CH-OH CH H
50 A4c O -CH-Cl CH H
51 A4b-1 NH -CH-OH C(CH) H
52 A4c NH -CH-Cl CH H
53 A4b-1 NH -CH-OH 2-furanyl CH
54 A4c NH -CH-Cl Br CH
57 A7b O -CH＝CH-COOH CH3 CH
TABLE 2
Intermediate number Example No. 2 X R Physical data
20 A3e NH -CHOH-CH
B. Preparation of the final compound.
Example B1
Preparation of Compound 1
A mixture of intermediate 3(0.034mol) and intermediate 5(0.0174mol) was stirred at 150 ℃ for 1 hour and with K2CO310％/CH2Cl2/CH3And (5) OH extraction. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (10g) was subjected to silica gel column chromatography (eluent: CH)2Cl2Ethyl acetate 80/20; 15-40 μm). Fraction 1 was crystallized from iPrOH. The precipitate was filtered and dried. Yield: 1.3g 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] ethyl ester]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 1) (20%).
Example B1A
Compound 1 can also be prepared as follows:
a mixture of 93.9g (0.45mol) of the hydrochloride salt of intermediate 3 (prepared according to example A1c) and 109g (0.4725mol) of intermediate 5, formulated in 1.8 litres of acetonitrile under nitrogen. The mixture was stirred and refluxed for 69 hours, then allowed to cool to 55 ℃. The mixture was filtered and the residue was washed with 200 acetonitrile and then dried under reduced pressure at 50 ℃ overnight. 144.6g (0.3666mol) of the resulting solid are placed in 1 l of K2CO310% aqueous solution. The mixture was stirred at room temperature and then filtered. The obtained residueThe retentate was washed 2 times with water and then dried at 50 ℃ under reduced pressure. The residue was taken up in 6.55 l of isopropanol and the mixture was refluxed, then stirred overnight and filtered at room temperature. The residue was dried under reduced pressure at 50 ℃. Yield: 113.2g (68.6%) 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] ethyl ester]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 1).
Example B1B
In addition, compound 1 can also be prepared as follows:
a) will CH3CN (7ml) of intermediate 58(0.00021mol) prepared according to example A11, Acrylonitrile (CH)2＝CH-CN)(0.00213mol)、Pd(OAc)2A mixture of (0.000043mol), N-diethylethylamine (0.000043mol) and tris (2-tolyl) phosphine (0.00021mol) was stirred in a sealed vessel at 150 ℃ overnight. Addition of H2And O. Subjecting the mixture to CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (0.15g) was subjected to silica gel column chromatography (eluent: CH)2Cl2Ethyl acetate 80/20; 15-40 μm). Fraction 1 was collected and the solvent was distilled to give 0.045g of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl group]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E/Z ═ 80/20). The solid was crystallized from diethyl ether. Yield: 0.035g 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl)]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 1) (55%).
b) 4.41g (10mmol) of intermediate 59 and 1ml of N, N-dimethylacetamide were placed in a 100ml flask under nitrogen. To the mixture was added 0.98g of sodium acetate (12mmol), 107mg (0.1mmol Pd) 10% Pd/C (wet) and 1ml (15mmol) acrylonitrile. The mixture was stirred at 140 ℃ and the progress of the reaction was followed by liquid chromatography. The reaction yielded 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E/Z ═ 80/20) which can be converted to 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E) as described above in example B1 Ba.
Example B2
a) Preparation of Compound 2
In DME (3ml)(prepared according to A3. d-1) (0.0002mol), 2-benzofuranylboronic acid (0.0005mol), Pd (PPh)3)4(0.00002mol) and Na2CO3(0.0007mol) of the mixture was stirred in a sealed tube at reflux for 3 hours, H was added2And O. The mixture was extracted with ethyl acetate. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (0.126g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.011g Compound 2 (10%).
b) Preparation of Compound 3
Adding dioxane (5ml)(prepared according to A3. d-1) (0.0002mol), tributyl-2-furanylstannane (0.0005mol) and Pd (PPh)3)4(0.00001mol) of the mixture was stirred at 80 ℃. The solvent is distilled. The residue was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was distilled. The residue (0.025g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.021g Compound 3 (22%).
c) Preparation of Compound 104
Mixing toluene (100ml) and ethanol/water (5: 10ml)(obtained according to A3. d) (0.005mol),[CAS73183-34-3](0.0055mol)、Pd(PPh3)4(0.29g) and K2CO3(2.8g) the mixture was stirred at reflux for a weekend period. 5-bromo-furan-2-carbaldehyde (0.0055mol) and K were added2CO3(1.4g, 0.01 mol). The mixture was stirred at reflux overnight. The mixture (2.25g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH100/0 to 99/1; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.135g of Compound 104 (6%).
Example B3
a) Preparation of Compound 4
Intermediate 15 (see Table 1) (prepared according to A4. c) (0.0005mol) in DMF (5ml) and NaCN (0.0011mol) were stirred overnight at 80 ℃ and decanted to H2O and extracted with ethyl acetate. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.15g) was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue (0.024g) was chromatographed on a Hypersil column (eluent: acetonitrile/H)2O52/48; 8 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.02g Compound 4 (10%).
Example B4
a) Preparation of Compound 5
Will be provided with(prepared according to A3. d) (0.0006mol) and thiomorpholine (0.5g) were stirred at 120 ℃ for 48 hours using CH2Cl2The solvent is extracted and distilled. The residue (0.44g) was chromatographed on a kromasyl column (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.06g (20%). The fraction was crystallized from diethyl ether/2-propanone. The precipitate was filtered and dried. Yield: 0.035g of Compound 5.
b) Preparation of Compound 6
Will CH3Intermediate 15 (see Table 1) (prepared according to A4. c) (0.000137mol), N, N, N' -trimethyl-1, 2-ethanediamine (2 eq., 0.000275mol) and K in CN (approx.) amounts2CO3(2 equiv., 0.000275mol) of the mixture was stirred at 80 ℃ for 12 h. Addition of H2And O. By CH2Cl2The mixture is extracted. The extract was distilled. The residue was purified by chromatography. The product fractions were collected and the solvent was distilled. Yield: 0.006g Compound 6 (20%).
c) Preparation of Compound 7
A mixture of intermediate 15 (see Table 1) (prepared according to A4. c) (0.0005mol) in 3-hydroxy-propylnitrile (2ml) was stirred overnight. Pouring out to H2In O with CH2Cl2And (4) extracting. Is separated byOrganic layer, drying (MgSO)4) Filtered and the solvent distilled. The residue was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 99/1/0.1; 15-40 μm). Two fractions (F1, F2) were collected and the solvent was distilled. Yield: 0.034g F1 and 0.514g F2. F2 was washed with HCl 3N and CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.039g Compound 7 (18%).
d) Preparation of Compound 105
A mixture of intermediate 50 (prepared according to A4 c) (0.001mol), KCN (0.0011mol) and KI (0.00005mol) in EtOH (15ml) was stirred at reflux for 4 hours. The solvent was distilled until dry. By CH2Cl2/H2O extracting the residue. By CH2Cl2The mixture is extracted. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.31g) was purified by kromasil column chromatography (eluent: cyclohexane/EtOAc 70/30; 10 μm). Three fractions were collected and the solvent was distilled. Yield: 0.044g of fraction 1, 0.11g of fraction 2 and 0.055g of fraction 3. Fraction 3 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.046g of compound 105 (12%) (mp.140 ℃ C.).
