CN101268072A - DNA-PK inhibitors - Google Patents
DNA-PK inhibitors Download PDFInfo
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- CN101268072A CN101268072A CNA2006800125570A CN200680012557A CN101268072A CN 101268072 A CN101268072 A CN 101268072A CN A2006800125570 A CNA2006800125570 A CN A2006800125570A CN 200680012557 A CN200680012557 A CN 200680012557A CN 101268072 A CN101268072 A CN 101268072A
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- aryl
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses compounds of formula (I) in use inhibiting DNA-PK,wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N; and (iii) CH, O, C.
Description
The present invention relates to compounds useful as DNA-PK inhibitors, their use and synthesis.
DNA-dependent protein kinases (DNA-PKs) are nuclear serine/threonine protein kinases that are activated upon binding to DNA. Biochemical and genetic data have shown that this kinase consists of a large catalytic subunit called DNA-PKcs and a regulatory component called Ku. DNA-PK has been shown to be an important component of both DNA Double Strand Break (DSB) repair apparatus and v (d) J recombination devices. In addition, recent work has involved DNA-PK components in a number of other processes, including regulation of chromatin structure and maintenance of telomeres (Smith, g.c.m. and Jackson, s.p., Genes and dev., 13, 916-934 (1999)).
DNA DSBs are considered the most lethal damage that cells can encounter. To combat the serious threat posed by DNA DSBs, eukaryotic cells have evolved several mechanisms that mediate their repair. In higher eukaryotes, most of these mechanisms are DNA non-homologous end joining (NHEJ), which is also known as non-canonical recombination. DNA-PK plays an important role in this pathway. The increase in DNA-PK activity has been demonstrated both in vitro and in vivo and is associated with tumor cell resistance to IR and bifunctional alkylating agents (Muller C et al, Blood, 92, 2213-2219(1998), Sirzen F. et al, Eur. J. cancer, 35, 111-116 (1999)). Thus, increased DNA-PK activity has been proposed as a mechanism of cellular and tumor resistance. Thus, inhibition of DNA-PK with small molecule inhibitors has proven effective in tumors, and DNA-PK overexpression is considered to be a resistance mechanism.
It has also been previously found that the PI 3-kinase inhibitor LY 294002:
can inhibit the function of DNA-PK in vitro (IZzard, R.A. et al, Cancer Res., 59, 2581-2586 (1999)). IC50 (concentration at 50% loss of enzyme activity) for LY294002 on DNA-PK was-1. mu.M, which was identical to IC50 on PI 3-kinase. In addition, LY294002 has been shown to also weakly sensitize cells to the effects of IR (Rosenzweig, K.E. et al, Clin. cancer Res., 3, 1149-.
WO03/024949 describes a number of classes of compounds useful as DNA-PK inhibitors, including 2-amino-benzopyran-4-ones of the general structure:
wherein,
as an example. This compound showed an IC of 0.76. mu.M50And a SER of 1.5(500nM) (see methods below).
Other examples of DNA-PK inhibitors include 1 (2-hydroxy-4-morpholin-4-yl-phenyl) -ethanone (ethanone) (Kashishian, A. et al, MoI. cancer Ther, 2, 1257-1264 (2003)):
and SU11752(Ismail, I.H. et al, Oncogene, 23, 873-:
if DNA-PK is involved in the DNA repair process and small molecule inhibitors have been shown to radiosensitize mammalian cells in culture, the use of specific DNA-PK inhibitor drugs will act as agents to enhance the efficacy of cancer chemotherapy and radiotherapy. DNA-PK inhibitors have also proven useful in the treatment of retroviral mediated diseases. For example, loss of DNA-PK activity has been shown to severely inhibit the retroviral integration process (Daniel R, et al, Science, 284, 644-7 (1999)).
The present inventors have now discovered other compounds that exhibit similar or improved levels of DNA-PK inhibition while possessing other useful properties for use as active drugs, in particular improved solubility and cellular efficiency.
Accordingly, in a first aspect the present invention provides a compound of formula I:
and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein A, B and D are independently selected from the group consisting of:
(i)CH、NH、C;
(ii) CH, N; and
(iii)CH、O、C;
the dotted lines represent two double bonds in place; rN1And RN2Independently selected from hydrogen, optionally substituted C1-7Alkyl radical, C3·20Heterocyclyl or C5-20Aryl or together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 4 to 8 ring atoms;
Z2、Z3、Z4、Z5and Z6Together with the carbon atoms to which they are bound form an aromatic ring;
Z2selected from the group consisting of CR2N, NH, S and O; z3Is CR3;Z4Selected from the group consisting of CR4N, NH, S and O; z5Is a direct bond or is selected from O, N, NH, S and CH; z6Selected from O, N, NH, S and CH;
R2is H;
R3selected from halogen or optionally substituted C5-20An aryl group;
R4selected from H, OH, NO2、NH2And Q-Y-X, wherein
Q is-NH-C (═ O) -or-O-;
y is optionally substituted C1-5An alkylene group;
x is selected from SRS1Or NRN3RN4Wherein
RS1or RN3And RN4Independently selected from hydrogen, optionally substituted C1-7Alkyl radical, C5-20Aryl or C3-20Heterocyclyl group, or RN3And RN4Together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having from 4 to 8 ring atoms;
if Q is-O-, then X may additionally be selected from-C (═ O) -NRN5RN6Wherein R isN5And RN6Independently selected from hydrogen, optionally substituted C1-7Alkyl radical, C5-20Aryl or C3-20Heterocyclyl group, or RN5And RN6Together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having from 4 to 8 ring atoms,
and if Q is-NH-C (═ O) -, then-Y-X may additionally be selected from C1-7An alkyl group.
Thus selecting Z2、Z3、Z4、Z5And Z6So that they form a structure comprising Z2And Z6An aromatic group bonded to a carbon atom.
In some embodiments of the invention, the compound of the first aspect may be a compound of formula II or more specifically formula IIa, wherein Z is2Is CR2、Z3Is CR3、Z4Is CR4And Z is5And Z6Are all CH:
a, B, D, R thereinN1、RN2、R2、R3And R4As described above. In these particular embodiments, if R3Is unsubstituted phenyl and RN1And RN2Form a morpholino group, then R4Is not H.
Selection of A, B and D yields a compound of the formula wherein Ar represents a group consisting of Z2、Z3、Z4、Z5And Z6Aromatic ring formed:
in a second aspect the present invention provides a composition comprising a compound of the first aspect and a pharmaceutically acceptable carrier or diluent.
A third aspect of the invention provides a compound of the first aspect useful in a method of treatment.
A fourth aspect of the invention provides the use of a compound of the first aspect for the manufacture of a medicament for the treatment of a disease, which ameliorates the disease by inhibition of DNA-PK.
Preferably the medicament of the fourth aspect selectively inhibits DNA-PK compared to PI 3-kinase and/or ATM. Selectivity is important because inhibition of other PI 3-kinase family members can lead to undesirable side effects associated with loss of function of these enzymes.
In particular, the compounds may be used for the preparation of a medicament for:
(a) as an adjunct (adjunct) in cancer therapy, or for potentiating tumour cells for treatment with ionising radiation or chemotherapeutic agents; or
(b) Treating retroviral mediated diseases.
A further aspect of the invention provides an active compound as described herein for use in a method of treatment of the human or animal body, wherein the active compound is preferably used in the form of a pharmaceutical composition.
Other aspects of the invention provide methods for inhibiting DNA-PK in vitro and in vivo comprising contacting a cell with an effective amount of an active compound as described herein.
Definition of
C1-7Alkyl groups: the term "C" as used herein1-7Alkyl "relates to C having from 1 to 7 carbon atoms1-7The monovalent moiety derived from an alkyl compound by removal of one hydrogen atom may be aliphatic or alicyclic or a combination thereof, and may be saturated, partially unsaturated, or fully unsaturated.
Saturated straight chain C1-7Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, and n-pentyl (pentyl).
Saturated branched chain C1-7Examples of alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, and neopentyl.
Saturated alicyclic C1-7Alkyl (also known as "C3-7Cycloalkyl ") include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as substituted groups (e.g., groups comprising such groups), such as methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropylmethyl, and cyclohexylmethyl.
Unsaturated C having one or more carbon-carbon double bonds1-7Alkyl (also known as "C2-7Alkenyl ") include, but are not limited to, vinyl (-CH ═ CH)2) 2-propenyl (allyl, -CH-CH ═ CH)2) Isopropenyl (-C (CH)3)=CH2) Butenyl, pentenyl and hexenyl groups。
Unsaturated C having one or more carbon-carbon triple bonds1-7Alkyl (also known as "C2-7Alkynyl ") include, but are not limited to, ethynyl and 2-propynyl (propargyl).
Unsaturated alicyclic (carbocyclic) C having one or more carbon-carbon double bonds1-7Alkyl (also known as "C3-7Cycloalkenyl ") include, but are not limited to, unsubstituted groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as substituted groups (e.g., groups comprising such groups) such as cyclopropenylmethyl and cyclohexenylmethyl.
C3-20Heterocyclic group: the term "C" as used herein3-20Heterocyclyl "involving from C3-20A monovalent moiety obtained by removing one hydrogen atom from a ring atom of a heterocyclic compound having one ring or two or more rings (e.g., spiro, fused, bridged), and having from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms, and wherein at least one of the rings is a heterocyclic ring. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. The ring heteroatom may preferably be selected from O, N, S and P. "C3-20"denotes a ring atom, whether carbon or a heteroatom.
C having one nitrogen ring atom3-20Examples of heterocyclic groups include, but are not limited to, those selected from aziridine, azetidine, pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2, 5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole), piperidine, dihydropyridine, tetrahydropyridine, and azepineThose derived.
C having one oxygen ring atom3-20Examples of heterocyclic groups include, but are not limited to, those selected from the group consisting of oxirane, oxetane, oxolane (tetrahydrofuran), oxole (dihydrofuran), oxolane (tetrahydropyran), dihydropyran, pyran(C6) And oxaThose derived. Substituted C3-20Examples of heterocyclyl groups include cyclic forms of sugars such as furanose and pyranose including, for example, ribose, lyxose, xylose, galactose, sucrose, fructose and arabinose.
C having one sulfur ring atom3-20Examples of heterocyclic groups include, but are not limited to, those derived from thietanes, thietanes (tetrahydrothiophenes), thietanes (tetrahydrothiopyrans), and thiepines.
C having two oxygen ring atoms3-20Examples of heterocyclic groups include, but are not limited to, those derived from dioxolane, dioxane, and dioxepane.
C having two nitrogen ring atoms3-20Examples of heterocyclyl groups include, but are not limited to, those derived from imidazolidine, pyrazolidine (oxazolidine), imidazoline, pyrazoline (dihydropyrazole), and piperazine.
C having one nitrogen ring atom and one oxygen ring atom3-20Examples of heterocyclic groups include, but are not limited to, those derived from tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine.
C having one oxygen ring atom and one sulfur ring atom3-20Examples of heterocyclic groups include, but are not limited to, those derived from oxathiolanes and oxathianes (thiaoxanes).
C having one nitrogen and one sulfur ring atom3-20Examples of heterocyclyl groups include, but are not limited to, those derived from thiazolines, thiazolidines, and thiomorpholines.
Other C3-20Examples of heterocyclic groups include, but are not limited to, oxadiazines and oxathiazines.
Examples of heterocycles additionally bearing one or more oxo (═ O) groups include, but are not limited to, those derived from:
C5heterocycles, such as furanones, pyrones, pyrrolidones, pyrazolones, imidazolidinones, thiazolinones (thiazolones), and isothiazolinones;
C6heterocycles, such as piperidone, piperiddione, piperazinone, piperazindione, pyridazinone and pyrimidinone (e.g. cytosine, thymine, uracil) and barbituric acid;
fused heterocycles, such as oxindoles, 6-hydroxypurines (e.g., guanine), benzoxazolinones, benzopyranones (e.g., coumarin);
cyclic anhydrides (ring-C (═ O) -O-C (═ O) -) including, but not limited to, maleic anhydride, succinic anhydride, and glutaric anhydride;
cyclic carbonates (cyclic-O-C (═ O) -O-in the ring), such as ethylene carbonate and 1, 2-propylene carbonate;
imides (in the ring-C (═ O) -NR-C (═ O) -) including, but not limited to, succinimides, maleimides, phthalimides, and glutarimides;
lactones (cyclic esters, in the ring-O-C (═ O) -) including, but not limited to, β -propiolactone, γ -butyrolactone, δ -valerolactone (2-piperidone), and ∈ -caprolactone;
lactams (cyclic amides, — NR-C in the ring (═ O) -) including, but not limited to, β -propiolactam, γ -butyrolactam (2-pyrrolidone), δ -valerolactam, and e-caprolactam;
cyclic carbamates (ring-O-C (═ O) -NR-) such as 2-oxazolidinone;
cyclic ureas (ring-NR-C (═ O) -NR-) such as 2-imidazolidinone and pyrimidine-2, 4-dione (e.g. thymine, uracil).
C5-20Aryl: the term "C" as used herein5-20Aryl "relates to from C5-20Aromatic hydrocarbonsA monovalent moiety obtained by removing one hydrogen atom from an aromatic ring atom of a compound having one ring or two or more rings (e.g., fused), and having 5 to 20 ring atoms, wherein at least one of the rings is an aromatic ring. Preferably, each ring has 5 to 7 ring atoms.
The ring atoms may all be carbon atoms, i.e. "carboaryl", in which case the group may suitably be referred to as "C5-20A carbon aryl group ".
C having no ring hetero atom5-20Aryl (i.e. C)5-20Carboaryl) includes, but is not limited to, benzene (i.e., phenyl) (C)6) Naphthalene (C)10) Anthracene (C)14) Phenanthrene (C)14) Tetracene (C)18) And pyrene (C)16) Those derived.
