WO2012061337A1 - Modulateurs de fgfr2 - Google Patents

Modulateurs de fgfr2 Download PDF

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Publication number
WO2012061337A1
WO2012061337A1 PCT/US2011/058710 US2011058710W WO2012061337A1 WO 2012061337 A1 WO2012061337 A1 WO 2012061337A1 US 2011058710 W US2011058710 W US 2011058710W WO 2012061337 A1 WO2012061337 A1 WO 2012061337A1
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Prior art keywords
pyridin
methyl
aminopyrimidin
carboxamide
oxy
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PCT/US2011/058710
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English (en)
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Matthew A. Williams
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Exelixis, Inc.
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Publication of WO2012061337A1 publication Critical patent/WO2012061337A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to compounds that inhibit, regulate and/or modulate kinases, particularly FGFR2. Kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above are modulated using compounds of the invention. Methods of using the compounds to treat kinase-dependent diseases and conditions are also an aspect of the invention.
  • Fibroblast growth factors (FGF1 - 10 and 16 - 23) are mitogenic signaling molecules that have roles in angiogenesis, wound healing, cell migration, neural outgrowth and embryonic development. FGFs bind heparan sulfate glycosaminoglycans (HSGAGs), which facilitates dimerization (activation) of FGF receptors (FGFRs). FGFRs are transmembrane catalytic receptors that have intracellular tyrosine kinase activity. There are four human genes encoding FGFRs, which produce different receptors (FGFR1, FGFR1, FGFR2, FGFR3, and FGFR4).
  • HSGAG-FGF-FGFR binding initiates FGFR dimerization, enabling the cytoplasmic kinase domains to transphosphorylate tyrosine residues and become activated. HSGAGs also function to stabilize FGF-FGFR binding and prevent FGF degradation. FGFRs couple to the PLCgamma, MAPK and PI3-K/Akt intracellular signaling cascades and there is evidence of cross talk with the Notch signaling pathway. In addition, some activated FGF-FGFR complexes are endocytosed and function directly in the cytosol and/or nucleus of the cell.
  • Alterations in the activity (expression) of the FGFR2 gene are associated with certain cancers.
  • the altered gene expression may enhance several cancer-related events such as cell division (proliferation), cell movement, and the development of new blood vessels that nourish a growing tumor.
  • the FGFR2 gene is overexpressed in certain types of stomach cancers, and this amplification is associated with a poorer outcome. Abnormal expression of the FGFR2 gene is also found in patients with prostate cancer. Altered FGFR2 gene expression is also associated with ovarian, cervical, pancreatic, and head and neck cancers.
  • the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate FGFR2 is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis.
  • R 3a , R 2 , R 3b , R 4b , L 1 , G and J are as defined in the specification.
  • compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities.
  • Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as atherosclerosis, myocardioinfarction, ischemia, pulmonary hypertension, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.
  • cancer cancer
  • immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis
  • cardiovascular diseases such as atherosclerosis, myocardioinfarction, ischemia, pulmonary hypertension, stroke and restenosis
  • other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic
  • G is CH or ;
  • L 1 is a bond or -C(0)-N(H)-;
  • each R 2 is independently -H, halo, or (Ci-C4)alkyl
  • R 3a is optionally substituted with 1, 2 or 3 R 5 groups;
  • R 4b is H, alkyl, or dialkylaminoalkyl
  • R 4b is H or alkyl
  • each R 5 group when R 5 exists, is selected from halo, alkyl, hydroxyalkyl, haloalkyl, (Ci- C6)cycloalkyl optionally substituted with hydroxyl, alkoxyl, alkynyl, phenyl, aloxycarbonyl, or -N(R C )R D ;
  • R c is H or alkyl
  • R D is H or alkyl.
  • the compound of Formula I is a compound according to Formula II,
  • R 3a is pyrazolyl, phenyl, pyrimidinyl, thiadiazoly, benzimidazolyl, oxazolyl, oxadiazolyl, or benzoxazolyl, wherein R 3a is substituted with 1, 2 or 3 R 5 groups;
  • each R 5 group is selected from halo, alkyl, hydroxyalkyl, haloalkyl, (Ci-C6)cycloalkyl optionally substituted with hydroxyl, alkoxyl, alkynyl, phenyl, aloxycarbonyl, or
  • L 1 , R 2 , G, R 3b and R 4b are as defined in claim 1.
