Aromatic amine compound and its application

Abstract

The present invention discloses an aromatic amine compound and its application. The aromatic amine compound can effectively inhibit the tyrosine kinase activity of Abelson protein (ABL1), Abelson-associated protein (ABL2) and related chimeric proteins, especially BCR-ABL1. The aromatic amine compound can be used to prepare inhibitors of Abelson protein (ABL1), Abelson-associated protein (ABL2) and related chimeric proteins, and can be used as a drug for treating diseases related to abnormal activity of BCR-ABL1 fusion protein.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to an aromatic amine compound and application thereof. Background Art

[0002] Aromatic amines are amines with an aromatic substituent, typically -NH2, -NH, or a nitrogen-containing group, attached to an aromatic hydrocarbon. Aromatic hydrocarbons typically contain one or more benzene rings, where the nitrogen atom is directly bonded to the carbon atoms in the benzene ring. Aromatic amines are highly reactive molecules and are widely found in many natural products, making them an important class of biologically active molecules.

[0003] Many aromatic amine compounds have been found to play important roles in biological metabolic pathways and may be inhibitors of various important protein kinases, with important biological functions. The medicinal research of aromatic amine compounds, including aromatic amines and aromatic hydrocarbon amines, has always been a hot topic in pharmaceutical research. Summary of the Invention

[0004] In response to the above-mentioned deficiencies or improvement needs of the prior art, the present invention provides an aromatic amine compound and its application, the purpose of which is to discover its inhibitory effect on Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, especially as a BCR-ABL1 fusion protein inhibitor for the preparation of drugs for treating diseases related to abnormal BCR-ABL1 fusion protein activity.

[0005] To achieve the above object, according to one aspect of the present invention, there is provided an aromatic amine compound, which is a compound having the general formula (I) and / or its isomers:

[0006]

[0007] in,

[0008] R1 is a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;

[0009] R2 is a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;

[0010] R3 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, -C(O)R6, -C(O)NHR6; -S(O2)R6 or -(CH2) r -4 to 7 membered heterocyclic ring; r is 0, 1 or 2;

[0011] R6 is selected from C 1-4 Alkyl or C 3-6Cycloalkyl;

[0012] Y is N or CH.

[0013] Preferably, the 5- to 10-membered heteroaryl group of the aromatic amine compound is unsubstituted or substituted by 1 to 4 R4 groups, wherein R4 is selected from halogen, =O, OH, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0014] Preferably, in the aromatic amine compound, R1 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 one R4 group.

[0015] Preferably, in the aromatic amine compound, R1 is a 5- to 6-membered heteroaryl group containing 1 to 3 N atoms; wherein the 5- to 6-membered heteroaryl group is unsubstituted or substituted with one R4 group.

[0016] Preferably, in the aromatic amine compound, R1 is a 5- to 6-membered heteroaryl group containing 1 to 2 N atoms; wherein the 5- to 6-membered heteroaryl group is unsubstituted or substituted with one R4 group.

[0017] Preferably, the aromatic amine compound, wherein R4 is selected from halogen, =O, OH, CN, NH2, NO2, or C 1-4 alkyl.

[0018] Preferably, the aromatic amine compound, wherein R4 is selected from halogen, =O, OH, CN, NH2, or C 1-4 alkyl.

[0019] Preferably, the aromatic amine compound, wherein R4 is selected from halogen, =O, OH, or C 1-4 alkyl.

[0020] Preferably, the aromatic amine compound, wherein R4 is selected from halogen or C 1-4 alkyl.

[0021] Preferably, in the aromatic amine compound, R1 is selected from pyrazolyl, pyridinyl, pyrimidinyl, 4-fluoropyrazolyl, 4-methylpyrazolyl, 3-methylpyrazolyl, 3-fluoropyridinyl, 4-methylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl.

[0022] Preferably, the aromatic amine compound, wherein R1 is selected from

[0023] Preferably, in the aromatic amine compound, the 5- to 6-membered heterocyclic group is substituted by 1 to 2 R5 groups, and R5 is selected from hydroxyl, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxyprop-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutyryl)oxy or amino-carbonyl.

[0024] Preferably, in the aromatic amine compound, R2 is a 5- to 6-membered heterocyclic group containing 1 to 3 N atoms; wherein the 5- to 6-membered heterocyclic group is substituted by 1 to 2 R5 groups.

