WO2013163190A1 - Dna-pk inhibitors - Google Patents
Dna-pk inhibitors Download PDFInfo
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- WO2013163190A1 WO2013163190A1 PCT/US2013/037811 US2013037811W WO2013163190A1 WO 2013163190 A1 WO2013163190 A1 WO 2013163190A1 US 2013037811 W US2013037811 W US 2013037811W WO 2013163190 A1 WO2013163190 A1 WO 2013163190A1
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- 0 [*+]c1ccc2[n](CCO)ncc2c1 Chemical compound [*+]c1ccc2[n](CCO)ncc2c1 0.000 description 6
- KDYVCOSVYOSHOL-UHFFFAOYSA-N Cc1ccc(cccn2)c2c1 Chemical compound Cc1ccc(cccn2)c2c1 KDYVCOSVYOSHOL-UHFFFAOYSA-N 0.000 description 1
- GYVUMHXXXAATFQ-UHFFFAOYSA-N Cc1ccc(ccnc2)c2c1 Chemical compound Cc1ccc(ccnc2)c2c1 GYVUMHXXXAATFQ-UHFFFAOYSA-N 0.000 description 1
- PPEJLOXOMBAXES-UHFFFAOYSA-N Cc1ccc(cncc2)c2c1 Chemical compound Cc1ccc(cncc2)c2c1 PPEJLOXOMBAXES-UHFFFAOYSA-N 0.000 description 1
- LUYISICIYVKBTA-UHFFFAOYSA-N Cc1ccc2ncccc2c1 Chemical compound Cc1ccc2ncccc2c1 LUYISICIYVKBTA-UHFFFAOYSA-N 0.000 description 1
- OSRARURJYPOUOV-UHFFFAOYSA-N Cc1ccc2nccnc2c1 Chemical compound Cc1ccc2nccnc2c1 OSRARURJYPOUOV-UHFFFAOYSA-N 0.000 description 1
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Definitions
- the present invention relates to compounds useful as inhibitors of DNA-dependent protein kinase (DNA-PK).
- the invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of cancer.
- Ionizing radiation induces a variety of DNA damage of which double strand breaks (DSBs) are the most cytotoxic. These DSBs can lead to cell death via apoptosis and/or mitotic catastrophe if not rapidly and completely repaired.
- certain chemotherapeutic agents including topoisomerase II inhibitors, bleomycin, and doxorubicin also cause DSBs. These DNA lesions trigger a complex set of signals through the DNA damage response network that function to repair the damaged DNA and maintain cell viability and genomic stability.
- NHEJ Non-Homologous End Joining Pathway
- NHEJ DNA-dependent protein kinase
- DNA-PKcs is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of serine/threonine protein kinases that also includes ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), mTOR, and four PI3K isoforms.
- PIKK phosphatidylinositol 3-kinase-related kinase
- ATM telangiectasia mutated
- ATR ataxia telangiectasia and Rad3-related
- mTOR mTOR
- DNA-PKcs is in the same protein kinase family as ATM and ATR, these latter kinases function to repair DNA damage through the Homologous Recombination (HR) pathway and are restricted to the S and G 2 phases of the cell cycle.
- HR Homologous Recombination
- ATM
- NHEJ is thought to proceed through three key steps: recognition of the DSBs, DNA processing to remove non-ligatable ends or other forms of damage at the termini, and finally ligation of the DNA ends.
- Recognition of the DSB is carried out by binding of the Ku heterodimer to the ragged DNA ends followed by recruitment of two molecules of DNA-PKcs to adjacent sides of the DSB; this serves to protect the broken termini until additional processing enzymes are recruited.
- Recent data supports the hypothesis that DNA-PKcs phosphorylates the processing enzyme, Artemis, as well as itself to prepare the DNA ends for additional processing. In some cases DNA polymerase may be required to synthesize new ends prior to the ligation step. The auto-phosphorylation of DNA-PKcs is believed to induce a conformational change that opens the central DNA binding cavity, releases DNA-PKcs from DNA, and facilitates the ultimate religation of the DNA ends.
- DNA-PK ⁇ ⁇ mice are hypersensitive to the effects of IR and that some non-selective small molecule inhibitors of DNA-PKcs can radiosensitize a variety of tumor cell types across a broad set of genetic backgrounds. While it is expected that inhibition of DNA-PK will radiosensitize normal cells to some extent, this has been observed to a lesser degree than with tumor cells likely due to the fact that tumor cells possess higher basal levels of endogenous replication stress and DNA damage
- IGRT image-guide RT
- IMRT intensity-modulated RT
- a DNA-PK inhibitor may have the ability to sensitize these potential metastatic progenitor cells to the effects of IR and select DSB-inducing
- DNA-PK inhibitory drugs Given the involvement of DNA-PK in DNA repair processes, an application of specific DNA-PK inhibitory drugs would be to act as agents that will enhance the efficacy of both cancer chemotherapy and radiotherapy. Accordingly, it would be desirable to develop compounds useful as inhibitors of DNA-PK.
- the invention also provides pharmaceutical compositions that include a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or vehicle. These compounds and pharmaceutical compositions are useful for treating or lessening the severity of cancer.
- the compounds and compositions provided by this invention are also useful for the study of DNA-PK in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
- compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
- substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
- the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
- substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
- an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
- Ci_ 3 alkyl if X is halogen, Ci_ 3 alkyl, or phenyl, wherein X is optionally substituted by J x , then both Ci_ 3 alkyl and phenyl may be optionally substituted by J x .
- groups such as H, halogen, N0 2 , CN, NH 2 , OH, or OCF 3 would not be included because they are not substitutable groups.
- a heteroaryl or heterocyclic ring containing an NH group can be optionally substituted by replacing the hydrogen atom with the substituent. If a substituent radical or structure is not identified or defined as "optionally substituted," the substituent radical or structure is unsubstituted.
- Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
- stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, preferably, their recovery, purification, and use for one or more of the purposes disclosed herein.
- a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
- alkyl or "alkyl group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated. Unless otherwise specified, alkyl groups contain 1-8 carbon atoms. In some embodiments, alkyl groups contain 1-6 carbon atoms, and in yet other embodiments, alkyl groups contain 1-4 carbon atoms (represented as “Ci_ 4 alkyl”). In other embodiments, alkyl groups are characterized as "Co_ 4 alkyl” representing either a covalent bond or a Ci_ 4 alkyl chain.
- alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec- butyl, and tert-butyl.
- alkylene represents a saturated divalent straight or branched chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene and the like.
- alkylidene represents a divalent straight chain alkyl linking group.
- alkenyl represents monovalent straight or branched chain hydrocarbon group containing one or more carbon-carbon double bonds.
- alkynyl represents a monovalent straight or branched chain hydrocarbon group containing one or more carbon-carbon triple bonds.
- cycloalkyl refers to a monocyclic C3-C 8 hydrocarbon or bicyclic C 8 -C 12 hydrocarbon that is completely saturated and has a single point of attachment to the rest of the molecule, and wherein any individual ring in said bicyclic ring system has 3-7 members.
- Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which at least one ring in the system contains one or more heteroatoms, which is the same or different, and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, and that has a single point of attachment to the rest of the molecule.
- the "heterocycle,” “heterocyclyl,” “heterocycloalkyl,” or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 8 ring members.
- heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
- heteroatom means one or more of oxygen, sulfur, nitrogen, or phosphorus, including any oxidized form of nitrogen, sulfur, or phosphorus; the quatemized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
- unsaturated as used herein, means that a moiety has one or more units of unsaturation.
- alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
- haloalkyl means alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
- halogen means F, CI, Br, or I.
- aralkoxy refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein said ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic and wherein each ring in the system contains 4 to 7 ring members.
- aryl may be used interchangeably with the term “aryl ring.” Examples of aryl rings include phenyl, naphthyl, and anthracene.
- heteroaryl used alone or as part of a larger moiety as in
- heteroarylkyl refers to a monocyclic, bicyclic, and tricyclic ring system having a total of five to fourteen ring members, wherein said ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphorus, and wherein each ring in the system contains 4 to 7 ring members.
- heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic.”
- heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,
- 3-pyridazinyl 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1 ,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (
- a bond drawn from a substituent to the center of one ring within a multiple-ring system represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system.
- Structure a represents possible substitution in any of the positions shown in Structure b.
- each substituent only represents substitution on the ring to which it is attached.
- Y is an optionally substituent for ring A only
- X is an optional substituent for ring B only.
- protecting group represent those groups intended to protect a functional group, such as, for example, an alcohol, amine, carboxyl, carbonyl, etc., against undesirable reactions during synthetic procedures. Commonly used protecting groups are disclosed in Greene and Wuts, Protective Groups In Organic Synthesis, 3 r Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Examples of nitrogen protecting groups include acyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,
- trichloroacetyl phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate groups such as
- benzyloxycarbonyl p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l- methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
- N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,
- structures recited herein are meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
- stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
- Such compounds can have either the R or S configuration.
- the chiral center(s) are labeled (R) or (S) in the drawing.
- the invention features compounds having the formula:
- Q is N or CH
- Ring A is a ring system selected from
- Ci_ 4 alkyl is hydrogen, halogen, Ci_ 4 alkyl, Co- 4 alkyl-C3_ 6 cycloalkyl, Co_ 4 alkyl-OR a , Co_ 4 alkyl- SR Ala , Co_ 4 alkyl-C(0)N(R Ala ) 2 , C 0 _ 4 alkyl-CN, C 0 - 4 alkyl-S(O)-Ci_ 4 alkyl, C 0 - 4 alkyl-S(O) 2 - Ci_ 4 alkyl, C 0 - 4 alkyl-C(O)OR Alb , Co- 4 alkyl-C(0)Ci_ 4 alkyl, C 0 - 4 alkyl-N(R Alb )C(O)R Ala , C 0 _ 4 alkyl-N(R Alb )S(0) 2 R Ala , C 0 - 4 alkyl-N(R Alb )S(0) 2 R Ala , C 0 -
- each R Ala is, independently, hydrogen, Ci_ 4 alkyl, C 3 _ 6 Cycloalkyl, C 4 _ 6 heterocyclyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, pyrrolidinyl, or piperidinyl, C 5 _ 6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, or two R Ala and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or
- each of said R Ala alkyl, cycloalkyl, heterocyclyl, or heteroaryl groups is optionally substituted with up to three F atoms, up to two Ci_ 2 alkyl groups, a C 3 _ 6cycloalkyl group, up to two Co- 2 alkyl-OR Alb groups, a Co_ 2 alkyl-N(R Alb ) 2 group, a SCi_ 4alkyl group, a C(0)R Alb group, a C(0)OR Alb group, a C(0)N(R Alb ) 2 group, or a -CN group;
- each R Alb is, independently, hydrogen, Ci_ 2 alkyl, or C 3 - 4 cycloalkyl
- R A2 is hydrogen, Ci_ 4 alkyl, Co_ 4 alkyl-C 3 _ 6 cycloalkyl, Co_ 2 alkyl-(4-6 membered)heterocyclyl, C 2 _ 4 alkyl-OR A2a , C 0 - 2 alkyl-C(O)N(R A2a ) 2 , C 0 - 2 alkyl-S(O) 2 -Ci_ 4 alkyl, C 0 _ 2 alkyl- C(0)OCi_ 4 alkyl, C 0 _ 2 alkyl-C(O)-(4-6 membered)heterocyclyl, wherein each of said heterocyclyl is selected from oxetanyl, tetrahydropyran, tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl,
- each R A2b is, independently, hydrogen, Ci_ 4 alkyl, or C3_ 4 cycloalkyl;
- R A3 is hydrogen or Ci_ 2 alkyl
- each R A4 is, independently, deuterium, halogen, CN, Ci_ 4 alkyl, or OCi_ 4 alkyl, wherein each R A4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OCi_ 2 alkyl, or two R A4 together with an intervening saturated carbon atom form a spiral cyclopropyl or cyclobutyl ring;
- n 0-3;
- Ring B is a ring system selected from
- R B1 is hydrogen, C alkyl, (CH 2 ) 0 -iC 3 - 6 cycloalkyl, C(0)Ci_ 2 alkyl, (CH 2 ) 0 _i-(4-6
- heterocyclic ring is selected from selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, dioxanyl, dioxolanyl, or pyrrolidinonyl, phenyl, benzyl, or (CH 2 )i_ 2 (5-6 membered)heteroaryl ring wherein said heteroaryl ring is selected from pyridinyl, imidazolyl, or pyrazolyl, and wherein each of said R B1 alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl or heteroaryl groups is optionally substituted with up to 3 F atoms, up to two Ci_ 2 alkyl groups, two non-geminal OH groups, or one OCi_ 2alkyl;
- R B2 is hydrogen, Ci_ 4 alkyl, OCi_ 4 alkyl
- each R B3 is, independently, hydrogen, halogen, Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, CN,
- each R B4 is, independently, hydrogen, halogen, Ci_ 4 alkyl, OCi_ 4 alkyl, SCi_ 4 alkyl, NH 2 , NH(Ci_ 4alkyl), N(Ci_ 4 alkyl) 2 , NHC(0)Ci_ 4 alkyl, C(0)OH, C(0)OCi_ 4 alkyl, C(0)NH 2 ,
- each R B4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OCi_ 2 alkyl;
- R B5 is hydrogen, Ci_ 4 alkyl, C(0)Ci_ 4 alkyl, C(0)OCi_ 4 alkyl, C(0)NH 2 , C(0)NHCi_ 4 alkyl, or C(0)N(Ci_ 4 alkyl) 2 , wherein said R B5 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OCi_ 2 alkyl and
- R B6 is F or Ci_ 2 alkyl, or two R B6 and an intervening carbon atom from a spirocyclopropyl or spirocyclobutyl ring.