  • the compound of any of the above aspects or embodiments is a compound of Formula III, IV, V, VI or VII:
  • A is N or CH
  • B is N or CH
  • D is N or O
  • each R 5 when R 5 exists, is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci- C6)cycloalkyl optionally substituted with hydroxyl, and alkoxyl,
  • the compound of any of the above aspects or embodiments, where it may apply is a compound of Formula Ilia, III or IIIc
  • R 5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl;
  • R 5b is halo, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, or alkoxyl.
  • the compound of any of the above aspects or embodiments, where it may apply is a compound of Formula Ilia, Ilia,
  • R 5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl;
  • R 5b is halo, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, or alkoxyl.
  • the compound of any of the above aspects or embodiments, where it may apply is a compound of Formula Illb .
  • R 5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl;
  • R 5b is halo, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, or alkoxyl.
  • the compound of any of the above aspects or embodiments, where it may apply is a compound of Formula IIIc
  • R 5a is halo, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )cycloalkyl optionally substituted with hydroxyl, or alkoxyl;
  • R 5b is halo, (Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )cycloalkyl optionally substituted with hydroxyl, or alkoxyl.
  • the compound of any of the above aspects or embodiments, where it may apply is a compound of Formula Vila
  • R 5a is (Ci-C 6 )alkyl or halo(Ci-C 6 )alkyl.
  • R 5a is (Ci-C3)alkyl or halo(Ci- C 3 )alkyl.
  • Another aspect of the invention relates to a pharmaceutical composition comprising the compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to method of modulating FGFR2, the method comprising administering to a mammal a compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof,, or a composition comprising according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to method of treating diseases or disorders comprising administering to a mammal, in need the treatment, a compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof,, or a composition comprising according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the cancer is prostate cancer, ovarian cancer, cervical cancer, pancreatic cancer, or head and neck cancers.
  • Another aspect of the invention relates to amethod of inhibiting proliferative activity in a cell, the method comprising administering to said cell an effective amount of a compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof,, or a composition comprising according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compound of the invention is one of the following compound in Table 1, or a pharmaceutically acceptable salt of any of the compound in Table 1.
  • Activity A is defined as an FGFR2 IC 50 value of less than 50 nM.
  • Activity B is defined as an FGFR2 IC50 value of less than 200 nM and greater than 50 nM.
  • Activity C is defined as an FGFR2 IC5 0 value of less than 5000 nM and greater than 200 nM.
  • Another embodiment of this invention relate to compounds in Table I that have Activity A.
  • Another embodiment of this invention relate to compounds in Table I that have Actvity B.
  • Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, trans dermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4, 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol
  • Suspensions in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
  • Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the compounds of this disclosure are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents.
  • Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s).
  • Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 18 0, . 17 0, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • Isotopically labeled compounds of the present invention as well as pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or other derivatives thereof, generally can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom at its natural abundance.
  • a position is designated as "H” or “hydrogen”
  • the position is to be understood to have hydrogen at its natural abundance isotopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis.
  • D or “deuterium”
  • the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position.
  • the methods disclosed herein also include methods of treating diseases by administering deuterated compounds of the invention or other isotopically-labeled compounds of the invention alone or as pharmaceutical compositions.
  • substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays such as positron emission tomgraphy (PET). Tritiated, ( 3 H) and carbon- 14 ( 14 C) isotopes are useful for these embodiments because of their detectability.
  • PET positron emission tomgraphy
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkoxy means the group -OR wherein R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyloctyloxy, and the like.
  • Alkoxycarbonyl means an alkoxy group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(O)OR 0 , wherein R° is alkyl, as defined herein).
  • alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and n- hexylcarbonyl.
  • Alkylamino means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R°, where R° is an alkyl group).
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, hexylamino, and the like.
  • Alkylaminocarbonyl means an alkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(0)N(H)R°, wherein R° is alkyl, as defined herein).
  • alkylaminocarbonyl groups include, but are not limited to, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t- butylaminocarbonyl, and n-hexylaminocarbonyl.
  • Amino means a - ⁇ 3 ⁇ 4 group.
  • Aryl means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms.
