WO2008128231A1 - Pyrimidine derivatives - Google Patents

Pyrimidine derivatives Download PDF

Info

Publication number
WO2008128231A1
WO2008128231A1 PCT/US2008/060366 US2008060366W WO2008128231A1 WO 2008128231 A1 WO2008128231 A1 WO 2008128231A1 US 2008060366 W US2008060366 W US 2008060366W WO 2008128231 A1 WO2008128231 A1 WO 2008128231A1
Authority
WO
WIPO (PCT)
Prior art keywords
heteroaryl
aryl
methyl
alkyl
indol
Prior art date
Application number
PCT/US2008/060366
Other languages
French (fr)
Inventor
Wei-Guo Su
Hong Jia
Weihan Zhang
Yumin Cui
Xiaoqiang Yan
Yongxin Ren
Jifeng Duan
Yang Sai
Original Assignee
Hutchison Medipharma Enterprises Limited
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
Priority to CA2684470A priority Critical patent/CA2684470C/en
Application filed by Hutchison Medipharma Enterprises Limited filed Critical Hutchison Medipharma Enterprises Limited
Priority to SI200831203T priority patent/SI2154967T1/en
Priority to NZ580671A priority patent/NZ580671A/en
Priority to JP2010504191A priority patent/JP5635398B2/en
Priority to BRPI0809715-1A priority patent/BRPI0809715A2/en
Priority to AU2008240084A priority patent/AU2008240084B2/en
Priority to ES08745881.6T priority patent/ES2465673T3/en
Priority to PL08745881T priority patent/PL2154967T3/en
Priority to DK08745881.6T priority patent/DK2154967T5/en
Priority to MX2009011199A priority patent/MX2009011199A/en
Priority to EP08745881.6A priority patent/EP2154967B9/en
Publication of WO2008128231A1 publication Critical patent/WO2008128231A1/en
Priority to HRP20140377AT priority patent/HRP20140377T2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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

Definitions

  • Angiogenesis is a physiological process of growing new blood vessels from pre-existing vessels. It takes place in a healthy subject to heal wounds, i.e., restoring blood flow to tissues after injury or insult. Excessive blood vessel growth may be triggered by certain pathological conditions such as cancer, age-related macular degeneration, rheumatoid arthritis, and psoriasis. As a result, new blood vessels feed diseased tissues and destroy normal tissues. In cancer, new blood vessels also allow tumor cells to escape into the circulation and lodge in other organs.
  • VEGF vascular endothelial growth factor
  • KDR kinase insert domain receptor
  • KDR inhibitors are therefore potential candidates for treating angiogenesis-related diseases.
  • This invention is based on the discovery that a number of pyrimidine compounds inhibit the activity of KDR.
  • One aspect of this invention features pyrimidine compounds of the following formula (I):
  • each of X and Y independently, is O, S, or NR, wherein R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; Z is CR' or N, wherein R' is H, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
  • V, U, and T together represent , * 5 Vs " - """ OV, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl; R 5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R 7 is alkyl.
  • R 1 , R 2 , R3, and R 4 is H and R5 is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
  • alkyl herein refers to a straight or branched hydrocarbon, containing 1-10 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, and /-butyl.
  • alkoxy refers to an -O-alkyl.
  • aryl refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14- carbon tricyclic aromatic ring system wherein each ring may have 1 to 4 substituents.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • cycloalkyl refers to a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, or S).
  • heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.
  • heteroarylkyl refers to an alkyl group substituted with a heteroaryl group.
  • heterocycloalkyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, or S).
  • heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.
  • Heterocycloalkyl can be a saccharide ring, e.g., glucosyl.
  • Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy mentioned herein include both substituted and unsubstituted moieties.
  • substituents include, but are not limited to, halo, hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, in which alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl cycloalkyl, and heterocycloalkyl may further substituted.
  • the pyrimidine compounds described above include their pharmaceutically acceptable salts, hydrate and prodrug, if applicable.
  • Another aspect of this invention features a method of treating an angiogenesis-related disorder (e.g., cancer or age-related macula degeneration).
  • the method includes administering to a subject having such an disorder an effective amount of one or more of the above-described pyrimidine compounds.
  • Still another aspect of this invention features a method of inhibiting the activity of kinase insert domain receptor by contacting the receptor with an effective amount of a pyrimidine compound of formula (II):
  • Ri is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl
  • each of R 2 and R 3 independently, is H, halogen, nitro, amino, CN, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylcarbonyl, carboxy, or alkoxycarbonyl
  • each of X and Y independently, is O, S, Or NR 4 , wherein R 4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl
  • Ar is aryl or heteroaryl.
  • Ar is indolyl, indazolyl, benzoimidazolyl, or benzoxazolyl;
  • X is O or NH and Y is NH;
  • Ri is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
  • Exemplary compounds 1-317 are shown in the Detailed Description section below.
  • Yet another aspect of this invention features a method of inhibiting angiogenesis, or treating age-related macular degeneration, by administrating to a subject in need thereof an effective amount of a pyrimidine compound of formula (II) as described above.
  • a composition containing one or more of the pyrimidine compounds described above and a pharmaceutically acceptable carrier for use in treating an angiogenesis-related disorder e.g., such cancer or age-related macular degeneration
  • use of one or more of the pyrimidine compounds for the manufacture of a medicament for treating the disorder.
  • the compounds described above can be synthesized from commercially available starting materials by methods well known in the art.
  • leaving groups e.g., chloride, p-TsO, MeS, or MeSO 2
  • N4-positions of a suitable pyrimidine compound with nucleophilic groups such as amino or hydroxyl via, e.g., Buchwald-Hartwig coupling reaction.
  • the replacement can be first effected either at the N2 position or the N4 position.
  • the compounds thus obtained can be further modified at their peripheral positions to provide the desired compounds.
  • an effective amount of one or more of these compounds can be therefore used to inhibit angiogenesis and treat a subject having an angiogenesis-related disorder.
  • an effective amount refers to the amount of a pyrimidine compound that is required to confer the intended effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents.
  • treating refers to administering one or more of the above-described pyrimidine compounds to a subject that has an angiogenesis-related disorder, or has a symptom of the disorder, or has a predisposition toward the disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of the disorder, or the predisposition toward the disorder.
  • a composition having one or more of the pyrimidine compounds of this invention can be administered orally, parenterally, by inhalation spray, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added to tablets.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
  • a sterile injectable composition e.g., aqueous or oleaginous suspension
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a topical composition can be formulated in form of oil, cream, lotion, ointment and the like.
  • suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C 12).
  • the preferred carriers are those in which the active ingredient is soluble.
  • Emulsif ⁇ ers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers can be found in U.S. Patents 3,989,816 and 4,444,762.
  • Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • An example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
  • An example of such an ointment is one which includes about 30% by weight almond and about 70% by weight white soft paraffin.
  • a carrier in a pharmaceutical composition must be "acceptable” in the sense that it is compatible with active ingredients of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with one or more of active pyrimidine compounds of the extract), can be utilized as pharmaceutical excipients for delivery of the active ingredients.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • Suitable in vitro assays can be used to preliminarily evaluate the efficacy of the above-described pyrimidine compounds in inhibiting the activity of KDR or inhibiting the activity of VEGF.
  • the compounds can further be examined for its efficacy in treating an angiogenesis-related disorder by in vivo assays.
  • the compounds can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects are then accessed. Based on the results, an appropriate dosage range and administration route can also be determined.
  • N-(2-chloropyrimidin-4-yl)-2-methyl-lH-indol-5-amine(0.1 mmol) and aniline (0.1 mmol) were dissolved in 0.5ml DMF.
  • p-TsOH monohydrate 0.2 mmol.
  • the reaction mixture was stirred at 60 C for 5 hours, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na 2 SO 4 , and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 85%.
  • Example 2-283 Synthesis of Compounds 2-283 Compounds 2-283 were each synthesized in a manner similar to that described in Example 1.
  • Example 307 Synthesis of N2-(3-ethynylphenyl)-N4-(2-methylbenzo[d]oxazol-6-yl) pyrimidine-2,4-diamine (Compound 307).
  • Example 318 KDR kinase activity assay using Z'-lyte kinase assay kit
  • Inhibition of kinase activity of a recombinant KDR catalytic domain was determined using Z'-LYTETM Tyrl Peptide assay kit (Invitrogen, Cat. PV3190) in a black 384-well plate (Thermo labsystems, Cambridge, U.K., Cat. 7805). The assay was performed according to the procedures recommended by the manufacturer.
  • a test compound (10 mM stock in DMSO) was diluted to 1 :4 with distilled water containing 8% DMSO. The solution was placed in a test well and three control wells (Cl, C2, and C3) at 2.5 ⁇ l/well.
  • Coumarin- fluorescein double-labeled peptide substrate was mixed with the KDR catalytic domain ("kinase"). 5 ⁇ l of the kinase/peptide mixture was added to each of the test, Cl, and C2 wells, but not C3 (Final concentration: 0.3 ⁇ g/ml of Kinase, 2 ⁇ M of peptide). 5 ⁇ l of Phosphor-Tyrl peptide was added to the C3 well.
  • a development reagent was diluted to 1 : 128 according to the recommendation of the manufacturer. 5 ⁇ l of the diluted development reagent was added to each well. The plate was spun at 1000 rpm to settle all solution down to the wells, and then sealed and shaken at 250 rpm and 25 0 C for 1 hour.
  • Cioo % Average Coumarin emission signal of the 100% Phos.
  • Control Co% Average Coumarin emission signal of the 0% Phos.
  • Control Fioo% Average Fluorescein emission signal of the 100% Phos.
  • Control Fo% Average Fluorescein emission signal of the 0% Phos.
  • the inhibition ratio was calculated as follows:
  • Inhibition% (Phos. in C2 well - Phos. in test well)/ (Phos. in C2 well) x 100%
  • the result showed that all of the tested compounds inhibited the activity of KDR.
  • the IC 50 values ranged from 0.001 to 10 ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Disclosed are pyrimidine compounds of formula (I) shown in the specification. Also disclosed is a method of treating an angiogenesis-related disorder, e.g., cancer or age-related macular degeneration, with such a compound.

