[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2011046991A2 - Certain substituted ureas as modulators of kinase activity - Google Patents

Certain substituted ureas as modulators of kinase activity Download PDF

Info

Publication number
WO2011046991A2
WO2011046991A2 PCT/US2010/052420 US2010052420W WO2011046991A2 WO 2011046991 A2 WO2011046991 A2 WO 2011046991A2 US 2010052420 W US2010052420 W US 2010052420W WO 2011046991 A2 WO2011046991 A2 WO 2011046991A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
acceptable salt
phenyl
chloro
Prior art date
Application number
PCT/US2010/052420
Other languages
French (fr)
Other versions
WO2011046991A3 (en
Inventor
David R. Brittelli
Original Assignee
Gilead Connecticut, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Connecticut, Inc. filed Critical Gilead Connecticut, Inc.
Publication of WO2011046991A2 publication Critical patent/WO2011046991A2/en
Publication of WO2011046991A3 publication Critical patent/WO2011046991A3/en

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • R 2 is chosen from fluoro, chloro, methoxy, and difluoromethoxy
  • n 0 or 1 ;
  • the compounds are deuterated.
  • Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration may improve the efficacy and increase the duration of action of drugs.
  • Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development.
  • a "chelate” is formed by the coordination of a compound to a metal ion at two (or more) points.
  • the term “compound” is intended to include chelates of compounds.
  • salts includes chelates of salts.
  • a detection Mix which includes 1 nM LANCE Eu-W1024 labeled anti-phosphotyrosine antibody PT66 (Perkin-Elmer, cat #AD0068) and 20 nM SA- APC (based on the SA moiety), is added.
  • the reaction plates are incubated at room temperature for at least 15 minutes after SA-APC detection mix addition.
  • the reaction plates are then read on an Envision plate reader (Perkin-Elmer) with 605nm excitation 615 nM and 640nm emission wavelengths. 2
  • a negative control i.e. a readout in which the kinases are not inhibited
  • the assay is run without any test compound added.
  • Staurosporine a general kinase inhibitor, is used as a positive control.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

At least one compound of Formula I or a pharmaceutically acceptable salt thereof, are provided herein. Pharmaceutical compositions comprising at least one one compound of Formula I or a pharmaceutically acceptable salt and one or more pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are also provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to angiogenic kinase modulation, which comprise administering to such patients an amount of at least one compound of Formula I or a pharmaceutically acceptable salt effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Methods of treatment include administering at least one compound of Formula I or a pharmaceutically acceptable salt as a single active agent or administering such at least one compound of Formula I or a pharmaceutically acceptable salt in combination with one or more other therapeutic agents. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with at least one compound of Formula I or a pharmaceutically acceptable salt under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase, and therefrom determining the presence or absence of the angiogenic kinase in the sample.