  • the monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, where at least one of the rings comprising a polycyclic radical is aromatic.
  • the polycyclic aryl radical includes fused, bridged, and spiro ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the aryl group, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.
  • Carbonyl means a -C(O)- group.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms.
  • the cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the cycloalkyl radical includes fused, bridged and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Dialkylamino means two alkyl groups, each independently as defined herein, appended to a parent moiety through a nitrogen atom (i.e., substituents of the form -N(R°) 2 , where each R° is an alkyl group).
  • dialkylamino groups include, but are not limited to N,N-dimethylamino, ⁇ , ⁇ -diethylamino, N-isopropyl-N-methylamino, N-ethyl-N- hexylamino, and the like.
  • fused ring system and "fused ring” refer to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups.
  • saturated carbons of such fused groups can contain two substitution groups.
  • Halo and halogen mean a fluoro, chloro, bromo or iodo group.
  • Haloalkyl means an alkyl radical, as defined herein, substituted with one or more halo atoms.
  • halo-substituted (Ci_4)alkyl includes trifluoromethyl
  • Heteroaryl means a monovalent monocyclic or poly cyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from -0-, -S(0) n - (n is 0, 1, or 2), -N-, -N(R X )-, and the remaining ring atoms are carbon atoms, where R x is hydrogen, alkyl, hydroxy, alkoxy, -C(O)R 0 or -S(0)2R°, where R° is alkyl.
  • the monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, where at least one of the rings comprising a polycyclic radical is aromatic.
  • the polycyclic heteoaryl radical includes fused, bridged and spiro ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, then R x is absent.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl,
  • 2.3- dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl,
  • the heterocycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • heterocycloalkyl includes fused, bridged and spiro ring systems. More specifically the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl
  • Heterocyclylalkyl means a heterocyclyl group appended to a parent moiety via an alkyl group, as defined herein.
  • heterocyclylalkyl groups include, but are not limited to, morpholin-4-ylmethyl, 2-(morpholin-4-yl)ethyl, morpholin-2-ylmethyl, 2- (morpholin-2-yl)ethyl, morpholin-3-ylmethyl, 2-(morpholin-3-yl)ethyl, piperazin- 1 -ylmethyl, 2-(piperazin-l-yl)ethyl, piperidin-1 -ylmethyl, 2-(piperidin-l-yl)ethyl, piperidin-2 -ylmethyl, 2-(piperidin-2-yl)ethyl, piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, pyrrolidin-1 -ylmethyl, 2-(pyrrolidin- 1 -ylmethyl, 2-(
  • Hydroxyalkyl means an alkyl group, as defined herein, substituted with at least one, for example one, two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2 -hydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3 -dihydroxybutyl,
  • substitution means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not.
  • substituents only sterically practical and/or synthetically feasible compounds are meant to be included.
  • this substitution occurs by replacing a hydrogen that is covalently bound to the variable with one these substituent(s). This meaning shall apply to all variables that are stated to be substituted or optionally substituted in the specification.
  • “Isomers” means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a "chiral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a “racemic mixture.” A compound that has more than one chiral center has 2 n l enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • a "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al, "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulf
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Aommon examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought.
  • the therapeutically effective amount for a given circumstance can be determined without undue experimentation.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • the compounds disclosed herein and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds disclosed herein can also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the compounds disclosed herein.
  • optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantiomers can be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomer enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds of this disclosure.
  • the protein is bound to a support, and a compound of the invention is added to the assay.
  • the compound of the invention is bound to the support and the protein is added.
  • Classes of candidate agents among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells.
  • assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and the like.
  • the determination of the binding of the candidate agent to, for example, FGFR2 protein may be done in a number of ways.
  • the candidate agent (the compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety and binding determined directly.
  • a labeled agent for example a compound of the invention in which at least one atom has been replaced by a detectable isotope
  • washing off excess reagent for example a compound of the invention in which at least one atom has been replaced by a detectable isotope
  • Various blocking and washing steps may be utilized as is known in the art.
  • label herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, for example, radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, and the like.
  • Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin, and the like.
  • the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above.
  • the label can directly or indirectly provide a detectable signal.
  • FGFR2 protein may be labeled at tyrosine positions using 125 I, or with fluorophores.
