WO2004046118A2 - 2-4-(di-phenyl-amino)-pyrimidine derivatives useful for treating hyper-proliferative disorders - Google Patents

2-4-(di-phenyl-amino)-pyrimidine derivatives useful for treating hyper-proliferative disorders Download PDF

Info

Publication number
WO2004046118A2
WO2004046118A2 PCT/US2003/014294 US0314294W WO2004046118A2 WO 2004046118 A2 WO2004046118 A2 WO 2004046118A2 US 0314294 W US0314294 W US 0314294W WO 2004046118 A2 WO2004046118 A2 WO 2004046118A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
optionally substituted
phenyl
halo
Prior art date
Application number
PCT/US2003/014294
Other languages
French (fr)
Other versions
WO2004046118A3 (en
Inventor
Jill E. Wood
Donald Bierer
Brian Bear
Catherine Brennan
Brent Chandler
Gang Chen
Yuanwei Chen
Julie Dixon
Wenlang Fu
Leatte Guernon
Donglei Liu
Andrea Mcclure
Karl Miranda
Dhanapalan Nagarathnam
Robert Sibley
Michael Turner
Sharad Verma
Chunguang Wang
Lin Yi
Jin Zhao
Qingming Zhu
Original Assignee
Bayer Pharmaceuticals Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharmaceuticals Corporation filed Critical Bayer Pharmaceuticals Corporation
Priority to AU2003299474A priority Critical patent/AU2003299474A1/en
Publication of WO2004046118A2 publication Critical patent/WO2004046118A2/en
Publication of WO2004046118A3 publication Critical patent/WO2004046118A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to novel 2-4-(diphenyl-amino)-pyrimidinyl compounds, pharmaceutical compositions containing such compounds, and the use of those compounds and/or compositions for treating hyper-proliferative disorders.
  • X is selected from (C C 3 )alkyl, CF 3 , and halo;
  • R 1 is H, OH, halo, CF 3 , C(O)R 10 , NR 11 R 11 ,C(NH)NH 2 , C(N)OH, C(N)(C C 3 )alkoxy, S(O) 2 (C C 6 )alkyl, S(O) 2 NH 2 , indolyl, pyridyl, quinolyl,
  • R 2 is H, S(O) 2 NH 2 , halo, ethynyl, OH, CF 3 , C(O)R 10 , a five membered heterocycle, benzodioxolyl, (C C 6 )alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
  • R 1 and R 2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
  • R 3 is selected from H, (C C 6 )alkyl, halo, S(O) 2 NH 2 , C(O)(C C 3 )alkyl, CF 3 , morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected
  • R 4 is selected from H, halo, ethynyl, C(O)(CrC 3 )alkyl, or with pyrazolyl optionally substituted with 1 or 2 independently selected (C C 6 )alkyl groups, or (C*
  • R 3 and R 4 together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substituted with (C*,-C 6 )alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C 3 )alkyl] 2 , and (C C 3 )alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole optionally substituted with 1 or 2 independently selected
  • R 5 , R 6 and R 7 must be H;
  • R 5 and R 6 are each independently selected from H, halo, and CF 3 ;
  • R 7 is H, halo or (C C 6 )alkoxy;
  • R 8 is H, (C C 6 )alkyl, (C r C 6 )alkoxy, or halo;
  • R 9 is H, or (C C 3 )alkoxy
  • R 10 is (C C 6 )alkyl, OH, NH 2 , NHOR 2 ,
  • R 11 is selected from H, C(O)R 10 , S(O) 2 (CrC 3 )alkyl, S(O) 2 N[(C C 3 )alkyl] 2 , S(O) 2 -five membered heterocycle said heterocycle being optionally substituted with (d-C 6 )alkyl and NHC(O) (C ⁇ -C 3 )alkyl
  • R 12 is selected from H, (C**-C 3 )alkyl, and tetrahydropyranyl;
  • Y is N[(C**-C 6 )alkyl] 2 , imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, NH-phenyl-(C C 6 )alkoxy, NH-O-phenyl-(C 1 -C 6 )alkoxy? or
  • R 4 must be selected from morpholinyl, pyrazolyl, and optionally substituted O- phenyl, or R 3 and R 4 together with the C atoms to which each is attached, must form a ring that is fused to the phenyl group to which they are attached to form optionally substituted indolyl or benzotriazole; or a pharmaceutically acceptable salt thereof.
  • a prefered embodiment of this invention is a compound of Formula I wherein X is halo, R 1 is selected from H, OH, C(O)R 10 , NR 11 R 11 , C(N)OH, C(N)(C C 6 )alkoxy, indolyl, pyridyl, quinolyl, (C C 6 )alkyl optionally substituted with C(O)OH, (N)(C 1 -C 3 )alkoxy, or with a five membered N containing heterocycle, (C* t -C 6 )alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C**-C 3 )alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
  • R 2 is selected from H, OH, CF 3 , C(O)R 10 , a five membered heterocycle, (C C 6 )alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
  • R 1 and R 2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
  • (C C 3 )alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl;
  • R 3 is selected from H, (C 1 -C 6 )alkyl, halo, C(O)(C*rC 3 )alkyl, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected (C C 6 )alkyl groups,
  • R 4 is selected from H, halo, ethynyl, C(O)(C C 3 )alkyl, (C*rC 6 )alkoxy optionally substituted with 1 or 2 OH group(s), and pyrazolyl optionally substituted with 1 or 2 independently selected (C C 6 )alkyl groups;
  • R 3 and R 4 together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with
  • (C C 6 )alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(CrC 3 )alkyl] 2 , and (C C 3 )alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole;
  • R 5 and R 6 are each H;
  • R 7 is selected from H, halo and (C**-C 6 )alkoxy;
  • R 8 is H
  • R 9 is selected from H and (C**-C 3 )alkoxy
  • R 10 is selected from (C*,-C 6 )alkyl, NHOR 12 , (C C 6 )alkoxy and NH(C C 6 )alkyl optionally substituted with 1 or 2 OH group(s);
  • R 11 is selected from H, C(O)R 10 , S(O) 2 (C C 3 )alkyl, S(O) 2 N[(C C 3 )alkyl] 2 , and
  • Y is selected from N[(C-
  • (CrC 3 )alkyl and “(CrC 6 )alkyl”, mean linear or branched saturated carbon groups having from about 1 to about 3 or about 6 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, r/-butyl, isobutyl, sec-butyl, fe/t-butyl, and the like.
  • the terms “(C C 3 )alkoxy” and “(C C 6 )alkoxy” mean a linear or branched saturated carbon group having from about 1 to about 3 or about 6 C atoms, said carbon group being attached to an O atom.
  • the O atom is the point of attachment of the alkoxy substituent to the pyridyl ring.
  • alkoxy substituents include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ferf-butoxy, and the like.
  • (C C 6 )alkyl optionally substituted” and “(C C 6 )alkoxy optionally substituted” mean an alkyl group or an alkoxy group, respectively, as defined above, wherein each C atom is bonded to 1 , 2 or 3 H atoms, as appropriate, or any H atom up to about the recited maximum number of H atoms on a C atom may be replaced with a recited substituent, or the alkyl or alkoxy groups may be substituted as otherwise described herein, with the proviso that combinations of recited substituents result in a chemically stable compound.
  • five membered heterocycle means an aromatic, saturated or partially saturated ring containing about 5 atoms and having 1 , 2 or 3 heteroatom(s) each selected independently from O, N, and S, the rest being C atoms, with the proviso that there can be no more than 1 O atom or 1 S atom in the heterocycle.
  • This heterocycle is attached through any available C or N atom to the rest of the molecule and is optionally substituted at any available C or N atom with the recited substituents.
  • Such groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and the like, in all their possible isomeric forms.
  • the term "six membered heterocycle” means a saturated or partially unsaturated ring containing about 6 atoms, 1 or 2 of which are each independently selected from N, O, and S, the rest being C atoms. There can be no more than 2 O atoms or 2 S atoms in any heterocycle, and when there are 2 O atoms in a heterocycle, they must be non- adjacent. This ring is attached through any available C or N atom to the rest of the molecule and is optionally substituted with the recited substituents on any available C and/or N atom.
  • This heterocycle includes piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl and the like.
  • N containing heterocycle means a saturated or partially saturated ring containing about 5 atoms, 1 , 2, or 3 of which are N atoms, the rest being C, where the heterocycle is attached through any available C or N atom to the rest of the molecule.
  • groups include imidazolyl, pyrrolidinyl, and the like.
  • fused ring means a group having from 9 to 14 atoms divided into 2 or 3 chemically stable rings, one of which is the phenyl ring to which R 1 and R 2 are attached.
  • Each ring is fused to another ring through adjacent C, C-N or N atoms and 3, 2 or 1 of the remaining atoms, respectively, in the fused ring are heteroatoms each independently selected from N or O, with the proviso that there can be no more than 1 O atom in any fused heterocycle.
  • the heteroatoms may be located at any available position in the fused moiety other than in the phenyl ring to which R 1 and R 2 are attached.
  • the fused ring is bicyclic, the one ring that is fused to the phenyl ring to which R 1 and R 2 are attached may be either aromatic, partially saturated or saturated. That is, if the one ring stood alone, it could be either aromatic partially saturated, or saturated.
  • the fused ring When the fused ring is tri-cyclic, the bicyclic ring that is fused to the phenyl ring to which R 1 and R 2 are attached may be either unsaturated or partially saturated. That is, if the bicyclic ring stood alone, it could be either partially saturated or saturated.
  • the resulting fused bi- or tri-cyclic ring is optionally substituted with the recited substituents at any available C and/or N atom(s).
  • Such groups include but are not limited to benzimidazolyl, benzimidazoly-2-one, indolin-2-one, benzotriazolyl, dihydrobenzoindazolyl, dihydrobenzodioxinyl, dihydroinden-1-oneoxime, dihydronaphthalenone, dihydrobenzoindazolyl, tetrahydropyrrolobenzoxazinyl, indazolyl, benzotriazolyl, benzocyclopentyl, benzocyclohexyl, indolyl and the like.
  • the substituent(s) may be attached to the phenyl ring at any available C atom, preferably at the 3, 4, or 5 C.
  • substituents on a phenyl ring each is selected independently from the other so that they may be the same or different.
  • HPLC - electrospray mass spectra for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 1200 amu using a variable ion time according to the number of ions in the source.
  • the eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient eiution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention.
  • Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity.
  • Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the use of pharmaceutically acceptable salts of the compounds of Formula I are also within the scope of this invention.
  • pharmaceutically acceptable salt refers to either inorganic or organic acid or base salts of a compound of the present invention that have properties acceptable for the therapeutic use intended. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides including benzyl and phenethyl bromides, and others. Unless the context clearly indicates to the contrary, whenever the term
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods.
  • the following preparative methods are presented as an example of the synthesis of the compounds of the present invention.
  • R 1 -R 9 and X groups have the same meaning as defined above for Formula I.
  • compounds of Formula (I) can be prepared in two steps. In the first step, a dichloropyrimidine, (Intermediate A), is allowed to react with an optionally substituted aniline or phenylalkylamine (Intermediate B) in the presence of a basic catalyst to give Intermediate C. In step two, Intermediate C is allowed to react with an aniline, represented as Intermediate D, in the presence of an acid catalyst.
  • Celite ® diatomaceous earth filtering agent registered trademark of Celite Corp
  • PS-NCO polystyrene isocyanate R f TLC retention factor rt room temperature
  • the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
  • Thin-layer chromatography (TLC) was performed on Whatman ® pre-coated glass- backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was performed using 230- 400 mesh EM Science ® silica gel.
  • Proton ( 1 H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric G/V-Omega 300 (300 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or residual protonated solvent (CHCI 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • Carbon ( 13 C) NMR spectra were measured with a General Electric G ⁇ /-Omega 300 (75 MHz) spectrometer with solvent (CDCI 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as standard.
  • HPLC - electrospray mass spectra for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient eiution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
  • the compound was prepared by reaction of 5-nitroindole (1.0 equiv) with [(4R)- 2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate (5.0 equiv) in the presence of cesium carbonate(2.0 equiv) in DMF at 80 °C for 48 h. A similar procedure is described in more detail in Method 4 below.
  • Step 1 Preparation of ⁇ /'- ⁇ 4- (2E)-3-(dimethylamino)-2-propenoyllphenyl)-A/,JV- dimethylimidoformamide
  • Step 1 Preparation of 8-nitro-2,3-dihydro-5H-1.4-benzodioxepin-5-one.
  • Step 1a Toluene-4-sulfonic acid (S,-2,2-dimethyl-ri ,31dioxolan-4-yl methyl ester
  • the solution was stirred and allowed to warm to room temperature overnight, then was poured into a mixture of water (120 mL) and hexane (240 mL) stirring in ice water.
  • the 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed successively with water (75 mL), then brine (75 mL) before drying over anhydrous sodium sulfate.
  • the 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed successively with water (75 mL), then brine (75 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded toluene-4- sulfonic acid (ft)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as a thick yellow oil; 1 H NMR shows the presence of residual p-toluenesulfonyl chloride.
  • Step 2 1-((S,-2.2-Dimethyl-ri .31dioxolan-4-ylmethyl ,-5-nitro-1 H-indole
  • Step 1 To 3-nitrophenol (10.00 g, 7 mmol) in EtOH (50 mL) was added sodium hydroxide (3.59 g, 9 mmol) in water (4 mL) and the reaction was heated to 80 °C for 10 min. To this was added 3-chloro-1 ,2-propanediol (3.59 g, 9 mmol) and the reaction was stirred at 80 °C for 18 h. It was then allowed to cool to room temperature, taken up in EtOAc, washed with 1N NaOH, washed with brine, dried with MgSO 4 , filtered and concentrated to give 14.92 g of 3-(3-nitrophenoxy)-1 ,2-propanediol (97%). Step 2.
  • Method 1b o a solution of K 2 CO 3 (44.5 g, 322 mmol) in water (125 mL) and /-PA (375 mL), were added 5-bromo-2,4-dichloropyrimidine (25.0 g, 108 mmol) and 4- fluroaniline (12.0 g, 107 mmol). The mixture was stirred at room temperature for 18 h then water (3000 mL) was added and the product was precipitated out. Filtered and dried to give 30.0 g (90%) 5-bromo-2-chloro-4-[(4-fluorophenyl)amino]-pyrimidine as a pale yellow powder. Step 2.
  • Method 1d In a 40 mL EPA vial, 100 mg (1 equivalent) of the 4-substituted pyrimidine intermediate was mixed with the calculated amount of amine (2 equivalent) in 2 mL 1 N HCI. The reaction mixture was capped and heated at 100 °C in a J-Kem Block with shaking for 1 or 2 days. After the reaction was completed, DMSO was added into the reaction mixture to dissolve all of the precipitate, then Et 3 N was added dropwise until the mixture was basic. After these steps, the mixture was purified by preparative HPLC.
  • the solid was vigorously stirred in a mixture of ethyl acetate (300 mL) and water (100 mL), sodium bicarbonate (2 g; 23.8 mmol) was added, and the mixture stirred until no undissolved solid remained.
  • the 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed with brine (100 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded solid, which was triturated and washed with dichloromethane; the filtrate was applied to a column of silica gel. The column was eluted with dichloromethane, then a methanol/ dichloromethane solvent gradient (1-5%).
  • Trifluoroacetic acid 150 mL; 1.94 mol was added to a suspension of 5-bromo-
  • the reaction mixture was partitioned between ethyl acetate (250 mL) and brine (500 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 125 mL).
  • the combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (anhydrous sodium sulfate), then filtered through a pad of silica gel. The pad was eluted with ethyl acetate, and the filtrate concentrated in vacuo to afford crude product.
  • Trifluoroacetic acid 160 mL; 2.08 mol was added to a suspension of 5-bromo- ⁇ / 2 -[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-/v -(4-fluoro-phenyl)- pyrimidine-2,4-diamine (10.9 g; 0.02 mol) in methanol (640 mL), stirring under argon. After stirring at room temperature overnight, the mixture was concentrated in vacuo.
  • reaction mixture was partitioned between ethyl acetate (150 mL) and brine (450 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 100 mL).
  • the combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (anhydrous sodium sulfate), then filtered through a pad of silica gel. The pad was eluted with ethyl acetate, and the filtrate concentrated in vacuo to afford crude product.
  • Trifluoroacetic acid 200 mL; 2.6 mol was added to a suspension of 5-bromo- ⁇ / 2 - [3-((/ : ?)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-phenyl]-/V 4 -(4-fluoro-phenyl)-pyrimidine- 2,4-diamine (13.71 g; 0.03 mol) in methanol (800 mL), stirring under argon. After stirring for 2 h at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between water, ethanol and dichloromethane, and the phases separated; upon washing the organic phase with brine, solid formed.
  • the amide was combined with thionyl chloride and methylene chloride. The reaction mixture was allowed to stir for 30 minutes and then warmed to room temperature. The mixture was concentrated and then dissolved in DMSO for HPLC purification.
  • Step 1 Preparation of 2.5-dichloro-A/-(4-fluorophenyl)-4-pyrimidinamine
  • Step 3 Preparation of ⁇ 5-bromo-4-r(4-methoxyphenyl)aminolpyrimidin-2-yl.(4-imidazolyl- 3-methylphenyl, amine
  • a desired salt can be prepared by separately reacting the purified compound in its free base or free acid form with a suitable organic or inorganic acid, or suitable organic or inorganic base, respectively, and isolating the salt thus formed.
  • the free base is treated with anhydrous HCI in a suitable solvent such as THF, and the salt isolated as a hydrochloride salt.
  • the salts may be obtained, for example, by treatment of the free acid with anhydrous ammonia in a suitable solvent such as ether and subsequent isolation of the ammonium salt.
  • compositions of the compounds of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment (including prophylactic treatment) for the particular condition or disease. Therefore, another embodiment of the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt or ester thereof, of the present invention.
  • a pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical • compositions.
  • the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn star
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • Additional excipients for example those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as
  • oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil.
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosucci nates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers
  • compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11 , 1991 , incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011 ,472, issued April 30, 1991.
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F 2 , F 2 CIC-CCIF 2 and CCIF 3 ); air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methyl
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not
  • compositions according to the present invention can be illustrated as follows: Sterile Injectable Solution
  • a suitable amount of pure active ingredient is dissolved in sterile, injectable water to a desired concentration, for example from about 1.0 mg/ml to about 50.0 mg/ml.
  • U.S.P. grade sodium chloride crystals (NaCI) is added to the solution such that the final concentration of NaCI is 0.9% by weight of water.
  • the pH of the solution is adjusted to range between approximately pH 2.0 and pH 6.0 by the addition of pure (99.999%purity) hydrochloric acid.
  • the solution is sterilized via filtration through a sterile 0.22 micron filter.
  • the sterile solution is stored in sealed sterile vials wherein each vial contains the desired dosage unit of active ingredient per ml of injection solution.
  • U.S.P. grade sodium chloride (NaCI) is dissolved in sterile, injectable water to a final concentration of 0.9% NaCI by weight of water.
  • An amount of pure (99.999% purity) hydrochloric acid is added to the NaCI solution to obtain a final pH in the range of approximately pH2.0 to pH6.0.
  • An amount of U.S.P. grade potassium chloride crystals (KCL) is dissolved in the solution such that the final concentration of KCI is 0.1% by weight.
  • From 0.5 part to about thirty parts by weight of active ingredient (depending on the desired end dosage unit) is added to the solution and is completely dissolved by agitation.
  • the pH of the solution is adjusted again to between pH2.0 and pH6.0 using pure hydrochloric acid.
  • the solution is sterilized via filtration through a sterile 0.22 micron filter and stored in sealed sterile injection vials, each containing approximately 0.5 mg to approximately 30 mg active ingredient, depending on the final dosage unit desired in the sterile injection solution.
  • Sterile IV Solution A 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.
  • Lyophilized powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
  • a large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the present invention also relates to a method of using the compounds or compositions described herein for the treatment or prevention of, or in the manufacture of a medicament for treating or preventing, mammalian hyper-proliferative disorders.
  • This method comprises administering to a mammalian patient, including a human, in need thereof, an amount of a compound, a pharmaceutically acceptable salt thereof, or a composition of this invention that is effective to treat or prevent the disorder.
  • the present invention also relates to a method for using the compounds and compositions of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to delay or diminish the onset of the disorder.
  • Hyper-proliferative disorders include diseases or conditions whose progression proceeds, at least in part, via proliferation.
  • Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma
  • liver cell carcinomas with or without fibrolamellar variant liver cell carcinomas with or without fibrolamellar variant
  • cholangiocarcinoma intrahepatic bile duct carcinoma
  • mixed hepatocellular cholangiocarcinoma mixed hepatocellular cholangiocarcinoma
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, and also exist with a similar etiology in other mammals which can also be treated by the administration of the compounds and/or pharmaceutical compositions of the present invention.
  • the utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
  • the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
  • taxol Silvestrini et al. Stem Cells 1993, 11(6), 528-35
  • taxotere Bissery et al. Anti Cancer Drugs 1995, 6(3), 339
  • topoisomerase inhibitors Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93 were demonstrated with the use of in vitro tumor proliferation assays.
  • the following assays are two methods by which compound activity relating to treatment of the disorders identified herein can be determined.
  • CCG Protocol HCT-116 cells are seeded onto a 96-well culture plate at a density of 3000 cells per well in 100 uL DMEM medium supplemented with 10% Fetal Calf Serum and incubated overnight at 37°C in 5% CO 2 in a humidified incubator. T 0 CTG measurements are taken as described below. Cells are then treated with test compounds serially diluted at 10, 3.3, 1.1 , 0.33, 0.11 , and 0.033uM and incubated for 3 days at 37°C in 5% CO 2 in a humidified incubator. Final concentration of DMSO in each well is 0.1 %.
  • This assay may also be run using HT1080 or DLD-1 cell lines following the same procedure.
  • D diameter of the tumor at major axis
  • d diameter of the tumor at minor axis
  • the effective dosage of the compounds of this invention can readily be determined for prevention and/or treatment of each desired indication.
  • the amount of the active ingredient to be administered in the prevention and/or treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the duration of treatment (including prophylactic treatment), the age and sex of the patient treated, and the nature and extent of the condition to be prevented and/or treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 300 mg/kg, and preferably from about 0.10 mg/kg to about 150 mg/kg body weight per day.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
  • the daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of administration and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional prevention and/or treatment tests.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with other anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment and/or prevention of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by
  • anti-hyper-proliferative agents suitable for use with the composition of this invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.