Description

CERTAIN SUBSTITUTED UREAS AS MODULATORS OF KINASE ACTIVITY
[0001] Provided herein are certain substituted ureas and related compounds, compositions comprising such compounds, and methods of their use.
[0002] Protein kinases, the largest family of human enzymes, encompass well over 500 proteins. Kinases play a key role in angiogenesis. Angiogenesis, the formation of new blood vessels from preexisting ones, plays a significant role in many pathological settings, including cancer, chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis, and macular degeneration. Anti- angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization.
[0003] The process of angiogenesis is complex, requiring the concerted actions of multiple angiogenic mediators as well as the participation of different cell types. Key angiogenesis mediators, including, VEGF, FGF, and angiopoietin 1 and 2 (Ang1 and Ang2) that bind to their cognate receptors (VEGFRs, FGFRs and Tie1 and Tie2, respectively) expressed on endothelial cells, as well as platelet-derived growth factor (PDGF) that binds to its receptor (PDGFRa) expressed on VEGF- producing stromal cells or its receptor (PDGFR ) expressed on pericytes and smooth muscle cells have been identified. Recent studies indicate that several members of the ephrin family and their receptor Eph family are also regulators of angiogenesis. VEGFRs, FGFRs, Tie1 , Tie2, PDGFRs, and Eph receptors all belong to the receptor protein tyrosine kinase (RTK) superfamily. Given the important roles of these RTKs in angiogenesis, their modulation would be pharmacologically desirable for the treatment of cancer and other disease.
[0004] Provided is at least one compound of Formula I
Figure imgf000002_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein
is chosen from chloro, bromo, and trifluoromethyl;
R2 is chosen from fluoro, chloro, methoxy, and difluoromethoxy;
m is 0 or 1 ;
if present, R3 is chosen from fluoro and methyl;
R4 is chosen from hydrogen and lower alkyl;
R5 is chosen from hydrogen and lower alkyl;
R6 is chosen from hydrogen, fluoro, and chloro;
n is 0 or 1 ;
if present, R7 is chosen from fluoro and methyl;
R8 is chosen from residues (a), (b), and (c); and
Figure imgf000003_0001
R9 and Rio are independently chosen from hydrogen and methyl,
provided that
(1) when R8 is residue (a), Ri is trifluoromethyl, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not methoxy;
(2) when R8 is residue (a), R9 is hydrogen, Ri0 is methyl, R is trifluoromethyl, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not fluoro; (3) when R8 is residue (a), Ri is trifluoromethyl, m is 0, n is 1 , R4 is hydrogen, R5 is hydrogen, R6 is hydrogen, and R7 is methyl, then R2 is not methoxy; and
(4) when R8 is residue (b), R- is chloro, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not methoxy or chloro.
[0005] Also provided is a pharmaceutical composition, comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients. Also provided is a packaged pharmaceutical composition, comprising the pharmaceutical composition described herein in a container; and instructions for using the composition to treat a patient suffering from a disease or disorder responsive to kinase activity modulation of one or more tyrosine kinase.
[0006] Also provided is a method of treating a patient having a disease or disorder responsive to kinase activity modulation comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a composition described herein.
[0007] Also provided is a method for treating a female patient having a female reproductive disorder or condition comprising administering to the female patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
[0008] Also provided is a method of modulating EphB4 kinase activity, the method comprising contacting cells expressing EphB4 with at least one compound described herein, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit EphB4 kinase activity in vitro.
[0009] Also provided is a method of modulating VEGFR2 kinase activity, the method comprising contacting cells expressing VEGFR2 with at least one compound described herein, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit VEGFR2 kinase activity in vitro.
[0010] Also provided is a method of modulating PDGFR kinase activity, the method comprising contacting cells expressing PDGFRp with at least one compound described herein, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit PDGFRp kinase activity in vitro. [0011] Also provided is a method of modulating c-Kit kinase activity, the method comprising contacting cells expressing c-Kit with at least one compound described herein, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit c-Kit kinase activity in vitro.
[0012] Also provided is a method of modulating an activity of at least one kinase chosen from VEGFR2, EphB4, PDGFRp, and c-Kit, the method comprising contacting cells expressing at least one kinase chosen from VEGFR2, EphB4, PDGFR , and c-Kit with at least one compound described herein, or a
pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit the activity of at least one kinase chosen from VEGFR2, EphB4, PDGFRp, and c-Kit in vitro.
[0013] Also provided is the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a patient having a disease responsive to inhibition of at least one kinase chosen from VEGFR2, EphB4, PDGFR , and c-Kit.
[0014] Also provided is a method for the manufacture of a medicament for the treatment of a patient having a disease responsive to inhibition of at least one kinase chosen from VEGFR2, EphB4, PDGFRp, and c-Kit, comprising including in said medicament at least one compound described herein, or a pharmaceutically acceptable salt thereof.
[0015] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout:
[0016] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. In accordance with the usual meaning of "a" and "the" in patents, reference, for example, to "a" kinase or "the" kinase is inclusive of one or more kinases.
[0017] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. [0018] "Lower alkyl" encompasses straight chain and branched chain having the one to four carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. When an alkyl residue having a specific number of carbons is named, all geometric combinations having that number of carbons are intended to be encompassed; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and isopropyl.
[0019] Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, such compounds include Z- and E- forms (or c/'s- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds described herein exist in various tautomeric forms, those compounds include all tautomeric forms.
[0020] Compounds of Formula I also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form," "polymorph," and "novel form" may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational
polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
[0021] Compounds of Formula I also include=different enriched isotopic forms, e.g., compounds enriched in the content of 2H, 3H, 11C, 13C and/or 1 C. In some embodiments, the compounds are deuterated. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration may improve the efficacy and increase the duration of action of drugs. [0022] Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp. CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21 , CODEN: TETRAB ISSN:0040-4020. CAN 1 12:20527 AN
1990:20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled
compounds, J. Radioanal. Chem., 1981 , 64(1-2), 9-32. CODEN: JRACBN
ISSN:0022-4081 , CAN 95:76229 AN 1981 :476229 CAPLUS.
[0023] Compounds of Formula I also include other pharmaceutically acceptable forms of the recited compounds, including prodrugs, solvates, chelates, non-covalent complexes, and mixtures thereof. Similarly, pharmaceutically acceptable salts of compounds of Formula I include other pharmaceutically acceptable forms of the salts.
[0024] As noted above, prodrugs also fall within the scope of compounds of Formula I. In some embodiments, the "prodrugs" described herein include any compound that becomes a compound of Formula I when administered to a patient, e.g., upon metabolic processing of the prodrug.
[0025] A "solvate" is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates of compounds. Similarly, "salts" includes solvates of salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
[0026] A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of compounds. Similarly, "salts" includes chelates of salts.
[0027] A "non-covalent complex" is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound'.
[0028] The term "hydrogen bond" refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry (G. C. Pimentel and A. L. McClellan, The
Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard,
"Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp. 320-326 (1984)).
[0029] "Hydrogen bond acceptor" refers to a group comprising an oxygen or nitrogen, especially an oxygen or nitrogen that is sp2 -hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.
[0030] The term "hydrogen bond donor" refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen. group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.
[0031] "Pharmaceutically acceptable salts" include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate,
methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and like salts. When the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in
accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
[0032] As used herein the terms "group", "radical" or "fragment" are
synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.
[0033] The term "active agent" is used to indicate a compound, or a
pharmaceutically acceptable salt thereof, which has biological activity. In certain embodiments, an "active agent" is a compound, or a pharmaceutically acceptable salt thereof, having pharmaceutical utility. For example an active agent may be an anti-cancer therapeutic.
[0034] As used herein, "modulation" refers to a change in kinase activity as a direct or indirect response to the presence of compounds as described herein, relative to the activity of the kinase in the absence of the compound. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the kinase, or due to the interaction of the compound with one or more other factors that in turn affect kinase activity. For example, the presence of the compound may, for example, increase or decrease kinase activity by directly binding to the kinase, by causing (directly or indirectly) another factor to increase or decrease the kinase activity, or by (directly or indirectly) increasing or decreasing the amount of kinase present in the cell or organism.
[0035] The term "therapeutically effective amount" means an amount effective, when administered to a human or non-human patient, to treat a disease, e.g., a therapeutically effective amount may be an amount sufficient to treat a disease or disorder responsive to kinase inhibition. The therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the compounds of Formula I, or theoretically, by calculating bioavailability.
[0036] By "significant" is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05.
[0037] "Patient" refers to an animal, such as a mammal, for example a human, that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments the patient is human.
[0038] By "angiogenic kinase" is meant a kinase involved in angiogenesis and includes but is not limited to a kinase chosen from EphB4 VEGFR2and PDGFR .
[0039] By "oncogenic kinase" is meant a kinase having a direct role in a cell signaling pathway that leads to cellular transformation. When overexpressed or aberrantly expressed, such kinases may have oncogenic activity. Oncogenic kinases include but are not limited to c-Kit.
[0040] "Treatment" or "treating" means any treatment of a disease in a patient, including:
a) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
b) inhibiting the disease;
c) slowing or arresting the development of clinical symptoms; and/or d) relieving the disease, that is, causing the regression of clinical symptoms.
[0041] "Diseases or disorders responsive to kinase modulation" refer to pathologic conditions that depend, at least in part, on the activity of one or more protein kinases, for example, angiogenic kinases and/or oncogenic kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including cell proliferation, differentiation, and invasion. Diseases responsive to kinase modulation include but are not limited to tumor growth, angiogenesis supporting solid tumor growth, and diseases characterized by excessive local vascularization such as diabetic retinopathy, macular degeneration, and inflammation.
[0042] "Change in angiogenesis" refers to a change in the vascular network or quality of vasculature. Change in angiogenesis may be measured by many parameters and, for instance, may be assessed by delayed appearance of neovascular structures, slowed development of neovascular structures, decreased occurrence of neovascular structures, changes in vascular permeability, changes in blood flow, slowed or decreased severity of angiogenesis-dependent disease effects, arrested angiogenic growth, or regression of previous angiogenic growth.
[0043] Provided herein is at least one compound of Formula I
Figure imgf000010_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein
Ri is chosen from chloro, bromo, and trifluoromethyl;
R2 is chosen from fluoro, chloro, methoxy, and difluoromethoxy;
m is 0 or 1 ;
if present, R3 is chosen from fluoro and methyl;
R4 is chosen from hydrogen and lower alkyl;
R5 is chosen from hydrogen and lower alkyl; R6 is chosen from hydrogen, fluoro, and chloro;
n is 0 or 1 ;
if present, R7 is chosen from fluoro and methyl;
R8 is chosen from residues (a), (b), and (c); and
Figure imgf000011_0001
R9 and Ri0 are independently chosen from hydrogen and methyl,
provided that
(1) when R8 is residue (a), Ri is tnfluoromethyl, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not methoxy;
(2) when R8 is residue (a), R9 is hydrogen, Rio is methyl, is tnfluoromethyl, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not fluoro;
(3) when R8 is residue (a), Ri is tnfluoromethyl, m is 0, n is 1 , R4 is hydrogen, R5 is hydrogen, R6 is hydrogen, and R is methyl, then R2 is not methoxy; and
(4) when R8 is residue (b), R-\ is chloro, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not methoxy or chloro.
[0044] In certain embodiments, Ri is chloro. In certain embodiments, Ri is bromo. In certain embodiments, Ri is tnfluoromethyl.
[0045] In certain embodiments, R2 is fluoro. In certain embodiments, R2 is chloro. In certain embodiments, R2 is methoxy. In certain embodiments, R2 is difluoromethoxy.
[0046] In certain embodiments, m is 0. In certain embodiments, m is 1.
[0047] In certain embodiments, R3 is fluoro. In certain embodiments, R3 is methyl.
[0048] In certain embodiments, R4 is hydrogen.
[0049] In certain embodiments, R5 is hydrogen.
[0050] In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is fluor. In certain embodiments, R6 is chloro.
[0051] In certain embodiments, n is 0. In certain embodiments, n is 1.
[0052] In certain embodiments, R7 is fluoro. In certain embodiments, R7 is methyl.
[0053] In certain embodiments, R8 is residue (a)
Figure imgf000012_0001
[0054] In certain embodiments, Re is residue (b)
Figure imgf000012_0002
[0055] In certain embodiments, Rs is residue (c)
Figure imgf000012_0003
[0056] Also provided is at least one compound chosen from
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3.(5-bromo-2-methoxyphenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4.(3.(5-chloro-2-methoxyphenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)-3-fluorophenoxy)picolin-amide;
4-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)-ureido)-3-fluorophenoxy)-picolinamide;
4-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
4-(3-fluoro-4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N- methylpicolinamide;
4-(4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;
4-(3-fluoro-4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-chloro-2-fluorophenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-chloro-2-fluorophenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-chloro-2-fluorophenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-chloro-2-fluorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-fluorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-fluorophenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-fluorophenyl)ureido)phenoxy)picolinamide; 4-(4-(3-(5-bromo-2-fluorophenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4.(3.(5-bromo-2-(difluoromethoxy)phenyl)ureido)-3-fIuorophenoxy)picolinamide;
4-(4-(3-(5-bromo-2-(difluoromethoxy)phenyl)ureido)phenoxy)picolinamide;
4-(4.(3.(5-bromo-2-(difluoromethoxy)phenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
4-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
4-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)picolinamide;
4-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
4-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N- methylpicolinamide;
1-(5-bromo-2-methoxyphenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(5-chloro-2-methoxyphenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-methoxy-5- (trifluoromethyl)phenyl)urea;
1-(2-chloro-4-(6J-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-(difluoromethoxy)-5- (trifiuoromethyl)phenyl)urea;
1-(5-chloro-2-(difluoromethoxy)phenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(5-bromo-2-(difluoromethoxy)phenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(5-bromo-2-chlorophenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2,5-dichlorophenyl)urea; 1-(2-chloro-4-(6J-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-chloro-5- (trifluoromethyl)phenyl)urea;
1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-fIuoro-5- (trifluoromethyl)phenyl)urea;
1-(5-chloro-2-fluorophenyl)-3-(2-chloro-4-(6J-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(5-bromo-2-fluorophenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-methoxyphenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-chloro-2-methoxyphenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-methoxy-5-(trifluoromethyl)phe
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-(difluoromethoxy)-5-
(trifluoromethyl)phenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-chloro-2-(difluoromethoxy)phenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-(difluoromethoxy)phenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-chlorophenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2,5-dichlorophenyl)urea;