Description

PYRIMIDINE DERIVATIVES
CROSS REFERENCE TO RELATEDAPPLICATIONS
This application claims priority to U.S. Provisional Application Serial No. 60/911,921, filed April 16, 2007. The contents of the prior application are hereby incorporated by reference in their entireties.
BACKGROUND
Angiogenesis is a physiological process of growing new blood vessels from pre-existing vessels. It takes place in a healthy subject to heal wounds, i.e., restoring blood flow to tissues after injury or insult. Excessive blood vessel growth may be triggered by certain pathological conditions such as cancer, age-related macular degeneration, rheumatoid arthritis, and psoriasis. As a result, new blood vessels feed diseased tissues and destroy normal tissues. In cancer, new blood vessels also allow tumor cells to escape into the circulation and lodge in other organs. Vascular endothelial growth factor (VEGF), a homodimeric glycoprotein, and its receptors, e.g., kinase insert domain receptor (KDR), constitute an important angiogenic pathway. Studies have shown that inhibition of KDR resulted in endothelial cell apoptosis and, thus, suppression of angiogenesis. See Rubin M. Tuder, Chest, 2000; 117: 281. KDR inhibitors are therefore potential candidates for treating angiogenesis-related diseases.
SUMMARY
This invention is based on the discovery that a number of pyrimidine compounds inhibit the activity of KDR. One aspect of this invention features pyrimidine compounds of the following formula (I):
Figure imgf000003_0001
in which each of X and Y, independently, is O, S, or NR, wherein R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; Z is CR' or N, wherein R' is H, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
or heterocycloalkyl; V, U, and T together represent
Figure imgf000003_0002
, * 5 Vs "-"""OV,
Figure imgf000003_0003
nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl; R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R7 is alkyl.
Referring to formula (I), one subset of the compounds features that R1, R2, R3, and R4 is H and R5 is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl. Another subset features that X is O or NH; Y is NH; V, U, and T together represent
Figure imgf000004_0001
, in which R6 can be H and R7 can be methyl; or Z is CR', in which R' is H, halo, or alkyl.
The term "alkyl" herein refers to a straight or branched hydrocarbon, containing 1-10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, and /-butyl. The term "alkoxy" refers to an -O-alkyl.
The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14- carbon tricyclic aromatic ring system wherein each ring may have 1 to 4 substituents. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "cycloalkyl" refers to a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, or S). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group.
The term "heterocycloalkyl" refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, or S). Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. Heterocycloalkyl can be a saccharide ring, e.g., glucosyl.
Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy mentioned herein include both substituted and unsubstituted moieties. Examples of substituents include, but are not limited to, halo, hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, in which alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl cycloalkyl, and heterocycloalkyl may further substituted.
The pyrimidine compounds described above include their pharmaceutically acceptable salts, hydrate and prodrug, if applicable.
Another aspect of this invention features a method of treating an angiogenesis- related disorder (e.g., cancer or age-related macula degeneration). The method includes administering to a subject having such an disorder an effective amount of one or more of the above-described pyrimidine compounds. Still another aspect of this invention features a method of inhibiting the activity of kinase insert domain receptor by contacting the receptor with an effective amount of a pyrimidine compound of formula (II):
. Ar X
Ri.γΛNAR3
(H), in which Ri is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each of R2 and R3, independently, is H, halogen, nitro, amino, CN, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylcarbonyl, carboxy, or alkoxycarbonyl; each of X and Y, independently, is O, S, Or NR4, wherein R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; and Ar is aryl or heteroaryl.
Referring to formula (II), one subset of the compounds features that Ar is indolyl, indazolyl, benzoimidazolyl, or benzoxazolyl; X is O or NH and Y is NH; or Ri is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
Exemplary compounds 1-317 are shown in the Detailed Description section below. Yet another aspect of this invention features a method of inhibiting angiogenesis, or treating age-related macular degeneration, by administrating to a subject in need thereof an effective amount of a pyrimidine compound of formula (II) as described above. Also within the scope of this invention are (1) a composition containing one or more of the pyrimidine compounds described above and a pharmaceutically acceptable carrier for use in treating an angiogenesis-related disorder (e.g., such cancer or age-related macular degeneration) and (2) use of one or more of the pyrimidine compounds for the manufacture of a medicament for treating the disorder. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION The compounds described above can be synthesized from commercially available starting materials by methods well known in the art. As an example, one can replace leaving groups (e.g., chloride, p-TsO, MeS, or MeSO2) at the active N2, N4-positions of a suitable pyrimidine compound with nucleophilic groups such as amino or hydroxyl via, e.g., Buchwald-Hartwig coupling reaction. The replacement can be first effected either at the N2 position or the N4 position.
The compounds thus obtained can be further modified at their peripheral positions to provide the desired compounds.
Synthetic chemistry transformations useful in synthesizing desirable pyrimidine compounds are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. Before use, the compounds can be purified by column chromatography, high performance liquid chromatography, crystallization, or other suitable methods. The pyrimidine compounds described above, when contacting with KDR, inhibit this receptor's activity. An effective amount of one or more of these compounds can be therefore used to inhibit angiogenesis and treat a subject having an angiogenesis-related disorder. The term "an effective amount" refers to the amount of a pyrimidine compound that is required to confer the intended effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents. The term "treating" refers to administering one or more of the above-described pyrimidine compounds to a subject that has an angiogenesis-related disorder, or has a symptom of the disorder, or has a predisposition toward the disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of the disorder, or the predisposition toward the disorder.
To practice this method, a composition having one or more of the pyrimidine compounds of this invention can be administered orally, parenterally, by inhalation spray, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added to tablets. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
A sterile injectable composition (e.g., aqueous or oleaginous suspension) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
A topical composition can be formulated in form of oil, cream, lotion, ointment and the like. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C 12). The preferred carriers are those in which the active ingredient is soluble. Emulsifϊers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers can be found in U.S. Patents 3,989,816 and 4,444,762. Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. An example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. An example of such an ointment is one which includes about 30% by weight almond and about 70% by weight white soft paraffin.
A carrier in a pharmaceutical composition must be "acceptable" in the sense that it is compatible with active ingredients of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which form specific, more soluble complexes with one or more of active pyrimidine compounds of the extract), can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
Suitable in vitro assays can be used to preliminarily evaluate the efficacy of the above-described pyrimidine compounds in inhibiting the activity of KDR or inhibiting the activity of VEGF. The compounds can further be examined for its efficacy in treating an angiogenesis-related disorder by in vivo assays. For example, the compounds can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects are then accessed. Based on the results, an appropriate dosage range and administration route can also be determined.
Without further elaboration, it is believed that the above description has adequately enabled the present invention. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Example 1 : Synthesis of N4-(2-methyl-lH-indol-5-yl)-N2-phenylpyrimidine-2,4- diamine (Compound 1)
Figure imgf000009_0001
Et3N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol) and 5-amino-2-methylindole (1 mmol) in 5 ml EtOH. The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition Of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to give N-(2- chloropyrimidin-4-yl)-2-methyl-lH-indo 1-5 -amine in a yield of 80%.
N-(2-chloropyrimidin-4-yl)-2-methyl-lH-indol-5-amine(0.1 mmol) and aniline (0.1 mmol) were dissolved in 0.5ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60 C for 5 hours, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 85%.
