WO2023088291A1 - 一种芳香胺化合物及其应用 - Google Patents

一种芳香胺化合物及其应用 Download PDF

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WO2023088291A1
WO2023088291A1 PCT/CN2022/132214 CN2022132214W WO2023088291A1 WO 2023088291 A1 WO2023088291 A1 WO 2023088291A1 CN 2022132214 W CN2022132214 W CN 2022132214W WO 2023088291 A1 WO2023088291 A1 WO 2023088291A1
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disease
aromatic amine
compound
amine compound
bcr
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French (fr)
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张玉慧
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武汉众诚康健生物医药科技有限公司
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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Definitions

  • the invention belongs to the field of medicinal chemistry, and more specifically relates to an aromatic amine compound and its application.
  • Aromatic amine compounds refer to amines with an aromatic substituent, ie -NH2, -NH or a nitrogen-containing group linked to an aromatic hydrocarbon.
  • the structure of aromatic hydrocarbons usually contains one or more benzene rings, that is, there are chemical bonds between the nitrogen atoms and the carbon atoms of the benzene rings.
  • Aromatic amine molecules have high reactivity, widely exist in many natural products, and are an important class of bioactive molecules.
  • aromatic amine compounds have been found to play an important role in biological metabolic pathways, and may be a variety of important protein kinase inhibitors with important biological functions.
  • the present invention provides an aromatic amine compound and applications thereof, the purpose of which is to discover its inhibition of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 fusion protein inhibitor BCR-ABL1 fusion protein inhibitor
  • an aromatic amine compound which is a compound of general formula (I) and/or its isomers:
  • R is a 5 to 10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;
  • R is a 5 to 6 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, -C(O)R 6 , -C(O)NHR 6 ; -S(O 2 ) R 6 or -(CH 2 ) r -4 to 7 membered heterocycle; r is 0, 1 or 2;
  • R 6 is selected from C 1-4 alkyl or C 3-6 cycloalkyl
  • Y is N or CH.
  • the R 1 is a 5 to 8 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S; wherein the 5 to 8 membered heteroaryl group is unsubstituted or substituted with 1 R4 group.
  • the R 1 is a 5-6 membered heteroaryl group containing 1 to 3 N atoms; wherein the 5-6 membered heteroaryl group is unsubstituted or replaced by 1 Each R 4 group is substituted.
  • the R 1 is a 5-6 membered heteroaryl group containing 1 to 2 N atoms; wherein the 5-6 membered heteroaryl group is unsubstituted or replaced by 1 Each R 4 group is substituted.
  • the R 4 is selected from halogen or C 1-4 alkyl.
  • the R is selected from pyrazolyl, pyridyl, pyrimidinyl, 4-fluoropyrazolyl, 4-methylpyrazolyl, 3-methylpyrazolyl , 3-fluoropyridyl, 4-methylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl.
  • the R is selected from
  • the 5 to 6 membered heterocyclic group is substituted by 1 to 2 R 5 groups, and R 5 is selected from hydroxyl, methyl, halogen, methoxy, hydroxy-methyl base, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutyl acyl)oxy or amino-carbonyl.
  • the R 2 is a 5-6 membered heterocyclic group containing 1 to 3 N atoms; wherein the 5-6 membered heterocyclic group is replaced by 1 to 2 R 5 group substitution.
  • the R 2 is a 5-6 membered heterocyclic group containing 1 N atom.
  • the 5- to 6-membered heterocyclic group is substituted by one R 5 group.
  • the R 5 is selected from hydroxyl, methyl, halogen, methoxy, or hydroxyl-methyl.
  • the R 5 is selected from hydroxyl, methoxy, or hydroxyl-methyl.
  • the R 5 is selected from hydroxyl.
  • the R2 is selected from 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3,4-dihydroxypyrrolidinyl, or 3-hydroxyl-4- Hydroxymethylpiperidine.
  • the R2 is selected from
  • the R 3 includes a carbon atom and 1 to 4 heteroatoms selected from N, O and S(O) p ; p is 0, 1 or 2.
  • the R 3 is selected from hydrogen; C 1-4 alkyl; C 1-4 haloalkyl; C 3-6 cycloalkyl or -C(O)R 6 .
  • the R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or -C(O)R 6 .
  • the R 3 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or -C(O)R 6 .
  • the R 3 is selected from hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl.
  • the R 3 is selected from hydrogen or C 1-4 alkyl.
  • R 3 is selected from hydrogen.
  • the aromatic amine compound has the following molecular formula:
  • the aromatic amine compound and its isomers include enantiomers, diastereomers, cis-trans isomers, and interconversion Isomer; any asymmetric carbon atom in the isomer can exist in (R)-, (S)- or (R, S)-configuration, preferably (R)- or (S)-configuration;
  • a pharmaceutical composition is provided, the active ingredient of which contains one or more combinations of aromatic amine compounds and pharmaceutically acceptable salts thereof provided in the present invention.
  • the pharmaceutical composition includes pharmaceutically acceptable excipients.
  • the pharmaceutical composition its pharmaceutically acceptable auxiliary materials include excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants agents, sweeteners and/or flavoring agents.
  • the excipient is an excipient formulated into a solid, semi-solid, liquid or gaseous preparation; the solid, semi-solid, liquid or gaseous preparation such as tablet, pill, capsule Agents, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • aromatic amine compound and its prodrug derivative, its derivative, and/or its pharmaceutically acceptable salt in the preparation of a drug for treating diseases in animals Application, which is applied to the preparation of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric protein inhibitors.
  • said application is applied to the preparation of BCR-ABL1 fusion protein inhibitors.
  • the said application is applied to the preparation of drugs against diseases related to abnormal activity of BCR-ABL1 fusion protein.
  • the disease associated with abnormal activity of the BCR-ABL1 fusion protein is a disease in which the activity of the BCR-ABL1 fusion protein contributes to the pathology and/or symptoms of the disease.
  • the disease related to the abnormal activity of the BCR-ABL1 fusion protein is a non-malignant disease, including CNS disease, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia Cellular leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases, viral infections, or CNS disorders.
  • CNS disease including CNS disease, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia Cellular leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases, viral infections, or CNS disorders.
  • diseases related to abnormal activity of the BCR-ABL1 fusion protein include neurodegenerative diseases, motor neuron diseases, muscular dystrophy, autoimmune diseases and inflammatory diseases, viral infections, prion diseases, chronic Myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and gastrointestinal stromal tumor; said neurodegenerative disease, such as Alzheimer's disease, or Parkinson's disease; said motor neuron disease, such as Amyotrophic lateral sclerosis; such inflammatory diseases as diabetes and pulmonary fibrosis.
  • the aromatic amine compounds provided by the invention can effectively inhibit the tyrosine kinase enzyme activity of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, especially BCR-ABL1, and can be applied to the preparation of Abelson protein (ABL1), Abelson-associated protein (ABL2) and related chimeric protein inhibitors are used as drugs against diseases related to abnormal activity of BCR-ABL1 fusion protein.
  • ABL1 Abelson protein
  • ABL2 Abelson-associated protein
  • related chimeric protein inhibitors are used as drugs against diseases related to abnormal activity of BCR-ABL1 fusion protein.
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by substituents, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5 to 6 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrazolyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzopyrazole, pyridopyrazole, pyrimidopyrazole, etc.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and that can exist as a monocyclic, bridged, or spiro ring.
  • Non-limiting examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, azacyclopentyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazine Base, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, etc.
  • alkyl refers to a branched or straight chain hydrocarbon group having 1 to 7 carbon atoms (C 1-7 alkyl) or 1 to 4 carbon atoms (C 1-4 alkyl).