Abstract

The present invention relates to a 2-4-(diphenyl-amino)-pyrimidinyl compound of Formula I useful for treating hyper-proliferative disorders.

Description

2-4-(Di-Phenyl-Amino,-Pyrimidine Derivatives Useful For Treating Hyper-Proliferative
Disorders
This application claims priority from US provisional application 06/378329, filed May 6, 2002.
Field of the Invention This invention relates to novel 2-4-(diphenyl-amino)-pyrimidinyl compounds, pharmaceutical compositions containing such compounds, and the use of those compounds and/or compositions for treating hyper-proliferative disorders.
Description of the Invention Compounds of the Invention One embodiment of this invention is a compound of Formula I
Figure imgf000002_0001
(I) wherein
X is selected from (C C3)alkyl, CF3, and halo;
R1 is H, OH, halo, CF3, C(O)R10, NR11R11,C(NH)NH2, C(N)OH, C(N)(C C3)alkoxy, S(O)2(C C6)alkyl, S(O)2NH2, indolyl, pyridyl, quinolyl,
(C C6)alkyl optionally substituted with C(O)OH, (N)(C C3)alkoxy, or with a five membered N containing heterocycle,
(C*|-C6)alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C-*-C3)alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
2 independently selected (C*ι-C6)alkyl group(s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C(O)OH, C(O)(C C3)alkyl, S(O)2(C C6)alkyl, S(O)2-phenyl said phenyl being optionally substituted with 1 or 2 independently selected halo atoms, or (C*rC6)alky[ optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (C C6)alkoxy, CF3, CN, N[(C*ι-C6)alkyl]2 group, and
(C C3)alkyl optionally substituted with CN, and O-pyridyl optionally substituted with halo or (C C3)alkoxy; R2 is H, S(O)2NH2, halo, ethynyl, OH, CF3, C(O)R10, a five membered heterocycle, benzodioxolyl, (C C6)alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
NH(C*ι-C6)alkyl optionally substituted with 1 or 2 OH groups, or with (C*rC3)alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C C6)alkoxy optionally substituted with 1 or 2 substituents selected from
N[(C*rC6)alkyl]2, OH and (C**-C3)aIkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperidinyl, NH(C*,-C6)alkyl-six membered heterocycle optionally substituted with C(O)OH, C(O)(C C3)alkyl, S(O)2(C C6)alkyl,
S(O)2-phenyl said phenyl being optionally substituted at any available C atom with 1 or 2 independently selected halo atoms, or with (C C6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with 1 or 2 substituents independently selected from
(Cι-C6)alkoxy, CN and halo, and pyrazole optionally substituted with (C C6)alkyl; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
(C C3)alkyl, (N)(C C3)alkoxy, (C1-C3)alkyl-N[(C C3)alkyl]2, C(O)NH2, (N)OH, OH and SH, and when the fused ring is indolyl, it may also be substituted with (C*ι-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C3)alkyl]2, and (C C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R3 is selected from H, (C C6)alkyl, halo, S(O)2NH2, C(O)(C C3)alkyl, CF3, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected
(C C6)alkyl groups, O-phenyl said phenyl being optionally substituted with halo, (C C3)alkoxy, or
C(O)O(C C3)alkyl, (C*|-C6)alkoxy optionally substituted with 1 or 2 substituents each independently selected from OH and (C*ι-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R4 is selected from H, halo, ethynyl, C(O)(CrC3)alkyl, or with pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups, or (C*|-C6)alkoxy optionally substituted with 1 or 2 OH group(s);
R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substituted with (C*,-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C3)alkyl]2, and (C C3)alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole optionally substituted with 1 or 2 independently selected
(C C6)alkyl group(s); and with the proviso that when R3 and R4 together form a cyclic moiety fused to the phenyl ring to which they are attached, then R5, R6 and R7 must be H; R5 and R6 are each independently selected from H, halo, and CF3; R7 is H, halo or (C C6)alkoxy;
R8 is H, (C C6)alkyl, (CrC6)alkoxy, or halo;
R9 is H, or (C C3)alkoxy;
R10 is (C C6)alkyl, OH, NH2, NHOR 2,
NHNHC(O)(C C6)alkyl optionally substituted with CN, or NH(C C6)alkyl optionally substituted with 1 or 2 OH group(s);
R11 is selected from H, C(O)R10, S(O)2(CrC3)alkyl, S(O)2N[(C C3)alkyl]2, S(O)2-five membered heterocycle said heterocycle being optionally substituted with (d-C6)alkyl and NHC(O) (Cι-C3)alkyl, R12 is selected from H, (C**-C3)alkyl, and tetrahydropyranyl; Y is N[(C**-C6)alkyl]2, imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, NH-phenyl-(C C6)alkoxy, NH-O-phenyl-(C1-C6)alkoxy? or
NH-(C*ι-C6)alkoxy-phenyl; with the provisos that a) when R1 is H then R2 must be other than H; b) when R2 is H then R1 must be other than H; c) when R3 is H then R4 must be other than H; d) when R4 is H then R3 must be other than H; e) when R1 is C(O)OH then at least one of R2 R8 and R9 must be other than H; f) when R2 is C(O)OH then at least one of R1, R8 and R9 must be other than H; g) when R2 is OCH2CH2Y, then R1 must be other than H; h) when R1 and R2 are fused then R8 and R9 are each H; and i) when R1 is S(O)2NH2, and when (CH2)0-2 is zero, then at least one of R3 and
R4 must be selected from morpholinyl, pyrazolyl, and optionally substituted O- phenyl, or R3 and R4 together with the C atoms to which each is attached, must form a ring that is fused to the phenyl group to which they are attached to form optionally substituted indolyl or benzotriazole; or a pharmaceutically acceptable salt thereof.
A prefered embodiment of this invention is a compound of Formula I wherein X is halo, R1 is selected from H, OH, C(O)R10, NR11R11, C(N)OH, C(N)(C C6)alkoxy, indolyl, pyridyl, quinolyl, (C C6)alkyl optionally substituted with C(O)OH, (N)(C1-C3)alkoxy, or with a five membered N containing heterocycle, (C*t-C6)alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C**-C3)alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
2 independently selected (C C6)alkyl group(s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C(O)OH,
C(O)(C C3)alkyl,
(C Cejalkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (C C6)alkoxy, CN, and N[(Cι-Cβ)alkyl]2; R2 is selected from H, OH, CF3, C(O)R10, a five membered heterocycle, (C C6)alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
NH(C C6)alkyl optionally substituted with 1 or 2 OH groups, or with (C*ι-C3)alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C C6)alkoxy optionally subsituted with 1 or 2 substitutents selected from N[(C C6)alkyl]2, OH and (C C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperadinyl, NH(C*ι-C6)alkyl-six membered heterocycle, phenyl substituted with 1 or 2 substituents independently selected from
(C C6)alkoxy, CN and halo, and pyrazole optionally substituted with (C*i-C6)alkyl; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
(Cι-C3)alkyl, (N)(C C3)alkoxy, (C1-C3)alkyl-N[(C1-C3)alkyl]2, C(O)NH2, (N)OH, and (N)O(C**-C3)alkyl, and when the fused ring is indolyl, it may also be substituted with
(C*ι-C6)alky[ said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C3)alkyl]2, and
(C C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R3 is selected from H, (C1-C6)alkyl, halo, C(O)(C*rC3)alkyl, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups,
O-phenyl said phenyl being optionally substituted with halo, (C C3)alkoxy, or
C(O)O(C1-C3)alkyl, (C C6)alkoxy optionally subsituted with 1 or 2 substitutents each independently selected from OH and (C**-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl;
R4 is selected from H, halo, ethynyl, C(O)(C C3)alkyl, (C*rC6)alkoxy optionally substituted with 1 or 2 OH group(s), and pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups; R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with
(C C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(CrC3)alkyl]2, and (C C3)alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole; R5 and R6 are each H; R7 is selected from H, halo and (C**-C6)alkoxy;
R8 is H;
R9 is selected from H and (C**-C3)alkoxy; R10 is selected from (C*,-C6)alkyl, NHOR12, (C C6)alkoxy and NH(C C6)alkyl optionally substituted with 1 or 2 OH group(s); R11 is selected from H, C(O)R10, S(O)2(C C3)alkyl, S(O)2N[(C C3)alkyl]2, and
S(O)2-five membered heterocycle said heterocycle being optionally substituted with (C C6)alkyl and NHC(O) (C C3)alkyl; R12 is selected from H, (C C3)alkyl, and tetrahydropyranyl; and
Y is selected from N[(C-|-C6)alkyl]2, imidazolyl, piperidinyl, and morpholinyl.
The terms identified above have the following meaning throughout: The term "optionally substituted" means that the moiety so modified may have from none to up to about the highest number of substituents indicated. When there are two or more substituents on any moiety, each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.
The terms "(CrC3)alkyl" and "(CrC6)alkyl", mean linear or branched saturated carbon groups having from about 1 to about 3 or about 6 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, r/-butyl, isobutyl, sec-butyl, fe/t-butyl, and the like. The terms "(C C3)alkoxy" and "(C C6)alkoxy" mean a linear or branched saturated carbon group having from about 1 to about 3 or about 6 C atoms, said carbon group being attached to an O atom. The O atom is the point of attachment of the alkoxy substituent to the pyridyl ring. Such groups include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ferf-butoxy, and the like.
The terms "(C C6)alkyl optionally substituted" and "(C C6)alkoxy optionally substituted" mean an alkyl group or an alkoxy group, respectively, as defined above, wherein each C atom is bonded to 1 , 2 or 3 H atoms, as appropriate, or any H atom up to about the recited maximum number of H atoms on a C atom may be replaced with a recited substituent, or the alkyl or alkoxy groups may be substituted as otherwise described herein, with the proviso that combinations of recited substituents result in a chemically stable compound.
The term "halo" means an atom selected from Cl, Br, F and I, where Cl, Br and F are preferred.
When "(N)" "(NH)" and "(O)" are used in a chemical formula, they mean =N, =NH and =O respectively. The formula "N[C C3)alkyl]2" and N[S(O)2(CrC6)alkyl]2", and the like, mean that each of the 2 possible alkyl groups attached to the N atom are selected independently from the other so that they may be the same or they may be different.
The term "five membered heterocycle" means an aromatic, saturated or partially saturated ring containing about 5 atoms and having 1 , 2 or 3 heteroatom(s) each selected independently from O, N, and S, the rest being C atoms, with the proviso that there can be no more than 1 O atom or 1 S atom in the heterocycle. This heterocycle is attached through any available C or N atom to the rest of the molecule and is optionally substituted at any available C or N atom with the recited substituents. Such groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and the like, in all their possible isomeric forms.
The term "six membered heterocycle" means a saturated or partially unsaturated ring containing about 6 atoms, 1 or 2 of which are each independently selected from N, O, and S, the rest being C atoms. There can be no more than 2 O atoms or 2 S atoms in any heterocycle, and when there are 2 O atoms in a heterocycle, they must be non- adjacent. This ring is attached through any available C or N atom to the rest of the molecule and is optionally substituted with the recited substituents on any available C and/or N atom. This heterocycle includes piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl and the like. The term "five membered N containing heterocycle" means a saturated or partially saturated ring containing about 5 atoms, 1 , 2, or 3 of which are N atoms, the rest being C, where the heterocycle is attached through any available C or N atom to the rest of the molecule. Such groups include imidazolyl, pyrrolidinyl, and the like. The term "fused ring" means a group having from 9 to 14 atoms divided into 2 or 3 chemically stable rings, one of which is the phenyl ring to which R1 and R2 are attached. Each ring is fused to another ring through adjacent C, C-N or N atoms and 3, 2 or 1 of the remaining atoms, respectively, in the fused ring are heteroatoms each independently selected from N or O, with the proviso that there can be no more than 1 O atom in any fused heterocycle. The heteroatoms may be located at any available position in the fused moiety other than in the phenyl ring to which R1 and R2 are attached. When the fused ring is bicyclic, the one ring that is fused to the phenyl ring to which R1 and R2 are attached may be either aromatic, partially saturated or saturated. That is, if the one ring stood alone, it could be either aromatic partially saturated, or saturated. When the fused ring is tri-cyclic, the bicyclic ring that is fused to the phenyl ring to which R1 and R2 are attached may be either unsaturated or partially saturated. That is, if the bicyclic ring stood alone, it could be either partially saturated or saturated. The resulting fused bi- or tri-cyclic ring is optionally substituted with the recited substituents at any available C and/or N atom(s). Such groups include but are not limited to benzimidazolyl, benzimidazoly-2-one, indolin-2-one, benzotriazolyl, dihydrobenzoindazolyl, dihydrobenzodioxinyl, dihydroinden-1-oneoxime, dihydronaphthalenone, dihydrobenzoindazolyl, tetrahydropyrrolobenzoxazinyl, indazolyl, benzotriazolyl, benzocyclopentyl, benzocyclohexyl, indolyl and the like.
When a phenyl ring may be substituted with one or more substituent, the substituent(s) may be attached to the phenyl ring at any available C atom, preferably at the 3, 4, or 5 C. When there is more than 1 substituent on a phenyl ring, each is selected independently from the other so that they may be the same or different.
Representative compounds of Formula I are shown in Table
Table 1
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
a LC/MS method used: HPLC - electrospray mass spectra (HPLC ES-MS) for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 1200 amu using a variable ion time according to the number of ions in the source. The eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient eiution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
The structure of each compound in Table 1 is consistent with the analytical data (1H NMR and LC-MS) also presented in the table above.
Table 2 IUPAC Names of Compound Examples
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
*The IUPAC Names were obtained using the ACD/ILab Web service.
The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention. Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The use of pharmaceutically acceptable salts of the compounds of Formula I are also within the scope of this invention. The term "pharmaceutically acceptable salt" refers to either inorganic or organic acid or base salts of a compound of the present invention that have properties acceptable for the therapeutic use intended. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate. The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of this invention are able to form. Examples of such forms are, for example, hydrates, alcoholates and the like.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides including benzyl and phenethyl bromides, and others. Unless the context clearly indicates to the contrary, whenever the term
"compounds of this invention," "compounds of the present invention", and the like, are used herein, they are intended to include the chemically feasible pharmaceutically acceptable salts and/or esters as well as all stereoisomeric forms of the referenced compounds.
Method of making the compounds of the present invention
In general, the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented as an example of the synthesis of the compounds of the present invention.
General Experimental Procedures The compounds of this invention can be synthesized according to the general method of Reaction Scheme 1 described below.
Reaction Scheme 1
General Method of Preparation of Compounds of Formula (I)
Figure imgf000091_0001
Intermediate A Intermediate B Intermediate C
Step 2.
Figure imgf000091_0002
Intermediate C Intermediate D
(I)
In Reaction Scheme 1 , the R1-R9 and X groups have the same meaning as defined above for Formula I. In general, compounds of Formula (I) can be prepared in two steps. In the first step, a dichloropyrimidine, (Intermediate A), is allowed to react with an optionally substituted aniline or phenylalkylamine (Intermediate B) in the presence of a basic catalyst to give Intermediate C. In step two, Intermediate C is allowed to react with an aniline, represented as Intermediate D, in the presence of an acid catalyst.
Where Intermediates A or D are not commercially available, they may be prepared by methods well known in the art or by those methods specifically described below for the preparation of intermediates.
Using the above general methods, the specific procedures described below, together with the knowledge of one skilled in the art, all of compounds of Formula I may be prepared. The following specific examples are presented to further illustrate the invention described herein, but they are not intended, nor should they be construed, to limit the scope of the invention in any way.
Abbreviations and Acronyms
When the following abbreviations are used herein, they have the following meaning:
AcOH acetic acid
AgOTf silver trifluoromethanesulfonate
AIMe3 trimethylaluminum abs absolute
AmmOH Ammonium Hydroxide
BH3THF borane-tetrahydrofuran complex
BOC terf-butoxycarbonyl n-BuLi butyllithium n-BuOH 1-butanol f-BuOH ferf-butyl alcohol
CBr4 carbon tetrabromide
CD3OD methanol-d4
CDCI3 chloroform-of
Celite® diatomaceous earth filtering agent, registered trademark of Celite Corp,
DCE 1 ,2-dichloroethane dH2O de-ionized water
DMAP 4-dimethylaminopyridine
DMF Λ/,/ -dimethylformamide
DMSO dimethylsulfoxide dppp 1 ,3-bis(diphenylphosphino)propane
EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride equiv equivalent(s)
EPA vial A 40 mL vial sold by Fisher Scientific and other common laboratory supply vendors
ESI-MS electrospray ionization mass spectrometry
Et3N triethylamine
EtOAc ethyl acetate
Et2O diethyl ether
EtOH ethanol HEPES 4-(2-hydroxyethyl)-1 -piperazineethane-sulfonic acid
HEX hexanes
1H NMR proton nuclear magnetic resonance
HPLC high performance liquid chromatography /-PA /so-Propyl alcohol
J-Kem Block A parallel synthesis block sold by J-Kem, Inc.
KOAc potassium acetate
KOH potassium hydroxide
LC/MS liquid chromatography / mass spectroscopy LiAIH4 lithium aluminum hydride mCPBA 3-chloroperoxybenzoic acid
MeOH methanol
MMTV murine mammary tumor virus
MS ES mass spectrometry with electrospray NaBH(OAc)3 sodium triacetoxyborohydride
NaCNBHs sodium cyanoborohydride
NaOAc sodium acetate
NaOH sodium hydroxide
NMM Λ/-methylmorpholine Pd/C palladium on carbon
Pd(dppf)CI2 [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
Pd(OAc)2 palladium (II) acetate
Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
PS-NCO polystyrene isocyanate Rf TLC retention factor rt room temperature
SnCI2 tin (II) chloride
TFA trifluoroacetic acid
THF tetrahydrofuran TMSCI chlorotrimethylsilane
TMSCN trimethylsilyl cyanide
TLC thin layer chromatography
RT retention time (HPLC)
Unless otherwise stated, the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. Thin-layer chromatography (TLC) was performed on Whatman® pre-coated glass- backed silica gel 60A F-254 250 μm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was performed using 230- 400 mesh EM Science® silica gel.
Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric G/V-Omega 300 (300 MHz) spectrometer with either Me4Si (δ 0.00) or residual protonated solvent (CHCI3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard.
Carbon (13C) NMR spectra were measured with a General Electric GΛ/-Omega 300 (75 MHz) spectrometer with solvent (CDCI3 δ 77.0; d3-MeOD; δ 49.0; d6-DMSO δ 39.5) as standard.
HPLC - electrospray mass spectra (HPLC ES-MS) for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient eiution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
Preparative HPLC, when used, was run using either a Gilson 215 Liquid Handler with a Gilson 322 pump and a Gilson UV-VIS-155 detector set at 254 nm or a Shimadzu LC-8A pump with a Shimadzu SPD-10A detector set at 220 nM both equipped with a
YMC Pac ProC18 column (150 x 20 mm). Alternatively, a YMC Pac ProC18 75 x 30 mm column was used with the Gilson HPLC. Eluant A is acetonitrile with 0.01% of trifluoroacetic acid and Eluant B is water with 0.01% trifluoroacetic acid. Typically, a gradient was run from 10% A / 90% B to 90%A / 10% B over a period of 15-25 min. The fractions of interest were collected and the solvent removed in vacuo to give the final compound as a trifluoroacetic acid salt. Preparation of Nitroarene Starting Materials Synthetic Methods N1-N9
Method N1 Preparation of Λ/,Λ/-Diethyl-2-[(3'-methoxy-4-nitro-1 ,r-biphenyl-2-yl,oxylethanamine
Figure imgf000095_0001
To a dry round-bottomed flask is added 4-bromo-3-(2-(diethylamino)ethoxy-1- nitrobenzene (1 equiv), 3-methoxylphenylboronic acid (1.5 equiv), sodium bicarbonate (4 equiv), and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (0.1 equiv). 1,4-
Dioxane (0.1 M) is added and Ar is then bubbled through the solution for 15 minutes. Water (0.02M) is added and the reaction is heated at 90°C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 (1x) followed by H2O (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and 1HNMR confirm the product.
Method N2 Preparation of 4-(2-methoxy-4-nitrophenyl)pyridine
Figure imgf000095_0002
To a dry round-bottomed flask is added (bromo compound)(1 equiv), appropriate boronic acid (1.5 equiv), sodium bicarbonate (4 equiv), and (1 ,1- bis(diphenylphosphino)ferrocene)-dichloropalladium (0.1 equiv). 1,4-dioxane (0.1 M) is added and Ar is then bubbled through the solution for 15 minutes. Water (0.02M) is added and the reaction is heated at 90°C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 (1x) followed by