1H NMR (CD3OD, 400 MHz): δ 7.831 (d, J=6.0Hz, IH), 7.633 (t, J=8.0- 7.6Hz, 3H), 7.262 (t, J=8.4-7.6 Hz, 3H), 7.064 (d, J=6.8 Hz, IH), 6.995 ((t, J=7.6-7.2 Hz, IH), 6.133 (t, J=6.4-2.0 Hz, 2H), 2.439 (s,3H); MS (m/e): 384.2 (M+l).
Example 2-283: Synthesis of Compounds 2-283 Compounds 2-283 were each synthesized in a manner similar to that described in Example 1.
Figure imgf000010_0001
(d, (d, J=6.4 (M)
J=6.0 Hz, IH), (m, J=8.0 Hz, 1) 7.746 (s, IH), Hz,
3H);
(d, (d, /=6.8 (d,
(s, IH),
Hz,
Hz, IH),
Figure imgf000011_0001
.6 Hz,
IH),
Hz, IH), t, /=8.0 Hz, /=7.2 (s, 2H),
2H);
Hz, (s, (M+l)
IH),
7.399 IH), Hz,
/=6.0 Hz,
6.020 (M+l)
Figure imgf000012_0001
Hz, Hz,
IH), 2.490
7.914( s, IH), Hz,
IH), 8.140 2H), Hz, 2H), 2.369
IH), 9.245 (m,
(d,
IH),
Figure imgf000013_0001
387.2
2H),
IH),
IH), 7.713(s,
2H),
IH), 9.754 (s,
IH),
Figure imgf000014_0001
343.4
(d, (d, /=7.6
(s, (d, /=2.8
/=3.2-
IH), /=8.0 Hz, IH), ( s, 3H),
Hz (s, IH), Hz, IH), Hz , 2H), ,2.165
(s, 1 H), 6.401- 6.012-
Figure imgf000015_0001
2.370 (m,
(s, IH), Hz,
3H);
(s,lH), IH), 7.703 IH),
(d,
2.591
IH),
2H),
416.5
Figure imgf000016_0001
Hz, (d,
Hz IH), (q,
IH), /=6.0 Hz, (d,
Hz 2H), Hz ,
(s, IH), 7.651 6.467 3H),
IH), 2H), IH), 1.480(s,
IH),
Figure imgf000017_0001
IH),
( s, (br, IH), 3.787
IH), IH),
7.974(s,
6.200(
(m, IH), /=3.2 IH),
IH), 7.983(s,
Figure imgf000018_0001
Hz, 6.528( 3.571
/=5.6 Hz, /=8.0
5.321
IH), 7.994 Hz,
(d,
(s, IH),
(d,
(s, 1 H), (m,
Hz, 6.139 IH),
Figure imgf000019_0001
(m,
(s,
8.837
/=7.6 (s, 3H);
8.760 7.376 (s, /=8.8- (t, (s,
IH), 7.915 7.58(d,
(s, IH),
3H);
Figure imgf000020_0001
IH), 8.898 (d,
(t,
IH), 8.775 (d,
(s,
8.959 Hz,
(s, IH), 8.745 2
(s,
IH), 8.209
Figure imgf000021_0001
(s,
IH), 8.143 IH),
(t, (m,
(s, IH), (d, /=5.6 Hz, IH),
l(d,
/=8.4- (d,
/=5.6Hz,
(m,
Figure imgf000022_0001
7.399
/=8.0 Hz, (m, (s,
7.347 6.410
2.401
IH), 7.378
Hz, (s,
7.418 (s, (m,lH), ,5.800 ,2H),
7.378 (s,
Figure imgf000023_0001
(d,
1.562- 1) 8.005 (s, (d,
IH), 413.4
2H),
3.027 0.596
(s,
2H), IH, (d,
(s,
IH),
(s, 3H),
Figure imgf000024_0001
71 N-methyl-3-(4-(2-methyl-lH-indol-5- MS (m/e): 372.4 (M) ylamino)pyrimidin-2-ylamino)benzamide
Figure imgf000025_0001
72 N2-(2-fluorophenyl)-N4-(2-methyl- IH- MS (m/e): 350.1 (M+ 1) indol-5-yl)pyrimidine-2,4-diamine
Figure imgf000025_0002
73 3 -(4-(2-methyl- 1 H-indol-5- MS (m/e): 341.2(M+1) ylamino)pyrimidin-2- ylamino)benzonitrile
Figure imgf000025_0003
74 N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (τn/e): 362.3 (M+ 1)
(methylthio)phenyl)pyrimidine-2,4- diamine
Figure imgf000025_0004
75 N,N-dimethyl-3-(4-(2-methyl-lH-indol-5- MS (m/e): 423.5 (M+ 1) ylamino)pyrimidin-2- ylamino)benzenesulfonamide
Figure imgf000026_0001
76 N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e): 465.4 (M+ 1)
(moφholinosulfonyl)phenyl)pyrimidine-
2,4-diamine
Figure imgf000026_0002
77 N2-(3,4-dimethoxyphenyl)-N4-(2-methyl- MS (m/e): 376.3(M+1) lH-indol-5-yl)pyrimidine-2,4-diamine
Figure imgf000026_0003
78 N2-(4-chlorophenyl)-N4-(2-methyl- 1 H- MS (m/e): 350.3 (M+ 1) indol-5-yl)pyrimidine-2,4-diamine
Figure imgf000026_0004
79 N2-(2,4-difluorophenyl)-N4-(2-methyl- MS (m/e): 352.2 (M+ 1) lH-indol-5-yl)pyrimidine-2,4-diamine
Figure imgf000026_0005
80 N2-(3-chloro-2-fluorophenyl)-N4-(2- MS (m/e): 368.3 (M+ 1) methyl-lH-indol-5-yl)pyrimidine-2,4- diamine
Figure imgf000027_0001
Figure imgf000028_0001
91 N2-(4-chloro-2-fluorophenyl)-N4-(2- MS (m/e): 368.3(M+1) methyl-lH-indol-5-yl)pyrimidine-2,4- diamine
Figure imgf000029_0001
92 N2-(3-(2- MS (m/e): 403.4 (M+ 1)
(dimethylamino)ethoxy)phenyl) -N4 - (2 - methyl- lH-indol-5-yl)pyrimidine-2,4- diamine
Figure imgf000029_0002
N2-(2-methyl-lH-indol-5-yl)-N4-(3-(3- MS (m/e): 452.3(M+1)
(methylsulfonyl)propoxy)phenyl)pyrimidi ne-2,4-diamine
Figure imgf000029_0003
94 2-(l-(3-(4-(2-methyl-lH-indol-5- MS (m/e): 457.4 (M+ 1) ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4- yl)ethanol
Figure imgf000029_0004
95 N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e):429Λ (M+ 1) (piperidin-4- ylmethoxy)phenyl)pyrimidine-2,4- diamine
Figure imgf000029_0005
96 N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e):4l6Λ (M+ 1)
(piperidin-3-yloxy)phenyl)pyrimidine-
2,4-diamine
Figure imgf000029_0006
97 l-(3-(4-(2-methyl-lH-indol-5- MS (m/e): 429.4(M+1) ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4-ol
Figure imgf000030_0001
98 (S)-N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e): 401.4(M+l)
(pyrrolidin-3-yloxy)phenyl)pyrimidine-
2,4-diamine
Figure imgf000030_0002
99 (S)-N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e): 479.5(M+1) ( 1 -(methylsulfonyl)pyrrolidin-3 - yloxy)phenyl)pyrimidine-2,4-diamine
Figure imgf000030_0003
100 N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e): 415.5 (M+ 1)
(piperidin-4-yloxy)phenyl)pyrimidine-
2,4-diamine
Figure imgf000030_0004
101 N4-(2-methyl-lH-indol-5-yl)-N2-(3-(3- MS (m/e): 536.6 (M+ 1) (4-(methylsulfonyl)piperazin- 1 - yl)propoxy)phenyl)pyrimidine-2,4- diamine
NwN'
H H
102 N4-(2-methyl-lH-indol-5-yl)-N2-(3-(3- MS (m/e): 459.6 (M+ 1) moφholinopropoxy)phenyl) pyrimidine-
2,4-diamine
H
H H
103 (R)-N4-(2-methyl-lH-indol-5-yl)-N2-(3- MS (m/e): 479.5 (M+ 1) ( 1 -(methylsulfonyl)pyrrolidm-3 - yloxy)phenyl)pyπmidme-2,4-diamme
Figure imgf000031_0001
104 (E)-N,N-dimethyl-3 -(3 -(4-(2-methyl- 1 H- MS (m/e): 413.2(M+1) mdol-5-ylamino)pyπmidm-2- ylammo)phenyl)acrylamide
Figure imgf000031_0002
105 4-(4-fluoro-2-methyl-lH-mdol-5-yl)-N- MS (m/e): 507.5(M+l) (3- (3-(thiomoφholino-l ',r- dioxide)propoxy)phenyl)pyrimidm-2- amine
Figure imgf000031_0003
106 N4-(2-methyl-lH-indol-5-yl)-N2-(3-(2- MS (m/e): 389.5(M+1)
(methylammo)ethoxy)phenyl)pyrimidme-
2,4-diamme
CXJ-
107 4-(4-fluoro-2-methyl-lH-mdol-5-yloxy)- MS (m/e): 491.5 (M+ 1) N-(3- (3-(thiomoφholmo-l '-oxide) propoxy) phenyl) pyπmidin-2-amme
Figure imgf000031_0004
108 N-(2-(3-(4-(2-methyl-lH-indol-5- MS (m/e): 453.4 (M+ 1) ylammo)pyπmidm-2- ylammo)phenoxy)ethyl)methanesulfonam ide
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
136 N- (3 - (2 - (dimethylamino)ethoxy)phenyl) - MS (m/e): 404.4(M+l) 4-(2 -methyl- lH-mdol-5-yloxy)pyrimidin- 2 -amine
Figure imgf000037_0002
137 N-cyclopropyl-2-(3 -(4-(2 -methyl- IH- MS (τn/e):414.4 (M+ 1) indol-5-yloxy)pyrimidin-2- ylamino)phenyl)acetamide
Figure imgf000037_0003
138 4-(2-methyl-lH-indol-5-yloxy)-N-(3-(3- MS (m/e): 453.4 (M+ 1)
(methylsulfonyl)propoxy)phenyl)pyrimidi n-2-amine
Figure imgf000037_0004
139 4-(2-methyl-lH-indol-5-yloxy)-N-(3- MS (m/e): 448.2 (M+ 1)
(piperidin-4- ylmethoxy)phenyl)pyrimidin-2-amine
Figure imgf000037_0005
140 4-(2-methyl-lH-indol-5-yloxy)-N-(3- MS (m/e): 416.2 (M+ 1) (piperidin-3-yloxy)phenyl)pyrimidin-2- amine r il N'
H
141 4-(2-methyl-lH-indol-5-yloxy)-N-(3- MS (m/e): 416.4 (M+ 1) (piperidin-4-yloxy)phenyl)pyrimidin-2- amine
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
amine
Figure imgf000043_0001
172 N-(3-(2-aminoethoxy)phenyl)-4-(2- MS (m/e): 376.3(M+1) methyl-lH-indol-5-yloxy)pyrimidin-2- amine
Figure imgf000043_0002
173 N-(3-(4-(2-methyl-lH-indol-5- MS (m/e): 424.4 (M+ 1) yloxy)pyrimidin-2- ylamino)benzyl)methanesulfonamide
Figure imgf000043_0003
174 N-(2-hydroxyethyl)-3 -(4-(2-methyl- IH- MS (m/e):404Λ (M+ 1) indol-5-yloxy)pyrimidin-2- ylamino)benzamide
Figure imgf000043_0004
175 4-(2-methyl-lH-indol-5-yloxy)-N-(3-(2- MS (m/e): 444.5 (M) (piperazin- 1 -yl)ethoxy)phenyl)pyrimidin- 2 -amine
Figure imgf000043_0005
176 3 -(4-(2-methyl- 1 H-indol-5- MS (m/e): 431.2 (M+ 1) yloxy)pyrimidin-2 -ylamino) -N- (2 - (methylamino)-2-oxoethyl)benzamide
Figure imgf000043_0006
177 3-(4-(2-methyl-lH-indol-5- MS (m/e): 473.0 (M+ 1) yloxy)pyrimidin-2 -ylamino) -N- (2 - moφholinoethyl)benzamide
Figure imgf000044_0001
-J- amme
Figure imgf000045_0001
184 N-methyl(3 -(4-(2-methyl- 1 H-indol-5- MS (m/e): 424.4 (M+ 1) yloxy)pyrimidin-2- ylamino)phenyl)methanesulfonamide
Figure imgf000045_0002
185 N-(6-methoxypyridin-3-yl)-4-(2-methyl- MS (m/e):348.2 (M+ 1) lH-indol-5-yloxy)pyrimidin-2-
Amine
Figure imgf000045_0003
186 methyl 2-(4-(4-(4-fluoro-2-methyl- IH- MS (m/ey.406.2 (M+ 1) indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acetate
Figure imgf000045_0004
187 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 364.2 (M+ 1) N2 - (2 -methoxyphenyl)pyrimidine -2,4- diamine
Figure imgf000045_0005
188 N2-(3-bromophenyl)-N4-(4-fluoro-2- MS (τn/e):412.3 (M+ 1) methyl-lH-indol-5-yl)pyrimidine-2,4- diamine
Figure imgf000046_0001
189 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 412.3(M+1) N2-(3 -(methylsulfonyl) phenyl)pyrimidine-2,4-diamine
Figure imgf000046_0002
190 3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 359.3 (M+ 1) ylamino)pyrimidin-2- ylamino)benzonitrile
Figure imgf000046_0003
191 N2-(2-chloro-4-fluorophenyl)-N4-(4- MS (m/e): 386.2 (M+ 1) fluoro-2-methyl-lH-indol-5- yl)pyrimidine-2,4-diamine
Figure imgf000046_0004
192 N-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 427.3(M+1) ylamino)pyrimidin-2- ylamino)phenyl)methanesulfonamide
Figure imgf000047_0001
193 N2-(3,4-difluorophenyl)-N4-(4-fluoro-2- MS (m/e): 370.2(M+l) methyl-lH-indol-5-yl)pyrimidine-2,4- diamine
Figure imgf000047_0002
194 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 463.4 (M+ 1) N2-(3-(2- moφholinoethoxy)phenyl)pyrimidine- 2,4-diamine
Figure imgf000047_0003
195 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e):5403 (M+ 1) N2-(3 -(2-(4-(methylsulfonyl)piperazin- 1 - yl)ethoxy)phenyl)pyrimidine-2,4-diamine
Figure imgf000047_0004
196 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 462.3 (M) N2-(2-(2- moφholinoethoxy)phenyl)pyrimidine- 2,4-diamine
Figure imgf000047_0005
197 N2-(3-(3- MS (m/e): 435.4 (M+ 1) (dimethylamino)propoxy)phenyl)-N4-(4- fluoro-2-methyl-lH-indol-5- yl)pyrimidine-2,4-diamine
Figure imgf000048_0001
198 N-cyclopropyl-2-(3-(4-(4-fluoro-2- MS (m/e): 431.4(M+1) methyl-lH-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acetamide
Figure imgf000048_0002
199 N-(2-(3-(4-(4-fluoro-2-methyl-lH-indol- MS (m/e): 471.4 (M+ 1) 5-ylamino)pyrimidin-2-yl amino) phenoxy)ethyl)methanesulfonamide
Figure imgf000048_0003