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- -nonyl, n-decyl and the like.
  • a substituted alkyl group is an alkyl group containing one or more substituents, such as 1, 2 or 3, selected from halogen, hydroxy or alkoxy.
  • Halogen-substituted alkyl and halogen-substituted alkoxy may be straight or branched and include methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy group, trifluoromethoxy group, etc.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl refers to a substituted alkyl group having one or more halo substituents.
  • haloalkyl includes mono-, di- and trifluoromethyl.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl, bicyclo[1.1.1]pent-1-yl, etc.
  • C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • BCR-ABL1 refers to a fusion protein formed by the N-terminal exon of the breakpoint cluster region (BCR) gene and the major C-terminal part (exons 2-11) of the Abelson (ABL1) gene.
  • the most common fusion transcript encodes a 210-kDa protein (p210BCR-ABL1), although more rare transcripts encode a 190-kDa protein (p190BCR-ABL1) and a 230-kDa protein (p230BCR-ABL1).
  • the ABL1 sequences of these proteins contain an ABL1 tyrosine kinase domain that is tightly regulated in the wild-type protein but constitutively activated in the BCR-ABL1 fusion protein. This dysregulated tyrosine kinase interacts with a variety of cell signaling pathways leading to dysregulation of cellular transformation and proliferation.
  • BCR-ABL1 mutant refers to numerous single-site mutations in BCR-ABL1, including: Glu255 ⁇ Lysine, Glu255 ⁇ Valine, Thr315 ⁇ Isoleucine, Met244 ⁇ Val, Phe317 ⁇ Leu, Leu248 ⁇ Val, Met343 ⁇ Thr, Gly250 ⁇ Ala, Met351 ⁇ Thr, Gly250 ⁇ Glu, Glu355 ⁇ Gly, Gln252 ⁇ His, Phe358 ⁇ Ala, Gln252 ⁇ Arg, Phe359 ⁇ Val, Tyr253 ⁇ His, Val379 ⁇ Ile, Tyr253 ⁇ Phe , Phe382 ⁇ Leu, Glu255 ⁇ Lys, Leu387 ⁇ Met, Glu255 ⁇ Val, His396 ⁇ Pro, Phe311 ⁇ Ile, His396 ⁇ Arg, Phe311 ⁇ Leu, Ser417 ⁇ Tyr, Thr315 ⁇ Ile, Glu459 ⁇ Lys, and Phe486 ⁇ Ser.
  • the tyrosine kinase activity of ABL1 protein is normally tightly regulated, and the N-terminal cap region of the SH3 domain plays an important role here.
  • One regulatory mechanism involves myristoylation of the N-terminal cap glycine-2 residue, which then interacts with the myristate-binding site in the SH1 catalytic domain.
  • CML chronic myeloid leukemia
  • Ph Philadelphia chromosome
  • BCR-ABL1 oncogene which encodes a lack of N-terminal cap and Chimeric BCR-ABL1 protein with a constitutively active tyrosine kinase domain.
  • drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via an ATP-competitive mechanism such as imatinib, nilotinib, and dasatinib
  • imatinib, nilotinib, and dasatinib are effective in the treatment of CML
  • some patients suffer from whereas relapses, in which mutations in the SH1 domain attenuate inhibitory binding.
  • nilotinib and dasatinib are effective against multiple imatinib-resistant mutations in BCR-ABL1
  • the T315I mutation is insensitive to all three drugs and can lead to drug resistance. Therefore, there remains an unmet clinical need to inhibit BCR-ABL1 mutations such as T315I.
  • BCR-ABL1 fusion proteins are responsible for a proportion of acute lymphoblastic leukemias, and drugs targeting ABL kinase activity are also effective in this indication.
  • Compounds from the present invention also have the potential to treat or prevent diseases associated with abnormally activated kinase activity of wild-type ABL1 where BCR-ABL1 fusion protein activity contributes to the pathology and/or symptoms of the disease, preferably
  • the diseases related to the abnormal activity of the BCR-ABL1 fusion protein are non-malignant diseases, including CNS diseases, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal mesenchymal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other proliferative or proliferative diseases, viral infections or CNS disorders; more preferably neurodegenerative diseases, motor neuron diseases, muscular dystrophy, autoimmune diseases and inflammatory diseases, viral infections, prion diseases, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic
  • the invention provides an aromatic amine compound, which can be used as an inhibitor of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, especially the tyrosine kinase of BCR-ABL1.
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • ABL2 Abelson-related protein
  • chimeric proteins especially the tyrosine kinase of BCR-ABL1.
  • R 1 is a 5 to 10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S; wherein the 5 to 10 membered heteroaryl group is unsubstituted or replaced by 1 to 4 R 4 group substitution;
  • R 2 is a 5 to 6 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; wherein the 5 to 6 membered heterocyclic group is substituted by 1 to 2 R groups;
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, -C(O)R 6 , -C(O)NHR 6 ; -S(O 2 ) R 6 or -(CH 2 ) r -4 to 7-membered heterocyclic ring; it contains carbon atoms and 1 to 4 heteroatoms selected from N, O and S(O) p ;
  • p 0, 1 or 2;
  • r 0, 1 or 2;
  • R is selected from hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl -amino, dimethyl-amino, 2-amino-3-methylbutyryl)oxy or amino-carbonyl;
  • R 6 is selected from C 1-4 alkyl or C 3-6 cycloalkyl.
  • the Y is N. In some embodiments, the Y is CH.
  • R is a 5 to 8 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein the 5 to 8 membered heteroaryl is unsubstituted or replaced by 1 R 4 group substitution;
  • R is a 5 to 8 membered heteroaryl containing 1 to 4 N atoms; wherein the 5 to 8 membered heteroaryl is unsubstituted or substituted with 1 R group;
  • R is a 5 to 6 membered heteroaryl containing 1 to 3 N atoms; wherein the 5 to 6 membered heteroaryl is unsubstituted or substituted with 1 R group;
  • R is a 5 to 6 membered heteroaryl containing 1 to 2 N atoms; wherein said 5 to 6 membered heteroaryl is unsubstituted or substituted with 1 R group;
  • R 4 is selected from halogen or C 1-4 alkyl.
  • R is selected from pyrazolyl, pyridyl, pyrimidinyl, 4-fluoropyrazolyl, 4-methylpyrazolyl, 3-methylpyrazolyl, 3-fluoropyridyl, 4-methylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl;
  • R is selected from
  • R is a 5 to 6 membered heterocyclyl containing 1 to 3 N atoms; wherein the 5 to 6 membered heterocyclyl is substituted by 1 to 2 R groups;
  • R is a 5-6 membered heterocyclyl containing 1 N atom; wherein the 5-6 membered heterocyclyl is substituted by 1 to 2 R groups;
  • R 2 is a 5-6 membered heterocyclyl containing 1 N atom; wherein the 5-6 membered heterocyclyl is substituted by 1 R 5 group;
  • R is selected from hydroxy, methyl, halo, methoxy, or hydroxy-methyl
  • R is selected from hydroxy, methoxy, or hydroxy-methyl
  • R is selected from hydroxyl ;
  • R is selected from 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3,4-dihydroxypyrrolidinyl, or 3-hydroxy-4-hydroxymethylpiperidine.
  • R is selected from
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or —C(O)R 6 .
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or —C(O)R 6 .
  • R 3 is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl.
  • R 3 is selected from hydrogen or C 1-4 alkyl.