- the compound has the following formula:
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- R A1 is Ci_ 4 alkyl, OCi_ 4 alkyl, or N(R Ala ) 2 , wherein each R Ala is, independently, hydrogen or Ci_ 4 alkyl, or two R a and an intervening nitrogen atom form a 3- 6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl,
- each of said R A1 alkyl or heterocyclyl groups is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two Ci_ 2 alkyl groups, a C 3 - 6 cycloalkyl group, up to two Co- 2 alkyl-OR Alb groups, a C 0 _ 2 alkyl-N(R Alb ) 2 group, a SCi_ 4 alkyl group, a C(0)R Alb group, a C(0)OR Alb group, a C(0)N(R Alb ) 2 group, or a -CN group, wherein each R Alb is, independently, hydrogen, Ci_ 2 alkyl, or C 3 - 4 cycloalkyl.
- the compound has one of the following formulae:
- the compound has the following formula:
- the compound has one of the following formulae
- the compound has one of the following formulae:
- the compound has the following formula:
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- the compound has one of the following formulae
- the compound has the following formula [0047] In one embodiment, the compound has one of the following formulae:
- the compound has the following formula:
- the compound has the following formula:
- the compound has the following formula:
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- the compound has the following formula:
- the compound has the following formula:
- the compound has the following formula:
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- the compound has the following formula:
- the compound has one of the following formulae:
- the compound has one of the following formulae
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- the compound has one of the following formulae:
- Q is CH for a compound of the invention.
- Ring A of compounds of the invention comprises a heterocyclyl or heteroaryl ring.
- Ring A is selected from
- Ring A is selected from
- R is hydrogen, Ci_ 4 alkyl, Co- 2 alkyl-C 3 - 6 cycloalkyl, Co_ 2 alkyl-(4-6
- each of said heterocyclyl is selected from oxetan-2-yl, azetidin-2-yl, piperidin-4-yl, or l,l-dioxothietan-2-yl, and each of said R A2 groups is optionally substituted with up to three F atoms, up to two Ci_ 2 alkyl groups, up to two OR A2b groups, a C 0 _ 2 alkyl-N(R A2b ) 2 group, a C(0)R A2b group, a C(0)OR A2b group, a C(0)N(R A2b ) 2 group
- Ring A is selected from ;
- R AZ is a hydrogen, Ci_ 4 alkyl, Co_ 2 alkyl-C 3 - 6 cycloalkyl, Co- 2 alkyl-(4-6 membered)heterocyclyl, C 2 _ 4 alkyl-OR A2a , C 0 - 2 alkyl-C(O)N(R A2a ) 2 , C 0 - 2 alkyl-S(O) 2 -Ci_ 4 alkyl, or C 0 _ 2 alkyl-C(O)OCi_ 4 alkyl, wherein each of said heterocyclyl is selected from oxetan-2-yl, azetidin-2-yl, piperidin- 4-yl, or l,l-dioxothietan-2-yl, and each of said R groups is optionally substituted with up to three F atoms, up to two Ci_ 2 alkyl groups, up to two OR A2b groups, a C 0 _ 2 alky
- Ring A is selected from ;
- R A1 is Ci_ 4 alkyl, C 0 - 4 alkyl-C 3 - 6 cycloalkyl, C 0 _ 4 alkyl-OR Ala , C 0 - 4 alkyl-C 3 _ 6 cycloalkyl, C 0 _ 4 alkyl- N(R Ala ) 2 , N(R Ala )C 2 _ 4 alkyl-N(R Ala ) 2 , wherein each of said R A1 alkyl or cycloalkyl is optionally substituted with up to three F atoms, up to three 2 H atoms, or up to two Co- 2 alkyl-
- each R a is, independently, hydrogen, Ci_ 4 alkyl, a C(0)R group, or two R Ala and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl,
- each of said alkyl or heterocyclyl group of R Ala is optionally substituted with up to three F atoms, up to two Ci_ 2 alkyl groups, up to two OR Alb groups, or a -CN group; each R Alb is, independently, hydrogen or Ci_ 2 alkyl; each R A4 is, independently, halogen, 2 H, Ci_ 4 alkyl, N(R la ) 2 , or OCi_ 4 alkyl, wherein each R A4 alkyl is optionally substituted with up to 3 F atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl, and wherein n is 0-3.
- Ring A is selected from
- each R is, independently, halogen, Ci_ 4 alkyl, or OCi_ 4 alkyl, wherein each R alkyl is optionally substituted with up to 3 F atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl, and wherein n is 0-2.
- Ring B of compounds of the invention comprises a heterocyclyl or heteroaryl ring.
- Ring B is selected from
- R is C(0)NHCi_4 alkyl, wherein said alkyl is optionally substituted with up to three F atoms, two non-geminal OH groups, or one OCi_ 2 alkyl;
- each R B4 is, independently, hydrogen, 2 H, F, Ci_ 4 alkyl, or OCi_ 4 alkyl, wherein each R B4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one
- Ring A is
- R A1 is F, Ci_ 4 alkyl, OC M alkyl, OC 0 - 4 alkyl-C 3 - 5 cycloalkyl, NH 2 , NHCi_ 4 alkyl, NHC 0 - 4 alkyl-C 3 _ 5 cycloalkyl, or Co- 4 alkyl-heterocyclyl, wherein said heterocyclic ring system is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, and each of said alkyl, cycloalkyl, or heterocyclyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl;
- each R A4 is, independently, F, 2 H, OC M alkyl, or NH 2 ; and n is 0-2.
- Ring B is
- each of R and R is, independently, hydrogen, halogen, or Ci_ 4 alkyl, wherein each of said
- R B3 or R B4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OCi_ 2 alkyl;
- R B5 is hydrogen, C alkyl, C(0)Ci_ 4 alkyl, C(0)OC alkyl, C(0)NH 2 , C(0)NHCi_ 4 alkyl, or
- R B5 alkyl is optionally substituted with up to 3 F atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl;
- R B6 is F or Ci_ 2 alkyl, or two R B6 and an intervening carbon atom from a spirocyclopropyl or spirocyclobutyl ring.
- the invention features a compound having formula
- X is N, CR A5 ;
- R A1 is F, Ci_ 4 alkyl, C 3 _ 5 cycloalkyl, OCi_ 4 alkyl, OCi_ 4 alkyl-C 3 _ 5 cycloalkyl, NH 2 , NHCi_ 4 alkyl, NHCi_ 4 alkyl-C 3 _ 5 Cycloalkyl, or Co_ 4 alkyl-heterocyclyl, wherein said heterocyclic ring system is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, or morpholinyl, and each of said alkyl, cycloalkyl, or heterocyclyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl; each R A4 is, independently, H or 2 H;
- R A5 is hydrogen, F, Ci_ 4 alkyl, or OCi_ 4 alkyl, wherein each of said alkyl is optionally
- R B3 is C(0)NHCi_4 alkyl, wherein said alkyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl; and each R B4 is, independently, hydrogen, deuterium, F, or Ci_ 4 alkyl.
- the invention features a compound having formula
- X is N, CR A3 ;
- R A1 is F, Ci_ 4 alkyl, C 3 _ 5 cycloalkyl, OCi_ 4 alkyl, OCi_ 4 alkyl-C 3 _ 5 cycloalkyl, NH 2 , NHCi_ 4 alkyl, NHCo_ 4 alkyl-C 3 _ 5 Cycloalkyl, or Co_ 4 alkyl-heterocyclyl, wherein said heterocyclic ring system is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, or morpholinyl, and each of said alkyl, cycloalkyl, or heterocyclyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl; each R A4 is, independently, H or 2 H;
- R A5 is hydrogen, F, Ci_ 4 alkyl, or OCi_ 4 alkyl, wherein each of said alkyl is optionally
- R B3 is C(0)NHCi_4 alkyl, wherein said alkyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OCi_ 2 alkyl; and each R B4 is, independently, hydrogen, deuterium, F, or Ci_ 4 alkyl [0079]
- the invention features a compound selected from the group of compounds listed in Table 1 or Table 2.
- the invention provides a pharmaceutical composition comprising a compound of any of the formulae described herein and a pharmaceutically acceptable excipient.
- the invention provides a pharmaceutical composition comprising a compound of Table 1 or Table 2.
- the composition additionally comprises an additional therapeutic agent.
- the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- the amount of compound in a composition of this invention is such that is effective to measurably inhibit a DNA-PK in a biological sample or in a patient.
- the amount of compound in the compositions of this invention is such that is effective to measurably inhibit DNA-PK.
- the composition of this invention is formulated for administration to a patient in need of such composition.
- the composition of this invention is formulated for oral administration to a patient.
- patient means an animal, preferably a mammal, and most preferably a human.
- a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
- the term "inhibitory active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of DNA-PK.
- the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as
- hydrochloric acid hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
- hydroiodide 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, Ci_8 sulfonate and aryl sulfonate.
- compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or
- any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
- Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin
- polyethylene glycol polyethylene glycol
- esters such as ethyl oleate and ethyl laurate
- agar buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
- compositions of the present invention may be administered orally,
- parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous,
- compositions are administered orally, intraperitoneally or intravenously.
- Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are examples of the acceptable oils.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- compositions of this invention may be administered in the form of suppositories for rectal administration.
- suppositories for rectal administration.
- suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
- compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
- the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride.
- the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
- the pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable
- preservatives include preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- compositions of this invention are formulated for oral administration.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adj
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of compound release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
- Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- buffering agents include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
- dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
- compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
- additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
- additional therapeutic agents which are normally administered to treat or prevent a particular proliferative condition or cancer are known as "appropriate for the disease, or condition, being treated.” Examples of additional therapeutic agents are provided infra.
- the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
- the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
- the invention provides a method of sensitizing a cell to an agent that induces a DNA lesion comprising the step of contacting the cell with one or more DNA-PK inhibitors of formula I or subformula thereof (e.g., formulae I-A-l, I-A-2, ... to I- A-51, 1-B-l, I-B-2, ... to I-B-42) or a DNA-PK inhibitor of formula II or formula III.
- one or more DNA-PK inhibitors of formula I or subformula thereof e.g., formulae I-A-l, I-A-2, ... to I- A-51, 1-B-l, I-B-2, ... to I-B-42
- a DNA-PK inhibitor of formula II or formula III e.g., formulae I-A-l, I-A-2, ... to I- A-51, 1-B-l, I-B-2, ... to I-B-42
- the invention further provides methods of potentiating a therapeutic regimen for treatment of cancer comprising the step of administering to an individual in need thereof an effective amount of a DNA-PK inhibitor of formula I, formula II, formula III, or subformulae thereof.
- the therapeutic regimen for treatment of cancer includes radiation therapy.