Examples of aryl groups containing fused rings, one of which is not an aromatic ring, include, but are not limited to, groups derived from indene and fluorene.
Alternatively, the ring atoms may include one or more heteroatoms, including but not limited to oxygen, nitrogen, and sulfur, i.e., "heteroaryl". In this case, the group may be suitably referred to as "C5-20Heteroaryl group "wherein" C5-20"denotes a ring atom, whether carbon or a heteroatom. Preferably, each ring has 5 to 7 ring atoms, of which 0 to 4 are ring heteroatoms.
C5-20Examples of heteroaryl groups include, but are not limited to, C derived from furan (oxacyclopentadiene), thiophene (thiacyclopentadiene), pyrrole (azacyclopentadiene), imidazole (1, 3-oxadiazole), pyrazole (1, 2-oxadiazole), triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and oxatriazole5A heteroaryl group; and C derived from isoxazoles, pyridines (azines), pyridazines (1, 2-diazines), pyrimidines (1, 3-diazines; e.g. cytosines, thymines, uracils), pyrazines (1, 4-diazines), triazines, tetrazoles and oxadiazoles (furazans)6A heteroaryl group.
C containing condensed rings5-20Heterocyclyl radicals (some of which are C)5-20Heteroaryl) include, but are not limited to, C derived from benzofuran, isobenzofuran, indole, isoindole, purine (e.g., adenine, guanine), benzothiophene, benzimidazole9A heterocyclic group; c derived from quinoline, isoquinoline, benzodiazine, pyridopyridine, quinoxaline10A heterocyclic group; c derived from carbazole, dibenzothiophene, dibenzofuran13A heterocyclic group; c derived from acridine, xanthene, phenoxathiin, phenazine, phenoxazine, phenothiazine14A heterocyclic group.
C above1-7Alkyl radical, C3-20Heterocyclyl and C5-20Aryl groups, either alone or part of another substituent, may themselves be optionally substituted with one or more groups selected from themselves and the following additional substituents.
Halogenation: -F, -Cl, -Br and-I.
Hydroxyl group: -OH.
Ether: -OR, wherein R is an ether substituent, e.g. C1-7Alkyl (also known as C)1-7Alkoxy, discussed below), C3-20Heterocyclyl (also known as C)3-20Heterocyclyloxy) or C5-20Aryl (also known as C)5-20Aryloxy), preferably C1-7An alkyl group.
C1-7Alkoxy groups: -OR, wherein R is C1-7An alkyl group. C1-7Examples of alkoxy groups include, but are not limited to, -OCH3(methoxy), -OCH2CH3(ethoxy) and-OC (CH)3)3(tert-butoxy).
Oxo (keto, -ketone): o. Examples of cyclic compounds and/or groups having an oxo group (═ O) as a substituent include, but are not limited to, carbocyclic rings such as cyclopentanone and cyclohexanone; heterocycles, such as pyrones, pyrrolidones, pyrazolones (pyrazolones), piperidones, piperazinones, and imidazolidinones; cyclic anhydrides including, but not limited to, maleic anhydride and succinic anhydride; cyclic carbonates such as propylene carbonate; imides, including but not limited to succinimides and maleimides; lactones (cyclic esters, in the ring-O-C (═ O) -) including, but not limited to, β -propiolactone, γ -butyrolactone, δ -valerolactone, and ∈ -caprolactone; and lactams (cyclic amides, — NR-C in the ring (═ O) -), including but not limited to β -propiolactam, γ -butyrolactam (2-pyrrolidone), δ -valerolactam, and ∈ -caprolactam.
Imino (imine): where R is an imino substituent, e.g. hydrogen, C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably hydrogen or C1-7An alkyl group. Examples of imino groups include, but are not limited to, ═ NH, ═ NMe, ═ NEt, and ═ NPh.
Formyl (aldehyde, formaldehyde): -C (═ O) H.
Acyl (keto group): -C (═ O) R, where R is an acyl substituent, e.g. C1-7Alkyl (also known as C)1-7Alkyl acyl or C1-7Alkanoyl) C3-20Heterocyclyl (also known as C)3-20Heterocycloyl) or C5-20Aryl (also known as C)5-20Arylacyl), preferably C1-7An alkyl group. Examples of acyl include, but are not limited to, -C (═ O) CH3(acetyl), -C (═ O) CH2CH3(propionyl), -C (═ O) C (CH)3)3(butyryl) and-C (═ O) Ph (benzoyl, benzophenone).
Carboxyl (carboxylic acid): -COOH.
Ester (carboxylic ester, ester of carboxylic acid, oxycarbonyl): -C (═ O) OR, where R is an ester substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of ester groups include, but are not limited to, -C (═ O) OCH3、-C(=O)OCH2CH3、-C(=O)OC(CH3)3and-C (═ O) OPh.
Acyloxy (reverse ester): -OC (═ O) R, where R is an acyloxy substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of acyloxy include, but are not limited to, -OC (═ O) CH3(acetoxy), -OC (═ O) CH2CH3、-OC(=O)C(CH3)3-OC (═ O) -Ph and-OC (═ O) CH2Ph。
Amide (carbamoyl, aminocarbonyl, carboxamide): -C (═ O) NR1R2Wherein R is1And R2Independently an amino substituent, as defined for amino. Examples of amide groups include, but are not limited to, -C (═ O) NH2、-C(=O)NHCH3、-C(=O)N(CH3)2、-C(=O)NH-CH2CH3and-C (═ O) N (CH)2CH3)2And amide groups wherein R is1And R2Together with the nitrogen atom to which they are attached form a heterocyclic structure, such as piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.
Acylamino group: -NR1C(=O)R2Wherein R is1Is an amido substituent, e.g. hydrogen, C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably hydrogen or C1-7Alkyl radical, R2Is an acyl substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably hydrogen or C1-7An alkyl group. Examples of acylamino include, but are not limited to, -NHC (═ O) CH3、-NHC(=O)CH2CH3and-NHC (═ O) Ph. R1And R2Can together form a cyclic structure, such as a succinimide, maleimide, and phthalimide group:
an ureido group: -N (R)1)C(O)NR2C(O)R3Wherein R is1And R2Independent of each otherOr a ureido substituent, e.g. hydrogen, C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably hydrogen or C1-7An alkyl group. R3Is an acyl group as defined for the acyl moiety. Examples of ureido groups include, but are not limited to, -NHCONHC (O) H, -NHCONMeC (O) H, -NHCONEtC (O) H, -NHCONMeC (O) Me, -NHCONEtC (O) Et, -NMeCONHC (O) Me, -NMeCONHC (O) Et, -NMeCONMeC (O) Me, -NMeCONEtC (O) Et, and-NMeCONHC (O) Ph.
Carbamate ester: -NR1-C(O)-OR2Wherein R is1Is an amino substituent as defined for amino, and R2Are ester groups as defined for ester groups. Examples of carbamates include, but are not limited to, -NH-C (O) -O-Me, -NMe-C (O) -O-Me, -NH-C (O) -O-Et, -NMe-C (O) -O-t-butyl, and-NH-C (O) -O-Ph.
Thioamide (thiocarbamoyl): -C (═ S) NR1R2Wherein R is1And R2Independently an amino substituent, as defined for amino. Examples of thioamide groups include, but are not limited to, -C (═ S) NH2、-C(=S)NHCH3、-C(=S)N(CH3)2and-C (═ S) NHCH2CH3。
Tetrazolyl group: a five-membered aromatic ring having four nitrogen atoms and one carbon atom,
amino group: -NR1R2Wherein R is1And R2Independently an amino substituent, e.g. hydrogen, C1-7Alkyl (also known as C)1-7Alkylamino or di-C1-7Alkylamino), C3-20Heterocyclyl or C5-20Aryl, preferably H or C1-7Alkyl, or in the case of "cyclic" amino, R1And R2Together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms. Examples of amino groups include, but are not limited to, -NH2、-NHCH3、-NHC(CH3)2、-N(CH3)2、-N(CH2CH3)2and-NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.
Imino groups: where R is an imino substituent, e.g. hydrogen, C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably H or C1-7An alkyl group.
Amidine: -C (═ NR) NR2Wherein each R is an amidine substituent, e.g. hydrogen, C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably H or C1-7An alkyl group. An example of an amidino group is-C (═ NH) NH2。
Carbazolyl (hydrazinocarbonyl): -C (O) -NN-R1Wherein R is1Is an amino substituent as defined for amino. Examples of azino radicals include, but are not limited to, -C (O) -NN-H, -C (O) -NN-Me, -C (O) -NN-Et, -C (O) -NN-Ph, and-C (O) -NN-CH2-Ph。
Nitro group: -NO2。
Nitroso: -NO.
Azido: -N3。
Cyano (nitrile, carbonitrile): -CN.
Isocyano group: -NC.
A cyanato group: -OCN.
Isocyanoyl: -NCO.
Thiocyano (thiocyanato): -SCN.
Isothiocyanato (isothiocyanato): -NCS.
Mercapto (thiol, mercapto): -SH.
Thioether (sulfide): -SR, wherein R is a thioether substituent, e.g. C1-7Alkyl (also known as C)1-7Alkylthio), C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. C1-7Examples of alkylthio groups include, but are not limited to-SCH3and-SCH2CH3。
Disulfide: -SS-R, wherein R is a disulfide substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7Alkyl (also known as C)1-7Alkyl disulfides). C1-7Examples of alkyl disulfide groups include, but are not limited to, -SSCH3and-SSCH2CH3。
Sulfone (sulfonyl): -S (═ O)2R, wherein R is a sulfone substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of sulfone groups include, but are not limited to, -S (═ O)2CH3(methylsulfonyl ), -S (═ O)2CF3(trifluoromethanesulfonyl), -S (═ O)2CH2CH3、-S(=O)2C4F9(nonafluorobutanesulfonyl), -S (═ O)2CH2CF3(trifluoroethylsulfonyl), -S (═ O)2Ph (phenylsulfonyl), 4-methylbenzenesulfonyl (tosyl), 4-bromobenzenesulfonyl (bromophenylsulfonyl) and 4-nitrophenylsulfonyl (nitrobenzenesulfonyl).
Sulfonium (sulfinyl, sulfoxide): -S (═ O) R, where R is a sulfonium substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of sulfonium groups include, but are not limited to, -S (═ O) CH3and-S (═ O) CH2CH3。
Sulfonyloxy group: -OS (═ O)2R, wherein R is a sulfonyloxy substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of sulfonyloxy include, but are not limited toNot limited to-OS (═ O)2CH3and-OS (═ O)2CH2CH3。
Sulfinyloxy: -OS (═ O) R, where R is a sulfinyloxy substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of sulfinato groups include, but are not limited to, -OS (═ O) CH3and-OS (═ O) CH2CH3。
Sulfonic amino (sulfonamide): -NR1S(=O)2OH, wherein R1Is an amino substituent as defined for amino. Examples of a sulfonic amino group include, but are not limited to, -NHS (═ O)2OH and-N (CH)3)S(=O)2OH。
Sulfonamido (sulfenamino): -NR1S (═ O) R, where R is1Is an amino substituent as defined for amino and R is a substituent of a sulfonamido group, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of sulfonamido groups include, but are not limited to, -NHS (═ O) CH3and-N (CH)3)S(=O)C6H5。
Aminosulfinyl (Sulfamyl): -S (═ O) NR1R2Wherein R is1And R2Independently an amino substituent as defined for amino. Examples of aminosulfinyl groups include, but are not limited to, -S (═ O) NH2、-S(=O)NH(CH3)、-S(=O)N(CH3)2、-S(=O)NH(CH2CH3)、-S(=O)N(CH2CH3)2And — S (═ O) NHPh.
Sulfonylamino (Sulfonamino): -NR1S(=O)2R, wherein R1Is an amino substituent as defined for amino and R is a sulfonylamino substituent, e.g. C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Examples of sulfonylamino substituents include, but are not limited toRestricted to-NHS (═ O)2CH3and-N (CH)3)S(=O)2C6H5. A particular class of sulfonylamino groups are those derived from sultams-in which R is1And one of R is C5-20Aryl, preferably phenyl, and the others R1And R is and C5-20Aryl-linked bidentate radicals, e.g. derived from C1-7The bidentate group of the alkyl group. Examples of such groups include, but are not limited to:
aminophosphinyl (phosphonamidite): -OP (OR)1)-NR2 2Wherein R is1And R2Is an amino-hydroxyphosphinyl substituent, e.g. -H, (optionally substituted) C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl radical, preferably-H, C1-7Alkyl or C5-20And (4) an aryl group. Examples of the aminohydroxyphosphinyl group include, but are not limited to, -OP (OCH)2CH3)-N(CH3)2、-OP(OCH2CH3)-N(i-Pr)2and-OP (OCH)2CH2CN)-N(J-Pr)2。
Phosphoramidate (phosphoramidate): -OP (═ O) (OR)1)-NR2 2Wherein R is1And R2Is an amino phosphate substituent, e.g. -H, (optionally substituted) C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl radical, preferably-H, C1-7Alkyl or C5-20And (4) an aryl group. Examples of aminophosphate include, but are not limited to, -OP (═ O) (OCH)2CH3)-N(CH3)2、-OP(=O)(OCH2CH3)-N(i-Pr)2and-OP (═ O) (OCH)2CH2CN)-N(i-Pr)2。
In many cases, the substituents themselves may also be substituted. E.g. C1-7The alkoxy radical may beTo be e.g. by C1-7Alkyl substitution (also known as C)1-7alkyl-C1-7Alkoxy), such as cyclohexylmethoxy; quilt C3-20Heterocyclic substitution (also known as C)5-20aryl-C1-7Alkoxy), such as phthalimidoethoxy; quilt C5-20Aryl substitution (also known as C)5-20aryl-C1-7Alkoxy) such as benzyloxy.