Example B5
a) Preparation of Compound 8
A mixture of intermediate 9(0.0001mol) and hydroxylamine (0.0002mol) in EtOH (7ml) was stirred at room temperature for 3 hours and decanted to 10% K2CO3In and use CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. Using DIPE/CH3The CN residue (0.1g) was crystallized. The precipitate was filtered and dried. Yield: 0.026g Compound 8.
b) Preparation of Compound 9
A mixture of intermediate 9(0.0002mol) and O-methylhydroxylamine (0.003mol) in EtOH (10ml) was stirred overnight at room temperature and decanted to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (0.13g) was chromatographed on a kromasil column (eluent: cyclohexane/iPrOH/NH)4OH; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue (0.06g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.036g Compound 9 (34%).
Example B6
a) Preparation of Compounds 1 and 10
Compound 1 ═ E; compound 10 ═ (Z)
A mixture of (cyanomethyl) triphenylphosphonium chloride (0.0022mol) and potassium tert-butoxide (0.0022mol) in THF (7ml) was stirred at 5 ℃ for 30 minutes and then at 5 ℃ for 30 minutes in a stream of nitrogen. A mixture of intermediate 13(0.0015mol) in THF (7ml) was added. The mixture was stirred in the dark for 8 hours and poured out to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (1.4g) was subjected to silica gel column chromatography (eluent: toluene/iPrOH/NH)4OH 96/4/0.1; 15-40 μm). Two fractions (F1, F2) were collected and distilledA solvent. Yield: 0.165gF1 (E/Z32/68) (30%) and 0.225g F2 (E/Z90/10) (41%). Using F2 as CH3CN/diethyl ether crystallization. Yield: 0.036g Compound 1 (7%). F1 was purified by kromasyl column chromatography (eluent: toluene/iPrOH/98/2; 5 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.029g Compound 10 (5%).
b) Preparation of Compound 11(Z) and Compound 103(E)
In N2Potassium tert-butoxide (0.0196mol) was added portionwise to a mixture of diethyl (1-cyanoethyl) phosphonium acid (0.0196mol) in THF (25ml) at 5 ℃. The mixture was stirred at 5 ℃ for 30 minutes, then at room temperature for 30 minutes. A solution of intermediate 13(0.0130mol) in THF (25ml) was added. The mixture was stirred at room temperature overnight and poured off to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (5.8g) was subjected to silica gel column chromatography (eluent: toluene/iPrOH/NH)4OH 92/8/0.5; 15-40 μm). Four fractions (F1, F2, F3, F4) were collected and the solvent was distilled. Yield: 0.21g F1 (mixture Z/E90/10), 0.836g F2 (mixture Z/E57/43), 0.9g F3 and 0.87g F4. F3 was crystallized from DIPE/iPrOH to give 0.7g of Compound 11 (14%). F4 was crystallized from DIPE/iPrOH to give 0.67g of Compound 103 (13%).
c) Preparation of Compounds 12 and 13
Compound 12 ═ (E)
Compound 13 ═ (Z)
In N2Potassium tert-butoxide (0.0008mol) was added portionwise to diethyl (cyanomethyl) phosphonium carboxylate in THF (20ml) at 5 deg.C(0.0005mol) in a mixture. The mixture was stirred at room temperature for 30 minutes. Dropwise addition of THF (4ml)(prepared according to A3. d-1) (0.0005mol) solution. The mixture was stirred at room temperature for 4 hours and poured out to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. Yield: 0.3 g. This fraction was subjected to kromasil column chromatography (eluent: CH)2Cl2/CH3OH 99/1; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.21 g. The fraction was purified by kromasil column chromatography (eluent: cyclohexane/ethyl acetate 50/50; 10 μm). Two fractions (F1, F2) were collected and the solvent was distilled. Yield: 0.04g F1 and 0.047g F2. F1 was dried at 70 ℃ for 2 hours. Yield: 0.038g Compound 13 (18%). F2 was dried at 70 ℃ for 2 hours. Yield: 0.041g Compound 12 (20%).
d) Preparation of Compound 14
In N2Potassium tert-butoxide (0.0013mol) was added to a mixture of diethyl (cyanomethyl) phosphonium acid (0.0013mol) in THF (10ml) at 5 ℃. The mixture was stirred at 5 ℃ for 30 minutes. Added to THF (10ml)(prepared according to A3. d-1) (0.0009mol) of the mixture. The mixture was stirred at room temperature for 4 hours and poured out to H2O and extracted with ethyl acetate. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.17g) was chromatographed on a kromasil column (eluent: CH)2Cl2100 to CH2Cl2/CH3OH 99/1; 5 μm) was purified. Two fractions (F1, F2) were collected and the solvent was distilled. Yield: 0.054g F1 and 0.05g F2. F1 was treated with DIPE/CH3And (4) crystallizing CN. The precipitate was filtered and dried. Yield: 0.046g Compound 14 (12%).
e) Preparation of Compound 15
4-Fluorophenylacetonitrile (1.2 eq, 0.000175ml) was added to CH3Intermediate 13(0.000146mol) in OH (1 ml). Adding NaOCH at room temperature3/CH3OH (1.2 equiv., 0.000175 mol). The mixture was stirred at 60 ℃ for 2 hours, then poured out into ice-water and washed with CH2Cl2And (4) extracting. The solvent is distilled. The residue was purified by chromatography. The product fractions were collected and the solvent was distilled. Yield: 0.009g Compound 15 (13.42%).
f) Preparation of Compound 106
A mixture of intermediate 13 (prepared according to A5. a) (0.0005mol) in ethanol (5ml) and piperidine (0.0005mol) was stirred at room temperature for 30 minutes. 4, 4-dimethyl-3-oxo-valeronitrile (0.0011mol) was added. The mixture was stirred at room temperature overnight and poured out to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.3g) was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue was crystallized from DIPE (0.2 g). The precipitate was filtered and dried. Yield: 0.141g of Compound 106 (54%) (mp.193 ℃ C.).
Example B7
Preparation of Compound 16
A mixture of intermediate 14(0.00005mol) and thiocarbonyldichloride (0.001mol) in dioxane (10ml) was stirred at room temperature and H was added2And O. By CH2Cl2The mixture is extracted. The fraction was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 90/10/0.1; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.027g Compound 16 (95.6%).
Example B8
Preparation of Compound 17
NaOCH in EtOH (10ml)3(0.001mol) and 2- (dimethylamino) -N-hydroxy-imidamide (ethanimide) (0.001mol) were stirred at room temperature for 30 minutes. Adding into(iii) in (prepared according to A3. d-1) (0.0005 mol). The mixture was stirred at reflux overnight. Addition of H2And O. By CH2Cl2The mixture is extracted. The residue was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 95/5/0.1; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.07g of Compound 17 (31%).