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-chloro-5-(trifluoromethyl)ph
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)ure^
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-chloro-2-fluorophenyl)urea; and
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-fluorophenyl)urea, or a pharmaceutically acceptable salt thereof.
[0057] Methods for obtaining the compounds described herein, or a pharmaceutically acceptable salt thereof, will be apparent to those of ordinary skill in the art, suitable procedures being described, for example, in the reaction scheme and example below.
Figure imgf000015_0001
[0058] Referring to Reaction Scheme 1 , Step A, a solution of a compound of Formula 101 , in an inert solvent such as CH2CI2 is added dropwise to a solution of a compound of Formula 102, in an inert solvent such as CH2CI2 at about 0° C. The resulting reaction mixture is stirred at room temperature for about 18 hours. The product, a compound of Formula 103, is isolated and optionally purified.
[0059] In some embodiments, at least one compound described herein, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition or formulation. Accordingly, also provided are pharmaceutical compositions comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
[0060] Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The vehicle can be inert or it can possess pharmaceutical benefits. The amount of vehicle employed in conjunction with at least one compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to provide a practical quantity of material for administration per unit dose of the at least one compound of Formula I, or a pharmaceutically acceptable salt thereof as described herein.
[0061] Exemplary pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents;
tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
[0062] Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compounds or pharmaceutically acceptable salts described herein. [0063] A therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, is mixed with a suitable
pharmaceutical acceptable vehicle. In instances in which the at least one compound of Formula I or a pharmaceutically acceptable salt thereof exhibits insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using
cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate.
[0064] Upon mixing or addition of the at least one compound of Formula I described herein, or a pharmaceutically acceptable salt thereof, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound of Formula I or a pharmaceutically acceptable salt thereof in the chosen vehicle. The therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof may be empirically determined.
[0065] At least one compound of Formula I as described herein or a pharmaceutically acceptable salt thereof may be administered orally, topically, parenterally, intravenously, by intramuscular injection, by inhalation or spray, sublingually, transdermal^, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit compositions.
[0066] Dosage compositions suitable for oral use, include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. In some embodiments, oral compositions contain from 0.1 to 99% of at least one compound of Formula I, or a pharmaceutically acceptable salt, as described herein. In some embodiments, oral compositions contain at least 5% (weight %) of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof as described herein. Some embodiments contain from 25% to 50% or from 5% to 75 % of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof as described herein.
[0067] Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The pharmaceutically acceptable carriers suitable for preparation of such compositions are well known in the art. Oral compositions may contain
preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, taste-masking agents, and coloring agents.
[0068] Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such
compositions may also contain a demulcent.
[0069] At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Moreover, compositions comprising these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monsoleate, or acacia), non-aqueous vehicles, which can include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).
[0070] For a suspension, typical suspending agents include methylcellulose, sodium carboxymethyl cellulose, AVICEL RC-591 , tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
[0071] Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are chosen form suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents; naturally-occurring phosphatides, for example, lecithin, and condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, and condensation products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, and condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan substitute. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate.
[0072] Oily suspensions may be formulated by suspending the active agents in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
[0073] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum
tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
[0074] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active agent in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
[0075] Tablets typically comprise conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time release and sustained release compositions) typically comprise one or more solid diluents disclosed above. The selection of carrier components often depends on secondary considerations like taste, cost, and shelf stability.
[0076] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
[0077] Compositions for oral use may also be presented as hard gelatin capsules wherein the active agent is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active agent is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
[0078] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be useful in the preparation of injectables.
[0079] At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques. At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many compositions for parenteral administration the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
[0080] At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
[0081] At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein described herein may be formulated for local or topical application, such as for topical application to the skin and mucous
membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye. Topical compositions may be in any form including, for example, solutions, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, and the like.
[0082] Such solutions may be formulated as 0.01 % -10% isotonic solutions, pH from 2 to 12, such as from 5 to 7, with appropriate salts. At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein may also be formulated for transdermal administration as a transdermal patch.
[0083] Topical compositions comprising at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
[0084] Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
[0085] Representative emollients include stearyl alcohol, glyceryl
monoricinoleate, glyceryl monostearate, propane-1 ,2-diol, butane-1 ,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2- pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.
[0086] At least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein may also be topically administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
[0087] Other compositions useful for attaining systemic delivery of at least one compound of Formula I or a pharmaceutically acceptable salt thereof include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included. [0088] Compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).
[0089] The compositions may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules that function in different ways to enhance or be independent of therapeutic effects of the compounds described herein. Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers.
[0090] Pharmaceutical compositions described herein may also contain additional active agents that can be chosen from a wide variety of molecules, which can function in different ways to enhance the therapeutic effects of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein. These optional other active agents, when present, are typically employed in the compositions at a level ranging from 0.01 % to 15%. Some embodiments contain from 0.1% to 10% by weight of the composition. Other embodiments contain from 0.5% to 5% by weight of the composition.
[0091] Also provided are packaged pharmaceutical compositions. Such packaged compositions include a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof, in a container and instructions for using the composition to treat a mammal (typically a human patient). In some embodiments, the instructions are for using the
pharmaceutical composition to treat a patient suffering from a disease responsive to kinase inhibition. Also provided is prescribing information; for example, to a patient or health care provider, or as a label in a packaged pharmaceutical composition. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical composition.