- Compounds of the invention are useful in instances where radiation therapy is indicated to enhance the therapeutic benefit of such treatment.
- radiation therapy frequently is indicated as an adjuvent to surgery in the treatment of cancer.
- the goal of radiation therapy in the adjuvant setting is to reduce the risk of recurrence and enhance disease-free survival when the primary tumor has been controlled.
- adjuvant radiation therapy is indicated in cancers, including but not limited to, breast cancer, colorectal cancer, gastric-esophageal cancer, fibrosarcoma, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, lung cancer, pancreatic cancer, and prostate cancer as described below.
- cancers including but not limited to, breast cancer, colorectal cancer, gastric-esophageal cancer, fibrosarcoma, glioblastoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, lung cancer, pancreatic cancer, and prostate cancer as described below.
- the invention also can be practiced by including another anti-cancer
- chemotherapeutic agent with a compound of the invention in a therapeutic regimen for the treatment of cancer, with or without radiation therapy.
- the combination of a DNA-PK inhibitor compound of the invention with such other agents can potentiate the
- the inhibitor compound of the invention can be administered with etoposide or bleomycin, agents known to cause DNA strand breakage.
- the invention further relates to radiosensitizing tumor cells utilizing a compound of formula I, formula II, formula III, or subformulae thereof.
- the preferred compounds are those as described for the pharmaceutical compositions of the invention.
- a compound that can "radiosensitize" a cell, as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amount to increase the sensitivity of cells to electromagnetic radiation and/or to promote the treatment of diseases that are treatable with electromagnetic radiation (e.g., X-rays).
- Diseases that are treatable with electromagnetic radiation include neoplastic diseases, benign and malignant tumors, and cancerous cells.
- the present invention also provides methods of treating cancer in an animal that includes administering to the animal an effective amount of a DNA-PK inhibitor such as, for example, a compound of the invention.
- the invention further is directed to methods of inhibiting cancer cell growth, including processes of cellular proliferation, invasiveness, and metastasis in biological systems.
- Methods include use of a compound of the invention as an inhibitor of cancer cell growth.
- the methods are employed to inhibit or reduce cancer cell growth, invasiveness, metastasis, or tumor incidence in living animals, such as mammals.
- Methods of the invention also are readily adaptable for use in assay systems, e.g., assaying cancer cell growth and properties thereof, as well as identifying compounds that affect cancer cell growth.
- Tumors or neoplasms include growths of tissue cells in which the multiplication of the cells is uncontrolled and progressive. Some such growths are benign, but others are termed “malignant” and can lead to death of the organism. Malignant neoplasms or “cancers” are distinguished from benign growths in that, in addition to exhibiting aggressive cellular proliferation, they can invade surrounding tissues and metastasize. Moreover, malignant neoplasms are characterized in that they show a greater loss of differentiation (greater "dedifferentiation") and their organization relative to one another and their surrounding tissues. This property is also called “anaplasia.”
- Neoplasms treatable by the present invention also include solid tumors, i.e., carcinomas and sarcomas.
- Carcinomas include those malignant neoplasms derived from epithelial cells which infiltrate (invade) the surrounding tissues and give rise to metastases.
- Adenocarcinomas are carcinomas derived from glandular tissue, or from tissues which form recognizable glandular structures.
- Another broad category of cancers includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective tissue.
- the invention also enables treatment of cancers of the myeloid or lymphoid systems, including leukemias, lymphomas, and other cancers that typically do not present as a tumor mass, but are distributed in the vascular or lymphoreticular systems.
- DNA-PK activity can be associated with various forms of cancer in, for example, adult and pediatric oncology, growth of solid tumors/malignancies, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma lung cancer, including small cell carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
- the invention provides a method of inhibiting DNA-PK activity in a biological sample that includes contacting the biological sample with a compound or composition of the invention.
- biological sample means a sample outside a living organism and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
- Inhibition of kinase activity, particularly DNA-PK activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. An example includes, but is not limited to, the inhibition of DNA-PK in a biological assay.
- the method of inhibiting DNA-P activity in a biological sample is limited to non-therapeutic methods.
- the compounds of this invention may be prepared by methods described herein or by other methods known to those skilled in the art.
- boronate or boronic acid from aryl or heteroaryl halides Procedures for preparing a boronate or boronic acid from aryl or heteroaryl halides are described in Boronic Acids, ISBN: 3-527-30991-8, Wiley- VCH, 2005 (Dennis G. Hall, editor).
- the halogen is bromine and the boronate is prepared by reacting the aryl or heteroaryl bromide with 4,4,5 ,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane.
- boronates or boronic acids so formed can be reacted with halopyrimidines in the presence of a palladium catalyst such as ⁇ , ⁇ bis(diphenylphosphino)- ferrocene dichloro-palladium » dichloromethane [Pd(dppf)Cl 2 ].
- a palladium catalyst such as ⁇ , ⁇ bis(diphenylphosphino)- ferrocene dichloro-palladium » dichloromethane [Pd(dppf)Cl 2 ].
- boronate or boronic acid intermediates can be prepared by reacting an aryl or heteroaryl, or vinyl halide with 4,4,5, 5-tetramethyl-2-(4,4, 5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane in the presence of a palladium catalyst such as ⁇ , ⁇ bis(diphenylphosphino)-ferrocene dichloro-palladium » dichloromethane [Pd(dppf)Cl 2 ].
- a palladium catalyst such as ⁇ , ⁇ bis(diphenylphosphino)-ferrocene dichloro-palladium » dichloromethane
- step 2-i of Scheme 2 to a solution of a compound of formula M (1 equiv.) and K 2 CO 3 (3 equiv.) in DMF (0.3 M) was added an alkyl bromide (2 equiv.) at room temperature. The reaction mixture was then stirred at 80 °C for 5 hours. The reaction was cooled down to room temperature and filtered over a pad of diatomaceous earth. The resulting cake was washed with EtOAc. To the filtrate was added H 2 0 and the two phases were separated. The aqueous phase was extracted with EtOAc and the organic phase was washed with brine. The combined organic phases were dried over Na 2 S0 4 and evaporated. The residue was purified by medium pressure silica gel chromatography (0— 100% EtOAc in hexanes) to provide intermediate N.
- step 2-ii of Scheme 2 A solution of the 5-bromo-pyrazolo[3,4- £]pyridine of formula N (1 equiv.), fos-pinacol borane (1.15 equiv.), KOAc (3 equiv.) in 2- methyl-THF (0.3 M) was degassed with a stream of N 2 for 20 min. Then, Pd(dppf)Cl 2 (0.05 equiv.) was added to the reaction mixture. The resulting solution was heated in a sealed tube at 120 °C for 3h in an oil bath. The solution was cooled down to room temperature and filtered over a pad of Florisil ® . The filtrate was evaporated and the resulting compound of formula O was produced. In many cases, these compounds could be subsequently used without any further purification.
- step 3-i of Scheme 3 to a solution of 2-bromophenol (15 g, 86.7 mmol) in DMF (180 mL) at 0°C was added 3-bromo-2-methyl-prop-l-ene (12.8 g, 9.61 mL, 95.37 mmol) followed by K 2 C0 3 (23.96 g, 173.4 mmol) and TBAI (384 mg, 1.04 mmol). The reaction mixture was then stirred at RT for 24 hours and quenched with H 2 0 (90 mL). The aqueous phase was extracted with EtOAc and the organic phase was dried over Na 2 S04.
- step 3-ii of Scheme 3 a solution of Compound 2001 (13.8 g, 60.7 mmol), NaOAc (12.46 g, 151.9 mmol), tetraethylammonium chloride hydrate (13.4 g, 72.9 mmol), and sodium formate (4.95 g, 72.9 mmol) in DMF (140 mL) was degassed for 30 min using a N 2 stream. Pd(OAc) 2 (682.1 mg, 3.04 mmol) was added and the mixture was heated to 90°C for 4 hours. The reaction mixture was cooled down to RT and diluted with Et 2 0 (50 mL).
- step 3-iii of Scheme 3 to a solution of TMEDA (3.93 g, 5.11 mL, 33.8 mmol) in Et 2 0 (60 mL) was added sec-butyllithium (22.3 mL of 1.4 M, 31.2 mmol) at -78°C. After 10 minutes at -78 °C, 3,3-dimethyl-2H-benzofuran (Compound 2002, 3.86 g,
- step 3-iv of Scheme 3 to a solution of 3,3-dimethyl-2H-benzofuran- 7-carbaldehyde (0.5 g, 2.837 mmol) in AcOH (11.1 mL) was added nitromethane (519.5 mg, 461.0 ⁇ , 8.511 mmol) and ammonium acetate (546.7 mg, 7.092 mmol) at RT. The reaction mixture was then heated at 110°C for 2 hours. The reaction mixture was then cooled and the volatiles removed under reduced pressure.
- step 3-v of Scheme 3 to a solution of LiAlH 4 (4.01 mL of 1 THF, 4.01 mmol) was added (E)-3,3-dimethyl-7-(2-nitrovinyl)-2,3-dihydrobenzofuran (160 mg, 0.72 mmol) in THF (14.0 mL) at RT. The yellow solution was stirred at RT for 15 hours. The reaction was quenched very slowly with water (15 mL) and extracted with Et 2 0 and EtOAc.
- step 3-vi of Scheme 3 a solution of 4,6-dichloropyrimidine (111.6 mg, 0.726 mmol), 2-(3,3-dimethyl-2H-benzofuran-7-yl)ethanamine (139 mg, 0.726 mmol), Na 2 C0 3 (231.1 mg, 2.180 mmol) in z ' -PrOH (5.56 mL) was sealed in a microwave-type tube and heated at 90 °C in an oil bath for 18 hours.
- step 3-vii of Scheme 3 a solution of -chloro-N-(2-(3,3-dimethyl-2,3- dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine (60 mg, 0.197 mmol), l-methyl-4-[5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (71.86 mg, 0.237 mmol), Na 2 C0 3 (296.2 ⁇ .
- step 4-i of Scheme 4 to a solution of diisopropylamine (6.70 g, 9.28 mL, 66.2 mmol) in THF (60 mL) at -78°C under N 2 was added n-butyllithium (33.1 mL of 2.0 M in cyclohexane, 66.2 mmol) and the solution was stirred for 40 minutes. A solution of 2- (2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) in THF (30 mL) was added dropwise, then the reaction was allowed to warm to room temperature over one hour.
- reaction was then cooled to -78°C and iodomethane (4.27 g, 1.87 mL, 30.1 mmol) was added to the reaction in one portion.
- iodomethane 4.27 g, 1.87 mL, 30.1 mmol
- the reaction was warmed to room temperature 18 hours, 15 mL of water was added, and the organics were collected and the volatiles removed under reduced pressure.
- the residue was acidified with IN HCl and the crude product extracted with Et 2 0 (3x).
- step 4-ii of Scheme 4 to a solution of 2-(2-methoxyphenyl)propanoic acid (1.50 g, 7.91 mmol) in THF (20 mL) at 0°C was added lithium aluminum hydride (31.6 mL of 0.5 M solution, 15.8 mmol) and the reaction was warmed to room temperature and stirred for 3.5 hours.
- step 4-iii of Scheme 4 a mixture of 2-(2-methoxyphenyl)-l-propanol (1.31 g, 7.08 mmol), phthalimide (1.09 g, 7.44 mmol), and PPh 3 resin (3.43 g, 10.6 mmol) was stirred at room temperature for 15 minutes to allow the resin to swell.
- step 4-iv of Scheme 4 to a stirred solution of 2-(2-(2- methoxyphenyl)propyl)isoindoline-l,3-dione (363 mg, 1.23 mmol) in MeOH (4.0 mL) was added hydrazine (39.4 mg, 38.6 ⁇ , 1.23 mmol) and the reaction was stirred for 18 hours.
- step 4-v of Scheme 4 a mixture of 4,6-dichloropyrimidine (817 mg, 5.49 mmol), 2-(2-methoxyphenyl)-l-propanamine (0.997 g, 6.03 mmol), and DIEA (2.13 g, 2.87 mL, 16.5 mmol) in isopropanol (5.0 mL) was stirred for 18 hours.