[0025] Preferably, in the aromatic amine compound, R2 is a 5- to 6-membered heterocyclic group containing 1 N atom.

[0026] Preferably, in the aromatic amine compound, the 5- to 6-membered heterocyclic group is substituted by one R5 group.

[0027] Preferably, in the aromatic amine compound, R5 is selected from hydroxyl, methyl, halogen, methoxy, or hydroxy-methyl.

[0028] Preferably, in the aromatic amine compound, R5 is selected from hydroxyl, methoxy, or hydroxy-methyl.

[0029] Preferably, in the aromatic amine compound, R5 is selected from hydroxyl group.

[0030] Preferably, in the aromatic amine compound, R2 is selected from 3-hydroxypyrrolidino, 3-hydroxymethylpyrrolidino, 3,4-dihydroxypyrrolidino, or 3-hydroxy-4-hydroxymethylpiperidine.

[0031] Preferably, the aromatic amine compound, wherein R2 is selected from

[0032] Preferably, the aromatic amine compound, wherein R3 comprises a carbon atom and 1 to 4 atoms selected from N, O and S(O) p p is 0, 1 or 2.

[0033] Preferably, the aromatic amine compound, wherein R3 is selected from hydrogen; 1-4 Alkyl; C 1-4 Haloalkyl; C 3-6 Cycloalkyl or -C(O)R6.

[0034] Preferably, the aromatic amine compound, wherein R3 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C3-6 Cycloalkyl or -C(O)R6.

[0035] Preferably, the aromatic amine compound, wherein R3 is selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or -C(O)R6.

[0036] Preferably, the aromatic amine compound, wherein R3 is selected from hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0037] Preferably, the aromatic amine compound, wherein R3 is selected from hydrogen or C 1-4 alkyl.

[0038] Preferably, in the aromatic amine compound, R3 is selected from hydrogen.

[0039] Preferably, the aromatic amine compound has the following molecular formula:

[0040]

[0041] Preferably, the aromatic amine compound, and its isomers, include enantiomers, diastereomers, cis-trans isomers, and tautomers of the aromatic amine compound having the general formula (I); any asymmetric carbon atom in the isomer may exist in (R)-, (S)- or (R,S)-configuration, preferably (R)- or (S)-configuration; the cis-trans isomers refer to substituents located on a double bond or, in particular, a ring, existing in cis- (=Z-) or trans (=E-) form.

[0042] According to another aspect of the present invention, a pharmaceutical composition is provided, the active ingredient of which contains one or more combinations of the aromatic amine compounds and pharmaceutically acceptable salts thereof provided by the present invention.

[0043] Preferably, the pharmaceutical composition comprises pharmaceutically acceptable excipients.

[0044] Preferably, the pharmaceutical composition, wherein the medically acceptable excipients include excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and / or flavoring agents.

[0045] Preferably, the excipient in the pharmaceutical composition is an excipient for preparing solid, semi-solid, liquid or gaseous preparations; the solid, semi-solid, liquid or gaseous preparations are such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0046] According to another aspect of the present invention, provided is the use of the aromatic amine compounds and their prodrug derivatives, derivatives, and / or pharmaceutically acceptable salts in the preparation of drugs for treating diseases in animals, which are used to prepare inhibitors of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins.

[0047] Preferably, the use is for preparing a BCR-ABL1 fusion protein inhibitor.

[0048] Preferably, the application is used for preparing drugs for treating diseases related to abnormal activity of BCR-ABL1 fusion protein.

[0049] Preferably, in the use, the disease associated with abnormal BCR-ABL1 fusion protein activity is a disease in which the activity of the BCR-ABL1 fusion protein contributes to the pathology and / or symptoms of the disease.

[0050] Preferably, in the application, the disease associated with abnormal BCR-ABL1 fusion protein activity is a non-malignant disease, including CNS diseases, in particular neurodegenerative diseases, motor neuron disease, muscular dystrophy, autoimmune diseases and inflammatory diseases, viral infections, or prion diseases; the neurodegenerative diseases are such as Alzheimer's disease or Parkinson's disease; the motor neuron disease is such as amyotrophic lateral sclerosis; the inflammatory diseases are such as diabetes and pulmonary fibrosis.