H2O (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and 1HNMR confirm the product. Method N3 Preparation of 2'-(4-methyl-1-piperazinyl)-5'-nitro-1 ,1'-biphenyl-4-carbonitrile
Figure imgf000096_0001
To ι dry round-bottomed flask
Figure imgf000096_0002
nitrophenyl)piperazine (1 equiv), 4-cyanophenylboronic acid (1.5 equiv), sodium bicarbonate (4 equiv), and (1 ,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (0.1 equiv). 1 ,4-dioxane (0.1 M) is added and Ar is then bubbled through the solution for 15 minutes. Water (0.02M) is added and the reaction is heated at 90°C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 (1x) followed by H2O (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and HNMR confirm the product.
Method N4 Preparation of Λ/,/V-diethyl-2-f2-(1H-indazol-5-vπ-5-nitrophenoxy1ethanamine
Figure imgf000096_0003
A two neck flask charged with the 5-bromo-1H-indazole (1 equiv), Pd(dppf)CI2 (0.03 equiv), KOAc (3 equiv) and bis(pinacolato)diboron (1.1 equiv) was flushed with Ar. DMF (0.25 M) was added via a syringe to form a red solution. The mixture was heated at 80 °C for 2h. After the reaction was cooled to rt, Pd(dppf)CI2 (0.03 equiv), the nitro bromide compound (1 equiv) and Na2CO3 aqueous solution (1 M, 5 equiv) were added. The mixture was stirred under Ar at 80 °C overnight. The reaction mixture was allowed to cool to rt, extracted with EtOAc and washed with brine. The extract was then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash silica column chromatography (EtOAc/MeOΗ=9:1) to afford the pure product which was confirmed by LC/MS and 1H NMR. Method N5 Preparation of 2-(4-methyl-1 -piperazinvπ-Λ/-r2-(4-morpholinyl)ethyll-5-nitroaniline
Figure imgf000097_0001
To a dry round-bottomed flask is added 1-methyl-4-(2-bromo-4- nitrophenyl)piperazine (1 equiv), 2-(4-morpholinyl)ethylamine (1.5 equiv), potassium tert- butoxide (1.4 equiv), rac-BINAP (0.2 equiv) and Pd2(dba)3 (0.1 equiv). 1 ,4-Dioxane (0.1M) is added and Ar is then bubbled through the solution for 15 minutes. The reaction is heated at 80°C. After 8h the reaction mixture is cooled, diluted with ethyl acetate, filtered through a Celite® plug. The plug is washed well with EtOAc. The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and 1HNMR confirm the product.
Method N6 Preparation of Λ/,Λ/-diethyl-2-(5-nitro-1H-indol-1-yl)ethanamine
Figure imgf000097_0002
A slurry of 5-nitroindole (1 equiv) and NaOH pellets (1 equiv) in H2O (7 M) was stirred for 10 min after which time p-xylene (1.4 M), K2CO3 (1.5 equiv) and corresponding alkyl halide (1 equiv) was added and the reaction heated to 100 °C for 4 h. The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1N NaOH (2 x) and H2O (1 x). The organic layer was dried (MgSO4) and concentrated in vacuo to furnish the resulting crude material that was confirmed by LC/MS and 1H NMR. Method N7
Preparation of 1-(3-nitrobenzyl,-1H-imidazole
Figure imgf000098_0001
To a round-bottomed flask is added 3-nitrobenzyl bromide (1 equiv) followed by imidazole (2 equiv) in TΗF (0.4M). The solution is heated at 60 °C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaΗCO3 (1x) followed by H2O (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and 1HNMR confirm the product.
Methods N8-N9 Preparation of 4-[2-(2-methoxy-5-nitrophenoxy,ethvπmorpholine
Figure imgf000098_0002
Step 1. Method N8 Preparation of 2-(2-bromoethoxy)-1-methoxy-4-nitrobenzene
Figure imgf000098_0003
A solution of 2-methoxy-5-nitrophenol (1 equiv) in CH3CN (0.72 M) was added
1 ,2-dibromoethane (1 equiv) and Cs2CO3 (3 equiv). The mixture was refluxed overnight.
After cooling to rt, the reaction mixture was diluted by EtOAc and washed with 1 N NaOH
(3x), water (1x) and brine (2x). The organic layer was dried (MgSO4) and concentrated in vacuo to afford the crude product which was confirmed by 1H NMR and used without further purification.
Step 2. Method N9 Preparation of 4-r2-(2-methoxy-5-nitrophenoxy,ethyllmorpholine
Figure imgf000098_0004
A solution of 3-(2-bromoethoxy)-4-methoxynitrobenzene (1 equiv), piperidine (2 equiv) and K CO3 (8 equiv) in acetone (0.10 M) was heated to 65 °C for 24 h. The reaction mixture was allowed to cool to rt, diluted with EtOAc and washed with H2O. The organic layer was concentrated in vacuo and the resulting crude solid or oil was purified 5 by silica gel column chromatography to furnish the intermediate nitro derivative which was confirmed by LC/MS and 1H NMR.
Preparation of Anilines: (Reactions Scheme I Intermediates B and D) Synthetic Methods B1-B7 and D1
10 Intermediate B-1
Method B1
Preparation of 1-flY4S,-2,2-dimethyl-1 ,3-dioxolan-4-yllmethyl|-1H-indol-5-amine
Figure imgf000099_0001
Step 1. Preparation of 1-CT(4S,-2,2-dimethyl-1 ,3-dioxolan-4-vnmethyl)-5-nitro-1H-indole
Figure imgf000099_0002
The compound was prepared by reaction of 5-nitroindole (1.0 equiv) with [(4R)- 2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate (5.0 equiv) in the presence of cesium carbonate(2.0 equiv) in DMF at 80 °C for 48 h. A similar procedure is described in more detail in Method 4 below.
20
Step 2. Method B1 Preparation of 1-(r(4S)-2,2-dimethyl-1.3-dioxolan-4-vnmethyll-1H- indol-5-amine
Figure imgf000099_0003
To 2.8 g (10 mmol, 1.0 equiv) 1-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl}-5- 5 nitro-1H-indole in EtOΗ (100 mL) and TΗF (10 mL) was added 6.8 g (30 mmol, 3equiv) tin(ll)chloride dihydrate and the reaction was heated to 100 °C for 24h. It was concentrated, taken up in K2CO3 and filtered through Celite®. The filtrate was extracted with EtOAc and the organic layers dried with MgSO4, filtered and concentrated to 2.5 g
(99%) 1 -{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl}-1 H-indol-5-amine.
Intermediate B-2
Methods B2a and B2b
Preparation of 1-methyl-5-amino-1H-indole S3
Figure imgf000100_0001
Step 1. Method B2a Preparation of 1-methyl-5-nitro-1H-indole
Figure imgf000100_0002
To 1.0 g (6 mmol, I.Oequiv) 5-nitroindole in acetone (12 mL) and H2O (3 mL) was added KOH (1.0 g, 18 mmol) followed by iodomethane (0.75 mL, 12 mmol). The reaction was allowed to stir for 24 h then was filtered to yield 0.8 g (78%-98%) 1-methyl- 5-nitro-1H-indole. Step 2. Method B2b Preparation of 1-methyl-5-amino-1H-indole
Figure imgf000100_0003
To 0.9 g (5mmol, I .Oequiv) 1-methyl-5-nitro-1H-indole in 10mL MeOΗ was added 0.01g 10% Pd/C (0.09mmol, 0.01equiv) and the reaction was stirred under 1atm hydrogen for 34 h. The reaction was filtered and concentrated to give 0.4g (43%-62%) 1- methyl-5-amino-1 H-indole. Intermediate B-3
Method B3 Preparation of 4-aminophenyl-pyrazole
Figure imgf000100_0004
Step 1 : Preparation of Λ/'-{4- (2E)-3-(dimethylamino)-2-propenoyllphenyl)-A/,JV- dimethylimidoformamide
Figure imgf000101_0001
A mixture of 1-(4-amino-phenyl)-ethanone (10.0 g, 74 mmol) and dimethoxymethyl-dimethyl-amine (20.0 g, 156 mmol) was heated at 110 °C for 24 h, cooled to room temperature and concentrated under reduced pressure. The crude product was used in the next step without purification. Step 2: Preparation of 4-aminophenyl-pyrazole
Figure imgf000101_0002
The crude product obtained from step one was treated with water (125.0 mL), 1 N
HCI (8.0 mL), and hydrazine monohydrate (7.4 g, 148 mmol). The mixture was heated at
110 °C for 18 h, cooled down to room temperature, neutralized with saturated NaHCO3 solution (10.0 mL) and extracted with EtOAc (200 mL) three times. Combined the extract and dried over MgSO4, concentrated under reduced pressure to about 100 mL. 1 N HCI in ether (74 mL) was added slowly while stirring vigorously. The precipitate was filtered and dried to give 1 1.5 g (80%) 4-aminophenyl-pyrazole hydrochloride as a yellow powder.
Intermediate B-4
Method B4
Preparation of methyl 4-amino-2-(2-hvdroxyethoxy)benzoate
Figure imgf000101_0003
Step 1 : Preparation of 8-nitro-2,3-dihydro-5H-1.4-benzodioxepin-5-one.
Figure imgf000101_0004
To a suspension of K2CO3 (3.7 g, 27 mmol) in DMF (50 mL), were added 2- hydroxy-4-nitrobenzoic acid (2.0 g, 11 mmol) and dibromoethane (5.1g, 27 mmol). The mixture was heated at 60 °C for 18 h then cooled down to room temperature and water (200 mL) was added. The product was precipitated, filtered, washed with EtOAc, and dried to give 1.0 g (51%) 8-nitro-2,3-dihydro-benzo[e][1 ,4]dioxepin-5-one as a pale yellow powder .
Step 2: Preparation of methyl 4-amino-2-(2-hvdroxyethoxy)benzoate
Figure imgf000102_0001
To a solution of 8-nitro-2,3-dihydro-benzo[e][1,4]dioxepin-5-one (1.0 g, 4.8 mmol) in MeOH and THF, were added 10% Pd/C (50 mg). The mixture was stirred under hydrogen atmosphere for 48 h. The mixture was filtered and concentrated under reduced pressure, the residue was diluted with 400 mL EtOAc and filtered again. Concentrated under reduced pressure to give 0.6 g (60%) 2-(2-hydroxy-ethoxy)-4-aminobenzoic acid methyl ester.
Intermediate B-5 Method B5 Preparation of 1-((S,-2,2-Dimethyl-H ,3ldioxolan-4-ylmethyl,-1H-indol-5-ylamine
Figure imgf000102_0002
Step 1a. Toluene-4-sulfonic acid (S,-2,2-dimethyl-ri ,31dioxolan-4-yl methyl ester
To a stirred solution of (R)-(-)-2,2-dimethyl-1 ,3-dioxolane-4-methanol (25 g; 0.19 mol) in anhydrous dichloromethane (153 mL) cooling under argon atmosphere in ice water was added, successively, triethylamine (28.4 mL; 0.2 mol)), p-toluenesulfonyl chloride (39.27 g; 0.2 mol), and 4-dimethylaminopyridine (0.23 g; 1.9 mmol). The solution was stirred and allowed to warm to room temperature overnight, then was poured into a mixture of water (120 mL) and hexane (240 mL) stirring in ice water. The 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed successively with water (75 mL), then brine (75 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded toluene-4- sulfonic acid (S)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl ester as a thick yellow oil; 1Η NMR shows the presence of residual p-toluenesulfonyl chloride. 1H NMR (CD2CI2) δ 7.7 (d, 2H), 7.4 (d, 2H), 4.2 (m, 1H), 4.01 (dd, 1H), 3.97 (d, 2H), 3.7 (dd, 1H), 2.5 (s, 3H), 1.32 (s, 3H),
1.3 (d, 3H). Step 1b. Toluene-4-sulfonic acid (f?)-2,2-dimethyl-[1 ,3ldioxolan-4-ylmethyl ester
Figure imgf000103_0001
To a stirred solution of (S)-(+)-2,2-dimethyl-1 ,3-dioxolane-4-methanol (20 g; 0.15 mol) in anhydrous dichloromethane (125 mL) cooling under argon atmosphere in ice water was added, successively, triethylamine (23 mL; 0.16 mol), p-toluenesulfonyl chloride (39.27 g; 0.16 mol), and 4-dimethylaminopyridine (0.23 g; 1.6 mmol). The solution was stirred and allowed to warm to room temperature; after 7 h the reaction was poured into a stirred mixture of water (125 mL) and hexane (250 mL). The 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed successively with water (75 mL), then brine (75 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded toluene-4- sulfonic acid (ft)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as a thick yellow oil; 1H NMR shows the presence of residual p-toluenesulfonyl chloride. 1H NMR (CD2CI2): 7.7δ (d, 2H), 7.4δ (d, 2H), 4.2δ (m, 1H), 4.01δ (dd, 1 H), 3.97δ (d, 2H), 3.7δ (dd, 1 H), 2.5δ (s, 3H), 1.32δ (s, 3H), 1.3δ (d, 3H).
Step 2. 1-((S,-2.2-Dimethyl-ri .31dioxolan-4-ylmethyl ,-5-nitro-1 H-indole
Figure imgf000103_0002
To a stirred solution of 5-nitroindole (10.41 g; 63.6 mmol) and toluene-4-sulfonic acid (S)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl ester (21.85 g; 76.3 mmol) in anhydrous Λ/,Λ/-dimethylformamide (100 mL) was added cesium carbonate (41.86 g; 127.2 mmol), and the mixture stirred overnight under argon at 80°C. After allowing the mixture to cool to room temperature, it was poured into a stirred mixture of hexanes and ethyl acetate (200 L each). The solids were filtered off and washed with more solvent. The filtrate was washed with water and brine (250 mL each) before drying (anhydrous sodium sulfate); filtration and concentration in vacuo afforded the theoretical weight of 1-((S)-2,2- dimethyl-[1 ,3]dioxolan-4-ylmethyl)-5-nitro-1 H-indole as a cloudy orange oil. TLC: Rt" 0.3
(50% EtOAc/hexanes), R O.6 (5% EtOAc/CΗ2CI2); 1H NMR (CD2CI2): 8.6δ (d, 1 H), 8.1δ
(dd, 1 H), 7.4δd, 1 H), 7.3δ (d, 1 H), 6.7δ (dd, 1 H), 4.4δ (m, 1 H), 4.3δ (dd,1 H), 4.2δ (dd,1 H),
4.1δ (dd, 1H), 3.7δ (dd, 1H), 1.4δ (s, 3H), 1.3δ (d, 3H).
Figure imgf000104_0001
Step 3. 1-((S)-2.2-Dimethyl-π .3ldioxolan-4-ylmethyl.-1H-indol-5-ylamine
To a solution of 1-((S)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)-5-nitro-1 H-indole in ethyl acetate and ethanol (50 mL each) was added 5% palladium on carbon (Degussa type), and the mixture stirred overnight at room temperature under an atmosphere of hydrogen. The mixture was filtered through Celite® and concentrated in vacuo to afford the theoretical weight of 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indol-5-ylamine as a dark red gum. TLC: Rf 0.18 (50% EtOAc/hexanes); 1Η NMR (CD2CI2): 7.2δ (m, 1H), 7.1δ (d, 1H), 6.9δ (dd, 1H), 6.6δ (m, 1 H), 6.3δ (dd, 1H), 5.3δ (dd, 1 H), 4.4δ (m, 1H), 4.1δ (dd, 2H), 4.0δ (dd, 1 H), 3.7δ (dd, 1 H), 3.5δ (broad exchangeable s, 2H), 1.46 (d, 3H), 1.35
(d, 3H).
Intermediate B-6
Method B6 Preparation of (3aS.-2,3,3a.4-tetrahvdro-1H-pvrrolor2,1 -ciri ,41benzoxazin-7-amine
Figure imgf000104_0002
Figure imgf000104_0003
(S)-Prolinol (1 equiv) and 3,4-difluoronitroaniline (1 equiv) were combined with DMSO followed by addition of KOΗ (2.45 equiv) and heated to 100 °C for 18 h. Then, the mixture was acidified and then filtered. Next, the crude solution was then subjected to the hydrogenation procedure as described above for Method B7c. Intermediate B-7
Methods B7a. B7b, B7c
Preparation of 3-r2-(Diethylamino,ethoxyl-4-(8-guinolinv0aniline
Figure imgf000105_0001
Step 1. Method B7a Demethylation of 1-methoxy-3-nitrophenols using hydrogen bromide
Figure imgf000105_0002
To a solution of 48% HBr (0.5 M) was added 2-(8-quinolinyl)-5-nitroanisole (1 equiv). The solution was heated at reflux for 3 days. The reaction mixture was allowed to cool to rt, diluted with H2O, and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give crude organic residue. Purification by silica gel column chromatography using 20%EtOAc/80%Hex as eluent, afforded the intermediate phenol which was confirmed by LC/MS and 1H NMR.
Step 2. Method B7b Preparation of 2-phenoxy ethylamines
Figure imgf000105_0003
A slurry of 2-(8-quinolinyl)-5-nitrophenol (1 equiv) and NaOH pellets (1 equiv) in H2O (7 M) was stirred for 10 min after which time p-xylene (1.4 M), K2CO3 (1.5 equiv) and aminoethylchloride HCI (1 equiv) was added and the reaction heated to 100 °C for 4 h. The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1 N NaOH (2 x) and H2O (1 x). The organic layer was dried (MgSO4) and concentrated in vacuo to furnish the resulting crude material which was confirmed by LC/MS and 1H NMR. Step 3. Method B7c Reduction of nitrophenols to anilines using Pd/C
Figure imgf000106_0001
A solution of 4-(8-quinolinyl)-3-(2-(diethylamino)ethoxy)nitrophenol in EtOH (0.2 M) was added via syringe to a flask containing Palladium on carbon (10 mol%). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H2 atmosphere. The reaction was allowed to stir overnight and then purged with Ar and evacuated three times until an Ar atmosphere had been achieved. The reaction solution was filtered through a pad of Celite® and washed with copious amounts of EtOH. The filtrate was concentrated in vacuo to afford the desired aniline which was confirmed by LC/MS and 1H NMR.
Intermediate D-1 Method D1 Preparation of 3-(3-Aminophenoxy,-1,2-propanediol
Figure imgf000106_0002
Step 1. To 3-nitrophenol (10.00 g, 7 mmol) in EtOH (50 mL) was added sodium hydroxide (3.59 g, 9 mmol) in water (4 mL) and the reaction was heated to 80 °C for 10 min. To this was added 3-chloro-1 ,2-propanediol (3.59 g, 9 mmol) and the reaction was stirred at 80 °C for 18 h. It was then allowed to cool to room temperature, taken up in EtOAc, washed with 1N NaOH, washed with brine, dried with MgSO4, filtered and concentrated to give 14.92 g of 3-(3-nitrophenoxy)-1 ,2-propanediol (97%). Step 2. To 3-(3-nitrophenoxy)-1 ,2-propanediol (14.92 g, 70 mmol) in ethanol (560 mL) was added tin (II) chloride dihydrate (63.17g, 280 mmol) and the reaction heated to 100 °C for 18 h. It was cooled and concentrated. The yellow oil was taken up in EtOAc and quenched with K2CO3 to pH=12, filtered, and then extracted with additional EtOAc to give 6.26 g of 3-(3-aminophenoxy)-1 ,2-propanediol as a yellow oil (49%). Preparation of Specific Compounds of the Invention
Example 1
Methods 1a ib, 1c, and 1d
Preparation of /V-{5-bromo-4-[(4-fluorophenvnaminol-2-pyrimidinyl)-A/-r3-(1-methyl-1H- pyrazol-3-vPphenvπamine
Figure imgf000107_0001
Figure imgf000107_0002
Step 1. Two methods were used:
Method 1a. To a solution of NaOAc (27.0 g, 330 mmol) in water (70 mL) and THF (140 mL) , were added 5-bromo-2,4-dichloropyrimidine (25.0 g, 110 mmol) and 4- fluoroaniline (12.2 g, 110 mmol). The mixture was stirred at room temperature for 18 h then saturated NaHCO3 solution (50 mL) was added and the aqueous layer was extracted with EtOAc (150 mL x 2); the combined organic layers were dried over MgSO ; filtered and concentrated under reduced pressure. The residue was treated with 200 mL hexane and filtered to give 5-bromo-2-chloro-4-[(4-fluorophenyl)amino]-pyrimidine as a 30.0 g pale yellow powder (90%).
Method 1b o a solution of K2CO3 (44.5 g, 322 mmol) in water (125 mL) and /-PA (375 mL), were added 5-bromo-2,4-dichloropyrimidine (25.0 g, 108 mmol) and 4- fluroaniline (12.0 g, 107 mmol). The mixture was stirred at room temperature for 18 h then water (3000 mL) was added and the product was precipitated out. Filtered and dried to give 30.0 g (90%) 5-bromo-2-chloro-4-[(4-fluorophenyl)amino]-pyrimidine as a pale yellow powder. Step 2.
Method 1c To a solution of 5-bromo-2-chloro-4-[(4-fluorophenyl)amino]-pyrimidine (0.85 g, 2.8 mmol) and 3-(1 -methyl-1 H-pyrazol-3-yi)-phenyl amine (0.49 g, 2.8 mmol) in t- BuOΗ (25 mL) was added concentrated ΗCI (0.1 mL). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. The precipitate was filtered and dried in vacuo to give 0.95 g (71%) desired product (ΗCI salt). ESI-LC/MS m/e calculated for C19Η14BrFN6: 424.0; Found: 425.3 (M+1)+; Rf = 0.40 (EtOAc/Hex=1/1). Combined Steps 1 and 2.
Method 1d. In a 40 mL EPA vial, 100 mg (1 equivalent) of the 4-substituted pyrimidine intermediate was mixed with the calculated amount of amine (2 equivalent) in 2 mL 1 N HCI. The reaction mixture was capped and heated at 100 °C in a J-Kem Block with shaking for 1 or 2 days. After the reaction was completed, DMSO was added into the reaction mixture to dissolve all of the precipitate, then Et3N was added dropwise until the mixture was basic. After these steps, the mixture was purified by preparative HPLC.
Example 2
Method 2
Preparation of JV-(5-bromo-4-[(4-fluorophenyl)aminol-2-pyrimidinyl)-Λ/-r3-(1H-pyrazol-3- vDphenyllamine
Figure imgf000108_0001
To a solution of 5-bromo-2-chloro-4-(4-fluoroanilino)pyrimidine (4.0 g, 13.2 mmol) and 3-(3-aminophenyl)-1H-pyrazole (2.3 g, 14.5 mmol) in dioxane (75 mL) was added 1 N ΗCI (75 mL). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. Sodium bicarbonate (8.4 g, 100 mmol) was added in several portions while stirring. The precipitate was filtered and dried in vacuo to give 3.87 g (69%) desired product. 1Η NMR (CD3OD): δ 8.16 (s, 1H), 7.80 (m, 1 H), 7.67 (d, 1 H), 7.56 (m, 1 H), 7.48 (dd, 2H), 7.31 (m, 2H), 6.92 (t, 2H), 6.56 (d, 1H); ESI-LC/MS m/e calculated for C19H14BrFN6: 424.0; Found: 425.3 (M+1)+; Rf = 0.70 (EtOAc). Example 3
Method 3
Preparation of (1E)-1-r4-({5-bromo-4-r(4-fluorophenyl)aminol-2-pyrimidinyl)amino) phenyllethanone oxime
Figure imgf000109_0001
To a suspension of 1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}- amino)phenyl]ethanone (HCI salt, 90 mg, 0.21 mmol) and NaOAc (67 mg, 0.82 mmol) in EtOH (4.0 mL) was added Hydroxylamine hydrochloride (43 mg, 0.62 mmol). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. Water (20 mL) was added while stirring; the precipitate was filtered and washed with water; dried in vacuo to give 61 mg (71%) of (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)phenyl]ethanone oxime. 1H NMR (CD3OD): δ 8.10 (s, 1 H), 7.55 (dd, 2H), 7.51 (d, 2H), 7.44 (d, 2H), 7.11 (t, 2H), 2.21 (s, 3H); ESI-LC/MS m/e calculated for C18H15BrFN5O: 415.0; Found: 416.2 (M+1)+; Rf = 0.54 (EtOAc/hex=1/1).
Example 4
Method 4
Preparation of /V-f5-bromo-2-IY4-fr(4 ?.-2.2-dimethyl-1.3-dioxolan-4- yl1methoxylphenyl)aminol-4-pyrimidinyl)-Λ/-(4-fluorophenyl)amine
Figure imgf000109_0002
To 10.0g (30mmol, 1.0 equiv) 4-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)phenol in 200mL DMF (moist) was added 20.1g (130 mmol, δ.Oequiv) (4S)-4-(chloromethyl)-2,2-dimethyl-1 ,3-dioxolane and 17.4g (50 mmol, 2.0equiv) cesium carbonate and the mixture was heated to 80 °C for 48 h. The reaction was cooled, taken up in EtOAc and washed with a saturated solution of ammonium chloride (3x200 mL). The organic layers were dried with MgSO4, filtered and concentrated. This was purified by flash column chromatography (0 then 50% EtOAC/Hex) on alumina to yield 4.8 g (5% to 98%) Λ/-{5-bromo-2-[(4-{[(4f?)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}phenyl)amino]-4- pyrimidinyl}-/V-(4-fluorophenyl)amine.
The above procedure was also used to make 1-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4- yl]methyl}-5-nitro-1 H-indole using 5-nitroindole and R(TJ)-2,2-dimethyl-1 ,3-dioxolane-4- methanoltoluene-4-sulfonate. Yields 90-99%.
Example 5
Method 5
Preparation of (2S)-3-f4-({5-bromo-4-[(4-fluorophenyl)aminol-2- pyrimidinyl)amino)phenoxy1-1 ,2-propanediol
Figure imgf000110_0001
To 4.8 g (10 mmol, 1.0 equiv) Λ/-{5-bromo-2-[(4-{[(4R)-2,2-dimethyl-1 ,3-dioxolan- 4-yl]methoxy}phenyl)amino]-4-pyrimidinyl}-/V-(4-fluorophenyl)amine in 90 mL MeOΗ/CΗ2CI2 (1 :1) was added cone. HCI (2.3 mL) and the reaction was allowed to stir for 2 h. The reaction was treated with sat. NaHCO3 to pH=7 and extracted with /-PA/CHCI3 (1 :3) to give 1.5 g (28-98%) (2S)-3-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)phenoxy]-1,2-propanediol.