  • R is selected from hydrogen
  • the aromatic compound has the following molecular formula:
  • tautomers thereof and/or (preferably pharmaceutically acceptable) salts thereof especially means that the compound of formula (I) can exist as such or as tautomers (for example due to keto-ene alcohol, lactam-lactam, amide-imidic acid or enamine-imine tautomerism) or (e.g. resulting from equivalent reactions) mixed with their tautomers, or as formula (I ) exists as a salt of the compound and/or as any one of these forms or as a mixture of two or more of said forms.
  • Said aromatic compounds also include said aromatic amine compounds which are the same as those described herein, but one or more atoms are replaced by atoms with atomic weight or mass number different from the atomic weight or mass number usually found in nature.
  • isotopes that can be bound to the aromatic amine compound include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, respectively. , 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled aromatic amine compounds such as those labeled with3H and14C are useful in compound and/or substrate tissue distribution assays. Tritiated ( ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled aromatic amine compounds can generally be prepared by the following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.
  • the aromatic amine compound may be asymmetric, eg, have one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • the compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
  • a pharmaceutical composition preferably also includes pharmaceutically acceptable excipients
  • the pharmaceutically acceptable Adjuvants include excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents;
  • the excipient is an excipient formulated into a solid, semi-solid, liquid or gaseous preparation; the solid, semi-solid, liquid or gaseous preparation is such as tablet, pill, capsule, powder, granule, ointment, emulsion , suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the aromatic amine compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, peritoneal Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition can be produced by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, freeze-drying and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may vary, depending on various factors, including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • a compound of the present application may be provided for parenteral administration as an aqueous physiologically buffered solution containing about 0.1-10% w/v of the compound.
  • Some typical dosages range from about 1 ⁇ g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • ABL2 Abelson-related protein
  • related chimeric protein inhibitors especially for the preparation of BCR-ABL1 fusion protein inhibitors
  • the disease associated with abnormal activity of the BCR-ABL1 fusion protein is a disease in which the activity of the BCR-ABL1 fusion protein contributes to the pathology and/or symptoms of the disease.
  • the diseases related to the abnormal activity of the BCR-ABL1 fusion protein are non-malignant diseases, including CNS diseases, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal mesenchymal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other proliferative or proliferative diseases, viral infections or CNS disorders;
  • CNS diseases chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal mesenchymal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other proliferative or proliferative diseases, viral infections or CNS disorders;
  • neurodegenerative diseases include Alzheimer's disease, or Parkinson's disease; said motor neuron disease such as amyotrophic lateral sclerosis; said inflammatory disease such as diabetes and pulmonary fibrosis.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art In an equivalent alternative, preferred implementations include but are not limited to the examples of the present application.
  • the compounds of the present application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:
  • R 1 , R 2 and R 3 are the same as in formula (I).