200 2-(2-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 394.4 (M+ 1) ylamino)pyrimidin-2- ylamino)phenoxy)ethanol
Figure imgf000048_0004
201 N2-(3-(2- MS (m/e): 421.4(M+1)
(dimethylamino)ethoxy)phenyl) -N4 - (4 - fluoro-2-methyl-lH-indol-5- yl)pyrimidine-2,4-diamine
Figure imgf000048_0005
202 ( 1 -(3 -(4-(4-fluoro-2-methyl- 1 H-indol-5- MS (m/e): 461.5(M+1) ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4-yl)methanol
Figure imgf000049_0001
203 3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (τn/e): 391.3(M+1) ylamino)pyrimidin-2-ylamino)-N- methylbenzamide
Figure imgf000049_0002
204 trifluoro-N-(3-(4-(4-fluoro-2-methyl-lH- MS (m/e): 481.3(M+1) indol-5-ylamino)pyrimidin-2- ylamino)phenyl)methanesulfonamide
Figure imgf000049_0003
205 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 446.22(M+1) N2-(3-(piperidin-4- ylmethoxy)phenyl)pyrimidine-2,4- diamine
Figure imgf000049_0004
206 (E)-3-(3-(4-(4-fluoiO-2-methyl-lH-indol- MS (m/e): 473.5 (M+ 1) 5-ylamino)pyrimidin-2-ylamino)phenyl)- 1 -moφholinoprop-2-en- 1 -one
Figure imgf000049_0005
207 trifluoro-N-(4-(4-(4-fluoro-2-methyl- 1 H- MS (/n/e):481.3 (M+ 1) indol-5-ylamino)pyrimidin-2- ylamino)phenyl)methanesulfonamide
Figure imgf000049_0006
208 N-(5-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 392.4 (M+ 1) ylammo)pyrimidm-2-ylamino)pyridin-2- yl)acetamide
Figure imgf000050_0001
209 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e):483.5 (M+ 1) N2-(3 -(moφholinosulfonyl) phenyl)pyrimidine-2,4- Diamine
Figure imgf000050_0002
210 3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 427.1(M+1) ylamino)pyrimidin-2-ylamino)-N- methylbenzenesulfonamide
Figure imgf000050_0003
211 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e):408.4 (M+ 1) N2-(3-(2- methoxyethoxy)phenyl)pyrimidine-2,4- diamine
Figure imgf000050_0004
212 4-(4-fluOTO-2-methyl-lH-indol-5-yl)-N- MS (m/e): 525.5(M+1) (3- (3-(thiomoφholino-l ',r- dioxide)propoxy)phenyl)pyrimidin-2- amine
Figure imgf000050_0005
213 N-(2-(dimethylamino)ethyl)-3-(4-(4- MS (m/e): 448.5 (M+ 1) fluoro-2-methyl-lH-indol-5- ylamino)pyrimidin-2- ylamino)benzamide
Figure imgf000051_0001
214 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 407.5(M+l)
N2-(3-(2-
(methylamino)ethoxy)phenyl)pyrimidine-
2,4- diamine
Figure imgf000051_0002
215 (E)-3-(3-(4-(4-fluoro-2-methyl-lH-indol- MS (m/e): 473.1(M+1) 5-ylamino)pyrimidin-2-ylamino)phenyl)- 1 -morpholinoprop-2-en- 1 -one
Figure imgf000051_0003
216 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 493.5(M+1) N2-(3-(3- thiomoφholinopropoxy)phenyl)pyrimidin e-2,4-diamine
Figure imgf000051_0004
217 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 511.4(M+1) N2-(3 -(2-moφholino ethylsulfonyl)phenyl)pyrimidine-2,4- diamine
Figure imgf000051_0005
218 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 479.4 (M+l) N2-(3 -(2-thiomoφholino ethoxy)phenyl)pyrimidine-2,4- diamine
Figure imgf000052_0001
219 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 447.4 (M+ 1) N2-(3-(2-(pyrrolidin-l- yl)ethoxy)phenyl)pyrimidine-2,4- diamine
Figure imgf000052_0002
220 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 510.4(M+l) N2-(3 -((4-(methylsulfonyl)piperazin- 1 - yl)methyl)phenyl)pyrimidine-2,4- diamine
Figure imgf000052_0003
221 2-(4-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 474.7 (M-I) ylamino)pyrimidin-2- ylamino)benzyl)piperazin- 1 - yl)ethanol
Figure imgf000052_0004
222 3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 428.4(M+1) ylamino)pyrimidin-2-ylamino) phenylmethanesulfonate
Figure imgf000052_0005
223 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 426.4(M+1) N2-(3 -(methylsulfonylmethyl) phenyl)pyrimidine-2,4- diamine
Figure imgf000053_0001
224 tert-butyl 4-(2-(3-(4-(2-methyl-lH-indol- MS (m/e): 544.4(M+1) 5-ylamino)pyrimidin-2-yl amino)phenoxy)ethyl)piperazine- 1 - carboxylate
Figure imgf000053_0002
225 tert-butyl 4-(2-(3-(4-(4-fluoiO-2-methyl- MS (m/e): 562.3 (M+ 1) lH-indol-5-ylamino)pyrimidin-2- ylamino)phenoxy)ethyl)piperazine- 1 - carboxylate
Figure imgf000053_0003
226 3-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 433.4 (M+ 1) ylamino)pyrimidin-2-ylamino))phenyl)- N,N-dimethylpropanamide
Figure imgf000053_0004
227 (E)-3-(3-(4-(4-fluoiO-2-methyl-lH-indol- MS (m/e): Ml 2 (M+ 1) 5-ylamino)pyrimidin-2-ylamino)phenyl)- N-methylacrylamide
Figure imgf000053_0005
228 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 448.4 (M+ 1) N2-(3 -((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)pyrimidine-2,4- diamine
Figure imgf000053_0006
229 N2-(3-(2-aminoethoxy)phenyl)-N4-(4- MS (m/e): 393.2 (M+ 1) fluoro-2-methyl-lH-indol-5- yl)pyrimidine-2,4-diamine
Figure imgf000054_0001
Figure imgf000055_0001
diamine
Figure imgf000056_0001
240 l-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 441.4(M+1) ylamino)pyrimidin-2- ylamino)benzyl) sulphonyl - methylamine
Figure imgf000056_0002
241 N4-(4-fluoro-2-methyl-lH-indol-5-yl)- MS (m/e): 365.4 (M+ 1) N2 - (6 -methoxypyridin- 3 -yl)pyrimidine- 2,4-diamine
Figure imgf000056_0003
242 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e): 464.4 (M+ 1) N-(3 -(2-moφholinoethoxy) phenyl)pyrimidin-2 - amine
Figure imgf000056_0004
243 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e):478.4 (M+ 1) N-(3 -(3 -moφholino propoxy)phenyl)pyrimidin-2-amine
Figure imgf000056_0005
244 2-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 395.4 (M+ 1) yloxy)pyrimidin-2- ylamino)phenoxy)ethanol
Figure imgf000057_0001
ylamino)benzamide
Figure imgf000058_0001
251 (l-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e):462A (M+ 1) yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4- yl)methanol
Figure imgf000058_0002
252 2-(l-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 476.5(M+1) yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4- yl)ethanol
Figure imgf000058_0003
253 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e): 408.4 (M+ 1) N-(3-(2-(methylamino)ethoxy) phenyl)pyrimidin-2 - amine
Figure imgf000058_0004
254 (E)-3-(3-(4-(4-fluoiO-2-methyl-lH-indol- MS (m/e): 474.5(M+1) 5-yloxy)pyrimidin-2-ylamino)phenyl)- 1 - moφholinoprop-2-en- 1 -one
Figure imgf000058_0005
255 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e):434.5 (M+ 1) N-(3 -(moφholino methyl)phenyl)pyrimidin-2 - amine
Figure imgf000058_0006
256 (S)-4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 498.4 (M+ 1) yloxy)-N-(3-(l- (methylsulfonyl)pyrrolidin-3 - yloxy)phenyl)pyrimidin-2 - amine
Figure imgf000059_0001
257 3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 392.4 (M+ 1) yloxy)pyrimidin-2-ylamino)-N- methylbenzamide
Figure imgf000059_0002
258 N-(2-(3-(4-(4-fluoro-2-methyl-lH-indol- MS (m/e): 472.4 (M+ 1) 5-yloxy)pyrimidin-2-ylamino)phenoxy) ethyl)me thane sulfonamide
Figure imgf000059_0003
259 trifluoro-N-(3-(4-(4-fluoro-2-methyl-lH- MS (m/e): 482.3(M+1) indol-5-yloxy)pyrimidin-2-yl amino) phenyl)methanesulfonamide
Figure imgf000059_0004
260 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e): 494.5 (M+ 1) N-(3 -(3 -thiomoφholinopropoxy) phenyl)pyrimidin-2 - amine
Figure imgf000059_0005
261 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e): 496.4 (M+ 1) N-(3 -(2-(pyrrolidin- 1 -yl)ethylsulfonyl) phenyl)pyrimidin-2-amine
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
yl)ethyl)benzamide
Figure imgf000063_0001
278 3-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 420.2 (M+ 1) yloxy)pyrimidin-2-ylamino)phenyl)-N- methylpropanamide
Figure imgf000063_0002
279 3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/ey.436.1 (M+ 1) yloxy)pyrimidin-2 -ylamino) -N- (2 - methoxyethyl)benzamide
Figure imgf000063_0003
280 N-(4-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 428.1(M+1) yloxy)pyrimidin-2-yl amino) phenyl)me thane sulfonamide
Figure imgf000063_0004
281 2-(3-(4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 505.1(M+l) yloxy)pyrimidin-2-ylamino)phenyl)-N-(2- moφholinoethyl)acetamide
Figure imgf000063_0005
282 4-(4-fluoro-2-methyl-lH-indol-5-yloxy)- MS (m/e): 457.2 (M+ 1) N-(3 -(2-(methylsulfonyl) ethoxy)phenyl)pyrimidin-2 - amine
Figure imgf000064_0002
Example 284: Synthesis of 3 -(4-(2 -methyl- lH-indol-5-ylamino)pyrimidin-2-yl amino)phenol (Compound 284):
Figure imgf000064_0001
Compound 8 Compound 284
A solution of N2-(3-methoxylphenyl)-N4-(2 -methyl- lH-indol-5- yl)pyrimidine-2,4-diamine (O.lmmol) in 5ml CH2Cl2 was placed in an ice bath. To this was added BBr3(0.5mmol). The reaction mixture was stirred overnight at room temperature, then poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to provide the desired product in a yield of 83%.
1H NMR (DMSO-J6, 400 MHz): δ 10.501 (s, IH), 9.115 (s, IH), 8.956 (s, IH), 8.868 (s, IH), 7.908 (d, J=6Hz, IH), 7.716 (s,lH), 7.271 (d, J=8Hz, IH), 7.210 (d, J=8.4Hz, IH), 7.114 (d, J=8Hz, IH) ,6.968 (t, J=8Hz, IH), 6.322 (dd, J=8,1.6Hz, IH), 6.097 (m, 2H), 2.377 (s, 3H); MS (m/e): 331.4 (M+l). Examples 285-295: Syntheses of Compounds 285-295
Compounds 285-295 were each synthesized in a manner similar to that described in Example 284.
Figure imgf000065_0001
IH), Hz, Hz, Hz, 3H);
(d,
(s, 3H);
(d,
Figure imgf000066_0001
6.839(t, (s,
8.164 2H), Hz,
Figure imgf000067_0001
Example 296 : Synthesis of N-(2 -methoxypyrimidin-4-yl)-N-(2 -methyl- lH-indol-5- yl)pyrimidine-2,4-diamine (Compound 296 ):
Figure imgf000067_0002
The solution of 2-chloropyrimidin-4-amine (lmmol) and sodiumn methoxide (1.5mmol) in 10ml methanol was refluxed for 2h, after removing of solvent, the residue was dissolved in CH2Cl2 and washed with water, dried over anhydrous NaSO4, concentrated in vacuo to give 2-methoxypyrimidin-4-amine.
Figure imgf000067_0003
compound 296 To a solution of 2-methoxypyrimidin-4-amine (O.lmmol) and N-(2- chloropyrimidin-4-yl)-2-methyl-lH-indol-5 -amine (O.lmmol) in 3ml dioxide, CsCC>3 (0.2mmol), Pd(OAc)2(I Ommol%) and Xantphos(10mmol%) were added. The mixture was stirred under microwave irradiation at 200°C for 40mins. After cooling the solution was filtered and the filtrate was concentrated in vacuo, the residue was purified by column chromatography(C-18) to give N-(2-methoxypyrimidin-4-yl)-N- (2 -methyl- lH-indol-5-yl)pyrimidine-2,4-diamine(yield 48%).