  • more than one component may be labeled with different labels; using 125 I for the proteins, for example, and a fluorophor for the candidate agents.
  • the compounds of the invention may also be used as competitors to screen for additional drug candidates, "candidate bioactive agent” or “drug candidate” or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity. They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. In the case where protein binding or activity is screened, some embodiments exclude molecules already known to bind to that particular protein. Exemplary embodiments of assays described herein include candidate agents, which do not bind the target protein in its endogenous native state, termed herein as "exogenous" agents. In one example, exogenous agents further exclude antibodies to FGFR2.
  • Candidate agents can encompass numerous chemical classes, though typically they are organic molecules having a molecular weight of more than about 100 and less than about 2,500 daltons.
  • Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl, hydroxyl, ether, or carboxyl group, for example at least two of the functional chemical groups.
  • the candidate agents often comprise cyclical carbon or heterocyclyl structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.
  • Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification to produce structural analogs.
  • the binding of the candidate agent is determined through the use of competitive binding assays.
  • the competitor is a binding moiety known to bind to FGFR2, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the candidate agent and the binding moiety, with the binding moiety displacing the candidate agent.
  • the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to FGFR2 protein for a time sufficient to allow binding, if present. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4°C and 40°C.
  • Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding.
  • the competitor is added first, followed by the candidate agent.
  • Displacement of the competitor is an indication the candidate agent is binding to FGFR2 and thus is capable of binding to, and potentially modulating, the activity of the FGFR22.
  • either component can be labeled.
  • the presence of label in the wash solution indicates displacement by the agent.
  • the candidate agent is labeled, the presence of the label on the support indicates displacement.
  • the candidate agent is added first, with incubation and washing, followed by the competitor.
  • the absence of binding by the competitor may indicate the candidate agent is bound to FGFR2 with a higher affinity.
  • the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to FGFR2.
  • FGFR2 binding site of FGFR2. This can be done in a variety of ways. In one embodiment, once FGFR2 has been identified as binding to the candidate agent, the FGFR2 is fragmented or modified and the assays repeated to identify the necessary components for binding.
  • Modulation is tested by screening for candidate agents capable of modulating the activity of FGFR2 comprising the steps of combining a candidate agent with FGFR2, as above, and determining an alteration in the biological activity of the FGFR2.
  • the candidate agent should both bind to (although this may not be necessary), and alter its biological or biochemical activity as defined herein.
  • the methods include both in vitro screening methods and in vivo screening of cells for alterations in cell viability, morphology, and the like.
  • differential screening may be used to identify drug candidates that bind to native FGFR2, but cannot bind to modified FGFR2.
  • Positive controls and negative controls can be used in the assays. For example, all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of samples is for a time sufficient for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples can be counted in a scintillation counter to determine the amount of bound compound.
  • a variety of other reagents can be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components can be added in any order that provides for the requisite binding.
  • Such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of FGFR2 kinases.
  • Such methods may be characterized by the following aspects: a) introducing into a suitable computer program, information defining a ligand binding domain of a FGFR2 kinase in a conformation (e.g.
  • aspects a-d are not necessarily carried out in the aforementioned order. Such methods may further entail: performing rational drug design with the model of the three-dimensional structure, and selecting a potential candidate agent in conjunction with computer modeling.
  • Such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for FGFR2 kinase modulation, and determining whether said candidate agent modulates FGFR2 kinase activity in the assay.
  • Such methods may also include administering the candidate agent, determined to modulate FGFR2 kinase activity, to a mammal suffering from a condition treatable by FGFR2 kinase modulation, such as those described above.
  • compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a FGFR2 kinase.
  • a method may be characterized by the following aspects: a) creating a computer model of a FGFR2 kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the FGFR2 kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.
  • Schemes 1 and 2 depict general synthetic routes for compounds of the invention and are not intended to be limiting. Specific examples are described subsequently to these general synthetic descriptions. In the generalizations below, specific reaction conditions, for example, added bases, acids, solvents, temperature, and the like were not described so as not to confuse the discussion. The general routes in conjunction with the specific examples contain sufficient information to allow one skilled in the art to synthesize compounds of the invention.
  • starting material 1 include, but are not limited to, 3,4-dichloro-l,2,5-thiadiazole, 3,4-dichloro-pyrazine, 5,6-dichloro-2,3- dicyanopyrazine, and the like.