Example B9
Preparation of Compound 18
In N2To the stream, nBuLi (0.0038mol) was added dropwise at-70 ℃ to iPr in THF (5ml)2NH (0.0038 mol). Mixing the raw materialsThe mixture was warmed to-20 ℃, stirred for 30 minutes and cooled again to-70 ℃. CH in THF (6ml) was added dropwise3CN (0.0038 mol). A mixture of intermediate 13(0.0009mol) in THF (1ml) was added. The mixture was stirred for 2 hours, poured out into ice at-30 ℃ and extracted with ethyl acetate. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.433g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 98/2; 35-70 μm). Two fractions were collected and the solvent was distilled. Yield: 0.056g F1 and 0.23g F2 (78%). Using DIPE/CH3CN crystal F1. The precipitate was filtered and dried. Yield: 0.036g of Compound 18.
Example B9A
a) Preparation of Compound 107
In N2In the stream nBuLi 1.6](0.0026mol) was added dropwise to a mixture of intermediate 13 (prepared according to A5. a) (0.0008mol) in THF (10ml) at-70 ℃. The mixture was stirred at-70 ℃ for 30 minutes. A solution of (chloromethyl) triphenylphosphonium chloride (0.0026mol) in THF (10ml) was added dropwise. The mixture was stirred at room temperature overnight and poured off to H2O and extracted with EtOAc. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (0.7g) was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue (0.155g) was chromatographed on a C18 column (eluent: CH)3CN/NH4Ac 0.5% 60/40). The pure fractions were collected and the solvent was distilled. The residue was crystallized from DIPE (0.051). The precipitate was filtered and dried. Yield: 0.029g of compound 107 (9%) (mp.250 ℃ C.).
b) Preparation of Compounds 108 and 109
Compound 108 Compound 109
In N2In the stream nBuLi 1.6](0.00261mol) was added dropwise to a mixture of (chloromethyl) triphenylphosphonium chloride (0.00261mol) in THF (10ml) at-70 ℃. The mixture was stirred for 30 minutes. A solution of intermediate 31 (prepared according to A4. a) (0.00087mol) in THF (5ml) was added dropwise. The mixture was stirred at room temperature overnight and then poured off to H2O and extracted with EtOAc. The organic layer was separated and dried (MgSO)4) The solvent was filtered and distilled. The residue (1.1g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 98/2/0.1; 15-40 μm). The pure fractions were collected and the solvent was distilled. The residue (0.3g) was chromatographed on a hypersil C18 column (eluent: CH)3OH/NH4Ac 0.5% 70/30). Two fractions (F1, F2) were collected and the solvent was distilled. Yield: 0.097g F1 and 0.085g F2. F1 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.045g of compound 108 (14%) (mp.165 ℃ C.). F2 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.049g of compound 109 (15%) (mp.200 ℃ C.).
c) Preparation of Compound 110
Mixing nBuLi [1.6 ]](1.1ml, 0.0017mol) 1, 1, 1,3, 3, 3-hexamethyldisilazane (HN (TMS))2) (0.0017 mol). The mixture was stirred at-70 ℃ for 30 minutes. Cyanofluoromethane (0.0017mol) was added. The mixture was stirred for 30 minutes. Diethyl chlorophosphate (phosphorus chlororic acid) (0.0017mol) was added. The mixture was stirred at-70 ℃ for 15 minutes. Dropwise adding nBuLi [1.6 ]](1.1ml, 0.0017 mol). The mixture was stirred for 30 minutes. A solution of intermediate 31 (prepared according to A4. a) (0.0008mol) in THF (4ml) was added. Placing the mixture in a chamberStirring overnight at room temperature, pouring to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.5g) was subjected to silica gel column chromatography (eluent: CH)2Cl2EtOAc 95/5; 15-40 μm). Four fractions (F1, F2, F3, F4) were collected and the solvent was distilled. Yield: 0.026g of Compound 110 (8%) (mp.254 ℃ C.).
d) Preparation of Compound 111
Reacting NH3(CuCl) in water (500. mu.l)2(0.00015mol) solution was added to a mixture of intermediate 21 (prepared according to A5. b) (0.0014mol) in DMSO (1 ml). CBr in DMSO (1.5ml) was added at 0 deg.C4(0.0044mol) of the solution. The mixture was stirred at room temperature overnight, poured out into ice and filtered. By CH2Cl2The organic layer was washed and dried (MgSO)4) Filtered and the solvent distilled. The residue (2.73g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH100/0 to 99/1; 15-40 μm). The two fractions were collected and the solvent was distilled. Yield: 0.007gF1 and 0.11 gF 0.11g F2. F2 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.075g of compound 111(mp.223 ℃ C.).
Example B9B
a) Preparation of compound 112.
Stirring CH2Cl2(10ml) and a mixture of intermediate 23(0.0005mol), 1-hydroxybenzotriazole (0.0007mol) and EDCI (0.0007mol) in THF (2 ml). Adding NH (CH)3)2HCl (0.0006mol) and Et3N (0.0005 mol). Mixing the mixture inStirred at room temperature for 12 hours. Addition of H2And O. By CH2Cl2The mixture is extracted. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH100/0 to 90/10; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.124g (58%). The fraction was subjected to kromasil column chromatography (eluent: CH)2Cl2/CH3OH 99/1; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.045g of compound 112 (21%) (mp.>264℃)。
b) Preparation of compound 113.
Stirring CH2Cl2(10ml) of a mixture of intermediate 57 (prepared according to A7. b) (0.0002mol), 1-hydroxybenzotriazole (0.0003mol) and EDCI (0.0003 mol). Adding N-methyl-1-butylamine [ CAS 110-68-9 ]](0.0002 mol). The mixture was stirred at room temperature for 12 hours. Addition of H2And O. By CH2Cl2The mixture is extracted. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. Yield: 0.149 g. This fraction was subjected to kromasil column chromatography (eluent: CH)2Cl2/CH3OH100/0 to 90/10; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.065 g. The fraction was extracted with DIPE. The precipitate was filtered and dried. Yield: 0.035g of Compound 113 (30%) (mp.212 ℃ C.).
c) Preparation of compound 114.
Stirring CH2Cl2Mixture (10ml) of intermediate 23 (prepared according to A7. a) (0.0005mol), 1-hydroxybenzotriazole (0.0007mol) and EDCI (0.0007mol) in THF (2ml)A compound (I) is provided. 3- (methylamino) propionitrile (0.0006mol) was added. The mixture was stirred at room temperature for 12 hours. Addition of H2And O. By CH2Cl2The mixture is extracted. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH100/0 to 90/10; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.068 g. The fraction was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.032g of Compound 114 (14%) (mp.168 ℃ C.).
d) Preparation of compound 115.