  • NBS N-bromosuccinimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • DIPEA N,N-diisopropylethylamine
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • DMF N,N-di methylformamide
  • DCM diichloromethane
  • NIS N-iodosuccinimide
  • Embodiment 2 (R)-N-(4-(one chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-2-(methylamino)-5-( 1H-pyrazol-5-yl) nicotinamide (compound 2)
  • Embodiment 4 compound 1 (method two)
  • ABL001 is a marketed drug asciminib.
  • mice weighing 18-22 g were selected, and after 3-5 days of adaptation, they were randomly divided into groups, 9 mice in each group, and given the compound solution by intragastric administration at a dose of 10 mg/kg.
  • intragastric administration On the day of grouping (d0 day), intragastric administration was started, and the administration volume was 2ml/kg. Intragastric administration twice a day, continuous administration, the tumor volume was measured 2-3 times a week, and weighed at the same time; the general performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.
  • Tumor volume, TV (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ); a is the long axis, b is the short axis.
  • TV 0 is the tumor volume on day d0, and
  • TV t is the tumor volume at each measurement.
  • T/C (%) T RTV /C RTV ⁇ 100%, T RTV : RTV of the treatment group; C RTV : RTV of the control group.
  • the test results are shown in Table 5.
  • the compound of table 5 is to the impact of human chronic myeloid leukemia Ba/F3 BCR-ABL T315I nude mouse subcutaneous xenograft tumor (d17)

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Abstract

本发明公开了一种芳香胺化合物及其应用，所述芳香胺类化合物能有效抑制Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白、特别是BCR-ABL1的酪氨酸激酶酶活性，能应用于制备Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白抑制剂，用作抗BCR-ABL1融合蛋白活性异常相关疾病的药物。

Description

一种芳香胺化合物及其应用 技术领域
本发明属于药物化学领域，更具体地，涉及一种芳香胺化合物及其应用。
背景技术
芳香胺类化合物是指具有一个芳香性取代基的胺，即-NH2、-NH或含氮基团连接到一个芳香烃上。芳香烃的结构中通常含有一个或多个苯环，即氮原子与苯环碳原子之间有化学键直接相连接。芳香胺分子反应活性较高，广泛存在于许多天然产物中，是一类重要的生物活性分子。
许多芳香胺类化合物，被发现在生物代谢通路上扮演重要角色，可能为多种重要的蛋白激酶抑制剂，具有重要的生物学功能。芳香胺类化合物的药用研究，包括芳胺类和芳烃胺类，一直是药物研究的热点。
发明内容
针对现有技术的以上缺陷或改进需求，本发明提供了一种芳香胺化合物及其应用，其目的在于发现其对于Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白的抑制作用，尤其是可作为BCR-ABL1融合蛋白抑制剂，应用于制备抗BCR-ABL1融合蛋白活性异常相关疾病的药物。
为实现上述目的，按照本发明的一个方面，提供了一种芳香胺类化合物，其为具有通式(I)的化合物和/或其异构体：
Figure PCTCN2022132214-appb-000001
其中，
R 1是含有1至4个选自N、O和S的杂原子的5至10元杂芳基；
R 2是含有1至3个选自N、O和S的杂原子的5至6元杂环基；
R 3选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、-C(O)R 6、-C(O)NHR 6；-S(O 2)R 6或-(CH 2) r-4至7元杂环；r为0、1或2；
R 6选自C 1-4烷基或C 3-6环烷基；
Y为N或CH。
优选地，所述芳香胺类化合物，其所述5至10元杂芳基是未被取代的或被1至4个R 4基团取代，R 4选自卤素、＝O、OH、CN、NH 2、NO 2、C 1-4烷基、C 1-4卤代烷基或C 3-6环烷基；
优选地，所述芳香胺类化合物，其所述R 1是含有1至4个选自N、O和S的杂原子的5至8元杂芳基；其中所述5至8元杂芳基是未被取代的或被1个R 4基团取代。
优选地，所述芳香胺类化合物，其所述R 1是含有1至3个N原子的5至6元杂芳基；其中所述5至6元杂芳基是未被取代的或被1个R 4基团取代。
优选地，所述芳香胺类化合物，其所述R 1是含有1至2个N原子的5至6元杂芳基；其中所述5至6元杂芳基是未被取代的或被1个R 4基团取代。
优选地，所述芳香胺类化合物，其所述R 4选自卤素、＝O、OH、CN、NH 2、NO 2、或C 1-4烷基。
优选地，所述芳香胺类化合物，其所述R 4选自卤素、＝O、OH、CN、NH 2、或C 1-4烷基。
优选地，所述芳香胺类化合物，其所述R 4选自卤素、＝O、OH、或C 1-4烷基。
优选地，所述芳香胺类化合物，其所述R 4选自卤素或C 1-4烷基。
优选地，所述芳香胺类化合物，其所述R 1选自吡唑基、吡啶基、嘧啶基、4-氟代吡唑基、4-甲基吡唑基、3-甲基吡唑基、3-氟吡啶基、4-甲基嘧啶基、3-氰基嘧啶基、或2-甲氧基-3-氰基嘧啶基。
优选地，所述芳香胺类化合物，其所述R 1选自
Figure PCTCN2022132214-appb-000002
Figure PCTCN2022132214-appb-000003
优选地，所述芳香胺类化合物，其所述5至6元杂环基是被1至2个R 5基团取代，R 5选自羟基、甲基、卤素、甲氧基、羟基-甲基、氨基、甲基-氨基、氨基-甲基、三氟甲基、2-羟基丙-2-基、甲基-羰基-氨基、二甲基-氨基、2-氨基-3-甲基丁酰基)氧基或氨基-羰基。
优选地，所述芳香胺类化合物，其所述R 2是含有1至3个N原子的5至6元杂环基；其中所述5至6元杂环基是被1至2个R 5基团取代。
优选地，所述芳香胺类化合物，其所述R 2是含有1个N原子的5至6元杂环基。
优选地，所述芳香胺类化合物，其所述5至6元杂环基是被1个R 5基团取代。
优选地，所述芳香胺类化合物，其所述R 5选自羟基、甲基、卤素、甲氧基、或羟基-甲基。
优选地，所述芳香胺类化合物，其所述R 5选自羟基、甲氧基、或羟基-甲基。
优选地，所述芳香胺类化合物，其所述R 5选自羟基。
优选地，所述芳香胺类化合物，其所述R 2选自3-羟基吡咯烷基、3-羟甲基吡咯烷基、3，4-二羟基吡咯烷基、或3-羟基-4-羟甲基哌啶。
优选地，所述芳香胺类化合物，其所述R 2选自
Figure PCTCN2022132214-appb-000004
Figure PCTCN2022132214-appb-000005
优选地，所述芳香胺类化合物，其所述R 3包含碳原子及1至4个选自N、O和S(O) p的杂原子；p为0、1或2。
优选地，所述芳香胺类化合物，其所述R 3选自氢；C 1-4烷基；C 1-4卤代烷基；C 3-6环烷基或-C(O)R 6。
优选地，所述芳香胺类化合物，其所述R 3选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或-C(O)R 6。
优选地，所述芳香胺类化合物，其所述R 3选自氢、C 1-4烷基、C 3-6环烷基或-C(O)R 6。
优选地，所述芳香胺类化合物，其所述R 3选自氢、C 1-4烷基或C 3-6环烷基。
优选地，所述芳香胺类化合物，其所述R 3选自氢或C 1-4烷基。
优选地，所述芳香胺类化合物，其R 3选自氢。
