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WO2018068739A1 - Composé hétérocyclique d'alcynyle pour inhiber l'activité de la protéine kinase - Google Patents

Composé hétérocyclique d'alcynyle pour inhiber l'activité de la protéine kinase Download PDF

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Publication number
WO2018068739A1
WO2018068739A1 PCT/CN2017/105789 CN2017105789W WO2018068739A1 WO 2018068739 A1 WO2018068739 A1 WO 2018068739A1 CN 2017105789 W CN2017105789 W CN 2017105789W WO 2018068739 A1 WO2018068739 A1 WO 2018068739A1
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group
ring
compound
aryl
mmol
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Chinese (zh)
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王义汉
邢青峰
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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Priority to CN201780004843.0A priority Critical patent/CN108473476B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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

Definitions

  • the invention belongs to the field of medicine. Specifically, the present invention relates to alkynyl heterocyclic compounds which have an inhibitory effect on protein kinase activity, pharmaceutical compositions containing them, and processes for their preparation and use.
  • Protein tyrosine kinases are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, which are activated by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues.
  • a proteinase system that functions as a functional protein.
  • Protein tyrosine kinases play an important role in the signaling pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death.
  • Abnormal expression of protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis.
  • the abnormal expression of protein tyrosine kinase is also closely related to tumor invasion and metastasis, tumor angiogenesis, and chemotherapy resistance of tumors.
  • the tyrosine kinase expressed by the Bcr-Abl fusion gene can cause changes in cell proliferation, adhesion and survival properties, leading to the production of various tumors.
  • the oncogene c-Abl on human chromosome 9 is linked to the breakpoint cluster region (Bcr) on chromosome 22, forming the p210Bcr-Abl fusion gene and the p185Bcr-Abl fusion gene, which make the corresponding fusion genes Bcr-Abl tyrosine kinase is continuously activated, causing changes in cell proliferation, adhesion, and survival properties, resulting in the production of chronic myeloid leukemia (CML) and acute myeloid leukemia (ALL), respectively.
  • CML chronic myeloid leukemia
  • ALL acute myeloid leukemia
  • Inhibition of Bcr-Abl tyrosine kinase is effective in inhibiting tumor growth.
  • Bcr-Abl kinase plays an important role in cell signal transduction and transformation by promoting phosphorylation and activation of a series of downstream substrates that promote the infinite proliferation of CML mature granulocytes. Bcr-Abl is not expressed in normal cells, so it is an ideal drug target for the treatment of CML.
  • Imatinib is an oral anti-chronic granulocyte leukemia small molecule tyrosine kinase inhibitor developed by Novartis AG. It pioneered a new era of treatment of diseases with kinases.
  • Imatinib binds to the ATP site of the Bcr-Abl kinase domain, prevents phosphorylation of amino acid residues, thereby blocking signaling pathways and inhibiting cell proliferation. Relieve CML. After treatment, the patient's 5-year survival rate can reach 90%, and it can specifically act on CML cancer cells, while it has almost no damage to normal cells, and the side effects are greatly reduced. With the use of imatinib, mutations in the Bcr-Abl gene led to the emergence of drug resistance, which greatly reduced the efficacy of imatinib.
  • Dasatinib is a multi-targeted oral kinase inhibitor targeting multiple kinases such as Bcr-Abl tyrosine kinase, Src kinase family (Src, Lck, Fyn), c-Kit and PDGFR-B.
  • Bcr-Abl tyrosine kinase Src kinase family (Src, Lck, Fyn)
  • c-Kit c-Kit
  • PDGFR-B kinases
  • Nilotinib a novel aniline pyrimidine derivative, was approved by the US FDA on October 29, 2007. It has a 20-fold higher affinity for Bcr-Abl kinase than imatinib and is widely active in patients with imatinib resistance (except for the T315I mutation). Most patients who use nilotinib to treat CML have common side effects such as gastrointestinal reactions, myelosuppression, and hyperbilirubinemia. For the resistance of imatinib, dasatinib and nilotinib, Wyeth Pharmaceuticals has developed 4-substituted aniline-3-quinoline plus carbonitrile drug Bosutinib for treatment CML was approved by the FDA on September 4, 2012.
  • Bosutinib can inhibit the autophosphorylation of Src protein in a variety of human tumor cells, and also inhibit the autophosphorylation of Bcr-Abl protein, and is resistant to KU812 and K562 cells (Bcr-Abl-containing CML cells).
  • Bcr-Abl-containing CML cells Bcr-Abl-containing CML cells.
  • Punatinib is an oral multi-target inhibitor that acts on Abl, PDGFR ⁇ , VEGFR2, FGFR1 and Src kinases. Due to its unique mechanism of action, administration can inhibit Bcr-Abl kinase activity, including the T315I mutation.
  • patients taking Ponatinib have serious cardiovascular problems.
  • the present invention provides a novel alkynyl heterocyclic compound and a composition comprising the same and use thereof, which have better Bcr-Abl kinase inhibitory activity and/or have better pharmacodynamics/pharmacokinetics It has low toxicity and can be used for the preparation of drugs mediated by Bcr-Abl kinase.
  • ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring; wherein the heteroaryl ring or heterocyclic ring contains 1-3 heteroatoms selected from N, O and S, and the ring It may be selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3- C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl Substituted with a substituent in a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylamino group or a C 1 -C 6 alkanoyl group;
  • K is selected from CH, NH or S
  • M is selected from CH, C or N;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently N or CR 1 , and R 1 is independently H, hydroxy, halogen, silane, nitrile, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl , C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl;
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides a compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug or an isotopic variant thereof, and other therapeutic agents, and a pharmaceutically acceptable compound, A kit of acceptable carriers, adjuvants or vehicles.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of an anti-tumor or other disease, in a particular embodiment, the disease being a proliferative disorder caused by Bcr-Abl.
  • the disease may be selected from the group consisting of: solid tumor, sarcoma, chronic myelogenous leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, acute myeloid leukemia, thyroid cancer, gastric cancer, rectal cancer, multiple Myeloma, neoplasia, and other proliferative or proliferative diseases.
  • the condition caused by the Bcr-Abl is chronic myeloid leukemia, gastrointestinal stromal tumor, acute myeloid leukemia, thyroid cancer, or a combination thereof.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • C 1- C 6 alkyl includes C 1, C 2, C 3 , C 4, C 5, C 6, C 1- C 6, C 1- C 5, C 1- C 4, C 1- C 3 , C 1 - C 2 , C 2 - C 6 , C 2 - C 5 , C 2 - C 4 , C 2 - C 3 , C 3 - C 6 , C 3 - C 5 , C 3 - C 4 , C 4- C 6 , C 4- C 5 and C 5- C 6 alkyl.
  • C 1- C 6 alkyl means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl.” In some embodiments, a C 1-4 alkyl group is particularly preferred. Examples of the alkyl group include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), uncle Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5), 3- methyl-2-butyl (C 5), tert-pentyl (C 5) and n-hexyl (C 6).
  • each alkyl group is independently optionally substituted, ie, unsubstituted (“unsubstituted alkyl") or substituted with one or more substituents (“substituted alkyl”) For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the alkyl group is unsubstituted C 1- C 6 alkyl (e.g., -CH 3).
  • the alkyl group is a substituted C 1- C 6 alkyl.
  • C 1- C 6 alkoxy refers to the group -OR, wherein, R is a substituted or unsubstituted C 1- C 6 alkyl. In some embodiments, a C 1-4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, N-Hexyloxy and 1,2-dimethylbutoxy.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the halo group is F, Cl or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1- C 6 haloalkyl and “C 1- C 6 haloalkoxy” mean the above-mentioned "C 1- C 6 alkyl group” and "C 1- C 6 alkoxy group" which are one or Multiple halogen groups are substituted.
  • C 1- C 4 haloalkyl groups are particularly preferred, more preferably C 1- C 2 haloalkyl.
  • a C 1-4 haloalkoxy group is particularly preferred, more preferably a C 1 -C 2 haloalkoxy group.
  • Exemplary haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • Exemplary haloalkoxy groups include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3 , and the like.
  • C3 - C10 carbocyclyl means a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3- C 6 carbocyclic group is particularly preferred, more preferably C 5- C 6 carbocyclyl. Carbocyclyl also includes ring systems wherein the above carbocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to be represented The number of carbons in the carbocyclic system.
  • carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo [2.2.1] Heptyl (C 7 ), bicyclo [2.2.2] octyl (C 8 ), cyclodecyl (C 9 ), cyclodecen
  • each of the carbocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclic ring"base").
  • the carbocyclic group is an unsubstituted C3 - C10 carbocyclic group.
  • a carbocyclyl is a substituted C3 - C10 carbocyclyl.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a 3- to 6-membered heterocyclic group is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclic ring.
  • each of the heterocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero Ring base").
  • the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl.
  • a heterocyclic group is a substituted 3-10 membered heterocyclyl.
  • the heterocyclic group further includes a ring system in which the above heterocyclic ring is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic ring, or wherein the above heterocyclic ring is bonded to one or more aryl groups or A heteroaryl fused ring system wherein the point of attachment is on a heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thiorenyl.
  • Exemplary 4-membered heterocyclic groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane.
  • Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxalanyl, oxasulfuranyl, disulfuranyl, and Azolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxoalkyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocyclic groups containing one hetero atom include, but are not limited to, azepanyl, oxaheptyl, and thiaheptanyl.
  • Exemplary 8-membered heterocyclic groups containing one hetero atom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thicyclooctyl.
  • Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a C6 aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.
  • C 6- C 14 aryl means a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms (eg, having A group of 6, 10 or 14 ⁇ electrons shared in a ring arrangement.
  • an aryl group having six ring carbon atoms ( "C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (" C10 aryl”; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms (" C14 aryl"; for example, fluorenyl).
  • C14 aryl for example, fluorenyl
  • a C 6-10 aryl group is particularly preferred, more preferably a C 6 aryl group.
  • the aryl group also includes a ring system in which the above aryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be represented. The number of carbon atoms in the aryl ring system.
  • each of the aryl groups is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
  • the aryl group is an unsubstituted C 6-14 aryl group.
  • the aryl group is a substituted C 6-14 aryl group.
  • C 5 -C 10 heteroaryl means a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms (for example, having a ring-shaped arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • a C5-6 heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms.
  • each of the heteroaryl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"base").
  • the heteroaryl is an unsubstituted 5-10 membered heteroaryl.
  • the heteroaryl is a substituted 5-10 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases.
  • non-toxic acid addition salts are salts of amino and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • amino and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "person,” “patient,” and “subject” are used interchangeably herein.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. Delay or minimize.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • the agents of the invention are also useful in the treatment of diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcers Colitis, Crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor, thyroid Cancer, systemic mastocytosis, eosinophilic granules Cytomegaly, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminoma, asexual Cell tumor, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial
  • a compound of the invention refers to a compound of formula (I) below, a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.
  • the invention relates to a compound of formula (I):
  • ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring; wherein the heteroaryl ring or heterocyclic ring contains 1-3 heteroatoms selected from N, O and S, and the ring It may be selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3- C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl Substituted with a substituent in a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylamino group or a C 1 -C 6 alkanoyl group;
  • K is selected from CH, NH or S
  • M is selected from CH, C or N;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently N or CR 1 , and R 1 is independently H, hydroxy, halogen, silane, nitrile, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl , C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl;
  • the ring comprising Ring A and Ring B has the structure:
  • M is C or N
  • ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring
  • R a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or C 1 -C 6 Alkanoyl, and m is 0, 1, 2, 3 or 4.
  • the parallel ring composed of ring A and ring B has the following structure:
  • X 6 , X 7 and X 8 are independently C(R a ) 2 , CR a , NR a , N, O or S, and R a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino Or a C 1 -C 6 alkanoyl group; where chemistry permits, the bond between X 6 , X 7 and X 8 may be selected from a single flu
  • the ring comprising ring A and ring B is selected from the group consisting of:
  • X 5 , X 6 , X 7 and X 8 are as defined above;
  • the ring comprising ring A and ring B is selected from the group consisting of:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CR 1
  • R 1 is independently H, hydroxy, halo, silane, nitrile, nitro, C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl.
  • X 1 , X 2 , X 3 , X 4 are CR 1
  • X 5 is N or CR 1
  • R 1 is independently H, hydroxy, halogen, silane, nitrile, nitro, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl.
  • ring C is:
  • R is as defined in claim 8 or 9, and L 1 is substituted or unsubstituted (CH 2 ) x , O(CH 2 ) x , NR(CH 2 ) x , S(CH 2 ) x , or (CH 2 ) x NRC(O)(CH 2 ) x , x is 1, 2 , 3 or 4.
  • ring C is selected from:
  • the compounds of the invention may be selected from the group consisting of:
  • the invention also includes all suitable isotopic variations of the compounds of the invention.
  • An isotopic variation of a compound of the invention is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. 18 F, 31 P, 32 P, 35 S and 36 Cl.
  • isotopic variations of the compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes e.g., hydrazine, i.e., 2 H
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures, for example by illustrative methods or by the preparations described in the Examples below, using appropriate isotopic variations of the appropriate reagents.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline form.
  • the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each This article is incorporated herein by reference.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the invention in dry powder form can be dried with a gel adhesive at about 1:2 The weight ratio is mixed. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the route of administration selected the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.
  • the amount of the compound actually administered can be determined by a physician.
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, E.g, Alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silica; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, salicylic acid Methyl or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, E.g, Alginic acid, Primo
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, part 8 of which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the agents of the invention are also useful in the treatment of diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcers Colitis, Crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor, thyroid Cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Al Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial neoplasia
  • the invention thus provides compounds (I) and salts, solvates, physiologically functional compounds thereof for use in therapy, particularly in the treatment of diseases and conditions mediated by inappropriate Bcr-Abl activity.
  • Inappropriate Bcr-Abl activity as referred to herein is any Bcr-Abl activity that deviates from the expected normal Bcr-Abl activity in a particular mammalian subject.
  • Inappropriate Bcr-Abl activity can be, for example, in the form of an abnormal increase in activity, or a timing and/or controlled aberration of Bcr-Abl activity.
  • Such inappropriate activity can result, for example, from overexpression or mutation of an activated protein kinase that results in inappropriate or uncontrolled.
  • the invention relates to a method of modulating, modulating or inhibiting Bcr-Abl for the prevention and/or treatment of a disorder associated with dysregulated or inappropriate Bcr-Abl activity.
  • condition mediated by Bcr-Abl activity is a respiratory disease.
  • condition is a proliferative disorder.
  • condition is cancer.
  • condition is leukemia.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, prepared for use in therapy for mediated by Bcr-Abl activity Use of the drug for the illness.
  • a further aspect of the invention resides in the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a Bcr-Abl mediated disease or a Bcr-Abl mediated condition.
  • the invention provides a method of treating a mammal having a condition mediated by Bcr-Abl activity, the method comprising: administering to the mammal an effective amount of Formula (I) a compound or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
  • an effective amount of a compound of the invention will generally be administered in a single or multiple doses at an average daily dose of from 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight.
  • the compounds of the invention may be administered to a patient in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg.
  • the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. It can be administered one or more times daily, weekly (or several days apart) or on an intermittent schedule.
  • the compound can be administered one or more times per day on a weekly basis (e.g., every Monday), continually or for several weeks, such as 4-10 weeks.
  • the administration may be continued for several days (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) without administration of the compound, and the cycle may be repeated indefinitely or repeated for a given number of times, such as 4-10 Cycles.
  • the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days, then intermittent for 9 days, and so on, optionally repeating the cycle or repeating 4-10 times.
  • Combination therapies according to the invention thus comprise the administration of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent.
  • One or more compounds of formula (I) and one or more other pharmaceutically active agents may be administered together or separately, and when administered separately, may be carried out simultaneously or sequentially in any order. The amount and relative timing of administration of one or more compounds of formula (I) and one or more other pharmaceutically active agents will be selected to achieve the desired combined therapeutic effect.
  • the compound of formula (I) can be combined with one or more anticancer agents.
  • anticancer agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (ed.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • One of ordinary skill in the art will be able to identify which combination of agents can be used based on the drug and the particular characteristics of the cancer involved.
  • Such anticancer agents include, but are not limited to: (1) estrogen receptor modulators such as diethyltibestral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluorotestosterone, and SH646; (2) Other hormonal agents include aromatase inhibitors (eg, aminoglutethimide, tetrazoranazol, letrozole, and exemestane), luteinizing hormone releasing hormone (LHRH) analogs, ketoconazole, Goserelin acetate, leuprolide, megestrol acetate and mifepristone; (3) androgen receptor modulators such as finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, Flutamide, bicalutamide, liazodazole, and abiraterone acetate; (4) retinoid receptor modulators such as bexarot
  • Cytotoxicity/cytostatic refers to compounds that primarily cause cell death or inhibit cell proliferation or inhibit or interfere with cell mitosis by direct interference with cellular functionalization, including alkylating agents, tumor necrosis factors, intercalators, hypoxia-activated compounds.
  • cytotoxic agents include, but are not limited to, sertenef, cachexia, cyclamate, cyclophosphamide, ifosfamide, nitrogen mustard, melphalan, uracil mustard, thiotepa, busulfan, carmustine , cyclohexyl nitrosourea, streptozotocin, tastatin, chloridamine, carboplatin, hexamethylene melamine, dacarbazine, procarbazine, prednisolone, dibromodusol, thunder Mistin, formoterol, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, mesalamine, trlophosphamide, nimustine, dibromospirochloramine, Pyridoxine, lobaplatin, celecoxime, porphyrin, cisplatin, ilofufen, dexfo
  • proteasome inhibitors include, but are not limited to, lactacystin and bortezomib.
  • microtubule inhibitor/microtubule stabilizing agents include vincristine, vinblastine, vindesine, vinorelbine, vinorelbine, vindesine sulfate, 3', 4'-didehydro-4' - deoxy-8'-norvinine ditartrate, podophyllotoxin (eg etoposide (VP-16) and teniposide (VM-26)), paclitaxel, docetaxel, rhizomycin , tail sea rabbit, mivobulin isethionate, auristatin, simatin, RPR109881, BMS184476, vinflunine, cryptophycin, anhydrovinblastine, N, N-dimethyl-L-prolyl-L-prolyl- N-methyl-L-prolyl-L-prolyl-L-valine-tert-butylamide, TDX258, epothilone (see, e.g., U.S. Patent Nos
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitatecan, 6-ethoxypropionyl-3', 4'-O-exo-benzylidene-teaching bacteria , letoticon, 7-[2-(N-isopropylamino)ethyl]-(20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, cable Buzool, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl- 6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo [c]-phenanthridine
  • histone deacetylase inhibitors include, but are not limited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98, valproic acid, and scriptaid.
  • “Inhibitors of kinases involved in mitotic processes” include, but are not limited to, Aurora kinase inhibitors, Polo-like kinase inhibitors (PLK; in particular inhibitors of PLK-1), Bub-1 inhibitors and Bub-R1 inhibitors.
  • PLK Polo-like kinase inhibitor
  • Bub-1 inhibitors Bub-R1 inhibitors.
  • An example of an “Aurora kinase inhibitor” is VX-680.
  • Anti-proliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enesitabine, carmofur, fluridine, pentastatin, deoxygenation Fluorouridine, trimethoate, fludarabine, capecitabine, gallotine, cytarabine, fosteabine sodium hydrate, raltitrexed, paltitrexid, ethidium fluoride, thiazole carboxylate Amine nucleoside, decitabine, loratrix, pemetrexed, naribine, 2'-deoxy-2'-methylidene cytidine, 2'-fluoromethylene-2'- Oxycytidine, N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-prop
  • Non-limiting examples of suitable agents for use in combination with a compound of formula (I) for use in the treatment of cancer include, but are not limited to, abarelix; aldileukin; alemtuzumab; alibretin; allopurinol; Hexamethyl melamine; amifostine; anastrozole; arsenic trioxide; asparaginase; azacitidine; bendamustine; bevacizumab; bexarotene; spectabilin; bortezomib; Ans; captopril; capecitabine; carboplatin; carmustine; cetuximab; tumanning; cisplatin; cladribine; clofarabine; cyclophosphamide; Carbazine; dactinomycin, actinomycin D; dalteparin sodium; erythropoietin; dasatinib; daunorubicin; degarelix; din
  • the other therapeutic component or ingredients may be added as a salt, such as an alkali metal or amine salt or an acid, or a prodrug, or an ester such as a lower alkyl ester. Or in the form of a solvate such as a hydrate to optimize the activity and/or stability and/or physical properties of the therapeutic component, such as solubility. It is also clear that the therapeutic ingredients can be used in optically pure form, where appropriate.
  • a pharmaceutical composition comprising the above combination and a pharmaceutically acceptable diluent or carrier represents a further aspect of the invention.
  • These combinations are particularly useful for respiratory diseases and are suitable for inhalation or intranasal delivery.
  • the individual compounds of this combination may be administered sequentially or simultaneously in separate or combined pharmaceutical compositions.
  • each compound is administered simultaneously in the form of a combined pharmaceutical composition.
  • Suitable dosages of known therapeutic agents are readily apparent to those skilled in the art.
  • the compounds of the present invention can be prepared according to conventional methods in the art and using suitable reagents, starting materials, and purification methods known to those skilled in the art.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • 6-Bromo-N 2 -methylpyrazine-2,3-diamine (0.29 g, 1.44 mmol) was added to 5 mL of tetrahydrofuran under nitrogen, and carbonyl diimidazole (CDI, 0.7 g, 4.32) was slowly added in an ice bath. Methyl), stirred for 10 minutes, warmed to reflux overnight. After the reaction was completed, it was cooled to room temperature, and then transferred to an ice-bath, and the mixture was evaporated to EtOAc (EtOAc). The solid was 0.26 g, and the yield was 80%.
  • LC-MS (APCI): m / z 230 (M + 1) +.
  • 6-ethynyl-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (65 mg, 0.37 mmol) and compound 3 (160 mg, 0.31 mmol) , Pd(PPh 3 ) 4 (16 mg, 0.01 mmol), CuI (5 mg, 0.02 mmol) and 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C. 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated.
  • Lithium aluminum hydride (0.24 g, 6.2 mmol) was added to 10 mL of tetrahydrofuran, and the mixture was cooled to -5 ° C, and benzyl (2-amino-5-bromopyridin-3-yl)carbamate was added dropwise.
  • stirring was continued for 30 minutes, the ice bath was removed, and the reaction was carried out for 2 hours at room temperature. The reaction was completely detected by TLC. The reaction was quenched by slowly dropping 0.3 mL of water in an ice bath.
  • 6-Bromooxazolo[4,5-b]pyridine-2(3H)-one (0.25 g, 1.14 mmol) and trimethylsilylacetylene (0.15 g, 1.48 mmol), Pd(PPh 3 ) 4 (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, and then added with 20 mL of water, and the mixture was washed with ethyl acetate. .
  • LC-MS (APCI): m / z 233 (M + 1) +.
  • 6-ethynyloxazolo[4,5-b]pyridine-2(3H)-one 60 mg, 0.37 mmol
  • compound 3 160 mg, 0.31 mmol
  • Pd(PPh 3 ) 4 16 mg, 0.01 mmol
  • CuI 5 mg, 0.02 mmol
  • 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated, evaporated.
  • 6-Bromothiazolo[4,5-b]pyrazine-2(3H)-one (0.26 g, 1.14 mmol) and trimethylsilylacetylene (0.15 g, 1.48 mmol), Pd(PPh 3 ) 4 (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. .
  • LC-MS (APCI): m / z 250 (M + 1) +.
  • 6-ethynylthiazolo[4,5-b]pyrazine-2(3H)-one 65 mg, 0.37 mmol
  • compound 3 160 mg, 0.31 mmol
  • Pd(PPh 3 ) 4 16 mg, 0.01 mmol
  • CuI 5 mg, 0.02 mmol
  • 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc (EtOAc) was evaporated.
  • 6-Bromoisothiazolo[4,3-b]pyridin-3-amine (1.88g, 8.2mmol) was dissolved in 50mL of 85% phosphoric acid and 15mL concentrated nitric acid, cooled to -5 ° C in ice bath, slowly added 6mL An aqueous solution of sodium nitrite (0.6 g, 8.7 mmol) was added and the mixture was stirred at -5 ° C for 30 minutes.
  • Reagents and consumables ABL (ThermoFisher, Cat. No PV3585), ABL T315I (Thermo Fisher, Cat. No. PR7429B), ATP (Sigma, Cat. No. A7699-1G), DMSO (Sigma, Cat. No. D2650) , 96-well plates (Corning, Cat. No. 3365), 384-well plates (Greiner, Cat. No. 784076), buffer (Thermo Fisher, Cat. No. PR4876B).
  • test compound was dissolved in DMSO to make a 20 mM mother liquor.
  • Compounds were diluted to 0.1 mM in DMSO prior to use and diluted 3 times in 3 fold increments. When dosing, dilute with buffer to 4 times the final concentration of the dilution.
  • Kinase detection method After preparing the buffer, the enzyme is mixed with different concentrations of the compound prepared by pre-diluting, and left at room temperature for 30 minutes, and each concentration is double-replicated. The corresponding substrate and ATP were added and reacted at room temperature for 60 minutes (in which a negative positive control was set). After the reaction was completed, the antibody was added for detection. After incubation at room temperature for 60 minutes, Evnvision was detected and data was collected. Data analysis and mapping according to XLfit5 software.
  • RPMI-1640 medium (GIBCO, catalog number A10491-01), fetal bovine serum (GIBCO, catalog number 10099141), antibiotic (Penicillin-Streptomycin), IL-3 (PeproTech), puromycin; cell line : Ba/F3, Ba/F3Bcr-Abl T315I (purchased from American Standard Biological Collection Center, ATCC), live cell assay kit CellTiter-Glo4 (Promega, catalog number G7572), 96-well black-wall clear flat-bottom cell culture plate ( Corning, catalog number 3340).
  • Example number Ba/F3 IC 50 Ba/F3Bcr-Abl T315I IC 50 Example 1 D B
  • Example 4 D C Example 5 D - Example 6 D A
  • Example 7 D B Example 8 D B
  • Example 9 D B Example 10 D B
  • Example 11 D C Example 12 D B
  • the compound of the present invention exhibits a relatively low inhibitory activity against Ba/F3 associated with drug side effects (IC 50 is greater than 1000 nM), and exhibits excellent inhibitory activity against cells of the Ba/F3Bcr-Abl T315I mutant (IC). 50 ⁇ 100 nM or 100 nM ⁇ IC 50 ⁇ 500 nM), therefore, the compound of the present invention can be used as a Bcr-Abl inhibitor for tumor patients suffering from resistance or resistance to tyrosine kinase inhibitor (TKI) treatment, such as chronic granulocytes. Chronic, blast, and accelerated patients with leukemia (CML) and Philadelphia chromosome-positive (Ph + ) chronic myeloid leukemia and acute lymphoblastic leukemia patients have good prospects.
  • TKI tyrosine kinase inhibitor
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 in supernatant was taken into a 96-well plate pre-charged with 100 ⁇ L of distilled water, mixed, and sample analysis was performed by LC-MS/MS.
  • Control group reference compound
  • Test group Example compounds, comparing their pharmacokinetic differences.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 4 5,000 rpm for 5 minutes to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the compounds of the present invention were tested in the pharmacokinetic experiments of the above rats, and the compounds of the present invention were found to have excellent pharmacokinetic properties.

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Abstract

La présente invention concerne des composés hétérocycliques d'alcynyle ayant des effets inhibiteurs sur l'activité de la protéine kinase, leur préparation et leur utilisation. En particulier, l'invention concerne des composés hétérocycliques d'alcynyle représentés par la formule (I) et une composition pharmaceutique comprenant les composés, un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate, un hydrate, une forme cristalline, un promédicament, ou un variant d'isotope de celui-ci. Les composés de la présente invention peuvent servir d'inhibiteurs de protéine kinase pour préparer des médicaments antitumoraux.
PCT/CN2017/105789 2016-10-13 2017-10-12 Composé hétérocyclique d'alcynyle pour inhiber l'activité de la protéine kinase Ceased WO2018068739A1 (fr)

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CN113307810A (zh) * 2021-03-31 2021-08-27 安徽珐诺伊医药科技有限公司 一种2,4氟-吡咯[1,2]嘧啶-7甲腈的合成方法及应用
CN113214182A (zh) * 2021-05-19 2021-08-06 佛山湘潭大学绿色智造研究院 一种苯并异噻唑类化合物及其制备方法
CN113214182B (zh) * 2021-05-19 2022-12-23 佛山湘潭大学绿色智造研究院 一种苯并异噻唑类化合物及其制备方法

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