CN116135851A - Aromatic amine compound and application thereof - Google Patents

Aromatic amine compound and application thereof Download PDF

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CN116135851A
CN116135851A CN202111362178.7A CN202111362178A CN116135851A CN 116135851 A CN116135851 A CN 116135851A CN 202111362178 A CN202111362178 A CN 202111362178A CN 116135851 A CN116135851 A CN 116135851A
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aromatic amine
disease
amine compound
group
compound
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张玉慧
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Wuhan Zhongcheng Kangjian Biomedical Technology Co ltd
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Wuhan Zhongcheng Kangjian Biomedical Technology Co ltd
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Priority to CN202111362178.7A priority Critical patent/CN116135851A/en
Priority to PCT/CN2022/132214 priority patent/WO2023088291A1/en
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    • 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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Abstract

The invention discloses an aromatic amine compound and application thereof, wherein the aromatic amine compound can effectively inhibit the tyrosine kinase enzyme activities of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric proteins, in particular BCR-ABL1, can be applied to the preparation of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric protein inhibitors, and can be used as medicaments for resisting diseases related to abnormal activities of BCR-ABL1 fusion proteins.

Description

Aromatic amine compound and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an aromatic amine compound and application thereof.
Background
Aromatic amine compounds refer to amines having one aromatic substituent, i.e., -NH2, -NH, or a nitrogen-containing group attached to an aromatic hydrocarbon. Aromatic hydrocarbons generally contain one or more benzene rings in their structure, i.e., the nitrogen atom is directly linked to a carbon atom of the benzene ring by a chemical bond. Aromatic amine molecules are highly reactive, widely found in many natural products, and are an important class of bioactive molecules.
Many aromatic amine compounds, which are found to play an important role in the biological metabolic pathway, may be a variety of important protein kinase inhibitors, and have important biological functions. Medicinal research of aromatic amine compounds, including aromatic amines and aromatic amines, has been a hotspot of drug research.
Disclosure of Invention
In view of the above-mentioned drawbacks or improvements of the prior art, the present invention provides an aromatic amine compound and its application, and aims to find its inhibitory effect on Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric proteins, especially as BCR-ABL1 fusion protein inhibitor, and to be applied in preparing medicines for resisting diseases related to abnormal activity of BCR-ABL1 fusion protein.
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):
Figure BDA0003359721260000021
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is a 5 to 10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;
R 2 is a 5-to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S;
R 3 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 selected from C 1-4 Alkyl or C 3-6 Cycloalkyl;
y is N or CH.
Preferably, the aromatic amine compound, the 5-to 10-membered heteroaryl of which is unsubstituted or substituted with 1 to 4R 4 Group substitution, R 4 Selected from halogen, = O, OH, CN, NH 2 、NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
preferably, said aromatic amine compound, said R thereof 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 is unsubstituted or substituted with 1R 4 And (3) group substitution.
Preferably, said aromatic amine compound, said R thereof 1 Is a 5 to 6 membered heteroaryl group containing 1 to 3N atoms; wherein the 5-to 6-membered heteroaryl is unsubstituted or substituted with 1R 4 And (3) group substitution.
Preferably, said aromatic amine compound, said R thereof 1 Is a 5 to 6 membered heteroaryl group containing 1 to 2N atoms; wherein the 5-to 6-membered heteroaryl is unsubstituted or substituted with 1R 4 And (3) group substitution.
Preferably, said aromatic amine compound, said R thereof 4 Selected from halogen, = O, OH, CN, NH 2 、NO 2 Or C 1-4 An alkyl group.
Preferably, said aromatic amine compound, said R thereof 4 Selected from halogen, = O, OH, CN, NH 2 Or C 1-4 An alkyl group.
Preferably, said aromatic amine compound, said R thereof 4 Selected from halogen, = O, OH, or C 1-4 An alkyl group.
Preferably, said aromatic amine compound, said R thereof 4 Selected from halogen or C 1-4 An alkyl group.
Preferably, the aromatic amineClass of compounds, said R 1 Selected from pyrazolyl, pyridinyl, pyrimidinyl, 4-fluoro-pyrazolyl, 4-methylpyrazolyl, 3-fluoropyridyl, 4-methylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl.
Preferably, said aromatic amine compound, said R thereof 1 Selected from the group consisting of
Figure BDA0003359721260000031
Figure BDA0003359721260000032
Preferably, the aromatic amine compound, the 5-to 6-membered heterocyclic group of which is substituted with 1 to 2R 5 Group substitution, R 5 Selected from hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropyl-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyl) oxy or amino-carbonyl.
Preferably, said aromatic amine compound, said R thereof 2 Is a 5-to 6-membered heterocyclic group containing 1 to 3N atoms; wherein the 5-to 6-membered heterocyclic group is substituted with 1 to 2R 5 And (3) group substitution.
Preferably, said aromatic amine compound, said R thereof 2 Is a 5-to 6-membered heterocyclic group containing 1N atom.
Preferably, the aromatic amine compound, the 5-to 6-membered heterocyclic group of which is substituted with 1R 5 And (3) group substitution.
Preferably, said aromatic amine compound, said R thereof 5 Selected from hydroxy, methyl, halogen, methoxy, or hydroxy-methyl.
Preferably, said aromatic amine compound, said R thereof 5 Selected from hydroxy, methoxy, or hydroxy-methyl.
Preferably, said aromatic amine compound, said R thereof 5 Selected from hydroxyl groups.
Preferably, said aromatic amine compound, said R thereof 2 Selected from 3-hydroxypyrrolidinyl,3-hydroxymethyl pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, or 3-hydroxy-4-hydroxymethyl piperidine.
Preferably, said aromatic amine compound, said R thereof 2 Selected from the group consisting of