  • first nucleophilic reagent Nu 1 include, but are not limited to, Boc-piperazine, t-butyl 1-homopiperazine carboxylate, 2,6-dimethyl-piperazine, 2,5-dimethyl-piperazine, and the like.
  • Intermediates of type 2 may also be purchased, obviating the need for the aforementioned synthetic conversion 1 ⁇ 2.
  • Nu 1 may be a preformed intermediate corresponding to "-X" in formula I, or a precursor to "-X,” in some instances as will be apparent from the examples below.
  • Intermediate 2 is combined with a second nucleophilic reagent, Nu 2 , to afford intermediate 3.
  • Nu 2 may be a preformed intermediate corresponding to "-Y-L-Z" in formula I, or a precursor to "-Y-L-Z.”
  • Examples of Nu 2 include, but are not limited to, pyridin-4-yl-methanol, 3-(dimethylamino- phenyl)-methanol, and the like. Therefore, there may be needed additional manipulation of Nu 1 and Nu 2 to synthesize compounds of formula I (as depicted), or intermediate 3 may itself be a compound according to formula I.
  • intermediate 3 may be coverted to compounds of formula I.
  • Intermediate 3 may be purchased, made as depicted in Scheme 1, or a commercially available or other starting material is coverted into 3, for example. This may entail, for example, a simple removal of a protecting group, reduction of an electrophilic moiety to make either of Nu 1 or Nu 2 , or in some cases a more complex manipulation.
  • Scheme 2 shows one example of a conversion strategy 3 ⁇ I to which any of the aforementioned scenarios would apply.
  • Intermediate 3 (where Nu 1 has a nucleophilic group thereon) is combined with an electrophile, E 1 to afford intermediate 4.
  • An example of this strategy is where Nu 1 is a piperazine (where in formation of 3 one of the piperazine nitrogens is attached to the aromatic ring) and in conversion to 4, a ring -NH- is "capped” with electro file E 1 .
  • Conversion of 4 ⁇ 5 may proceed in much the same way, for example when Nu 2 has a free nucleophilic site, then an electrophile E 2 may be added as depicted. There may be needed additional manipulation of 5 to synthesize compounds of formula I (as depicted), or intermediate 5 may itself be a compound according to formula I.
  • HC1 4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)piperazine-l-carboxylate (1.3 g, 3.38 mmol) was added HC1 (4N in dioxane, 20 mL) and the reaction mixture was stirred at ambient temperature for 3 h. After completion was observed by LC/MS, the reaction mixture was filtered using dioxane to rinse. The HC1 was basified with NaOH (4N, aq.) and the aqueous layer was saturated with solid NaCl, extracted with EtOAc (3X), dried with Na 2 S0 4 , filtered, and concentrated. LC/MS indicated that no product remained in the aqueous layer.
  • Example 3 The following compounds were prepared by a similar procedure as in Example 7 using the appropriate amine and 4-((2-(piperazin-l-yl)pyridine-3-yloxy)methyl)pyrimidin-2- amine (Example 3) or 4-((3-(piperazin-l-yl)pyrazin-2-yloxy)methyl)pyrimidin-2-amine (WO 2004083235) or 4-((2-(piperazin-l-yl)pyridin-3-yl)ethynyl)pyrimidin-2-amine (Example 1) or 4-((2-(piperazin-l-yl)pyridin-3-ylamino)methyl)pyrimidin-2-amine (Example 2).
  • 6-tert-butyl-2- methylpyrimidin-4-ol (627 mg) as a solid.
  • a suspension of 6-tert-butyl-2-methylpyrimidin- 4-ol (300 mg, 1.8 mmol) in phosphorus oxychloride (2 mL) was heated at 90 °C for 1.5 h.
  • the reaction mixture was cooled to room temperature, poured into ice-water, 5 N NaOH was added until the pH was approximately 7 and the mixture was extracted with (3 ⁇ 4(3 ⁇ 4.
  • 2-Ethyl-6-(trifluoromethyl)pyrimidin-4-amine Prepared from ethyl 4,4,4-trifluoro-3- oxobutanoate and propionamidine hydrochloride.
  • 6-tert-Butyl-N 2 ,N 2 -dimethylpyrimidine-2,4-diamine 4-tert-butyl-6-chloro-N,N-dimethylpyrimidin-2-amine was prepared by reaction of methyl 4,4-dimethyl-3-oxopentanoate (1.58 g, 10 mmol) and dimethylguanidine sulfate (1.36 g, 5 mmol) to yield the hydroxypyrimidine (698 mg) which was treated with phosphorus oxy chloride, To a solution of the crude chloropyrimidine (700 mg, 3.3 mmol) in 2-propanol (1 mL) was added 2,4-dimethoxybenzylamine (1.5 mL, 9.9 mmol) and the mixture was heated for 100 °C for 4 h and was partitioned between ether and 10% K2CO 3 .
  • 6-tert-butyl-2-(trifluoromethyl)pyrimidin-4-amine Prepared from methyl 4,4-dimethyl-3- oxopentanoate and 2,2,2-trifluoroacetamidine. 3 ⁇ 4 NMR (400 MHz, CDC1 3 ) ⁇ 6.49 (s, 1H), 5.30 (s, 2H), 1.31 (s, 9H).
  • Example 3 The following compounds were prepared using a similar procedure as in Example 1 1 using the appropriate amine and 4-((2-(piperazin-l-yl)pyridine-3-yloxy)methyl)pyrimidin-2-amine (Example 3) or 4-((3-(piperazin-l-yl)pyrazin-2-yloxy)methyl)pyrimidin-2-amine (WO 2004083235) or 4-((2-(piperazin-l-yl)pyridin-3-yl)ethynyl)pyrimidin-2-amine (Example 1) or 4-((2-(piperazin-l-yl)pyridin-3-ylamino)methyl)pyrimidin-2-amine (Example 2) or 4-((3- (piperazin- 1 -yl)pyridin-2-yloxy)methyl)pyrimidin-2-amine (Example 15).
  • One measure of inhibition is 3 ⁇ 4.
  • the 3 ⁇ 4 or Ka is defined as the dissociation rate constant for the interaction of the agent with a FGFR2.
  • Exemplary compositions have Ki's of, for example, less than about 100 ⁇ , less than about 10 ⁇ , less than about 1 ⁇ , and further for example having Ki's of less than about 100 nM, and still further, for example, less than about 10 nM.
  • the Ki for a compound is determined from the IC5 0 based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity.
  • the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations).
  • the enzymatic rate of the enzyme-inhibitor complex is zero.
  • the rate data i.e. compound concentration
  • V max is the rate of the free enzyme
  • I 0 is the inhibitor concentration
  • Eo is the enzyme concentration
  • 3 ⁇ 4 is the dissociation constant of the enzyme-inhibitor complex.
  • FGFR1, FGFR2, FGFR3 and FGFR4 Kinase activities of FGF receptors (FGFR1, FGFR2, FGFR3 and FGFR4) are measured by monitoring the phosphorylation of a tyrosine-containing, fluorescein-labeld peptide substrate(Glu:Tyr, 4: 1). The extent of phosphorylation of the substrate peptide is quantified using a terbium labeled phosphospecific antibody, which upon binding and excitation at 340 nm leads to a time resolved FRET signal due to its proximity to the fluorescent label. In a black 384-well plate enzyme and test compound are combined and incubated for 10 min, followed by addition of ATP and fluorescently labeled substrate.
  • terbium labeled phosphospecific antibody final 2 nM
  • a time resolved fluorescence read using an excitation wavelength of 340 nm followed by a time resolved fluorescence read using an excitation wavelength of 340 nm, and detection of emission at 490 and 520 nm.
  • the data are expressed as the ratio of emission intensity at 520nm/490 nm.
  • the ATP concentrations used in the various assays were approximately equal to or less than the KM for each of the respective kinases.
  • Dose-response experiments were performed using an intra-plate dilution scheme with 10 different inhibitor concentrations in a 384-well microtiter plate. IC50 values were calculated by nonlinear regression analysis.

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Abstract

L'invention concerne un composé de la formule (I), ou un sel de qualité pharmaceutique de celui-ci, où : R3a, R2, R3b, R4b, L1, G et J sont tels que définis dans la description, ainsi que leurs compositions pharmaceutiques et leurs procédés d'utilisation.
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US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
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