C1-5Alkylene group: the term "C" as used herein1-5Alkylene "refers to a bidentate moiety obtained by removing two hydrogen atoms from the same carbon atom or one hydrogen atom from each of two different carbon atoms of an aliphatic linear hydrocarbon compound having 1 to 5 carbon atoms (unless otherwise specified), wherein the aliphatic linear hydrocarbon compound is saturated, partially unsaturated, or fully unsaturated. Thus, the term "alkylene" includes the subclasses discussed below: alkenylene (alkenylene), alkynylene (alklylene), and the like.
Saturated C1-5Examples of alkylene include, but are not limited to- (CH)2)nIn which n is an integer from 1 to 5, e.g. -CH2- (methylene), -CH2CH2- (ethylene), -CH2CH2CH2- (propene) and-CH2CH2CH2CH2- (butenes).
Partially unsaturated C1-5Examples of alkylene groups include, but are not limited to, -CH ═ CH- (1, 2-ethenylene), -CH ═ CH-CH2-、-CH2-CH=CH2-、-CH=CH-CH2-CH2-、-CH=CH-CH2-CH2-CH2-, -CH-and-CH-CH2-。
The substituents listed above may be substituents on the alkylene group.
Other forms of inclusion
The above also includes the well-known ions, salts, solvates and protected forms of these substituents. For example, reference to a carboxylic acid (-COOH) also includes an anionIon (carboxylate) form (-COO)-) Salts or solvates thereof and conventional protected forms. Similarly, references to amino groups include the protonated form (-N)+HR1R2) Salts or solvates of amino groups, for example the hydrochloride, and the conventional protected forms of amino groups. Similarly, reference to a hydroxyl group also includes the anionic form (-O)-) Salts or solvates thereof and the conventionally protected forms of the hydroxy group.
Isomers, salts, solvates, protected forms and prodrugs
Certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis-and trans-forms; e-and Z-forms; c-, t-and r-forms; inner and outer form; r, S-and meso-forms; d-and L-forms; d-and l-forms; (+) and (-) forms, keto, enol and enolate forms; cis and trans forms; cis-and trans-error forms, alpha-and beta-forms; axial and flat versions; the boat, chair, twist, envelope, and half-chair forms, and combinations thereof, are hereinafter referred to as "isomers" (or "isomeric forms").
It should be noted that, except for the tautomeric forms described below, the term "isomer" as used herein does not include structural (or compositional) isomers (i.e., isomers in which the bonds between atoms differ, not merely the spatial positions of the atoms). For example, methoxy-OCH as indicated3Cannot be interpreted to mean the structural isomer hydroxymethyl-CH2And (5) OH. Similarly, the reference to o-chlorophenyl is not to be construed as the structural isomer m-chlorophenyl. However, reference to a class of structures may include structural isomeric forms (e.g., C) within that class1-7Alkyl groups include n-propyl and isopropyl; butyl includes n-, iso-, sec-and tert-butyl; methoxyphenyl includes o-, m-, and p-methoxyphenyl).
The above exclusion does not refer to tautomeric forms, such as keto, enol and enolate forms, such as the following tautomeric pairs: keto/enol, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo and nitro/acid nitro.
It should be noted that specifically included within the term "isomer" are compounds having one or more isotopic substitutions. For example, H can be in any isotopic form, including1H、2H, (D) and3h (T); c may be in any isotopic form, including12C、13C and14c; o may be in any isotopic form, including16O and18o, and the like.
Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic forms and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatography methods) of the isomeric forms are well known in the art or are readily obtained in a well known manner by adapting the methods taught or known herein.
Unless otherwise indicated, reference to a particular compound also includes, for example, the ionic, salt, solvate and protected forms thereof, as described below.
It may be convenient or desirable to prepare, purify and/or handle a corresponding salt, e.g. a pharmaceutically acceptable salt, of the active compound. Examples of pharmaceutically acceptable salts are described in Berge et al, j.pharm.sci., 66, pages 1-19 (1977).
For example, if the compound is anionic, or contains functional groups which can form anions (e.g., -COOH can form-COO-) Salts may be formed with appropriate cations.Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+And K+Alkaline earth metal cations such as Ca2+And Mg2+And other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH)4 +) And substituted ammonium ions (e.g. NH)3R+、NH2R2 +、NHR3 +、NR4 +). Some examples of suitable substituted ammonium ions are ammonium ions derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amino acids such as lysine and arginine. An example of a quaternary ammonium ion commonly used is N (CH)3)4 +。
If the compound is cationic, or contains functional groups capable of forming cations (e.g. -NH)2Can form-NH3 +) Salts may be formed with appropriate anions. Examples of suitable inorganic anions include, but are not limited to, anions derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. Suitable organic anions include, but are not limited to, anions derived from organic acids such as: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, isethionic, valeric, lactobionic, and gluconic acids. Examples of suitable polymeric anions include, but are not limited to, anions derived from polymeric acids: tannic acid, carboxymethyl cellulose.
It may be convenient or desirable to prepare, purify and/or handle the corresponding solvates of the active compounds. The term "solvate" as used herein refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent. If the solvent is water, the solvate is often referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, and the like.
It may be convenient or desirable to prepare, purify and/or handle the active compound in a chemically protected form. The term "chemically protected form" as used herein refers to compounds in which one or more reactive functional groups are protected from unwanted chemical reactions, i.e., in the form of protected or protecting groups (also referred to as masked or masking groups or blocked or blocking groups). By protecting the reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group; the protecting group is typically removed in a subsequent step without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T.Green and P.Wuts, Wiley, 1991).
For example, the hydroxy group may be represented by an ether (-OR) OR an ester (-OC (═ O) R) such as tert-butyl ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether or acetyl ester (-OC (═ O) CH3-OAc) in the form of a protective coating.
For example, the aldehyde or keto group may be protected in the form of an acetal or ketal, respectively, in which the carbonyl group (> C ═ O) is converted to a diether (> C (or))2). Aldehyde and ketone groups can be readily regenerated by hydrolysis with a large excess of water in the presence of an acid.
For example, the amine group may be protected, for example, in the form of an amide or a urethane, for example, as a methylamide (-NHCO-CH)3) (iii) benzyloxyamide (-NHCO-OCH)2C6H5-NH-Cbz), tert-butoxyamide (-NHCO-OC (CH)3)3-NH-Boe), 2-biphenyl-2-propoxyamide (-NHCO-OC (CH)3)2C6H4C6H5-NH-Bpoc), 9-fluorenylmethoxyamide (-NH-Fmoc), 6-nitroveratryloxyamide (-NH-Nvoc), 2-trimethylsilylethoxyamide (-NH-Teoc), 2, 2, 2-trichloroethoxyamide (-NH-Troc), allyloxyamide (-NH-Alloc), (2-phenylsulfonyl) ethoxyamide (-NH-Psec) or, where appropriate, N-oxide (> NO).
For example, the carboxylic acid group may be in the form of an ester such as C1-7Alkyl esters (e.g. methyl, tert-butyl), C1-7Haloalkyl esters (e.g. C)1-7Trihaloalkyl ester), tri-C1-7alkylsilyl-C1-7Alkyl esters or C5-20aryl-C1-7Protection is effected in the form of alkyl esters (e.g. benzyl ester, nitrobenzyl ester) or amides such as methyl amide.
For example, the mercapto group may be present as a thioether (-SR) such as benzyl thioether; acetaminomethyl ether (-S-CH)2NHC(=O)CH3) Is protected.
It may be convenient or desirable to prepare, purify and/or handle the active compound in prodrug form. The term "prodrug" as used herein refers to a compound that, when metabolized (e.g., in vivo), produces a desired active compound. Prodrugs are generally inactive, or less active than the active compound, but have advantageous handling, administration, or metabolic properties.
For example, certain prodrugs are esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. During metabolism, the ester group (-C (═ O) OR) is cleaved to produce the active drug. The ester may be formed, for example, by esterification of any one of the carboxylic acid groups (-C (═ O) OH) in the parent compound, if desired, by first protecting any other reactive groups present in the parent compound and then deprotecting as required. Examples of such metabolically labile esters include those wherein R is C1-7Alkyl (e.g., -Me, -Et); c1-7Aminoalkyl radicals (e.g. aminoethyl, 2- (N, N-diethylamino)) Ethyl, 2- (4-morpholinyl) ethyl) and acyloxy-C1-7Esters of alkyl groups (e.g., acyloxymethyl, acyloxyethyl groups, such as pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethylcarbonyloxyethyl, 1- (benzoyloxy) ethyl, isopropoxycarbonyloxymethyl, 1-isopropoxy-carbonyloxyethyl, cyclohexyl-carbonyloxymethyl, 1-cyclohexyl-carbonyloxyethyl, cyclohexyloxy-carbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxyethyl, (4-tetrahydropyranyl) carbonyloxymethyl and 1- (4-tetrahydropyranyl) carbonyloxyethyl).
Alternatively, some prodrugs can be activated enzymatically to yield the active compound, or can yield a compound which can be reacted further chemically to yield the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Selective inhibition
By 'selective inhibition' is meant inhibition of one enzyme to a greater extent than inhibition of one or more other enzymes. This selectivity inhibits 50% activity (IC) of an enzyme by comparison50) Required concentration of compound and 50% inhibition of other enzymes (IC)50) The concentration of the same compound required (see below). The results are expressed as ratios. If the ratio is greater than 1, the compound tested exhibits some selectivity in its inhibitory activity.
The compounds of the invention preferably exhibit selectivity for DNA-PK over PI 3-kinase of greater than 3, 10, 20 or 50.
The compounds of the invention preferably exhibit selectivity for DNA-PK over ATM of greater than 5, 10, 50 or 100.
The IC for assessing selectivity is preferably determined by the method described in WO03/02494950Values, the documents cited therein being incorporated herein by reference.
Further preferred are
Z2、Z3、Z4、Z5And Z6
When Z is5When not a single bond, Z2、Z3、Z4、Z5And Z6And Z2And Z6The bound carbon atoms form a six-membered aromatic ring, and Z is preferred2、Z4、Z5And Z6One or two of which are N and the remainder are CH. When Z is5When it is a single bond, Z2、Z3、Z4、Z5And Z6And Z2And Z6The carbon atoms bonded form a five-membered aromatic ring, and preferably Z2、Z4And Z6One or two of which are selected from S, O and N, and the remainder are CH. Preferably Z2、Z4And Z6One of which is selected from O and S and the others are CH, or one is N and the other is CH.
Z2、Z3、Z4、Z5And Z6And together with the carbon atom to which they are bound preferably form a substituted aryl group selected from substituted phenyl, thienyl, furyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, isoxazolyl, oxazolyl, isothiazolyl. More preferably, they form a group selected from substituted phenyl, thiazolyl, thienyl or pyridyl.
Z2Preferably S or CR2Wherein R is2Preferably H.
Z3Preferably CR3。R3Preferably optionally substituted C5-20Aryl, more preferably C5-6And (4) an aryl group.
R of some preferred embodiments3Is C5Heteroaryl, pyridyl and phenyl, with phenyl being most preferred. R3Preferably unsubstituted.
At R3Is C5-20In embodiments of aryl groups, they may include one or more fused rings. In these embodiments, R3Preferably selected from naphthyl, indolyl, quinolyl and isoquinolyl.
At R3Is C5In embodiments of heteroaryl groups, they are preferably selected from the group consisting of those derived from furan, thiophene, 2-methyl-thiophene, 2-nitrothiophene, thiophen-2-ylamine, thiazole, imidazole, and 1-methyl-1H-imidazole.
In which R is3In embodiments that are substituted aryl, the optional substituents are preferably selected from halogen (most preferably fluorine), C5-20Aryl, R, OR, SO2R and COR, wherein R is C1-7An alkyl group.
Z4Preferably N or CR4Wherein R is4Is H or Q-Y-X.
Z5Preferably a direct bond or CH.
Z6Preferably N, S or CH.
R4
When Z is2、Z3、Z5And Z6All represent CH and Z4Represents CR4When R is4Q-Y-X is preferred. If Z is2、Z3、Z5And Z6At least one of O, N or S, then R4Preferably H.
When Q is-NH-C (═ O) -, X is preferably NRN3RN4. Further preferably, Y is optionally substituted C1-3Alkylene, more preferably optionally substituted C1-2Alkylene, and most preferably C1-2An alkylene group.
When Q is-O-, and X is NRN3RN4When Y is preferably optionally substituted C1-3Alkylene, more preferably optionally substituted C1-2Alkylene, and most preferably C1-2An alkylene group.
In some embodiments, RN3And RN4Preferably independently selected from H and optionally substituted C1-7Alkyl, more preferably H and optionally substituted C1-4Alkyl, and most preferably H and optionally substituted C1-3Alkyl (e.g., methyl, ethyl, isopropyl, n-propyl). Preferred optional substituents include, but are not limited to, hydroxy, methoxy, -NH2Optionally substituted C6Aryl and optionally substituted C5-6A heterocyclic group.
In other embodiments, RN3And RN4Together with the nitrogen atom to which they are attached form an optionally substituted nitrogen containing heterocyclic ring having from 4 to 8 ring atoms. Preferably, the heterocyclic ring has 5 to 7 ring atoms. Examples of preferred groups include morpholino, piperidinyl, piperazinyl, homopiperazinyl (homopiperazinyl) and tetrahydropyrrolo-, with piperazinyl being particularly preferred. These groups may be substituted, and particularly preferred groups are optionally substituted piperazinyl, wherein the substituent is preferably on the 4-nitrogen atom. Preferred N-substituents include optionally substituted C1-4Alkyl, optionally substituted C6Aryl and acyl radicals (in C)1-4Alkyl as acyl substituent).