1H NMR(DMSO-t/5,400MHz): 10.839(s, 1 H), 9.718 (s, 1 H), 9.281 (s, 1 H), 8.162 (d, , J=6.0Hz, IH ), 8.032(m, 2H), 7.693 (s, IH), 7.251 (d, , J=8.8Hz, IH), 7.099 (d, , J=7.2 Hz, IH), 6.300 (d, , J=6.0 Hz, IH), 6.107 (s, IH), 3.863 (s,3H), 2.383 (s, 3H); MS (m/e): 348.2 (M+ 1)
Examples 297-299: Syntheses of Compounds 297-299
Compounds 297-299 were each synthesized in a manner similar to that described in Example 296. compound Name 1H NMR (DMSO-dg, 400 MHz)/MS
297 N-(2-methoxypyridin-4-yl)-N-(2-methyl- 10.837(s, 1 H), 9.421 (s, 1 H), 9.144 (s, 1 H), lH-indol-5-yl)pyrimidine-2,4-diamine 7.978 (d, /=6.0Hz, IH ), 7.838(d, /=6.0Hz, IH), 7.606 (s, IH), 7.333-7.303 (m, 2H), 7.249 (d, /=8.4 Hz, IH), 7.084 (d, /=8.0 Hz, IH), 6.205(d, /=5.6 Hz, IH), 6.088 (s, IH), 3.775 (s,3H), 2.382 (s, 3H); MS (m/e): 347.2 (M+ 1)
298 N- (2 -methoxypyridin-4 -yl) -N-(2 -methyl- 11.258 (s, 1 H), 10.400 (br, 1 H), 9.036 (s, 1 H), lH-indol-5-yl)pyrimidine-2,4-diamine 8.829 (s, 1 H), 8.509 (s, 1 H), 8.048 (d, /=8.4 Hz, IH), 7.911 (d, /=5.6 Hz, IH), 7.007-7.122 (m, 2H), 6.743 (dd, /=8.4 Hz, 1.6 Hz, IH ), 6.194 (s,
Figure imgf000068_0001
IH), 6.012 (br,lH), 3.166 (s, 3H), 2.397 (s,3H); MS (m/e): 428.1 (M+ 1) 299 N-(5-(4-(2-methyl-lH-indol-5- MS (m/e): 411.4 (M+ 1) yloxy)pyrimidin-2-ylamino)pyridin-2- yl)methanesulfonamide
Figure imgf000069_0001
Example 300: Synthesis of N-(2-(4-fluorophenoxy)pyrimidin-4-yl)-2-methyl- 1 H- indol-5 -amine (Compound 300)
Figure imgf000069_0002
Compound 300 N-(2-chloropyrimidin-4-yl)-2-methyl-lH-indol-5 -amine (0.1 mmol) and p- fluorophenol (O.lmmol) were dissolved in 0.5 ml DMF. To this was added K2CO3 (0.2mmol). After stirred at 6O0C for 5 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried by anhydrous Na2SO4, and concentrated. The resulting oil residue was purified by column chromatography to provide compound 300 in a yield of 76%.
1H NMR (DMSO-d6, 400 MHz): δ 10.802 (s, IH), 9.491 (s, IH), 7.990 (d, J=5.4 Hz IH), 7.495 (s, IH), 7.295 (m, J=8.4-3.6Hz, 4H), 7.236 (d, J=5.4 Hz IH), 7.133 (d, J=5.6 Hz, IH), 6.486 (d, J=5.6 Hz, IH), 5.902 (s, IH), 2.402 (s, 3H); MS (m/e): 335.1 (M+ 1). Example 301-303: Syntheses of Compounds 301-303
Compounds 301-303 were prepared in a similar manner to that described in Example 300. 7.681 (d, 2H), (d,
(s,
IH), /=8.0
Figure imgf000070_0001
Example 304: Synthesis of 5-(2-(3-methoxyphenoxy)pyrimidin-4-yloxy)-2-methyl- lH-indole (Compound 304):
Figure imgf000070_0002
Compound 304
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-hydroxy-2- methylindole (1 mmol) in 5ml EtOH was added Et3N(InImOl). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting oil residue was purified by column chromatography to give 5- (2-chloropyrimidin-4-yloxy)-2 -methyl- lH-indole in a yield of 75%.
5-(2-Chloropyrimidin-4-yloxy)-2-methyl-lH-indole (0.1 mmol) and m- methoxyphenol (0.1 mmol) were dissolved in 0.5 ml DMF. K2CO3 (0.2 mmol) was then added. After the reaction mixture was stirred at 6O0C for 5 h, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography to provide compound 304 in a yield of 76%.
1H NMR (CD3OD, 400 MHz): δ 8.303 (d, J=5.6 Hz, IH), 8.084 (s, IH), 7.305-7.262 (m, 3H), 6.908 (dd, J=8.8 Hz, J=2.4 Hz, IH), 6.816-6.764 (m, 3H), 6.463 (d, J=5.6 Hz, IH), 6.226 (s, IH), 3.780 (s,3H), 2.465 (s, 3H); MS (m/e): 346.5 (M-I).
Example 305: Synthesis of 3 -(4-(2 -methyl- lH-indol-5 -ylamino)pyrimidin-2- ylamino)benzonitrile (Compound 305)
Figure imgf000071_0001
Compound 305
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-Aminobenzimidazole (1 mmol) in 5ml EtOH, was added Et3N(I mmol). The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give N-(2- chloropyrimidin-4-yl)-lH-benzo[d]imidazol-5-amine in a yield of 80%.
N-(2-chloropyrimidin-4-yl)-lH-benzo[d]imidazol-5-amine (0.1 mmol), 3- aminobenzonitrile (0.1 mmol), and p-TsOH monohydrate (0.2 mmol) were dissolved in 0.5ml DMF. After the reaction mixture was stirred at 6O0C for 5 h, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulted oil was purified by column chromatography to provide compound 305 in a yield of 76%. 1H NMR (CD3OD, 400 MHz): δ 8.178 (s, IH), 7.942 (d, J=6.4Hz,2H), 7.825
(br, IH), 7.633-7.603 (m, 2H), 7.469 (dd, J=8.8Hz, 5Hz, IH), 7.212 (t, J=8.4 Hz, IH), 7.075 (d, J=8.0Hz, IH), 6.254 (d, J=6.0 Hz, IH), 3.345 (s, IH); MS: 327.2 (M+ 1).
Example 306: Synthesis ofN2-(3-methoxyphenyl)-N4-(2-methylbenzo[d]oxazol-6- yl) pyrimidine-2,4-diamine (Compound 306)
Figure imgf000072_0001
Compound 306
To a solution of 2,4-dichloropyrimidine (1 mmol) and 2 -methyl- 1,3- benzoxazol-5 -amine (1 mmol) in 5ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give N-(2-chloro pyrimidin-4-yl)-2-methylbenzo[d]oxazol-6-amine in a yield of 73%. N-(2-chloropyrimidin-4-yl)-2-methylbenzo[d]oxazol-6-amine (0.1 mmol), 3- methoxyaniline (0.1 mmol), and p-TsOH monohydrate (0.2 mmol) were dissolved in 0.5ml DMF. After the reaction mixture was stirred at 6O0C for 5 h, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting oil residue was purified by column chromatography to provide compound 306 in a yield of 82%. 1H NMR (DMSO-d6, 400 MHz): δ 9.431 (s, IH), 9.158 (s, IH), 8.136 (s, IH),
8.022 (d, J=5.6 Hz,lH), 7.566 (d, J=8.8 Hz, IH), 7.517 (d, J=8.8 Hz, IH), 7.418 (s, IH), 7.367 (d, J=8.0 Hz IH), 7.126 (t, J=8.4 Hz, IH), 6.490 (m, IH), 6.224 (d, J=5.2 Hz,lH), 3.674 (s, 3H), 2.609 (s, 3H); MS(We): 348.3 (M+l).
Example 307: Synthesis of N2-(3-ethynylphenyl)-N4-(2-methylbenzo[d]oxazol-6-yl) pyrimidine-2,4-diamine (Compound 307).
Compound 307 was synthesized in a similar manner to that described in Example 306.
1H NMR (DMSO-d6, 400 MHz): δ 9.566 (d, J=5.2 Hz, IH), 9.309 (s, IH), 8.099 (s, IH), 8.038 (d, J=6.0 Hz, IH), 7.917 (s, IH), 7.805 (d, J=8.4 Hz, IH), 7.574 (m, 2H), 7.231 (m, IH), 6.996 (d, J=7.6 Hz, IH), 7.278 (d, J=5.6 Hz,lH), 4.059 (s, IH), 2.608 (s, 3H); MS(We): 342.2 (M+l).
Example 308: Synthesis ofN2-(3-ethynylphenyl)-N4-(lH-indazol-6-yl)pyrimidine- 2,4-diamine (Compound 308)
Figure imgf000073_0001
Compound 308
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-aminoindazole (1 mmol) dissolved in 5ml EtOH was added Et3N (1 mmol). The reaction mixture was refluxed for 5 h. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aquesous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulted oil was purified by column chromatography to give N-(2- chloropyrimidin-4-yl)-lH-indazol-5 -amine in a yield of 80%.
N-(2-chloropyrimidin-4-yl)-lH-indazol-5 -amine (0.1 mmol), 3-ethnylaniline (0.1 mmol), and p-TsOH(0.2mmol, monohydrate) were dissolved in 0.5ml DMF. After the reaction mixture was stirred at 6O0C for 5 h, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to provide compound 308 in a yield of 74%. 1H NMR (DMSO-de, 400 MHz): δ 12.966 (brs, IH), 9.344 (brs,lH), 9.234
(brs, IH), 8.145 (s, IH), 8.005 (m, 2H), 7.893 (s, IH), 7.795 (d, IH), 7.527 (d, J=8.8 Hz, IH), 7.471 (d, J=8.8 Hz, IH), 7.212 (t, IH), 7.021 (d, IH), 6.626 (d, IH), 4.037 (s, IH); MS (m/e): 327.2 (M+l).
Example 309: Synthesis of N2-(3-methoxylphenyl)-N4-(2-methyl-lH-indol-5-yl) pyrimidine-2,4-diamine (Compound 309)
Figure imgf000074_0001
Compound 309 2,4-Dichloro-5-fluoropyrimidine (1 mmol) and 5-amino-2-methylindole
(1.5 mmol) were dissolved in 3 ml CH3OH and 9 ml H2O. After the reaction mixture was stirred at room temperature for Ih, it was diluted with H2O, acidified with 2N
HCl, and sonicated. The reaction mixture was then filtered, washed with H2O and dried to give N-(2-chloro-5-fluoropyrimidin-4-yl)-2 -methyl- lH-indol-5 -amine in a yield of 78%.
N-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-lH-indol-5 -amine (0.1 mmol), m-methoxyaniline (0. lmmol), p-TsOH monohydrate (0.2 mmol) were dissolved in
0.5 ml DMF. After the reaction mixture was stirred at 6O0C for 5 h, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to provide compound 309 in a yield of 60%.
1H NMR (CD3OD, 400 MHz, δ ppm ): 7.854 (d, J=4.0 Hz, IH), 7.703 (d, J =1.6, IH), 7.248 (s, 2H), 7.177 (br, 2H), 7.054 (t, J=4.2 Hz, 2H), 6.942 (s, 2H), 3.506 (s, 3H), 2.235 (s, 3H); MS(We): 364.2 (M+l).
Example 310: Synthesis of 2-(3-methoxyphenylamino)-4-(2 -methyl- lH-indol-5- ylamino) pyrimidine-5-carbonitrile (Compound 310)
Figure imgf000075_0001
Figure imgf000075_0002
Compound 310
2-Methyl-2-thiopseudourea (5 mmol) and ethyl ethoxymethylenecyanoacetate
(5 mmol) were dissolved in 20 ml EtOH. To this was added K2CO3 (10 mmol). After the mixture was refluxed for 48 h, it was cooled to room temperature and filtered. The solvent was concentrated in vacuo and purified by column chromatography to give 4-hydroxy-2-(methylthio) pyrimidine-5-carbonitrile in a yield of 65%. 4-Hydroxy-2-(methylthio) pyrimidine-5-carbonitrile (3 mmol) and m- anisidine (3 mmol) in pentan-1-ol was refluxed for 40 h under nitrogen. The reaction mixture was concentrated in vacuo. The residue was washed with water and dried to afford 4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile. To a solution of 4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5- carbonitrile in POCI3 was added DMF 0.5 ml. The solution was refluxed for 3 h. The reaction mixture was cooled to room temperature and poured into ice-water. The solution was adjusted to pH=8-9 by aqueous sodium carbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to afford 4-chloro-2-(3- methoxyphenylamino)pyrimidine-5-carbonitrile.
4-Chloro-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile was converted to compound 310 in a similar manner to that described in Example 1.
1H NMR (DMSO-d6, 400 MHz): δ 10.925(s, IH), 9.710 (d, J=I 1.2 Hz, IH), 9.349 (d, J=10.4 Hz, IH), 8.441 (s, IH), 7.474 (s, IH), 7.252 (s, IH), 7.223 (d, J=6.8 Hz, IH), 7.187 (s, IH), 7.062 (m, J= IH), 6.923 (d, J=2.0 Hz, IH), 6.485 (t, IH); 6.098 (s, IH), 3.453 (s, 3H), 2.387 (s, 3H); MS(We): 371.2 (M+l).