[0051] In general, the above technical solutions conceived by the present invention can achieve the following beneficial effects compared with the prior art:

[0052] The aromatic amine compounds provided by the present invention can effectively inhibit the tyrosine kinase activity of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, especially BCR-ABL1, and can be used to prepare inhibitors of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, and used as drugs for treating diseases related to abnormal activity of BCR-ABL1 fusion protein. DETAILED DESCRIPTION

[0053] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely for the purpose of explaining the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

[0054] Terms and Definitions:

[0055] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0056] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0057] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 6-membered ring, or a plurality of fused rings containing 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrazolyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzopyrazole, pyridopyrazole, pyrimidopyrazole, etc.

[0058] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring or a spirocycle. Non-limiting examples of heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, azacyclopentyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0059] The term "alkyl" refers to a group having 1 to 7 carbon atoms (C 1-7 alkyl) or 1 to 4 carbon atoms (C 1-4 The term "alkyl" refers to a branched or straight-chain hydrocarbon group (e.g., a halogen-substituted alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Substituted alkyl is an alkyl group containing one or more substituents such as 1, 2 or 3 selected from halogen, hydroxyl or alkoxy. Halogen-substituted alkyl and halogen-substituted alkoxy can be straight or branched and include methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, etc.

[0060] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0061] The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-, and trifluoromethyl.

[0062] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring 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, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.

[0063] "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 portion (exons 2–11) of the Abelson (ABL1) gene. The most common fusion transcript encodes a 210-kDa protein (p210BCR-ABL1), although rarer transcripts encode 190-kDa (p190BCR-ABL1) and 230-kDa proteins (p230BCR-ABL1). The ABL1 sequences of these proteins contain the ABL1 tyrosine kinase domain that is tightly regulated in the wild-type protein but constitutively active in the BCR-ABL1 fusion protein. This dysregulated tyrosine kinase interacts with multiple cellular signaling pathways that lead to dysregulated cell transformation and proliferation.

[0064] The term "BCR-ABL1 mutant" refers to a number of 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, Gln 252→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.

[0065] The tyrosine kinase activity of the ABL1 protein is normally tightly regulated, with the N-terminal cap region of the SH3 domain playing a key role. 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. A hallmark of chronic myeloid leukemia (CML) is the formation of the Philadelphia chromosome (Ph) by a reciprocal translocation of the t(9,22) chromosome in hematopoietic stem cells, which carries the BCR-ABL1 oncogene, encoding a chimeric BCR-ABL1 protein that lacks the N-terminal cap and possesses a constitutively active tyrosine kinase domain. Although drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via an ATP-competitive mechanism, such as imatinib, nilotinib, and dasatinib, are effective in treating CML, some patients relapse due to the development of drug resistance, where mutations in the SH1 domain weaken inhibitory binding. Although nilotinib and dasatinib are effective against various imatinib-resistant mutations of BCR-ABL1, the T315I mutation is insensitive to all three drugs and can lead to drug resistance. Therefore, there is still an unmet clinical need for inhibiting BCR-ABL1 mutations (such as T315I). In addition to CML, the BCR-ABL1 fusion protein is also the cause of a certain proportion of acute lymphoblastic leukemia, and drugs targeting ABL kinase activity are also effective in this indication. The compounds from the present invention also have the potential to treat or prevent diseases associated with abnormally activated kinase activity of wild-type ABL1, including non-malignant diseases, such as CNS diseases, particularly neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), motor neuron disease (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, prion diseases, etc.

[0066] The present invention provides an aromatic amine compound that can be used as an inhibitor of tyrosine kinase of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, especially BCR-ABL1, and is represented by the general formula (I) and / or its isomers:

[0067]

[0068] in,

[0069] R1 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 substituted with 1 to 4 R4 groups;

[0070] R2 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 R5 groups;

[0071] R3 is selected from hydrogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, -C(O)R6, -C(O)NHR6; -S(O2)R6 or -(CH2) r -4 to 7 membered heterocyclic ring; which contains carbon atoms and 1 to 4 atoms selected from N, O and S(O) p heteroatoms;

[0072] p is 0, 1, or 2;

[0073] r is 0, 1, or 2;

[0074] R4 is selected from halogen, =O, OH, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;

[0075] R5 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-methylbutanoyl)oxy or amino-carbonyl;

[0076] R6 is selected from C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0077] In some embodiments, said Y is N. In some embodiments, said Y is CH.