RN5And RN6
To RN5And RN6May be selected from the pairs R described aboveN3And RN4The selection of (2) is the same.
RN1And RN2
In the compounds of formula I, when R isN1And RN2When taken together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 8 atoms, it may form C as defined above4-20The moiety of a heterocyclyl (except for a minimum of 4 ring atoms) must contain at least one nitrogen ring atom. Preferably RN1And RN2Together with the nitrogen atom to which they are attached form a heterocyclic ring having 5, 6 or 7 atoms, more preferably 6 ring atoms.
Monocyclic rings having one nitrogen atom comprising nitrogenAzetidine, pyrrolidine (tetrahydropyrrole), pyrroline (e.g. 3-pyrroline, 2, 5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole), piperidine, dihydropyridine, tetrahydropyridine and azepineMonocyclic rings having two nitrogen atoms include imidazolidine, pyrazolidine (oxazolidine), imidazoline, pyrazoline (dihydropyrazole), and piperazine; monocyclic rings having one nitrogen and one oxygen include tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine; monocyclic rings having one nitrogen and one sulfur include thiazolines, thiazolidines, and thiomorpholines.
Preferred rings are those which contain a heteroatom in addition to nitrogen, and specifically preferred heteroatoms are oxygen and sulfur. Thus, preferred groups include morpholino, thiomorpholino, thiazolinyl. Preferred groups without additional heteroatoms include pyrrolidino.
The most preferred groups are morpholino and thiomorpholino.
As mentioned above, these heterocyclic groups may themselves be substituted; a preferred class of substituents is C1-7An alkyl group. When the heterocyclic group is morpholino, one or more substituents are preferably methyl or ethyl, more preferably methyl. The single methyl substituent is most preferably located at the 2-position.
Rings with bridges or cross-links are also contemplated in addition to the monocyclic groups listed above. Examples of such rings containing nitrogen and oxygen atoms are:
they are respectively named 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl, 6-oxa-3-aza-bicyclo [3.1.0] hex-3-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl and 7-oxa-3-aza-bicyclo [4.1.0] hept-3-yl.
General synthetic method
Wherein R is4Compounds of formula II that are Q-Y-X, and Q is-NH-C (═ O) -, may be represented by formula 1:
in which-Y-X is not C1-7Alkyl compounds may be prepared from compounds of formula 2:
wherein L is a leaving group, such as chlorine or bromine, by reaction with a suitable amine or thiol group. The reaction may be carried out at room temperature, or may be heated as necessary.
The compound of formula 2 can be prepared by reacting a compound of formula 3
With a compound of formula 4 in the presence of an organic base such as triethylamine:
wherein-Y-X is C1-7The compounds of formula 1 of alkyl can be synthesized by reacting a compound of formula 3 with a compound of formula 4a in the presence of an organic base such as triethylamine:
the compound of formula 3 may be synthesized by reducing the compound of formula 5 with a suitable reducing agent such as zinc in acetic acid:
the compounds of formula 5 can be synthesized by coupling the compounds of formulas 6 and 7 by Suzuki-Miyaura:
wherein X' is a group such as bromo or OTf. The coupling moieties may be reversed.
The above-described methods for synthesizing compounds of formula II can be modified to synthesize compounds of formula I.
The compound of formula 7 can be synthesized as follows.
A compound of formula 7a
Can be selected from the formula 8a
Synthesized by cyclic condensation via pyrolysis.
Compounds of formula 8a may be prepared by reacting a compound of formula 9a with a compound of formula HNR in a suitable solventN1RN2By reaction with the appropriate amine.
Compounds of formula 9a may be prepared by reacting compounds of formula 10a
With a Meldrum acid derivative of formula 11a in a suitable solvent.
A compound of formula 7b
Can be synthesized by reacting a compound of formula 8b with triflic anhydride in the presence of a base such as triethylamine in a solvent such as DCM.
Compounds of formula 8b may be prepared from compounds of formula 9b by treatment with a compound of formula HNR1R2Nucleophilic substitution of chlorine by amines.
The compound of formula 9b may be prepared by using a chlorinating agent such as POCl3A compound of formula 10b is chlorinated.
A compound of formula 10b
Can be synthesized by reacting a compound of formula 11b with diethyl malonate or an equivalent thereof.
A compound of formula 7 c:
the route to the compound of formula 7c is described in WO03/024949 (synthetic route 6).
Wherein R is4Is Q-Y-X, Q is-O-, and X is selected from SRS1Or NRN3RN4The compound of formula II may be represented by formula 13;
wherein X' represents SRS1Or NRN3RN4. These compounds can be synthesized from compounds of formula 14:
Where L is a group removed by reaction with an appropriate amine or thiol group, such as chlorine or bromine. This reaction may be carried out at room temperature, or may be heated as necessary.
The compound of formula 14 can be synthesized by reacting a compound of formula 15 with a compound of formula 16:
with a compound of formula 16:
where, in the presence of, for example, potassium carbonate, it is preferred that L is not Br if Y is asymmetric.
The compound of formula 15 can be synthesized from the compound of formula 3 by diazotization-hydrolysis. The process is carried out first, for example, with HBF4The amino group is converted to a diazofluoroborate and the butyl nitrite is then hydrolyzed with, for example, aqueous copper (I) oxide-copper (II) nitrate.
Wherein Q is-O-and X is-C (═ O) -NRN5RN6May be represented by formula 17:
wherein X' ″ tableShown in NRN5RN6. These compounds can be synthesized by reacting a compound of formula 18 with an appropriate amine in the presence of HBTU and HOBT.
Compounds of formula 18 can be prepared by using compounds of formula 19
With sodium hydroxide in methanol. Compounds of formula 19 can be synthesized by reacting a compound of formula 15 with a compound of formula 20 in the presence of, for example, potassium carbonate:
wherein R is4The compounds of the invention that are H can be prepared by coupling the appropriate boronic acid to the compound of formula 7 in a similar manner as described above.
Wherein Z3Is CR3And R is3Is C5-6Aryl compounds of the invention can be synthesized by coupling compounds of formula 7, 21 and 22 via a bis-suzuki coupling:
wherein Ar' represents C5-6Aryl radical, and X2Suitable halides.
In particular, wherein Z3Is CR3;Z2、Z4、Z5And Z6Are all CH; A. b, D represents CH, O, C; and R is3Is C5-6The aryl compounds of the present invention can be synthesized by coupling compounds 7c, 21a and 22a twice with suzuki:
wherein Ar represents C5-6Aryl and X is a suitable halide.
Use of the Compounds of the invention
The present invention provides active compounds, in particular active 8-aryl-2-amino-4-yl-quinolin-4-ones, pyridopyrimidin-4-ones and benzopyran-4-ones.
The term "active" as used herein relates to compounds capable of inhibiting DNA-PK activity, and specifically includes compounds (drugs) having intrinsic activity as well as prodrugs of such compounds, wherein the prodrugs may themselves exhibit little or no intrinsic activity.
An assay that can be used to assess the DNA-PK inhibition provided by a particular compound is described in the examples below.
The invention further provides a method of inhibiting DNA-PK in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. The method may be performed in vitro or in vivo.
For example, a sample of cells (e.g., from a tumor) can be grown in vitro, the active compound contacted with the cells along with an agent having a known therapeutic effect, and the enhanced therapeutic effect of the compound on those cells observed.
The invention further provides active compounds that inhibit DNA-PK activity and methods of inhibiting DNA-PK activity in vitro or in vivo comprising contacting a cell with an effective amount of an active compound in vitro or in vivo.
The active compounds may also be used as cell culture additives to inhibit DNA-PK, for example, in order to sensitize cells in vitro to known chemotherapeutic agents or ionizing radiation therapy.
The active compounds may also be used as part of an in vitro assay, for example to determine whether a candidate host is likely to benefit from treatment with the compound in question.
The invention further provides the use of the active compounds in a method of treatment of the human or animal body. The method comprises administering to the subject a therapeutically effective amount of an active compound, wherein the active compound is preferably in the form of a pharmaceutical composition.
In the context of treating a disease, the term "treatment" as used herein generally refers to both treatment and therapy, whether human or animal (e.g., veterinary applications), in which a certain desired therapeutic effect is achieved, such as inhibiting the progression of the disease, including a decrease in the rate of progression, a cessation of the rate of progression, amelioration of the disease, and cure of the disease. Treatment as a prophylactic measure (i.e., prophylaxis) is also included.
The term "therapeutically effective amount" as used herein, refers to an amount of an active compound, or a substance, composition or dosage form comprising an active compound, effective to produce a certain desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
The term "adjuvant" as used herein relates to the use of active compounds in combination with known therapeutic methods. Such methods include drug cytotoxic protocols and/or ionizing radiation for the treatment of different cancer types. Examples of adjunctive anti-cancer agents that can be combined with the compounds of the invention include, but are not limited to, the following: an alkylating agent: nitrogen mustard, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil; nitrosoureas: carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), aziridine/methyl melamine, thiethylene melamine (TEM), triethyleneThiotepa (thiotepa), altretamine (HMM); methanesulfonic acid esters; busulfan; triazine, Dacarbazine (DTIC); an antimetabolite; folic acid analogs, methotrexate, trimetrexate, pyrimidine analogs, 5-fluorouracil, fluorodeoxyuracil, gemcitabine, cytosine cytarabine (AraC, cytarabine), 5-azacytidine, 2' -difluorodeoxycytidine: a purine analog; 6-mercaptopurine, 6-thioguanine, azathioprine, 2-desoxymetamycin (pentostatin, Erythrohydroxynonyladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine (cladribine, 2-CdA): topoisomerase I inhibitors, camptothecin, topotecan, irinotecan, rubitecan: natural products, antimitotic drugs, paclitaxel, vinca alkaloids, Vinblastine (VLB), vincristine, vinorelbine, TaxotereTM(docetaxel), estramustine phosphate, epipodophyllotoxin, etoposide, teniposide: (ii) an antibiotic; actinomycin D, daunorubicin, doxorubicin (adriamycin), mitoxantrone, idarubicin, bleomycin, plicamycin (mithramycin), mitomycin C, dactinomycin: an enzyme; l-asparaginase, rnase a: a biological response modifier; interferon- α, IL-2, G-CSF, GM-CSF: a differentiating agent; retinoic acid derivatives: a radiosensitizer; metronidazole, misonidazole, desmetholonidazole, pimonidazole, etanidazole, nimorazole, RSU 1069, EO9, RB 6145, SR4233, niacinamide, 5-bromodeoxyuridine, 5-iododeoxyuridine, bromodeoxycytidine: a platinum complex; cisplatin, carboplatin: an anthracenedione; mitoxantrone, AQ4N substituted urea, hydroxyurea; methylhydrazine derivatives, N-Methylhydrazine (MIH), procarbazine; adrenocortical suppressants, mitotane (o.p' -DDD), aminoglutethimide: a cytokine; interferons (α, β, γ), interleukins; hormones and antagonists; adrenocortical steroid/antagonist, prednisone and equivalents, dexamethasone, aminoglutethimide; progesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate; estrogen, diethylstilbestrol, ethinyl estradiol/equivalent; estrogen antagonists, tamoxifen; estrogen, testosterone propionate, fluoxymesterone/equivalent; antiandrogen agent, flutamide, down acceleratorSex hormone releasing hormone analog, leuprolide acetate; non-steroidal antiandrogens, flutamide; an EGFR inhibitor; a VEGF inhibitor; a proteasome inhibitor.
Cancer (carcinoma)
The present invention provides active compounds as anticancer agents or as adjuncts in the treatment of cancer. One skilled in the art can readily determine whether a candidate compound can treat, alone or in combination, a cancerous condition of any particular cell type.
Examples of cancer include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, intestinal cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, kaposi's sarcoma, melanoma, and leukemia.
Any cell type that can be treated includes, but is not limited to, lung, gastrointestinal (including, e.g., intestine, colon), breast, ovary, prostate, liver, kidney, bladder, pancreas, brain, and skin.
The anti-cancer treatment defined above may be applied as a sole therapy or may involve conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. The chemotherapy may include one or more antineoplastic agents of the following classes:
(i) other antiproliferative/antineoplastic agents and combinations thereof for medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea), antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines such as 5 fluorouracil, and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea), antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, dactinomycin, and plicamycin), antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as taxol and taxotere and okinoase inhibitors), And topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);
(ii) cytostatic agents such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and exemestane) and 5*-reductase inhibitors such as finasteride;
(iii) anti-invasive agents (e.g. inhibitors of the c-Src kinase family, such as 4- (6-chloro-2, 3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy ] -5-tetrahydropyran-4-yloxyquinazoline (AZD 0530; International patent application WO 01/94341) and N- (2-chloro-6-tolyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl ] -2-methylpyrimidin-4-ylamino } thiazole-5-carboxamide (dasatinib, BMS-354825; J.Med.Chem., 2004, 47, 6658-6661) and metalloproteinase inhibitors such as marimastat, Inhibitors of urokinase plasminogen activator receptor function or heparanase antibodies);
(iv) growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., trastuzumab [ herceptin T ] antibody against erbB2, panitumumab antibody against EGFR, cetuximab [ erbB 1] antibody against erbB 35225 and Stern et al, clinical reviews in environmental/haematology, 2005, vol.54, pp11-29 antibodies to any of the growth factors or growth factor receptors disclosed therein); such antibodies also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, and the like, Inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (e.g. inhibitors of the Ras/Raf signalling system such as famesyl transferase inhibitors, e.g. sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, inhibitors of IGF receptor (insulin-like growth factor) kinase, inhibitors of aurora kinases (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and inhibitors of cyclin-dependent kinases such as inhibitors of CDK2 and/or CDK 4;
(v) anti-angiogenic agents, for example those which inhibit the action of vascular endothelial growth factor [ e.g. the anti-vascular endothelial growth factor antibody bevacizumab (Avastin T) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD 6474; example 2 in WO 01/32651), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171; example 240 in WO 00/47212), vatalanib (PTK 787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814) ], Compounds such as those disclosed in international patent applications WO97/22596, WO97/30035, WO 97/32856 and WO 98/13354, as well as compounds that act by other mechanisms (e.g., linoamine, inhibitors of integrin avb3 function and angiostatins) ];
(vi) vascular damaging agents such as combretastatin a4 and the compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, such as those directed against the above targets, e.g., anti-ras antisense agent ISIS 2503;
(viii) gene therapy methods including, for example, methods of replacing a variant gene, e.g., variant p53 or variant BRCA1 or BRCA2, GDEPT (enzyme prodrug therapy for the gene), those methods that use, e.g., cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods of increasing patient tolerance to chemotherapy or radiation therapy, e.g., multi-drug resistance gene therapy; and
(ix) immunotherapeutic methods, including, for example, methods of increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor, methods of reducing T cell non-cellular immunoreactivity, methods of using transfected immune cells such as cytokine-transfected dendritic cells, methods of using cytokine-transfected tumor cells, and methods of using anti-idiotypic antibodies, both in vitro and in vivo.