Example 6
Method 6
Preparation of (2fi,-3-r3-((5-bromo-4-r(4-fluorophenyl ,aminol-2- pyrimidinyl)amino,phenoxyl-1 ,2-propanediol
Figure imgf000110_0002
To 0.5g (0.1 mmol, I .Oequiv) 3-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)phenol in 2.5mL EtOH was added 0.07g NaOH (2mmol, 1.25equiv) in 1mL H2O and the reaction was heated to 80°C for 1 h. To this was added 0.2g (2R)-3- chloro-1 ,2-propanediol (2mmol, 1.2equiv) and the reaction continued to heat at 80°C for 24 h It was cooled and treated with 1N HCI to pH=7 and extracted with EtOAc. The organic layers were dried with MgSO , filtered and concentrated. This was taken up in MeOH and filtered to yield 0.3g (2ft)-3-[3-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)phenoxy]-1 ,2-propanediol (43%-61%).
Example 3
Method 7
Preparation of (1E)-1-r4-((5-bromo-4-r(4-fluorophenyl)aminol-2- pyrimidinyl>amino)phenyllethanone oxime
Figure imgf000111_0001
To a suspension of 1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}- amino)phenyl]ethanone (HCI salt, 90 mg, 0.21 mmol) and NaOAc (67 mg, 0.82 mmol) in EtOH (4.0 mL) was added hydroxylamine hydrochloride (43 mg, 0.62 mmol). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. Water (20 mL) was added while stirring; the precipitate was filtered and washed with water; dried in vacuo to give 61 mg (71%) of (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)phenyl]ethanone oxime. 1H NMR (CD3OD): δ 8.10 (s, 1 H), 7.55 (dd, 2H), 7.51 (d, 2H), 7.44 (d, 2H), 7.11 (t, 2H), 2.21 (s, 3H); ESI-LC/MS m/e calculated for C18H15BrFN5O: 415.0; Found: 416.2 (M+1)+; Rf = 0.54 (EtOAc/hex=1/1).
Example 8
Method 8
Preparation of 4-({5-bromo-4-r^-fluorophenyl,amino1-2-pyrimidinyl)amino,-2-(2- hvdroxyethoxy)benzoic acid
Figure imgf000111_0002
A suspension of 4-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-2-(2- hydroxy-ethoxy)-benzoic acid methyl ester (3.7 g, 27 mmol) in MeOH (5.0 mL) and 1 N NaOH (5.0 mL) was heated at 60 °C for 18 h then cooled down to room temperature and neutralized with 1 N HCI (5.0 mL). Extracted with EtOAc, dried over MgSO4, concentrated to give 85 mg (87%) 4-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-2-(2- hydroxy-ethoxy)-benzoic acid.
Example 9 Preparation of 5-Bromo-/V2-M-((/:?,-2,2-dimethyl-ri .3ldioxolan-4-ylmethyl.-1H-indol-5-vn- /V*-(4-fluoro-phenvD-pyrimidine-2,4-diamine
Figure imgf000112_0001
To a solution of 1-((S)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)-1H-indol-5-ylamine (5.38 g; 21.8 mmol) in n-butanol (20 mL) was added (5-bromo-2-chloro-pyrimidin-4-yl)-(4- fluoropheny[)amine (6.61 g; 21.8 mmol) and 1 drop of concentrated hydrochloric acid, and the stirred mixture heated in an oil bath to reflux. After 5 minutes the bath was lowered and the mixture allowed to cool to room temperature. The solid was filtered off , triturated and washed with diethyl ether to afford a mixture of 2 products, 5-bromo-Λ^-[1- ((fϊ^^-dimethyl-fl .SJdioxolan^-ylmethyO-IH-indol-δ-yll-r ^-fluoro-pheny -pyrimidine- 2,4-diamine and (R)-3-{5-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-indol-1- yl}-propane-1 ,2-diol, as hydrochloride salts. The solid was vigorously stirred in a mixture of ethyl acetate (300 mL) and water (100 mL), sodium bicarbonate (2 g; 23.8 mmol) was added, and the mixture stirred until no undissolved solid remained. The 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed with brine (100 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded solid, which was triturated and washed with dichloromethane; the filtrate was applied to a column of silica gel. The column was eluted with dichloromethane, then a methanol/ dichloromethane solvent gradient (1-5%). The purest (by TLC) of 2 fractions was concentrated in vacuo, and the solid triturated with 50% dichloromethane/hexanes, filtered off and washed with more solvent. After drying in vacuo, there was obtained 0.82 g of 5-bromo-Λ^-[1-((H)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethy -IH-indol-δ-y -r ^-fluoro-pheny -pyrimidine^^-diamine as a colorless solid, mp 130 - 132°C; TLC: Rf 0.28 (50% EtOAc/hexanes); 1Η NMR (CD2CI2): 8.15 (s, 1H), 7.86 (d, 1H), 7.66 (m, 2H), 7.36 (d, 1H), 7.26 (m, 1H), 7.16 (broad s, 1H), 7.06 (m, 3H), 4.46 (m, 1H), 4.26 (dd, 2H), 4.0δ (dd, 1 H), 3.7δ (dd, 1H), 1.45 (s, 3H), 1.36 (s, 3H); LCMS m/z 512 + 514 (M+H+), RT = 2.6 min. Anal. Calcd. for C24H23BrFN5O2: C, 56.26; H, 4.52; N, 13.67. Found: C, 55.96; H, 4.22; N, 13.66. The remaining fraction was concentrated in vacuo, and the solid triturated with 25% dichloromethane/hexanes to afford another
3.55 g (4.37 g total, 39%) of pure 5-bromo-Λ/2-[1-((R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethyl)-1H-indol-5-yl]-r* -(4-fluoro-phenyl)-pyrimidine-2,4-diamine.
Example 10 Method 10 Preparation of (R)-3-{5-f5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylaminol-indoI-1- yll-propane-1 ,2-diol
Figure imgf000113_0001
To a stirred mixture of 5-bromo-/V2-[1-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)- IH-indol-δ-yO-r ^-fluoro-pheny -pyrimidine^^-diamine (15.36 g; 30.0 mmol) in methanol (500 mL) was added 1 N hydrochloric acid (120 mL); the stirred suspension was heated to 60 °C. After 30 minutes the mixture was allowed to cool to room temperature; the solid was filtered off, washed with methanol and dried. The solid was vigorously stirred in water containing sodium bicarbonate (4.1 g; 48.8 mmol); the resulting solid was filtered off, washed with water, ethanol and hexanes, then dried to afford 10.3 g (73%) of (f?)-3-{5-[δ-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-indol-1-yl}-propane-1,2- diol as a colorless solid, mp 206.6 - 209 °C. 1Η NMR (DMSO-d6): 9.16 (broad, exchangeable s, 1 H), δ.δδ (broad, exchangeable s, 1 H), 8.15 (s, 1 H), 7.86 (d, 1H), 7.65 (t, 2H), 7.36 (d, 1 H), 7.26 (d, 1H), 7.15 (m, 3H), 6.26 (d, 1H), 4.9δ (exchangeable d, 1H), 4.76 (exchangeable t, 1H), 4.26 (dd, 1 H), 4.06 (dd, 1H), 3.7δ (m, 1 H), 3.36 (m, 1H), 3.26 (m, 1H); LCMS m/z 472 + 474 (M+H+), RT = 2.0 min. Anal. Calcd. for C21H19BrFN5O2: C,
53.4; H, 4.05; N, 14.83. Found: C, 53.38; H, 4.09; N, 14.85; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm., 1.0 mL/min., 280 nm, hexane + 0.1% TFA/ isopropanol + 0.1% TFA gradient):RT = 12.0 min., ee >98%. Example 4
Method 11
5-Bromo-Λ/2-r4-((R.-2,2-dimethyl-π .31dioxolan-4-ylmethoxy.-phenvπ-/V4-(4-fluoro-phenvn- pyrimidine-2,4-diamine
Figure imgf000114_0001
A stirred suspension of 4-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2- ylamino]-phenoϊ (11.3 g; 30.0 mmol), toluene-4-sulfonic acid (S)-2,2-dimethyl-
[1 ,3]dioxolan-4-ylmethyl ester (17.1 g; 60.0 mmol) and cesium carbonate (34.39 g; 100 mmol) in anhydrous Λ/,Λ/-dimethylformamide (120 mL) was heated under argon atmosphere at 90 °C for 1 hour, then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (250 mL) and brine (500 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 125 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (anhydrous sodium sulfate), filtered and concentrated in vacuo to afford crude product.
Purification by column chromatography on silica gel (hexane/ dichloromethane/ ethyl acetate solvent gradient) afforded 5-bromo- v2-[4-((f?)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethoxy)-phenyl]-/V*-(4-fluoro-phenyl)-pyrimidine-2,4-diamine as a pastel orange solid (10.57 g; 72%). A sample purified further (colorless solid, mp 119-122° C) gave the following data: TLC: Rf 0.5 (25% EtOAc/CH2CI2); 1H NMR (CD2CI2): 8.1δ (s, 1H), 7.56 (m,
2H), 7.46 (m, 2H), 7.16 (m, 4H), 6.86 (m, 2H), 4.45 (m, 1H), 4.16 (dd, 1 H), 4.05 (dd, 1H), 3.96 (dd, 1 H), 3.86 (dd, 1 H), 1.45 (d, 3H), 1.4 (d, 3H); LCMS m/z 489 + 491 (M+H+), RT = 2.6 min.; Anal. Calcd. for C22H22BrFN4O3: C, 54.0; H, 4.53; N, 11.45. Found: C, 53.98; H, 4.55; N, 11.21. Example 5
Method 12 (S)-3-{4-r5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylaminol-phenoxy)-propane-1 ,2- diol
Figure imgf000115_0001
Trifluoroacetic acid (150 mL; 1.94 mol) was added to a suspension of 5-bromo-
Λ/2-[4-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-phenyl]-Λ -(4-fluoro-phenyl)- pyrimidine-2,4-diamine (10.57 g; 0.02 mol) in methanol (675 mL), stirring under argon. After stirring at room temperature overnight, the mixture was concentrated in vacuo. The solid was triturated with diethyl ether, filtered, washed and dried under vacuum; it was then suspended in ethanol, and sodium bicarbonate (3.44 g; 0.04 mol) added to the stirred mixture. After stirring for 1.5 h the solid was filtered off, then stirred in water for 30 minutes. After filtering the solid and washing with water, ethanol and hexanes, 6.77 g (70%) of (S)-3-{4-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-phenoxy}- propane-1,2-diol as a colorless solid, mp 207-210° C, was obtained. 1H NMR (DMSO-d6): 9.15 (broad, exchangeable s, 1H), 8.65 (broad, exchangeable s, 1H), 8.1δ (s, 1 H), 7.6δ (m, 2H), 7.4δ (d, 2H), 7.26 (m, 2H), 6.7δ (d, 2H), 4.96 (broad, exchangeable s, 1 H), 4.6δ (broad, exchangeable s, 1H), 3.9δ (dd, 1H), 3.8δ (m, 2 H), 3.46 (d, 2H); LCMS m/z 449 + 451 (M+H+), RT = 1.9 min.; Anal. Calcd. for C19H18BrFN4O3: C, 50.79; H, 4.04; N, 12.47.
Found: C, 50.77; H, 3.91; N, 12.39; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm., 1.0 mL/min., 280 nm, hexane + 0.1% TFA/ isopropanol + 0.1% TFA gradient): RT = 12.0 min., ee >98%.
Example 13 5-Bromo-Λ/2-r4-((SV2.2-dimethyl-ri.31dioxolan-4-ylmethoxy)-phenvn-A/4-(4-fluoro-phenvπ- pyrimidine-2,4-diamine
Figure imgf000115_0002
A stirred suspension of 4-[5-bromo-4-(4-fluoro-phenylamino)-pyhmidin-2-ylamino]- phenol (11.14 g; 0.03 mol), toluene-4-sulfonic acid (R)-2,2-dimethyl-[1 ,3]dioxolan-4- ylmethyl ester (10.2 g; 0.04 mol) and cesium carbonate (29.31 g; 0.09 mol) in anhydrous Λ/,/V-dimethylformamide (120 mL) was heated under argon atmosphere at 90° C for 1.5 h, then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (250 mL) and brine (500 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 125 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (anhydrous sodium sulfate), then filtered through a pad of silica gel. The pad was eluted with ethyl acetate, and the filtrate concentrated in vacuo to afford crude product. Purification by column chromatography on silica gel (hexane/ dichloromethane/ ethyl acetate solvent gradient) afforded 5-bromo- Λ/2-[4-((S)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-phenyl]- v4-(4-fluoro-phenyl)- pyrimidine-2,4-diamine as a tan solid (11 g; 74.5%), mp slowly melts 95-116.5° C. 1H NMR (CD2CI2): 8.16 (s, 1H), 7.56 (m, 2H), 7.36 (m, 2H), 7.1δ (m, 3H), 7.06 (broad, exchangeable s, 1H), 6.8δ (m, 2H), 4.46 (m, 1H), 4.16 (dd, 1 H), 4.0δ (dd, 1H), 3.96 (dd, 1
H), 3.8δ (dd, 1 H), 1.45 (d, 3H), 1.4 (d, 3H); LCMS m/z 489 + 491 (M+H+), RT = 2.6 min.
Example 14 (R)-3-(4-r5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylaminol-phenoxy)-propane-1 ,2-
Figure imgf000116_0001
Trifluoroacetic acid (160 mL; 2.08 mol) was added to a suspension of 5-bromo- Λ/2-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-/v -(4-fluoro-phenyl)- pyrimidine-2,4-diamine (10.9 g; 0.02 mol) in methanol (640 mL), stirring under argon. After stirring at room temperature overnight, the mixture was concentrated in vacuo. The solid was triturated with diethyl ether and filtered; it was then suspended in water (250 mL), and sodium bicarbonate (3.74 g; 0.04 mol) added to the vigorously stirred mixture. After 20 minutes the solid was filtered off, washed with water, ethanol and hexanes to afford (R)-3-{4-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylamino]-phenoxy}- propane-1 ,2-diol as 8.65 g (88%) of nearly colorless solid, mp 206.5-208.5° C. 1H NMR (DMSO-d6): 9.15 (broad, exchangeable s, 1 H), 8.65 (broad, exchangeable s, 1 H), 8.15
(s, 1 H), 7.65 (m, 2H), 7.45 (d, 2H), 7.25 (m, 2H), 6.75 (d, 2H), 4.95 (broad, exchangeable s, 1H), 4.6δ (broad, exchangeable s, 1 H), 3.96 (dd, 1H), 3.8δ (m, 2 H), 3.4δ (d, 2H); LCMS m/z 449 + 451 (M+H+),RT = 1.9 min.; Anal. Calcd. for C19H18BrFN4O3: C, 50.79; H, 4.04; N, 12.47. Found: C, 50.57; H, 4.0; N, 12.32; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm., 1.0 mL/min., 280 nm, hexane + 0.1% TFA isopropanol + 0.1% TFA gradient): RT = 14.0 min., ee >99%.
Example 15 5-Bromo-Λ/2-r3-((f?)-2,2-dimethyl-ri.31dioxolan-4-ylmethoxy)-phenyll-/V4-(4-fluoro-phenvπ- pyrimidine-2,4-diamine
Figure imgf000117_0001
A stirred suspension of 3-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2- ylamino]-phenol (14.27 g; 0.04 mol), toluene-4-sulfonic acid (S)-2,2-dimethyl- [1 ,3]dioxolan-4-ylmethyl ester (21.78 g; 0.08 mol) and cesium carbonate (43.82 g; 0.13 mol) in anhydrous Λ/,Λ/-dimethylformamide (150 mL) was heated under argon atmosphere at 90° C for 1 hour, then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (150 mL) and brine (450 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 100 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (anhydrous sodium sulfate), then filtered through a pad of silica gel. The pad was eluted with ethyl acetate, and the filtrate concentrated in vacuo to afford crude product. Purification by column chromatography on silica gel (hexane/ dichloromethane/ ethyl acetate solvent gradient) afforded 5-bromo-Λ/2-[3-((R)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-phenyl]-Λ/4-(4-fluoro- phenyl)-pyrimidine-2,4-diamine as a foam (13.85 g; 74.5%). 1H NMR (CD2CI2): 8.16 (s, 1H), 7.5δ (m, 2H), 7.36 (t, 2H), 7.26 (broad, exchangeable s, 1H), 7.1δ (m, 3H), 7.0δm, 1H), 6.6δ (m, 1H), 4.46 (m, 1 H), 4.16 (dd, 1 H), 4.06 (dd, 1H), 3.96 (dd, 1 H), 3.86 (dd, 1 H), 1.436 (s, 3H), 1.46 (s, 3H); LCMS m/z 489 + 491 (M+H+), RT = 2.9 min. Example 16 (S)-3-{3-f5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylaminol-phenoxy)-propane-1.2- diol (add to table)
Figure imgf000118_0001
Trifluoroacetic acid (200 mL; 2.6 mol) was added to a suspension of 5-bromo-Λ/2- [3-((/:?)-2,2-dimethyl-[1 ,3]dioxolan-4-ylmethoxy)-phenyl]-/V4-(4-fluoro-phenyl)-pyrimidine- 2,4-diamine (13.71 g; 0.03 mol) in methanol (800 mL), stirring under argon. After stirring for 2 h at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between water, ethanol and dichloromethane, and the phases separated; upon washing the organic phase with brine, solid formed. The solid was filtered off, then suspended in water (250 mL), and sodium bicarbonate (4.71 g; 0.06 mol) added to the vigorously stirred mixture. After stirring overnight, the solid was filtered off, washed with water, ethanol and hexanes to afford 7.3 g (58%) of (S)-3-{3-[5-bromo-4-(4-fluoro- phenylamino)-pyrimidin-2-ylamino]-phenoxy}-propane-1 ,2-diol as a nearly colorless solid, mp 169.5-172° C. 1H NMR (DMSO-d6): 9.2δ (exchangeable s, 1H), 8.6δ (exchangeable s, 1H), 8.26 (s, 1H), 7.6δ (m, 2H), 7.26 (m, 4H), 7.0δ (t, 1H), 6.56 (m, 1H), 4.9δ (broad, exchangeable s, 1H), 4.66 (broad, exchangeable s, 1H), 3.96 (d, 1H), 3.76 (m, 2H), 3.4δ (broad s, 2H); LCMS m/z 449 + 451 (M+H+), RT = 2.1 min.; Anal. Calcd. for C19H18BrFN4O3: C, 50.79; H, 4.04; N, 12.47. Found: C, 50.76; H, 3.91; N, 12.42; chiral
HPLC (CHIRALPAK AD-H, 4.6 X 250 mm., 1.5 mL/min., 280 nm, hexane + 0.1% TFA/ 25% methanokisopropanol + 0.1% TFA gradient): RT = 19.9 min., ee >99%.
Example 17
Methods 17a and 17b
Preparation of4-({5-bromo-4-r(4-fluorophenyl.aminol-2-pyrimidinyl)amino)-.V-H-
(hvdroxymethyl)-3-methylbutyllbenzamide
Figure imgf000119_0001
Step 1. Method 17a Preparation of 4-(l5-bromo-4-r(4-fluorophenyl)aminol-2- pyrimidinyllamino.benzoyl chloride
SOCIP
Figure imgf000119_0002
Figure imgf000119_0003
A mixture of the carboxylic acid (2.48mmol) was treated with 20 mL of thionyl chloride and allowed to stir at room temperature for 1 hour. The solution was then allowed to stir at 50°C for 18 h. The solution was then concentrated and the crude product was used directly in amide coupling reactions.
Step 2. Method 17b Preparation of 4-({5-bromo-4-r(4-fluorophenyl)aminol-2- pyrimidinyl>amino)-/V-|'1-(hvdroxymethvπ-3-methylbutyllbenzamide
Figure imgf000119_0004
A solution of the acid chloride and the amine (or hydrazine) were combined, followed by the addition of pyridine and dichloromethane. The reaction was allowed to stir at rt for 18 h. The reaction was then filtered and washed with methylene chloride. The product was purified by HPLC, and was used directly in a subsequent step without purification. Example 18
Method 18
Preparation of 4-((5-bromo-4-[(4-fluorophenyl)amino1-2-pyrimidinyl)amino)-/\/-(5-isobutyl-
4.5-dihvdro-1 ,3-oxazol-2-vPbenzamide (need table entry)
Figure imgf000120_0001
The amide was combined with thionyl chloride and methylene chloride. The reaction mixture was allowed to stir for 30 minutes and then warmed to room temperature. The mixture was concentrated and then dissolved in DMSO for HPLC purification.
Example 19
Method 19
Preparation of Ethyl 3-{4-f(2-Chloro-5-fluoro-4-pyrimidinv0aminolphenoxy}-benzoate
(19a) and Ethyl 3-(4-(r2-({4-r3(Ethoxycarbonyl)phenoxylphenyl)amino)-5-fluoro-4- pyrimidinvπamino)phenoxy)benzoate (19b)
Figure imgf000120_0002
(19b)
A solution of 2,4-dichloro-5-fluoropyrimidine (3.24 g, 19.4 mmol) and ethyl 3-(4- aminophenoxy)benzoate (1.00 g, 3.89 mmol) in 4M HCI in dioxane (20 mL) was refluxed for
1 h. TLC analysis indicates two products. The reaction was cooled, quenched with 10%
K2CO3 (150 mL) and quickly extracted with EtOAc (3 X 300 mL). The organic layers were dried (Na2SO4) and concentrated. The crude products were separated and purified by silica gel chromatography (ethyl acetate/hexane) to give ethyl 3-{4-[(2-chloro-5-fluoro-4- pyrimidinyl)amino]phenoxy}-benzoate (19a) as a tan solid in 40% yield (0.630 g, 1.63 mmol) and ethyl 3-(4-{[2-({4-[3(ethoxycarbonyl)phenoxy]phenyl}amino)-5-fluoro-4-pyrimidinyl]- amino}phenoxy)benzoate (19b) as a tan solid in 20% yield (0.470 g, 0.772 mmol). Ethyl 3-{4-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]phenoxy}-benzoate (19a): TLC: Rf = 0.36 (30% EtOAc/hexane; LC-MS (ESI): [M+H]+ 388.2 @ RT 3.41 min.; 1H NMR (DMSO) 6 10.03 (1H, s), 8.30 (1H, d, J = 3.3 Hz), 7.70 (3H, m), 7.53 (1H, t, J = 8.1 Hz), 7.44 (1 H, s), 7.30 (1H, dd, J = 2.7, 8.4 Hz), 7.10 (2H, d, J = 8.7Hz), 4.28 (2H, quart, J = 6.9 Hz), 1.27 (3H, t, J = 6.9 Hz).
Ethyl 3-(4-{[2-({4-[3(ethoxycarbonyl)phenoxy]phenyl}amino)-5-fluoro-4-pyrimidinyl]- amino}phenoxy)benzoate(19b): TLC: Rf = 0.21 (30% EtOAc/hexane; LC-MS (ESI): [M+H]+ 609.5 @ RT 3.21 min.; 1H NMR (DMSO) δ 9.44 (1 H, s), 9.28 (1H, s), 8.10 (1 H, d, J = 3.9 Hz), 7.80 (2H, d, J = 9 Hz), 7.70 (2H, d, J = 9 Hz), 7.59 (2H, t, J = 7.8 Hz), 7.43 (2H, t, J = 7.8 Hz), 7.36 (2H, m), 7.21 (2H, m), 7.03 (2H, d, J = 9 Hz), 6.93 (2H, d, J = 9 Hz), 4.23 (4H, quart, J = 7.2 Hz), 1.24 (6H, t, J = 6.6 Hz).
Example 20
Method 20
Preparation of ethyl 3-(4-ir2-({2-f2-(diethylamino)ethoxyl-4'-methoxy-1 ,1'-biphenyl-4- yl>amino)-5-fluoro-4-pyrimidinyllamino)phenoxy)benzoate
Figure imgf000121_0001
To a solution of ethyl 3-{4-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]phenoxy} benzoate (51 mg, 0.13 mmol) and 2-[2-(diethylamino)ethoxy]-4'-methoxy-1,1'-biphenyl-4- amine (33 mg, 0.10 mmol) in CH2CI (5 L) was added 4M HCI in dioxane (3 mL) and the solution heated in an open vial at 110 °C. The reaction was slowly concentrated over 4 h to a gum as the solvent was boiled off. The reaction was cooled and the gum was dissolved in EtOH (10 mL) and quenched with 10% K2CO3 (50 mL). This was quickly extracted with EtOAc (2 X 150 mL), and the organic layers dried (Na2SO4) and concentrated in vacuo to give a crude amber oil. This was purified by reverse-phase prep-HPLC (RT = 6.28 min), and the TFA salt of the isolated product dissolved in CH2CI2 and free based by washing with 5% K2CO3. The organic layer was concentrated in vacuo to give the product as a hygroscopic brown solid in 54% yield (38 mg, 0.057 mmol). TLC: Rf = 0.34 (50/45/5 CH3CN/MeOH/H2O); LC-MS (ESI): [M+H]+ 666.6 @ RT 2.60 min.; 1H NMR (DMSO) δ 7.93 (1H, d, J = 3.0 Hz), 7.74 (3H, m), 7.59 (1H, d, J = 1.2 Hz), 7.41 (1H, t, J = 7.8), 7.31 (3H, m), 7.23 (2H, m), 7.07 (1 H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.7 Hz), 6.87 (2H, d, J = 8.4 Hz), 4.29 (2H, quart, J = 6.9 Hz), 3.93 (2H, t, J = 6.0 Hz), 3.81 (3H, s), 2.80 (2H, t, J = 5.7 Hz), 2.52 (4H, quart, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz), 0.94 (6H, t, J = 7.5 Hz).
Example 21
Method 21
Preparation of 2-chloro-/V-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-pyrimidinamine and
A/-(2.4-dichloro-5-methoxyphenyl)-Λ/-{2-r(2,4-dichloro-5-methoχyphenyl)aminol-5-fluoro-4-
PyrimidinvDamine
Figure imgf000122_0001
A homogenous mixture of 2,4-dichloro-5-fluoropyrimidine 1 (2.61 g, 15.5 mmol) and 2,4-dichloro-5-methoxyaniline 7 (1.00 g, 5.16 mmol) and concentrated HCI (1.72 mL, 20.6 mmol) was heated at 110 °C for 2.5 h. The reaction was quenched with saturated K2CO3 (150 mL) and extracted with EtOAc (3 X 300 mL). The organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was suspended in CH2CI2 (100 mL) and the white solid hydrolysis by-product filtered off. The filtrate was purified by silica gel chromatography (EtOAc/hexane), and the semi-pure residue was suspended in EtOAc. Λ/- (2,4-dichloro-5-methoxyphenyl)-Λ/-{2-[(2,4-dichloro-5-methoxyphenyl)amino]-5-fluoro-4- pyrimidinyl}amine was isolated as an insoluble white solid in 5% yield (55 mg, 0.12 mmol). The filtrate was re-purified by silica gel chromatography (MeOH/ CH2CI2) to give 2-chloro-Λ/- (2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-pyrimidinamine as a white solid in 33% yield (566 mg, 1.72 mmol).
2-Chloro-Λ/-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-pyrimidinamine: TLC: Rf = 0.34 (20% EtOAc/hexane; LC-MS (ESI): [M+H]+ 322.1 @ RT 3.09 min.; 1H NMR (DMSO) δ 8.46 (1 H, s), 8.18 (1H, d, J = 2.4 Hz), 7.56 (1H, b s), 7.43 (1 H, s), 3.98 (3H, s). Λ/-(2,4-dichloro-5-methoxyphenyl)-/V-{2-[(2,4-dichloro-5-methoxyphenyl)amino]-5-fluoro-4- pyrimidinyl}amine: TLC: Rf = 0.34 (20% EtOAc/hexane; LC-MS (ESI): [M+H]+ 479.2 @ RT 3.87 min.; 1H NMR (DMSO) 6 8.23 (1H, s), 8.21 (1H, s), 8.10 (1H, d, J = 2.7 Hz), 7.43 (1 H, s), 7.37 (1H, s), 7.34 (2H, b s), 3.79 (3H, s), 3.75 (3H, s).