优选地，所述芳香胺类化合物，其所述芳香类化合物具有以下分子式：
Figure PCTCN2022132214-appb-000006
优选地，所述芳香胺类化合物，其所述异构体，包括具有通式(I)芳香胺化合物的对映异构体、非对映异构体、顺反异构体、以及互变异构体；所述异构体中任意不对称碳原子可以以(R)-、(S)-或(R，S)-构型存在，优选(R)-或(S)-构型；所述顺反异构体指位于双键或者尤其环上的取代基为以顺式-(＝Z-)或反式(＝E-)形式存在。
按照本发明的另一个方面，提供了一种药物组合物，其活性成分含有本发明提供的芳香胺化合物及其可药用的盐中的一种或多种的组合。
优选地，所述药物组合物，其包括药学上可接受的辅料。
优选地，所述药物组合物，其所述药学上可接受的辅料包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂。
优选地，所述药物组合物，其所述赋形剂为配制成固态、半固态、液态或气态制剂的赋形剂；所述固态、半固态、液态或气态制剂如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
按照本发明的另一个方面，提供了所述的芳香胺类化合物及其前药衍生物、其衍生物、和/或其可药用的盐在制备用于在动物中治疗疾病的药物中的应用，其应用于制备Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白抑制剂。
优选地，所述应用，其应用于制备BCR-ABL1融合蛋白抑制剂。
优选地，所述应用，其应用于制备抗BCR-ABL1融合蛋白活性异常相关疾病的药物。
优选地，所述应用，其所述BCR-ABL1融合蛋白活性异常相关疾病为BCR-ABL1融合蛋白活性有助于该疾病的病状和/或症候的疾病。
优选地，所述应用，其所述BCR-ABL1融合蛋白活性异常相关疾病为非恶性疾病，包括CNS疾病、慢性髓系白血病、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病、病毒感染或CNS障碍。
优选地，所述应用，其所述BCR-ABL1融合蛋白活性异常相关疾病，包括神经变性疾病、运动神经元病、肌营养不良、自身免疫疾病和炎症性疾病、病毒感染、朊病毒病、慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病以及胃肠道间质瘤；所述神经变性疾病例如阿尔茨海默病、或帕金森病；所述运动神经元病例如肌萎缩侧索硬化；所述炎症性疾病例如糖尿病和肺纤维化。
总体而言，通过本发明所构思的以上技术方案与现有技术相比，能够取得下列有益效果：
本发明提供的芳香胺类化合物，能有效抑制Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白、特别是BCR-ABL1的酪氨酸激酶酶活性，能应用于制备Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白抑制剂，用作抗BCR-ABL1融合蛋白活性异常相关疾病的药物。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。此外，下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
术语和定义：
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个5至6元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡唑基、嘧啶基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并吡唑、吡啶并吡唑、嘧啶并吡唑等。
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。杂环基的非限制性实例包括但不限于四氢呋喃基、二氢呋喃基、吡咯烷基、氮杂环戊烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。
术语“烷基”是指具有1至7个碳原子(C 1-7烷基)或1至4个碳原子(C 1-4烷基)的支链或直链的烃基。烷基的代表性的实例包括但不限于甲基、乙基、正-丙基、异-丙基、正-丁基、仲-丁基、异-丁基、叔丁基、正-戊基、异戊基、新戊基、正-己基、3-甲基己基、2，2-二甲基戊基、2，3-二甲基戊基、正-庚基、正-辛基、正-壬基、正-癸基等。被取代的烷基是含一个或多个诸如1、2或3个选自卤素、羟基或烷氧基的取代基的烷基。卤素取代的烷基和卤素取代的烷氧基可以是直链或支链的，并包括甲氧基、乙氧基、二氟甲基、三氟甲基、五氟乙基、二氟甲氧基、三氟甲氧基等。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“卤代烷基”是指具有一或多个卤素取代基的被取代的烷基。例如，“卤代烷基”包括单-、二-和三氟甲基。
术语“环烷基”指完全饱和的并且可以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。例如，C 3-4环烷基包括环丙基和环丁基。
“BCR-ABL1”是指由裂点簇区(BCR)基因的N-端外显子和Abelson(ABL1)基因的主要的C-端部分(外显子2–11)形成的融合蛋白。最常见的融合转录物编码210-kDa蛋白质(p210BCR-ABL1)，虽然更罕见的转录物编码190-kDa蛋白质(p190BCR-ABL1)和230-kDa蛋白质(p230BCR-ABL1)。这些蛋白的ABL1序列包含在野生型蛋白质中严格调节、但在BCR-ABL1融合蛋白中组成性激活的ABL1酪氨酸激酶域。该失调的酪氨酸激酶与多种导致细胞转化和增殖失调的细胞信号传导通路相互作用。
“BCR-ABL1突变体”是指BCR-ABL1中的众多单一位点突变，包括:Glu255→赖氨酸、Glu255→缬氨酸、Thr315→异亮氨酸、Met244→Val、Phe317→Leu、Leu248→Val、Met343→Thr、Gly250→Ala、Met351→Thr、Gly250→Glu、Glu355→Gly、Gln252→His、Phe358→Ala、Gln252→Arg、Phe359→Val、Tyr253→His、Val379→Ile、Tyr253→Phe、Phe382→Leu、Glu255→Lys、Leu387→Met、Glu255→Val、His396→Pro、Phe311→Ile、His396→Arg、Phe311→Leu、Ser417→Tyr、Thr315→Ile、Glu459→Lys和Phe486→Ser。
ABL1蛋白的酪氨酸激酶活性通常受到严格调节，SH3域的N-端帽区在此起重要作用。一个调节机制涉及将N-端帽甘氨酸-2残基肉豆蔻酰化，然后与SH1催化结构域中的肉豆蔻酸酯结合部位相互作用。慢性髓系白血病(CML)的一个标志是费城染色体(Ph)由造血干细胞中的t(9，22)染色体相互易位形成，该染色体携带BCR-ABL1癌基因，其编码缺乏N-端帽并具有组成性激活的酪氨酸激酶域的嵌合的BCR-ABL1蛋白。尽管 经由ATP-竞争性机制抑制BCR-ABL1的酪氨酸激酶活性的药物、诸如伊马替尼、尼洛替尼和达沙替尼在治疗CML中有效，但一些患者由于耐药性的出现而复发，其中SH1域中的突变减弱了抑制结合。尽管尼洛替尼和达沙替尼对BCR-ABL1的多种伊马替尼耐药突变有效，但其中T315I突变对所有三种药物都不敏感，且能导致耐药。因此，对抑制BCR-ABL1突变(例如T315I)仍有未满足的临床需求。除CML之外，BCR-ABL1融合蛋白还是一定比例的急性淋巴细胞白血病的原因，且靶向ABL激酶活性药物在该适应症中也具有疗效。
来自本发明的化合物还具有治疗或预防与野生型ABL1的异常激活的激酶活性相关疾病的潜力，所述疾病为BCR-ABL1融合蛋白活性有助于该疾病的病状和/或症候的疾病，优选所述BCR-ABL1融合蛋白活性异常相关疾病为非恶性疾病，包括CNS疾病、慢性髓系白血病、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病、病毒感染或CNS障碍；进一步优选神经变性疾病、运动神经元病、肌营养不良、自身免疫疾病和炎症性疾病、病毒感染、朊病毒病、慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病以及胃肠道间质瘤；所述神经变性疾病例如阿尔茨海默病、或帕金森病；所述运动神经元病例如肌萎缩侧索硬化；所述炎症性疾病例如糖尿病和肺纤维化。
本发明提供了一种芳香胺类化合物，可用作Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白、特别是BCR-ABL1的酪氨酸激酶的抑制剂，为具有通式(I)的化合物和/或其异构体：
Figure PCTCN2022132214-appb-000007
其中，
R 1是含有1至4个选自N、O和S的杂原子的5至10元杂芳基；其中所述5至10元杂芳基是未被取代的或被1至4个R 4基团取代；
R 2是含有1至3个选自N、O和S的杂原子的5至6元杂环基；其中所述5至6元杂环基是被1至2个R 5基团取代；
R 3选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、-C(O)R 6、-C(O)NHR 6；-S(O 2)R 6或-(CH 2) r-4至7元杂环；其包含碳原子及1至4个选自N、O和S(O) p的杂原子；
p为0、1或2；
r为0、1或2；