Administration of
The active compound or pharmaceutical composition comprising the active compound can be administered to a subject by any suitable route of administration, whether systemic/peripheral or at the site of desired action, including but not limited to oral (e.g., ingestion); topical (including, e.g., transdermal, intranasal, ocular, buccal, and sublingual); lung (e.g. inhalation or insufflation therapy, using for example an aerosol, e.g. through the mouth or nose); a rectum; the vagina; parenteral, e.g., injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; reservoir implants, e.g. subcutaneous or intramuscular.
The subject can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a canine (e.g., dog), a feline (e.g., cat), an equine (e.g., horse), a primate, a simian (e.g., simian or ape), an ape (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Preparation
Although it is possible for the active compounds to be administered alone, it is preferred to provide them in pharmaceutical compositions (e.g., formulations) comprising at least one active compound as defined above in combination with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other materials well known to those skilled in the art, and optionally other therapeutic or prophylactic agents.
Thus, the present invention further provides a pharmaceutical composition as defined above and a process for the preparation of a pharmaceutical composition comprising mixing together at least one active compound as defined above and one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers or other materials as described herein.
The term "pharmaceutically acceptable" as used herein, pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, excipients, etc. can be found in standard pharmaceutical literature, e.g., "Remington's pharmaceutical Sciences", 18 th edition, Mack publishing company, Easton, Pa., 1990.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier, which carrier constitutes one or more accessory ingredients. In general, the formulations are prepared by: the active compound is mixed homogeneously and intimately with liquid carriers or finely divided solid carriers or both, and the product is then shaped if necessary.
The formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, aerosols, foams, lotions, oils, boluses, lozenges or aerosols.
Formulations suitable for oral administration (e.g., ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; big pills; a medicinal sugar agent; or a paste.
Tablets may be prepared by conventional means, for example by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by: a free-flowing form of the active compound, such as a powder or granules, is compressed in a suitable machine, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose), fillers or diluents (e.g., lactose, microcrystalline cellulose, dibasic calcium phosphate), lubricants (e.g., magnesium stearate, talc, silicon dioxide), disintegrants (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium), surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate), and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be prepared by: a mixture of the powdered compound moistened with an inert liquid diluent is molded in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active compound therein, for example using hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. The tablets may optionally have an enteric coating to provide release of the moiety in the intestinal tract rather than the stomach.
Formulations suitable for topical administration (e.g., transdermal, intranasal, ocular, buccal, and sublingual) may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, the formulation may comprise a patch or dressing, such as a bandage or adhesive plaster impregnated with the active compound and optionally one or more excipients or diluents.
Formulations suitable for topical administration in the mouth include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
Formulations suitable for nasal administration in which the carrier is a solid include coarse powders, e.g., in the range of about 20 to about 500 microns in size, which are administered by nasal inhalation, i.e., by rapid inhalation through the nostrils from a powder container placed immediately under the nose. Suitable formulations for administration in which the carrier is a liquid are, for example, nasal sprays, nasal drops or aerosols administered by means of a nebulizer, including aqueous or oily solutions of the active compound.
Formulations suitable for administration by inhalation include those delivered as an aerosol spray from pressurized packs, using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
Formulations suitable for topical application via the skin include ointments, creams and emulsions. When formulated in an ointment, the active compound may optionally be used with a paraffinic or water-miscible ointment base. Alternatively, the active compound may be formulated in a cream using an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include compounds that enhance absorption or penetration of the active compound through the skin or other affected areas. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.
When formulated as a topical emulsion, the oily phase may optionally comprise only emulsifiers, or it may comprise a mixture of at least one emulsifier with a fat or oil or a fat and an oil. Preferably, hydrophilic emulsifiers are included as well as lipophilic emulsifiers that act as stabilizers. It is also preferred to include both oil and fat. The emulsifiers and optionally stabilizers together constitute the so-called emulsifying wax, which together with the oils and/or fats constitutes the so-called emulsifying ointment base, which constitutes the oil-dispersed phase of the cream.
Suitable emulsifiers and emulsion stabilizers include tween 60, span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of oil or fat suitable for formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsions can be very low. Thus, the cream should preferably be a non-greasy, non-fading and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain mono-or dibasic alkyl esters such as, for example, diesters of isoadipic acid, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or blends of branched chain esters known as Crodamol CAP may be used, the latter three being preferred esters. They may be used alone or in combination, depending on the desired properties.
Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils may be used.
Formulations suitable for rectal administration may be in the form of suppositories, suitable bases including, for example, cocoa butter or salicylates.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration (e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents; and liposomes or other particulate systems designed to target the compound to a blood component or one or more organs. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, ringer's solution, or lactated ringer's injection. Typically, the concentration of the active compound in the solution is from about 1ng/ml to about 10. mu.g/ml, for example from about 10ng/ml to about 1. mu.g/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The formulations may be in the form of liposomes or other particulate systems designed to target the active compound to a blood component or one or more organs.
Dosage form
It will be appreciated that the appropriate dosage of the active compound and the composition comprising the active compound may vary from patient to patient. Determining the optimal dose will generally involve a balance between the level of therapeutic benefit of the treatment of the invention and any risk or deleterious side effects. The selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and the route of administration will ultimately depend on the judgment of the practitioner, although in general the local concentration at the site of action achieved by the dose will achieve the desired effect without causing substantial harm or deleterious side effects.
In vivo administration may be carried out in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods for determining the most effective means and dosage for administration are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cells being treated and the subject being treated. Single or multiple administrations may be carried out at dosage levels and in a manner selected by the attending physician.
In general, suitable doses of active compound are in the range of about 100 μ g to about 250mg per kg body weight of the subject per day. If the active compound is a salt, ester, prodrug, or the like, the amount administered is calculated based on the parent compound and, therefore, the actual weight employed will increase proportionately.
Examples
The following are examples merely illustrative of the present invention and are not intended to limit the scope of the invention as described herein.
Abbreviations
For convenience, many chemical components are represented by well-known abbreviations, including, but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), t-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).
For convenience, many chemical compounds are represented by well-known abbreviations, including, but not limited to, methanol (MeOH), ethanol (EtOH), isopropanol (i-PrOH), Methyl Ethyl Ketone (MEK),Ether or diethyl ether (Et)2O), acetic acid (AcOH), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), Dimethylformamide (DMF), Tetrahydrofuran (THF), and Dimethylsulfoxide (DMSO).
Detailed description of the general experiments
Chemical reagents were purchased from Aldrich Chemical Company, Lancaster Synthesis Ltd and Acros Organics (Fisher Scientific UK Ltd). THF was freshly distilled from sodium/benzophenone. Methanol and ethanol were distilled from magnesium/iodine. DCM was dried by distillation over phosphorus pentoxide. Acetone is dried by distillation over calcium hydride. All solvents not immediately used in molecular sieves (3-5mm beads) under nitrogen. Sureseal from Aldrich in anhydrous DMFTMObtained in a bottle. Triethylamine was dried by distillation over calcium hydride and stored under nitrogen over potassium hydroxide.
Thin Layer Chromatography (TLC) silica gel 60F precoated with Merck on an aluminum plate254It is then dried and developed with short-wave (254nm) UV light or by treatment with ninhydrin or sulfuric acid, followed by vanillin. Flash column chromatography was performed on Davisil silica gel (40-63 μm) at medium pressure.
Melting points were determined using a Stuart Scientific SMP3 apparatus and were not corrected.1H and13nuclear Magnetic Resonance (NMR) spectra of C Using Bruker Spectrospin AC 300E spectrometer (C)1H300 MHz or13C75 MHz) or Bruker Spectrospin AC 500E spectrometer (1H500 MHz or13C125 MHz). Chemical shifts are reported in parts per million (δ), low magnetic field of tetramethylsulfone using residual solvent peak as internal standard. Diversity is expressed in s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), or combinations thereof. LC/MS spectra were obtained using a Micromass Platform instrument operating in the cationic or anionic electrospray mode. The separation was carried out using a C18 column (50X 4.6 mm; Supelco Discovery or Waters Symmetry), andelution was carried out with a gradient of 0.05% formic acid and methanol (10-90%) for 15 minutes. The IR spectra were recorded as pure samples on a Bio-Rad FTS 3000MX Diamond ATR.
Synthesis of key intermediates
(ii) Synthesis of 9-trifluoromethanesulfonic acid-2-morpholin-4-yl-pyrido [2, 1-a ] pyrimidin-4-one (5)
(a)2, 9-dihydroxypyrido [2, 1-a ] pyrimidin-4-one (2)