- step 4-vi of Scheme 4 a mixture of 6-chloro-N-(2-(2- methoxyphenyl)propyl)pyrimidin-4-amine (75.0 mg, 0.270 mmol), l-methyl-4-[5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (Compound 2007, 90.1 mg, 0.297 mmol), Pd(OAc) 2 (1.21 mg, 0.00540 mmol), [3-(2-dicyclohexylphosphanylphenyl)-2,4- dimethoxy-phenyljsulfonyloxysodium (VPhos, 11.1 mg, 0.0216 mmol), and Na 2 C0 3 (405 ⁇ _, of 2 M, 0.810 mmol) in IPA (2 mL) was degassed and back-filled with N 2 (repeated 2x), then heated to 90°C for 4 hours.
- the chirality of asymmetric 1 -carbon center of 2-aminoethyl-B-Ring moieties can be ascertained by preparing intermediates analogous to Compound 2016 and using such intermediates in the preparation of the compounds of the invention. Accordingly, the chirality of Compound 34 was ascertained by preparing Compound 2009 as a mixture of racemates having an enantiomeric excess greatly in favor the ( ⁇ -configuration. See Evans D.A. et al., in J. Am. Chem. Soc, Vol 104, 1737-1739 (1982).
- step 5-i of Scheme 5 to a solution of 2-(2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) and Et 3 N (6.70 g, 9.23 mL, 66.2 mmol) in THF (150 mL) at -15°C was added pivaloyl chloride (3.70 g, 3.78 mL, 30.7 mmol) and the resulting solution was stirred for 15 minutes.
- Lithium chloride (1.53 g, 36.1 mmol) and (45)-4-benzyloxazolidin-2-one (6.29 g, 35.5 mmol) were added to the solution and the reaction was warmed to room temperature over 18 hours.
- step 5-ii of Scheme 5 to a solution of sodium hexamethyldisilazide (NaHMDS, 5.06 g, 26.2 mmol) in THF (100 mL) under an atmosphere of nitrogen at -78°C was added (45)-4-benzyl-3-[2-(2-methoxyphenyl)acetyl]oxazolidin-2-one (7.11 g, 21.9 mmol) and the reaction was stirred for 1.5 hours. Methyl iodide (3.08 g, 1.35 mL, 21.7 mmol) was then added dropwise and stirring continued at -78°C for 4 hours, then the reaction was warmed to room temperature over 18 hours.
- NaHMDS sodium hexamethyldisilazide
- step 5-iii of Scheme 5 to an ice-cooled solution of (45)-4-benzyl-3- [(2S)-2-(2-methoxyphenyl)-propanoyl]oxazolidin-2-one (3.10 g, 9.13 mmol) in THF (183 mL) and MeOH (1.24 mL) was added LiBH 4 (9.13 mL of 2.0 M solution, 18.3 mmol) and the reaction was stirred at 0°C for 2 hours, then warmed to room temperature over 18 hours. A solution of NaOH (18.6 mL of 2.0 M solution) was added and the reaction stirred until both layers were clear. The layers were separated and the aqueous layer was extracted with Et 2 0 (2x).
- tert-butyl (2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)allyl)carbamate (Compound 1017, 1.455 g, 5.138 mmol), 7-chlorofuro[3,2- 6]pyridine (0.789 g, 5.138 mmol), NaHC0 3 (8.56 mL of 1.2 M, 10.276 mmol), DMF (14.3 mL), and H 2 0 (4.8 mL) were combined. The resultant mixture was flushed with nitrogen gas for 10 minutes.
- step 6-ii of Scheme 6 a mixture of tert-butyl (2-(furo[3,2-£]pyridin- 7-yl)allyl)carbamate (0.940 g, 3.427 mmol), Pd/C (10%, 364.7 mg, 3.427 mmol), EtOAc (34.3 mL) and MeOH (34.3 mL) was stirred under H 2 at 1 atm for 16 hours. The reaction mixture was filtered through diatomaceous earth and the filter pad was rinsed with 1 : 1 EtOAc/MeOH. The combined filtrate was concentrated under reduced pressure.
- step 6-iv of Scheme 6 to a suspension of 2-(2,3-dihydrofuro[3,2- 3 ⁇ 4]pyridin-7-yl)propan-l-amine-2HCl and 4,6-dichloropyrimidine (456.0 mg, 3.061 mmol) in z ' -PrOH (17.01 mL) was added Et 3 N (1.291 g, 1.778 mL, 12.76 mmol). The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, and partitioned between saturated aqueous NaHC0 3 and EtOAc.
- step 6-v of Scheme 6 (5)-6-chloro-N-(2-(2,3-dihydrofuro[3,2- £]pyridin-7-yl)propyl)pyrimidin-4-amine (29.2 mg, 0.1003 mmol), N-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (30.7 mg, 0.2006 mmol), Na 2 C0 3 (150.4 ⁇ , of 2 M aqueous solution, 0.3009 mmol), and z ' -PrOH (2.0 mL) were combined and flushed with nitrogen gas for 10 minutes.
- dichloropalladium(II), dichloromethane complex (1.53 g, 1.87 mmol) the mixture was flushed with nitrogen gas for another 5 minutes.
- the reaction mixture was heated at 85°C for 2 hours followed by the addition of MTBE (400 mL) and water (100 mL).
- step 7-ii of Scheme 7 tert-butyl N-tert-butoxycarbonyl-N-[2-(2,3- dihydro-[l,4]dioxino[2,3-3 ⁇ 4]pyridin-8-yl)allyl]carbamate (18.9 g, 48.2 mmol) was stirred in EtOAc (200 mL) with 10% palladium/carbon (550 mg, 5.14 mmol). The reaction mixture was purged of atmosphere which was replaced with hydrogen gas (3x) and stirred under an atmosphere of hydrogen for 5 hours.
- step 7-iv of Scheme 7 (5)-tert-butyl N-tert-butoxycarbonyl-N-[2- (2,3-dihydro-[l,4]dioxino[2,3-3 ⁇ 4]pyridin-8-yl)propyl]carbamate (7.74 g, 39.8 mmol) was dissolved in EtOH, HC1 in IPA (60 mL of 4 M solution, 240 mmol) was added and the reaction mixture was ref uxed for 1 hour. The reaction mixture was concentrated under reduced pressure to a minimum volume, Et 2 0 was added, and the resulting suspension stirred for 16 hours.
- step 7-v of Scheme 7 (5)-2-(2,3-dihydro-[l,4]dioxino[2,3-3 ⁇ 4]pyridin- 8-yl)propan-l -amine, dihydrochloride (10.0 g, 49.5 mmol), 4,6-dichloropyrimidine (8.11 g, 54.5 mmol), and TEA (15.03 g, 20.7 mL, 148.6 mmol) stirred in NMP (125 mL) at 50°C for 3.5 hours.
- step 7-vi of Scheme 7 6-chloro-N-[2-(2,3-dihydro-[l,4]dioxino[2,3- 3 ⁇ 4]pyridin-8-yl)propyl]pyrimidin-4-amine (410 mg) was dissoved in IPA (0.75 mL). N-methyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (23 mg) was added, followed by the addition of 2M Na 2 C0 3 (122 ⁇ ) and l, -bis(diphenylphosphino)ferrocene] dichloropalladium(II), dichloromethane complex (7 mg).
- reaction vessel was sealed and heated at 80°C overnight.
- the mixture was cooled, diluted with ethyl acetate, washed with water, dried over Na 2 S0 4 , filtered, concentrated under reduced pressure and purified by reversed-phase HPLC, 5-50% ACN/H 2 O/0.1% TFA.
- N-(2-bromoallyl)-6-(6-methyl-3- pyridyl)pyrimidin-4-amine (240 mg, 0.7792 mmol, Compound 2027; which was prepared by reacting 4-chloro-6-(6-methylpyridin-3-yl)pyrimidine with 2-bromoprop-2-en-l -amine under basic conditions), 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro- [l,4]dioxino[2,3-6]pyridine (287.0 mg, 1.091 mmol), and Na 2 C0 3 (1.169 mL of 2 M, 2.338 mmol) were stirred in DMSO (5.945 mL) .
- N-[2-(2,3-dihydro-[l,4]dioxino[2,3-3 ⁇ 4]pyridin- 8-yl)allyl]-6-(6-methyl-3-pyridyl)pyrimidin-4-amine 150 mg, 0.4151 mmol was dissolved in MeOH and the reaction mixture was placed under an atmosphere of H 2 .
- N-(2-(2,3-dihydro-[l,4]dioxino[2,3-3 ⁇ 4]pyridin- 8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine was purified by supercritical fluid chromatography using a ChiralPak® ICTM column (10 mm x 250 mm, 1/1 C0 2 /EtOH, 35°C, 12 mL/min, 100 atm.) Fractions of the first eluting product with a retention time of 11.08 min were combined to produce (5)-N-(2-(2,3-dihydro-[l,4]dioxino[2,3-]pyridin-8-yl)propyl)-6-(6- methylpyridin-3-yl)pyrimidin-4-amine (Compound 443).
- step 9-i of Scheme 9 As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g, 1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mL water. The mixture was flushed with nitrogen gas for 30 minutes and Pd(PPh 3 ) 4 (22.05 g 19.08 mmol) was added.
- the resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes, heated to reflux, and a nitrogen-flushed solution of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine (140 g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours.
- the resulting dark red solution was refiuxed under an atmosphere of nitrogen for 16 hours. After this time the mixture was cooled to RT and 300 mL of water was added. The mixture was then cooled to 5°C and stirred for 40 minutes.
- the resulting precipitate (6- chloro-2'-methyl-4,5'-bipyrimidine, compound 2039) was collected by filtration, washed with 50 mL water, followed by washing with 150 mL EtOAc. The filtrate was separated into two layers and the aqueous layer extracted with EtOAc (2 x 1 L). The combined organics were dried over Na 2 S0 4 , concentrated under reduced pressure, diluted with 300 mL of DCM, and purified by medium pressure silica gel chromatography (0 - 100% EtOAc/DCM). Fractions containing pure product were concentrated under reduced pressure and the concentrate treated with 400 mL of hexanes to produce compound 2039 as a solid.
- This material was combined with the solid product previously collected and treated with 400 mL of 1 : 1 THF/DCM.
- the resulting suspension was heated and transferred to a filtration funnel containing a plug of Florisil® .
- the plug was washed with additional 1 : 1 THF/DCM to dissolve any remaining solid material and then washed with 4: 1 EtOAc/DCM (2 x 1L).
- step 9-ii of Scheme 9 2-bromoaniline (520 g, 3.023 mol) was melted at 50°C in an oven and then added to a reaction vessel containing stirring acetic acid (3.12 L). Methanesulfonic acid (871.6 g, 588.5 mL, 9.069 mol) was then added over 15 minutes. The reaction mixture was heated to 60°C and methyl vinyl ketone (377 mL, 1.5 equiv.) was added over 5 minutes and the reaction mixture stirred for 1 hour at 90°C. After this time another 50 mL (0.2 equiv.) of methyl vinyl ketone was added and the reaction mixture stirred for an additional 16 hours.
- step 9-iii of Scheme 9 selenium dioxide (764.7 g, 6.754 mol) was taken up in 3.25 L of dioxane and 500 mL of water. The stirred solution was heated to 77°C and 8-bromo-4-methylquinoline (compound 2030, 500 g, 2.251 mol) was added in one portion. The reaction mixture was stirred at reflux for 30 minutes and then cooled with a water bath to about 45°C, at which temperature a precipitate was observed. The suspension was filtered through diatomaceous earth which was subsequently washed with the hot THF to dissolve any residual solids.
- step 9-iv of Scheme 9 to a stirred suspension of 8-bromoquinoline-4- carbaldehyde (531.4 g, 2.25 mol) in THF (4.8 L) was added water (4.8 L) and monosodium phosphate (491.1 g, 4.05 mol). The mixture was cooled to 5°C and, keeping the reaction temperature below 15°C, sodium chlorite (534.4 g, 4.727 mol) was slowly added portionwise as a solid over about 1 hour. After addition was complete the reaction mixture was stirred at 10°C for 1 hour followed by the portionwise addition of IN Na 2 S 2 0 3 (1.18 L) whilst keeping the temperature below 20°C.