[0092] In all of the foregoing at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein can be administered alone, as mixtures, or in combination with other active agents.
[0093] The compounds described herein, or a pharmaceutically acceptable salt thereof, can be useful for the treatment of diseases and disorders responsive to kinase modulation. [0094] In certain embodiments, compounds described herein, or
pharmaceutically acceptable salts thereof, are modulators of protein kinases. In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are inhibitors of the protein kinases. In certain
embodiments, the compounds or pharmaceutically acceptable salts thereof inhibit at least one kinase chosen from EphB4, c-Kit, PDGFR , and VEGFR2 kinases. In certain embodiments, the compounds or pharmaceutically acceptable salts thereof inhibit more than one kinase chosen from EphB4, c-Kit, PDGFRP, and VEGFR2 kinases.
[0095] Accordingly, provided is a method of treating a patient, such as a human patient, having a disease or disorder responsive to kinase modulation, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof as described herein.
[0096] A method of treating a patient having a disease or disorder responsive to kinase modulation, particularly VEGFR2 modulation, comprising administering to the patient a therapeutically effective amount of one or more of the compounds of Formula I or a pharmaceutically acceptable salt thereof is provided.
[0097] Also provided is the use of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for the treatment of a patient having a disease or disorder responsive to kinase modulation, particularly VEGFR2 modulation. Also provided is the use of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for the treatment of a patient having angiogenesis.
[0098] In some embodiments, the compound of Formula I, or a
pharmaceutically acceptable salt thereof, inhibits at least one kinase chosen from EphB4, c-Kit, PDGFR , and VEGFR2 and can be useful for the treatment of diseases and disorders responsive to modulation of at least one of such kinases. In some embodiments, the disease or disorder is characterized by angiogenesis supporting solid tumor growth or dysregulated local vascularization.
[0099] Methods of treatment also include modulating kinase activity, by inhibiting ATP binding or hydrolysis by a kinase or by some other mechanism, in vivo, in a patient suffering from a disease or disorder responsive to kinase modulation, by administering a therapeutically effective amount of at least one compound of Formula I described herein or a pharmaceutically acceptable salt thereof to inhibit kinase activity in vitro.
[00100] In some embodiments, the condition responsive to kinase modulation is cancer or a disease or disorder characterized by a change in angiogenesis.
[00101] Also provided is a method of treating a patient having cancer or a disease or disorder characterized by a change in angiogenesis by administering at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein. Also provided are methods of treatment in which a compound or salt is the only active agent given to a patient and also includes methods of treatment in which at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein is given to a patient in combination with one or more additional active agents.
[00102] Certain compounds described herein, or pharmaceutically acceptable salts thereof, can be useful for treating a patient suffering from a disease or disorder responsive to kinase modulation.
[00103] In certain embodiments, the conditions, diseases and/or disorders that are affected using compounds of Formula I, or pharmaceutically acceptable salts thereof, and compositions comprising such compounds include, but are not limited to, psoriasis, angiogenesis, cancer (for example, chronic myelogenous leukemia, gastrointestinal stromal tumors, non-small cell lung cancer, breast cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer such as hormonal refractory prostate cancer, kidney cancer, head and neck cancer, or colorectal cancer), immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, Parkinson's disease, Alzheimer's disease, diabetes (for example insulin resistance or diabetic retinopathy), septic shock, and the like.
[00104] In certain embodiments, the conditions, diseases and/or disorders that are affected using at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein and compositions comprising such compounds of Formula I, or pharmaceutically acceptable salts thereof, are female reproductive female reproductive disorders and conditions. In certain embodiments, the female reproductive disorders and conditions are chosen from endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.
[00105] Because kinases play an active role in angiogenesis certain
compounds described herein can be useful for modulating angiogenesis.
Angiogenesis, the formation of new blood vessels from preexisting ones, plays a critical role in many pathological settings, including cancer, chronic inflammation, diabetic retinopathy and macular degeneration. Angiogenesis is regulated by multiple cell-signaling pathways, including pathways controlled by cellular kinases. Blocking angiogenesis, through the modulation of cell kinases, therefore, can represent effective approach to the treatment of diseases such as cancer. Thus methods of treatment include administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein described herein to treat these diseases or disorders, e.g., to decrease the symptoms or slow the progression of these diseases or disorders by inhibiting the rate of angiogenesis in a tissue.
[00106] Also provided are methods for combination drug therapy, in which a compound or salt is given to a patient together with one or more other active agents. Thus also provided is a method of treating cancer, which comprises administering to a patient in need thereof an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein together with a second active agent, which can be useful for treating cancer. For example the second agent may be an antitumor agent. Treatment with the second active agent may be prior to, concomitant with, or following treatment with at least one compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof.
[00107] In certain embodiments, at least one compound of Formula I or a pharmaceutically acceptable salt thereof, is combined with at least one second active agent in a single dosage form. Radiotherapeutic anti-tumor agents may also be used alone or in combination with chemotherapeutic agents. Suitable anti-tumor therapeutics that may be used in combination with at least one compound of Formula I as described herein or a pharmaceutically acceptable salt thereof.
Examples of anti-tumor therapeutics include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol), docetaxel (also known as
Taxotere), epothilone A, epothilone B, desoxyepothilone A, desoxyepothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
[00108] Example classes of anti-tumor therapeutics include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins. Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, herceptin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11 , topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
[00109] In certain embodiments, at least one compound of Formula I or a pharmaceutically acceptable salt thereof, can be administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold-containing compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate. Examples of NSAIDs include ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., a compound that inhibits COX-2 with an IC50 that is at least 50-fold lower than the IC50 for COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib. In certain embodiments, the antiinflammatory agent can be a salicylate. Salicylates include acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates. The antiinflammatory agent can also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone. In certain embodiments, the anti-inflammatory agent can be a gold-containing compound such as gold, sodium thiomalate or auranofin. In certain embodiments, the anti-inflammatory agent can be a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide. Certain embodiments of the present disclosure include combinations in which at least one antiinflammatory compound can be an anti-C5 monoclonal antibody (such as
eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody, and combinations in which at least one active agent is an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.
[00110] Dosage levels of the order of from 0.1 mg to 140 mg per kilogram, such as 1 to 50 mg per kilogram, of body weight per day can be useful in the treatment of the above- indicated conditions (0.5 mg to 7 g per patient per day). The amount of active agent that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain from 1 mg to 500 mg of an active agent.
[00111] Frequency of dosage may also vary depending on the compound used and the particular disease treated. In certain embodiments, a dosage regimen of 4 times daily or less is used. In certain embodiments, a dosage regimen of 1 or 2 times daily is used.
[00112] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy.
EXAMPLES
[00113] The invention is further illustrated by the following non-limiting examples.
[00114] In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. g = gram