A mixture of bis- (2, 4, 6-trichloro-phenyl) malonate (17.33 g; 37.5mmol) and 3-hydroxy-2-amino-pyridine (1) (4.12 g; 37.5mmol) dissolved in bromobenzene (37mL) was heated at reflux for 3 hours. After cooling, the reaction mixture was filtered and the solid was washed with ethanol. The solid was dissolved in 1M NaOH and AcOH was added dropwise to precipitate the product as a pale yellow solid (6.53 g). The yield was 98%. m.p.: 320 ℃ (degradation); rf=0.11,MeOH∶DCM(3∶17);UV:λmax=252nm;IR:(cm-1)2862、1688、1564、1374、1295、1102、783;1H NMR,(DMSO,300MHz),δ(ppm):5.22(1H,s,CH-3),7.12(1H,t,JH6-H7=7Hz,Harom-7),7.27(1H,d,JH7-H8=8Hz,Harom-8),8.43(1H,d,JH6-H7=7Hz,Harom-6);13CNMR,(CDCl3,75MHz),δ(ppm):103.25、116.46、117.05、119.03、143.97、148.82、157.26、157.50。
(b) 2-chloro-9-hydroxy-pyrido [2, 1-a ] pyrimidin-4-one (3)
In a round bottom flask, 2, 9-dihydroxy-pyrido [2, 1-a ]]Pyrimidin-4-one (2) (1.07 g; 6.0mmol) was dissolved in phosphorus oxychloride (7.5 mL). The solution was heated to reflux for 48 hours. After cooling, the reaction mixture was carefully poured into ice-cold water (100mL) and added by additionThe saturated sodium carbonate solution adjusted the pH to 7. The aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to give a brown solid. This solid was purified by flash chromatography using dichloromethane as eluent to afford the title compound as a white solid (712 mg). The yield was 60%. m.p.: 162 ℃; rf0.34, MeOH: DCM (1: 19); mass spectrum: (M/z)196.93[ M +1]+(Rt 4.67 min, 12 min gradient); UV: lambda [ alpha ]max=210nm;IR:(cm-1)3103、1684、1630、1511、1458、1297、1105;1H NMR,(CDCl3,300MHz),δ(ppm):6.4(1H,s,CH-3),7.11(1H,t,JH6-H7=7Hz,Harom-7),7.25(1H,d,JH7-H8=8Hz,Harom-8),8.51(1H,d,JH6-H7=7Hz,Harom-6);13C NMR,(CDCl3,75MHz),δ(ppm):103.25、116.46、117.05、119.03、143.97、148.82、157.26、157.50。
(c) 9-hydroxy-2-morpholin-4-yl-pyrido [2, 1-a ] pyrimidin-4-one (4)
In a round-bottom flask, 2-chloro-9-hydroxy-pyrido [2, 1-a ]]Pyrimidin-4-one (3) (141.7 mg; 0.721mmol) and morpholine (314. mu.L; 3.605mmol) were dissolved in ethanol (5 mL). The solution was heated to reflux with vigorous stirring for 18 hours. After cooling, the solvent was evaporated. The yellow crude solid was recrystallized from ethanol to yield 173.8mg of white crystals. Yield 97%. m.p.: 245 ℃; rf0.27, MeOH: DCM (1: 19); mass spectrum: (M/z)248.08[ M +1]+(Rt 4.92 min, 12 min gradient); UV: lambda [ alpha ]max=267nm;IR:(cm-1)3302、1690、1644、1551、1427、1224、1110;1H NMR,(CDCl3,500MHz),δ(ppm):3.56(4H,m,N-CH2Morpholine), 3.75(4H, m, O-CH)2Morpholine), 5.55(1H, s, CH-3), 6.80(1H, t, J)H6-H7=7Hz,Harom-7),7.02(1H,dd,JH7-H8=8Hz,JH6-H8=1.3Hz,Harom-8),7.33(1H,s,OH),8.37(1H,dd,JH6-H7=7Hz,JH6-H8=1.3Hz,Harom-6);13C NMR,(CDCl3,125MHz),δ(ppm):45.27、67.02、82.16、113.46、114.18、119.05、143.00、147.51、159.00、161.00。
(d) 9-Trifluoromethanesulfonic acid-2-morpholin-4-yl-pyrido [2, 1-a ] pyrimidin-4-one (5)
In a three-necked round-bottom flask with thermometer, 9-hydroxy-2-morpholin-4-yl-pyrido [2, 1-a ] is introduced]Pyrimidin-4-one (4) (2.11 g; 8.54mmol) was dissolved in DCM (70mL), cooled to-30 ℃ and triethylamine (3.572 mL; 25.63mmol) was added. After 5 min, trifluoromethanesulfonic anhydride (2.101 mL; 12.81mmol) dissolved in 10mL DCM was added dropwise to the reaction mixture over a period of 30 min via an addition funnel. During the addition, the temperature of the reaction mixture was kept below-20 ℃. After 3 hours, saturated Na was used2CO3The reaction mixture was washed with (50mL) solution and extracted with DCM (3X 30 mL). The organic layer was dried over magnesium sulfate and evaporated to give a brown solid. This solid was purified by flash chromatography with dichloromethane as eluent to afford the title compound as an orange solid (2.91 g). The yield was 90%. m.p.: 146-147 ℃; rf0.42; MeOH: DCM (1: 19); mass spectrum: (M/z)380.16[ M +1]+(Rt 3.34 min, 12 min gradient); UV: lambda [ alpha ]max=271nm;IR:(cm-1)1705、1644、1551、1189、1112、939、769;1H NMR,(CDCl3,300MHz),δ(ppm):3.56(4H,m,N-CH2Morpholine), 3.71(4H, m, O-CH)2Morpholine), 5.53(1H, s, CH-3), 6.80(1H, t, J)H6-H7=7Hz,Harom-7),7.46(1H,dd,JH7-H8=8Hz,JH6-H8=1.3Hz,Harom-8),8.79(1H,dd,JH6-H7=7Hz,JH6-H8=1.3Hz,Harom-6);13C NMR,(CDCl3,75MHz),δ(ppm):45.19、66.87、81.76、110.16、112.61、116.85、121.10、125.34、127.86、128.13、141.46、145.79、158.07、160.42。
(iv) Synthesis of 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one (12)
(a)5- (Di-methylsulfanyl-methylene) -2, 2-dimethyl- [1, 3] dioxane-4, 6-dione (8)
In a 250mL two-necked flask, a well-stirred solution of 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (6) (Meldrum's acid) (4.09 g; 28.4mmol) in DMSO (14mL) was formed. To this mixture was added triethylamine (7.92 mL; 56.8mmol) and carbon disulfide (1.71 mL; 28.4mmol) rapidly, in that order. The mixture was then stirred vigorously at room temperature for 1 hour, after which it was cooled in an ice bath. To the mixture was added slowly methyl iodide (3.54 mL; 56.8mL) with cooling (ice bath). When the addition was complete, the reaction mixture was warmed to room temperature and stirred for a further 4 hours, then diluted with ice-cold water (25 mL). The precipitated mixture is scraped off, the product is filtered off and washed with gasoline. The product was obtained as a yellow solid (2.76g) and was sufficiently pure for the subsequent reaction. Yield 45%. m.p.: 118 deg.C (literature)28:116-118℃);IR:(cm-1)3728、1668、1373、1302、1264、1199;1H NMR,(CDCl3,300MHz),δ(ppm):1.54(6H,s,2CH3),2.58(6H,s,2CH3-S);13C NMR,(CDCl3,75MHz),δ(ppm):21.86、27.22、103.32、160.33、194。
(b)5- [ 2-Bromoanilino- (methylthio) -methylene ] -2, 2-dimethyl-4, 6-dione (10)
In a 10mL round-bottom flask with a cooler and nitrogen bubbler, isopropylidene dimethylthiomethylene malonate (8) (900 mg; 3.63mmol) and 2-bromoaniline (15) (624 mg; 3.63mmol) were dissolved in 2, 2, 2-trifluoroethanol (3.6 mL). The mixture was stirred and heated to reflux for 22 hours. After cooling, the solvent was evaporated. The residue was recrystallized from methanol to give the title compound (1.192g) as white crystals. Yield 88%. m.p.: 159 ℃ C;Rf=0.31,DCM;IR:(cm-1)2990、1706、1653、1535、1370、1199;UV:λmax=313nm;1H NMR,(CDCl3,300MHz),δ(ppm):1.69(6H,s,2CH3),2.15(3H,S,CH3-S),7.18(1H,dt,JH4-H5=8Hz,JH4-H6=2Hz,Harom-4),7.35(2H,m,Harom-5 and Harom-6),7.61(1H,dd,JH3-H4=8Hz,JH3-H5=1.2Hz,Harom-3),12.51(1H,s,N-H);13C NMR,(CDCl3,75MHz),δ(ppm):18.75、26.48、87.54、103.32、120.45、127.78、128.46、129.48、133.57、136.91、163.87、178.70。
(c)5- [ (2-bromo-anilino) -morpholin-4-yl-methylene ] -2, 2-dimethyl- [1, 3] dioxane-4, 6-dione (11)
In a 10mL round-bottom flask with a cooler and nitrogen bubbler, 5- [ 2-bromoaniline- (methylthio) -methylene]-2, 2-dimethyl-4, 6-dione (10) (234 mg; 0.629mmol) and morpholine (110. mu.L; 1.257mmol) were dissolved in 2, 2, 2-trifluoroethanol (1 mL). The mixture was stirred and heated to reflux for 18 hours. After cooling, the solvent was evaporated. The residue was recrystallized from methanol to give the title compound (0.124g) as white crystals. Yield 50%. m.p.: 212-213 ℃; rf=0.05;DCM;IR:(cm-1)1627、1342、1305、1100、1022、934;UV:λma=241nm;1H NMR,(CDCl3,300MHz),δ(ppm):1.77(6H,s,2CH3),3.24(4H,t,Jab=5Hz,2CH2-N morpholine), 3.66(4H, t, J)ab=5Hz,2CH2-O morpholine), 7.18(2H, m, H)aram-4 and Harom-6),7.40(1H,t,JH5-H6=8Hz,Harom-5),7.69(1H,dd,JH3-H4=8Hz,JH3-H5=1.4Hz,Harom-3),9.62(1H,s,N-H);13C NMR,(CDCl3,75MHz),δ(ppm):26.83、51.14、65.62、87.54、102.84、120.45、127.15、128.92、129.03、134.48、138.46、164.92、178.70。
(d) 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one (12)
In a Hitach tube (SchIenk tube), 5- [ (2-bromoaniline) -morpholin-4-yl-methylene]-2, 2-dimethyl- [1, 3]Dioxane-4, 6-dione (11) (103.3 mg; 0.2513mmol) was dissolved in diphenyl ether (0.7 mL). The mixture was stirred and heated to reflux for 4 hours. After cooling, petroleum ether was added. The product was collected by suction. The residue was purified by flash chromatography using dichloromethane/methanol (95: 5) as eluent. The product was obtained as a brown oil (65.1 mg). The yield was 84%. Rf0.25, MeOH: DCM (1: 19); mass spectrum: (M/z)310.98[ M +1]+(Rt 5.24 min, 12 min gradient); IR: (cm)-1)3395、2959、2849、1617、1577、1487、1421、1384、1327、1263、1229、1188、1152、1111、1066、999、902、785;UV:λmax=254nm;1H NMR,(CDCl3,300MHz),δ(ppm):3.72(4H,t,Jab=5Hz,2CH2-N morpholine), 3.75(4H, t, J)ab=5Hz,2CH2-O morpholine), 5.95(1H, s, H-3), 7.04(1H, t, J)H6-H7=8Hz,Harom-6),7.69(1H,dd,JH6-H7=8Hz,JH5-H7=1.3Hz,Harom-7),8.09(1H,d,JH5-H6=8Hz,Harom-5);13C NMR,(CDCl3,75MHz),δ(ppm):46.35、66.59、92.50、114.53、123、123.50、124.73、134.45、138、156.06、172.6。
Example 1: parallel Synthesis from 9-Trifluoromethanesulfonic acid-2-morpholin-4-yl-pyrido [2, 1-a ] pyrimidin-4-one (5)
To a rotating disk transfer tube (carousel tube) were introduced the appropriate boric acid (0.395mmol) and potassium carbonate (109.3 mg; 0.7914 mmol). The flask was evacuated and cleaned with argon. This operation was repeated three times. In a schieker tube, 9-trifluoromethanesulfonic acid-2-morpholin-4-yl-pyrido [2, 1-a ] pyrimidin-4-one (5) (100 mg; 0.2638 mmol; per carousel transfer tube) was dissolved in dioxane (2 mL per carousel transfer tube). Argon was bubbled into the solution and then sonicated for 15 minutes. In another zernike tube, tetrakis- (triphenylphosphine) -palladium (15.2 mg; 0.013 mmol; per rotating disk transfer tube) was dissolved in dioxane (2 mL per rotating disk transfer tube). Argon was bubbled into the solution and then sonicated for 15 minutes. 2mL of each solution were mixed in a rotating disk transfer tube, stirred and heated at 95 ℃ for 48 hours. After cooling, the solution was filtered through a Radleysdiscovery technology solid phase extraction column of 500mg silica placed on a stalker parallel purification system. The column was washed with ethyl acetate (20mL) and collected as phase 1. The column was then washed with dichloromethane/methanol (85: 15) (20mL) and collected as phase 2. Both phases were checked for product by LC/MS. In some cases, phase 2 contained only impurities, in other cases, the two phases were combined and evaporated. Purification was performed by HPLC or flash chromatography, depending on the product.
Results of NMR
13a:1H NMR,(CDCl3,300MHz),δ(ppm):3.42(4H,m,N-CH2-morpholine); 3.56(4H, m, O-CH)2-morpholine); 5.40(1H, s, CH-3); 6.87(1H, t, J)H6-H7=7Hz,Haram-7);7.26-7.83(10H,m,Harom-biphenyl and Harom-8);8.87(1H,dd,JH6-H7=7.1Hz,JH6-H8=1.6Hz,Haram-6)。
13C-NMR,(CDCl3,300MHz),δ(ppm):44.92(CH2-N-morpholine); 66.87 (CH-O-morpholine); 81.24 (CH-3); 112.90 (CH-7); 127.22, respectively; 127.35, respectively; 127.56, respectively; 127.91, respectively; 128.81, respectively; 129.01, respectively; 129.24, respectively; 129.39, respectively; 135.74, respectively;136.74;137.59;141.11;149.46;159.41(Cq);160.72(Cq)。
example 2: parallel Synthesis from 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one (12)
Appropriate boric acid (0.486mmol) and potassium carbonate (269.2 mg; 1.946mmol) were introduced into a rotating disk transfer tube. The flask was evacuated and cleaned with argon. This operation was repeated three times. In a Schlenk tube, 8-bromo-2-morpholin-4-yl-1H-quinolin-4-one (12) (100 mg; 0.324 mmol; per carousel transfer tube) was dissolved in dioxane (2 mL per carousel transfer tube). Argon was bubbled into the solution and then sonicated for 15 minutes. In another zeeker tube, tetrakis- (triphenylphosphine) -palladium (18.7 mg; 0.016 mmol; 2mL per carousel transfer tube) was dissolved in dioxane. Argon was bubbled into the solution and then sonicated for 15 minutes. 2mL of each solution were mixed in a rotating disk transfer tube, stirred and heated at 95 ℃ for 48 hours. After cooling, the solution was filtered through a Radleys Discovery technology solid phase extraction column of 500mg silica placed on a stalker parallel purification system. The column was washed with ethyl acetate (20mL) and collected as phase 1. The column was then washed with dichloromethane/methanol (85: 15) (20mL) and collected as phase 2. Both phases were checked for product by LC/MS. In some cases, phase 2 contained only impurities, in other cases, the two phases were combined and evaporated. Purification was performed by HPLC or flash chromatography, depending on the product.