- step 9-v of Scheme 9 to a suspension of 8-bromoquinoline-4- carboxylic acid (compound 2032, 779.4 g, 3.092 mol) in DCM (11.7 L) was added anhydrous DMF (7.182 mL, 92.76 mmol). The reaction mixture was cooled to 10°C and oxalyl chloride (413 mL, 4.638 mol) was added dropwise over 30 minutes. The reaction mixture was stirred an additional 30 minutes after addition was complete, transferred to an evaporation flask, and the volatiles removed under reduced pressure. Anhydrous THF (2 L) was added and the volatiles were once more removed under reduced pressure in order to remove any residual oxalyl chloride.
- the evaporation vessel used to store the acid chloride was rinsed with anhydrous THF and aqueous MeNH 2 (500 mL) and this added to the reaction mixture, which was allowed to come to room temperature over 16 hours.
- the organic volatiles were removed under reduced pressure and the remaining mostly aqueous suspension diluted with water (1.5 L).
- the solids were collected by filtration, washed with water until the filtrate had a pH of less than 11, washed with MTBE (2 x 800 mL), and dried in a convection oven at 60°C to provide 8-bromo-N-methyl-quinoline-4-carboxamide
- step 9-vi of Scheme 9 8-bromo-N-methyl-quinoline-4-carboxamide (compound 2033, 722 g, 2.723 mol) and fert-butyl-N-[2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)allyl]carbamate (compound 2034, 925.4 g, 3.268 mol) were combined in a reaction flask. Na 2 C0 3 (577.2 g, 5.446 mol) was added followed by the addition of water (2.17 L).
- the resulting precipitate cake was split into two equal portions. Each portion was dissolved in THF/DCM (4 L) and poured onto a plug of Florisil® (3 L filtration funnel with about 1.5 L of florisil, using DCM to wet plug). The plug was subsequently washed with MeTHF until it was determined by thin layer chromatography analysis that no product remained in the filtrate. The filtrates from both cake portions were combined and concentrated under reduced pressure to give an orange solid. TBME (1 L) was added and the resulting suspension was filtered.
- Additional product (34.9 g, 74% total yield) was obtained by concentrating the filtrate under reduced pressure, dissolving the residue in THF, filtering the solution through a plug of Florisil® as before, washing the plug with MeTHF, concentrating the filtrate under reduced pressure, adding 250 mL of TBME, stirring for 0.5 hours, collecting the resulting precipitate by filtration, washing the solid with EtOAc (40 mL), acetonitrile (50 mL), and drying the solid under high vacuum overnight.
- step 9-vii of Scheme 9 to a stirring suspension of tert-butyl (2-(4- (methylcarbamoyl)quinolin-8-yl)allyl)carbamate (compound 2035, 425 g, 1.245 mol) in EtOH (4.25 L) was added 5.5M HC1 in iPrOH (1.132 L, 6.225 mol). The reaction mixture was stirred at reflux (76°C internal temp) for 30 minutes and then over 90 minutes while it was allowed to cool to 40°C. EtOAc (2.1 L) was added and the mixture was stirred for an additional 2 hours.
- step 9-viii of Scheme 9 8-[l-(aminomethyl)vinyl]-N-methyl- quinoline-4-carboxamide, dihydrochloride (compound 2036, 168.8 g, 537 mmol) was stirred in MeOH (1.688 L) and TEA (114.2 g, 157.3 mL, 1.129 mol) was added, followed by the addition of 5% Pd on BaS0 4 (22.88 g, 10.75 mmol). The atmosphere of the reaction mixture was replaced with hydrogen gas and the reaction stirred at under 1 atmosphere of hydrogen atmosphere for 16 hours.
- step 9-ix of Scheme 9 the two racemates of 8-(l-aminopropan-2-yl)- N-methylquinoline-4-carboxamide (compound 137, 1380.5 g) were separated by chiral HPLC. Accordingly, 260 mL aliquots of racemic mixture (6 mg/mL) were loaded onto a Chiralpak AYTM column (11 cm x 25 cm) and eluted with acetonitrile (0.2% TEA) at a flow rate of 400 mL/minute. Two major peaks eluted. Peak 1 had a retention time of 7.7 min. and peak 2 had a retention time of 12.2 min.
- the HC1 salt was formed by adding 5N HC1/IPA (220 mL, 1.100 mol) to an ice-bath cooled stirring solution of 8-[(15)-2-amino-l-methyl-ethyl]-N- methyl-quinoline-4-carboxamide (244.5 g, 1.005 mmol) in 980 mL of 1 :1 MeOH/DCM. The ice bath was removed and 1470 mL of Et 2 0 was added portionwise.
- step 9-x of Scheme 9 As shown in step 9-x of Scheme 9, to a stirring solution of 4-chloro-6-(2- methylpyrimidin-5-yl)pyrimidine (compound 2039, 60 g, 290.4 mmol) and 8-[(15)-2-amino- l-methyl-ethyl]-N-methyl-quinoline-4-carboxamide, hydrochloride (compound 2038, 82.87 g, 296.2 mmol) in THF (600 mL) was added water (168.0 mL) and then 2M Na 2 C0 3 (aq.) (363 mL, 726.3 mmol). The reaction mixture was stirred at reflux for 16 hours.
- step 10-i of Scheme 10 tert-butyl (2-(4-(methylcarbamoyl)quinolin- 8-yl)allyl)carbamate (compound 2035, 83 g, 243.1 mmol) was taken up in EtOH and stirred for 10 minutes. To the solution was added HCl/i-PrOH (5M, 194.5 mL, 972.4 mmol) at RT. The reaction mixture was warmed to 60°C and stirred for 2 hours. After cooling, the mixture was concentrated under reduced pressure followed by azeotropic removal of trace water with toluene under reduced pressure.
- Trituration with EtOAc afforded a tan solid (74 g) which was dissolved in a mixture of water/THF (415 mL/300 mL).
- Sodium bicarbonate (61.27 g, 729.3 mmol) was added portionwise at RT and the reaction mixture stirred for 10 minutes after the addition was complete.
- acetic anhydride (68.81 mL, 74.45 g, 729.3 mmol) in THF (120 mL) was added dropwise. The reaction mixture was allowed to come to RT and stirred for 12 hours. Dilution with water produced a white solid which was collected by filtration and washed with MTBE (2 x 500 mL).
- step 10-ii of Scheme 10 under an atmosphere of nitrogen 8-(3- acetamidoprop-l-en-2-yl)-N-methylquinoline-4-carboxamide (12.4 g, 43.77 mmol) and cycloocta-l ,5-diene/(2R,5R)-l-[2-[(2R,5R)-2,5-diethylphospholan-l-yl]phenyl]-2,5-diethyl- phospholane: rhodium(+l) cation- trifluoromethanesulfonate (Rh( COO)(R,R )-Et-DuPhos- OTf, 316.3 mg, 0.4377 mmol) in methanol (372.0 mL) were combined and warmed to 35- 40°C until the solids were solubilized.
- rhodium(+l) cation- trifluoromethanesulfonate Rh( COO)(R,R
- the reaction mixture was placed in a hydrogenation apparatus, the atmosphere replaced with hydrogen, and the mixture agitated under 100 p.s.i. of hydrogen at 50°C for 14 hours. After cooling to RT, the mixture was filtered through a bed of Florisil®, which was subsequently washed with MeOH (2 x 50 mL). The filtrate was concentrated under reduced pressure and any trace water removed via a DCM azeotrope under reduced pressure.
- the enantiomeric excess (e.e.) was determined by chiral HPLC (ChiralPac IC, 0.46 cm x 25 cm], flow rate 1.0 mL/min for 20 min at 30 °C (20:30:50 methanol/ ethanol/ hexanes and 0.1 % diethylamine) with a retention time for the (i?)-enantiomer of 5.0 min, and for the (5)-enantiomer of 6.7 min.
- step 10-iii of Scheme 10 (5)-8-(l-acetamidopropan-2-yl)-N- methylquinoline-4-carboxamide (11.0 g, 38.55 mmol) in 6M aqueous HC1 (192.7 mL, 1.156 mol) was warmed to 60°C. After stirring for 2 days at this temperature, the reaction mixture was cooled and an additional 20 mL of 6M HC1 was added. Stirring was continued for an additional 2 days at 70°C. The reaction mixture was cooled with an ice bath and the pH adjusted to about 11 with 6M NaOH (aq).
- step 10-iv of Scheme 10 8-[(lS)-2-amino-l-methyl-ethyl]-N-methyl- quinoline-4-carboxamide, hydrochloride (compound 2038, 24.0 g, 72.86 mmol) was taken up in THF (230 mL) and water (40 mL) and stirred for 5 minutes. Sodium carbonate (15.44g, 145.7 mmol) in 100 mL of water was added and the reaction mixture stirred for 10 minutes. 4,6-Dichloropyrimidine (12.18 g, 80.15 mmol) was added and the reaction mixture heated at reflux at 66°C for 2 hours.
- the reaction mixture was cooled to RT, diluted with 200 mL of EtOAc, the organic layer separated, and the aqueous layer extracted with 100 mL EtOAc.
- the combined organics were washed with water (60 mL), brine (100 mL), dried over Na2S04, filtered through a bed of silica gel (100 g), and concentrated under reduced pressure.
- step 10-v of Scheme 10 to a solution of 4,6-dichloro-2-methyl- pyrimidin-5 -amine (14.04 g, 78.88 mmol) stirred in methanol-d 4 (140.4 mL) was added formic acid-d 2 (7.77 g, 161.7 mmol) and Pd black (765 mg, 7.19 mmol, wetted in methanol- d 4 ), followed by triethylamine (16.36 g, 22.53 mL, 161.7 mmol). The reaction mixture was sealed in a tube and stirred at RT overnight. The mixture was then filtered and concentrated under reduced pressure.
- step 10-vi of Scheme 10 to 4,6-dideutero-2-methyl-pyrimidin-5- amine (5.35 g, 48.14 mmol) in CH 3 CN (192.5 mL) was added dibromocopper (16.13 g, 3.38 mL, 72.21 mmol) followed by t-butylnitrite (8.274 g, 9.54 mL, 72.21 mmol). After 1 hour, the reaction was filtered through diatomaceous earth with dichloromethane.
- step 10-vii of Scheme 10 a mixture of 5-bromo-4,6-dideutero-2- methyl-pyrimidine (8.5 g, 48.57 mmol), bis(pinacolato)diboron (13.57 g, 53.43 mmol), and KOAc (14.30 g, 145.7 mmol) in 2-methyltetrahydrofuran (102.0 mL) was degassed by flushing with nitrogen. To this was added dichloro-bis(tricyclohexylphosphoranyl)-palladium (PdCl 2 [P(cy) 3 ] 2 , 1.01 g, 1.364 mmol) and the reaction mixture stirred in a sealed tube overnight at 100 °C.
- step 10-viii of Scheme 10 (5)-8-(l-((6-chloropyrimidin-4- yl)amino)propan-2-yl)-N-methylquinoline-4-carboxamide (2.542 g, 7.146 mmol) , 2-methyl- 4,6-dideutero-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (2.204 g, 7.146 mmol, 72% by weight) , Na 2 C0 3 (10.72 mL of 2 M (aq.), 21.44 mmol) , and Silacat® DPP Pd (SiliCycle, Inc., 1.429 g, 0.3573 mmol) were taken up in dioxane (30.00 mL), the solution flushed with nitrogen gas for 5 min, and the reaction mixture stirred at 90°C for 16 hours.
- the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, dissolved in DMSO, and purified by reversed-phase chromatography (10-40%) CH 3 CN/H 2 0, 0.1 % TFA).
- the product fractions were combined and DCM and MeOH were added, followed by the addition of IN NaOH until a pH of greater than 7 was obtained.
- step 11-i of Scheme 11 l-(2-amino-3-hydroxyphenyl)ethanone (4.0 g, 26.5 mmol) and formamide (20 mL, 45 mmol) were heated at 180°C under microwave irradiation for 45 minutes. After cooling, water was added and the reaction mixture concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (2% MeOH/DCM) to produce 4-methylquinazolin-8-ol (compound 2046, 3.81 g, 90% yield) as a yellow solid. This product was used as is in subsequent reactions.