THF (5mL) and Et were stirred at room temperature3In N (0.054ml)(0.000195mol) and dimethylamine (2 eq, 0.000390 mol). EDCI (2 equiv., 0.000390mol) and 1-hydroxy-benzotriazole (2 equiv., 0.000390mol) were added. The mixture was stirred at room temperature for 12 hours and taken up to H2And (4) in O. The organic layer was separated, dried, filtered, and the solvent was distilled. The residue was purified by column chromatography. Yield: 0.026g Compound 115 (17.92%).
Example B9C
Preparation of compound 116.
Ethanol (1ml) and CH2Cl2A mixture of intermediate 13 (prepared according to A5. a) (0.000291mol) and isonicotinyl hydrazide (2.5 eq., 0.000728mol) in (2ml) was stirred at reflux for 12 h. The solvent was distilled until dry. The residue was purified by chromatography. Yield: 0.033g compound 116 (24.50%).
Example B9D
a) Preparation of Compound 117
In N2To this stream was added sodium cyanoborohydride (0.0024mol) at room temperature, formaldehyde (0.5ml) and CH3CN (20ml) in a solution of intermediate 26 (prepared according to A9) (0.0008 mol). Acetic acid (0.5ml) was added. The mixture was stirred at room temperature for 2 hours. Pouring out to H2O/10％ K2CO3In and use CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.3g) was subjected to column chromatography over supersol (eluent: CH)2Cl2/CH3OH 97/3; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.08g (28%). The fraction was crystallized from 2-propanone/ether. The precipitate was filtered and dried. Yield: 0.012g of Compound 117 (5%) (mp.132 ℃ C.).
b) Preparation of Compound 118
Adding into acetic acid (10ml)(prepared as described in A9) (0.0015mol) and tetrahydro-2, 5-dimethoxyfuran (0.0077mol) were stirred under reflux for 1 hour, then poured off until ice-water and K2CO3In and use CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (1g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 95/5; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.23 g. The fraction was crystallized from DIPE/diethyl ether. The precipitate was filtered and dried. Yield: 0.075 g. The partCrystallized from DIPE/diethyl ether. The precipitate was filtered and dried. Yield: 0.027g Compound 118 (5%).
Example B9E
a) Preparation of Compound 119
Tributylphosphine (0.0015mol) was added to a mixture of but-2-enedinitrile (0.0015mol) in THF (8 ml). The mixture was stirred at reflux for 2 hours. Adding into(prepared according to A5. a) (0.0005 mol). The mixture was stirred at reflux overnight. Addition of H2And O. By CH2Cl2The mixture is extracted. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.618g) was chromatographed on a kromasil column (eluent: CH)2Cl2100, respectively; 10 μm) was purified. Two fractions were collected and the solvent was distilled. Yield: 0.03g of Compound 119 (13%).
b) Preparation of Compound 120
Intermediate 13 (prepared according to A5. a) (0.002mol) was added to a mixture of malononitrile (0.004mol) and piperidine (0.004mol) in ethanol (10 ml). The mixture was stirred at room temperature for 5 minutes. The solvent is distilled. Residue is CH2Cl2Extracting and passing through silica gel column chromatography (eluent: CH)2Cl2/CH3OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.6g of Compound 120.
Example B9F
Preparation of Compound 122
In N2In the stream nBuLi 1.6M](0.0016mol) was added dropwise to a mixture of intermediate 27 (prepared according to A10) (0.0004mol) in THF (10ml) at-78 ℃. The mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature, stirred for 30 minutes and cooled to-78 ℃. A solution of 2-pyridinecarboxaldehyde (0.0004mol) in THF (10ml) was added. The mixture was stirred at rt for 2h, poured out into ice and extracted with EtOAc. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.32g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 98/2/0.1; 10 μm) was purified. Two fractions were collected and the solvent was distilled. Yield: 0.021g of compound 122 (10.4%) (mp.120 ℃ C.).
Example B10
Preparation of Compound 20
In N2NaBH4(0.0015mol) was added portionwise to CH at 5 ℃ in a stream3OH (15ml) in a mixture of compound 19 (see Table 3) (prepared according to B1) (0.0014 mol). The mixture was stirred at 5 ℃ for 1 hour and poured off to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.15g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue was crystallized from DIPE (0.068g, 12%). The precipitate was filtered and dried. Yield: 0.032g of Compound 20.
Example B11
Preparation of Compound 21
DME (3ml) was added to compound 2 (see Table 3) (0.0002mol), 3-thiopheneboronic acid (0.0005mol), Pd (PPh)3)4(0.00002mol) and Na2CO3(0.0007mol) the mixture was stirred in a sealed tube at reflux for 3 hours. Addition of H2And O. The mixture was extracted with ethyl acetate. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was distilled. Yield: 0.04g Compound 21 (40%).
Example B12
Preparation of Compound 23
Will CH3A mixture of compound 22 (see Table 3) (prepared according to B4. a) (0.0002mol) in OH (10ml) and Raney nickel (0.1g) at 2 bar H2Stirred under pressure at room temperature for 15 minutes. Then filtered through celite. By CH3OH washes the diatomaceous earth. The filtrate was distilled. Yield: 0.48 g. This fraction was subjected to kromasyl column chromatography (eluent: CH)2Cl2/CH3OH 99/1; 15-40 μm). Two fractions (F1, F2) were collected and the solvent was distilled. Yield: 0.13g F1 and 0.13g F2. F2 was crystallized from diethyl ether. The precipitate was filtered and dried. Yield: 0.09g of Compound 23 (20%).
Example B13
Preparation of Compound 24
Will CH3Compound 1(0.0004mol) and Pd/C (0.07g) mixture in OH (10ml) at 3 bar H2Hydrogenation was carried out at room temperature under pressure for 5 hours. Then filtered through celite. By CH2Cl2And (6) washing. The solvent was distilled until dry. The residue was crystallized from DIPE. The precipitate was filtered and dried. The residue (0.7g) was chromatographed on a kromasyl column (eluent: CH)2Cl2/CH3OH100/0 to 99/1; 5 μm) was purified. The pure fractions were collected and the solvent was distilled. The residue was crystallized from DIPE (0.06 g). The precipitate was filtered and dried. Yield: 0.04g Compound 24 (27%).
Example B14
Preparation of Compound 26
60% NaH (0.0004) was added to a mixture of Compound 5 (see Table 4) (prepared according to B6. c) (0.0004mol) in THF (30 ml). The mixture was stirred at room temperature for 1 hour. Addition of ICH in THF3(0.0004mol) solution (30ml), the mixture was stirred at 60 ℃ for 2 hours, then cooled and poured off to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.12g) was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.049g Compound 26 (32%).
Example B15
a) Preparation of Compound 123
In N2Jones reagent (0.0056mol) was added to a mixture of compound 18 (made according to B9) (0.0029mol) in 2-propanone (20ml) at 5 ℃ in a stream. The mixture was stirred at 5 ℃ for 2 hours and then poured off to H2In O, with NaHCO3Alkalizing and using CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (1.5g) was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH/NH4OH 98/2/0.1; 15-40 μm). Two (F1, F2) fractions were collected and the solvent was distilled. Yield: 0.122g F1 (11%) and 0.19g F2 (17%). F2 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.034g of Compound 123(mp.150 ℃ C.).
b) Preparation of Compound 124
Adding POCl3(1.5ml) A mixture of compound 123(0.0005mol) was stirred at 80 ℃ for 24 hours and poured out to ice and 10% K2CO3In and use CH2Cl2/CH3And (5) OH extraction. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.14g) was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH 99/1; 10 μm) was purified. The pure fractions were collected and the solvent was distilled. Yield: 0.026g Compound 124.