[0078] In some embodiments, R1 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;

[0079] In some embodiments, R1 is a 5- to 8-membered heteroaryl group containing 1 to 4 N atoms; wherein the 5- to 8-membered heteroaryl group is unsubstituted or substituted with 1 R4 group;

[0080] In some embodiments, R1 is a 5- to 6-membered heteroaryl group containing 1 to 3 N atoms; wherein the 5- to 6-membered heteroaryl group is unsubstituted or substituted with 1 R4 group;

[0081] In some embodiments, R1 is a 5- to 6-membered heteroaryl group containing 1 to 2 N atoms; wherein the 5- to 6-membered heteroaryl group is unsubstituted or substituted with 1 R4 group;

[0082] In some embodiments, R4 is selected from halogen, =O, OH, CN, NH2, NO2, or C 1-4 alkyl.

[0083] In some embodiments, R4 is selected from halogen; =O, OH, CN, NH2, or C 1-4 alkyl.

[0084] In some embodiments, R4 is selected from halogen, =O, OH, or C 1-4 alkyl.

[0085] In some embodiments, R4 is selected from halogen or C 1-4 alkyl.

[0086] In some embodiments, R1 is selected from pyrazolyl, pyridinyl, pyrimidinyl, 4-fluoropyrazolyl, 4-methylpyrazolyl, 3-methylpyrazolyl, 3-fluoropyridinyl, 4-methylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl;

[0087] In some embodiments, R1 is selected from

[0088] In some embodiments, R2 is a 5- to 6-membered heterocyclyl containing 1 to 3 N atoms; wherein the 5- to 6-membered heterocyclyl is substituted with 1 to 2 R5 groups;

[0089] In some embodiments, R2 is a 5- to 6-membered heterocyclyl containing 1 N atom; wherein the 5- to 6-membered heterocyclyl is substituted with 1 to 2 R5 groups;

[0090] In some embodiments, R2 is a 5- to 6-membered heterocyclyl containing 1 N atom; wherein the 5- to 6-membered heterocyclyl is substituted with 1 R5 group;

[0091] In some embodiments, R5 is selected from hydroxy, methyl, halogen, methoxy, or hydroxy-methyl;

[0092] In some embodiments, R5 is selected from hydroxy, methoxy, or hydroxy-methyl;

[0093] In some embodiments, R5 is selected from hydroxyl;

[0094] In some embodiments, R2 is selected from 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3,4-dihydroxypyrrolidinyl, or 3-hydroxy-4-hydroxymethylpiperidine.

[0095] In some embodiments, R2 is selected from

[0096] In some embodiments, R3 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C3-6 Cycloalkyl or -C(O)R6.

[0097] In some embodiments, R3 is selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or -C(O)R6.

[0098] In some embodiments, R3 is selected from hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0099] In some embodiments, R3 is selected from hydrogen or C 1-4 alkyl.

[0100] In some embodiments, R3 is selected from hydrogen.

[0101] In some embodiments, the aromatic compound has the following molecular formula:

[0102]

[0103] The isomers include enantiomers, diastereomers, cis-trans isomers, and tautomers of the aromatic amine compound of general formula (I); any asymmetric carbon atom in the isomer may exist in (R)-, (S)-, or (R,S)-configuration, preferably (R)- or (S)-configuration; the cis-trans isomers refer to substituents located on a double bond or, in particular, a ring, which may exist in cis- (=Z-) or trans (=E-) form; the aromatic compound exists in the following tautomers:

[0104]

[0105] To illustrate the phenomenon of tautomerism, the following specific example is used: (R)-2-amino-N-(4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (the structure on the right below) is a tautomer of (R)-2-amino-N-(4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-3-yl)nicotinamide (the structure on the left below), and vice versa:

[0106]

[0107] The term "and / or tautomers thereof and / or their (preferably pharmaceutically acceptable) salts" means in particular that the compounds of formula (I) can exist as such or as tautomers (e.g. due to keto-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism) or as a mixture with their tautomers (e.g. resulting from equivalence reactions), or as salts of compounds of formula (I) and / or as any one of these forms or as a mixture of two or more of said forms.

[0108] The aromatic compounds also include isotope-labeled aromatic amine compounds that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into the aromatic amine compounds 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. 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 et al.

[0109] Certain isotope-labeled aromatic amine compounds (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to 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 following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0110] In addition, the use of heavier isotopes such as deuterium (i.e. 2H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein 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 this application.