- step 11-ii of Scheme 11 to a solution of 4-methylquinazolin-8-ol (4.87 g, 30.40 mmol) in DCM at 0°C was added cesium carbonate (9.9 g, 40 mmol) and N- phenyl-bis(trifluoromethanesulfinimde (PhN(Tf) 2 ,14.12 g, 39.52 mmol). The cooling bath was removed and the reaction mixture was stirred overnight at RT. The organics were washed with water, 5% HC1, then 5% NaHC03.
- trifluoromethanesulfonate (1.19 g, 4.07 mmol) and selenium dioxide (1.0 g, 9.0 mmol) were taken up in 15 mL pyridine and the reaction mixture stirred at 60°C for 4 hours.
- the reaction mixture was diluted with 100 mL of THF and O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU, 3.1 g, 8.14 mmol) was added. After stirring at RT for 30 minutes, a 2M methylamine/THF solution (5.0 mL, 10.0 mmol) was added.
- reaction mixture was stirred at RT for 1 hour and the volatiles removed under reduced pressure.
- the residue was taken up in DCM and washed with saturated NH 4 C1.
- the aqueous wash was back-extracted with DCM (2x) and the combined organics dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure.
- step 11-iv of Scheme 11 A nitrogen-flushed solution of tert-butyl N- [2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]carbamate (compound 2034, 990 mg, 3.5 mmol), 4-(methylcarbamoyl)quinazolin-8-yl trifluoromethanesulfonate (980 mg, 2.9 mmol) Na 2 C0 3 (3 mL of 2 M (aq), 5.9 mmol) and Pd(dppf)Cl 2 (119mg, 0.14 mmol) in DMF (35 ml ) was heated at 100°C for 3h.
- step 11-vi of Scheme 11 to a suspension of 4-chloro-6-(6-methyl-3- pyridyl)pyrimidine (70 mg, 0.289 mmol), 8-[l-(aminomethyl)vinyl]-N-methyl-quinazoline-4- carboxamide, trifluroacetate (70 mg, 0.20 mmol) and Na 2 C0 3 (92 mg, 0.86 mmol) was heated at 100°C for 60 hours. After cooling, the volatiles were removed under reduced pressure, the residue dissolved in DCM, and the organics washed with water.
- N-methyl-8-(3-((6-(6-methylpyridin-3- yl)pyrimidin-4-yl)amino)prop-l-en-2-yl)quinazoline-4-carboxamide 48 mg, 0.12 mmol
- MeOH (2 mL) and Rh(COD)(i?,i?)-Et-DuPhos-OTf 3 mg
- the reaction mixture was flushed with hydrogen gas then stirred under an atmosphere of 100 psi hydrogen for 24 hours at 60°C in a stainless steel Parr high pressure reactor.
- step 12-i of Scheme 12 8-[l-(aminomethyl)vinyl]-N-methyl- quinazoline-4-carboxamide, trifluoroacetate (850 mg, 2.39 mmol) was dissolved in THF (30 mL). The solution was treated with Et 3 N (2.4 mL, 17.5 mmol) and trifluoroacetic anhydride (0.5 mL, 3.8 mmol). The reaction mixture was stirred for 15 hours at RT. The volatiles were removed under reduced pressure and the residue suspended in water, extracted with EtOAc (3x), and the combined organics dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure.
- N-methyl-8-(3-(2,2,2- trifluoroacetamido)prop-l-en-2-yl)quinazoline-4-carboxamide 700 mg, 2.07 mmol
- MeOH 35 mL
- Rh(COD)(i?J?)-Et-DuPhos-OTf 50 mg
- the reaction mixture was flushed with hydrogen gas and stirred under an atmosphere of 100 psi hydrogen for 24 hours at 60°C in a stainless steel Parr high pressure reactor. After cooling, the reaction atmosphere was flushed with nitrogen.
- step 12-iii of Scheme 12 a solution of (S)-N-methyl-8-(l -(2,2,2- trifluoroacetamido)propan-2-yl)quinazoline-4-carboxamide (200 mg, 0.588 mmol), K 2 CO 3 (406 mg, 2.94 mmol) in MeOH (10 mL) and water (0.5 mL) was heated at 60°C for 1 hour. The reaction mixture concentrated under reduced pressure and dried under high vacuum to provide (5)-8-(l-aminopropan-2-yl)-N-methylquinazoline-4-carboxamide (compound 2054). LC-MS: 245.09 (M+), which was used in the following reaction as is.
- step 12-iv of Scheme 12 compound 2054 was suspended in iPrOH (lOmL) and 4,6-dichloropyrimidine (130 mg, 0.80 mmol) was added. The suspension was heated at 90°C for 1 hour. After cooling, the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc, washed with water, and the aqueous phase back- extracted with EtOAc (2x). The combined organics were dried over Na 2 S0 4 , filtered, concentrated under reduced pressure, and purified by medium pressure silica gel
- step 12-v of Scheme 12 a mixture of (5)-8-(l-((6-chloropyrimidin-4- yl)amino)propan-2-yl)-N-methylquinazoline-4-carboxamide (60 mg, 0.27 mmol), 2-methyl- 4,6-dideuterium-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidine (compound 2042, 96 mg, 0.27 mmol), 2M Na 2 C0 3 (aq) (0.3 mL), and Pd(dppf)Cl 2 (8 mg) in dioxane (5 mL) were heated under microwave irradiation at 1 10°C for 1 hour.
- Tables 1 and 2 provide structures and analytical characterization data for compounds of the invention (blank cells indicate that the test was not performed).
- the assay was carried out in 384-well plates to a final volume of 50 per well containing approximately 6 iiM DNA-PK, 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 25 mM NaCl, 0.01% BSA, 1 mM DTT, 10 ⁇ /mL sheared double-stranded DNA (obtained from Sigma), 0.8 mg/mL DNA-PK peptide (Glu- Pro-Pro-Leu-Ser-Gln-Glu-Ala-Phe-Ala-Asp-Leu-Trp-Lys-Lys- Lys, obtained from American Peptide), and 100 ⁇ ATP.
- compounds of the invention were dissolved in DMSO to make 10 mM initial stock solutions. Serial dilutions in DMSO were then made to obtain the final solutions for the assay. A 0.75 ⁇ ⁇ aliquot of DMSO or inhibitor in DMSO was added to each well, followed by the addition of ATP substrate solution containing 33 P-ATP (obtained from Perkin Elmer). The reaction was started by the addition of
- Each of compounds 1 to 983 has a K; of less than or equal to 0.30 micromolar for the inhibition of DNA-PK.
- glioblastoma cell lines tested appeared generally less sensitive to radiation alone and, therefore, demonstrated less radiosensitization with compound 578 in this assay.
- HS68 normal human fibroblast cell line
- ARPE19 normal human bronchial epithelial cells
- SAEC smooth airway epithelial cells
- HNSCC Carcinoma
- %T/C tumor/control
- %T/Ti the reduction in tumor volume compared to the starting tumor volume.
- Compound 578 [in 16% Captisol®+ HPMC/PVP] was administered orally (b.i.d. at 0 and 4 hours) at 25, 50, 100 mg/kg and (q.d.) 200 mg/kg on Day 19 post implantation. A single 2-Gy dose of whole body IR was given 15 minutes after compound administration. Control animals were given vehicle orally b.i.d. (0 and 4 hours). On Day 26 post
Abstract
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US15/426,150 US10076521B2 (en) | 2012-04-24 | 2017-02-07 | DNA-PK inhibitors |
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US16/042,206 US10391095B2 (en) | 2012-04-24 | 2018-07-23 | DNA-PK inhibitors |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005026129A1 (en) * | 2003-09-15 | 2005-03-24 | Gpc Biotech Ag | Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases |
WO2008042639A1 (en) * | 2006-10-02 | 2008-04-10 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
Family Cites Families (177)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5571506A (en) | 1989-08-14 | 1996-11-05 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aromatic oligomeric compounds useful as mimics of bioactive macromolecules |
WO1991009594A1 (en) | 1989-12-28 | 1991-07-11 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
US6004979A (en) | 1991-02-07 | 1999-12-21 | Hoechst Marion Roussel | Nitrogenous bicycles |
DE69221175T2 (en) | 1991-02-07 | 1998-01-15 | Roussel Uclaf | Bicyclic nitrogen compounds, their preparation, intermediates obtained, their use as medicaments and pharmaceutical compositions containing them |
EP0519211A1 (en) | 1991-05-17 | 1992-12-23 | Hoechst Schering AgrEvo GmbH | Substituted 4-aminopyrimidine, process for their preparation and their use as parasiticide |
DE4208254A1 (en) | 1992-03-14 | 1993-09-16 | Hoechst Ag | SUBSTITUTED PYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PEST CONTROL AND FUNGICIDE |
WO1993022291A1 (en) | 1992-04-24 | 1993-11-11 | E.I. Du Pont De Nemours And Company | Arthropodicidal and fungicidal aminopyrimidines |
US5595756A (en) | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
DE4437406A1 (en) | 1994-10-19 | 1996-04-25 | Hoechst Ag | Quinoxalines, process for their preparation and their use |
US5977117A (en) | 1996-01-05 | 1999-11-02 | Texas Biotechnology Corporation | Substituted phenyl compounds and derivatives thereof that modulate the activity of endothelin |
JP4495257B2 (en) | 1997-02-19 | 2010-06-30 | バーレツクス ラボラトリーズ インコーポレーテツド | N-heterocyclic derivatives as NOS inhibitors |
JPH10251255A (en) | 1997-03-14 | 1998-09-22 | Nissan Chem Ind Ltd | Azine derivative |
CA2291750A1 (en) | 1997-05-28 | 1998-12-03 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases |
DE19801598C2 (en) | 1998-01-17 | 2000-05-11 | Aventis Res & Tech Gmbh & Co | Catalytic synthesis of N-alkylated anilines from olefins and anilines |
DE19836697A1 (en) | 1998-08-13 | 2000-02-17 | Hoechst Marion Roussel De Gmbh | New substituted 4-amino-2-aryl-pyrimidines, are soluble guanylate cyclase activators useful e.g. for treating atherosclerosis, hypertension, angina pectoris, thrombosis, asthma or diabetes |
EP1147094A1 (en) | 1999-01-15 | 2001-10-24 | Novo Nordisk A/S | Non-peptide glp-1 agonists |
JP2003511378A (en) * | 1999-10-07 | 2003-03-25 | アムジエン・インコーポレーテツド | Triazine kinase inhibitors |
GB9924092D0 (en) | 1999-10-13 | 1999-12-15 | Zeneca Ltd | Pyrimidine derivatives |
US6552016B1 (en) | 1999-10-14 | 2003-04-22 | Curis, Inc. | Mediators of hedgehog signaling pathways, compositions and uses related thereto |
US6777413B2 (en) | 2000-02-01 | 2004-08-17 | Millennium Pharmaceuticals, Inc. | 2-[1H]-quinolone and 2-[1H]-quinoxalone inhibitors of factor Xa |
WO2001064642A2 (en) | 2000-02-29 | 2001-09-07 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor xa |
US6605615B2 (en) | 2000-03-01 | 2003-08-12 | Tularik Inc. | Hydrazones and analogs as cholesterol lowering agents |
DE10013318A1 (en) | 2000-03-17 | 2001-09-20 | Merck Patent Gmbh | Quinoxaline derivatives are used as photo-stable UV filters in cosmetic or pharmaceutical sunscreens for the hair or skin |
US7498304B2 (en) | 2000-06-16 | 2009-03-03 | Curis, Inc. | Angiogenesis-modulating compositions and uses |
EP1351946A2 (en) | 2000-09-01 | 2003-10-15 | Icos Corporation | Materials and methods to potentiate cancer treatment |