Example B16
a) Preparation of Compound 125
Compound 104 (see Table 3) (prepared according to B2. c) (0.0003mol) and NH in ethanol (10ml) was added dropwise to 5N NaOH (2ml) at 50 deg.C2OH·HCl (0.0004 mol). The mixture was stirred at 50 ℃ for 2 hours, and two thirds of the mixture was distilled off. Pouring the mixture to H2In O with CH2Cl2And (4) extracting. With 10% K2CO3The organic layer was washed and dried (MgSO)4) Filtered and the solvent distilled. Yield: 0.21g of Compound 125.
b) Preparation of Compound 126
1, 1' -carbonyldiimidazole (0.0012mol) was added to a mixture of compounds 125(0.0003mol) in THF (20 ml). The mixture was stirred at reflux overnight and poured off to H2In O with CH2Cl2And (4) extracting. The organic layer was separated and dried (MgSO)4) Filtered and the solvent distilled. The residue (0.17g) was chromatographed on a kromasil column (eluent: CH)2Cl2/CH3OH 98/2; 10 μm) was purified. Two fractions were collected and the solvent was distilled. Yield: 0.035g F1 and 0.05g F2. The two components were mixed and crystallized from diethyl ether. The precipitate was filtered and dried. Yield: 0.05g of Compound 126 (38%) (mp.>260℃)。
Example B17
Preparation of Compound 253
a) 2.53ml of acetonitrile, 0.056g (0.253mmol) of Pd (OAc)2 and 0.154g (0.506mmol) of tris (2-tolyl) phosphine were placed in a 100ml flask under nitrogen, and the mixture was stirred for 10 minutes. To the mixture was added 1g (2.53mmol) of intermediate 58, 0.51ml (3.8mmol) of N, N-diethylethylamine and 0.36g (5.06mmol) of acrylamide. The mixture was heated to reflux (80 ℃) for 5 days to give 28% of compound 253.
b) In N2To a 100ml flask were added 0.8g (4.33 mmol; 1 eq.) of intermediate 3a (E), 1g (4.33 mmol; 1 eq.) of intermediate 5 and 16ml of 2-propanol. To this mixture was added 0.72ml of 6N HCl in 2-propanol. The mixture was stirred at reflux for 72 hours and then cooled to give compound 253 as the hydrochloride salt, compound 254.
Compound 254 can be converted to the free base according to methods known in the art (see example B1A).
Compound 253 can be converted to compound 1 following the procedure described above in example A1c) y).
The compounds of formula (I) prepared according to one of the above examples (example No.) are listed in tables 3,4 and 5 below.
TABLE 3
*(MH+) Represents the mass of the protonated compound; it is determined by means of a micro-mass spectrometer equipped with a quadrupole analyzer and an electrospray probe.
TABLE 4
*(MH+) Represents the mass of the protonated compound; it is determined by means of a micro-mass spectrometer equipped with a quadrupole analyzer and an electrospray probe.
TABLE 5
Compound number Example No. 2 R R R X Physical data mp. deg.C
227 B13 -CH-CH-CN CH H -NH mp.186℃
228 B4b -CH-N(CH)-CH-CN CH H -NH mp.138℃
229 B6b -CH＝C(CH)-CN CH H -NH mp.190℃
230 B6c -CH＝CH-CN CH H -O- (E)，mp.254℃
231 B6b -CH＝C(CH)-CN CH H -O- mp.150℃
232 B6c -C(CH)＝CH-CN CH H -O- (E)，mp.234℃
105 B4d -CH-O-CH-CH CH H -O- mp.140℃
233 B6b -CH＝C(CH)-CN CH Cl -NH mp.214℃
234 B13 -CH-CH-CN CH H -O- mp.199℃
235 B13 -CH(CH)-CH-CN CH H -O- mp.195℃
236 B13 -CH-CH(CH)-CN CH H -O- mp.161℃
237 B6c -CH＝CH-CN CH H -NH (E)，mp.>264℃
238 B3 -CH-CN CH Cl -NH mp.184℃
239 B6c -CH＝CH-CN CH 2-furyl radical -NH (E)mp.175℃
119 B9E -CH＝C(CN)-CH-CN CH 2-furyl radical -NH
C. Pharmacological examples
The pharmacological activity of the compounds of the invention was determined by the following assay.
In vitro evaluation of anti-HIV drugs was performed using rapid, sensitive and automated assay methods. The present invention is described in the prior art (Koyanagi et al, int.j. cancer,36445-451, 1985) showed a high degree of HIV infectionSensitive and susceptible HIV-1 was transformed into T4-cell line, MT-4, as a target cell line. The inhibition of HIV-induced cytopathic effects was used as the end point. Viability of HIV-infected and pseudo-infected cells was assessed spectrophotometrically with a reduced amount of 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) in situ. Cytotoxic Concentration (CC) of 50%50In M) is defined as the concentration of compound that reduces absorption by 50% of the-infected control sample. The percent protection by compound in HIV-infected cells was calculated by the following formula:
expressed in% by weight, the total amount of the active ingredient,
wherein (ODT)HIVOptical density determined for a given concentration of test compound in HIV-infected cells; (OD)C)HIVOptical density determined for untreated HIV-infected cell control; (OD)C)MOCKOptical density determined for an untreated control of pseudo-infected cells; all optical density values were determined at 540 nm. The dose at 50% percent protection obtained according to the above formula was defined as the 50% inhibitory concentrationDegree (IC)50In units of M). Will CC50And IC50The ratio of (b) is defined as the Selectivity Index (SI).
Table 6 shows the pIC of the compounds of formula (I)50(-logIC50)、pCC50(-logCC50) And pSI (pCC)50-pIC50) The value is obtained. E.g. with IC50Value of 10-9M, i.e. pIC509, and CC50Value of 10-5M, i.e. pCC50Compound of formula 5 having an SI value of 10-5M/10-9M is 10,000, i.e. pSI is 5-9-4.
