WO2013013614A1 - 4-(3-hétéroarylarylamino)quinazoline et 1-(3-hétéroarylarylamino)isoquinoline utilisées en tant qu'inhibiteurs de la voie hedgehog et leur utilisation - Google Patents

4-(3-hétéroarylarylamino)quinazoline et 1-(3-hétéroarylarylamino)isoquinoline utilisées en tant qu'inhibiteurs de la voie hedgehog et leur utilisation Download PDF

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WO2013013614A1
WO2013013614A1 PCT/CN2012/079120 CN2012079120W WO2013013614A1 WO 2013013614 A1 WO2013013614 A1 WO 2013013614A1 CN 2012079120 W CN2012079120 W CN 2012079120W WO 2013013614 A1 WO2013013614 A1 WO 2013013614A1
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amine
chlorophenyl
imidazol
benzo
group
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PCT/CN2012/079120
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Chinese (zh)
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蔡遂雄
田野
王晓珠
谢凯
栗思存
余增辉
顾诚云
刘丽军
吴利珍
陈圣志
殷峰
康思顺
孟正
许庆兵
张秀艳
费洪强
王冬梅
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南京英派药业有限公司
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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

  • the invention belongs to the field of medicinal chemistry.
  • the present invention particularly relates to 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline, and as a therapeutically effective hedgehog pathway inhibitor, and The application of cancer drugs. Background technique
  • the Hedgehog protein was originally a highly conserved family of proteins found in Drosophila, which plays a crucial role in embryonic development.
  • the most studied mammalian homologous hedgehog proteins associated with humans include three genes, Sonic hedgehog (Shh), Indian hedgehog, and Desert hedgehog.
  • Shh is not only important in embryonic development, but also has many evidences that it also plays an important role in the carcinogenic mechanisms of some cancers including basal cell carcinoma (Caro, I. and JA Low, Clin Cancer Res, 2010. 16(13) ): 3335- 9).
  • Shh first synthesized a 45 kDa precursor protein in vivo and produced a 20 kDa N-terminal fragment by self-resection.
  • This N-terminal fragment possesses all the biological activities known to date.
  • the carcinogenic mechanism of Shh is not well understood, its function includes activation of the hedgehog information pathway within the cell.
  • the main members of this information pathway include patched (PTCH), G-like protein and receptor oncogene smoothened (SM0), and transcription factor Gl i (Bale, AE and KP Yu, Hum Mol Genet, 2001. 10(7): 757-62).
  • PTCH patched
  • SM0 G-like protein and receptor oncogene smoothened
  • Gl i transcription factor
  • Mutation analysis of members of the hedgehog signaling pathway in basal cell carcinoma showed that most of the mutations occurred on PTCH-1 and SM0 (Von Hoff, DD, et al., N Engl J Med, 2009. 361(12): 1164-72) .
  • PTCH-1 is a membrane protein with 12 membrane-penetrating structures, which is a direct acting receptor for Shh. In the absence of Shh, PTCH-1 interacts with SM0 to inhibit the biological viability of SM0. The combination of Shh and PTCH-1 causes PTCH-1 to leave SM0, freeing SM0 from the suppressed state.
  • the Gl i transcription factor is controlled by SM0, which plays a switching role in gene transcription, and the main members include Gl il, Gl i2 and Gl i3. The entire hedgehog pathway plays a crucial role in the normal development of the embryo.
  • SM0 fetal malformations
  • PTCH-1 binds to SM0 and inhibits its biological activity, so the entire pathway is in a state of no vitality or low vitality.
  • the binding of the hedgehog protein to the PTCH-1 receptor causes it to detach from SM0, thereby losing the inhibition of SM0.
  • SM0 further activates the transcription factor G1 i-1 to regulate gene transcription and cell growth.
  • Hedgehog signaling pathway activation is critical for the differentiation of mouse mesenchymal stem cells, C3H10T1/2, into osteoblasts.
  • C3H10T1/2 When C3H10T1/2 is differentiated into osteoblasts, the activity of intracellular alkaline phosphatase is greatly enhanced. Inhibition of the activity of the Hedgehog pathway leads to a decrease in the activity of intracellular alkaline phosphatase. Therefore, C3H10T1/2 is induced to differentiate into osteoblasts by activating Hedgehog signaling, and the activity of hedgehog pathway inhibitors is screened and assayed by measuring the activity of intracellular alkaline phosphatase (Peukert, S. and K. Miller-Moslin, ChemMedChem, 2010). 5(4): 500-12; Tremblay, MR, et al., J. Med. Chem., 2009, 52: 4400-18).
  • US20030144308 discloses 4-(phenylamino)quinazoline as a fructose 1,6-bisphosphatase inhibitor.