Example 311-317: Syntheses of Compounds 311-317
Compounds 311-317 were prepared in a similar manner to that described in Example 310.
compound Name/Structure 1HNMR(DMSO-d6,400Hz)/ MS
311 4-(2-methyl-lH-indol-5-ylamino)-2-(3-(3- 11.184 (s, IH), 10.745 (s, IH), 9.492 (s,lH), moφholinopropoxy)phenylamino)pyrimid 8.396 (s, IH), 7.322 (s, IH), 7.292 (d, J=7.2, ine-5-carbonitrile IH), 7.147 (m, IH), 6.919 (m, IH), 6.815 (d, j=8.8, IH), 6.416 (d, J=7.2, IH), 6.261 (t, j=4.8, IH), 6.129 (s, IH), 3.447 (m, 2H), 3.547
Figure imgf000076_0001
(m, 4H), 2.398 (s, 3H), 2.337 (m, 6H), 1.747 (m, 2H).MS (m/e): 484.2 (M+l)
312 4-(2-methyl-lH-indol-5-yloxy)-2-(3-(3- MS (m/e): 485.3 (M+l) moφholinopropoxy)phenylamino)pyrimid ine-5-carbonitrile
Figure imgf000076_0002
313 4-(2-metnyl-lH-indol-5-ylamino)-2-(3-(2- MS (m/e): 470.5 (M+l) moφholinoethoxy)phenylamino)pyrimidi ne - 5 - c arbonitrile
Figure imgf000077_0001
314 4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): Ml 2 (M+ 1) ylamino)-2-(3-
(trifluoromethyl)phenylamino) pyrimidine - 5 - carbonitrile
Figure imgf000077_0002
315 2-(3,4-dimethoxyphenylamino)-4-(2- MS (m/e): 401.4 (M+ 1) methyl-lH-indol-5-ylamino)pyrimidine-5- c arbonitrile
Figure imgf000077_0003
316 4-(4-fluoro-2-methyl-lH-indol-5- MS (m/e): 488.5 (M+ 1) ylamino)-2-(3-(2- moφholinoethoxy)phenylamino) pyrimidine - 5 - carbonitrile
Figure imgf000077_0004
317 2-(5-cyano-2-(3,4- MS (m/e): 391.1 (M+ 1) dimethoxyphenylamino) pyrimidin-4- ylamino)benzamide
Figure imgf000077_0005
Example 318: KDR kinase activity assay using Z'-lyte kinase assay kit
Inhibition of kinase activity of a recombinant KDR catalytic domain (Invitrogen, Carlsbad, CA, U.S.A., Cat. PV3660) was determined using Z'-LYTE™ Tyrl Peptide assay kit (Invitrogen, Cat. PV3190) in a black 384-well plate (Thermo labsystems, Cambridge, U.K., Cat. 7805). The assay was performed according to the procedures recommended by the manufacturer.
Briefly, a test compound (10 mM stock in DMSO) was diluted to 1 :4 with distilled water containing 8% DMSO. The solution was placed in a test well and three control wells (Cl, C2, and C3) at 2.5 μl/well. Coumarin- fluorescein double-labeled peptide substrate was mixed with the KDR catalytic domain ("kinase"). 5 μl of the kinase/peptide mixture was added to each of the test, Cl, and C2 wells, but not C3 (Final concentration: 0.3 μg/ml of Kinase, 2 μM of peptide). 5 μl of Phosphor-Tyrl peptide was added to the C3 well. 2.5 μl of 40 μM ATP was added to the test well and C2 well and 2.5 μl of 1.33 x kinase buffer (1 xbuffer: 50 mM HEPES, pH7.5, 0.01% Brij-35, 5 mM MgCl2, 5 mM MnCl2, and 1 mM EGTA) was added to the Cl and C3 wells. The plate was briefly spun at 1000 rpm to settle all solution down to the bottom of the wells and then sealed and shaken at 250 rpm and 250C for 1 hour.
A development reagent was diluted to 1 : 128 according to the recommendation of the manufacturer. 5 μl of the diluted development reagent was added to each well. The plate was spun at 1000 rpm to settle all solution down to the wells, and then sealed and shaken at 250 rpm and 250C for 1 hour.
5 μl of a stop reagent was added to each well. The plate was spun at 1000 rpm to settle all solution down to the wells, and then sealed at 250 rpm and 250C for 2 minutes. Emission of the solution at each well was measured by a VictorTM3 micro- plate reader at Excitation 400 nm/Emission 445 nm and 520 nm. The emission ratio and phosphorylation ("Phos.") percentage were calculated by the following equations:
Coumarin Emission (445 nm) Emission Ratio =
Fluorescein Emission (520 nm)
(Emission Ratio x FiOO%) - CiOO%
%Phosphorylation = 1 - (C0o/o - Cioo%) + [Emission Ratio x (F 100% - F0%)]
where: Cioo% = Average Coumarin emission signal of the 100% Phos. Control Co% = Average Coumarin emission signal of the 0% Phos. Control Fioo% = Average Fluorescein emission signal of the 100% Phos. Control Fo% = Average Fluorescein emission signal of the 0% Phos. Control
The inhibition ratio was calculated as follows:
Inhibition% = (Phos. in C2 well - Phos. in test well)/ (Phos. in C2 well) x 100%
The result showed that all of the tested compounds inhibited the activity of KDR. The IC50 values ranged from 0.001 to 10 μM.
Other Embodiments
All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. For example, compounds structurally analogous to the compounds of this invention can be made and used to practice this invention. Thus, other embodiments are also within the claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of the following formula:
Figure imgf000080_0001
in which each of X and Y, independently, is O, S, or NR, wherein R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl;
Z is CR' or N, wherein R' is H, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocycloalkyl;
V, U, and T together represent
Figure imgf000080_0002
, or
Figure imgf000080_0003
each of Ri, R2, R3, R4, and R6, independently, is H, halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl; R5 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and
R7 is alkyl.
2. The compound of claim 1 , wherein X is O or NH.
3. The compound of claim 2, wherein Y is NH.
4. The compound of claim 3, wherein V, U, and T together represent
Figure imgf000081_0001
5. The compound of claim 4, wherein R6 is H and R7 is methyl.
6. The compound of claim 5, wherein R5 is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
7. The compound of claim 1 , wherein V, U, and T together represent
Figure imgf000081_0002
and Z is CR', R' being H, halo, or alkyl.
8. The compound of claim 7, wherein R6 is H and R7 is methyl.
9. The compound of claim 1, wherein R5 is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
10. The compound of claim 1 , wherein Y is NH.
11. The compound of claim 1 , wherein the compound is one of compounds 1-316.
12. A method of treating an angiogenesis-related disorder comprising, administering to a subject in need thereof an effective amount of a compound of claim 1.
13. The method of claim 12, wherein the angiogenesis-related disorder is cancer or age-related macula degeneration.
14. A method of inhibiting the activity of kinase insert domain receptor comprising contacting the receptor with an effective amount of a compound of formula (I):
,Ar
X
R-YΛNΛR3
(I), wherein:
Ri is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each ofR2 and R3, independently, is H, halogen, nitro, amino, CN, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylcarbonyl, carboxy, or alkoxycarbonyl; each of X and Y, independently, is O, S, or NR4, wherein R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; and
Ar is aryl or heteroaryl.
15. The method of claim 14, wherein Ar is indolyl, indazolyl, benzoimidazolyl, or benzoxazolyl.
16. The method of claim 15, wherein X is O or NH and Y is NH.
17. The method of claim 16, wherein Ri is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
18. A method of inhibiting angiogenesis, comprising administrating to a subject in need thereof an effective amount of a compound of the formula:
Figure imgf000083_0001
wherein:
Ri is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each of R2 and R3, independently, is H, halogen, nitro, amino, CN, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylcarbonyl, carboxy, or alkoxycarbonyl; each of X and Y, independently, is O, S, or NR4, wherein R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; and Ar is heteroaryl.
19. The method of claim 18, wherein Ar is indolyl, indazolyl, benzoimidazolyl, or benzoxazolyl.
20. The method of claim 19, wherein X is O or NH and Y is NH.
21. The method of claim 20, wherein Ri is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
22. A method of treating age-related macular degeneration, comprising administrating to a subject in need thereof an effective amount of a compound of the formula:
Figure imgf000084_0001
wherein:
Ri is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each ofR2 and R3, independently, is H, halogen, nitro, amino, CN, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylcarbonyl, carboxy, or alkoxycarbonyl; each of X and Y, independently, is O, S, or NR4, wherein R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; and
Ar is heteroaryl.
23. The method of claim 22, wherein Ar is indolyl, indazolyl, benzoimidazolyl, or benzoxazolyl.
24. The method of claim 23, wherein X is O or NH and Y is NH.
25. The method of claim 24, wherein Ri is aryl or heteroaryl, optionally substituted with halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.
PCT/US2008/060366 2007-04-16 2008-04-15 Pyrimidine derivatives WO2008128231A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
AU2008240084A AU2008240084B2 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
SI200831203T SI2154967T1 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
NZ580671A NZ580671A (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
JP2010504191A JP5635398B2 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
BRPI0809715-1A BRPI0809715A2 (en) 2007-04-16 2008-04-15 "compound, method of treating an angiogenesis-related disorder, method of inhibiting kinase insert domain receptor activity, method of angiogenesis inhibition, and method of treating macular degeneration"
CA2684470A CA2684470C (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
ES08745881.6T ES2465673T3 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
MX2009011199A MX2009011199A (en) 2007-04-16 2008-04-15 Pyrimidine derivatives.
DK08745881.6T DK2154967T5 (en) 2007-04-16 2008-04-15 Pyriminderivater
PL08745881T PL2154967T3 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
EP08745881.6A EP2154967B9 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives
HRP20140377AT HRP20140377T2 (en) 2007-04-16 2014-04-24 Pyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US91192107P 2007-04-16 2007-04-16
US60/911,921 2007-04-16