TABLE 6
Compound number pIC(M) pCC(M) pSI
21 8.4 4.9 -3.5
3 8.4 5.5 -2.9
1 9.4 5.0 -4.4
34 8.0 4.8 -3.2
19 8.4 4.8 -3.6
45 8.7 5.0 -3.8
49 8.0 4.8 -3.2
70 8.1 4.8 -3.3
75 9.0 5.0 -4.0
78 8.4 4.9 -3.5
79 8.0 5.3 -2.7
84 9.0 4.5 -4.5
18 8.8 4.9 -4.0
25 9 4 -5
24 9.1 5.7 -3.4
81 9.1 5.6 -3.5
11 9.2 5.7 -3.5
10 9.2 6.3 -2.9
174 8.8 5.3 -3.5
227 9.5 <4.0 <-5.5
144 8.6 6.4 -2.2
Compound number pIC(M) pCC(M) pSI
229 8.8 <4.0 <-4.8
118 8.4 4.1 <-4.1
177 8.3 <4.0 <-4.3
106 7.7 5.2 -2.5
145 8.7 5.3 -3.4
147 9.4 5.7 -3.7
148 8.8 4.9 -3.9
230 9.2 <4.0 <-5.2
231 9.2 <4.0 <-5.2
232 8.4 <4.0 <-4.4
105 7.2 <4.0 <-3.2
110 8.6 4.3 -4.3
233 9.3 5.7 -3.6
234 8.7 <4.0 <-4.7
235 9.3 <4.0 <-5.3
236 8.8 <4.0 <-4.8
149 9.1 5.3 -3.8
150 8.8 4.8 -4.0
237 8.9 <4.0 <-4.9
151 9.1 5.5 -3.6
152 9.1 4.8 -4.3
178 8.8 5.7 -3.1
179 8.9 <4.0 <-4.9
153 9.2 6.3 -2.9
124 8.5 4.7 -3.8
238 9.5 5.6 -3.9
112 9.1 4.9 -4.2
244 9.2 4 -5.2
209 8.6 4.9 -3.7
210 8.3 4.8 -3.5
155 8.8 6.3 -2.5
156 7.7 5.1 -2.6
158 8 5.5 -2.5
212 9.1 5 -4.1
114 8.6 5.1 -3.5
Compound number pIC(M) pCC(M) pSI
213 9 4.8 4.2
214 8.6 5.1 -3.5
215 9.1 5.5 -3.6
216 8.2 5 -3.6
219 9.1 5 -4.1
245 8.8 4 -4.8
146 8.4 5.4 -3
247 9.2 6.2 -3
248 9.3 5.7 -3.5
249 8.5 4 -4.5
42 9 6.3 -2.7
251 8.9 5 -3.9
133 9.2 4 -5.2
9 8.8 4.8 -4
239 8.9 5 -3.9
241 9.4 5.3 -4.1
126 8.4 4.9 -3.5

Claims (31)

1. A compound of the formula,
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof, wherein
-a1＝a2-a3＝a4-represents a divalent radical of formula,
-CH＝CH-CH＝CH- (a-1)
-b1＝b2-b3＝b4-represents a divalent radical of formula,
-CH＝CH-CH＝CH- (b-1)
n is 1;
m is 1, 2, 3 or 4;
R1represents hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyloxy substituted C1-6An alkyl group; quilt C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
each R is2Independently of each other
Cyano radicals, or
-C(＝O)-NH2；
And is
X1is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、C1-4Alkanediyl, -CHOH-, -S (═ O)P-、-X2-C1-4alkanediyl-or-C1-4alkanediyl-X2-；
X2represents-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-CHOH-、-S-、-S(＝O)P-；
R3Represents NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a C substituted by cyano or aminocarbonyl2-6An alkyl group; by NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and is selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally substituted by one or more substituents each independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；
X3is-NR5-、-NH-NH-、-N＝N-、-O-、-C(＝O)-、-S-、-S(＝O)P-、-X2-C1-4Alkanediyl-, -C1-4alkanediyl-X2a-、-C1-4alkanediyl-X2b-C1-4Alkanediyl, -C (═ N-OR)8)-C1-4Alkanediyl-;
wherein X2ais-NH-NH-, -N-, -O-, -C (O) -, -S (O)P-; and
wherein X2bis-NH-NH-, -N-, -C (O) -, -S (O)P-；
R4Represents halogen, hydroxy, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy, cyano, nitro, polyhaloC1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, C1-6Alkoxycarbonyl, C1-6An alkylcarbonyl group, a formyl group, a,Amino, mono-or di (C)1-4Alkyl) amino or R7；
R5Is hydrogen; an aryl group; a formyl group; c1-6An alkylcarbonyl group; c1-6An alkyl group; c1-6An alkoxycarbonyl group; by formyl, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl or C1-6Alkylcarbonyloxy substituted C1-6Alkyl radical, C1-6Alkoxycarbonyl substituted C1-6Alkoxy radical C1-6An alkylcarbonyl group;
R6is C1-4Alkyl, amino, mono-or di (C)1-4Alkyl) amino or polyhaloC1-4An alkyl group;
R7represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each said carbocycle or heterocycle ring system optionally may be substituted with one, two, three, four or five each independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8)、R7a、-X3-R7aOr R7a-C1-4Alkyl substituent substitution;
R7ais a saturated, partially saturated or aromatic carbocyclic ring or a saturated, partially saturated or aromatic heterocyclic ring of a monocyclic, bicyclic or tricyclic ring, wherein each of said carbocyclic or heterocyclic ring systems optionally may be substituted by one, two, three, four or five independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl, formyl, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, -CH (═ N-O-R)8) Substituted with the substituent(s);
R8is hydrogen, C1-4Alkyl, aryl or aryl C1-4An alkyl group;
R9and R10Each independently is hydrogen; a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein each of C mentioned above1-6The alkyl groups optionally may each be independently selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s); or
R9And R10May together form a divalent group of the formula;
-CH2-CH2-CH2-CH2- (d-1)
-CH2-CH2-CH2-CH2-CH2- (d-2)
-CH2-CH2-O-CH2-CH2- (d-3)
-CH2-CH2-S-CH2-CH2- (d-4)
-CH2-CH2-NR12-CH2-CH2- (d-5)
-CH2-CH＝CH-CH2- (d-6)
R9arepresents a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl; -CH (═ NR)11) Or R7Wherein R is9aEach C in the definition1-6The alkyl groups optionally each independently may be selected from hydroxy, C1-6Alkoxy, hydroxy C1-6An alkoxy group; carboxy, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino; polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Substituted with the substituent(s);
R9amay also be reacted with R10Together form a divalent radical of formula (d-1), (d-2), (d-3), (d-4), (d-5) or (d-6)
R11Is cyano; optionally is covered with C1-4Alkoxy, cyano, amino, mono-or di (C)1-4Alkyl) amino or aminocarbonyl substituted C1-4An alkyl group; c1-4An alkylcarbonyl group; c1-4Alkoxycarbonyl, aminocarbonyl, mono-or di (C)1-4Alkyl) aminocarbonyl;
R12is hydrogen or C1-4An alkyl group;
R13and R14Each independently being C optionally substituted by cyano or aminocarbonyl1-6Alkyl, C optionally substituted by cyano or aminocarbonyl2-6Alkenyl, C optionally substituted by cyano or aminocarbonyl2-6An alkynyl group;
R15is C substituted by cyano or aminocarbonyl1-6An alkyl group;
R16is C optionally substituted by cyano or aminocarbonyl1-6Alkyl, or R7；
p represents 1 or 2;
aryl is phenyl or substituted by one, two, three, four or five each independentlyThe site is selected from halogen, hydroxyl, sulfydryl and C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, R7or-X3-R7Phenyl substituted with the substituent(s) of (1).