R 4选自卤素、＝O、OH、CN、NH 2、NO 2、C 1-4烷基、C 1-4卤代烷基或C 3-6环烷基；
R 5选自羟基、甲基、卤素、甲氧基、羟基-甲基、氨基、甲基-氨基、氨基-甲基、三氟甲基、2-羟基丙-2-基、甲基-羰基-氨基、二甲基-氨基、2-氨基-3-甲基丁酰基)氧基或氨基-羰基；
R 6选自C 1-4烷基或C 3-6环烷基。
在一些实施方案中，所述Y为N。在一些实施方案中，所述Y为CH。
在一些实施方案中，R 1是含有1至4个选自N、O和S的杂原子的5至8元杂芳基；其中所述5至8元杂芳基是未被取代的或被1个R 4基团取代；
在一些实施方案中，R 1是含有1至4个N原子的5至8元杂芳基；其中所述5至8元杂芳基是未被取代的或被1个R 4基团取代；
在一些实施方案中，R 1是含有1至3个N原子的5至6元杂芳基；其中所述5至6元杂芳基是未被取代的或被1个R 4基团取代；
在一些实施方案中，R 1是含有1至2个N原子的5至6元杂芳基；其中所述5至6元杂芳基是未被取代的或被1个R 4基团取代；
在一些实施方案中，R 4选自卤素、＝O、OH、CN、NH 2、NO 2、或C 1-4烷基。
在一些实施方案中，R 4选自卤素；＝O、OH、CN、NH 2、或C 1-4烷基。
在一些实施方案中，R 4选自卤素、＝O、OH、或C 1-4烷基。
在一些实施方案中，R 4选自卤素或C 1-4烷基。
在一些实施方案中，R 1选自吡唑基、吡啶基、嘧啶基、4-氟代吡唑基、4-甲基吡唑基、3-甲基吡唑基、3-氟吡啶基、4-甲基嘧啶基、3-氰基嘧啶基、或2-甲氧基-3-氰基嘧啶基；
在一些实施方案中，R 1选自
Figure PCTCN2022132214-appb-000008
Figure PCTCN2022132214-appb-000009
在一些实施方案中，R 2是含有1至3个N原子的5至6元杂环基；其中所述5至6元杂环基是被1至2个R 5基团取代；
在一些实施方案中，R 2是含有1个N原子的5至6元杂环基；其中所述5至6元杂环基是被1至2个R 5基团取代；
在一些实施方案中，R 2是含有1个N原子的5至6元杂环基；其中所述5至6元杂环基是被1个R 5基团取代；
在一些实施方案中，R 5选自羟基、甲基、卤素、甲氧基、或羟基-甲基；
在一些实施方案中，R 5选自羟基、甲氧基、或羟基-甲基；
在一些实施方案中，R 5选自羟基；
在一些实施方案中，R 2选自3-羟基吡咯烷基、3-羟甲基吡咯烷基、3，4-二羟基吡咯烷基、或3-羟基-4-羟甲基哌啶。
在一些实施方案中，R 2选自
Figure PCTCN2022132214-appb-000010
Figure PCTCN2022132214-appb-000011
在一些实施方案中，R 3选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或-C(O)R 6。
在一些实施方案中，R 3选自氢、C 1-4烷基、C 3-6环烷基或-C(O)R 6。
在一些实施方案中，R 3选自氢、C 1-4烷基或C 3-6环烷基。
在一些实施方案中，R 3选自氢或C 1-4烷基。
在一些实施方案中，R 3选自氢。
在一些实施方案中，所述芳香类化合物具有以下分子式：
Figure PCTCN2022132214-appb-000012
所述异构体，包括具有通式(I)芳香胺化合物的对映异构体、非对映异构体、顺反异构体、以及互变异构体；所述异构体中任意不对称碳原子可以以(R)-、(S)-或(R，S)-构型存在，优选(R)-或(S)-构型；所述顺反异构体指位于双键或者尤其环上的取代基 可以以顺式-(＝Z-)或反式(＝E-)形式存在；所述芳香类化合物存在以下互变异构体：
Figure PCTCN2022132214-appb-000013
为阐述互变异构现象使用以下具体实例，(R)-2-氨基-N-(4-(一氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺(以下右侧结构)为(R)-2-氨基-N-(4-(一氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-3-基)烟酰胺(以下左侧结构)的互变异构体，且反之亦然：
Figure PCTCN2022132214-appb-000014
术语“和/或其互变异构体和/或其(优选可药用的)盐”尤其意指式(I)的化合物可以照原样存在或作为互变异构体(例如由于酮-烯醇、内酰胺-内酰亚胺、酰胺-亚胺酸或烯胺-亚胺互变异构现象)或(例如等价反应导致的)与其互变异构体混合存在，或者作为式(I)的化合物的盐存在和/或作为这些形式中的任何一种或者作为两种或更多种所述形式的混合物存在。
所述芳香类化合物还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的所述芳香胺化合物。可结合到所述芳香胺化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的所述芳香胺化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的所述芳香胺化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
所述芳香胺化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
因此所述化合物可以作为异构体的混合物或优选纯的异构体存在、优选作为纯的非对映异构体或纯的对映体存在。
一种药物组合物，其活性成分含有本发明提供的芳香胺化合物及其可药用的盐中的一种或多种的组合，优选还包括药学上可接受的辅料，所述药学上可接受的辅料包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂；
所述赋形剂为配制成固态、半固态、液态或气态制剂的赋形剂；所述固态、半固态、液态或气态制剂如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予所述芳香胺化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
所述药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本发明提供的芳香胺化合物及其前药衍生物、其衍生物、和/或其可药用的盐在制备用于在动物中治疗疾病的药物中的应用，其应用于制备Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白抑制剂；尤其是应用于制备BCR-ABL1融合蛋白抑制剂；
优选应用于制备抗BCR-ABL1融合蛋白活性异常相关疾病的药物；
优选所述BCR-ABL1融合蛋白活性异常相关疾病为BCR-ABL1融合蛋白活性有助于该疾病的病状和/或症候的疾病。
所述BCR-ABL1融合蛋白活性异常相关疾病为非恶性疾病，包括CNS疾病、慢性 髓系白血病、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病、病毒感染或CNS障碍；
进一步优选神经变性疾病、运动神经元病、肌营养不良、自身免疫疾病和炎症性疾病、病毒感染、朊病毒病、慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病以及胃肠道间质瘤；所述神经变性疾病例如阿尔茨海默病、或帕金森病；所述运动神经元病例如肌萎缩侧索硬化；所述炎症性疾病例如糖尿病和肺纤维化。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
在一些实施方案中，本申请的化合物可以由有机合成领域技术人员参考以下路线来制备：
Figure PCTCN2022132214-appb-000015
R 1、R 2、R 3定义同式(Ⅰ)。
在以下实施例中给出的缩写：NBS(N-溴代丁二酰亚胺)；EDCI(1-(3-二甲胺基丙基)-3-乙基碳二亚胺)；DIPEA(N，N-二异丙基乙胺)；Pd(dppf)Cl 2([1，1'-双(二苯基膦基)二茂铁]二氯化钯)；DMF(N，N-二甲基甲酰胺)；DCM(二氯甲烷)；NIS(N-碘代丁二酰亚胺)。
以下为实施例：
实施例1:(R)-2-氨基-N-(4-(一氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺(化合物1)
Figure PCTCN2022132214-appb-000016
1)化合物1-b的制备方法：
向100ml反应器中加入1-a(2.5g)、NBS(2.7g)和DCM(50ml)，室温反应4h，减压浓缩至干。向残余物中加入50ml水，室温搅拌30分钟，过滤，滤饼于50℃干燥3小时，得到3.0克1-b。ESI-MS:m/z＝250.95[M+H] +。
2)化合物1-d的制备方法：
向50ml反应器中加入1-b(120mg)、1-c(93mg)、EDCI(137mg)和吡啶(10ml)，室温反应4小时，层析柱纯化得到1-d(120mg)。ESI-MS:m/z＝426.04[M+H] +。
3)化合物1-f的制备方法：
向50ml反应器中加入1-d(0.5g)、1-e(1.5g)、DIPEA(0.3g)和异丙醇(20ml)、N2保护，140℃反应4小时，层析柱纯化得到1-f(0.3g)。ESI-MS:m/z＝477.02[M+H] +。
4)化合物1-h的制备方法：
向50ml反应器中加入1-f(150mg)、1-g(130mg)、Pd(dppf)Cl 2(23mg)、K 2CO 3(130mg)、水(1ml)和1，4-二氧六环(10ml)，氮气保护，95℃反应4h，反应液直接用于下步反应。ESI-MS:m/z＝549.24[M+H] +。
5)化合物1的制备方法:
向上步反应液中加入TFA(5ml)，室温反应5小时。将反应液过滤，滤液浓缩至干，经HPLC纯化得到化合物1(15mg)。ESI-MS:m/z＝465.26[M+H] +。
1H NMR(500MHz，Methanol-d4)δ7.85(s，1H)，7.69-7.64(m，2H)，7.62(d， 1H)，7.21(d，2H)，6.37(d，1H)，3.47(td，1H)，3.40(dd，1H)，3.35(s，2H)，3.15(d，1H)，1.98(s，1H)，1.90(dtd，1H)，1.82(tt，1H)。
实施例2:(R)-N-(4-(一氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-2-(甲氨基)-5-(1H-吡唑-5-基)烟酰胺(化合物2)
Figure PCTCN2022132214-appb-000017
1)化合物2-b的制备方法:
向100ml反应器中加入2-a(1g)和DMF(20ml)，降温至0℃。缓慢加入65％钠氢(0.45g)，搅拌10分钟。滴加碘甲烷(0.8g)，滴毕继续搅拌反应4h。向反应体系中加入100ml水和100ml二氯甲烷，搅拌，分层。二氯甲烷层减压蒸干，层析柱纯化得到2-b(0.4g)。ESI-MS:m/z＝278.93[M+H] +。
2)化合物2-c的制备方法:
向100ml反应器中加入2-b(0.4g)，氢氧化钠(42mg)和水(50ml)的溶液，室温反应2h。用1M盐酸调节PH至2.0，减压浓缩至干，层析柱纯化得到2-c(0.2g)。ESI-MS:m/z＝264.95[M+H] +。
3)化合物2-d的制备方法:
参考实施例1中“2)化合物1-d的制备方法”，将其中的化合物1-b换成化合物2-c，得到化合物2-d。ESI-MS:m/z＝440.04[M+H] +。
4)化合物2-e的制备方法:
参考实施例1中“3)化合物1-f的制备方法”，将其中的化合物1-d换成化合物2-d，得到化合物2-e。ESI-MS:m/z＝491.07[M+H] +。
5)化合物2-f的制备方法:
参考实施例1中“4)化合物1-h的制备方法”，将其中的化合物1-f换成化合物2-e，得到化合物2-f的反应液。ESI-MS:m/z＝563.27[M+H] +。
6)化合物2的制备方法:
参考实施例1中“5)化合物1的制备方法”，将其中的“上步反应液”换成本步骤2-f的反应液，得到化合物2。ESI-MS:m/z＝479.22[M+H] +。
1H NMR(500MHz，Methanol-d 4)δ7.83(s，1H)，7.72–7.51(m，3H)，7.25–7.16(m，2H)，6.36(s，1H)，4.58(s，1H)，4.31(s，1H)，3.52(d，1H)，3.46(dd，1H)，3.36(t，1H)，3.21(d，1H)，3.03(s，3H)，1.92(dtd，4.4Hz，1H)，1.83(t，1H)。
实施例3:(R)-N-(4-(一氯二氟甲氧基)苯基)-2-(环丙甲酰氨基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺(化合物3)
Figure PCTCN2022132214-appb-000018
1)化合物3-a的制备方法：
向50ml反应器中加入1-d(2g)、环丙甲酰氯(540mg)和DCM(20ml)，搅拌，室温反应过夜。反应液蒸干，柱层析分离得到化合物3-a(860mg)，收率：37％。ESI-MS:m/z＝493.87[M+H] +。
2)化合物3-b的制备方法：
向50ml反应器中加入3-a(500mg)、1-e(1g)、DIPEA(260mg)和异丙醇(10ml)，搅拌，回流反应3小时。反应液蒸干，柱层析分离得到化合物3-b(440mg)，收率：80％。ESI-MS:m/z＝545.13[M+H] +。
3)化合物3-c的制备方法：
参考实施例1中“4)化合物1-h的制备方法”，将其中的化合物1-f换成化合物3-b，得到化合物3-c的反应液。ESI-MS:m/z＝617.22[M+H] +。
4)化合物3的制备
参考实施例1中“5)化合物1的制备方法”，将其中的“上步反应液”换成本步骤3-c的反应液，得到化合物3。ESI-MS:m/z＝533.24[M+H] +。
实施例4:化合物1(方法二)
Figure PCTCN2022132214-appb-000019
1)化合物4-b的制备方法：
向100ml反应器中加入1-a(650mg)和乙腈(30ml)，室温搅拌10min后，加入NIS(1.7g)，继续室温反应4h，反应液减压浓缩至干。向残余物中加入50ml水，室温搅拌30分钟，过滤，滤饼于50℃干燥3小时，得到4-b(630mg)，产率：56％。
1H NMR(400MHz，Methanol-d4)δ8.39(s，1H)。
2)化合物4-d的制备方法：
向100ml反应器中加入4-b(500mg)、1-c(324.3mg)、EDCI(481.72mg)和吡啶(30ml)，室温反应4h，减压浓缩至干。按顺序用饱和NH 4Cl、饱和Na 2CO 3、饱和NaCl洗涤，EA相减压浓缩至干。层析柱纯化得到纯白色固体4-d(500mg)，产率：63％。
1H NMR(400MHz，Methanol-d4)δ8.37(s，1H)，7.73(d，J＝9.1Hz，2H)，7.23(d，J＝9.1Hz，2H)。
3)化合物4-f的制备方法：
向50ml反应器中加入4-d(50mg)、4-e(25.56mg)、pd(dppf)Cl 2(7.72mg)、K 2CO 3(43.73mg)、水(2ml)和1，4-二氧六环(10ml)，在N 2保护下，90℃下反应4h，减压浓缩至干。层析柱纯化得到纯白色固体4-f(37mg)，产率：81％。
1H NMR(400MHz，DMSO-d6)δ8.43(s，1H)，7.82(dt，J＝9.3，3.3Hz，3H)，7.36(d，J＝8.6Hz，2H)，6.68(s，1H)。
4)化合物1的制备方法：
向50ml反应器中加入4-f(37mg)、1-e(11.67mg)、DIPEA(46.7m)、异丙醇(15ml)，N 2保护下，140℃下反应5h，减压浓缩至干。层析柱纯化得到纯白色固体1(30mg)，产率：72％。
1H NMR(400MHz，Methanol-d4)δ7.81(s，1H)，7.66–7.59(m，2H)，7.58(s，1H)，7.16(d，J＝8.6Hz，2H)，6.32(d，J＝2.0Hz，1H)，3.39–3.35(m，1H)，3.35–3.29(m，1H)，3.26(p，J＝1.6Hz，2H)，3.09(dt，J＝12.1，1.8Hz，1H)，1.98(dq，J＝11.4，6.5，5.5Hz，1H)，1.84(dq，J＝8.7，4.3Hz，1H)，1.79–1.75(m，1H)。
实施例5：(S)-2-氨基-N-(4-(一氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺(化合物4)
Figure PCTCN2022132214-appb-000020
用5-g
Figure PCTCN2022132214-appb-000021
替代1-e
Figure PCTCN2022132214-appb-000022
按照实施例4“化合物1(方法二)”制备得到化合物4。ESI-MS:m/z＝465.26[M+H]+。
1H NMR(500MHz，DMSO-d 6)δ12.69(s，1H)，9.85(s，1H)，7.95(s，1H)，7.76(d，J＝8.7Hz，2H)，7.63(s，1H)，7.28(d，J＝8.6Hz，2H)，7.18(s，1H)，6.53(s，1H)，6.28(s，1H)，4.83(s，1H)，4.16(s，1H)，3.36(d，J＝8.6Hz，1H)，3.23(d，J＝12.4Hz，2H)，2.94(d，J＝11.8Hz，1H)，1.79(d，J＝9.9Hz，1H)，1.70(s，1H)。
实施例6：(R)-2-氨基-N-(4-(一氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-嘧啶-5-基)烟酰胺(化合物5)
Figure PCTCN2022132214-appb-000023
用6-e
Figure PCTCN2022132214-appb-000024
替代4-e
Figure PCTCN2022132214-appb-000025
按照实施例4“化合物1(方法二)”制备得到化合物5。ESI-MS:m/z＝477.12[M+H] +。
1H NMR(400MHz，MeOD)δ9.04(d，J＝6.0Hz，1H)，8.83(d，J＝4.5Hz，2H)，7.88(s，1H)，7.69(t，J＝6.3Hz，2H)，7.21(d，J＝8.9Hz，2H)，4.33(d，J＝1.9Hz，1H)，3.51–3.37(m，2H)，3.25–3.14(m，1H)，3.10(d，J＝11.7Hz，1H)，1.96–1.80(m，2H)。
实验例1 hABL(WT)和hABL(T315I)蛋白的热稳定性作用
hABL(WT)或hABL(T315I)蛋白溶液(50ng/μl)，按每孔16μL加入至检测孔中，再加入2μl不同化合物，使化合物终浓度为5μM，2个复孔，同时设对照孔。将蛋白染料SYPRO Orange dye(厂家sigma)，按每孔2μl加入至检测孔中，总反应体积为20ul，离心混匀。荧光定量PCR仪检测，运行体系为20℃15s；30℃～90℃0.02℃/s；20℃15s。使用软件分析得到熔解温度(Tm)，优选大于45℃；更优选大于50℃。结果见表1。