US6610677B2 (en) | 2000-09-15 | 2003-08-26 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US6613776B2 (en) | 2000-09-15 | 2003-09-02 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
CA2422371C (en) | 2000-09-15 | 2010-05-18 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US7473691B2 (en) | 2000-09-15 | 2009-01-06 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
WO2002046184A1 (en) | 2000-12-05 | 2002-06-13 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
US20030105090A1 (en) | 2000-12-21 | 2003-06-05 | David Bebbington | Pyrazole compounds useful as protein kinase inhibitors |
JP2004521901A (en) | 2001-02-02 | 2004-07-22 | グラクソ グループ リミテッド | Pyrazoles as TGF inhibitors |
MY130778A (en) | 2001-02-09 | 2007-07-31 | Vertex Pharma | Heterocyclic inhibitiors of erk2 and uses thereof |
JP4160401B2 (en) | 2001-03-29 | 2008-10-01 | バーテックス ファーマシューティカルズ インコーポレイテッド | Inhibitors of C-JUNN terminal kinase (JNK) and other protein kinases |
WO2002083667A2 (en) | 2001-04-13 | 2002-10-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
AU2002305205A1 (en) | 2001-04-20 | 2002-11-05 | Jingrong Cao | 9-deazaguanine derivatives as inhibitors of gsk-3 |
WO2002092573A2 (en) | 2001-05-16 | 2002-11-21 | Vertex Pharmaceuticals Incorporated | Heterocyclic substituted pyrazoles as inhibitors of src and other protein kinases |
US6762179B2 (en) | 2001-05-31 | 2004-07-13 | Vertex Pharmaceuticals Incorporated | Thiazole compounds useful as inhibitors of protein kinase |
ATE339418T1 (en) | 2001-06-01 | 2006-10-15 | Vertex Pharma | THIAZOLE COMPOUNDS THAT ARE SUITABLE AS INHIBITORS OF PROTEIN KINASES |
US6825190B2 (en) | 2001-06-15 | 2004-11-30 | Vertex Pharmaceuticals Incorporated | Protein kinase inhibitors and uses thereof |
DE60214198T2 (en) | 2001-07-03 | 2007-08-09 | Vertex Pharmaceuticals Inc., Cambridge | ISOXAZOLYL-PYRIMIDINES AS INHIBITORS OF SRC AND LCK PROTEIN KINASES |
DE60236322D1 (en) | 2001-12-07 | 2010-06-17 | Vertex Pharma | PYRIMIDIN-BASED COMPOUNDS AS A GSK-3 HEMMER |
CA2475633C (en) | 2002-02-06 | 2013-04-02 | Vertex Pharmaceuticals Incorporated | Heteroaryl compounds useful as inhibitors of gsk-3 |
US20030199525A1 (en) | 2002-03-21 | 2003-10-23 | Hirst Gavin C. | Kinase inhibitors |
US20030207873A1 (en) | 2002-04-10 | 2003-11-06 | Edmund Harrington | Inhibitors of Src and other protein kinases |
US7304061B2 (en) | 2002-04-26 | 2007-12-04 | Vertex Pharmaceuticals Incorporated | Heterocyclic inhibitors of ERK2 and uses thereof |
KR20050006237A (en) | 2002-05-06 | 2005-01-15 | 버텍스 파마슈티칼스 인코포레이티드 | Thiadiazoles or oxadiazoles and their use as inhibitors of JAK protein kinase |
MXPA04011956A (en) | 2002-05-30 | 2005-03-31 | Vertex Pharma | Inhibitors of jak and cdk2 protein kinases. |
MY141867A (en) | 2002-06-20 | 2010-07-16 | Vertex Pharma | Substituted pyrimidines useful as protein kinase inhibitors |
US20040208608A1 (en) | 2002-06-24 | 2004-10-21 | Alex Tager | Dispersion compensation architecture for switch-ready optical networks |
WO2004005283A1 (en) | 2002-07-09 | 2004-01-15 | Vertex Pharmaceuticals Incorporated | Imidazoles, oxazoles and thiazoles with protein kinase inhibiting activities |
PL375447A1 (en) | 2002-08-14 | 2005-11-28 | Vertex Pharmaceuticals Incorporated | Protein kinase inhibitors and uses thereof |
US7419984B2 (en) | 2002-10-17 | 2008-09-02 | Cell Therapeutics, Inc. | Pyrimidines and uses thereof |
AU2003286876A1 (en) | 2002-11-01 | 2004-06-07 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of jak and other protein kinases |
CA2506773A1 (en) | 2002-11-04 | 2004-05-21 | Vertex Pharmaceuticals Incorporated | Heteroaryl-pyramidine derivatives as jak inhibitors |
EP1581526B1 (en) | 2002-12-18 | 2009-03-11 | Vertex Pharmaceuticals Incorporated | Benzisoxazole derivatives useful as inhibitors of protein kinases |
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
CA2514092C (en) | 2003-01-21 | 2013-03-19 | S.S.C.I., Inc. | Novel cocrystallization of hydrochloric acid salt of an active agent |
EP1611125A1 (en) | 2003-02-07 | 2006-01-04 | Vertex Pharmaceuticals Incorporated | Heteroaryl substituted pyrolls useful as inhibitors of protein kinases |
WO2004083203A1 (en) | 2003-03-13 | 2004-09-30 | Vertex Pharmaceuticals Incorporated | Compositions useful as protein kinase inhibitors |
US8404681B2 (en) | 2003-03-24 | 2013-03-26 | Luitpold Pharmaceuticals, Inc. | Xanthones, thioxanthones and acridinones as DNA-PK inhibitors |
JP2006524688A (en) | 2003-03-25 | 2006-11-02 | バーテックス ファーマシューティカルズ インコーポレイテッド | Thiazoles useful as protein kinase inhibitors |
US6875781B2 (en) | 2003-04-04 | 2005-04-05 | Cell Therapeutics, Inc. | Pyridines and uses thereof |
US7189724B2 (en) | 2003-04-15 | 2007-03-13 | Valeant Research And Development | Quinoxaline derivatives having antiviral activity |
EP1697375A2 (en) | 2003-12-02 | 2006-09-06 | Vertex Pharmaceuticals Incorporated | Heterocyclic protein kinase inhibitors and uses thereof |
CA2548172A1 (en) | 2003-12-04 | 2005-06-23 | Vertex Pharmaceuticals Incorporated | Quinoxalines useful as inhibitors of protein kinases |
TW200533357A (en) | 2004-01-08 | 2005-10-16 | Millennium Pharm Inc | 2-(amino-substituted)-4-aryl pyrimidines and related compounds useful for treating inflammatory diseases |
PT1729770E (en) | 2004-03-15 | 2010-02-08 | Sunesis Pharmaceuticals Inc | Sns-595 and methods of using the same |
GB0405985D0 (en) | 2004-03-17 | 2004-04-21 | Novartis Forschungsstiftung | Kinase |
MXPA06013208A (en) | 2004-05-14 | 2007-01-16 | Vertex Pharma | Prodrugs of pyrrolylpyrimidine erk protein kinase inhibitors. |
JP4449580B2 (en) | 2004-05-31 | 2010-04-14 | 宇部興産株式会社 | 4-Aralkylaminopyrimidine derivatives and antibacterial agents |
DK1756084T3 (en) | 2004-06-04 | 2009-03-23 | Arena Pharm Inc | Substituted aryl and heteroaryl derivatives as modulators of metabolism and the prevention and treatment of disorders related thereto |
CN101039933B (en) | 2004-09-17 | 2012-06-06 | 沃泰克斯药物股份有限公司 | Diaminotriazole compounds useful as protein kinase inhibitors |
EP1812071A2 (en) | 2004-10-13 | 2007-08-01 | PTC Therapeutics, Inc. | Compounds for nonsense suppression, use of these compounds for the manufacture of a medicament for treating somatic mutation-related diseases |
WO2006040568A1 (en) | 2004-10-15 | 2006-04-20 | Astrazeneca Ab | Quinoxalines as b raf inhibitors |
HN2005000795A (en) | 2004-10-15 | 2010-08-19 | Aventis Pharma Inc | PYRIMIDINS AS ANTAGONISTS OF PROSTAGLANDINA D2 RECEPTOR |
US20060166936A1 (en) | 2004-10-29 | 2006-07-27 | Hayley Binch | Diaminotriazole compounds useful as inhibitors of protein kinases |
US7517870B2 (en) | 2004-12-03 | 2009-04-14 | Fondazione Telethon | Use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization |
US20060142572A1 (en) | 2004-12-14 | 2006-06-29 | Gabriel Martinez-Botella | Inhibitors of ERK protein kinase and uses thereof |
EP1833820A1 (en) | 2004-12-23 | 2007-09-19 | Vertex Pharmaceuticals Incorporated | Selective inhibitors of erk protein kinase and uses therof |
CA2597134C (en) | 2005-02-04 | 2015-05-26 | Senomyx, Inc. | Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions |
CN101184395A (en) | 2005-04-06 | 2008-05-21 | Irm责任有限公司 | Diarylamine-containing compounds and compositions, and their use as modulators of steroid hormone nuclear receptors |
AR053358A1 (en) | 2005-04-15 | 2007-05-02 | Cancer Rec Tech Ltd | DNA INHIBITORS - PK |
WO2006125616A2 (en) | 2005-05-25 | 2006-11-30 | Ingenium Pharmaceuticals Ag | Pyrimidine-based cdk inhibitors for treating pain |
WO2006138418A2 (en) | 2005-06-14 | 2006-12-28 | President And Fellows Of Harvard College | Improvement of cognitive performance with sirtuin activators |
JP2007008045A (en) | 2005-06-30 | 2007-01-18 | Mitsui Chemicals Inc | Optical recording medium and 1h-quinoxaline-2-on derivative |
US7874452B2 (en) | 2005-07-22 | 2011-01-25 | Berkeley Law & Technology Group, Llp | Cup cover |
WO2007014250A2 (en) | 2005-07-26 | 2007-02-01 | Vertex Pharmaceuticals Incorporated | Abl kinase inhibition |
GB0520657D0 (en) | 2005-10-11 | 2005-11-16 | Ludwig Inst Cancer Res | Pharmaceutical compounds |
JP2009514875A (en) | 2005-11-02 | 2009-04-09 | サイトキネティクス・インコーポレーテッド | Chemicals, compositions and methods |
BRPI0619708A2 (en) | 2005-11-03 | 2011-10-11 | Vertex Pharma | compound, composition, method for inhibiting aurora kinase activity in a biological sample, method for treating proliferative disorder and method for treating cancer |
CN101360740A (en) | 2005-11-16 | 2009-02-04 | 沃泰克斯药物股份有限公司 | Aminopyrimidines useful as kinase inhibitors |
WO2007082899A1 (en) | 2006-01-17 | 2007-07-26 | Vib Vzw | Inhibitors of prolyl-hydroxylase 1 for the treatment of skeletal muscle degeneration |
JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | PI-3 Kinase inhibitors and methods of their use |
UY30118A1 (en) | 2006-01-31 | 2007-06-29 | Tanabe Seiyaku Co | AMIS TRISUSTITUDE COMPUTER |
WO2007109783A2 (en) | 2006-03-23 | 2007-09-27 | Janssen Pharmaceutica, N.V. | Substituted pyrimidine kinase inhibitors |
US20080280891A1 (en) | 2006-06-27 | 2008-11-13 | Locus Pharmaceuticals, Inc. | Anti-cancer agents and uses thereof |
WO2008008852A2 (en) | 2006-07-11 | 2008-01-17 | Emory University | Cxcr4 antagonists including heteroatoms for the treatment of medical disorders |
TW200811134A (en) | 2006-07-12 | 2008-03-01 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
PE20080403A1 (en) | 2006-07-14 | 2008-04-25 | Amgen Inc | FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE |
WO2008006583A1 (en) | 2006-07-14 | 2008-01-17 | Novartis Ag | Pyrimidine derivatives as alk-5 inhibitors |
US7635683B2 (en) | 2006-08-04 | 2009-12-22 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl tripeptide hepatitis C virus inhibitors |
US8541428B2 (en) | 2006-08-22 | 2013-09-24 | Technion Research And Development Foundation Ltd. | Heterocyclic derivatives, pharmaceutical compositions and methods of use thereof |
EP1903038A1 (en) | 2006-09-07 | 2008-03-26 | Bayer Schering Pharma Aktiengesellschaft | N-(1-hetaryl-piperidin-4-yl)-(het)arylamide as EP2 receptor modulators |
US7875603B2 (en) | 2006-09-21 | 2011-01-25 | Nova Southeastern University | Specific inhibitors for vascular endothelial growth factor receptors |