  • Q pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, furyl, quinolinyl, imidazolyl, Pyridyl, pyrimidinyl;
  • T 1 hydrogen, methyl, ethyl, OR 10 , SR 10 , cyano, cyclopropyl, cyclobutyl, NH 2 , NHR 10 , N (R 10 ) 2 , NHNH 2 , CHR 10 OH, CH 2 R 10 , C0C3 ⁇ 4, CON (R 10 ) 2 ;
  • R 1 , R 2 , R 3 , R 4 hydrogen, halogen, trifluoromethyl, 4-chloro
  • W02004030672 discloses aminoquinazoline as a protein kinase B inhibitor and an anticancer drug.
  • W09609294 discloses quinoline and quinazoline as protein tyrosine kinase inhibitors.
  • R 1 NH 2 , H, halogen , hydroxy, N0 2 , C0 2 H, CF 3 , CF 3 0, ureido, etc.;
  • R 4 hydrogen, hydroxy, halogen, alkyl, alkoxy, sulfur-containing alkyl, cyano, nitro, trifluoro Methyl, etc.;
  • n 1-3;
  • R 5 hydrogen, halogen, trifluoromethyl, alkyl, alkoxy;
  • R 6 substituted hydroxy, and the like.
  • the present invention provides novel 4-(3-heteroarylarylamino)quinazolines and 1-(3-heteroarylarylamino)iso Quinoline acts as a hedgehog pathway inhibitor.
  • the invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II or Formula III for use in the treatment of cancer.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition may further comprise at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.
  • the present invention also relates to a process for the preparation of the novel compounds of Structural Formula I, Formula II and Formula III. Detailed ways
  • the present invention finds novel 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquine
  • the porphyrin acts as a hedgehog pathway inhibitor.
  • a specific compound is a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof:
  • ring c is a monocyclic or bicyclic nitrogen-containing heteroaryl group which may be substituted
  • A is N or CR 1 ;
  • R is hydrogen, .
  • R-R 10 is independently hydrogen, halogen, amino group which may be substituted, alkoxy group.
  • R 3 and R 4 together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens.
  • ring C is a benzothiazolyl group which may be substituted, pyridyl, pyrazinyl, oxazolyl, oxadiazolyl, quinoxalinyl, pyrimidinyl, pyridazinyl, ⁇ , isodecyl, 3 fluorenyl, pyridazinyl, oxazolyl, fluorenyl, 4 quinazinyl, isoquinolinyl, quinolinyl, pyridazinyl, naphthyridinyl, acridinyl, Naphthalene, dinitro(hetero)phenyl, phenanthroline, phenazinyl, isothiazolyl, phen
  • ring c is a monocyclic or bicyclic nitrogen-containing heteroaryl group which may be substituted
  • R is hydrogen, .
  • R 2 -R 10 are independently hydrogen, halogen, amino group which may be substituted, alkoxy group.
  • R 3 and together with the carbon to which they are attached form a 5- or 6-membered heterocyclic ring containing two oxygens.
  • a group of preferred compounds of the invention is represented by a compound of formula Ilia or Illb or a pharmaceutically acceptable salt or prodrug thereof:
  • B ⁇ 0, S, 0 ⁇ or 15;
  • B 2 is 0, S, 0? 12 or NR 16;
  • B 3 is 0, S, 0? 13 or 17;
  • B 4 is 0, S, 0? 14 Or 18 ;
  • R is hydrogen, .
  • R 2 -R 14 are independently hydrogen, halogen, amino group which may be substituted, alkoxy group.
  • R 15 -R 18 are independently hydrogen, Cwo alkyl, haloalkyl, aryl, carbocyclyl, heterocyclyl, heteroaryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, Aryl alkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl; or
  • R 12 or R 13 are aryl or heteroaryl groups which may be substituted.
  • ring C is a benzzimidazolyl, benzothiazolyl or pyridyl group which may be substituted, including but not limited to, for example, 1 benzo[t]imidazol-2-yl, benzene And [t] thiazol-2-yl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • the substituent on the ring C may be, for example, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a cyano group, an amino group, a heteroaryl group (e.g., morpholinyl group), an aryl group (e.g., an alkyl group). , alkoxy, halogen substituted phenyl) and the like.
  • ring C or a BfB ⁇ containing ring is a substituted benzimidazolyl group, for example, Ibenzo[t]imidazol-2-yl.
  • the ring may be 1, 2 or 3 selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, heteroaryl (eg morpholinyl), aryl (eg phenyl) Substituted by a substituent.
  • ring C or a ring containing -4 4 is a phenylimidazolyl group which may be substituted, including but not limited to 4-phenylimidazol-2-yl which may be substituted And 5-phenylimidazol-2-yl and the like.
  • Substituents include, but are not limited to, 1, 2 or 3 groups selected from the group consisting of alkyl, alkoxy and halogen.