Results of NMR
14a:1H NMR,(CDCl3,300MHz),δ(ppm):3.13(4H,s,N-CH2-morpholine);3.70(4H,s,O-CH2-morpholine); 5.78(1H, s, CH-3); 7.28-7.47(5H, m, H)arom-biphenyl and Harom-7);7.47-7.72(6H,m,Harom-biphenyl); 8.14(1H, s, H)arom-8);8.32(1H,s,Harom-6)。
13C-NMR,(CDCl3,300MHz),δ(ppm):46.73(CH2-N-morpholine); 66.27 (CH-O-morpholine); 92.86 (CH-3); 122.72, respectively; 123.58, respectively; 124.17, respectively; 125.93, respectively; 127.39, respectively; 127.54, respectively; 127.81, respectively; 128.01, respectively; 128.45, respectively; 128.98, respectively; 129.16, respectively; 129.43, respectively; 129.81, respectively; 130.51, respectively; 132.65, respectively; 135.56, respectively; 137.42, respectively; 140.29, respectively; 143.16, respectively; 154.31, respectively; 178.88.
example 3
(a)8- (6-hydroxy-biphenyl-3-yl) -2-morpholin-4-yl-chromen-4-one (17)
(i) 5-iodo-biphenyl-2-ol (15)
A solution of 6.02g (35.37mmol, 1 eq) 2-phenylphenol, 5.30g sodium iodide (35.37mmol, 1 eq), 1.56g sodium hydroxide (35.37mmol, 1 eq) in 150mL methanol was cooled to 0 ℃. 26.32g NaOCl was added dropwise via syringe over a period of 30 minutes. After each drop was added, the solution developed an orange color and faded immediately. The reaction mixture was stirred at 0 ℃ for 1 hour and then heated with 10% aqueous sodium thiosulfate (60 mL). The pH of the reaction mixture was adjusted to 7 with HCl and diethyl ether (150mL) was added. The layers were separated and the organic layer was washed with brine over MgSO4Dried, filtered and evaporated. Chromatography on silica gel (elution: DCM) afforded the title compound as a white solid (9.27g, 89%).1H NMR(300MHz,CDCl3) δ 5.51 (width, 1H); 6.79(d, J ═ 8.5Hz, 1H); 7.37-7.53(m, 7H);13C NMR(75MHz,CDCl3)δ83.9、118.8、129.2、129.5、129.8、130.9、135.8、138.7、139.5、152.3。
(ii) 2-morpholin-4-yl-8- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -chromen-4-one (16)
A round bottom flask containing 500mg (1.32mmol, 1 eq) of benzopyrone triflic acid (see WO03/024949), 402mg (1.58mmol, 1.2 eq) of dioxaborolan, 388mg (3.95mmol, 3 eq) of potassium acetate and 15mL of 1, 4-dioxane was sonicated for 15 minutes. Adding PdCl to the reaction mixture2dppf (54mg, 0.07mmol, 5 mol%) and dppf (39mg, 0.07mmol, 5 mol%). The reaction was heated under argon at 90 ℃ overnight. After completion, the reaction mixture was diluted with diethyl ether and the organic layer was washed with saturated NaCl solution over MgSO4Dried, filtered and evaporated. Chromatography on silica gel (elution: ethyl acetate/methanol, gradient) afforded the title compound (378mg, 1.06mmol, 80%).1H NMR(300MHz,CDCl3)δ1.19(s,12H);3.61-3.64(m,4H);3.74-3.78(m,4H);5.51(s,3H);7.27(t,J=7.5Hz,1H);7.94(d,J=7.2Hz);8.20(d,J=6.3Hz,1H);13C NMR(75MHz,CDCl3)δ24.9、25.4、45.1、66.5、83.5、84.3、86.8、124.7、129.6、140.6、158.1、162.0、178.0。
(iii)8- (6-hydroxy-biphenyl-3-yl) -2-morpholin-4-yl-chromen-4-one (17)
In a Schlenk tube, 107mg (0.30mmol) of a borate ester (16), 80mg (0.27mmol) of an iodide, 4mg (0.023mmol) of PdCl were placed2(PPh3)2And 3mL of aqueous 2MNa2CO3. THF (12mL) was degassed before addition and the reaction mixture was heated to reflux for 2 hours. Water (10mL) was added and the reaction mixture was extracted with DCM (60 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by reprecipitation provided 89mg (83% yield) of the title compound. M.p.243-247 ℃; UV lambdamax=304nm;IR(cm-1)2854、1618、1556、1406、1243、1114、989、777、557;1H NMR(300MHz,CDCl3)δ3.32(m,4H);3.57(m,4H);5.55(s,1H);7.20-7.65(m,10H);8.15(d;J=7.3Hz;1H);13C NMR(75MHz,CDCl3)δ44.7;60.4;65.9;86.4;116.5;123.3;124.4;124.9;127.7;128.4;128.8;129.0;129.7;130.0;132.1;133.1;137.6;150.6;153.8;162.6;171.3;177.6。
(b) 2-morpholin-4-yl-8- (3-thiophen-3-ylphenyl) -chromen-4-one (20) and 2-morpholin-4-yl-8- (3-thiophen-2-yl-phenyl) -chromen-4-one (21)
(i)8- (3-hydroxy-phenyl) -2-morpholin-4-yl-chromen-4-one (18)
Placing equimolar amount of borate and trifluoromethanesulfonic acid in a Hilenk tube, and adding PdCl2(PPh3)2And aqueous 2M Na2CO3. THF was degassed before addition and the reaction mixture was heated to reflux for 2 hours. Water was added and the reaction mixture was extracted with DCM. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by reprecipitation yielded 693mg of product (90% yield). M.p.203-205 ℃;1H NMR(300MHz,CDCl3) δ 3.29(s (width), 4H); 3.64(s (wide), 4H); 5.51(s, 1H); 6.95(d, J ═ 7.3Hz, 1H); 7.00(d, J ═ 8.6Hz, 1H); 7.27-7.42(m, 3H); 7.49(d, J ═ 7.5 Hz; 1H); 8.11 (d; J ═ 7.5 Hz; 1H);13C NMR(75MHz,CDCl3)δ44.9;66.2;116.0;117.1;120.7;125.0;125.4;130.3;130.6;131.0;134.1;137.3;140.3;151.2;157.5;162.7;UVλmax=302nm;IR(cm-1)2862、1614、1553、1414、1244、1112、993、779。
(ii) trifluoromethanesulfonic acid 3- (2-morpholin-4-yl-4-oxo-4H-benzopyran-8-yl) -phenyl ester (19)
At the round bottomThe flask was charged with 8- (3-hydroxy-phenyl) -2-morpholin-4-yl-chromen-4-one (18) (277mg, 0.86mmol, 1 eq.), N-phenyltrifluoromethanesulfonimide (1.224g, 3.43mmol, 4 eq.), Et3N (480. mu.L, 3.43mmol, 4 equiv.) and 10mL THF. The reaction mixture was stirred at room temperature overnight and water (10mL) was added. The mixture was extracted with DCM and the organic layers were combined over MgSO4Dried, filtered and concentrated. Chromatography on silica gel (elution: ethyl acetate/methanol gradient) afforded the title compound as a white solid (300mg, 0.66mmol, 77%).1HNMR(300MHz,CDCl3)δ3.28-3.31(m,4H);3.69-3.72(m,4H);5.49(s,1H);7.28-7.60(m,6H);8.18(d;J=7.8Hz,1H);13C NMR(75MHz,CDCl3)δ44.6;65.4;87.6;120.8;121.6;124.6;124.9;126.0;129.1;130.9;133.1;139.5;149.1;150.4;162.5;171.1;177.1。
(iii) 2-morpholin-4-yl-8- (3-thiophen-3-yl-phenyl) -chromen-4-one 46(20)
Suzuki-Miyaura coupling was performed as described above to give the target compound.1H NMR(300MHz,CDCl3)δ3.31(m;4H);3.64(m;4H);5.54(s;1H);7.43-7.60(m;6H);7.64-7.68(m;2H);7.80(s;1H);8.22(d;J=6.0Hz,1H);13C NMR(75MHz,CDCl3)δ44.7;65.8;87.0;120.6;123.4;124.9;125.2;125.9;126.2;126.3;126.8;127.7;130.1;133.3;135.9;136.8;141.6;150.6;162.5;177.2;UVλmax=301nm;IR(cm-1)3094、2847、1615、1556、1404、1244、1066、985、769。
(iv) 2-morpholin-4-yl-8- (3-thiophen-2-yl-phenyl) -chromen-4-one 47(21)
Suzuki-Miyaura coupling was performed as described above to give the target compound.1H NMR(300MHz,CDCl3)δ3.34(m;4H);3.65(m;4H);5.56(s;1H);7.09-7.12(m;1H);7.26-7.52(m;5H);7.62-7.68(m;2H);7.92(s;1H);8.20(d;J=6.0Hz,1H);13C NMR(75MHz,CDCl3)δ44.7;65.8;87.0;123.3;123.4;124.9;125.3;125.9;127.1;127.5;128.3;128.4;129.2;129.9;133.4;134.5;136.9;143.6;150.5;162.5;177.1;UVλmax=296nm;IR(cm-1)2921、2855、1639、1570、1396、1240、1115、1074、765。
The hydroxy derivative (17) was dissolved in anhydrous DMF. Potassium carbonate and methyl bromoacetate were added and the reaction mixture was stirred at 60 ℃ overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give a methyl ester. This ester was dissolved in methanol and aqueous NaOH was added. The reaction mixture was stirred at 60 ℃ for one hour until completion, after which it was evaporated to dryness to give the sodium salt. The sodium salt was dissolved in DMF and aliquoted into tubes containing the appropriate amine, HOBT and TBTU. The reaction mixture was stirred at room temperature overnight and diluted with methanol before purification.
(d)
Compound 17, 1, 2-dibromoethane, potassium carbonate and anhydrous DMF were introduced into a round bottom flask. The reaction mixture was stirred at room temperature. After completion, the reaction mixture was divided and added to the reaction tube together with the appropriate amine. The resulting mixture was stirred at room temperature overnight and diluted with methanol before purification.
Example 4
(a)8- (6-amino-biphenyl-3-yl) -2-morpholin-4-yl-chromen-4-one (27)
(i) 5-bromo-biphenyl-2-ylamine (26)
In a two-necked round-bottomed flask were placed the starting materials 2-phenylaniline (2.035g, 12.03mmol, 1 eq.), 1.295g NH4Br (13.23mmol, 1.1 equiv.) and 24mL of glacial acetic acid. Hydrogen peroxide (1.64g of a 27.5% w/w solution, 13.23mmol, 1.1 equiv.) was added dropwise via syringe and the reaction mixture was stirred for 24 hours. After disappearance of the starting material, saturated Na is added2CO3The solution was extracted with DCM. The combined organic layers were dried over MgSO4Dried, filtered and concentrated under vacuum. The crude mixture was purified by flash chromatography on silica gel (eluting gasoline/DCM 4: 1, then gradient) to afford the expected product as a beige solid (2.076g, 70%).
1H NMR(300MHz,CDCl3)δ3.76(broad s,2H);6.67(d,J=7.3Hz,1H);7.27(d,J=7.9Hz,1H);7.37-7.52(m,6H)。
13C NMR(75MHz,CDCl3)δ110.6;117.5;128.1;129.3;129.4;129.8;131.5;133.2;138.5;143.0。
(ii)8- (6-amino-biphenyl-3-yl) -2-morpholin-4-yl-chromen-4-one (27)
145mg (0.41mmol) of benzopyrone borate (16), 101mg (0.41mmol) of benzidine bromide, 48mg (0.041mmol) of Pd (PPh) were placed in a Schlenk tube3)4And 338mg (2.44mmol) of K2CO3. Dioxane (10mL) was degassed prior to addition and the reaction mixture was heated to reflux for 12 hours. Water (10mL) was added and the reaction mixture was extracted with DCM (60 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. Silica gel chromatography (eluting with ethyl acetate/methanol 95: 5, then gradient) afforded the title compound as a white powder in 52% yield.
1H NMR(300MHz,CDCl3)δ3.26-3.33(m;4H);3.67-3.71(m;4H);5.49(s;1H);7.28-7.58(m,10H),8.14(d;J=7.4Hz;1H)。
13C NMR(75MHz,CDCl3)δ45.0;60.7;66.3;87.2;116.7;123.7;124.4;125.0;127.9;128.6;128.7;129.1;129.8;130.5;132.0;133.3;136.6;150.9;154.0;162.8;171.5;177.7。
UV:λmax=305nm
IR:(cm-1)1616、1560、1400、1242、983、905、700。
Mass spectrum: (M/z)399[ M +1]+。
HPLC test system: LCMS RtGradient 3.82 min, 5 min.
TLC∶Rf=0.54(EA/MeOH,9∶1)
(b)
The amino derivative (27) was dissolved in anhydrous DMA. Triethylamine and chloroacetyl chloride were added and the reaction mixture was stirred at room temperature for 4 hours. An aliquot of the reaction mixture was added to a tube containing the appropriate amine. The reaction mixture was stirred at room temperature overnight and diluted with methanol before purification.
(c)
Compound 27, triethylamine, 3-bromopropionyl chloride, and anhydrous DMA were introduced into a round bottom flask. The reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was divided and added to the reaction tube together with the corresponding amine. The resulting mixture was stirred at room temperature overnight and diluted with methanol before purification.
Example 5
To synthesize compounds with heteroaryl-phenyl substituents, two suzuki couplings were used. The reaction was carried out at 150 ℃ for 5 minutes in the presence of microwaves, which contained the following reagents in addition to the reaction compounds: PdCl2(PPh3)2、Na2CO3 aq.、DME/H2O/EtOh (7: 3: 2). The compound is then purified.
Example 6
a)8- (2-chloro-pyridin-4-yl) -2-morpholin-4-yl-chromen-4-one (33)
To a solution of 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate (1.00g, 2.64mmol) in anhydrous dioxane (40mL) was added under N2 a portion of 2-chloropyridine-4-boronic acid (0.436g, 2.77mmol) followed by a portion of tetrakis (triphenylphosphine) palladium (0) (0.147g, 0.132mmol) and a portion of pulverized potassium carbonate (1.093g, 7.91 mmol). Is provided with a condenser andthe reaction was heated to 110 ℃. After 48 hours, the reaction was cooled to RT and filtered through celite, washing with dichloromethane. The combined organics were washed with saturated brine solution (1X 10mL) over MgSO4Dried, filtered, and concentrated in vacuo. After the addition of hexane, the solid precipitate that appeared during 12 hours was collected by filtration to yield the title compound (considered to be 100%) and no further purification was required.
b)8- (2-substituted-pyridin-4-yl) -2-morpholin-4-yl-chromen-4-one (34)
8- (2-chloro-pyridin-4-yl) -2-morpholin-4-yl-chromen-4-one (0.30g, 0.875mmol) was dissolved in N, N-dimethylformamide (10 mL). An aliquot (1mL) was then added to a vial containing powdered potassium carbonate (0.029g, 0.210mmol), the desired boronic acid (0.096mmol) and bis (tri-tert-butylphosphine) palladium (0) (6mg, 0.003 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 300 seconds. The resulting solution was filtered through a SEP silica cartridge, washed with methanol, and then purified by HPLC.