2. A compound according to claim 1, wherein R3Is selected from at least one of NR9R10Or R7C substituted by a substituent of1-6An alkyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7And wherein two hydrogen atoms attached to the same carbon atom are substituted by C1-4C substituted by alkanediyl1-6An alkyl group; by hydroxy and a second group selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of1-6An alkyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of2-6An alkenyl group; by at least one member selected from cyano, aminocarbonyl, NR9R10Or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7；R4Is halogen, hydroxy, C1-6Alkyl radical, C3-7Cycloalkyl radical, C1-6Alkoxy, cyano, nitro, polyhaloC1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, C1-6Alkoxycarbonyl, C1-6Alkylcarbonyl, formyl, amino, mono-or di (C)1-4Alkyl) amino; r7Is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbonCyclic or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems optionally may be substituted with one, two, three, four or five each independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl, R7a、-X3-R7aOr R7a-C1-4Alkyl substituent substitution; r7aIs a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring, wherein each of said carbocyclic or heterocyclic ring systems optionally may be substituted with one, two, three, four or five independently selected from halogen, hydroxy, mercapto, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, mono-or di (C)1-6Alkyl) amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C3-7Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkoxycarbonyl, C1-6Alkylthio, cyano, nitro, polyhalo C1-6Alkyl, polyhalo C1-6Alkoxy, aminocarbonyl; r9And R10Each independently is hydrogen; a hydroxyl group; c1-6An alkyl group; c1-6An alkoxy group; c1-6An alkylcarbonyl group; c1-6An alkoxycarbonyl group; an amino group; mono-or di (C)1-6Alkyl) amino; mono-or di (C)1-6Alkyl) aminocarbonyl or R7Wherein each of the above C1-6The alkyl groups may optionally be independently selected from hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy, carboxyl, C1-6Alkoxycarbonyl, cyano, amino, imino, mono-or di (C)1-4Alkyl) amino, polyhalomethyl, polyhalomethoxy, polyhalomethylthio, -S (═ O)PR6、-NH-S(＝O)PR6、-C(＝O)R6、-NHC(＝O)H、-C(＝O)NHNH2、-NHC(＝O)R6、-C(＝NH)R6、R7Is substituted with the substituent(s).
3. A compound according to claim 1 having the formula
Wherein-b1＝b2-b3＝b4、R1、R2、R3、R4M, and X1As defined in claim 1;
n' is 0;
R2’is cyano or aminocarbonyl.
4.A compound according to claim 3, wherein R3Is NHR13；NR13R14；-C(＝O)-NHR13；-C(＝O)-NR13R14；-C(＝O)-R15；-CH＝N-NH-C(＝O)-R16(ii) a By NR9R10、-C(＝O)-NR9aR10、-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; is two or more independently selected from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7And wherein two hydrogen atoms attached to the same carbon atom are replaced by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; optionally, theIs selected from one or more of cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6Alkoxy radical C1-6An alkyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkenyl group; is selected from one or more of halogen, cyano, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7。
5.A compound according to claim 3, wherein R3is-CH-N-NH-C (═ O) -R16(ii) a By NR9R10，-C(＝O)-NR9aR10，-C(＝O)-C1-6Alkyl or R7Substituted C1-6An alkyl group; by two or more radicals independently selected from cyano, NR9R10，-C(＝O)-NR9R10，-C(＝O)-C1-6Alkyl or R7C substituted by a substituent of1-6An alkyl group; is selected from one or more of cyano, NR9R10，-C(＝O)-NR9R10，-C(＝O)-C1-6Alkyl or R7And wherein 2 hydrogen atoms bonded to the same carbon atom are substituted by C1-4Alkanediyl-substituted C1-6An alkyl group; by hydroxy and from cyano, NR9R10，-C(＝O)-NR9R10，-C(＝O)-C1-6Alkyl or R7C substituted with the second substituent of (1)1-6An alkyl group; may optionally be each independently selected from cyano, NR9R10，-C(＝O)-NR9R10，-C(＝O)-C1-6Alkyl or R7C substituted by one or more substituents of1-6Alkoxy radical C1-6An alkyl group; are each independently selected from halogen, cyano, NR9R10，-C(＝O)-NR9R10，-C(＝O)-C1-6Alkyl or R7C substituted by one or more substituents of2-6An alkenyl group; are each independently selected from halogen, cyano, NR9R10，-C(＝O)-NR9R10，-C(＝O)-C1-6Alkyl or R7C substituted by one or more substituents of2-6An alkynyl group; -C (═ N-O-R)8)-C1-4An alkyl group; r7or-X3-R7。
6. A compound according to claim 3, wherein R3Represents an ethyl group substituted by a cyano group.
7.A compound according to claim 3, wherein R3Represents C substituted by cyano2-6An alkenyl group.
8. A compound according to any one of claims 3 to 7, wherein R2’Is cyano.
9. A compound according to any one of claims 1 to 7, wherein m is 2.
10. A compound according to any one of claims 1 to 7, wherein R4Is C1-6An alkyl group.
11. The compound according to any one of claims 1 to 7, wherein X1Is NH.
12. A compound according to claim 1 having the formula
R R -CH＝CH-CN H (E) -CH＝CH-CN H (Z) -C(CH)＝CH-CN H (E) -CH＝C(CH)-CN H (E) -CH＝C(CH)-CN H (Z)
R R -CH＝CH-CN H -CH＝C(CH)-CN H (E) -CH＝C(CH)-CN H (Z)
R R R X -CH＝C(CH)-CN CH C1 -NH -CH＝CH-CN CH 2-furyl radical -NH (E) -CH＝C(CH)-CN CH Br -NH -CH＝CH-CN CH Br -NH (E) -CH＝CH-CN CH Cl -NH (E)
An N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.
13. The compound according to claim 12, wherein the compound is 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E), an N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof.
14. The compound according to claim 12, wherein the compound is 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E), or a pharmaceutically acceptable addition salt thereof.
15. The compound according to claim 12, wherein the compound is 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E), or an N-oxide thereof.
16. The compound according to claim 12, wherein the compound is 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E).
17. The compound according to claim 14, wherein said compound is the hydrochloride salt of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile (E).
18. Use of a compound as defined in any one of claims 1 to 17 for the manufacture of a medicament for the prophylaxis or treatment of human immunodeficiency virus infection.
19. Use of a compound as defined in claim 18 for the manufacture of a medicament for the treatment of human immunodeficiency virus infection.
20. Use of a compound according to claim 18 for the manufacture of a medicament for the prevention or treatment of drug resistant human immunodeficiency virus infection.
21. Use of a compound according to claim 20 for the manufacture of a medicament for the treatment of drug resistant human immunodeficiency virus infection.
22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 17.
23. A process for preparing a pharmaceutical composition according to claim 22, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 17 is intimately mixed with a pharmaceutically acceptable carrier.