h = hour
mg = milligram
min = minutes
mL = milliliter
mmol = millimoles
mM = millimolar
ng - nanogram
nm = nanometer
nM = nanomolar
PBS = phosphate buffered saline
μΐ = microliter
μΜ = micromolar
EXAMPLE 1.
Figure imgf000029_0001
[00115] 3-(5-bromo-2-methoxyphenyl)-1 -(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)-phenyl)urea: A solution of 0.768 g of 5-bromo-2-methoxyphenyl isocyanate (3.0 mmol) in CH2CI2 (10 mL) is added dropwise to a solution of 0.730g of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (3.0 mmol) in CH2CI2 (4 mL) at 0° C. The mixture is stirred at room temperature for 18 h, then the resulting yellow solid is filtered, the solid washed with CH2CI2 (2 x 5 mL) and dried under reduced pressure at 40° C. to afford 3-(5-bromo-2-methoxyphenyl)-1-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)-phenyl)urea as a light yellow solid.
[00116] The other compounds described herein may be prepared using procedures similar to those described above. Those of ordinary skill in the art of organic synthesis will recognize when starting materials or reaction conditions should be varied to obtain the desired compound. EXAMPLE 2. ASSAY FOR EPHB4 KINASE ACTIVTY
[00117] The following is a procedure for a standard biochemical assay for EphB4 Kinase Activity that can be used to test compounds disclosed in this application.
Materials:
96-well, ½ area flat bottom, white polystyrene plates are purchased from Costar, cat #3693.
[00118] The cytoplasmic domain of recombinant EphB4 kinase (amino acids 596-987, Homo sapiens EphB4, GENBANK Accession No. AY056047.1) with a C- terminal V5-(his)6 tag is purified from S 9 cells. Purity of >95% is assessed by Sypro-Ruby staining of SDS gels.
[00119] PTK Biotinylated Peptide Substrate 2, is purchased from Promega, cat #V288A.
[00120] LANCE Eu-W1024 labeled anti-phosphotyrosine antibody (PT66) is purchased from Perkin-Elmer, cat #AD0068. Kinase Buffer is purchased from Cell Signaling, cat #9802.
[00121] Dilutions of compounds are made in 100% DMSO at 20X the final desired concentration. Compounds in 100% DMSO are transferred (1.25 μΙ_) to the 96 well assay plate. A 18.75 μΙ_ volume of master mix containing the final concentrations (in 25 ul) of 0.01 % BSA, 1X Cell Signaling Kinase Buffer, 0.5 μΜ PTK Biotinylated Peptide Substrate 2, and 18.6 ng/well ng/well of EphB4 kinase is added to all wells, except the four negative control wells (which contain no kinase), and mixed. To initiate the reaction, 5 μί of 550 uM ATP is added to each well. (Final Concentration of ATP = 110 μΜ). The reactions are incubated for 1 hour at room temperature (RT). After incubation a quantity of 8.35 μΙ_ of a 4X SA-APC Detection Mix is added to each well. The final concentration of Eu-labelled PT66 antibody is 1 nM and the SA-APC is 20 nM (based on the SA moiety). The reaction plates are incubated at RT for at least 15 minutes after SA-APC Detection Mix addition. The reaction plates are read on an Envision plate reader (Perkin-Elmer) with 605nm Excitation at 605nm and 640nm Emission wavelengths. Values are corrected for the fluorescence in the absence of enzyme and inhibition curves are fit to the data using a Logit curve-fitting algorithm. IC50 values are determined from these inhibition curves.
EXAMPLE 3. EPHB4 CELLULAR ASSAY
[00122] The following is a procedure for a standard cell-based assay for EphB4 kinase activity that can be used to test compounds disclosed in this application.
[00123] HEK293 cells stably expressing V5-epitope tagged EphB4 are grown to ~75% confluency, and then incubated for 90 min at 37 °C in low serum media (Optimem) containing test compound. Cells are stimulated for 10 minutes at 37 °C with 500ng/ml EphrinB2/Fc chimera and 50ng/ml goat-anti-human IgG (FC-specific) in low serum media containing test compound. Cells are washed in ice-cold PBS, lysed, and protein assays are performed on the cleared lysates. Equal protein amounts of each sample are subjected to SDS-PAGE and western blotting with either an anti-phosphotyrosine antibody or an anti-V5 antibody to control for total amounts of V5-epitope-tagged EphB4 in each lysate.
EXAMPLE 4 BIOCHEMICAL ASSAYS
[00124] The following is a procedure for a standard biochemical assay that can be used to test activity of compounds disclosed herein as inhibitors of c-Kit,
PDGFR , and VEGFR2, kinase activity.
[00125] Test compounds are diluted 1 :20 from an original 200 μΜ DMSO stock and incubated with recombinant c-Kit (10 ng), or VEGFR2 (1 ng) enzyme (ProQinase GmbH, Germany), biotinylated peptide (PTK peptide 2, Promega) in Cell Signalling kinase buffer (c-Kit) or Upstate Kinase buffer (VEGFR2) and 5 ul of ATP (final concentrations: 85 uM for the VEGFR2 assayand 150 μΜ for the c-Kit assay) for 60 minutes at room temperature. For PDGFR , test compounds are diluted 1 :20 from an original 200 μΜ DMSO stock and incubated with recombinant PDGFRp (2 ng) (ProQinase GmbH, Germany), biotinylated peptide (PTK peptide 2, Promega), 1 uM poly-L-lysine (Sigma) in Upstate Kinase buffer and 5 ul of ATP (final concentration: 2.5 uM) for at least 15 minutes at room temperature. The final assay volume is 25 μΙ. After incubation a detection Mix, which includes 1 nM LANCE Eu-W1024 labeled anti-phosphotyrosine antibody PT66 (Perkin-Elmer, cat #AD0068) and 20 nM SA- APC (based on the SA moiety), is added. The reaction plates are incubated at room temperature for at least 15 minutes after SA-APC detection mix addition. The reaction plates are then read on an Envision plate reader (Perkin-Elmer) with 605nm excitation 615 nM and 640nm emission wavelengths. 2
[00126] For a negative control, i.e. a readout in which the kinases are not inhibited, the assay is run without any test compound added. Staurosporine, a general kinase inhibitor, is used as a positive control.
[00127] IC50 values are determined from an 1 1 -point saturation binding curve for test compounds that show significant inhibition of one of the tyrosine kinases. In these assays concentration of test compound ranges from 10 μΜ to 20nM.
Equilibrium binding parameters are determined by fitting the allosteric Hill equation to the measured values with the aid of the computer program, such as FitP™
(BIOSOFT, Ferguson, MO).
EXAMPLE 5. TEST RESULTS
[00128] Compounds and pharmaceutically acceptable salts described herein may be tested in the assays for EphB4 kinase activity (as outlined in Examples 2 and 3), and may exhibit an IC50 of 1 micromolar or less. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 500 nM or less in these assays. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 50 nM or less in these assays.
[00129] Compounds and pharmaceutically acceptable salts described herein may be tested in the assay for PDGFR kinase activity (as outlined in example 4), and may exhibit an IC50 of 1 micromolar or less. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 500 nM or less in the assay for PDGFR kinase activity. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 100 nM or less in this assay.
[00130] Compounds and pharmaceutically acceptable salts described herein may be tested in the assay for c-Kit kinase activity (as outlined in example 4) and may exhibit an IC50 of 1 micromolar or less. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC5o Of 500 nM or less in the assay for c-Kit kinase activity. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 50 nM or less in this assay.
[00131] Compounds and pharmaceutically acceptable salts described herein may also be tested in the assay for VEGFR2 kinase activity (as outlined in example 4). Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 1 micromolar or less. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC50 of 100 nM or less in this assay. Certain of those compounds and pharmaceutically acceptable salts may exhibit an IC5o of 50 nM or less in this assay.
[00132] Compounds and pharmaceutically acceptable salts described herein may also be tested in the assays described herein and may exhibit an IC5o of 1 micromolar or less against two or more kinases chosen from EphB4, PDGFRp, c-Kit, and VEGFR2. Certain compounds and pharmaceutically acceptable salts described may also be tested in the assays described herein and may exhibit an IC50 of 100 nm or less against two or more kinases chosen from EphB4, PDGFR , c-Kit, and
VEGFR2.
[00133] Compounds and pharmaceutically acceptable salts described herein may also be tested in the assays described herein and may exhibit an IC5o of 1 micromolar or less against three or more kinases chosen from EphB4, PDGFRp, c- Kit, and VEGFR2. Certain compounds and pharmaceutically acceptable salts may also be tested in the assays described herein and may exhibit an IC50 of 100 nm or less against three or more kinases chosen from EphB4, PDGFRβ, c-Kit, and
VEGFR2.
[00134] Compounds and pharmaceutically acceptable salts described herein may also be tested in the assays described herein and may exhibit an IC50 of 1 micromolar or less against each of EphB4, PDGFR , c-Kit, and VEGFR2. Certain compounds and pharmaceutically acceptable salts may also be tested in the assays described herein and may exhibit an IC50 of 100 nm or less against each of EphB4, PDGFRp, c-Kit, and VEGFR2.
[00135] While certain embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations.