[0111] The aromatic amine compound can be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of the present application can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0112] The compounds may therefore be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.

[0113] A pharmaceutical composition, the active ingredient of which comprises a combination of one or more of the aromatic amine compounds and pharmaceutically acceptable salts thereof provided by the present invention, and preferably further comprises pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and / or flavoring agents;

[0114] The excipient is an excipient for preparing solid, semi-solid, liquid or gaseous preparations; the solid, semi-solid, liquid or gaseous preparations are such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0115] Typical routes of administration of the aromatic amine compound or its pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0116] The pharmaceutical composition can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

[0117] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound 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, and the like for oral administration to a patient.

[0118] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores.

[0119] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0120] The therapeutic dose of the compounds of the present invention may depend, for example, on the specific therapeutic application, the manner in which the compound is administered, the patient's health and condition, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the present invention in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg of body weight per day. In certain embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.

[0121] The aromatic amine compounds provided by the present invention, their prodrug derivatives, their derivatives, and / or their pharmaceutically acceptable salts are used in the preparation of drugs for treating diseases in animals, and are used in the preparation of inhibitors of Abelson protein (ABL1), Abelson-related protein (ABL2), and related chimeric proteins; in particular, in the preparation of inhibitors of BCR-ABL1 fusion protein.

[0122] It is preferably used in the preparation of drugs for treating diseases related to abnormal activity of BCR-ABL1 fusion protein;

[0123] Preferably, the disease associated with abnormal BCR-ABL1 fusion protein activity is a disease in which BCR-ABL1 fusion protein activity contributes to the pathology and / or symptoms of the disease.

[0124] The diseases associated with abnormal BCR-ABL1 fusion protein activity are non-malignant diseases, including CNS diseases, particularly neurodegenerative diseases, motor neuron diseases, muscular dystrophy, autoimmune diseases and inflammatory diseases, viral infections, or prion diseases; neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease; motor neuron diseases such as amyotrophic lateral sclerosis; and inflammatory diseases such as diabetes and pulmonary fibrosis.

[0125] 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, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0126] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0127] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0128]

[0129] R1, R2, and R3 are defined the same as in formula (I).

[0130] Abbreviations given in the following examples: NBS (N-bromosuccinimide); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); DIPEA (N,N-diisopropylethylamine); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride); DMF (N,N-dimethylformamide); DCM (dichloromethane).

[0131] The following are examples:

[0132] Example 1: (R)-2-amino-N-(4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (Compound 1)

[0133]

[0134] 1) Preparation method of compound 1-b:

[0135] 1-a (2.5 g), NBS (2.7 g), and DCM (50 ml) were added to a 100 ml reactor and reacted at room temperature for 4 h. The mixture was then concentrated to dryness under reduced pressure. 50 ml of water was added to the residue, stirred at room temperature for 30 min, filtered, and the filter cake dried at 50°C for 3 h to yield 3.0 g of 1-b. ESI-MS: m / z = 250.95 [M+H] + .

[0136] 2) Preparation method of compound 1-d:

[0137] 1-b (120 mg), 1-c (93 mg), EDCI (137 mg) and pyridine (10 ml) were added to a 50 ml reactor and reacted at room temperature for 4 hours. 1-d (120 mg) was purified by column chromatography. ESI-MS: m / z = 426.04 [M+H] + .

[0138] 3) Preparation method of compound 1-f:

[0139] 1-d (0.5 g), 1-e (1.5 g), DIPEA (0.3 g), and isopropanol (20 ml) were added to a 50 ml reactor under N2 protection, and the reaction was carried out at 140°C for 4 hours. Purification by column chromatography gave 1-f (0.3 g). ESI-MS: m / z = 477.02 [M+H] + .

[0140] 4) Preparation method of compound 1-h:

[0141] To a 50 ml reactor, 1-f (150 mg), 1-g (130 mg), Pd(dppf)Cl2 (23 mg), K2CO3 (130 mg), water (1 ml), and 1,4-dioxane (10 ml) were added. Under nitrogen protection, the reaction was carried out at 95°C for 4 h. The reaction solution was used directly in the next step. ESI-MS: m / z = 549.24 [M+H] + .

[0142] 5) Preparation method of compound 1:

[0143] TFA (5 ml) was added to the reaction mixture in the previous step and the mixture was reacted at room temperature for 5 hours. The reaction mixture was filtered, the filtrate was concentrated to dryness, and purified by HPLC to obtain compound 1 (15 mg). ESI-MS: m / z = 465.26 [M+H] + .