DE102006050512A1 (en) | 2006-10-26 | 2008-04-30 | Bayer Healthcare Ag | New substituted dihydropyrazole- and dihydrotriazole derivatives are hypoxia-inducible transcription factor-prolyl-4-hydroxylase inhibitors useful to treat/prevent e.g. cardiovascular diseases, heart-circulation diseases and anemia |
AU2007317435A1 (en) | 2006-11-02 | 2008-05-15 | Vertex Pharmaceuticals Incorporated | Aminopyridines and aminopyrimidines useful as inhibitors of protein kinases |
CN101679371A (en) | 2006-12-04 | 2010-03-24 | 艾美罗股份公司 | Substituted pyrimidines as adenosine receptor antagonists |
NZ577768A (en) | 2006-12-19 | 2012-01-12 | Vertex Pharma | Aminopyrimidines useful as inhibitors of protein kinases |
JP2010514808A (en) | 2006-12-28 | 2010-05-06 | アンブルックス,インコーポレイテッド | Amino acids and polypeptides substituted with phenazine or quinoxaline |
CA2702647C (en) | 2007-01-31 | 2016-03-22 | Ym Biosciences Australia Pty Ltd | Thiopyrimidine-based compounds and uses thereof |
WO2008106202A1 (en) | 2007-02-27 | 2008-09-04 | Housey Gerard M | Theramutein modulators |
JP5393489B2 (en) | 2007-03-09 | 2014-01-22 | バーテックス ファーマシューティカルズ インコーポレイテッド | Aminopyrimidines useful as inhibitors of protein kinases |
JP2010520887A (en) | 2007-03-09 | 2010-06-17 | バーテックス ファーマシューティカルズ インコーポレイテッド | Aminopyridines useful as inhibitors of protein kinases |
ES2435997T3 (en) | 2007-03-09 | 2013-12-26 | Vertex Pharmaceuticals, Inc. | Aminopyrimidines useful as protein kinase inhibitors |
CN101675041A (en) | 2007-03-20 | 2010-03-17 | 沃泰克斯药物股份有限公司 | Amino-metadiazine compound as kinase inhibitor |
DE102007015169A1 (en) | 2007-03-27 | 2008-10-02 | Universität des Saarlandes Campus Saarbrücken | 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of hormone-dependent diseases |
JP2010523700A (en) | 2007-04-13 | 2010-07-15 | バーテックス ファーマシューティカルズ インコーポレイテッド | Aminopyrimidines useful as kinase inhibitors |
US7910587B2 (en) | 2007-04-26 | 2011-03-22 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl dipeptide hepatitis C virus inhibitors |
MX2009011811A (en) | 2007-05-02 | 2010-01-14 | Vertex Pharma | Aminopyrimidines useful as kinase inhibitors. |
WO2008137621A1 (en) | 2007-05-02 | 2008-11-13 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
MX2009011810A (en) | 2007-05-02 | 2010-01-14 | Vertex Pharma | Thiazoles and pyrazoles useful as kinase inhibitors. |
EP2150255A4 (en) | 2007-05-10 | 2011-10-05 | Glaxosmithkline Llc | Quinoxaline derivatives as p13 kinase inhibitors |
WO2008144253A1 (en) | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
MX2009012719A (en) | 2007-05-24 | 2010-02-04 | Vertex Pharma | Thiazoles and pyrazoles useful as kinase inhibitors. |
CN101687790B (en) | 2007-05-25 | 2015-02-11 | Abbvie公司 | Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mglu2 receptor) |
WO2009004621A1 (en) | 2007-07-02 | 2009-01-08 | Technion Research & Development Foundation Ltd. | Compositions, articles and methods comprising tspo ligands for preventing or reducing tobacco-associated damage |
EP2170338A2 (en) | 2007-07-06 | 2010-04-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Dna-pkcs modulates energy regulation and brain function |
UY31232A1 (en) | 2007-07-19 | 2009-03-02 | COMPOUNDS DERIVED FROM DIBENZOTIFENILAMINO-CROMEN-4-ACTIVE WAVES REPLACED AND ITS ISOMERS AND APPLICATIONS | |
AU2008283629B2 (en) | 2007-08-01 | 2013-03-21 | Ihara Chemical Industry Co., Ltd. | Oxopyrazine derivative and herbicide |
EP2190466A4 (en) | 2007-08-10 | 2011-12-21 | Burnham Inst Medical Research | Tissue-nonspecific alkaline phosphatase (tnap) activators and uses thereof |
DE102007044032A1 (en) | 2007-09-14 | 2009-03-19 | Bayer Healthcare Ag | New substituted heteroaryl compounds are hypoxia-inducible factor prolyl-4-hydroxylase inhibitors useful to treat and/or prevent e.g. circulatory heart diseases, heart failure, anemia, chronic kidney diseases and renal failure |
EP2212297B1 (en) | 2007-10-12 | 2011-05-25 | Ingenium Pharmaceuticals GmbH | Inhibitors of protein kinases |
CN101902912A (en) | 2007-11-06 | 2010-12-01 | 纳幕尔杜邦公司 | Fungicidal amines |
US20120009151A1 (en) | 2007-12-21 | 2012-01-12 | Progenics Pharmaceuticals, Inc. | Triazines And Related Compounds Having Antiviral Activity, Compositions And Methods Thereof |
CA2714743C (en) | 2008-02-19 | 2017-01-17 | Janssen Pharmaceutica N.V. | Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase |
EP2253618A1 (en) | 2008-02-27 | 2010-11-24 | Takeda Pharmaceutical Company Limited | Compound having 6-membered aromatic ring |
CN101952258B (en) | 2008-03-05 | 2014-03-19 | 默克专利有限公司 | Quinoxalinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes |
US8268834B2 (en) | 2008-03-19 | 2012-09-18 | Novartis Ag | Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme |
JPWO2009147990A1 (en) | 2008-06-02 | 2011-10-27 | Msd株式会社 | New isoxazole derivatives |
EP2285786B1 (en) | 2008-06-16 | 2013-10-09 | Merck Patent GmbH | Quinoxalinedione derivatives |
EP2138488A1 (en) * | 2008-06-26 | 2009-12-30 | sanofi-aventis | 4-(pyridin-4-yl)-1H-[1,3,5]triazin-2-one derivatives as GSK3-beta inhibitors for the treatment of neurodegenerative diseases |
JP2011529062A (en) | 2008-07-23 | 2011-12-01 | バーテックス ファーマシューティカルズ インコーポレイテッド | Pyrazolopyridine kinase inhibitor |
WO2010048149A2 (en) | 2008-10-20 | 2010-04-29 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
JP5743897B2 (en) | 2008-11-20 | 2015-07-01 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーGlaxoSmithKline LLC | Compound |
WO2010065899A2 (en) | 2008-12-05 | 2010-06-10 | Molecular Insight Pharmaceuticals, Inc. | Technetium-and rhenium-bis(heteroaryl)complexes and methods of use thereof |
PT3354650T (en) | 2008-12-19 | 2022-06-20 | Vertex Pharma | Compounds useful as inhibitors of atr kinase |
JP2012517448A (en) | 2009-02-11 | 2012-08-02 | リアクション バイオロジー コープ. | Selective kinase inhibitor |
JP2010111702A (en) | 2009-02-16 | 2010-05-20 | Tetsuya Nishio | Heterocyclic compound, method for producing the same and use thereof |
AR077468A1 (en) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | PIRAZOLO COMPOUNDS (1,5-A) PYRIMIDINE SUBSTITUTED AS TRK-QUINASA INHIBITORS |
US8906914B2 (en) | 2009-08-18 | 2014-12-09 | Janssen Pharmaceutica Nv | Ethylene diamine modulators of fatty acid hydrolase |
AR077999A1 (en) | 2009-09-02 | 2011-10-05 | Vifor Int Ag | ANTIGONISTS OF PYRIMIDIN AND TRIAZIN-HEPCIDINE |
IN2012DN03312A (en) | 2009-10-22 | 2015-10-23 | Fibrotech Therapeutics Pty Ltd | |
ES2360333B1 (en) | 2009-10-29 | 2012-05-04 | Consejo Superior De Investigaciones Cientificas (Csic) (70%) | DERIVATIVES OF BIS (ARALQUIL) AMINO AND AROMATICS SYSTEMS OF SIX MEMBERS AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE PATHOLOGIES, INCLUDING ALZHEIMER'S DISEASE |
WO2011052756A1 (en) | 2009-10-30 | 2011-05-05 | 持田製薬株式会社 | Novel 3-hydroxy-5-arylisoxazole derivative |
BR112012015612A2 (en) | 2009-12-25 | 2016-03-15 | Mochida Pharm Co Ltd | new 3-hydroxy-5-arylisothiazole derivative |
UY33213A (en) | 2010-02-18 | 2011-09-30 | Almirall Sa | PIRAZOL DERIVATIVES AS JAK INHIBITORS |
BR112012022868A2 (en) | 2010-03-16 | 2018-06-05 | Merck Patent Gmbh | morpholinylquinazolines |
TWI516264B (en) | 2010-05-06 | 2016-01-11 | 臺北醫學大學 | Aroylquinoline compounds |
JP2011246389A (en) | 2010-05-26 | 2011-12-08 | Oncotherapy Science Ltd | Condensed-ring pyrazole derivative having ttk inhibiting action |
DE102010025786A1 (en) | 2010-07-01 | 2012-01-05 | Merck Patent Gmbh | Pyrazolochinoline |
DE102010035744A1 (en) | 2010-08-28 | 2012-03-01 | Merck Patent Gmbh | Imidazolonylchinoline |
US9464065B2 (en) | 2011-03-24 | 2016-10-11 | The Scripps Research Institute | Compounds and methods for inducing chondrogenesis |
MX2013011450A (en) | 2011-04-05 | 2014-02-03 | Vertex Pharma | Aminopyrazine compounds useful as inhibitors of tra kinase. |
GB201114051D0 (en) | 2011-08-15 | 2011-09-28 | Domainex Ltd | Compounds and their uses |
WO2013032951A1 (en) | 2011-08-26 | 2013-03-07 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
JP6093768B2 (en) | 2011-09-14 | 2017-03-08 | ニューファーマ, インコーポレイテッド | Specific chemical entities, compositions and methods |
WO2013043935A1 (en) | 2011-09-21 | 2013-03-28 | Neupharma, Inc. | Certain chemical entites, compositions, and methods |
WO2013049701A1 (en) | 2011-09-30 | 2013-04-04 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
DE102011118830A1 (en) | 2011-11-18 | 2013-05-23 | Merck Patent Gmbh | Morpholinylbenzotriazine |
GB201120993D0 (en) | 2011-12-06 | 2012-01-18 | Imp Innovations Ltd | Novel compounds and their use in therapy |
WO2013112950A2 (en) | 2012-01-25 | 2013-08-01 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
RU2638540C1 (en) * | 2012-04-24 | 2017-12-14 | Вертекс Фармасьютикалз Инкорпорейтед | Dna-pk inhibitors |
EP2916838B1 (en) | 2012-11-12 | 2019-03-13 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
HRP20211855T1 (en) | 2013-03-12 | 2022-03-04 | Vertex Pharmaceuticals Incorporated | Dna-pk inhibitors |
PL3424920T3 (en) | 2013-10-17 | 2020-11-16 | Vertex Pharmaceuticals Incorporated | Co-crystals of (s)-n-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and deuterated derivatives thereof as dna-pk inhibitors |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005026129A1 (en) * | 2003-09-15 | 2005-03-24 | Gpc Biotech Ag | Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases |
WO2008042639A1 (en) * | 2006-10-02 | 2008-04-10 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
Non-Patent Citations (9)
Title |
---|
"Boronic Acids", 2005, WILEY-VCH |
"Handbook of Chemistry and Physics", 1994 |
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS |
"The ACS Style Guide: A Manual for Authors and Editors", 1997, AMERICAN CHEMICAL SOCIETY |
DENMARK SE ET AL., J. AM. CHEM. SOC., vol. 132, 2010, pages 3612 - 3620 |
EVANS D.A. ET AL., J. AM. CHEM. SOC., vol. 104, 1982, pages 1737 - 1739 |
GREENE; WUTS: "Protective Groups In Organic Synthesis", 1999, JOHN WILEY & SONS |
MATSUMOTO T ET AL., BULL. CHEM. SOC. JPN., vol. 58, 1985, pages 340 - 345 |
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS |
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