Example 22 Method 22 Preparation of A/-r4-(l5-chloro-4-r(4fluorophenyl)aminol-2-pyrimidinyl)amino)-2- methylphenyllacetamide
Figure imgf000123_0001
Step 1 : Preparation of 2.5-dichloro-A/-(4-fluorophenyl)-4-pyrimidinamine
Figure imgf000123_0002
To a suspension 2,4,5-trichloropyrimidine (3.00 g, 16.4 mmol) and Na2CO3 (6.93 g, 65.4 mmol) in EtOH (200 mL) was added 4-fluoroaniline (2.18 g, 19.6 mmol) dropwise. The reaction mixture was stirred at rt overnight. TLC and LCMS showed the reaction was complete. The mixture was filtered and the solvent evaporated in vacuo. The residue was dissolved in DCM and washed with brine. The organic layer was dried (Na2SO4) and concentrated to give 3.89 g of a white solid (92%). 1H NMR (CD3OD): 6 8.20 (s, 1 H),
7.59-7.55 (q, 2H), 7.14-7.09 (t, 2H); LCMS RT = 2.79 min; [M+H]+ 258. Step 2: Preparation of A/-r4-({5-chloro-4-r(4-fluorophenyl)aminol-2-pyrimidinyl)amino)-2- methylphenvπacetamide
Figure imgf000123_0003
A suspension of 2,5-dichloro-/V- (4-fluorophenyl)-4-pyrimidinamine (121 mg, 0.47 mmol) and 1-(4-amino-2-methyl)phenylacetamide (93 mg, 0.56 mmol) in π-BuOH (1 mL) was stirred at 110 °C for 24 h. The resulting precipitate was filtered and washed with EtOH followed by Et2O to give 179 mg of a yellow solid (98%). 1H NMR (CD3OD) 6 8.07 (s, 1 H), 7.55-7.51 (q, 2H), 7.32-7.30 (d, 1 H), 7.25 (d, 1H), 7.18-7.13 (m, 3H), 2.18 (s, 6H); LCMS RT = 2.56 min; [M+H]+ 386.
Example 23 Method 23 Preparation of Λ/-(4-amino-3-methylphenvπ-A/-(5-chloro-4-r(4-fluorophenyl)aminol-2- pyrimidinvDamine
Figure imgf000124_0001
To a suspension of Λ/-[4-({5-chloro-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}amino)- 2-methylphenyl]-acetamide (125 mg, 0.30 mmol) in n-BuOH (10mL) was added cone. HCI (2mL) dropwise. The mixture was stirred at 100 °C for 24 h. TLC and LCMS showed the reaction was complete. The reaction solution was evaporated in vacuo, and the residue was dissolved in DCM (210 mL). This was washed with 1M NaOH (10 mL) then brine (10 mL). The organic layers were dried (Na2SO4) and evaporated to furnish 92 mg of a white powder (89%). 1H NMR (CD3OD) δ 7.90 (s, 1 H), 7.61-7.58 (q, 2H), 7.12-7.11 (d, 1H), 7.05-7.00 (m, 3H), 6.66-6.64 (d, 1H), 2.11 (s, 3H); LCMS RT=0.32 min; [M+H]+ 344.
Example 24
Method 24
Preparation of A/-(4-{5-fluoro-4-r5-(1-methylcvclopropyl)-2H-pyrazol-3-ylamino1-pyrimidin-
2-ylaminoV-2-methylphenyl,-acetamide
Figure imgf000124_0002
Step 1 : Preparation of 5-(1-rnethylcvclopropyl)-2H-pyrazol-3-ylamine
Figure imgf000124_0003
A suspension of NaH (60% dispersion in mineral oil) (4.20 g, 175 mmol) in anhydrous THF (100 mL) was treated with anhydrous CH3CN (9.14 mL, 175 mmol), and the suspension was stirred at ambient temperature for 10 min. To this was added 1- methylcyclopropane-1-carboxylic acid methyl ester (9.70 g, 83.3 mmol), and the reaction was heated to reflux for 24 h. The reaction was quenched by addition of abs EtOH (75 mL), and the slurry concentrated to a white solid. This was dissolved in H2O (100 mL) and further quenched with cone. HCI (20 mL) at 5 °C to a final pH of 2. This was extracted with EtOAc (3 X 250 mL), the combined organic layers dried (Na2SO4), and the solvent removed in vacuo to give the crude α-cyanoketone intermediate as an amber oil. This was dissolved in abs EtOH (75 mL), hydrazine hydrate (8.62 g, 172 mmol) was added, and the solution was heated to reflux for 24 h. The reaction was concentrated in vacuo to an oil, which was purified by silica gel chromatography (5% MeOH/DCM) to give the product as an orange oil in 54% yield (7.11 g, 51.8 mmol). 1H NMR (CDCI3) 6 5.34 (s, 1 H), 1.38 (s, 3H), 0.84 and 0.73 (2 m, 4H); LCMS RT = 0.77 min; [M+H]+ = 138.1. Step 2: Preparation of (2-chloro-5-fluoropyrimidin-4-ylH5-(1-methylcvclopropyl)-2H- p yrazo l-3-yll-a m i ne
Figure imgf000125_0001
A solution of 2,4-dichloro-5-fluoropyrimidine (1.11 g, 6.58 mmol), 5-(1- methylcyclopropyl)-2H-pyrazol-3-ylamine (1.00 g, 6.58 mmol), and KOAc (0.780 g, 7.90 mmol) in Η2O (10 mL) and THF (20 mL) was heated to 45 °C for 24 h. The reaction was quenched with sat. NaHCO3 (100 mL) and extracted with EtOAc (2 X 250 mL). The combined organic layers were dried (Na2SO ) and concentrated to a white solid. The crude material was purified by silica gel chromatography (50% EtOAc/Hex) to give the product as a white solid in 93% yield (1.69 g, 6.31 mmol). 1H NMR (DMSO-d6) δ 12.17 (b s, 1H), 10.35 (s, 1H), 8.22 (d, J = 3.6 Hz, 1H), 6.28 (s, 1H), 1.37 (s, 3H), 0.87 and 0.75 (2 m, 4H); LCMS RT = 2.32 min; [M+H]+ = 268.3. Step 3. Preparation of /V-(4-{5-fluoro-4-r5-(1-methylcvclopropyl)-2H-pyrazol-3-ylaminol- pyrimidin-2-ylamino)-2-methylphenyl)-acetamide
Figure imgf000126_0001
The compound was prepared by the method described for Example 22, step 2, using the product of Example 24, step 2, and Λ/-(4-amino-2-methylphenyl)-acetamide as starting materials. 1Η NMR (DMSO-d6) 5 10.39 (b s, 1H), 10.04 (s, 1H), 9.43 (s, 1 H), 8.19 (d, J = 3.9 Hz, 1H), 7.96 (m, 2H), 7.34 (d, J = 8.7 Hz, 1 H), 6.18 (s, 1H), 2.10 (s, 3H), 1.37 (s, 3H), 0.90 and 0.75 (2 m, 4H); LCMS RT = 2.11 min; [M+Hf = 450.3. Example 25
Method 25
Preparation of Λ/-(methylsulfonyl)-Λ/-r4-r(5-methyl-4-{r2-(trifluoromethyl)benzyllamino>-2-
Pyrimidinyl)aminol-2-(trifluoromethyl)phenyllmethanesulfonamide
Figure imgf000126_0002
To a mixture of Λ/-[4-amino-3-(trifluoromethyl)phenyl]-Λ/-(5-methyl-4-{[2-
(trifluoromethyl)benzyl]amino}-2-pyrimidinyl)amine (200 mg, 0.45 mmol) and Et3N (44 mg, 1.36 mmol) in DCM (5 mL) was added methanesulfonyl chloride (62 mg, 0.54 mmol) at 0 °C. The solution was stirred at room temperature for 4 h then quenched with water. DCM was added (25 mL) and the organic layer was washed with brine. The organic layer was dried (Na2SO4) and concentrated. The crude material was recrystallized from
EtOAc/Hex (1:1) to give the product as white solid in 56% yield (152 mg). 1H NMR (DMSO-d6) 6 9.54 (s, 1H); 8.26 (d, 1 H); 7.84 (m, 2H); 7.75 (d, 1H); 7.61 (t, 1 H); 7.45 (m, 3H); 7.34 (d, 1H); 4.87 (d, 2H); 3.48 (s, 6H); 2.06 (s, 3H); LCMS RT = 2.56 min; [M+H]+ 598.0 Example 26
Method 26
Preparation of A/-{5-chloro-4-F(4-fluorophenyl)amino1-2-pyrimidinyl>-Λ/-(4-{4-[(4- fluorophenyl,sulfonvπ-1-piperazinyl)phenyl .amine
Figure imgf000127_0001
To a solution of /V-(4-amino-3-trifluoromethylphenyl)-/V-{5-bromo-4-[(4- bromophenyl)amino]-2-pyrimidinyl}amine (8.00 g, 15.9 mmol) and 4- (dimethylamino)pyridine (1.94 g, 15.9 mmol) in pyridine (250 mL) at 0 °C was added 1- methylimidazole-4-sulphonyl chloride (4.88 g, 27.0 mmol) in several portions. The reaction was stirred at rt for 48 h then quenched with MeOH. The reaction was concentrated and MeOH (100 mL) was added to the resulting residue. The resulting white precipitate was filtered and washed with Hex/EtOAc (1 :1) followed by MeOH to obtain the desired product in 84% yield (8.77 g). 1H NMR (DMSO-d6): δ 9.69 (s, 1H), 9.47 (s, 1 H), 8.80 (s, 1 H), 8.29 (s, 1 H), 7.90-7.88 (dd, 2H), 7.82-7.78 (dd, 1 H), 7.69 (d, 1H), 7.57 (d, 2H), 7.48 (d, 2H), 7.11 (d, 1H), 3.72 (s, 3H); LCMS RT = 2.90 min; [M+H]+ = 646.0; Anal.
Calcd. for C21Hi6Br2F3N7O2S: C, 38.97; H, 2.49; N, 15.15. Found: C, 38.97; H, 2.49; N, 15.11.
Example 27 Method 27 Preparation of Λ/-(5-chloro-4-l(4-fluorophenyl)aminol-2-pyrimidinyl)-A/-(4-{4-r(4- fluorophenyl,sulfonvH-1-piperazinyl)phenyl, amine
Figure imgf000127_0002
To a solution of Λ/-{5-chloro-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-/V-[4-(1- piperazinyl)phenyl]amine (100 mg, 0.25 mmol) in DCM (2.0 mL) was added Et3N (0.10 mL, 0.75 mmol). After 5 min, 4-fluorobenzenesulfonyl chloride (146 mg, 0.75 mmol) was added, and the mixture stirred at rt for 24 h. The reaction was diluted with EtOAc (75 mL) and washed with sat. NaHCO3 (75 mL) and brine (75 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was rinsed with MeOH (5 mL) followed by DCM (5 mL) to afford pure product in 29% yield (40 mg). 1H NMR (DMSO-d6) δ 9.10 (s, 1 H), 8.81 (s, 1 H), 8.06 (s, 1 H), 7.85 (t, 2H), 7.65 (t, 2H), 7.54 (t, 2H), 7.39 (d, 2H), 7.16 (t, 2H), 6.75 (d, 2H), 3.09 (b, 4H), 3.02 (b, 4H); LCMS RT =
2.78 min; [M+H]+ 557.2.
Example 28 Method 28 Preparation of •f5-bromo-4-r(4-methoxyphenyl)aminolpyrimidin-2-yl)(4-imidazolyl-3- methylphenyl, amine
Figure imgf000128_0001
Step 1 : Preparation of 1-(2-Methyl-4-nitro-phenyl)-"?H-imidazole
Figure imgf000128_0002
To a solution of 2-fluoro-5-nitrotoluene (5.00 g, 32.2 mmol) and '/H-imidazole
(2.19 g, 32.2 mmol) in DMF (75 mL) was added K2CO3 (6.68 g, 48.3 mmol) in several portions. The reaction was heated to 80 °C overnight. The solvent was removed under vacuum. The residue was diluted with EtOAc (250 mL). The solution was washed with brine (75 mL X 5). The solution was concentrated in vacuo. The residue was filtered and washed with hexanes (20 mL X 3). The filter cake was then dried under vacuum to afford desired product as a yellow solid in 68% yield (4.43 g). 1Η-NMR (CD3OD): 5 8.28 (d, 1 H), 8.15 (d, 1 H), 7.89 (s, 1H), 7.53 (d, 1 H), 7.37 (s, 1 H), 7.16 (s, 1H), 2.31 (s, 3H); LCMS RT = 0.84 min; [M+H]+ = 204.1. Step 2: Preparation of 4-lmdazole-1-yl-3-methyl-phenylamine
Figure imgf000129_0001
A solution of 1-(2-methyl-4-nitro-phenyl)-7H-imidazole (3.43 g, 16.9 mmol) in EtOΗ (380 mL) was added to a flask containing 10% palladium on carbon (360 mg). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a Η2 atmosphere. The reaction was allowed to stir overnight and then purged with Ar and evacuated three times until an Ar atmosphere had been achieved. The reaction solution was filtered through a pad of Celite® and washed with copious amounts of EtOH. The filtrate was concentrated under vacuum to afford desired product in 94% yield (2.90 g) as a yellow solid. 1H-NMR
(CD3OD): 5 7.60 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 6.90 (d, 1H), 6.65 (d, 1H), 6.52-6.58 (dd, 1 H), 1.97 (s, 3H); LCMS RT = 0.71 min; [M+H]+ = 174.2.
Step 3: Preparation of {5-bromo-4-r(4-methoxyphenyl)aminolpyrimidin-2-yl.(4-imidazolyl- 3-methylphenyl, amine
Figure imgf000129_0002
The compound was prepared by the method described for Example 22, step 2, step 2, using the product of Example 29, step 2 and 2,5-dichloro-Λ/-(4-methoxyphenyl)-4- pyrimidinamine as starting materials. 1H NMR (CD3OD) 8.06 (s, 1 H), 7.66 (s, 1 H), 7.55 (s,
1H), 7.38-7.32 (m, 3H), 7.15(s, 1H) 7.08 (s, 1 H), 6.99 (d, 1 H), 6.94 (s, 1 H), 6.91 (s, 1H), 3.76 (s, 3H), 1.93 (s, 3H); LCMS RT = 1.91 min; [M+H]+ = 451.3.
The compounds of Table I were made using a combination of the above described procedures, and the appropriate starting materials. The actual sequence of steps used to prepare each compound are indicated in Table I in the column labeled "method" for that compound, in which the entries refer to the specific synthetic methods described above. Thus the preparation of each compound is achieved by carrying out each synthetic step in the order listed, using the appropriately substituted starting materials, as would be obvious to one skilled in the art. Variations of the compounds of the invention can be readily prepared using the processes described above, or by other standard chemical processes known in the art, by employing appropriate starting materials that are readily available and/or are already described herein, as would be known by one skilled in the art. Generally, a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
For example, a desired salt can be prepared by separately reacting the purified compound in its free base or free acid form with a suitable organic or inorganic acid, or suitable organic or inorganic base, respectively, and isolating the salt thus formed. In the case of basic compounds, for example, the free base is treated with anhydrous HCI in a suitable solvent such as THF, and the salt isolated as a hydrochloride salt. In the case of acidic compounds, the salts may be obtained, for example, by treatment of the free acid with anhydrous ammonia in a suitable solvent such as ether and subsequent isolation of the ammonium salt. These methods are conventional and would be readily apparent to one skilled in the art.
The purification of isomers of a compound of this invention, and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
Compositions of the compounds of this invention The compounds of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment (including prophylactic treatment) for the particular condition or disease. Therefore, another embodiment of the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt or ester thereof, of the present invention.
A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical • compositions. The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil.
Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosucci nates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures. The parenteral compositions of this invention will typically contain from about
0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011 ,472, issued April 30, 1991.
The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics
Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171. Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3); air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); ' antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include but are not limited to edetate disodium and edetic acid); colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate); flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono- palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
It is believed that one skilled in the art, utilizing the preceding information, can utilize the present invention to its fullest extent. Nevertheless, the following are examples of pharmaceutical formulations that can be used in the method of the present invention.
They are for illustrative purposes only, and are not to be construed as limiting the invention in any way.
Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile Injectable Solution
A suitable amount of pure active ingredient is dissolved in sterile, injectable water to a desired concentration, for example from about 1.0 mg/ml to about 50.0 mg/ml. U.S.P. grade sodium chloride crystals (NaCI) is added to the solution such that the final concentration of NaCI is 0.9% by weight of water. The pH of the solution is adjusted to range between approximately pH 2.0 and pH 6.0 by the addition of pure (99.999%purity) hydrochloric acid. The solution is sterilized via filtration through a sterile 0.22 micron filter. The sterile solution is stored in sealed sterile vials wherein each vial contains the desired dosage unit of active ingredient per ml of injection solution.
Sterile Injectable Solution
U.S.P. grade sodium chloride (NaCI) is dissolved in sterile, injectable water to a final concentration of 0.9% NaCI by weight of water. An amount of pure (99.999% purity) hydrochloric acid is added to the NaCI solution to obtain a final pH in the range of approximately pH2.0 to pH6.0. An amount of U.S.P. grade potassium chloride crystals (KCL) is dissolved in the solution such that the final concentration of KCI is 0.1% by weight. From 0.5 part to about thirty parts by weight of active ingredient (depending on the desired end dosage unit) is added to the solution and is completely dissolved by agitation. The pH of the solution is adjusted again to between pH2.0 and pH6.0 using pure hydrochloric acid. The solution is sterilized via filtration through a sterile 0.22 micron filter and stored in sealed sterile injection vials, each containing approximately 0.5 mg to approximately 30 mg active ingredient, depending on the final dosage unit desired in the sterile injection solution.
Sterile IV Solution: A 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.
Lyophilized powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.
Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:
50 mg/mL of the desired, water-insoluble compound of this invention 5 mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80
9 mg/mL sodium chloride 9 mg/mL benzyl alcohol Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Method of treating pharmacological disorders
The present invention also relates to a method of using the compounds or compositions described herein for the treatment or prevention of, or in the manufacture of a medicament for treating or preventing, mammalian hyper-proliferative disorders. This method comprises administering to a mammalian patient, including a human, in need thereof, an amount of a compound, a pharmaceutically acceptable salt thereof, or a composition of this invention that is effective to treat or prevent the disorder.
The present invention also relates to a method for using the compounds and compositions of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to delay or diminish the onset of the disorder.
The present compounds and compositions exhibit anti-proliferative activity and are thus useful to treat the disorders that are described below and/or otherwise known in the art. Hyper-proliferative disorders include diseases or conditions whose progression proceeds, at least in part, via proliferation.
Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma
(liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal
/ nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, and also exist with a similar etiology in other mammals which can also be treated by the administration of the compounds and/or pharmaceutical compositions of the present invention.
The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below. The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art. For example, the therapeutic utility of taxol (Silvestrini et al. Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti Cancer Drugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) were demonstrated with the use of in vitro tumor proliferation assays. The following assays are two methods by which compound activity relating to treatment of the disorders identified herein can be determined.
Cellular Proliferation Assay (CTG) Protocol HCT-116 cells are seeded onto a 96-well culture plate at a density of 3000 cells per well in 100 uL DMEM medium supplemented with 10% Fetal Calf Serum and incubated overnight at 37°C in 5% CO2 in a humidified incubator. T0 CTG measurements are taken as described below. Cells are then treated with test compounds serially diluted at 10, 3.3, 1.1 , 0.33, 0.11 , and 0.033uM and incubated for 3 days at 37°C in 5% CO2 in a humidified incubator. Final concentration of DMSO in each well is 0.1 %. Following three days of incubation, 100 microliters of substrate/buffer mixture of CTG (Promega Cell Titer Glo Luminescent® assay kit) are added to each well and incubated at room temperature for 30 minutes. Plates are then read in a luminometer to measure the amount of ATP present in the cell lysates, which corresponds to the number of viable cells. Values read at the time of compound administration to cells are subtracted as Day 0. For determination of IC50's, a linear regression analysis are used to determine drug concentration which results in a 50% inhibition of cell proliferation. Percent inhibition is calculated as follows: % inhibition = 1-(T72test-To)/(T72Ctri-To) x 100, where T 2test = Value read in the presence of test compound at T = 72h T72ctri = Value read in the absence of test compound at T = 72h
T0 = Value read in the absence of test compound at T = Oh
This assay may also be run using HT1080 or DLD-1 cell lines following the same procedure.
In vivo assay: Groups of female Ncr nude mice [Taconic Laboratories, NY] were inoculated with 3x106 cells of HCT-116, a CRC xenograft on day 0. When tumors reached a 75 to 150 mm3 in size (typically 6-8 days), animals were administered compounds of interest p.o. in a Cremaphor (12.5%; Sigma Aldrich, St. Louis, MO): Ethanol (12.5%): Saline (75%) vehicle for 14 days. The treatment volumes were 0.1 mLI-test article/10g body weight. A group of 10 untreated animals was included to assess tumor response to test article vehicles. During the course of the study the animals tumor growth measurements and body weights were determined twice a week. All animals were observed for clinical signs daily and after compound administration. Tumor volume was calculated using the ellipsoid formula: (D x (d2))/2 where,
D = diameter of the tumor at major axis d = diameter of the tumor at minor axis
Use of compounds of this invention in the assays described above demonstrate inhibition of cell proliferation.
Based upon the above and other standard laboratory techniques known to evaluate compounds useful for the prevention and/or treatment of the diseases or disorders described above by standard toxicity tests and by standard pharmacological assays for the determination of the prevention and/or treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for prevention and/or treatment of each desired indication. The amount of the active ingredient to be administered in the prevention and/or treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the duration of treatment (including prophylactic treatment), the age and sex of the patient treated, and the nature and extent of the condition to be prevented and/or treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 300 mg/kg, and preferably from about 0.10 mg/kg to about 150 mg/kg body weight per day. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of administration and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional prevention and/or treatment tests.
The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with other anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
For example, optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment and/or prevention of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by
McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
Other anti-hyper-proliferative agents suitable for use with the composition of this invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.
It is believed that one skilled in the art, using the preceding information and information available in the art, can utilize the present invention to its fullest extent.