[0144] 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).

[0145] Example 2: (R)-N-(4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-2-(methylamino)-5-(1H-pyrazol-5-yl)nicotinamide (Compound 2)

[0146]

[0147] 1) Preparation method of compound 2-b:

[0148] To a 100 ml reactor, add 2-a (1 g) and DMF (20 ml) and cool to 0°C. Slowly add 65% sodium hydroxide (0.45 g) and stir for 10 minutes. Add iodomethane (0.8 g) dropwise and continue stirring for 4 hours. Add 100 ml of water and 100 ml of dichloromethane to the reaction system, stir, and separate. The dichloromethane layer is evaporated to dryness under reduced pressure and purified by column chromatography to obtain 2-b (0.4 g). ESI-MS: m / z = 278.93 [M+H] + .

[0149] 2) Preparation method of compound 2-c:

[0150] A solution of 2-b (0.4 g), sodium hydroxide (42 mg), and water (50 ml) was added to a 100 ml reactor and allowed to react at room temperature for 2 h. The pH was adjusted to 2.0 with 1 M hydrochloric acid, the mixture was concentrated to dryness under reduced pressure, and purified by column chromatography to afford 2-c (0.2 g). ESI-MS: m / z = 264.95 [M+H] + .

[0151] 3) Preparation method of compound 2-d:

[0152] Referring to "2) Preparation of Compound 1-d" in Example 1, Compound 1-b was replaced with Compound 2-c to obtain Compound 2-d. ESI-MS: m / z = 440.04 [M+H] + .

[0153] 4) Preparation method of compound 2-e:

[0154] Referring to "3) Preparation of Compound 1-f" in Example 1, Compound 1-d was replaced with Compound 2-d to obtain Compound 2-e. ESI-MS: m / z = 491.07 [M+H] + .

[0155] 5) Preparation method of compound 2-f:

[0156] Referring to "4) Preparation of Compound 1-h" in Example 1, Compound 1-f was replaced with Compound 2-e to obtain Compound 2-f. ESI-MS: m / z = 563.27 [M+H] + .

[0157] 6) Preparation method of compound 2:

[0158] Referring to "5) Preparation of Compound 1" in Example 1, the "previous reaction solution" was replaced with the previous reaction solution of this step to obtain Compound 2. ESI-MS: m / z = 479.22 [M+H] + .

[0159] 1 H NMR(500MHz,Methanol-d4)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).

[0160] Example 3: (R)-N-(4-(trifluoromethoxy)phenyl)-2-(cyclopropylcarboxamido)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (Compound 3)

[0161]

[0162] 1) Preparation method of compound 3-a:

[0163] To a 50 ml reactor, 1-d (2 g), cyclopropanecarbonyl chloride (540 mg), and DCM (20 ml) were added, stirred, and allowed to react overnight at room temperature. The reaction solution was evaporated to dryness and separated by column chromatography to obtain compound 3-a (860 mg) in a 37% yield. ESI-MS: m / z = 493.87 [M+H] + .

[0164] 2) Preparation method of compound 3-b:

[0165] 3-a (500 mg), 1-e (1 g), DIPEA (260 mg), and isopropanol (10 ml) were added to a 50 ml reactor, stirred, and refluxed for 3 hours. The reaction solution was evaporated to dryness and separated by column chromatography to obtain compound 3-b (440 mg) in an 80% yield. ESI-MS: m / z = 545.13 [M+H] + .

[0166] 3) Preparation method of compound 3-c:

[0167] Referring to "4) Preparation of Compound 1-h" in Example 1, replace Compound 1-f with Compound 3-b to obtain Compound 3-c. ESI-MS: m / z = 617.22 [M+H] + .

[0168] 4) Preparation of Compound 3

[0169] Referring to "5) Preparation of Compound 1" in Example 1, the "previous reaction solution" was replaced with the previous reaction solution of this step to obtain Compound 3. ESI-MS: m / z = 533.24 [M+H] + .