Example 7
a)8- (4-bromo-pyridin-2-yl) -2-morpholin-4-yl-chromen-4-one (35)
To a solution of 2-morpholin-4-yl-8- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -chromen-4-one (0.321g, 0.90mmol) in a 1: 1 mixture of toluene: ethanol (15mL) was added one part of 2, 4-dibromopyridine (0.315g, 0.99mmol), followed by one part of trans-dichlorobis (triphenylphosphine) palladium (II) (0.011g, 0.015mmol) and one part of pulverized potassium carbonate (0.435g, 3.15 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 300 seconds. The resulting solution was filtered, washed with ethanol, and the combined organics concentrated in vacuo. The crude product was purified by flash chromatography (SiO2) (EtOAc: EtOH 100: 1, then DCM: MeOH 20: 1) to yield the title compound as a brown foam (0.275g, 79%).
b)8- (4-substituted-pyridin-2-yl) -2-morpholin-4-yl-chromen-4-one (36)
8- (4-bromo-pyridin-2-yl) -2-morpholin-4-yl-chromen-4-one (0.275g, 0.710mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL). An aliquot (1mL) was then added to a vial containing powdered potassium carbonate (0.029g, 0.210mmol), the desired boronic acid (0.105mmol) and bis (tri-tert-butylphosphine) palladium (0) (2mg, 0.004 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 300 seconds. The resulting solution was filtered through a SEP silica cartridge, washed with methanol, and then purified by HPLC.
Example 8
a)8- (5-chloro-thiophen-2-yl) -2-morpholin-4-yl-chromen-4-one (37)
To a solution of 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate (0.341g, 0.90mmol) in a mixture of 1, 4-dioxane: N, N-dimethylacetamide (15mL) at 10: 1 was added a catalytic amount of triethylamine followed by 5-chloro-2-thiopheneboronic acid (0.292g, 1.80 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 120 seconds. Further 5-chloro-2-thiopheneboronic acid (0.292g, 1.80mmol) was added, and then microwave irradiation at 150 ℃ was repeated twice for 120 seconds. After filtration, the filtrate was concentrated in vacuo and the resulting solid was triturated with tetrahydrofuran. A second filtration showed the title compound (0.222g, 71%) and no further purification was required.
b)8- (5-substituted-thiophen-2-yl) -2-morpholin-4-yl-chromen-4-one (38)
8- (5-chloro-thiophen-2-yl) -2-morpholin-4-yl-chromen-4-one (0.222g, 0.64mmol) was dissolved in N, N-dimethylformamide (10 mL). An aliquot (1mL) was then added to a vial containing powdered potassium carbonate (0.026g, 0.19mmol), the desired boronic acid (0.066mmol) and bis (tri-tert-butylphosphine) palladium (0) (1-2mg, 0.003 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 120 seconds. The resulting solution was filtered through a SEP silica cartridge, washed with methanol, and then purified by HPLC.
Example 9
a)8- (5-bromo-thiazol-2-yl) -2-morpholin-4-yl-chromen-4-one (39)
To a solution of 2-morpholin-4-yl-8- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -chromen-4-one (0.535g, 1.50mmol) in a 1: 1 mixture of toluene: ethanol (25mL) was added one part of 2, 5-dibromothiazole (0.400g, 1.65mmol), followed by one part of tetrakis (triphenylphosphine) palladium (0) (0.087g, 0.075mmol) and one part of pulverized potassium carbonate (0.621g, 4.50 mmol). The mixture was then subjected to microwave irradiation at 130 ℃ for 3600 seconds. The resulting solution was filtered, washed with ethanol, and the combined organics concentrated in vacuo. The crude product was purified by flash chromatography (SiO2) (EtOAc: EtOH 20: 1, then 20: 3) to yield the title compound as a black solid (0.255g, 43%).
b)8- (5-substituted-thiazol-2-yl) -2-morpholin-4-yl-chromen-4-one (40)
8- (5-bromo-thiazol-2-yl) -2-morpholin-4-yl-chromen-4-one (0.255g, 0.650mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL). An aliquot (1mL) was then added to a vial containing powdered potassium carbonate (0.029g, 0.210mmol), the desired boronic acid (0.098mmol) and bis (tri-tert-butylphosphine) palladium (0) (2mg, 0.004 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 300 seconds. The resulting solution was filtered through a SEP silica cartridge, washed with methanol, and then purified by HPLC.
Example 10
a)8- (5-bromo-thiazol-2-yl) -2-morpholin-4-yl-chromen-4-one (41)
To a solution of 2-morpholin-4-yl-8- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -chromen-4-one (0.535g, 1.50mmol) in a 1: 1 mixture of toluene: ethanol (25mL) was added one part of 2, 5-dibromothiazole (0.400g, 1.65mmol), followed by one part of tetrakis (triphenylphosphine) palladium (0) (0.087g, 0.075mmol) and one part of pulverized potassium carbonate (0.621g, 4.50 mmol). The mixture was then subjected to microwave irradiation at 130 ℃ for 3600 seconds. The resulting solution was filtered, washed with ethanol, and the combined organics concentrated in vacuo. The crude product was purified by flash chromatography (SiO2) (EtOAc: EtOH 20: 1, then 20: 3) to yield the title compound as a black solid (0.255g, 43%).
b)8- (5-substituted-thiazol-2-yl) -2-morpholin-4-yl-chromen-4-one (42)
8- (5-bromo-thiazol-2-yl) -2-morpholin-4-yl-chromen-4-one (0.255g, 0.650mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL). An aliquot (1mL) was then added to a vial containing powdered potassium carbonate (0.029g, 0.210mmol), the desired boronic acid (0.098mmol) and bis (tri-tert-butylphosphine) palladium (0) (2mg, 0.004 mmol). The mixture was then subjected to microwave irradiation at 150 ℃ for 300 seconds. The resulting solution was filtered through a SEP silica cartridge, washed with methanol, and then purified by HPLC.
Biological examples
DNA-PK inhibitory Effect
To evaluate the inhibitory activity of compounds on DND-PK in vitro, IC was determined using the following assay50The value is obtained.
Mammalian DNA-PK (500ng/ml) was isolated from Hela nuclear extracts by chromatography using Q-Sepharose, S-Sepharose and heparin Sepharose (GeII, D. and Jackson. P., Nucleic Acids Res.27: 3494-3502 (1999)). DNA-PK (250ng) Activity in 96-well Polypropylene plates at 30 ℃ in a final volume of 40. mu.l containing 25mM Hepes, pH7.4, 12.5mM MgCl250mM KCl, 1mM DTT, 10% glycerol, 0.1% NP-40, and 1mg of the substrate GST-p53N66 (66 amino acid residues at the amino terminus of human wild-type p53 fused to glutathione-S-transferase). To the assay mixture was added different concentrations of inhibitor (1% final concentration in DMSO). After 10 minutes of incubation, the reaction was initiated by the addition of ATP at a final concentration of 50. mu.M and a 30mer double-stranded DNA oligonucleotide (final concentration 0.5 ng/ml). After shaking for 1 hour, 150. mu.l Phosphate Buffered Saline (PBS) was added to the reaction, and then 5. mu.L was transferred to a 96-well opaque white plate containing 45. mu.l PBS per well, in which the GSTp53N66 substrate was allowed to bind to the wells for 1 hour in the 96-well plate. To detect the DNA-PK-induced phosphorylation event at serine 15 residue of p53, the p53 phosphoserine-15 antibody (Cell Signaling Technology) was used in a basic ELISA method. HRP-conjugated secondary rabbit antibodies (Pierce) were then used in ELISA followed by addition of chemiluminescent reagent (NEN Renaissance) and detection by reaction with TopCount NXT (Pa)cockard) count the chemiluminescence to detect a signal.
The enzyme activity of each compound was then calculated using the following equation:
% inhibition 100- [ (unknown cpm-mean negative cpm) x 100/(mean positive cpm-mean negative cpm) ]
The result is the IC discussed below50Value (concentration inhibiting 50% of the enzyme activity). These are measured at different concentration ranges, usually from 10. mu.M down to 0.001. mu.M. To integrate such IC50Values were used as comparative values to identify increased compound effects.
Survival enhancement rate (survival enhancement ratio)
The Survival Enhancement Rate (SER) is the rate of enhanced cell killing by DNA-PK inhibitors after 2 gray irradiation compared to non-irradiated control cells. DNA-PK inhibitor was fixed at a concentration of 500 nM. Radiation was delivered by a Faxitron43855D machine at a dose rate of 1Gy per minute. The SER under 2 gray radiation was calculated using the following formula:
SER ═ (cell survival in the presence of DNA-PK inhibitor/cell survival of control cells) x (cell survival after IR/cell survival after IR in the presence of DNA-PK inhibitor)
The extent of cell killing was monitored by standard clonogenic cell survival assays. Briefly, HeLa cells were seeded at appropriate concentrations in tissue culture treated 6-well plates with 100-200 colonies per well and returned to the incubator for cell adherence. After four hours, compound or vehicle controls were added to the cells. The cells were then incubated for 1 hour in the presence of the inhibitor, followed by 2 gray irradiation using a Faxitron43855D box X-ray apparatus. The cells were then incubated for a further 16 hours and the medium was replaced with fresh medium without DNA-PK inhibitors. After 8 days, the colonies formed were fixed, stained with giemsa (Sigma, Poole, UK) and counted with an automatic colony counter (Oxford optronics Ltd, Oxford, UK). The data is calculated as described above.
Results
All compounds showed DNA-PK inhibitory activity, some exhibited IC's of less than about 500nM50。
All compounds showed SER of 1 or greater.
Claims (19)
1. A compound of formula I, and isomers, salts, solvates, chemically protected forms and prodrugs thereof:
wherein A, B and D are independently selected from:
(i)CH、NH、C;
(ii) CH, N; and
(iii)CH、O、C;
the dotted line represents two double bonds in place;
RN1and RN2Independently selected from hydrogen, optionally substituted C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, or together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 4 to 8 ring atoms;
Z2、Z3、Z4、Z5and Z6Together with the carbon atoms to which they are attached form an aromatic ring;
Z2selected from the group consisting of CR2N, NH, S and O; z3Is CR3;Z4Selected from the group consisting of CR4N, NH, S and O; z5Is a direct bond or is selected from O, N, NH, S and CH; z6Selected from O, N, NH, S and CH;
R2is H;
R3selected from halogen or optionally substituted C5-20An aryl group;
R4selected from H, OH, NO2、NH2And Q-Y-X, wherein Q is-NH-C (═ O) -or-O-;
y is optionally substituted C1-5An alkylene group;
x is selected from SRS1Or NRN3RN4Wherein
RS1or RN3And RN4Independently selected from hydrogen, optionally substituted C1-7Alkyl radical, C5-20Aryl or C3-20Heterocyclyl group, or RN3And RN4Together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having from 4 to 8 ring atoms;
if Q is-O-, then X may additionally be selected from-C (═ O) -NRN5RN6Wherein R isN5And RN6Independently selected from hydrogen, optionally substituted C1-7Alkyl radical, C5-20Aryl or C3-20Heterocyclyl group, or RN5And RN6Together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having from 4 to 8 ring atoms, and
if Q is-NH-C (═ O) -, then-Y-X may additionally be selected from C1-7An alkyl group.
2. A compound according to claim 1, wherein Z2、Z3、Z4、Z5And Z6Together with the carbon atom to which they are bound form a substituted aryl group selected from substituted phenyl, thienyl, furyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, isoxazolyl, oxazolyl, isothiazolyl.
3. A compound according to claim 2, wherein Z2、Z3、Z4、Z5And Z6Together with the carbon atom to which they are bound form a group selected from substituted phenyl, thiazolyl, thienyl or pyridyl.
4. A compound according to any one of claims 1-3, wherein R3Is selected from C5Heteroaryl, pyridyl and phenyl.
5. A compound according to claim 1, wherein Z2Is CR2、Z3Is CR3、Z4Is CR4And Z is5And Z6Are both CH.
6. A compound according to claim 5, wherein R3Is unsubstituted phenyl, RN1And RN2Form a morpholino group, and R4Is not H.
7. The compound according to any one of claims 1-6, wherein R4Is Q-Y-X.
8. A compound according to claim 7, wherein Q is-NH-C (═ O) -and X is NRN3RN4。
9. A compound according to claim 7, wherein Q is-O-, X is NRN3RN4And Y is optionally substituted C1-3An alkylene group.
10. The compound according to any one of claims 1-9, wherein RN1And RN2Together with the nitrogen atom to which they are attached form a heterocyclic ring having from 4 to 8 atoms.
11. The compound according to any one of claims 1-9, wherein RN1And RN2Together with the nitrogen atom to which they are attached form a group selected from morpholino and thiomorpholino.
12. A composition comprising a compound according to any one of claims 1-11 and a pharmaceutically acceptable carrier or diluent.
13. A compound according to any one of claims 1-11 for use in a method of treatment.
14. Use of a compound according to any one of claims 1-11 for the manufacture of a medicament for the treatment of a disease ameliorated by the inhibition of DNA-PK.
15. Use of a compound according to any one of claims 1 to 11 for the preparation of a medicament for:
(a) the medicament is used as an adjuvant in cancer therapy, or for enhancing the effect of tumor cells treated with ionizing radiation or chemotherapeutic agents; or
(b) The medicament is for the treatment of retroviral mediated diseases.
16. A compound according to any one of claims 1-11 for use in the treatment of a disease ameliorated by the inhibition of DNA-PK.
17. The compound according to any one of claims 1 to 11,
(a) as an adjunct in cancer therapy, or for enhancing the effect of tumor cells treated with ionizing radiation or chemotherapeutic agents; or
(b) For use in the treatment of retroviral mediated diseases.
18. A method of treating a subject having a disease ameliorated by the inhibition of DNA-PK, comprising administering to said subject a compound according to any one of claims 1-11.
19. A method of inhibiting DNA-PK in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of claims 1-11.
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