It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein. Numerous modifications and variations in the invention as described in the above illustrative examples are expected to occur to those skilled in the art and consequently only those limitations as appear in the appended claims should be placed thereon. Accordingly it is intended in the appended claims to cover all such equivalent variations which come within the scope of the invention as claimed.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula
Figure imgf000146_0001
(I) wherein
X is selected from (C C3)alkyl, CF3, and halo;
R1 is selected from H, OH, halo, CF3, C(O)R10, NR11R11,C(NH)NH2, C(N)OH,
C(N)(C C3)alkoxy,
S(O)2(C C6)alkyl, S(O)2NH2, indolyl, pyridyl, quinolyl,
(CrC6)alkyl optionally substituted with C(O)OH, (N)(Cι-C3)alkoxy, or with a five membered N containing heterocycle,
(C*t-C6)alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C C3)alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
2 independently selected (CrC6)alkyl group(s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C(O)OH,
C(O)(C C3)alkyl, S(O)2(C C6)alkyl,
S(O)2-phenyl said phenyl being optionally substituted with 1 or 2 independently selected halo atoms, or
(C*ι-C6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (C*ι-C6)alkoxy, CF3, CN,
N[(C*rC6)alkyl]2 group, and
(C*ι-C3)alkyl optionally substituted with CN, and
O-pyridyl optionally substituted with halo or (C C3)alkoxy;
R2 is selected from H, S(O)2NH2, halo, ethynyl, OH, CF3, C(O)R10, a five membered heterocycle, benzodioxolyl,
(C*ι-C6)alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with NH(C C6)alkyl optionally substituted with 1 or 2 OH groups, or with (C C3)alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C*i-C6)alkoxy optionally subsituted with 1 or 2 substitutents selected from
N[(C*rC6)alkyl]2, OH and (C C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperadinyl, NH(C C6)alkyl-six membered heterocycle optionally substituted with C(O)OH, C(O)(C C3)alkyl, S(O)2(C C6)alkyl,
S(O) -phenyl said phenyl being optionally substitued at any available C atom with 1 or 2 independently selected halo atoms, or with (C*rC6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with 1 or 2 substituents independently selected from
(CrC6)alkoxy, CN and halo, and pyrazole optionally substituted with (C*rC6)alkyl; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
(CrC3)alkyl, (N)(C C3)alkoxy, (C1-C3)alkyl-N[(C1-C3)alkyl]2, C(O)NH2, (N)OH, OH and SH, and when the fused ring is indolyl, it may also be substituted with
(C-ι-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C*t-C3)alkyl]2, and (CrC3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R3 is selected from H, (C C6)alkyl, halo, S(O)2NH2, C(O)(CrC3)alkyl, CF3, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected
(C Ce)alkyl groups, O-phenyl said phenyl being optionally substituted with halo, (C*rC3)alkoxy, or
C(O)O(C C3)alkyl, (C*ι-C6)alkoxy optionally subsituted with 1 or 2 substitutents each independently selected from OH and (C*ι-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R4 is selected from H, halo, ethynyl, C(O)(C C3)alkyl,
(C C6)alkoxy optionally substituted with 1 or 2 OH group(s), and pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups; R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with
(C*ι-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C3)alkyl]2, and (C C3)alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole optionally substituted with 1 or 2 independently selected (C C6)alkyl group(s); R5 and R6 are each independently selected from H, halo, and CF3; R7 is selected from H, halo and (C*rC6)alkoxy; R8 is selected from H, (C C6)alkyl, (C C6)alkoxy, and halo; R9 is selected from H, and (C C3)alkoxy;
R10 is selected from (C C6)alkyl, OH, NH2, NHOR12, (C C6)alkoxy, NHNHC(O)(C C6)alkyl optionally substituted with CN, and NH(C1-C6)alkyl optionally substituted with 1 or 2 OH group(s); R11 is selected from H, C(O)R10, S(O)2(C*rC3)alkyl, S(O)2N[(C C3)alkyl]2, and S(O)2-five membered heterocycle said heterocycle being optionally substituted with (C C6)alkyl and NHC(O) (C C3)alkyl; R12 is selected from H, (C1-C3)alkyl, and tetrahydropyranyl; Y is selected from N[(CrC6)alkyl]2, imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, NH-phenyl-(C*rC6)alkoxy, NH-O-phenyl-(C C6)alkoxy and NH-(Cι-C6)alkoxy-phenyl; with the provisos that a) when R1 is H then R2 must be other than H; b) when R2 is H then R1 must be other than H; c) when R3 is H then R4 must be other than H; d) when R4 is H then R3 must be other than H; e) when R1 is C(O)OH then at least one of R2 R8 and R9 must be other than H; f) when R2 is C(O)OH then at least one of R1 , R8 and R9 must be other than H; g) when R2 is OCH2CH2Y, then R1 must be other than H; h) when R1 and R2 are fused then R8 and R9 are each H; i) when R3 and R4 together form a cyclic moiety fused to the phenyl ring to which they are attached, then R5, R6 and R7 must be H; j) when R1 is S(O)2NH2, and when (CH2)0-2 is zero, then at least one of R3 and R4 must be selected from morpholinyl, pyrazoylyl, and optionally substituted O-phenyl, or R3 and R4 together with the C atoms to which each is attached, must form a ring that is fused to the phenyl group to which they are attached to form optionally substituted indolyl or benzothazole; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein R1 is selected from morpholinyl, optionally susituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperadinyl, NH2, NHC(O)(C C6)alkyl, NHS(O)2-imidazole-(CrC3)alkyl, N[S(O)2(C C3)alkyl]2, imidazolyl, C(O)NH(C-*-C3)alkyl, and optionally substituted benzimidazolyl; and R8 and R9 are each H.
3. A compound of claim 1 wherein R2 is selected from halo, (C**-C3)alkyl and CF3; and R8 and R9 are each H.
4. A compound of claim 1 wherein R1 and R2 together with the C atoms to which they are attached form a ring that is fused to the phenyl ring to which R1 and R2 are attached to form a bicyclic ring that is optionally subsituted indolyl; and R8 and R9 are each H.
5. A compound of claim 1 wherein R3 is selected from halo, morpholinyl, NH2S(O)2, C(O)(C1-C6)alkyl, (C C6)alkoxy, imidzole and (C C6)alkyl.
6. A compound of claim 5 wherein R4, R6 and R7are each H.
7. A compound of claim 5 wherein R4, R5, R6, and R7 are each H.
8. A compound of claim 1 wherein R4 is selected from halo, CF3, C(O)(Cι-C3)alkyl, optionally substituted (C C6)alkoxy, and optionally substituted pyrazolyl.
9. A compound of claim 1 wherein R3, R5 and R6 are each H.
10. A compound of claim 8 wherein R3, R5 and R6 are each H.
11. A compound of claim 8 wherein R5, R6, and R7 are each H.
12. A compound of claim 8 wherein R3, R5, R6, and R7 are each H.
13. A compound of claim 5 wherein R4 is selected from halo, CF3, C(O)(C1-C3)alkyl, (C C3)alkoxy, imidazolyl and morpholinyl.
14. A compound of claim 4 wherein R4 is selected from halo, CF3, C(O)(C C3)alkyl, (C C3)alkoxy, imidazolyl and morpholinyl.
15. A compound of claim 1 wherein R4, R5, R6, and R7 are each H.
16. A compound of claim 1 wherein X is halo.
17. A compound of claim 1 wherein R1 is selected from optionally subsituted (C C6)alkoxy, C(O)R10, optionally subsituted (C C6)alkyl, indolynyl, quinolinyl and pyridinyl.
18. A compound of claim 17 wherein R8 and R9 are each H.
19. A compound of claim 1 wherein R2 is selected from optionally substituted (C C6)alkoxy and optionally substituted (C*ι-C3)alkyl.
20. A compound of claim 19 wherein R8 and R9 are each H.
21. A compound of claim 1 wherein R3 is halo, optionally substituted (C*t-C6)alkoxy, C(O)R10, and O-phenyl, said phenyl being optionally substituted.
22. A compound of claim 21 wherein R8 and R9 are each H.
23. A compound of claim 1 wherein R4 is selected from halo, (C C3)alkoxy, ethynyl, imidzolyl and C(O)R10.
24. A compound of claim 23 wherein R6 and R7 are each H.
25. A compound of claim 23 wherein R4, R6 and R7 are each H.
26. A compound of claim 1 wherein R3 and R4 together with the C atoms to which they are attached form a ring that is fused to the phenyl ring to which R3 and R4 are attached to form a bicyclic ring that is optionally subsituted indolyl; and R5, R6 and R7 are each H.
27. A compound of claim 19 wherein R3 is halo, optionally substituted (C**-C6)alkoxy, C(O)R10, and O-phenyl, said phenyl being optionally substituted.
28. A compound of claim 19 wherein R8 and R9 are each H.
29. A compound of claim 21 wherein R1 is selected from optionally subsituted (C-- C6)alkoxy, C(O)R10, optionally subsituted (C C6)alkyl, indolynyl, quinolinyl and pyridinyl.
30. A compound of claim 29 wherein R8 and R9 are each H.
31. A compound of claim 1 wherein R8 and R9 are each H.
32. A compound of claim 1 wherein X is halo,
R1 is selected from H, OH, C(O)R10, NR11R11, C(N)OH, C(N)(C C6)alkoxy, indolyl, pyridyl, quinolyl, (C C6)alkyl optionally substituted with C(O)OH, (N)(C C3)alkoxy, or with a five membered N containing heterocycle, (C*|-C6)alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C C3)alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
2 independently selected (C C6)alkyl group(s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C(O)OH, C(O)(C C3)alkyl,
(C*rC6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (C*ι-C6)alkoxy, CN, and N[(C Cβ)alkyl]2; R2 is selected from H, OH, CF3, C(O)R10, a five membered heterocycle, (C C6)alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
NH(C|-C6)alkyl optionally substituted with 1 or 2 OH groups, or with (C*ι-C3)alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C*ι-C6)alkoxy optionally subsituted with 1 or 2 substitutents selected from
N[(Cι-C6)alkyl]2, OH and (C*ι-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperadinyl, NH(C C6)alkyl-six membered heterocycle, phenyl substituted with 1 or 2 substituents independently selected from
(C C6)alkoxy, CN and halo, and pyrazole optionally substituted with (C C6)alkyl; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from (Cι-C3)alkyl, (N)(C C3)alkoxy, (C1-C3)alkyl-N[(CrC3)alkyl]2, C(O)NH2, (N)OH, and (N)O(C C3)alkyl, and when the fused ring is indolyl, it may also be substituted with
(C*t-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(Cι-C3)alkyl]2, and (C*ι-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R3 is selected from H, (C C6)alkyl, halo, C(O)(C C3)alkyl, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected
(Cι-C6)alkyl groups, O-phenyl said phenyl being optionally substituted with halo, (C C3)alkoxy, or C(O)O(C,-C3)alkyl, (C C6)alkoxy optionally subsituted with 1 or 2 substitutents each independently selected from OH and (C C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R4 is selected from H, halo, ethynyl, C(O)(C C3)alkyl,
(C*ι-C6)alkoxy optionally substituted with 1 or 2 OH group(s), and pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups; R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with
(C C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C*i-C3)alkyl]2, and (C1-C3)alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole; R5 and R6 are each H;
R7 is selected from H, halo and (C C6)alkoxy; R8 is H;
R9 is selected from H and (C*ι-C3)alkoxy; R10 is selected from (C C6)alkyl, NHOR12, (C*,-C6)alkoxy and
NH(C-ι-C6)alkyl optionally substituted with 1 or 2 OH group(s); R11 is selected from H, C(O)R10, S(O)2(C C3)alkyl, S(O)2N[(C1-C3)alkyl]2, and S(O)2-five membered heterocycle said heterocycle being optionally substituted with (C C6)alkyl and NHC(O) (C C3)alkyl; R12 is selected from H, (C C3)alkyl, and tetrahydropyranyl; and Y is selected from N[(C**-C6)alkyl]2, imidazolyl, piperidinyl, and morpholinyl.
33. A composition comprising a compound of Formula I
Figure imgf000153_0001
(I) wherein
X is selected from (C1-C3)alkyl, CF3, and halo;
R1 is selected from H, OH, halo, CF3, C(O)R10, NR11R11,C(NH)NH2, C(N)OH,
C(N)(C C3)alkoxy,
S(O)2(C1-C6)alkyl, S(O)2NH2, indolyl, pyridyl, quinolyl,
(C C6)alkyl optionally substituted with C(O)OH, (N)(C C3)alkoxy, or with a five membered N containing heterocycle,
(C*t-C6)alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C C3)alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
2 independently selected (C**-C6)alkyl group(s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C(O)OH,
C(O)(C C3)alkyl, S(O)2(C C6)alkyl,
S(O)2-phenyl said phenyl being optionally substituted with 1 or 2 independently selected halo atoms, or
(C*|-C6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (C*ι-C6)alkoxy, CF3, CN,
N[(CrC6)alkyl]2 group, and
(C*ι-C3)alkyl optionally substituted with CN, and
O-pyridyl optionally substituted with halo or (C*ι-C3)alkoxy;
R2 is selected from H, S(O)2NH2, halo, ethynyl, OH, CF3, C(O)R10, a five membered heterocycle, benzodioxolyl,
(C C6)alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
NH(C C6)alkyl optionally substituted with 1 or 2 OH groups, or with
(C*t-C3)alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C C6)alkoxy optionally subsituted with 1 or 2 substitutents selected from
N[(C*ι-C6)alkyl]2, OH and (C C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperadinyl, NH(C*ι-C6)alkyl-six membered heterocycle optionally substituted with C(O)OH, C(O)(C C3)alkyl, S(O)2(C C6)alkyl,
S(O)2-phenyl said phenyl being optionally substitued at any available C atom with 1 or 2 independently selected halo atoms, or with (C*ι-C6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with 1 or 2 substituents independently selected from
(C C6)alkoxy, CN and halo, and pyrazole optionally substituted with (C-|-C6)alkyl; R and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
(C1-C3)alkyl, (N)(C C3)alkoxy, (d-C^alkyl-N^d-C^alkylJs, C(O)NH2, (N)OH, OH and SH, and when the fused ring is indolyl, it may also be substituted with
(CrC6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(CrC3)alkyl]2, and (C*ι-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R3 is selected from H, (C C6)alkyl, halo, S(O)2NH2, C(O)(C C3)alkyl, CF3, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected
(C C6)alkyl groups, O-phenyl said phenyl being optionally substituted with halo, (C C3)alkoxy, or
C(O)O(C C3)alkyl, (C C6)alkoxy optionally subsituted with 1 or 2 substitutents each independently selected from OH and (C**-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R4 is selected from H, halo, ethynyl, C(O)(C C3)alkyl,
(C*ι-C6)alkoxy optionally substituted with 1 or 2 OH group(s), and pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups; R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with
(C*t-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C3)alkyl]2, and (C C3)alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole optionally substituted with 1 or 2 independently selected (C C6)alkyl group(s); R5 and R6 are each independently selected from H, halo, and CF3; R7 is selected from H, halo and (C**-C6)alkoxy; R8 is selected from H, (C C6)alkyl, (C C6)alkoxy, and halo; R9 is selected from H, and (C C3)alkoxy;
R10 is selected from (C1-C6)alkyl, OH, NH2, NHOR12, (C C6)alkoxy, NHNHC(O)(CrC6)alkyl optionally substituted with CN, and NH(C1-C6)alkyl optionally substituted with 1 or 2 OH group(s); R11 is selected from H, C(O)R10, S(O)2(C C3)alkyl, S(O)2N[(C C3)alkyl]2, and S(O)2-five membered heterocycle said heterocycle being optionally substituted with (C C6)alkyl and NHC(O) (C C3)alkyl; R12 is selected from H, (C C3)alkyl, and tetrahydropyranyl; Y is selected from N[(C C6)alkyl]2, imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, NH-phenyl-(C C6)alkoxy, NH-O-phenyl-(C**-C6)alkoxy and NH-(CrC6)alkoxy-phenyl; with the provisos that a) when R1 is H then R2 must be other than H; b) when R2 is H then R1 must be other than H; c) when R3 is H then R4 must be other than H; d) when R4 is H then R3 must be other than H; e) when R1 is C(O)OH then at least one of R2 R8 and R9 must be other than H; f) when R2 is C(O)OH then at least one of R1 , R8 and R9 must be other than H; g) when R2 is OCH2CH2Y, then R1 must be other than H; h) when R1 and R2 are fused then R8 and R9 are each H; i) when R3 and R4 together form a cyclic moiety fused to j) the phenyl ring to which they are attached, then R5, R6 and R7 must be H; k) when R1 is S(O) NH2, and when (CH2)o-2 is zero, then at least one of R3 and R4 must be selected from morpholinyl, pyrazoylyl, and optionally substituted O-phenyl, or R3 and R4 together with the C atoms to which each is attached, must form a ring that is fused to the phenyl group to which they are attached to form optionally substituted indolyl or benzotriazole; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
34. A method of treating a hyper-proliferative disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula I
Figure imgf000156_0001
(I) wherein
X is selected from (C C3)alkyl, CF3, and halo;
R1 is selected from H, OH, halo, CF3, C(O)R10, NR11R11,C(NH)NH2, C(N)OH,
C(N)(d-C3)alkoxy,
S(O)2(CrC6)alkyl, S(O)2NH2, indolyl, pyridyl, quinolyl,
(C*τC6)alkyl optionally substituted with C(O)OH, (N)(d-C3)alkoxy, or with a five membered N containing heterocycle,
(C*ι-C6)alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (C*t-C3)alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or
2 independently selected (C C6)alkyl group(s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C(O)OH,
C(O)(CrC3)alkyl, S(O)2(C1-C6)alkyl,
S(O)2-phenyl said phenyl being optionally substituted with 1 or 2 independently selected halo atoms, or (C C6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (CrC6)alkoxy, CF3, CN, N[(C*rC6)alkyl]2 group, and (C C3)alkyl optionally substituted with CN, and O-pyridyl optionally substituted with halo or (C C3)alkoxy; R2 is selected from H, S(O)2NH2, halo, ethynyl, OH, CF3, C(O)R10, a five membered heterocycle, benzodioxolyl,
(C*i-C6)alkyl optionally substituted with C(O)OH, morpholinyl, with a five membered N containing heterocycle, with
NH(Cι-C6)alkyl optionally substituted with 1 or 2 OH groups, or with (C C3)alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C-*-C6)alkoxy optionally subsituted with 1 or 2 substitutents selected from
N[(Cι-C6)alkyl]2, OH and (C*t-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperadinyl, NH(Cι-C6)alkyl-six membered heterocycle optionally substituted with C(O)OH, C(O)(C C3)alkyl, S(O)2(C*,-C6)alkyl,
S(O)2-phenyl said phenyl being optionally substitued at any available C atom with 1 or 2 independently selected halo atoms, or with (C*|-C6)alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with 1 or 2 substituents independently selected from
(C C6)alkoxy, CN and halo, and pyrazole optionally substituted with (C*ι-C6)alkyl; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from
(C C3)alkyl, (N)(C.,-C3)alkoxy, (C1-C3)alkyl-N[(C1-C3)alkyl]2, C(O)NH2, (N)OH, OH and SH, and when the fused ring is indolyl, it may also be substituted with
(C*ι-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C C3)alkyl]2, and (C*ι-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R3 is selected from H, (d-C6)alkyl, halo, S(O)2NH2, C(O)(CrC3)alkyl, CF3, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected
(d-C6)alkyl groups, O-phenyl said phenyl being optionally substituted with halo, (C C3)alkoxy, or
C(O)O(C C3)alkyl, (d-C6)alkoxy optionally subsituted with 1 or 2 substitutents each independently selected from OH and (C1-C3)alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl; R4 is selected from H, halo, ethynyl, C(O)(C C3)alkyl,
(C C6)alkoxy optionally substituted with 1 or 2 OH group(s), and pyrazolyl optionally substituted with 1 or 2 independently selected (C C6)alkyl groups; R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with
(d-C6)alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(d-C3)alkyl]2, and (d-C3)alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, and benzotriazole optionally substituted with 1 or 2 independently selected (d-C6)alkyl group(s); R5 and R6 are each independently selected from H, halo, and CF3; R7 is selected from H, halo and (C C6)alkoxy; R8 is selected from H, (C**-C6)alkyl, (d-C6)alkoxy, and halo; R9 is selected from H, and (C C3)alkoxy;
R10 is selected from (C C6)alkyl, OH, NH2, NHOR12, (C C6)alkoxy, NHNHC(O)(C C6)alkyl optionally substituted with CN, and NH(C C6)alkyl optionally substituted with 1 or 2 OH group(s); R11 is selected from H, C(O)R10, S(O)2(C1-C3)alkyl, S(O)2N[(d-C3)alkyl]2, and S(O)2-five membered heterocycle said heterocycle being optionally substituted with (C C6)alkyl and NHC(O) (C C3)alkyl; R12 is selected from H, (C C3)alkyl, and tetrahydropyranyl; Y is selected from N[(C C6)alkyl]2, imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, NH-pheny[-(d-C6)alkoxy, NH-O-phenyl-(C C6)alkoxy and NH-(C C6)alkoxy-phenyl; with the provisos that a) when R1 is H then R2 must be other than H; b) when R2 is H then R1 must be other than H; c) when R3 is H then R4 must be other than H; d) when R4 is H then R3 must be other than H; e) when R1 is C(O)OH then at least one of R2 R8 and R9 must be other than H; f) when R2 is C(O)OH then at least one of R1, R8 and R9 must be other than H; g) when R2 is OCH2CH2Y, then R1 must be other than H; h) when R1 and R2 are fused then R8 and R9 are each H; i) when R3 and R4 together form a cyclic moiety fused to j) the phenyl ring to which they are attached, then R5, R6 and R7 must be H; k) when R1 is S(O)2NH2, and when (CH2)0.2 is zero, then at least one of R3 and R4 must be selected from morpholinyl, pyrazoylyl, and optionally substituted O-phenyl, or R3 and R4 together with the C atoms to which each is attached, must form a ring that is fused to the phenyl group to which they are attached to form optionally substituted indolyl or benzotriazole; or a pharmaceutically acceptable salt thereof.
PCT/US2003/014294 2002-05-06 2003-05-06 2-4-(di-phenyl-amino)-pyrimidine derivatives useful for treating hyper-proliferative disorders WO2004046118A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003299474A AU2003299474A1 (en) 2002-05-06 2003-05-06 2-4-(di-phenyl-amino)-pyrimidine derivatives useful for treating hyper-proliferative disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37832902P 2002-05-06 2002-05-06
US60/378,329 2002-05-06