24. A process for the preparation of a compound according to claim 1, characterized in that
a) Reacting the intermediate of formula (II) with the intermediate of formula (III),
wherein, W1Is a suitable leaving group, R1、R2、R3、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
b) reacting an intermediate of formula (IV) with an intermediate of formula (V) in the presence of a suitable catalyst, a suitable salt and a suitable solvent
Wherein W2Is a suitable leaving group, R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1; and R7’Represents a monocyclic, bicyclic or tricyclic aromatic ring system and RaRepresents a borate group or a tri (C)1-4Alkyl) stannyl;
c) reacting an intermediate of formula (IV) with an intermediate of formula (VI)
Wherein W2Is a suitable leaving group, R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1; r7”Represents a monocyclic, bicyclic or tricyclic saturated ring system;
d) reacting an intermediate of formula (VII) with an appropriate cyanate in the presence of a suitable solvent
Wherein W3Is a suitable leaving group, R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
e) reacting an intermediate of formula (VII) with an intermediate of formula (VIII), optionally in the presence of a suitable salt and a suitable solvent
Wherein W3Is a suitable leaving group, R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1; q represents R7；NR9R10Or optionally CN, R7Or NR9R10Substituted C1-6An alkoxy group;
f) reacting an intermediate of formula (IX) with an intermediate of formula (X) in the presence of a suitable solvent
Wherein R is1、R2、R4、R8、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
g) reacting an intermediate of formula (XI) with a reagent of formula (XII) Wittig or Horner-Emmons, representing a suitable phosphorus ylide precursor, in the presence of a suitable salt and a suitable solvent
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1; rcRepresents hydrogen or C1-4Alkyl radical, Rc’Represents hydrogen, C1-4Alkyl or R7Provided that CR isc’＝CRcRestricted to C only2-6Alkenyl, and RbRepresents (phenyl)3P+-C1-Or (CH)3CH2-O)P(＝O)-；
h) Reacting an intermediate of formula (XI) with an intermediate of formula (XIII) in the presence of a suitable solvent
Wherein R is1、R2、R4、R7、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1; rcRepresents hydrogen or C1-4Alkyl radical, Rc”Represents NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7；
i) Reacting an intermediate of formula (XI-b) with 2-butenedionitrile in the presence of tributylphosphine and a suitable solvent
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
j) reacting an intermediate of formula (XI-b) with malononitrile in the presence of a suitable base and a suitable solvent
k) Reacting an intermediate of formula (XI-b) with CH in the presence of a suitable proton-abstracting agent, a suitable substrate for the proton-abstracting agent and a suitable solvent3-CN reaction
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
l) reacting an intermediate of formula (XI) with a reagent of formula (XII') Wittig or Horner-Emmons, representing a suitable phosphorus ylide precursor, in the presence of n-BuLi and a suitable solvent
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1, RcRepresents hydrogen or C1-4Alkyl radical, Rc’Represents hydrogen, C1-4Alkyl or R7Provided that CR isc’＝CRcRestricted to C only2-6Alkenyl radical, Rb-represents (phenyl)3P+-Cl-Or (CH)3CH2-O)2P(＝O)-；
m) reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII') in the presence of a suitable Horner-Emmons reagent, nBuLi, 1, 1, 1-trimethyl-N- (trimethylsilyl) -silylamine and a suitable solvent
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1, RcRepresents hydrogen or C1-4Alkyl radical, Rc”’Represents CN, NR9R10、-C(＝O)-NR9R10、-C(＝O)-C1-6Alkyl or R7；
n) reacting an intermediate of formula (XVIII) with CBr in the presence of a suitable catalyst salt, a suitable base and a suitable solvent4Reaction of
o) reacting an intermediate of formula (XIV) with Cl in the presence of a suitable solvent2Reaction of C ═ S
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
p) reacting the intermediate of formula (XV) with the intermediate of formula (XVI) in the presence of a suitable solvent
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
q) reacting an intermediate of formula (XXIX) with an intermediate of formula (XXX) in the presence of hydroxybenzotriazole and ethyldimethylaminopropyl carbodiimide, a suitable solvent and optionally in the presence of a suitable base
Wherein R is1、R2、R4、R9、R10、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-is as defined in claim 1 and C2-6Alkenyl' represents C optionally substituted by cyano2-6An alkenyl group;
r) reacting an intermediate of formula (XXXI) with an intermediate of formula (XXXII-1) or (XXXII-2) in the presence of hydroxybenzotriazole and ethyldimethylaminopropyl carbodiimide and a suitable solvent and optionally in the presence of a suitable base
Wherein R is1、R2、R4、R13、R14、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4As defined in claim 1;
s) reacting an intermediate of formula (XI-b) with an intermediate of formula (XXXIII) in the presence of a suitable solvent
Wherein R is1、R2、R4、R16、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
t) reductive methylation of an intermediate of formula (XXXIV) with formaldehyde in the presence of a suitable catalyst, a suitable reducing agent and a suitable solvent
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
u) reaction of the intermediate of formula (XXXIV) with 2, 5-dimethoxytetrahydrofuran in the presence of a suitable acid
Wherein R is1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
v) reacting an intermediate of formula (XXXV) with an intermediate of formula (XXXVI) in the presence of nBuLi and a suitable solvent
Wherein R is1、R2、R4、R7、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1;
and, optionally, the compounds of formula (I) may be converted into each other according to art-known conversion reactions; and, optionally, converting the compound of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid or, conversely, converting the acid addition salt form into the free base by treatment with a base; and, optionally, stereochemically isomeric forms, N-oxide forms and quaternary ammonium salts thereof are prepared.
25. A product comprising (a) a compound according to any one of claims 1 to 17, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of human immunodeficiency virus infection.
26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredients, (a) a compound according to any one of claims 1 to 17, and (b) another antiretroviral compound.
27. A compound of the formula,
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-is as defined in claim 1, and W3Represents a suitable leaving group.
28. A compound of the formula,
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-as defined in claim 1.
29. A compound of the formula,
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-is as defined in claim 1, and C2-6Alkenyl' represents C optionally substituted by cyano2-6An alkenyl group.
30. A compound of the formula,
N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof, wherein
R1、R2、R4、X1、m、n、-a1＝a2-a3＝a4-and-b1＝b2-b3＝b4-is as defined in claim 1, and C2-6Alkenyl' represents C optionally substituted by cyano2-6An alkenyl group.
31. A compound of the formula,
A N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein R4And X1As defined in claim 1, 10 or 11; with the proviso that the compound does not comprise 3- (3, 4, 5-trimethoxyphenyl) -2-acrylonitrile.
HK05102760.9A 2001-08-13 2002-08-09 Hiv inhibiting pyrimidines derivatives HK1070066B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP01203090 2001-08-13
EP01203090.4 2001-08-13
EP02077748 2002-06-10
EP02077748.8 2002-06-10
PCT/EP2002/008953 WO2003016306A1 (en) 2001-08-13 2002-08-09 Hiv inhibiting pyrimidines derivatives

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HK1070066A1 HK1070066A1 (en) 2005-06-10
HK1070066B true HK1070066B (en) 2010-04-09

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