  • R 3 —R 5 are each independently preferably 11, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfonyl (for example methyl sulfonate).
  • R 3 , R 5 and R 9 are each independently H, halo, alkyl or alkoxy.
  • R 4 is H, halo, alkyl, haloalkyl, haloalkoxy, alkylsulfonyl (eg methylsulfonyl), nitro, amino, hetero
  • An aryl group e.g., morpholinyl
  • an optionally substituted phenyl group e.g., a haloalkyl substituted phenyl group.
  • a preferred group of compounds of formula I, II, Ilia or Illb is 11, alkoxy or alkyl.
  • a preferred group of compounds of formula I, II, Ilia or Illb in, R 6 is H, alkyl, haloalkyl or amino.
  • a preferred group of compounds of formula I, II, Ilia or Illb is 11, haloalkyl or alkyl.
  • R, R 2 , R 6 , R 7 , R 8 , R 9 are H;
  • R 10 (or R 9 ) is Halogen or alkyl;
  • the quinazoline or isoquinoline is substituted at the 6 and 8 positions, the substituent being selected from the group consisting of halogen, alkyl and alkoxy.
  • R 3 , R 4 form a methylene dioxybenzene or cycloethylene dioxybenzene ring with the phenyl group to which they are attached.
  • Preferred compounds of Formula I, Formula II and Formula III include, but are not limited to:
  • alkyl refers to the alkyl group itself or as part of another group, which is a straight or branched group of up to ten carbon atoms.
  • Useful alkyl groups include straight or branched chains.
  • An alkyl group preferably a linear or branched d- 6 alkyl group, more preferably an alkyl group. typical.
  • Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl.
  • alkenyl refers to an alkenyl group itself or as part of another group, which is a straight or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains one A group of double bonds.
  • a preferred alkenyl group is an alkenyl group having 2 to 4 carbon atoms.
  • Typical alkenyl groups include ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
  • alkynyl refers to an alkyne substantially or as part of another group, which is a straight or branched chain containing from 2 to 10 carbon atoms, wherein at least one of the two carbon atoms in the chain contains one The group of the ⁇ bond.
  • a preferred alkynyl group is an alkynyl group having 2 to 4 carbon atoms.
  • Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • alkoxy groups include those substituted by alkyl groups, for example as described above.
  • the alkyl-substituted oxy group is preferably substituted by the above C M alkyl group (i.e., C M alkoxy group), more preferably d- 3 alkoxy group.
  • Useful alkylthio groups include any of the above.
  • An alkyl group preferably, a d- 6 alkyl group, more preferably a d- 3 alkyl group
  • substituted thio group the alkyl group in the alkylthio group may be substituted.
  • alkylthio sulfoxides and sulfones are also included.
  • Useful amino groups include -NH 2 , -1 19 and - 19 . , where R 19 and. Yes.
  • An alkyl group preferably ( 3 alkyl) or ( 3 - ( 8 -cycloalkyl, or R 19 and. Forms a ring such as piperidine with N- or R 19 and R 2 . with N and with other groups)
  • a ring such as piperazine is formed.
  • the alkyl group and the ring may be substituted.
  • examples of the amino group include dimethylamino group and the like.
  • an alkyl group, an alkoxy group, an alkylthio group, an alkenyl group, an alkynyl group, a cycloalkyl group, a carbocyclic ring, and a heterocyclic ring may be one or more (for example, 1, 2, 3) Or 4) substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, amine, nitro, cyano, C M acylamino, C M acyloxy, d- 6 alkoxy, aryl Oxyl, alkylthio, C 6 -C 1() aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, Ce-Ci.
  • the alkoxy group may be substituted by one or more (e.g., 1 to 4 or 1 to 3 unequal) substituents selected from the group consisting of halogen, morpholinyl, and ammonia including alkylamines. And dialkylamines, and carboxy esters.
  • an aryl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group, a heteroaryl group, and a heteroarylalkyl group may be one or more (for example, 1, 2) , 3 or 4) Substituents substituted from the following groups: halogen, C M alkyl, methylenedioxy, dC 6 haloalkyl, C 6 -C 1 () aryl, C 4 -C 7 ring Alkyl, C 2 -C 6 alkenyl, C 2 -c 6 alkynyl, c 6 -c 10 aryl ( Ci-C 6 ) fluorenyl, c 6 _c 10 aryl ( c 2 -c 6 ) alkene Base, c 6 _c 10 aryl ( c 2 -c 6 ) alkyne , CfCe hydroxyalkyl, nitro, amino, amino,
  • aryl refers to a aryl group or as part of another group, and refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms.
  • Useful aryl groups include C 6 - 14 aryl group, more preferably an aryl group.
  • Typical (6 - 14 aryl groups include phenyl, naphthyl, phenanthryl, anthryl, indenyl, biphenyl, biphenylene, and Fuji.