Publications (2)

Publication Number Publication Date
WO2004046118A2 true WO2004046118A2 (en) 2004-06-03
WO2004046118A3 WO2004046118A3 (en) 2004-08-12

Family

ID=29420382

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2003/013604 WO2003095448A1 (en) 2002-05-06 2003-05-02 Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders
PCT/US2003/014294 WO2004046118A2 (en) 2002-05-06 2003-05-06 2-4-(di-phenyl-amino)-pyrimidine derivatives useful for treating hyper-proliferative disorders

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2003/013604 WO2003095448A1 (en) 2002-05-06 2003-05-02 Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders

Country Status (2)

Country Link
AU (2) AU2003231231A1 (en)
WO (2) WO2003095448A1 (en)

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056786A2 (en) * 2002-12-20 2004-07-08 Pfizer Products Inc. Pyrimidine derivates for the treatment of abnormal cell growth
WO2006004776A1 (en) * 2004-06-29 2006-01-12 Rigel Pharmaceuticals, Inc. 4-pyrimidineamine compounds and their uses as anti-proliferative agents
WO2006012502A2 (en) * 2004-07-23 2006-02-02 Rigel Pharmaceuticals, Inc. Formulation of insoluble small molecule therapeutics in lipid-based carriers
WO2006037117A1 (en) * 2004-09-27 2006-04-06 Amgen Inc. Substituted heterocyclic compounds and methods of use
WO2006021454A3 (en) * 2004-08-27 2006-05-04 Novartis Ag Pyrimidine derivatives
US7060827B2 (en) 2002-02-01 2006-06-13 Rigel Pharmaceuticals, Inc. Intermediates useful for making 2,4-pyrimidinediamine compounds
US7109337B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7109335B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7122542B2 (en) 2003-07-30 2006-10-17 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7145008B2 (en) 2004-05-14 2006-12-05 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7208499B2 (en) 2004-05-14 2007-04-24 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7235562B2 (en) 2004-05-14 2007-06-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
WO2007098507A2 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2007105023A1 (en) * 2006-03-15 2007-09-20 Csir Modulation of phosphoryl transferase activity of glutamine synthetase
WO2007114827A1 (en) * 2006-04-06 2007-10-11 Amgen Inc. Substituted heterocyclic compounds and methods of use
JP2008510765A (en) * 2004-08-27 2008-04-10 ノバルティス アクチエンゲゼルシャフト Pyrimidine derivatives
WO2008049123A3 (en) * 2006-10-19 2008-06-19 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine derivatives as inhibitors of jak kinases for the treatment of autoimmune diseases
WO2008074515A1 (en) * 2006-12-20 2008-06-26 Bayer Schering Pharma Aktiengesellschaft Novel hetaryl-phenylene-diamine pyrimidine as protein kinase inhibitors
WO2008079907A1 (en) * 2006-12-20 2008-07-03 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
FR2911137A1 (en) * 2007-01-05 2008-07-11 Sanofi Aventis Sa New 2,4-diaminopyrimidine derivatives useful for treating inflammatory diseases, diabetes or cancer
WO2008129380A1 (en) 2007-04-18 2008-10-30 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
JP2008543778A (en) * 2005-06-08 2008-12-04 ライジェル ファーマシューティカルズ， インコーポレイテッド Compositions and methods for inhibition of the JAK pathway
GB2451594A (en) * 2006-03-15 2009-02-04 Csir Modulation of phosphoryl transferase activity of glutamine synthetase
WO2009071535A1 (en) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Diaminopyridines for the treatment of diseases which are characterised by excessive or anomal cell proliferation
JP2009524632A (en) * 2006-01-26 2009-07-02 アストラゼネカ アクチボラグ Pyrimidine derivatives
WO2009103652A1 (en) * 2008-02-22 2009-08-27 F. Hoffmann-La Roche Ag Modulators for amyloid beta
WO2009136995A2 (en) 2008-04-16 2009-11-12 Portola Pharmaceuticals, Inc. Inhibitors of syk protein kinase
US20100029588A1 (en) * 2007-03-12 2010-02-04 Bayer Cropscience Ag Substituted phenylamidines and the use thereof as fungicides
US7812029B1 (en) 2002-07-29 2010-10-12 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7820648B2 (en) 2005-12-21 2010-10-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7851480B2 (en) 2004-11-24 2010-12-14 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
WO2011018518A1 (en) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Regioselective preparation of 2 -amino-5-trifluoromethylpyrimidine derivatives
WO2011018517A1 (en) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives
US7923450B2 (en) 2008-01-11 2011-04-12 Hoffmann-La Roche Inc. Modulators for amyloid beta
WO2010034626A3 (en) * 2008-09-29 2011-07-21 Henkel Ag & Co. Kgaa Novel developer components
US8039479B2 (en) 2006-12-08 2011-10-18 Irm Llc Compounds and compositions as protein kinase inhibitors
US8084609B2 (en) 2006-12-22 2011-12-27 Hoffman-La Roche Inc. Spiropiperidine derivatives
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8148391B2 (en) 2006-10-23 2012-04-03 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
WO2012061418A2 (en) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
WO2012061415A1 (en) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines as syk modulators
JP2012515206A (en) * 2009-01-15 2012-07-05 ライジェル ファーマシューティカルズ， インコーポレイテッド Protein kinase C inhibitors and uses thereof
US8246984B2 (en) 2005-12-06 2012-08-21 Rigel Pharmaceuticals, Inc. Formulation of insoluble small molecule therapeutics in lipid-based carriers
US8258144B2 (en) 2008-04-22 2012-09-04 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
US8389717B2 (en) 2008-10-09 2013-03-05 Hoffmann-La Roche Inc. Modulators for amyloid beta
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
US9006241B2 (en) 2011-03-24 2015-04-14 Noviga Research Ab Pyrimidine derivatives
US9102625B2 (en) 2010-11-01 2015-08-11 Portola Pharmaceuticals, Inc. Nicotinamides as JAK kinase modulators
JP2015528440A (en) * 2012-08-10 2015-09-28 コーリア リサーチ インスティテュート オブ ケミカル テクノロジー N2, N4-bis (4- (piperazin-1-yl) phenyl) pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof, and cancer containing this derivative or salt as an active ingredient Composition for treating
AU2014201847B2 (en) * 2007-04-18 2015-12-24 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
US9249124B2 (en) 2011-03-30 2016-02-02 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase inhibitors and methods of making and using thereof
JP2016513661A (en) * 2013-03-14 2016-05-16 トレロ ファーマシューティカルズ， インコーポレイテッド JAK2 and ALK2 inhibitors and methods of use thereof
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US9676756B2 (en) 2012-10-08 2017-06-13 Portola Pharmaceuticals, Inc. Substituted pyrimidinyl kinase inhibitors
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
AU2016201820B2 (en) * 2007-04-18 2018-03-08 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
US10106507B2 (en) * 2014-08-03 2018-10-23 H. Lee Moffitt Cancer Center and Research Insitute, Inc. Potent dual BRD4-kinase inhibitors as cancer therapeutics
CN109776522A (en) * 2017-10-30 2019-05-21 广东东阳光药业有限公司 Substituted heteroaryl compound and combinations thereof and purposes
US10323023B2 (en) 2017-06-30 2019-06-18 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US10329282B2 (en) 2017-06-30 2019-06-25 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US20190248778A1 (en) * 2011-11-17 2019-08-15 Dana-Farber Cancer Institute, Inc. Inhibitors of c-jun-n-terminal kinase (jnk)
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis
WO2019200254A1 (en) 2018-04-13 2019-10-17 Tolero Pharmaceuticals, Inc. Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer
WO2020006724A1 (en) * 2018-07-05 2020-01-09 清华大学 Compound for targeted degradation of fak protein and use thereof
US10577381B2 (en) 2005-01-19 2020-03-03 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
CN111163839A (en) * 2017-05-26 2020-05-15 癌症研究科技有限公司 Benzimidazolone-derived BCL6 inhibitors
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
USRE48175E1 (en) 2012-10-19 2020-08-25 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US10870651B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10875864B2 (en) 2011-07-21 2020-12-29 Sumitomo Dainippon Pharma Oncology, Inc. Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors
US10906889B2 (en) 2013-10-18 2021-02-02 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
US11040957B2 (en) 2013-10-18 2021-06-22 Dana-Farber Cancer Institute, Inc. Heteroaromatic compounds useful for the treatment of proliferative diseases
US11142507B2 (en) 2015-09-09 2021-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
CN114105887A (en) * 2021-09-16 2022-03-01 沈阳药科大学 Aminopyrimidine derivative and preparation method and application thereof
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US11390609B2 (en) 2017-06-30 2022-07-19 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
US11471456B2 (en) 2019-02-12 2022-10-18 Sumitomo Pharma Oncology, Inc. Formulations comprising heterocyclic protein kinase inhibitors
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
GB0305929D0 (en) 2003-03-14 2003-04-23 Novartis Ag Organic compounds
SG145749A1 (en) * 2003-08-15 2008-09-29 Novartis Ag 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
KR100602320B1 (en) * 2005-05-03 2006-07-18 주식회사 하이닉스반도체 Non-volatile memory device having uniform programming speed
JP2010520222A (en) * 2007-03-01 2010-06-10 スーパージェン， インコーポレイテッド Use of pyrimidine-2,4-diamine derivatives and pyrimidine-2,4-diamine derivatives as JAK2 kinase inhibitors
BRPI0910921B1 (en) 2008-04-16 2022-06-21 Portola Pharmaceuticals, Inc Syk kinase protein inhibitors, pharmaceutical composition, kit and uses of said inhibitors
ES2645689T3 (en) 2008-05-21 2017-12-07 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US8877760B2 (en) 2011-11-23 2014-11-04 Portola Pharmaceuticals, Inc. Substituted pyrazine-2-carboxamide kinase inhibitors
EP2606884A1 (en) * 2011-12-21 2013-06-26 Ecole Polytechnique Fédérale de Lausanne (EPFL) Inhibitors of notch signaling pathway and use thereof in treatment of cancers
BR112020020246A8 (en) 2018-04-05 2022-10-18 Sumitomo Dainippon Pharma Oncology Inc AXL KINASE INHIBITORS AND THEIR USE
CN111362922A (en) * 2018-12-26 2020-07-03 上海喆邺生物科技有限公司 2, 4-diaminopyrimidine derivatives and their use