Publications (1)

Publication Number Publication Date
WO2008128231A1 true WO2008128231A1 (en) 2008-10-23

Family

ID=39854302

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/060366 WO2008128231A1 (en) 2007-04-16 2008-04-15 Pyrimidine derivatives

Country Status (17)

Country Link
US (2) US8349859B2 (en)
EP (1) EP2154967B9 (en)
JP (1) JP5635398B2 (en)
KR (1) KR101424847B1 (en)
BR (1) BRPI0809715A2 (en)
CA (1) CA2684470C (en)
DK (1) DK2154967T5 (en)
ES (1) ES2465673T3 (en)
HR (1) HRP20140377T2 (en)
MX (1) MX2009011199A (en)
NZ (1) NZ580671A (en)
PL (1) PL2154967T3 (en)
PT (1) PT2154967E (en)
RU (1) RU2455994C2 (en)
SI (1) SI2154967T1 (en)
TW (1) TWI484960B (en)
WO (1) WO2008128231A1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011016472A1 (en) * 2009-08-06 2011-02-10 オンコセラピー・サイエンス株式会社 Pyridine and pyrimidine derivatives having ttk-inhibiting activity
WO2011039344A1 (en) * 2009-10-02 2011-04-07 Boehringer Ingelheim International Gmbh Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors
WO2011144742A1 (en) 2010-05-21 2011-11-24 Chemilia Ab Novel pyrimidine derivatives
EP2395001A1 (en) 2010-05-21 2011-12-14 Chemilia AB Novel pyrimidine derivatives
CN102292322A (en) * 2008-11-24 2011-12-21 贝林格尔.英格海姆国际有限公司 Substituted pyrimidines for the treatment of diseases such as cancer
EP2433636A1 (en) * 2010-09-27 2012-03-28 Medizinische Universität Wien Treatment of Malignant Diseases
CN102648194A (en) * 2009-11-23 2012-08-22 和记黄埔医药（上海）有限公司 Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
EP2502924A1 (en) 2011-03-24 2012-09-26 Chemilia AB Novel pyrimidine derivatives
WO2012127032A1 (en) 2011-03-24 2012-09-27 Chemilia Ab Novel pyrimidine derivatives
EP2711364A1 (en) 2012-09-21 2014-03-26 Chemilia AB 4-(Indolyl or benzimidazolyl)amino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
EP2711365A1 (en) 2012-09-21 2014-03-26 Chemilia AB 4-Indazolylamino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
EP3225619A4 (en) * 2014-11-24 2018-05-23 Shanghai Institute Of Materia Medica Chinese Academy of Sciences 2-aminopyrimidine compound and pharmaceutical composition and use thereof
CN111004221A (en) * 2019-12-13 2020-04-14 长治学院 Pyrimidine/benzimidazole heterozygote, preparation method and medical application
US10766879B2 (en) 2015-02-27 2020-09-08 Nantbioscience, Inc. Pyrimidine derivatives as kinase inhibitors and their therapeutical applications
WO2020253862A1 (en) * 2019-06-21 2020-12-24 上海翰森生物医药科技有限公司 Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7763609B2 (en) 2003-12-15 2010-07-27 Schering Corporation Heterocyclic aspartyl protease inhibitors
AR074209A1 (en) 2008-11-24 2010-12-29 Boehringer Ingelheim Int USEFUL PYRIMIDINE DERIVATIVES FOR CANCER TREATMENT
EP2621276B1 (en) 2010-09-30 2017-12-27 Merck Sharp & Dohme Corp. 2-alkoxy pyrimidine pde10 inhibitors
WO2013054351A1 (en) * 2011-08-08 2013-04-18 Cadila Healthcare Limited Heterocyclic compounds
BR112015010109A2 (en) 2012-11-05 2017-07-11 Nant Holdings Ip Llc substituted indol-5-ol derivatives and their therapeutic applications
CN105377261B (en) 2013-03-15 2017-12-15 南特生物科学公司 The substituted amphyl of indoles 5 and their treatment use
US10981899B2 (en) 2016-04-28 2021-04-20 Cornell University Inhibitors of soluble adenylyl cyclase

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6235741B1 (en) * 1997-05-30 2001-05-22 Merck & Co., Inc. Angiogenesis inhibitors
US20030149041A1 (en) * 1999-12-28 2003-08-07 Pharmacopeia, Inc. Pyrimidine and triazine kinase inhibitors
US6723726B1 (en) * 1996-07-13 2004-04-20 Smithkline Beecham Corporation Protein tyrosine kinase inhibitors
US20040092750A1 (en) * 2001-03-01 2004-05-13 Tomoyuki Hasegawa 2-methylindole-4-acetic acid, process for producing the same, and process for producing intermediate therefor