  • Carbocycle as used herein includes cycloalkyl and partially saturated carbocyclic groups.
  • Useful cycloalkyl groups are C 3 - 8 cycloalkyl.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Useful partially saturated carbocyclic groups include cycloalkenyl groups such as cyclopentenyl, cycloheptenyl and cyclooctyl
  • Useful halogen or halogen groups include fluorine, chlorine, bromine and iodine.
  • arylalkyl as used above includes any of a C 6 -... 14 aryl-substituted ( ⁇ alkyl aryl group is preferably an alkyl group (preferably an alkyl group of 4 arylalkyl It is a benzyl group, a phenethyl group or a naphthylmethyl group.
  • aryl group substituted - "arylalkenyl” includes any of the above C 6 [0024] As used herein. Alkenyl group
  • aryl group substituted - "arylalkynyl” includes any of the above C 6 [0025] As used herein.
  • aryloxy includes an oxy group substituted by any of the above C 6 -14 aryl groups, the aryl group of which may be substituted.
  • Useful aryloxy groups include phenoxy and 4-methylphenoxy.
  • arylalkoxy includes substituted with any of the above aryl groups.
  • the alkoxy group, the aryl group thereof may be substituted.
  • Useful arylalkoxy groups include benzyloxy and phenylethoxy.
  • Useful haloalkyl groups include those substituted by one or more fluorine, chlorine, bromine or iodine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, ⁇ , i-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl.
  • acylamino is any d- 6 acyl (alkanoyl) attached to an amine nitrogen, such as acetamido, chloroacetamido, propionamide, butanamide, pentanamide And hexanoamide groups, and aryl substituted C M acylamino groups, such as benzamide groups.
  • a useful acyloxy group is any C M acyl (alkanoyl) attached to oxygen (-0-), such as formyloxy, acetoxy, propionyloxy, butyryloxy, valeryl Oxyl and hexanoyloxy.
  • a heterocyclic ring refers to a saturated or partially saturated 3-7 membered monocyclic ring, or a 7-10 membered bicyclic ring system, which is selected from the group consisting of carbon atoms and optionally from the heteroatoms 0, N and S.
  • heterocyclic ring may have a substituent on the carbon or nitrogen atom.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indanyl, iso-dihydro Mercapto, quinuclidinyl, morpholinyl, heterochromyl, chromanyl, pyrazolidinyl and pyrazolinyl.
  • heteromatic ring means having 5 to 14 ring atoms and having 6, 10 or 14 ⁇ electrons are shared on the ring system. Further, the ring atoms contained are carbon atoms and optionally 1-3 hetero atoms from oxygen, nitrogen and sulfur.
  • Useful heteroaryl groups include benzothiazolyl, thienyl, benzothienyl, benzo[2,3-6]thienyl, thioxyl, furyl, pyranyl, isobenzopyran Base, chromenyl, oxime, phenoxanthi inyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridine , pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, isodecyl, 3H-fluorenyl, pyridazinyl, oxazolyl, fluorenyl, 4 quinazinyl, isoquinolinyl , quinolyl, pyridazinyl, naphthyridinyl, acridinyl, naphthyldiaza(hetero)
  • such a nitrogen atom may be in the form of an N-oxide such as a pyridyl N-oxide, a pyrazinyl N-oxide and a pyrimidinyl N-oxide.
  • Heteroaryloxy as used herein, includes an oxy group substituted by any of the above heteroaryl groups, wherein the heteroaryl group may have a substituent.
  • Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and phenylthiooxy.
  • heteroarylalkoxy refers to substituted by any of the above heteroaryl groups.
  • stereoisomers including optical isomers.
  • the present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as the individual enantiomers which can be separated according to methods well known to those skilled in the art.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid salts such as hydrochlorides, hydrobromides, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salt and oxalate; and alkali Inorganic and organic base salts formed by sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine.
  • inorganic and organic acid salts such as hydrochlorides, hydrobromides, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salt and oxalate
  • alkali Inorganic and organic base salts formed by sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine alkali Inorganic and organic base salts formed by sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS,
  • prodrugs of the compounds of the invention include simple esters of carboxylic acid containing compounds (for example esters obtained by condensation with ( 4 alcohols) according to methods known in the art; esters of hydroxyl containing compounds (eg, 6 esters obtained by acid or anhydrides such as succinic anhydride, fumaric anhydride and condensation) - by methods known in the art and d- 4 carboxylic acids, C 3; imine compound containing an amino group (e.g., according to known in the art Method by imine obtained by condensation with ( 4 aldehyde or ketone); carbamate of amino group-containing compound, such as Leu et al. (7: fed i3 ⁇ 4 effl.
  • esters of hydroxyl containing compounds eg, 6 esters obtained by acid or anhydrides such as succinic anhydride, fumaric anhydride and condensation
  • imine compound containing an amino group e.g., according to known in the art Method by imine obtained by condensation with ( 4 aldehyde
  • the compounds of the invention can be prepared using methods known to those skilled in the art or by the novel methods of the invention. Specifically, the compound of the present invention having the formula I, formula II or formula III can be obtained as shown in the reaction examples in Reaction Scheme 1. 2-Chloro-5-nitrobenzoic acid is reacted with oxalyl chloride to give 2-chloro-5-nitrobenzoyl chloride. 2-Chloro-5-nitrobenzoyl chloride is reacted with o-phenylenediamine to give the product aminophenyl)-2-chloro-5-nitrobenzamide.
  • the compounds of the present invention can be prepared as shown in the reaction examples in Reaction Scheme 2. 3, 5-Dimethoxybenzoic acid and oxalyl chloride are reacted. Then, it was reacted with 2,2-dimethoxyethylamine in triethylamine and dichloromethane to obtain 3,5-dimethoxy-(dimethoxymethyl)-benzamide. The reaction of 3,5-dimethoxy-(dimethoxymethyl)-benzamide with concentrated sulfuric acid gives 5,7-dimethoxyisoquinolin-1-(2 ⁇ )one.
  • the 5,7-dimethoxyisoquinoline-1-(2 ⁇ ) ketone is reacted with phosphorus oxychloride at 100 C to give 1-chloro-5,7-dimethoxyisoquinoline.
  • 1-Chloro-5,7-dimethoxyisoquinoline is reacted with 3-(1 benzo[]imidazol-2-yl)-4-chloroaniline in isopropanol and concentrated hydrochloric acid to give the desired product N ⁇ (3 - (l benzo[ ]imidazol-2-yl)-4-chlorophenyl)-5,7-dimethoxyisoquinolin-1-amine.
  • Other compounds can be prepared in a similar manner.
  • 4-chloro-3-(pyridin-2-yl)aniline can be used in place of 3-(I benzo[]imidazol-2-yl)-4-chloroaniline to synthesize chloro-3-(pyridin-2-yl) Phenyl)-5,7-dimethoxyisoquinolin-1-amine.
  • the compounds of the present invention can be prepared as shown in the reaction examples in Reaction Scheme 3.
  • 2-Amino-3,5-dimethoxybenzoic acid was reacted with acetic anhydride to 135 °C. Then add ammonia water and react at 135 ° C.
  • 6, 8-dimethoxy-2-methylquinazolin-4 (3-keto. 6, 8-dimethoxy-2-methylquinazolin-4 (3 ⁇ -ketone with trichloroox Phosphine reaction gives 4-chloro-6, 8-dimethoxy-2-methylquinazoline.
  • This compound is 3-(l benzo[d]imidazole-2- Reaction of 4-chloroaniline in isopropanol to give the desired product (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxy-2-chloro Methyl quinazolin-4-amine.
  • (I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-fluoromethylquinazoline can be synthesized by using fluoroacetonitrile instead of chloroacetonitrile. 4-amine.
  • the present invention also encompasses methods of treating an animal with an effective amount of a compound of Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or prodrug thereof.
  • the method of treatment is used to treat various conditions (i.e., hedgehog mediated diseases) caused by abnormal hedgehog activity, such as cancer.
  • various disorders or hedgehog-mediated diseases caused by abnormal hedgehog activity include cancer, including but not limited to basal cell carcinoma, medulloblastoma, basal cell nevus syndrome (BCNS), liver cancer, black Neoplasms, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, Testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant Carcinoid cancer, choriocarcinoma, mycosis fungoides, head or neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia
  • BCNS basal
  • an effective amount of a pharmaceutical formulation is administered to a patient having one or more of these conditions.
  • the pharmaceutical preparations contain a therapeutically effective concentration of a compound of formula I, formula II or formula I II, formulated for oral, intravenous, topical or topical administration for the treatment of cancer and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is a dose sufficient to ameliorate or otherwise alleviate the symptoms associated with the disease.
  • Such a dose may be administered as a single dose or may be administered in accordance with an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the invention also relates to the use of a compound of the formula I, formula II or formula I I I for the manufacture of a medicament for the treatment or prevention of a disease caused by an abnormality in hedgehog activity.
  • the disease caused by the abnormality of the hedgehog activity includes cancer.
  • the disease is selected from the group consisting of cancer.
  • the disease is selected from the group consisting of basal cell carcinoma, medulloblastic carcinoma, and basal cell nevus syndrome.
  • the medicament may also contain other known anticancer agents including, but not limited to, the various known anticancer agents described herein.
  • a pharmaceutical composition comprising a compound of Formula I, Formula II or Formula I I I, or a pharmaceutically acceptable salt thereof, as a hedgehog pathway inhibitor, and a pharmaceutically acceptable carrier.
  • Another embodiment of the invention relates to a pharmaceutical composition effective for treating cancer comprising a compound of Formula I, Formula II or Formula I II as a hedgehog pathway inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, It is used in combination with at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug.
  • RNA damage chemotherapeutic anticancer drugs including alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide , temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin and carboplatin; topoisomerase I preparations such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarithromycin, mitoxantrone, el l iptinium, and temtopip; RNA/DNA antimetabolites such as 5-azapine, gemcitabine, 5 - Fluorine urinary and methotrexate; DNA antimetabolites such as 5-fluoro-2, -deoxyuridine, fludarabine, nelarabine ara
  • anticancers for anticancer combination therapy Drugs include tamoxifen, letrozole, fulvestrant, mitogu azone , octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, salidol and lenalidomide.
  • the compounds of the invention may be administered as a single pharmaceutical composition with at least one known anti-cancer drug.
  • the compounds of the invention may be administered separately from at least one known anticancer drug.
  • the compound of the invention is administered at about the same time as at least one known anticancer drug, i.e., all drugs are administered simultaneously or sequentially, as long as the compound achieves a therapeutic concentration in the blood simultaneously.
  • the compound of the invention and at least one known anticancer drug are administered according to a respective dosage regimen as long as the compound reaches a therapeutic concentration in the blood.
  • Another embodiment of the present invention is a bioconjugate of the compound which is effective for inhibiting tumors.
  • This bioconjugant capable of inhibiting tumors consists of the compound with a therapeutic antibody such as Herceptin or Rituxan, or an auxin such as DGF or NGF, or a cytokine such as interleukin 2 or 4, or any A molecular composition that binds to the cell surface.
  • the antibody and other molecules are capable of delivering the compound to its target, making it an effective anticancer drug.
  • This bioconjugate can also increase the anticancer effect of medically active antibodies such as Herceptin or Rituxan.
  • Another embodiment of the present invention relates to a pharmaceutical composition effective for inhibiting tumors, comprising a compound of Formula I, Formula II or Formula III as a hedgehog pathway inhibitor, or a pharmaceutically acceptable salt or prodrug thereof, Combined with radiation therapy.
  • the compounds of the invention may be administered at the same time or at different times as the radiation therapy.
  • Another embodiment of the present invention relates to a pharmaceutical composition effective for post-operative treatment of cancer, comprising Formula I, Formula II or Formula III as a hedgehog pathway inhibitor, or a pharmaceutically acceptable salt thereof or Prodrug.
  • the present invention also relates to a method of treating a cancer in a mammal by surgically removing the tumor and then using the pharmaceutical composition of the present invention.
  • the pharmaceutical composition of the present invention may also contain the bioconjugate of the present invention as an active ingredient, and the bioconjugate may be, for example, a compound of the formula I, II or III of the present invention as described above.
  • the formation of antibodies for medical action can also be included in the pharmaceutical compositions.
  • the pharmaceutical composition of the present invention includes all of the pharmaceutical preparations of the present invention in an amount effective to achieve their intended purpose. While the needs of each individual are different, one skilled in the art can determine the optimal dosage for each portion of the pharmaceutical formulation.
  • the compound, or a pharmaceutically acceptable salt thereof is administered orally to a mammal daily, in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, it is about 0.01 to 10 mg per kg orally. If a known anticancer drug is also administered, the dose should be effective to achieve its intended purpose.
  • the optimal dosage of these known anticancer drugs is well known to those skilled in the art.
  • the unit oral dose may comprise from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg of the compound of the invention.
  • the unit dose may be administered one or more times per day, one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently about 0.25 to 10 mg of the compound of the present invention or a solvate thereof.
  • the concentration of the compound may be about 0.01 to 100 mg per gram of the carrier.
  • the compounds of the invention can be administered as unprocessed pharmaceuticals.
  • the compounds of the invention may also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including adjuvants, adjuvants).
  • a pharmaceutically acceptable carrier including adjuvants, adjuvants.
  • These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable pharmaceutical preparations.
  • the preferred pharmaceutical preparations especially those of the oral and preferred modes of administration, such as tablets, troches and capsules, and solutions suitable for injection or oral administration, containing from about 0.01% to about 99%, preferably from about 0. 25% to 75% of active compound and excipients.
  • the scope of the invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the invention.
  • the acid addition salt is formed by mixing a non-toxic pharmaceutically acceptable acid solution and a solution of the compound of the present invention.
  • the acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like.
  • the base addition salt is formed by mixing a non-toxic pharmaceutically acceptable base solution and a solution of the compound of the present invention.
  • the base is, for example, sodium hydroxide, potassium hydroxide, hydrogen choline, sodium carbonate, Tris, N-methyl-glucosamine or the like.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals are human and veterinary animals, although the invention is not intended to be so limited.
  • the pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose.
  • it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, intranasally, intrathecally, intracranically, nasally or externally.
  • it can be administered orally.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by conventional mixing, granulating, tableting, dissolving, or freeze drying processes. In the manufacture of oral formulations, the mixture can be selectively milled in combination with the solid adjuvant and the active compound. If necessary or necessary, after adding appropriate amounts of auxiliaries, the granule mixture is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, These include corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, These include corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrroli
  • a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.
  • Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates, such as calcium magnesium stearate, Stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dose of an active ingredient.
  • Other orally available pharmaceutical preparations include pressure-bonded capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerin or sorbitol.
  • the pressure-bonded capsules may contain the active compound in the form of granules mixed with a filler such as lactose, a binder such as a starch, a lubricant such as talc or magnesium stearate, and a stabilizer.
  • the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.
  • Formulations suitable for parenteral administration include aqueous solutions of the active compounds, such as solutions of aqueous salts and basic solutions.
  • an oily injection suspension of the appropriate active compound may be employed.
  • Suitable lipophilic solvents or vehicles include oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate, triglycerides or polyethylene glycol 400, cremophor, or cyclodextrin.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Suspension stabilizers may also be included.
  • the external preparation of the present invention can be formulated into an oil, a cream, an emulsion, an ointment or the like by a preferably suitable carrier.
  • suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular alcohols (greater than C 12).
  • Preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants, as well as agents which impart color or aroma, if desired, may also be included.
  • these external preparations may contain a transdermal penetration enhancer. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • the cream is preferably prepared by mixing a mixture of mineral oil, self-emulsifying beeswax and water with an active ingredient dissolved in a small amount of oil such as almond oil.
  • a typical example of a cream includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.
  • the ointment may be formulated by mixing a vegetable oil containing an active ingredient such as almond oil and warm soft paraffin, and then cooling the mixture.
  • a typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.
  • the present application also relates to the use of a compound of the formula I, II or II II according to the invention for the preparation of a composition (for example a pharmaceutical composition) for inhibiting hedgehog activity.
  • a composition for example a pharmaceutical composition
  • the following examples are illustrative and not limiting of the methods and formulations of the present invention. Others will be apparent to those skilled in the art, and appropriate modifications and improvements to the various conditions and parameters that are commonly encountered in clinical practice are within the spirit and scope of the invention.
  • the reagents used are all of a commercial quality.
  • the solvents were dried and purified according to standard methods.
  • Mass spectrometry data was determined using an electrospray single quadrupole mass spectrometer (Platform II, Agilent 6110).
  • the hydrogen spectrum was determined by a Brilcker AMX 300 mega NMR at 300K. Chemical shifts were recorded as TML as an internal standard (0.0 ppm) from the low field in ppm and coupling constants/values in Hertz.
  • the ice water bath was cooled to 5 V, and the prepared acid chloride was slowly added by a syringe. After the addition was completed, it was naturally allowed to react to room temperature for 16 hours. The solvent was evaporated, and the residue was poured into 30 mL of iced water and extracted with dichloromethane (3 ⁇ 20 mL). The combined organic layers were washed with EtOAc EtOAc m.
  • N ⁇ (3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-7-aminoquinazolin-4-amine will be SnCl 2 3 ⁇ 40 (0. 13 g, 0. 56 mmol
  • N ⁇ (3-(I benzo[t]imidazol-2-yl)-4-chlorophenyl)-6,8-dimethoxy-2-fluoromethylquinazolin-4-amine is similar to The synthetic method of Example 81 was carried out to prepare the starting material as 2-amino-3,5-dimethoxybenzoic acid, fluoroacetonitrile and 3-(l benzo[£]imidazol-2-yl)- 4-chloroaniline.
  • Benzoic acid (1 g, 5 mmol), 2-(7-aza-I benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HATU, 2.85 g, 7.5 mmol) and DCM (20 mL).
  • the mixture was cooled to EtOAc.
  • EtOAc EtOAc
  • the reaction solution was evaporated to dryness, and the solvent was evaporated, and then, 10 ml of water, and ethyl acetate (50 mL ⁇ 3).
  • Example 88 (3-(5-(phenyl-1,3,4-oxadiazol-2-yl)-4-chlorophenyl)-6,8-dimethoxyquinazolin-4-amine is similar to The synthetic method of Example 87 was carried out to prepare starting materials of 2-chloro-5-nitrobenzoic acid, benzoylhydrazine, and 4-chloro-6,8-dimethoxyquinazoline.
  • C3H10T1/2 cells I benzo[t]imidazol-2-yl)-4-chlorophenyl-6, 8-dimethoxyquinazolin-4-amine and its analogue inhibition Hedgehog signaling pathway-activated mouse mesenchymal stem cells C3H10T1/2 (C3H/10T1/2, Clone 8 mouse embryonic fibroblasts, Chinese Academy of Sciences cell bank) induced by hedgehog pathway to differentiate into osteoblasts, while intracellular Alkaline phosphatase expression is a loyal sign in this differentiation process. This process can be used as a means of detecting the activity of hedgehog pathway inhibitors.
  • the healthy growth period C3H10T1/2 cells were plated at 10,000 cells per well in a 96-well cell culture dish one day before the test. The cells were cultured overnight in growth medium DMEM (Hyclone) containing 10% fetal calf serum (FBS, Hyclone) at 37 ° C and 5% C0 2 . The test day was equipped with induction medium and inhibitor as follows: Reference compound and test compound were serially diluted to a concentration of 7 compounds with DMS0 at 1:3 and 1:10, and the eighth was a blank DMSO control. Ten-fold dilutions were prepared by mixing 10 ⁇ M DMS0 dilution with 90 ⁇ L fresh complete growth medium.
  • DMEM Hyclone
  • FBS fetal calf serum
  • a pre-packed 1 mM hedgehog pathway activator SAG (Yang, H. et al. J. Biol. Chem. 2009, 284, 20876-84) was added to the DMS0 mother liquor at a ratio of 1:1000 to 10% FBS.
  • the concentration of SAG was 1 ⁇
  • the concentration of DMS0 was 0.1%.
  • the activity of alkaline phosphatase in the cells was measured, and the detection methods included the following:
  • Solution ⁇ Configure 0.5 mM MgCl 2 solution (Sigma Prod. No. M- 0250) for use.
  • Solution B A 1 M solution of diethanolamine was placed. Take 10. 51 g of diethanolamine (Sigma Prod. No. D-
  • Solution C 3.71 mg p-NPP (molecular weight 371. 14) was added to 10 mL of double distilled water to a final concentration of 1 mM, which was fully dissolved.
  • Substrate reaction solution Add 250 ⁇ M solution ⁇ and 200 ⁇ M solution C to 10 mL of Solution B and mix.
  • the cell culture dish was taken out, the supernatant was discarded, and the cells were washed twice with PBS, and 20 ⁇ M of the lysate was added per well (0.2%).
  • Triton solution After shaking for 30 min at room temperature, add 80 ⁇ M of substrate reaction solution to each well. Put in the VariSkan Flash microplate reader and read 0D 4 . 5 absorbance values as background readings. The dish was then placed back in the 37 ° C incubator for 30 min and scanned again to read 0D 4 . 5 absorption value.
  • the compounds of the invention exhibit an inhibitory effect on the hedgehog pathway, wherein A 3-( l benzo[ t ]imidazol-2-yl)-4-chlorophenyl)-6, 8-dimethoxyquinazoline- 4-amine (Example 28) and its analogs showed a strong inhibitory effect on the hedgehog pathway.

Abstract

L'invention concerne une 4-(3-hétéroarylarylamino)quinazoline et une 1-(3-hétéroarylarylamino)isoquinoline représentées par la formule (I) dans laquelle les noyaux C, A, R et R2-R10 sont comme définis dans le descriptif. Le composé de formule (I) est un inhibiteur de la voie Hedgehog et peut ainsi s'utiliser pour le traitement de maladies dues à une activité Hedgehog anormale, telles que le cancer.
PCT/CN2012/079120 2011-07-28 2012-07-25 4-(3-hétéroarylarylamino)quinazoline et 1-(3-hétéroarylarylamino)isoquinoline utilisées en tant qu'inhibiteurs de la voie hedgehog et leur utilisation WO2013013614A1 (fr)

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US10626121B2 (en) 2016-09-08 2020-04-21 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11021487B2 (en) 2016-09-08 2021-06-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11104685B2 (en) 2016-09-08 2021-08-31 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2018082587A1 (fr) 2016-11-04 2018-05-11 上海瑛派药业有限公司 Application d'un inhibiteur de la voie hedgehog servant au traitement de maladies fibrotiques
CN106866507B (zh) * 2017-01-04 2019-08-02 武汉博诚恒瑞医药科技有限公司 一种维莫地尼的合成方法
CN106866507A (zh) * 2017-01-04 2017-06-20 武汉博诚恒瑞医药科技有限公司 一种维莫地尼的合成方法
JP2020536855A (ja) * 2017-09-26 2020-12-17 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア がんを治療するための組成物及び方法
CN112174940A (zh) * 2019-07-05 2021-01-05 上海中医药大学 3-(6,7-双(2-甲氧乙氧基)-喹唑啉-4-胺基)苯基-1h-三氮唑衍生物

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