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019065A1 (en) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
WO2000039101A1 (en) * 1998-12-24 2000-07-06 Astrazeneca Ab Pyrimidine compounds
WO2001064655A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab 2, 4-di(hetero-)arylamino (-oxy)-5-substituted pyrimidines as antineoplastic agents
WO2001064656A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab 2,4,di(hetero-)arylamino(-oxy)-5-substituted pyrimidines as antineoplastic agents
WO2001064654A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab Pyrimidine compounds
WO2003031406A2 (en) * 2001-10-12 2003-04-17 Irm Llc Kinase inhibitor scaffolds and methods for their preparation
WO2003032997A1 (en) * 2001-10-17 2003-04-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pyrimidine derivatives, pharmaceutical agent containing said compounds, use and method for making same
WO2003040141A1 (en) * 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Oxazolyl-phenyl-2,4-diamino-pyrimidine compounds and methods for treating hyperproliferative disorders

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW225528B (en) * 1992-04-03 1994-06-21 Ciba Geigy Ag
US5543520A (en) * 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019065A1 (en) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
WO2000039101A1 (en) * 1998-12-24 2000-07-06 Astrazeneca Ab Pyrimidine compounds
WO2001064655A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab 2, 4-di(hetero-)arylamino (-oxy)-5-substituted pyrimidines as antineoplastic agents
WO2001064656A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab 2,4,di(hetero-)arylamino(-oxy)-5-substituted pyrimidines as antineoplastic agents
WO2001064654A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab Pyrimidine compounds
WO2003040141A1 (en) * 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Oxazolyl-phenyl-2,4-diamino-pyrimidine compounds and methods for treating hyperproliferative disorders
WO2003031406A2 (en) * 2001-10-12 2003-04-17 Irm Llc Kinase inhibitor scaffolds and methods for their preparation
WO2003032997A1 (en) * 2001-10-17 2003-04-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pyrimidine derivatives, pharmaceutical agent containing said compounds, use and method for making same

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DING ET AL: "A Combinatorial Scaffold Approach toward Kinase-Directed Heterocycle Libraries" 2 February 2002 (2002-02-02), JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, PAGE(S) 1594-1596 , XP002210160 ISSN: 0002-7863 table 2 *
GHOSH D: "2,4-BIS(ARYLAMINO)-6-METHYL PYRIMIDINES AS ANTIMICROBIAL AGENTS" JOURNAL OF THE INDIAN CHEMICAL SOCIETY, THE INDIAN CHEMICAL SOCIETY, CALCUTTA, IN, vol. 58, no. 5, May 1981 (1981-05), pages 512-513, XP000918018 ISSN: 0019-4522 *
GHOSH, D.; MUKHERJEE,M.: "2,4-Bis(arylamino)-5-methylpyrimidines as Antimicrobial Agents" J. MED. CHEM., vol. 10, 1967, pages 974-975, XP002281234 *

Cited By (162)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7060827B2 (en) 2002-02-01 2006-06-13 Rigel Pharmaceuticals, Inc. Intermediates useful for making 2,4-pyrimidinediamine compounds
US9499493B2 (en) 2002-02-01 2016-11-22 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7589200B2 (en) * 2002-02-01 2009-09-15 Rigel Pharmaceuticals, Inc. 5-Fluoro-4N-phenyl-4-pyrimidineamine compounds
US9133133B2 (en) * 2002-02-01 2015-09-15 Rigel Pharmaceuticals, Inc. 2,4-pyridinediamine compounds and their uses
US10682350B2 (en) 2002-02-01 2020-06-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9540334B2 (en) 2002-02-01 2017-01-10 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US10369148B2 (en) 2002-02-01 2019-08-06 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US10709703B2 (en) 2002-02-01 2020-07-14 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US20140303154A1 (en) * 2002-02-01 2014-10-09 Rigel Pharmaceuticals, Inc. 2,4-pyridinediamine compounds and their uses
US8334296B2 (en) 2002-02-01 2012-12-18 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7906644B2 (en) 2002-02-01 2011-03-15 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US11007193B2 (en) 2002-02-01 2021-05-18 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7820819B2 (en) 2002-02-01 2010-10-26 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7655797B2 (en) 2002-02-01 2010-02-02 Rigel Pharmaceuticals, Inc. Intermediates for making 2,4-pyrimidinediamine compounds
US7803939B2 (en) 2002-02-01 2010-09-28 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7812029B1 (en) 2002-07-29 2010-10-12 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7825116B2 (en) 2002-07-29 2010-11-02 Rigel Pharmaceuticals, Inc. N2, N4-bis-aryl-5-fluoro-2,4-pyrimidinediamines
US7741336B2 (en) 2002-12-20 2010-06-22 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
NL1025071C2 (en) * 2002-12-20 2004-12-30 Pfizer Prod Inc Compounds for the treatment of abnormal cell growth.
US7674796B2 (en) 2002-12-20 2010-03-09 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7351712B2 (en) 2002-12-20 2008-04-01 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
WO2004056786A2 (en) * 2002-12-20 2004-07-08 Pfizer Products Inc. Pyrimidine derivates for the treatment of abnormal cell growth
US7109335B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
WO2004056786A3 (en) * 2002-12-20 2004-10-21 Pfizer Prod Inc Pyrimidine derivates for the treatment of abnormal cell growth
US7109337B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US9751893B2 (en) 2003-07-30 2017-09-05 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7122542B2 (en) 2003-07-30 2006-10-17 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7235562B2 (en) 2004-05-14 2007-06-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7145008B2 (en) 2004-05-14 2006-12-05 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7208499B2 (en) 2004-05-14 2007-04-24 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7482351B2 (en) 2004-06-29 2009-01-27 Rigel Pharmaceuticals, Inc. 4-pyrimidineamine compounds and their uses as anti-proliferative agents
WO2006004776A1 (en) * 2004-06-29 2006-01-12 Rigel Pharmaceuticals, Inc. 4-pyrimidineamine compounds and their uses as anti-proliferative agents
WO2006012502A3 (en) * 2004-07-23 2006-03-16 Rigel Pharmaceuticals Inc Formulation of insoluble small molecule therapeutics in lipid-based carriers
WO2006012502A2 (en) * 2004-07-23 2006-02-02 Rigel Pharmaceuticals, Inc. Formulation of insoluble small molecule therapeutics in lipid-based carriers
WO2006021454A3 (en) * 2004-08-27 2006-05-04 Novartis Ag Pyrimidine derivatives
JP2008510765A (en) * 2004-08-27 2008-04-10 ノバルティス アクチエンゲゼルシャフト Pyrimidine derivatives
JP2008510763A (en) * 2004-08-27 2008-04-10 ノバルティス アクチエンゲゼルシャフト Pyrimidine derivatives
WO2006037117A1 (en) * 2004-09-27 2006-04-06 Amgen Inc. Substituted heterocyclic compounds and methods of use
US7851480B2 (en) 2004-11-24 2010-12-14 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
US10577381B2 (en) 2005-01-19 2020-03-03 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
US11198689B2 (en) 2005-06-08 2021-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8415365B2 (en) 2005-06-08 2013-04-09 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US9732073B2 (en) 2005-06-08 2017-08-15 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US9593082B2 (en) 2005-06-08 2017-03-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
JP2008543778A (en) * 2005-06-08 2008-12-04 ライジェル ファーマシューティカルズ， インコーポレイテッド Compositions and methods for inhibition of the JAK pathway
US11827628B2 (en) 2005-06-08 2023-11-28 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
JP2012229217A (en) * 2005-06-08 2012-11-22 Rigel Pharmaceuticals Inc Composition and method for inhibition of jak pathway
US8399472B2 (en) 2005-06-08 2013-03-19 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US10421752B2 (en) 2005-06-08 2019-09-24 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8246984B2 (en) 2005-12-06 2012-08-21 Rigel Pharmaceuticals, Inc. Formulation of insoluble small molecule therapeutics in lipid-based carriers
US7820648B2 (en) 2005-12-21 2010-10-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
JP2009524632A (en) * 2006-01-26 2009-07-02 アストラゼネカ アクチボラグ Pyrimidine derivatives
US11667611B2 (en) 2006-02-24 2023-06-06 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8962643B2 (en) 2006-02-24 2015-02-24 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
WO2007098507A2 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2007105023A1 (en) * 2006-03-15 2007-09-20 Csir Modulation of phosphoryl transferase activity of glutamine synthetase
GB2451594A (en) * 2006-03-15 2009-02-04 Csir Modulation of phosphoryl transferase activity of glutamine synthetase
WO2007114827A1 (en) * 2006-04-06 2007-10-11 Amgen Inc. Substituted heterocyclic compounds and methods of use
US8729087B2 (en) 2006-10-19 2014-05-20 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8193197B2 (en) 2006-10-19 2012-06-05 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
JP2010507588A (en) * 2006-10-19 2010-03-11 ライジェル ファーマシューティカルズ， インコーポレイテッド 2,4-Pyrimidineamine derivatives as inhibitors of JAK kinase for the treatment of autoimmune diseases
WO2008049123A3 (en) * 2006-10-19 2008-06-19 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine derivatives as inhibitors of jak kinases for the treatment of autoimmune diseases
US9040543B2 (en) 2006-10-19 2015-05-26 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
US8552186B2 (en) 2006-10-23 2013-10-08 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors
US8148391B2 (en) 2006-10-23 2012-04-03 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
US8377921B2 (en) 2006-12-08 2013-02-19 Irm Llc Compounds and compositions as protein kinase inhibitors
US8399450B2 (en) 2006-12-08 2013-03-19 Irm Llc Compounds and compositions as protein kinase inhibitors
US8957081B2 (en) 2006-12-08 2015-02-17 Irm Llc Compounds and compositions as protein kinase inhibitors
US8039479B2 (en) 2006-12-08 2011-10-18 Irm Llc Compounds and compositions as protein kinase inhibitors
US8372858B2 (en) 2006-12-08 2013-02-12 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2008079907A1 (en) * 2006-12-20 2008-07-03 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
EP1939185A1 (en) * 2006-12-20 2008-07-02 Bayer Schering Pharma Aktiengesellschaft New types of hetaryl-phenylendiamin-pyrimidines as protein kinase inhibitors for the treatment of cancer
WO2008074515A1 (en) * 2006-12-20 2008-06-26 Bayer Schering Pharma Aktiengesellschaft Novel hetaryl-phenylene-diamine pyrimidine as protein kinase inhibitors
US8084609B2 (en) 2006-12-22 2011-12-27 Hoffman-La Roche Inc. Spiropiperidine derivatives
FR2911137A1 (en) * 2007-01-05 2008-07-11 Sanofi Aventis Sa New 2,4-diaminopyrimidine derivatives useful for treating inflammatory diseases, diabetes or cancer
WO2008099072A3 (en) * 2007-01-05 2008-11-13 Sanofi Aventis New 2, 4-dianilinopyrimidines, preparation thereof as drugs, pharmaceutical compositions and use thereof essentially as ikk inhibitors
WO2008099072A2 (en) * 2007-01-05 2008-08-21 Sanofi-Aventis New 2, 4-dianilinopyrimidines, preparation thereof as drugs, pharmaceutical compositions and use thereof essentially as ikk inhibitors
US20100029588A1 (en) * 2007-03-12 2010-02-04 Bayer Cropscience Ag Substituted phenylamidines and the use thereof as fungicides
US8334237B2 (en) * 2007-03-12 2012-12-18 Bayer Cropscience Ag Substituted phenylamidines and the use thereof as fungicides
US8440822B2 (en) 2007-04-18 2013-05-14 Michael Joseph Luzzio Sulfonyl amide derivatives for the treatment of abnormal cell growth
EA016679B1 (en) * 2007-04-18 2012-06-29 Пфайзер Продактс Инк. Sulfonyl amide derivatives for the treatment of abnormal cell growth
WO2008129380A1 (en) 2007-04-18 2008-10-30 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
US7928109B2 (en) 2007-04-18 2011-04-19 Pfizer Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth
US10450297B2 (en) 2007-04-18 2019-10-22 Pfizer, Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
KR101132880B1 (en) * 2007-04-18 2012-06-28 화이자 프로덕츠 인크. Sulfonyl amide derivatives for the treatment of abnormal cell growth
CN103951658B (en) * 2007-04-18 2017-10-13 辉瑞产品公司 Sulfamide derivative for treating abnormal cell growth
AU2014201847B2 (en) * 2007-04-18 2015-12-24 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
AU2008240359B2 (en) * 2007-04-18 2014-06-26 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
CN103951658A (en) * 2007-04-18 2014-07-30 辉瑞产品公司 Sulfonyl amide derivatives for the treatment of abnormal cell growth
CN101678215B (en) * 2007-04-18 2014-10-01 辉瑞产品公司 Sulfonyl amide derivatives for the treatment of abnormal cell growth
US8247411B2 (en) 2007-04-18 2012-08-21 Pfizer Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth
AU2016201820B2 (en) * 2007-04-18 2018-03-08 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
WO2009071535A1 (en) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Diaminopyridines for the treatment of diseases which are characterised by excessive or anomal cell proliferation
JP2011505407A (en) * 2007-12-03 2011-02-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Diaminopyridine for treating diseases characterized by excessive or abnormal cell proliferation
US8461147B2 (en) 2007-12-03 2013-06-11 Boehringer Ingelheim International Gmbh Diaminopyridines for the treatment of diseases which are characterised by excessive or anomal cell proliferation
US7923450B2 (en) 2008-01-11 2011-04-12 Hoffmann-La Roche Inc. Modulators for amyloid beta
CN101952275A (en) * 2008-02-22 2011-01-19 弗·哈夫曼-拉罗切有限公司 Modulators for amyloid beta
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
WO2009103652A1 (en) * 2008-02-22 2009-08-27 F. Hoffmann-La Roche Ag Modulators for amyloid beta
KR101247840B1 (en) * 2008-02-22 2013-03-26 에프. 호프만-라 로슈 아게 Modulators for amyloid beta
JP2011512380A (en) * 2008-02-22 2011-04-21 エフ．ホフマン−ラ ロシュ アーゲー Modulator of amyloid β
US8937070B2 (en) 2008-04-16 2015-01-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US9868729B2 (en) 2008-04-16 2018-01-16 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US10533001B2 (en) 2008-04-16 2020-01-14 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8501944B2 (en) 2008-04-16 2013-08-06 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
WO2009136995A2 (en) 2008-04-16 2009-11-12 Portola Pharmaceuticals, Inc. Inhibitors of syk protein kinase
US11414410B2 (en) 2008-04-16 2022-08-16 Alexion Pharmaceuticals, Inc. Inhibitors of protein kinases
US9139581B2 (en) 2008-04-22 2015-09-22 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8258144B2 (en) 2008-04-22 2012-09-04 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
WO2010034626A3 (en) * 2008-09-29 2011-07-21 Henkel Ag & Co. Kgaa Novel developer components
US8389717B2 (en) 2008-10-09 2013-03-05 Hoffmann-La Roche Inc. Modulators for amyloid beta
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
JP2012515206A (en) * 2009-01-15 2012-07-05 ライジェル ファーマシューティカルズ， インコーポレイテッド Protein kinase C inhibitors and uses thereof
WO2011018518A1 (en) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Regioselective preparation of 2 -amino-5-trifluoromethylpyrimidine derivatives
WO2011018517A1 (en) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
WO2012061415A1 (en) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines as syk modulators
US9102625B2 (en) 2010-11-01 2015-08-11 Portola Pharmaceuticals, Inc. Nicotinamides as JAK kinase modulators
EP3176154A1 (en) 2010-11-01 2017-06-07 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
WO2012061418A2 (en) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis
US9006241B2 (en) 2011-03-24 2015-04-14 Noviga Research Ab Pyrimidine derivatives
US9249124B2 (en) 2011-03-30 2016-02-02 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase inhibitors and methods of making and using thereof
US9597329B2 (en) 2011-03-30 2017-03-21 H. Lee Moffitt Cancer Center And Research Institute, Inc Aurora kinase inhibitors and methods of making and using thereof
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US10875864B2 (en) 2011-07-21 2020-12-29 Sumitomo Dainippon Pharma Oncology, Inc. Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors
US10981903B2 (en) 2011-11-17 2021-04-20 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-terminal kinase (JNK)
US20190248778A1 (en) * 2011-11-17 2019-08-15 Dana-Farber Cancer Institute, Inc. Inhibitors of c-jun-n-terminal kinase (jnk)
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
JP2015528440A (en) * 2012-08-10 2015-09-28 コーリア リサーチ インスティテュート オブ ケミカル テクノロジー N2, N4-bis (4- (piperazin-1-yl) phenyl) pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof, and cancer containing this derivative or salt as an active ingredient Composition for treating
US9676756B2 (en) 2012-10-08 2017-06-13 Portola Pharmaceuticals, Inc. Substituted pyrimidinyl kinase inhibitors
USRE48175E1 (en) 2012-10-19 2020-08-25 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
JP2016513661A (en) * 2013-03-14 2016-05-16 トレロ ファーマシューティカルズ， インコーポレイテッド JAK2 and ALK2 inhibitors and methods of use thereof
JP2020125354A (en) * 2013-03-14 2020-08-20 トレロ ファーマシューティカルズ， インコーポレイテッド Jak2 and alk2 inhibitors and methods for their use
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US10906889B2 (en) 2013-10-18 2021-02-02 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
US11040957B2 (en) 2013-10-18 2021-06-22 Dana-Farber Cancer Institute, Inc. Heteroaromatic compounds useful for the treatment of proliferative diseases
US10526291B2 (en) 2014-08-03 2020-01-07 H. Lee Moffitt Cancer Center And Research Institute, Inc. Potent dual BRD4-kinase inhibitors as cancer therapeutics
US10106507B2 (en) * 2014-08-03 2018-10-23 H. Lee Moffitt Cancer Center and Research Insitute, Inc. Potent dual BRD4-kinase inhibitors as cancer therapeutics
US10870651B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US11142507B2 (en) 2015-09-09 2021-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
US11643396B2 (en) 2015-10-13 2023-05-09 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
JP2020521771A (en) * 2017-05-26 2020-07-27 キャンサー・リサーチ・テクノロジー・リミテッドＣａｎｃｅｒ Ｒｅｓｅａｒｃｈ Ｔｅｃｈｎｏｌｏｇｙ Ｌｉｍｉｔｅｄ BCL6 inhibitor derived from benzimidazolone
CN111163839A (en) * 2017-05-26 2020-05-15 癌症研究科技有限公司 Benzimidazolone-derived BCL6 inhibitors
US10323023B2 (en) 2017-06-30 2019-06-18 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US11390609B2 (en) 2017-06-30 2022-07-19 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
US10329282B2 (en) 2017-06-30 2019-06-25 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
CN109776522A (en) * 2017-10-30 2019-05-21 广东东阳光药业有限公司 Substituted heteroaryl compound and combinations thereof and purposes
CN109776522B (en) * 2017-10-30 2020-12-29 广东东阳光药业有限公司 Substituted heteroaryl compounds, compositions and uses thereof
WO2019200254A1 (en) 2018-04-13 2019-10-17 Tolero Pharmaceuticals, Inc. Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer
WO2020006724A1 (en) * 2018-07-05 2020-01-09 清华大学 Compound for targeted degradation of fak protein and use thereof
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
US11471456B2 (en) 2019-02-12 2022-10-18 Sumitomo Pharma Oncology, Inc. Formulations comprising heterocyclic protein kinase inhibitors
CN114105887A (en) * 2021-09-16 2022-03-01 沈阳药科大学 Aminopyrimidine derivative and preparation method and application thereof
CN114105887B (en) * 2021-09-16 2023-12-01 沈阳药科大学 Aminopyrimidine derivative and preparation method and application thereof

Also Published As

Publication number Publication date
WO2004046118A3 (en) 2004-08-12
AU2003299474A1 (en) 2004-06-15
WO2003095448A1 (en) 2003-11-20
AU2003231231A1 (en) 2003-11-11
AU2003299474A8 (en) 2004-06-15

Similar Documents

Publication Publication Date Title
WO2004046118A2 (en) 2-4-(di-phenyl-amino)-pyrimidine derivatives useful for treating hyper-proliferative disorders
EP1565455A1 (en) Indolyl pyrazinone derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
EP1957078B1 (en) Pyrrolotriazine derivatives useful for treating cancer through inhibition of aurora kinase
EP2113500A1 (en) MAPK/ERK kinase inhibitors
CN110016021B (en) Immunomodulator
KR20100016617A (en) Inhibitors of hypoxia inducible factor (hif) useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
WO2006085685A1 (en) Pyrazole compound
AU2006292429A1 (en) Carbazole derivatives
HRP20040874A2 (en) Benzofuran and benzothiophene derivatives useful in the treatment of hyper-proliferative disorders
US6337342B1 (en) Bis-aryl or heteroaryl indoles
JP4709757B2 (en) Benzofuran derivatives useful for the treatment of hyperproliferative disorders
WO2004110989A1 (en) N-hydroxy-7-(arylamino)heptanamide derivatives useful for treating hyper-proliferative disorders
EP4066895A1 (en) Compound having lysophosphatidic acid receptor agonistic activity and pharmaceutical use of said compound
EP1620397A1 (en) Hydroxamic acids useful in the treatment of hyper-proliferative disorders
US20060004011A1 (en) Indolyl pyrazinone derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
WO2004039359A2 (en) Use of pyrimidine derivates for the manifacture of a medicament for the treatment of hyper-proliferative disorders
US20040180891A1 (en) Pyrazole derivatives useful in the treatment of hyper-proliferative disorders
US20060142295A1 (en) Method of treating cancer with quinolone carboxylic acid derivatives
WO2005051957A1 (en) Indolyl-thieno`3,4-b!pyrazin-3-one derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
MX2008007030A (en) Chromane substituted benzimidazoles and their use as acid pump inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP