WO2015038868A1 - Dérivés de 2,4-diaminopyrimidine bicycliques condensés - Google Patents

Dérivés de 2,4-diaminopyrimidine bicycliques condensés Download PDF

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Publication number
WO2015038868A1
WO2015038868A1 PCT/US2014/055346 US2014055346W WO2015038868A1 WO 2015038868 A1 WO2015038868 A1 WO 2015038868A1 US 2014055346 W US2014055346 W US 2014055346W WO 2015038868 A1 WO2015038868 A1 WO 2015038868A1
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Prior art keywords
ylamino
methoxy
tetrahydro
chloro
benzocyclohepten
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PCT/US2014/055346
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English (en)
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Gregory R. Ott
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Cephalon, Inc.
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Publication of WO2015038868A1 publication Critical patent/WO2015038868A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Ring A is phenyl, a 6-7 membered cycloalkyl, or pyridinyl;
  • R 4 is H or Ci_ 6 alkyl
  • Compounds of formula ⁇ / ⁇ have ALK and/or FAK inhibitory activity and may be used to treat disorders or conditions characterized by aberrant ALK and/or FAK activity in mammals, including humans.
  • the present application further provides pharmaceutical compositions comprising at least one compound of formula I/I' together with at least one pharmaceutically acceptable excipient.
  • Anaplastic Lymphoma Kinase is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al, Oncogene, 2001, 20, 5623-5637).
  • ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NPM) and the intracellular domain of ALK.
  • NPM nucleophosmin
  • This mutant protein, NPM- ALK possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors.
  • transforming EML4-ALK fusion gene has been identified in non-small-cell lung cancer (NSCLC) patients (Soda, M., et al, Nature, 2007, 448, 561 - 566) and represents another in a list of ALK fusion proteins that are promising targets for ALK inhibitor therapy.
  • NSCLC non-small-cell lung cancer
  • ALK chimeric ALK
  • IMTs myofibroblastic tumors
  • pleiotrophin putative ligand, pleiotrophin
  • An ALK inhibitor would be expected to either permit durable cures when combined with current chemotherapy for ALCL, IMT, proliferative disorders, glioblastoma and possible other solid tumors, or, as a single therapeutic agent, could be used in a maintenance role to prevent cancer recurrence in those patients.
  • ALK inhibitors have been reported, such as indazoloisoquino lines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).
  • Focal adhesion kinase is an evolutionarily conserved non-receptor tyrosine kinase localized at focal adhesions, sites of cellular contact with the ECM (extra-cellular matrix) that functions as a critical transducer of signaling from integrin receptors and multiple receptor tyrosine kinases, including EGF-R, HER2, IGF-R1, PDGF-R and VEGF-R2 and TIE-2 (Parsons, JT; Slack-Davis, J; Tilghman, R; Roberts, WG. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin.
  • FAK over expression and activation appear to be associated with an enhanced invasive and metastatic phenotype and tumor angiogenesis in these malignancies (Owens, LV; Xu, L; Craven, RJ; et al. Over expression of the focal adhesion kinase (pi 25 FAK) in invasive human tumors. Cancer Res., 1995, 55, 2752-2755; Tremblay, L; Hauck, W. Focal adhesion kinase (ppl25FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. Int. J. Cancer, 1996, 68, 164-171; Kornberg, IJ.
  • Roberts et al, (2008) showed that PF-562,271 inhibited bone metastases, prevented bone resorption, and increased osteogenesis in breast and androgen-independent prostate cancer patients with and without bone metastases, supporting an additional benefit of FAK inhibition in these specific malignancies.
  • FAK activation protects tumor cells from chemotherapy-induced apoptosis, contributing to tumor resistance; modulation of FAK activity (by siRNA or pharmacologically) potentiates efficacy of chemotherapeutic agents in vivo (e.g., doxorubicin, docetaxel and gemcitabine), suggesting the utility for rational combination therapies in specific cancers.
  • chemotherapeutic agents e.g., doxorubicin, docetaxel and gemcitabine
  • WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors.
  • the lead drug candidate disclosed in the '547 application is CEP-28122.
  • This compound is a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models.
  • CEP-28122 had progressed to IND-enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monkeys.
  • the structure of CEP-28122 is shown below.
  • this application provides and describes compounds of the general Formula ⁇ / ⁇
  • R 4 is H or Ci_ 6 alkyl;
  • C a -b a prefix designating the minimum and maximum number of carbon atoms in the moiety
  • C a -balkyl indicates an alkyl moiety of the integer "a” to the integer "b” carbon atoms, inclusive.
  • Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure.
  • the terms "a to b-membered” or “having between a to b members” refer to a moiety having the integer "a” to the integer "b” number of atoms, inclusive.
  • alkyl and Ci- 6 alkyl refer to straight or branched hydrocarbon groups containing the requisite number of carbon atoms as described above. As used herein, alkyl groups may be optionally substituted. Representative examples of alkyl groups include, but are not limited to, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.
  • aromatic refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.
  • aromatic refers to and includes ring systems that contain only carbon atoms (i.e. "aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. "heteroaromatic” or “heteroaryl”).
  • aryl ring systems that contain only carbon atoms
  • heteroatoms i.e. "heteroaromatic” or “heteroaryl”
  • an aromatic ring system may be optionally substituted.
  • aryl refers to monocyclic and polycyclic aromatic hydrocarbon ring systems containing the requisite number of carbon atoms as described above, which may be optionally substituted. Representative examples include phenyl and napthyl, either of which may be optionally substituted.
  • cycloalkyl refers to monocyclic and polycyclic hydrocarbon ring systems containing the requisite number of carbon atoms as described above, which may be optionally substituted. Cycloalkyl refers to and includes ring systems that are fully saturated or contain at least one double bond, as well as multi-ring systems with fully saturated and/or aromatic portions, such as, for example, 1 ,2,3,4-tetrahydro-naphthalenyl.
  • these terms further refer to and include bridged and/or fused polycyclic structures such as, for example, tetrahydro-5H-benzocycloheptenyl, bicyclo[3.2.1]octanyl, bicyclo[5.2.0]nonanyl, bicyclo[2.2.1]heptenyl and the like, as well as spirocyclic ring systems such as, for example, spiro[3.4]octanyl, spiro[3.5]nonyl and the like.
  • cycloalkyl groups include, but are not limited to, e.g., cyclopropyl, methylcyclopropyl, cyclobutyl, cyclobutenyl, isopropylcyclobutyl, cyclopentyl, 1,3-dimethylcyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 2,3-dihydro-lH-inden-2-yl, norbornyl, decahydronaphthalenyl, etc.
  • halo and halogen include fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).
  • heterocycloalkyl refers to monocyclic and polycyclic ring systems containing the requisite number of carbon atoms as described above and at least one heteroatom selected from P, N, O, or S and may be optionally substituted. These terms further refer to and include ring systems that are fully saturated or contain at least one double bond, as well as ring systems with fully saturated, aromatic and/or non-aromatic portions, such as for example, 1,2,3,4- tetrahydroquinolinyl.
  • polycyclic heterocycloalkyl groups further include fused, bridged and spirocyclic ring systems and ring systems in which the P, N or S is oxidized, such as for example, i.e., 1,1-dioxide-thiomorpholinyl (1,1- dioxidothiomorpholinyl), 1-oxo-piperidinyl or 4-oxo-azaphosphinanyl.
  • heterocycloalkyl groups include, but are not limited to, e.g., oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, tetrahydrothiopyranyl, thiopyranyl, piperidinyl, 1 ,4-dioxanyl, 1,4-oxathianyl, morpholinyl, thiomorpholinyl, 1 ,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1 ,4-dioxepanyl, 1,4-oxathiepanyl, 1 ,4
  • heteroaryl refers to monocyclic and polycyclic aromatic ring systems containing the requisite number of carbon atoms, as described above, and at least one heteroatom selected from N, O, or S.
  • a heteroaromatic ring system refers to and includes polycyclic ring systems that contain aromatic portions, while other portions of the ring system may be fully saturated or non-aromatic. Heteroaromatic rings may be optionally substituted.
  • Representative examples include, but are not limited to, e.g., pyrrolyl, furanyl, thiophenyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5- thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridin
  • pharmaceutically acceptable indicates that the designated entity such as, for example, e.g. carrier, vehicle, diluent, excipient, or salt, is generally chemically and/or physically compatible with the other ingredients comprising a formulation and/or is generally physiologically compatible with the recipient thereof.
  • subject(s) and “patient(s)” refer to mammals, including humans.
  • substituted indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom may be referred to a "substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s) when used in conjunction with the phrase “...optionally substituted" unless otherwise specified.
  • treating include preventative (e.g., prophylactic), ameliorative, palliative, and curative uses and results, or any combination thereof.
  • preventative e.g., prophylactic
  • ameliorative e.g., palliative
  • curative e.g., palliative
  • curative e.g., palliative
  • curative e.g., palliative
  • curative e.g., palliative
  • curative e.g., palliative
  • curative e.g., palliative
  • the terms “therapeutic” and “therapeutically effective amount”, whether used alone or in conjunction with another term or terms, denote an amount of a compound, composition or medicament that (a) treats or prevents a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder; (c) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)-(c).
  • a "therapeutically active agent” refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease or disorder and is not described by Formula ⁇ / ⁇ .
  • the compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt.
  • salt(s) and salt form(s) used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified.
  • industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use.
  • Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
  • Pharmaceutically acceptable salts, as used herein are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof.
  • Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e.
  • salts are not limited to salts that are typically administered or approved (by a regulatory authority such as FDA) for clinical or therapeutic use in humans.
  • FDA regulatory authority
  • a practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
  • salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s).
  • Salts of the present application may also be formed via a "salt switch" or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge.
  • salts may be prepared and/or isolated using a single method or a combination of methods.
  • Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like.
  • salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
  • Certain compounds of Formula I/I' may have one or more asymmetric centers and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, as well as diastereomers and mixtures of different diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
  • resolution and isolation of pure enantiomers can be achieved using methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent.
  • the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form.
  • the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.
  • Compounds of Formula ⁇ / ⁇ that exist as diastereoisomers may be isolated by methods known to those skilled in the art, for example, by crystallization, gas-liquid or liquid chromatography.
  • intermediates in the course of a synthesis that exist as racemic mixtures may be subjected to resolution by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.
  • prodrugs may be administered as prodrugs.
  • prodrug refers to a compound that is transformed in vivo to yield a compound of Formula I.
  • the in vivo transformation may occur by various mechanisms, such as hydrolysis, in the blood or other biological fluids.
  • a prodrug of a compound of Formula I may be formed in a conventional manner with one or more functional groups in the compound, such as an amino, hydroxyl or carboxyl group.
  • a prodrug can comprise: (1) an ester formed by the replacement of a hydrogen of the acid group with a group such as (Ci-C 6 )alkyl or (C 6 -Cio) aryl; (2) an activated ester formed by the replacement of the hydrogen of the acid group with groups such as -(CR 2 )COOR' , where CR 2 is a spacer and R can be groups such as H or methyl and R' can be groups such as (Ci-C 6 )alkyl or (C 6 -Cio) aryl; and/or (3) a carbonate formed by the replacement of the hydrogen of the acid with groups such as CHROCOOR' where R can be groups such as H or methyl and R' can be groups such as (Ci-C 6 )alkyl or (C 6 - Cio)aryl.
  • a prodrug can be formed via the replacement of the hydrogen of the alcohol with groups such as (Ci-C 6 )alkanoyloxymethyl or (Ci-Ce)alkanoyloxyaryl or by forming an ester via condensation with, for example, an amino acid.
  • a prodrug may comprise, for example, an amide formed by the replacement of one or both of the hydrogens of the amino group with (Ci- Cio)alkanoyl or (C 6 -Cio)aroyl.
  • Other prodrugs of amines are well known to those skilled in the art.
  • certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.
  • prodrugs as Novel Delivery Systems
  • T. Higuchi and W. Stella Vol. 14 of the ACS Symposium Series
  • Bioreversible Carriers in Drug Design Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • replacement groups may be found in the aforementioned references.
  • LCMS results were obtained on either of two instruments: Waters Aquity Ultra Performance LC with a 2.1 mm x 50 mm Waters Aquity UPLC BEH CI 8 1.7 ⁇ column.
  • the target column temperature was 45°C, with a run time of two (2) minutes, a flow rate of 0.600 mL/min, and a solvent mixture of 5% (0.1% formic acid/water): 95% (acetonitrile/0.1% formic acid) or a Micromass LC-ZQ 2000 quadrupole mass spectrometer. Automated column chromatography was performed on a CombiFlash Companion (ISCO, Inc.). Melting points were taken on a Mel-Temp apparatus and are uncorrected.
  • Schemes are indicative of reaction sequences that may be utilized to synthesize compounds of Formula ⁇ / ⁇ .
  • Both Scheme 1 and Scheme 2 rely on an alpha-tetralone starting material that is treated with a Wittig reagent (Steps 1 and ).
  • the olefin is then treated with a thallium reagent to undergo a ring-expansion reaction to generate the 6/7-fused bicyclic ring system (Steps 2 and 2').
  • a nitration reaction installs the requisite nitrogen functionality (though this reaction is not stereospecific, separation is easily carried out on silica gel) to afford the nitro-derivatives (Steps 3 and 3').
  • the requisite amine may be introduced via reductive amination (Steps 4 and 4').
  • This amine can either be functionalized in the next reaction or at a later point in the reaction sequence.
  • a variety of amines will undergo this transformation.
  • An exemplary list of amines is provided below the reaction schemes.
  • a person of ordinary skill will readily appreciate that amines of a wide structural variety may be used and are not limited to those listed herein.
  • the reduction of the nitro group can be achieved via hydrogeno lysis (Steps 5 and 5') to give the desired amine.
  • Steps 6 and 6' yield the desired coupling partner to the product of reactions 5 and 5', respectively.
  • the Ring A amine of Step 6 and 6' can be structurally diverse.
  • Exemplary amines of the formula R J R 2 NH that can be used in Steps 4 and 4 'include, but are not limited to, the following:
  • Exemplary amines that can be used in Steps 6 and 6 'include, but are not limited to, the following:
  • Example 10 2- ⁇ 5-Chloro-2-[ 1 -methoxy-6-(4-methyl-piperazin- 1 -yl)-6,7,8,9-tetrahydro-5H- benzocyclohepten-2-ylamino] -pyrimidin-4-ylamino ⁇ -N,N-dimethyl-benzenesulfonamide
  • Stepl 5-Methoxy-l-methylene-l,2,3,4-tetrahydro-naphthalene: To a slurry of 5- Methoxy-3,4-dihydro-2H-naphthalen-l-one (25g, 0.14 mol) and
  • Step 2 l-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one: 5-Methoxy-l-methylene- 1,2,3,4-tetrahydro-naphthalene (23.8 g, 0.137 mol) in 150 mL MeOH added in one portion to freshly prepared solution of thallium(III)nitrate trihydrate (1.0 eq) in 300 mL MeOH. Stirred one minute and 400 mL chloroform added. The solution was filtered and the organics partitioned between dichloromethane and water. The organics were dried (MgS04) and concentrated.
  • Step 4 l-(l-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-4-methyl- piperazine: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one (0.475 g, 0.00202 mol) in methylene chloride was treated with 1-Methylpiperazine (1.12 mL, 0.0101 mol) followed by Acetic acid (1.15 mL, 0.0202 mol) The mixture was stirred @ 50°C for 2 hrs, cooled to 0°C.
  • Step 5 1 -Methoxy-6-(4-methyl-piperazin- 1 -yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten- 2-ylamine: l-(l-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-4- methyl-piperazine (0.408 g, 1.28 mmol) combined with Ethanol (10 mL, 200 mmol), Hydrazine hydrate (205 uL, 4.22 mmol), 10% Pd/C, 50% wet (5:45:50, Palladium: carbon black:Water, 0.272 g, 0.128 mmol), heat to 90°C, for 1.5h, cooled to rt and stirred overnight.
  • Ethanol 10 mL, 200 mmol
  • Hydrazine hydrate 205 uL, 4.22 mmol
  • 10% Pd/C 50% wet (5:45:50,
  • Step 6 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide: 2- Amino-N,N-dimethyl-benzenesulfonamide (10.00 g, 49.94 mmol) in N,N-
  • Step 7 2- ⁇ 5-Chloro-2-[l-methoxy-6-(4-methyl-piperazin-l-yl)-6,7,8,9-tetrahydro-5H- benzocyclohepten-2-ylamino] -pyrimidin-4-ylamino ⁇ - ⁇ , ⁇ -dimethyl-benzenesulfonamide : Combined [A] 1 -Methoxy-6-(4-methyl-piperazin- 1 -yl)-6,7,8,9-tetrahydro-5H- benzocyclohepten-2-ylamine (83.4 mg, 0.288 mmol) and 2-(2,5-Dichloro-pyrimidin-4- ylamino)-N,N-dimethyl-benzenesulfonamide (100 mg, 0.3 mmol) with 4 M ofHydrogen Chloride in 1,4-Dioxane(0.40 mL, 0.0016 mol) in 2-Butanol (3.0
  • This application further provides a method of treating an ALK- or FAK-mediated disorder or condition in a subject comprising: administering to the subject in recognized need thereof a compound of formula ⁇ / ⁇ or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula ⁇ / ⁇ or a pharmaceutically acceptable salt thereof for use in treating an ALK- or FAK-mediated disorder or condition in a subject in recognized need thereof.
  • the compound of formula ⁇ / ⁇ or a pharmaceutically acceptable salt thereof is administered to the subject as a composition comprising a pharmaceutically acceptable excipient.
  • the compound of formula ⁇ / ⁇ or a pharmaceutically acceptable salt thereof is administered to the subject in a therapeutically effective amount.
  • the ALK- or FAK-mediated condition or disorder is cancer.
  • the ALK- or FAK-mediated condition or disorder is selected from anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), neuroblastoma, glioblastoma, prostate cancer, squamous cell carcinoma (SCC), and breast cancer.
  • the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK-positive NSCLC, neuroblastoma, glioblastoma, androgen-independent prostate cancers, breast cancers, and head and neck squamous cell carcinomas (FINSCCs).
  • the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK- positive NSCLC, neuroblastoma, androgen-independent prostate cancers, breast cancers, and FINSCCs.
  • the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK-positive NSCLC, neuroblastoma, and glioblastoma.
  • the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK-positive NSCLC, and neuroblastoma.
  • FAK-mediated condition or disorder is an ALK-mediated condition or disorder.
  • the ALK- or FAK-mediated condition or disorder is a FAK-mediated condition or disorder.
  • the ALK- or FAK-mediated condition or disorder is a myofibroblastic tumor.
  • the ALK- or FAK-mediated condition or disorder is a myo fibroblastic tumor with TPM3-ALK or TPM4-ALK oncogenes.
  • the ALK- or FAK-mediated condition or disorder is a myofibroblastic tumor with TPM3-ALK oncogenes.
  • the ALK- or FAK-mediated condition or disorder is a myofibroblastic tumor with TPM4-ALK oncogenes.
  • the ALK- or FAK- mediated disorder can be treated prophylactically, acutely, or chronically using compounds of the present invention, depending on the nature of the disorder or condition.
  • the subject in each of these methods is human.
  • the compounds of the present invention can be prepared and administered in a wide variety of dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention are administered intravenously or subcutaneously.
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally.
  • the compounds of the present invention are delivered orally.
  • the compounds can also be delivered rectally, bucally or by insufflation.
  • the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • a typical dose is about 1 mg to about 1,000 mg per day, such as about 5 mg to about 500 mg per day. In certain embodiments, the dose is about 10 mg to about 300 mg per day, such as about 25 mg to about 250 mg per day.
  • the ability of compounds to inhibit the kinase activity of baculovirus-expressed human FAK was measured using a 96-well plate time-resolved fluorescence (TRF) assay system.
  • Recombinant human full-length GST-tagged FAK (activated in vitro by His-tagged src) was obtained from Invitrogen (Cat# PV3832).
  • Enzyme (10 ng/mL FAK) was added and the reaction was allowed to proceed at room temperature for 30 min. Detection of the phosphorylated product was performed by adding 100 ⁇ , ⁇ of Eu-Nl labeled PY100 antibody diluted 1 :75000 in 0.25% BSA in TBS-T (PerkinElmer #AD0041). Samples were incubated at room temperature for 1 h, followed by addition of 100 enhancement solution (PerkinElmer #1244-105). Plates were agitated for 10 min and fluorescence of the resulting solution measured using the PerkinElmer En Vision ® 2102 or 2104 multi-label plate reader. Inhibition data were analyzed using ActivityBase and IC 50 curves generated using XLFit.
  • Example compounds were tested for their ability to inhibit the kinase activity of baculovirus-expressed ALK using a modification of the ELISA protocol reported for trkA in Angeles, T. S. et al, Anal. Biochem. 1996, 236, 49-55, which is incorporated herein by reference in its entirety.
  • TRF time-resolved fluorescence
  • the reaction was initiated by adding enzyme (30 ng/ml ALK) and was allowed to proceed at 37°C for 15 minutes. Detection of the phosphorylated product was performed by adding 100 ⁇ /well of Eu-Nl labeled PT66 antibody (Perkin Elmer # AD0041). Incubation at 37°C then proceeded for one (1) hour, followed by addition of 100 ⁇ , enhancement solution (Wallac #1244-105). The plate was gently agitated and after thirty minutes, the fluorescence of the resulting solution was measured using the En Vision 2100 (or 2102) multilabel plate reader (Perkin Elmer).
  • IC 50 values were calculated by plotting percent inhibition versus logio of the concentration of compound and fitting to the nonlinear regression sigmoidal dose-response (variable slope) equation in XLFit (IDBS, Guilford, UK)

Abstract

La présente invention concerne des composés bicycliques condensés qui comportent les substituants décrits dans la description. Ces composés présentent une activité d'inhibition d'ALK et/ou de FAK, et peuvent être utilisés pour traiter des troubles ou des états pathologiques caractérisés par une activité aberrante d'ALK et ou de FAK chez des mammifères, y compris l'être humain. La présente invention concerne en outre des compositions pharmaceutiques comprenant au moins un de ces composés conjointement avec au moins un excipient pharmaceutiquement acceptable.
PCT/US2014/055346 2013-09-13 2014-09-12 Dérivés de 2,4-diaminopyrimidine bicycliques condensés WO2015038868A1 (fr)

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WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
CN108948019A (zh) * 2017-05-18 2018-12-07 广东东阳光药业有限公司 黏着斑激酶抑制剂及其用途
CN111704603A (zh) * 2020-06-12 2020-09-25 四川省人民医院 一种抗肿瘤化合物及其应用
US11248003B2 (en) 2017-12-07 2022-02-15 Oncobix Co., Ltd. Pyrimidine derivative having effect of inhibiting cancer cell growth and pharmaceutical composition containing same
CN114829352A (zh) * 2019-12-16 2022-07-29 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
WO2023045816A1 (fr) * 2021-09-22 2023-03-30 南京正大天晴制药有限公司 Composé benzocycloheptane utilisé comme inhibiteur d'axl
WO2023093859A1 (fr) * 2021-11-26 2023-06-01 南京正大天晴制药有限公司 Sel d'inhibiteur de kinase axl, son procédé de préparation et son utilisation
WO2023093861A1 (fr) * 2021-11-26 2023-06-01 南京正大天晴制药有限公司 Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci
CN116870016A (zh) * 2022-12-01 2023-10-13 希格生科（深圳）有限公司 杂芳环化合物及其医药用途

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CN106146525A (zh) * 2015-04-10 2016-11-23 山东轩竹医药科技有限公司 三并环类间变性淋巴瘤激酶抑制剂
WO2016171372A1 (fr) * 2015-04-22 2016-10-27 한국화학연구원 Dérivé de 4-(2-amino-tétrahydronaphtalényl)pyrimidine, son procédé de préparation et composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter un cancer
US10369149B2 (en) 2015-04-22 2019-08-06 Korea Research Institute Of Chemical Technology 4-(2-amino-tetrahydronaphthalenyl)pyrimidine derivative, preparation method therefor, and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient
KR101653571B1 (ko) * 2015-04-22 2016-09-05 한국화학연구원 4-(2-아미노-테트라하이드로나프탈렌닐)피리미딘 유도체, 이의 제조 방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
JP2020503271A (ja) * 2016-11-30 2020-01-30 アリアド ファーマシューティカルズ， インコーポレイテッド 造血前駆体キナーゼ１（ｈｐｋ１）阻害剤としてのアニリノピリミジンａｓ
JP7025426B2 (ja) 2016-11-30 2022-02-24 アリアド ファーマシューティカルズ， インコーポレイテッド 造血前駆体キナーゼ１（ｈｐｋ１）阻害剤としてのアニリノピリミジンａｓ
US11180482B2 (en) 2016-11-30 2021-11-23 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (HPK1) inhibitors
CN108948019A (zh) * 2017-05-18 2018-12-07 广东东阳光药业有限公司 黏着斑激酶抑制剂及其用途
US11248003B2 (en) 2017-12-07 2022-02-15 Oncobix Co., Ltd. Pyrimidine derivative having effect of inhibiting cancer cell growth and pharmaceutical composition containing same
CN114829352A (zh) * 2019-12-16 2022-07-29 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
CN111704603B (zh) * 2020-06-12 2021-10-26 四川省人民医院 一种抗肿瘤化合物及其应用
CN111704603A (zh) * 2020-06-12 2020-09-25 四川省人民医院 一种抗肿瘤化合物及其应用
WO2023045816A1 (fr) * 2021-09-22 2023-03-30 南京正大天晴制药有限公司 Composé benzocycloheptane utilisé comme inhibiteur d'axl
WO2023093859A1 (fr) * 2021-11-26 2023-06-01 南京正大天晴制药有限公司 Sel d'inhibiteur de kinase axl, son procédé de préparation et son utilisation
WO2023093861A1 (fr) * 2021-11-26 2023-06-01 南京正大天晴制药有限公司 Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci
CN116870016A (zh) * 2022-12-01 2023-10-13 希格生科（深圳）有限公司 杂芳环化合物及其医药用途

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