表1蛋白活性
Figure PCTCN2022132214-appb-000026
注：ABL001为上市药物asciminib。
实验例2 K562细胞增殖抑制活性测定
取处于生长状态良好的K562细胞，调整细胞密度至3×10 4个/ml，100μl/孔接种于96孔板，细胞培养箱培养过夜，每孔加入不同浓度的化合物2μl，设2个复孔，同时设置对照孔。细胞培养箱中继续培养72小时后，10μl/孔加入检测试剂CCK-8，细胞培养箱中孵育1.5小时后，多功能读板仪450nm处检测其吸光值，采用四参数拟合，计算IC 50。结果见表2。
实验例3 Ba/F3 BCR-ABL T315I细胞增殖抑制活性测定
取处于生长状态良好的Ba/F3 BCR-ABL T315I细胞，调整细胞密度至3×10 4个/ml，100μl/孔接种于96孔板，细胞培养箱培养过夜，每孔加入不同浓度的化合物2μl，设2个复孔，同时设置对照孔。细胞培养箱中继续培养72小时后，10μl/孔加入检测试剂CCK-8，细胞培养箱中孵育1h后，多功能读板仪450nm处检测其吸光值，采用四参数拟合，计算IC50。结果见表2。
表2细胞活性
Figure PCTCN2022132214-appb-000027
试验例4体外肝微位体稳定性
化合物(终浓度1μM)与PBS缓冲液(PH7.4)、肝微粒体溶液(0.5mg/ml)、NADPH+MgCl 2溶液于37℃、300rpm孵育1小时。同时将受试化合物(终浓度1μM)与PBS缓冲液(PH7.4)、肝微粒体溶液(0.5mg/ml)混合作为0小时对照。样本用含内标的乙腈溶液进行蛋白沉淀离心后制备上清液，稀释后用于LC/MS/MS测定。结果见表3。
表3在肝微粒体中的稳定性结果
Figure PCTCN2022132214-appb-000028
试验例5小鼠体内药代动力学
选取18～22g的ICR小鼠，适应3～5天后随机分组，每组9只，按10mg/kg剂量灌胃给予化合物溶液。
灌胃后15min、30min、1h、2h、3h、4h、6h、8h、10h、24h，进行眼眶取血制备待测血浆样本。
取20μl待测血浆和标曲样品，用含内标的乙腈溶液进行蛋白沉淀离心后制备上清液，稀释后用于LC/MS/MS测定，计算药代参数。结果见表4。
表4化合物小鼠药代参数
Figure PCTCN2022132214-appb-000029
试验例6体内药效评价(在Ba/F3 BCR-ABL  T315I人慢性髓系白血病裸小鼠异种移植瘤模型中的药效学评价)
将1×10 5个Ba/F3 BCR-ABL T315I细胞接种于SPF级雌性BALB/C裸小鼠右侧腋窝皮下。肿瘤平均体积达100mm 3左右时，将动物分成4组，模型对照组(溶媒对照)、阳性对照组(20mpk)、受试化合物低剂量组(10mpk)、受试化合物高剂量组(20mpk)，每组8只。
分组当天(d0天)开始灌胃给药，给药体积为2ml/kg。每日灌胃给药两次，连续给药，每周测2-3次瘤体积，同时称重；每日观察与记录小鼠一般表现。实验结束时取瘤并称重、拍照。
计算公式：
肿瘤体积，TV(mm 3)＝1/2×(a×b 2)；a为长径，b为短径。
相对肿瘤体积，RTV＝TV t/TV 0；TV 0为d0天肿瘤体积，TV t为每一次测量时的肿瘤体积。
相对肿瘤增殖率，T/C(％)＝T RTV/C RTV×100％，T RTV：治疗组RTV；C RTV：对照组RTV。
肿瘤抑制率，TGI(％)，TGI％＝(1-治疗组瘤重量/对照组瘤重量)×对照组瘤重量。试验结果见表5。
表5化合物对人慢性髓系白血病Ba/F3 BCR-ABL  T315I裸小鼠皮下移植瘤的影响(d17)
Figure PCTCN2022132214-appb-000030
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包 含在本发明的保护范围之内。

Claims (10)

  1. 一种芳香胺类化合物，其特征在于，为具有通式(I)的化合物和/或其异构体：
    Figure PCTCN2022132214-appb-100001
    其中，
    R 1是含有1至4个选自N、O和S的杂原子的5至10元杂芳基；
    R 2是含有1至3个选自N、O和S的杂原子的5至6元杂环基；
    R 3选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、-C(O)R 6、-C(O)NHR 6；-S(O 2)R 6或-(CH 2) r-4至7元杂环；r为0、1或2；
    R 6选自C 1-4烷基或C 3-6环烷基；
    Y为N或CH。
  2. 如权利要求1所述的芳香胺类化合物，其特征在于，所述5至10元杂芳基是未被取代的或被1至4个R 4基团取代，R 4选自卤素、＝O、OH、CN、NH 2、NO 2、C 1-4烷基、C 1-4卤代烷基或C 3-6环烷基；优选所述R 1是含有1至2个N原子的5至6元杂芳基；优选所述R 4选自卤素、＝O、OH、CN、NH 2、NO 2、或C 1-4烷基；优选所述R 4选自卤素或C 1-4烷基；
    优选所述R 1选自吡唑基、吡啶基、嘧啶基、4-氟代吡唑基、4-甲基吡唑基、3-甲基吡唑基、3-氟吡啶基、4-甲基嘧啶基、3-氰基嘧啶基、或2-甲氧基-3-氰基嘧啶基；或优选所述R 1选自
    Figure PCTCN2022132214-appb-100002
    Figure PCTCN2022132214-appb-100003
  3. 如权利要求1所述的芳香胺类化合物，其特征在于，所述5至6元杂环基是被1至2个R 5基团取代，R 5选自羟基、甲基、卤素、甲氧基、羟基-甲基、氨基、甲基-氨基、氨基-甲基、三氟甲基、2-羟基丙-2-基、甲基-羰基-氨基、二甲基-氨基、2-氨基-3-甲基丁酰氧基或氨基-羰基；所述R 2是含有1至3个N原子的5至6元杂环基；其中所述5至6元杂环基是被1至2个R 5基团取代；优选所述R 2是含有1个N原子的5至6元杂环基；优选所述5至6元杂环基是被1个R 5基团取代；更优选所述R 5选自羟基；
    优选所述R 2选自3-羟基吡咯烷基、3-羟甲基吡咯烷基、3，4-二羟基吡咯烷基、或3-羟基-4-羟甲基哌啶或优选所述R 2选自
    Figure PCTCN2022132214-appb-100004
    Figure PCTCN2022132214-appb-100005
  4. 如权利要求1所述的芳香胺类化合物，其特征在于，所述R 3包含碳原子及1至4个选自N、O和S(O) p的杂原子；p为0、1或2；优选所述R 3选自氢；C 1-4烷基；C 1-4卤代烷基；C 3-6环烷基或-C(O)R 6；更优选R 3选自氢。
  5. 如权利要求1所述的芳香胺类化合物，其特征在于，所述芳香类化合物具有以下分子式：
    Figure PCTCN2022132214-appb-100006
    Figure PCTCN2022132214-appb-100007
  6. 如权利要求1所述的芳香胺类化合物，其特征在于，所述异构体，包括具有通式(I)芳香胺化合物的对映异构体、非对映异构体、顺反异构体、以及互变异构体；所述异构体中任意不对称碳原子可以以(R)-、(S)-或(R，S)-构型存在，优选(R)-或(S)-构型；所述顺反异构体指位于双键或者尤其环上的取代基为以顺式-(＝Z-)或反式(＝E-)形式存在。
  7. 一种药物组合物，其特征在于，其活性成分含有如权利要求1至6任意一项所述的芳香胺化合物及其可药用的盐中的一种或多种的组合。
  8. 如权利要求7所述的药物组合物，其特征在于，其包括药学上可接受的辅料；优选所述药学上可接受的辅料包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂；优选所述赋形剂为配制成固态、半固态、液态或气态制剂的赋形剂；所述固态、半固态、液态或气态制剂如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
  9. 如权利要求1至6任意一项所述的芳香胺类化合物及其前药衍生物、其衍生物、和/或其可药用的盐在制备用于在动物中治疗疾病的药物中的应用，其特征在于，其应用于制备Abelson蛋白(ABL1)、Abelson相关蛋白(ABL2)和相关的嵌合蛋白抑制剂。
  10. 如权利要求9所述的应用，其特征在于，应用于制备BCR-ABL1融合蛋白抑制剂；优选应用于制备抗BCR-ABL1融合蛋白活性异常相关疾病的药物；所述BCR-ABL1融合蛋白活性异常相关疾病为BCR-ABL1融合蛋白活性有助于该疾病的病状和/或症候的疾病，优选所述BCR-ABL1融合蛋白活性异常相关疾病为非恶性疾病，包括CNS疾病、慢性髓系白血病、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病、病毒感染或CNS障碍；进一步优选神经变性疾病、运动神经元病、肌营养不良、自身免疫疾病和炎症性疾病、病毒感染、朊病毒病、慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病以及胃肠道间质瘤；所述神经变性疾病例如阿尔茨海默病、或帕金森病；所述运动神经元病例如肌萎缩侧索硬化；所述炎症性疾病例如糖尿病和肺纤维化。
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