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9300059D0 (en) * 1992-01-20 1993-03-03 Zeneca Ltd Quinazoline derivatives
GB9705361D0 (en) * 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
RU2262935C2 (en) 1999-02-10 2005-10-27 Астразенека Аб Derivatives of quinazoline as inhibitors of angiogenesis
GB9914258D0 (en) * 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
GB9924862D0 (en) * 1999-10-20 1999-12-22 Celltech Therapeutics Ltd Chemical compounds
EP1257546A1 (en) * 2000-02-17 2002-11-20 Amgen Inc. Kinase inhibitors
GB0004890D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
WO2002016348A1 (en) * 2000-08-09 2002-02-28 Astrazeneca Ab Antiangiogenic bicyclic derivatives
US20020137755A1 (en) 2000-12-04 2002-09-26 Bilodeau Mark T. Tyrosine kinase inhibitors
WO2002059110A1 (en) * 2000-12-21 2002-08-01 Glaxo Group Limited Pyrimidineamines as angiogenesis modulators
WO2002102783A1 (en) * 2001-06-19 2002-12-27 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2003030909A1 (en) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
EP1487824B1 (en) 2002-03-01 2007-06-20 SmithKline Beecham Corporation Diamino-pyrimidines and their use as angiogenesis inhibitors
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
AR037647A1 (en) 2002-05-29 2004-12-01 Novartis Ag USED DIARILUREA DERIVATIVES FOR THE TREATMENT OF DEPENDENT DISEASES OF THE PROTEIN KINase
IL165286A0 (en) 2002-06-17 2005-12-18 Smithkline Beecham Corp Chemical process
CN1678321A (en) * 2002-07-29 2005-10-05 里格尔药品股份有限公司 Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
RU2310651C2 (en) * 2002-08-30 2007-11-20 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Nitrogen-containing aromatic derivatives, pharmaceutical composition containing thereof, method for treatment and using
WO2004032882A2 (en) 2002-10-10 2004-04-22 Smithkline Beecham Corporation Chemical compounds
AU2003288198A1 (en) 2002-11-28 2004-06-18 Schering Aktiengesellschaft CHK-,PDK- and AKT-inhibitory pyrimidines, their production and use as pharmaceutical agents
US7531553B2 (en) 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
US7442698B2 (en) 2003-07-24 2008-10-28 Amgen Inc. Substituted heterocyclic compounds and methods of use
WO2005026129A1 (en) * 2003-09-15 2005-03-24 Gpc Biotech Ag Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases
GB0321710D0 (en) 2003-09-16 2003-10-15 Novartis Ag Organic compounds
AU2004272288B2 (en) * 2003-09-18 2008-11-13 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders
EP1684762A4 (en) * 2003-11-13 2009-06-17 Ambit Biosciences Corp Urea derivatives as kinase modulators
US7718697B2 (en) 2003-12-17 2010-05-18 Alcon, Inc. Method for treating glaucoma comprising administering α-lipoic acid
GEP20084572B (en) 2003-12-23 2008-12-25 Pfizer Novel quinoline derivatives
DE102004044556A1 (en) * 2004-09-15 2006-03-30 Bayer Healthcare Ag Use of kinase inhibitors (e.g. serine/threonine kinase inhibitors) for treating viral infections caused by human cytomegalo virus
TW200628463A (en) * 2004-11-10 2006-08-16 Synta Pharmaceuticals Corp Heteroaryl compounds
EP1827447A1 (en) * 2004-11-19 2007-09-05 Synta Pharmaceuticals Corporation Pyrimidine compounds and uses thereof
KR100735639B1 (en) 2004-12-29 2007-07-04 한미약품 주식회사 Quinazoline derivatives inhibiting the growth of cancer cell and preparation thereof
WO2006071079A1 (en) 2004-12-29 2006-07-06 Hanmi Pharm. Co., Ltd. Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof
US20060247263A1 (en) * 2005-04-19 2006-11-02 Amgen Inc. Substituted heterocyclic compounds and methods of use
US20060270694A1 (en) * 2005-05-03 2006-11-30 Rigel Pharmaceuticals, Inc. JAK kinase inhibitors and their uses
WO2006138304A2 (en) 2005-06-14 2006-12-28 Taigen Biotechnology Pyrimidine compounds
WO2007035309A1 (en) * 2005-09-15 2007-03-29 Merck & Co., Inc. Tyrosine kinase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6723726B1 (en) * 1996-07-13 2004-04-20 Smithkline Beecham Corporation Protein tyrosine kinase inhibitors
US6235741B1 (en) * 1997-05-30 2001-05-22 Merck & Co., Inc. Angiogenesis inhibitors
US20030149041A1 (en) * 1999-12-28 2003-08-07 Pharmacopeia, Inc. Pyrimidine and triazine kinase inhibitors
US20040092750A1 (en) * 2001-03-01 2004-05-13 Tomoyuki Hasegawa 2-methylindole-4-acetic acid, process for producing the same, and process for producing intermediate therefor

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Encyclopedia of Reagehts for Organic Synthesis", 1995, JOHN WILEY AND SONS
L. FIESER; M. FIESER: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS
R. LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS
RUBIN M. TUDER, CHEST, vol. 117, 2000, pages 281
See also references of EP2154967A4 *
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102292322B (en) * 2008-11-24 2015-11-25 贝林格尔.英格海姆国际有限公司 Be used for the treatment of the pyrimidine of the replacement of the disease of such as cancer
CN104478865A (en) * 2008-11-24 2015-04-01 贝林格尔·英格海姆国际有限公司 Substituted pyrimidines for the treatment of diseases such as cancer
CN102292322A (en) * 2008-11-24 2011-12-21 贝林格尔.英格海姆国际有限公司 Substituted pyrimidines for the treatment of diseases such as cancer
JP2012509864A (en) * 2008-11-24 2012-04-26 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 New compounds
WO2011016472A1 (en) * 2009-08-06 2011-02-10 オンコセラピー・サイエンス株式会社 Pyridine and pyrimidine derivatives having ttk-inhibiting activity
JP2013506636A (en) * 2009-10-02 2013-02-28 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 Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors
WO2011039344A1 (en) * 2009-10-02 2011-04-07 Boehringer Ingelheim International Gmbh Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors
US8466155B2 (en) 2009-10-02 2013-06-18 Boehringer Ingelheim International Gmbh Pyrimidines
CN102695700A (en) * 2009-10-02 2012-09-26 贝林格尔.英格海姆国际有限公司 Pyrimidine derivatives as protein tyrosine kinase 2 inhibitors
EP2504331A4 (en) * 2009-11-23 2013-04-17 Hutchison Medipharma Ltd Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
AU2010321366B2 (en) * 2009-11-23 2014-07-24 Hutchison Medipharma Limited Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
EP2504331A1 (en) * 2009-11-23 2012-10-03 Hutchison Medipharma Limited Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
JP2013511475A (en) * 2009-11-23 2013-04-04 ハッチソン メディファーマ リミテッド Compound, certain new forms thereof, pharmaceutical compositions thereof and methods of formulation and use
CN102648194A (en) * 2009-11-23 2012-08-22 和记黄埔医药（上海）有限公司 Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
US8658658B2 (en) 2009-11-23 2014-02-25 Hutchison Medipharma Limited Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
US8946249B2 (en) 2009-11-23 2015-02-03 Hutchison Medipharma Limited Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
WO2011144742A1 (en) 2010-05-21 2011-11-24 Chemilia Ab Novel pyrimidine derivatives
EP2395001A1 (en) 2010-05-21 2011-12-14 Chemilia AB Novel pyrimidine derivatives
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
EP2433636A1 (en) * 2010-09-27 2012-03-28 Medizinische Universität Wien Treatment of Malignant Diseases
WO2012127032A1 (en) 2011-03-24 2012-09-27 Chemilia Ab Novel pyrimidine derivatives
EP2502924A1 (en) 2011-03-24 2012-09-26 Chemilia AB Novel pyrimidine derivatives
WO2014044754A1 (en) 2012-09-21 2014-03-27 Chemilia Ab 4-indazolylamino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
EP2711365A1 (en) 2012-09-21 2014-03-26 Chemilia AB 4-Indazolylamino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
EP2711364A1 (en) 2012-09-21 2014-03-26 Chemilia AB 4-(Indolyl or benzimidazolyl)amino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
EP3225619A4 (en) * 2014-11-24 2018-05-23 Shanghai Institute Of Materia Medica Chinese Academy of Sciences 2-aminopyrimidine compound and pharmaceutical composition and use thereof
US10059694B2 (en) 2014-11-24 2018-08-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 2-aminopyrimidine compound and pharmaceutical composition and use thereof
US10766879B2 (en) 2015-02-27 2020-09-08 Nantbioscience, Inc. Pyrimidine derivatives as kinase inhibitors and their therapeutical applications
WO2020253862A1 (en) * 2019-06-21 2020-12-24 上海翰森生物医药科技有限公司 Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof
CN111004221A (en) * 2019-12-13 2020-04-14 长治学院 Pyrimidine/benzimidazole heterozygote, preparation method and medical application

Also Published As

Publication number Publication date
EP2154967B9 (en) 2014-07-23
DK2154967T3 (en) 2014-04-07
MX2009011199A (en) 2010-03-17
US20080255172A1 (en) 2008-10-16
EP2154967B1 (en) 2014-03-05
US8901143B2 (en) 2014-12-02
EP2154967A1 (en) 2010-02-24
US20130065890A1 (en) 2013-03-14
HRP20140377T2 (en) 2015-01-16
AU2008240084A1 (en) 2008-10-23
DK2154967T5 (en) 2014-11-17
BRPI0809715A2 (en) 2019-11-05
JP2010524952A (en) 2010-07-22
KR101424847B1 (en) 2016-07-08
ES2465673T3 (en) 2014-06-06
PT2154967E (en) 2014-06-05
NZ580671A (en) 2012-03-30
HRP20140377T1 (en) 2014-05-23
JP5635398B2 (en) 2014-12-03
ES2465673T9 (en) 2014-11-14
EP2154967A4 (en) 2010-05-19
PL2154967T3 (en) 2014-08-29
CA2684470C (en) 2016-02-09
TWI484960B (en) 2015-05-21
TW200848049A (en) 2008-12-16
RU2009141982A (en) 2011-05-27
RU2455994C2 (en) 2012-07-20
KR20100016592A (en) 2010-02-12
CA2684470A1 (en) 2008-10-23
SI2154967T1 (en) 2014-06-30
US8349859B2 (en) 2013-01-08

Similar Documents

Publication Publication Date Title
EP2154967B9 (en) Pyrimidine derivatives
ES2726882T3 (en) Thienopyrimidine derivatives that have inhibitory activity for protein kinase
TWI458724B (en) Quinazoline derivatives
TWI407962B (en) Quinazoline derivatives
JP2011504927A (en) BCR-ABL low molecular weight myristic acid ester inhibitor and method of using the same
WO2012059932A1 (en) 2, 4 -diaminopyrimidine derivatives as protein kinase inhibitors
JP5836963B2 (en) Quinazoline compounds
AU2008240084B2 (en) Pyrimidine derivatives
WO2010025138A2 (en) Pyrimidine compounds
KR20160147170A (en) Novel pazopanib derivatives and pharmaceutical composition comprising the same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08745881

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2684470

Country of ref document: CA

Ref document number: 2010504191

Country of ref document: JP

Ref document number: 2008240084

Country of ref document: AU

Ref document number: MX/A/2009/011199

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008745881

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 580671

Country of ref document: NZ

Ref document number: 3701/KOLNP/2009

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20097023882

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2009141982

Country of ref document: RU

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: PI0809715

Country of ref document: BR

Free format text: APRESENTE NOVAS VIAS DA CESSAO DA PRIORIDADE US 60/911,921 DE 16.04.2007 INDICANDO O NUMERO DA PRIORIDADE CEDIDA UMA VEZ QUE A CESSAO APRESENTADA NA PETICAO 018090055593 DE 15/12/2009 NAO INFORMA O NUMERO DA MESMA.

ENP Entry into the national phase

Ref document number: PI0809715

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20091016