Claims

What is claimed is:
1. A compound of Formula I
Figure imgf000034_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein
Ri is chosen from chloro, bromo, and trifluoromethyl;
R2 is chosen from fluoro, chloro, methoxy, and difluoromethoxy; m is 0 or 1 ;
if present, R3 is chosen from fluoro and methyl;
R4 is chosen from hydrogen and lower alkyl;
R5 is chosen from hydrogen and lower alkyl;
R6 is chosen from hydrogen, fluoro, and chloro;
n is 0 or 1 ;
if present, R7 is chosen from fluoro and methyl;
R8 is chosen from residues (a), (b), and (c); and
Figure imgf000034_0002
Figure imgf000035_0001
R9 and Rio are independently chosen from hydrogen and methyl,
provided that
(1) when R8 is residue (a), Ri is trifluoromethyl, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not methoxy;
(2) when R8 is residue (a), R9 is hydrogen, Rio is methyl, R-i is
trifluoromethyl, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not fluoro;
(3) when R8 is residue (a), Ri is trifluoromethyl, m is 0, n is 1 , R4 is hydrogen, R5 is hydrogen, R6 is hydrogen, and R7 is methyl, then R2 is not methoxy; and
(4) when R8 is residue (b), Ri is chloro, m is 0, n is 0, R4 is hydrogen, R5 is hydrogen, and R6 is hydrogen, then R2 is not methoxy or chloro.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ri is chloro.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ri is bromo.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ri is trifluoromethyl.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is fluoro.
6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is chloro.
7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is methoxy.
8. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is difluoromethoxy.
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein m is 0.
10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein m is 1.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3 is fluoro.
12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.
16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R6 is fluoro.
17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R6 is chloro.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein n is 0.
19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein n is 1.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R7 is fluoro.
21. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.
22. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R8 is residue (a).
Figure imgf000037_0001
23. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R8 is residue (b).
Figure imgf000038_0001
24. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R8 is residue (c).
Figure imgf000038_0002
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is chosen from
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-bromo-2-methoxyphenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-chloro-2-methoxyphenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)-3-fluorophenoxy)picolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)phenoxy)picolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(5-bromo-2-chlorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)phenoxy)-N-methylpicolinamide;
4-(4-(3-(2,5-dichlorophenyl)ureido)phenoxy)picolinamide; -(4-(3-(2,5-dichlorophenyl)ureido)-3-fluorophenoxy)picolin-amide;
-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)-ureido)-3-fluorophenoxy)-picolinamide;-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;
-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinami-(4-(3-(2-chloro-5-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
-(3-fluoro-4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N- methylpicolinamide;
-(4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;-(4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)p enoxy)picolinamide;
-(3-fluoro-4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;-(4-(3-(5-chloro-2-fluorophenyl)ureido)-3-fluorophenoxy)picolinamide;
-(4-(3-(5-chloro-2-fluorophenyl)ureido)phenoxy)picolinamide;
-(4-(3-(5-chloro-2-fluorophenyl)ureido)phenoxy)-N-methylpicolinamide;
-(4-(3-(5-chloro-2-fluorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;-(4-(3-(5-bromo-2-fluorophenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide;-(4-(3-(5-bromo-2-fluorophenyl)ureido)phenoxy)-N-methylpicolinamide;
-(4-(3-(5-bromo-2-fluorophenyl)ureido)phenoxy)picolinamide;
-(4-(3-(5-bromo-2-fluorophenyl)ureido)-3-fluorophenoxy)picolinamide;
-(4-(3-(5-bromo-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)picolinamide;-(4-(3-(5-bromo-2-(difluoromethoxy)phenyl)ureido)phenoxy)picolinamide;
-(4-(3-(5-bromo-2-(difluoromethoxy)phenyl)ureido)phenoxy)-N-methylpicolinamide;-(4-(3-(5-bromo-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide;
-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)phenoxy)-N-methylpicolinamide;-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)-3-fluorophenoxy)picolinamide;-(4-(3-(5-chloro-2-(difluoromethoxy)phenyl)ureido)phenoxy)picolinamide;
-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)phenoxy)picolinamide;-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)picolinamide;
-(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N- methylpicolinamide; -(4-(3-(2-(difluoromethoxy)-5-(trifluoromethyl)phenyl)ureido)phenoxy)-N- methylpicolinamide;
-(5-bromo-2-methoxyphenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(5-chloro-2-methoxyphenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-methoxy-5-
(trifluoromethyl)phenyl)urea;
-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-(difluoromethoxy)-5-
(trifluoromethyl)phenyl)urea;
-(5-chloro-2-(difluoromethoxy)phenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(5-bromo-2-(difluoromethoxy)phenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(5-bromo-2-chlorophenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2,5-dichlorophenyl)urea;-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-chloro-5-
(trifluoromethyl)phenyl)urea;
-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(2-fluoro-5-
(trifluoromethyl)phenyl)urea;
-(5-chloro-2-fluorophenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(5-bromo-2-fluorophenyl)-3-(2-chloro-4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)urea;
-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-methoxyphenyl)urea;
-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-chloro-2-methoxyphenyl)urea;
-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea; -(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-(difluoromethoxy)-5-
(trifluoromethyl)phenyl)urea;
-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-chloro-2-(difluoromethoxy)phenyl)urea; -(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-(difluoromethoxy)phenyl)urea; -(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-chlorophenyl)urea;
-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2,5-dichlorophenyl)urea; 1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-chloro-5-(trifluoromethyl)ph 1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)pheny^
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-chloro-2-fluorophenyl)urea; and
1-(4-(3-amino-1 H-indazol-4-yl)phenyl)-3-(5-bromo-2-fluorophenyl)urea.
26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the compound exhibits an IC5o of 1 micromolar or less in a standard in vitro assay of EphB4 kinase activity.
27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC5o of 500 nanomolar or less in a standard in vitro assay of EphB4 kinase activity.
28. The compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 50 nanomolar or less in a standard in vitro assay of EphB4 kinase activity.
29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 1 micromolar or less in a standard in vitro assay of PDGFF^ kinase activity.
30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 500 nanomolar or less in a standard in vitro assay of PDGFRp kinase activity.
31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 100 nanomolar or less in a standard in vitro assay of PDGFR kinase activity.
32. The compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 1 micromolar or less in a standard in vitro assay of VEGFR2 kinase activity.
33. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 500 nM or less in a standard in vitro assay of VEGFR2 kinase activity.
34. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 50 nM or less in a standard in vitro assay of VEGFR2 kinase activity.
35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 1 micromolar or less in a standard in vitro assay of c-Kit kinase activity.
36. The compound according to claim 35, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 500 nanomolar or less in a standard in vitro assay of c-Kit kinase activity.
37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC50 of 50 nanomolar or less in a standard in vitro assay of c-Kit kinase activity.
38. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof, exhibits an IC5o of 1 micromolar or less in a standard in vitro assay of EphB4 kinase activity; an IC5o of 1 micromolar or less in a standard in vitro assay of PDGFRp kinase activity; and an IC50 of 1 micromolar or less in a standard in vitro assay of VEGFR2 kinase activity.
39. A pharmaceutical composition, comprising at least one compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
40. A pharmaceutical composition of claim 39, wherein the composition is formulated in a form chosen from injectable fluids, aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmic solutions, and transdermal patches.
41. A method of treating a patient having a disease or disorder responsive to kinase activity modulation comprising administering to the patient a therapeutically effective amount of at least one compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 39 or 40.
42. The method of claim 41 wherein the patient is a human.
43. The method of claim 41 wherein the patient is chosen from cats and dogs.
44. A method of any one of claims 41 to 43 wherein the disease or disorder responsive to kinase activity modulation is chosen from cancer and diseases characterized by a change in angiogenesis.
45. The method of claim 44, wherein the disease characterized by a change in angiogenesis is chosen from cancerous tumor, macular degeneration, and diabetic retinopathy.
46. The method of any one of claims 41 to 45 wherein the at least one compound or a pharmaceutically acceptable salt thereof, is administered by a method chosen from intravenously, intramuscularly, and parenterally.
47. A packaged pharmaceutical composition, comprising the pharmaceutical composition of claim 39 or 40 in a container; and instructions for using the composition to treat a patient suffering from a disease or disorder responsive to kinase activity modulation of one or more tyrosine kinase.
48. The packaged pharmaceutical composition of claim 47 wherein the disease or disorder responsive to kinase activity modulation is chosen from cancer and diseases characterized by a change in angiogenesis.
49. The packaged pharmaceutical composition of claim 48 wherein the disease characterized by a change in angiogenesis is chosen from cancerous tumor, macular degeneration, and diabetic retinopathy.
50. A method of modulating EphB4 kinase activity, the method comprising contacting cells expressing EphB4 with at least one compound of any one of claims 26 to 28, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit EphB4 kinase activity in vitro.
51. A method of modulating VEGFR2 kinase activity, the method comprising contacting cells expressing VEGFR2 with at least one compound of any one of claims 32 to 34, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit VEGFR2 kinase activity in vitro.
52. A method of modulating c-Kit kinase activity, the method comprising contacting cells expressing c-Kit with at least one compound of any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit c-Kit kinase activity in vitro.
53. A method of modulating PDGFRp kinase activity, the method comprising contacting cells expressing PDGFRp with at least one compound of any one of claims 29 to 31 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit PDGFRp kinase activity in vitro.
54. A method of modulating an activity of at least one kinase chosen from
VEGFR2, EphB4, PDGFRp, and c-Kit, the method comprising contacting cells expressing at least one kinase chosen from VEGFR2, EphB4, PDGFRp, and c-Kit with at least one compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in an amount sufficient to detectably inhibit the activity of at least one kinase chosen from VEGFR2, EphB4, PDGFRp, and c-Kit in vitro.
55. The use of at least one compound for the manufacture of a medicament for the treatment of a patient having a disease responsive to inhibition of at least one kinase chosen from VEGFR2, EphB4, PDGFRp, and c-Kit, wherein the at least one compound is a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.
56. The use of claim 55, wherein the disease responsive to inhibition of at least one kinase is responsive to inhibition of VEGFR2 kinase activity.
57. The use of claim 56, wherein the disease responsive to inhibition of VEGFR2 kinase activity is chosen from cancer and diseases characterized by a change in angiogenesis.
58. The use of claim 57, wherein the diseases characterized by a change in angiogenesis are chosen from cancerous tumor, macular degeneration, and diabetic retinopathy.
59. A method for the manufacture of a medicament for the treatment of a patient having a disease responsive to inhibition of at least one kinase chosen from
VEGFR2, EphB4, PDGFRp, and c-Kit, comprising including in said medicament at least one compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.
60. The method of claim 59, wherein the disease responsive to inhibition of at least one kinase is responsive to inhibition of VEGFR2 kinase activity.
61. The method of claim 60, wherein the disease responsive to inhibition of VEGFR2 kinase activity is chosen from cancer and diseases characterized by a change in angiogenesis.
62. The method of claim 61 , wherein the diseases characterized by a change in angiogenesis are chosen from cancerous tumor, macular degeneration, and diabetic retinopathy.
63. A method for treating a female patient having a female reproductive disorder or condition comprising administering to the female patient a therapeutically effective amount of at least one compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 39 or 40.
64. A method of claim 63 wherein the female reproductive disorder or condition is chosen from endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS),and
menopausal dysfunction.
65. The method of claim 63 or 64 wherein the at least one compound, or a pharmaceutically acceptable salt thereof, is administered by a method chosen from intravenously, intramuscularly, and parenterally.
66. The method of claim 63 or 64 wherein an effective amount of said at least one compound, or a pharmaceutically acceptable salt thereof, is administered orally.
PCT/US2010/052420 2009-10-15 2010-10-13 Certain substituted ureas as modulators of kinase activity WO2011046991A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25198009P 2009-10-15 2009-10-15
US61/251,980 2009-10-15