[0170] Experimental Example 1 Thermal Stability of hABL (WT) and hABL (T315I) Proteins

[0171] hABL (WT) or hABL (T315I) protein solution (50 ng / μl) was added to the assay wells at a rate of 16 μl per well. 2 μl of each compound was then added to the assay wells to a final concentration of 5 μM. Two replicates were performed, with control wells also included. SYPROOrange dye (Sigma) protein dye was added to the assay wells at a rate of 2 μl per well for a total reaction volume of 20 μl. Mix by centrifugation. Quantitative fluorescence PCR was performed using a cycle time of 20°C for 15 s, 30°C to 90°C at 0.02°C / s, and 20°C for 15 s. The melting temperature (Tm) was determined using software analysis, preferably greater than 45°C and more preferably greater than 50°C. Results are shown in Table 1.

[0172]

[0173] Experimental Example 2 K562 cell proliferation inhibitory activity assay

[0174] Take K562 cells in good growth state and adjust the cell density to 3×10 4Cells / ml, 100 μl / well were inoculated into 96-well plates and cultured in a cell culture incubator overnight. 2 μl of compound at different concentrations was added to each well, with two replicates and a control well. After 72 hours of incubation in the cell culture incubator, 10 μl / well of detection reagent CCK-8 was added. After incubation in the cell culture incubator for 1.5 hours, the absorbance was measured at 450 nm using a multi-function plate reader. The IC was calculated using a four-parameter model. 50 The results are shown in Table 2.

[0175] Experimental Example 3 Determination of Ba / F3_BCR-ABL1 T315I Cell Proliferation Inhibitory Activity

[0176] Take Ba / F3_BCR-ABL1 T315I cells in good growth state and adjust the cell density to 3×10 4 Cells were incubated overnight in a cell culture incubator at 100 μl / well. Different concentrations of the compound were added to each well at 2 μl, with duplicate wells and a control well. After 72 hours of incubation in the cell culture incubator, the detection reagent CCK-8 was added at 10 μl / well. After incubation in the cell culture incubator for 1 hour, the absorbance was measured at 450 nm on a multi-function plate reader. IC50 values ​​were calculated using a four-parameter simulation. Results are shown in Table 2.

[0177] Table 2 Cell activity

[0178]

[0179] It will be easily understood by those skilled in the art that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. An aromatic amine compound, characterized in that is a compound of the general formula (I) and / or its isomers: Wherein, the substituent of R1 is 1H pyrrolidine, the substituent of R2 is 3-hydroxypyrrolidine, and R3 is selected from hydrogen, methane or Y is N or CH.

2. The aromatic amine compound according to claim 1, wherein The aromatic compound has the following molecular formula:

3. The aromatic amine compound according to claim 1, wherein The isomers include enantiomers, diastereomers and tautomers of the aromatic amine compound having the general formula (I); any asymmetric carbon atom in the isomers exists in (R)-, (S)- or (R, S)-configuration.

4. A pharmaceutical composition, characterized in that The active ingredient contains one or more combinations of the aromatic amine compounds and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3.

5. The pharmaceutical composition according to claim 4, wherein It includes pharmaceutically acceptable excipients; the pharmaceutically acceptable excipients include excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and / or flavoring agents; the excipients are excipients for preparing solid, semi-solid, liquid or gaseous preparations; the solid, semi-solid, liquid or gaseous preparations are tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

6. Use of the aromatic amine compound and / or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a medicament for treating a disease in an animal, characterized in that: The invention is used for preparing Abelson protein (ABL1) and Abelson-related protein (ABL2) inhibitors.

7. The use according to claim 6, characterized in that Used for the preparation of BCR-ABL1 fusion protein inhibitors.

8. The use according to claim 7, characterized in that The invention is used for preparing drugs for treating diseases associated with abnormal BCR-ABL1 fusion protein activity, wherein the disease associated with abnormal BCR-ABL1 fusion protein activity is a disease in which the activity of the BCR-ABL1 fusion protein contributes to the pathology and / or symptoms of the disease.

9. The use according to claim 8, characterized in that The disease associated with abnormal BCR-ABL1 fusion protein activity is a non-malignant disease, and the non-malignant disease is a CNS disease.

10. The use according to claim 9, characterized in that The CNS disease is a neurodegenerative disease, motor neuron disease, muscular dystrophy, autoimmune disease and inflammatory disease, viral infection, or prion disease; the neurodegenerative disease is Alzheimer's disease or Parkinson's disease; the motor neuron disease is amyotrophic lateral sclerosis; and the inflammatory disease is diabetes and pulmonary fibrosis.

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