Publications (2)

Publication Number Publication Date
WO2011046991A2 true WO2011046991A2 (en) 2011-04-21
WO2011046991A3 WO2011046991A3 (en) 2011-08-18

Family

ID=43876837

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/052420 WO2011046991A2 (en) 2009-10-15 2010-10-13 Certain substituted ureas as modulators of kinase activity

Country Status (1)

Country Link
WO (1) WO2011046991A2 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214479A (en) * 2012-01-18 2013-07-24 武汉东宇生物医药科技有限公司 Pyrazole naphthylurea tyrosine kinase inhibitor and its application
WO2013120896A1 (en) * 2012-02-13 2013-08-22 Harmonic Pharma Compound for use in the prevention and/or treatment of a neurogenerative disease or a disease involving an activation of phosphodiesterase-4 (pde4)
WO2015043342A1 (en) * 2013-09-29 2015-04-02 镇江蓝德特药业科技有限公司 Novel a-naphthylurea derivative and medical application of same
WO2015051149A1 (en) * 2013-10-04 2015-04-09 The Trustees Of Columbia University In The City Of New York Sorafenib analogs and uses thereof
CN104788366A (en) * 2014-01-21 2015-07-22 王若文 Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof
WO2018035346A1 (en) * 2016-08-17 2018-02-22 Ichan School Of Medicine At Mount Sinal Kinase inhibitor compounds, compositions, and methods of treating cancer
CN108117551A (en) * 2016-11-29 2018-06-05 华东理工大学 Substitute (1H- pyrazoles [3,4-b] pyridine) carbamide compounds and its anticancer usage

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0104153D0 (en) * 2001-02-20 2001-04-11 Reckitt Benckiser Inc Improvements in or relating to organic compositions
CA2666005C (en) * 2002-03-01 2016-01-19 Dyax Corp. Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy
US7932044B2 (en) * 2005-07-01 2011-04-26 Cell Signaling Technology, Inc. Identification of non-small cell lung carcinoma (NSCLC) tumors expressing PDGFR-α
WO2007076034A2 (en) * 2005-12-21 2007-07-05 Abbott Laboratories Anti-viral compounds

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214479A (en) * 2012-01-18 2013-07-24 武汉东宇生物医药科技有限公司 Pyrazole naphthylurea tyrosine kinase inhibitor and its application
WO2013120896A1 (en) * 2012-02-13 2013-08-22 Harmonic Pharma Compound for use in the prevention and/or treatment of a neurogenerative disease or a disease involving an activation of phosphodiesterase-4 (pde4)
WO2015043342A1 (en) * 2013-09-29 2015-04-02 镇江蓝德特药业科技有限公司 Novel a-naphthylurea derivative and medical application of same
US9469639B2 (en) 2013-09-29 2016-10-18 Radiant Pharma & Tech. Co., Ltd. Naphthylurea derivatives and medical applications thereof
WO2015051149A1 (en) * 2013-10-04 2015-04-09 The Trustees Of Columbia University In The City Of New York Sorafenib analogs and uses thereof
CN104788366A (en) * 2014-01-21 2015-07-22 王若文 Raf kinase inhibitor pentafluoride sulfur-based aryl urea, and preparation method and applications thereof
WO2018035346A1 (en) * 2016-08-17 2018-02-22 Ichan School Of Medicine At Mount Sinal Kinase inhibitor compounds, compositions, and methods of treating cancer
CN110072526A (en) * 2016-08-17 2019-07-30 西奈山伊坎医学院 Kinase inhibitor compounds, composition and the method for the treatment of cancer
JP2019528279A (en) * 2016-08-17 2019-10-10 アイカーン スクール オブ メディシン アット マウント サイナイ Kinase inhibitor compounds, compositions, and methods of treating cancer
US10519113B2 (en) 2016-08-17 2019-12-31 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds, compositions, and methods of treating cancer
US11066370B2 (en) 2016-08-17 2021-07-20 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds, compositions, and methods of treating cancer
CN108117551A (en) * 2016-11-29 2018-06-05 华东理工大学 Substitute (1H- pyrazoles [3,4-b] pyridine) carbamide compounds and its anticancer usage
CN108117551B (en) * 2016-11-29 2020-03-27 华东理工大学 Substituted (1H-pyrazolo[3,4-b]pyridine) urea compounds and their antitumor use

Also Published As

Publication number Publication date
WO2011046991A3 (en) 2011-08-18

Similar Documents

Publication Publication Date Title
US7625931B2 (en) Certain substituted diphenyl ureas, as modulators of kinase activity
EP1858879B1 (en) 1,3-diaryl substituted ureas as modulators of kinase activity
US8222421B2 (en) Certain substituted ureas, as modulators of kinase activity
Mahmoud et al. Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity
Zhang et al. Design and synthesis of selective degraders of EGFRL858R/T790M mutant
TWI398439B (en) Certain substituted amides, method of making, and method of use thereof
WO2011046991A2 (en) Certain substituted ureas as modulators of kinase activity
CN114057771B (en) Macrocyclic compounds, their preparation and use
US20090176809A1 (en) Raf inhibitor compounds and methods
WO2004072081A1 (en) Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of kinase activity
CA2587192A1 (en) Imidazo[1 , 2-a] pyrazin-8-ylamines useful as modulators of kinase activity
EP1189899B1 (en) Pyrazinone thrombin inhibitors
CN107501279B (en) Furanoquinoline dione compound and medical application thereof
CN115583938A (en) Small molecule compounds targeting BCL9/β-catenin interaction
CN101163691A (en) 1,3-diaryl substituted ureas as modulators of kinase activity
CN118772141A (en) DNA polymerase Theta inhibitors for cancer treatment
CN116836161A (en) PARP1 inhibitors
HK1114392A (en) 1,3-diaryl substituted ureas as modulators of kinase activity
WO2023088291A1 (en) Aromatic amine compound and application thereof
HK40049062A (en) Tetrahydroquinolino derivatives for the treatment of metastatic and chemoresistant cancers

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: 10823984

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10823984

Country of ref document: EP

Kind code of ref document: A2