Figure BDA0003359721260000041
Figure BDA0003359721260000042
/>
Preferably, said aromatic amine compound, said R thereof 3 Containing carbon atoms and 1 to 4 atoms selected from N, O and S (O) p Is a heteroatom of (2); p is 0, 1 or 2.
Preferably, said aromatic amine compound, said R thereof 3 Selected from hydrogen; c (C) 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; c (C) 3-6 Cycloalkyl or-C (O) R 6 。
Preferably, said aromatic amine compound, said R thereof 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or-C (O) R 6 。
Preferably, said aromatic amine compound, said R thereof 3 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or-C (O) R 6 。
Preferably, said aromatic amine compound, said R thereof 3 Selected from hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl groups.
Preferably, said aromatic amine compound, said R thereof 3 Selected from hydrogen or C 1-4 An alkyl group.
Preferably, the aromatic amine compound, R thereof 3 Selected from hydrogen.
Preferably, the aromatic amine compound has the following formula:
Figure BDA0003359721260000051
preferably, the aromatic amine compound, the isomers thereof, include enantiomers, diastereomers, cis-trans isomers, and tautomers of the aromatic amine compound having the general formula (I); any asymmetric carbon atom in the isomers may exist in the (R) -, (S) -or (R, S) -configuration, preferably the (R) -or (S) -configuration; the cis-trans isomer means that the substituents on the double bond or especially the ring are present in cis- (=z-) or trans (=e-) form.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising as an active ingredient a combination of one or more of the aromatic amine compounds provided herein and pharmaceutically acceptable salts thereof.
Preferably, the pharmaceutical composition comprises pharmaceutically acceptable excipients.
Preferably, the pharmaceutical composition, wherein the pharmaceutically acceptable excipients comprise excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents.
Preferably, the pharmaceutical composition, wherein the excipient is an excipient formulated as a solid, semi-solid, liquid or gaseous formulation; such as tablet, pill, capsule, powder, granule, unguent, emulsion, suspension, suppository, injection, inhalant, gel, microsphere, aerosol, etc.
According to another aspect of the present invention there is provided the use of said aromatic amine compounds and prodrug derivatives thereof, and/or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease in an animal, for the manufacture of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric protein inhibitors.
Preferably, the use thereof for the preparation of BCR-ABL1 fusion protein inhibitors.
Preferably, the application is applied to preparing medicines for resisting diseases related to abnormal activity of the BCR-ABL1 fusion protein.
Preferably, the use, wherein the disease associated with aberrant BCR-ABL1 fusion protein activity is a disease in which BCR-ABL1 fusion protein activity contributes to the condition and/or symptoms of the disease.
Preferably, said use, wherein said BCR-ABL1 fusion protein activity abnormality related disease is a non-malignant disease, including CNS disease, in particular neurodegenerative disease, motor neuron disease, muscular dystrophy, autoimmune disease and inflammatory disease, viral infection, prion disease, etc.; such as Alzheimer's disease, or Parkinson's disease; motor neuron diseases such as amyotrophic lateral sclerosis; such as diabetes and pulmonary fibrosis.
In general, the above technical solutions conceived by the present invention, compared with the prior art, enable the following beneficial effects to be obtained:
the aromatic amine compound provided by the invention can effectively inhibit the activity of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric proteins, especially the tyrosine kinase enzyme activity of BCR-ABL1, can be applied to the preparation of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric protein inhibitors, and can be used as medicaments for resisting diseases related to abnormal activity of BCR-ABL1 fusion proteins.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
Terminology and definition:
the following terms used in this application have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "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. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrazolyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzopyrazole, pyridopyrazole, pyrimidopyrazole, and the like.
The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Non-limiting examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, azapyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.
The term "alkyl" refers to a radical having 1 to 7 carbon atoms (C 1-7 Alkyl) or 1 to 4 carbon atoms (C 1-4 Alkyl) branched or straight chain hydrocarbyl groups. Representative examples of alkyl groups 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-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Substituted alkyl is alkyl containing one or more substituents such as 1, 2 or 3 substituents selected from halogen, hydroxy or alkoxy. Halogen substituted alkyl and halogen substituted alkoxy groups may be straight or branched and include methoxyEthoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy and the like.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl.
The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups 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 includes cyclopropyl and cyclobutyl.
"BCR-ABL1" refers to a fusion protein formed from the N-terminal exon of the split cluster region (BCR) gene and the major C-terminal portion (exons 2-11) of the Abelson (ABL 1) gene. The most common fusion transcript encodes the 210-kDa protein (p 210BCR-ABL 1), although the more rare transcripts encode the 190-kDa protein (p 190BCR-ABL 1) and the 230-kDa protein (p 230BCR-ABL 1). The ABL1 sequences of these proteins comprise ABL1 tyrosine kinase domains that are tightly regulated in wild-type proteins, but constitutively activated in BCR-ABL1 fusion proteins. The deregulated tyrosine kinase interacts with a variety of cell signaling pathways that lead to deregulation of cell 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 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, ile, leu and Phe 486.
The tyrosine kinase activity of ABL1 proteins is usually tightly regulated, the N-terminal region of the SH3 domain playing an important role here. One regulatory mechanism involves myristoylation of the N-terminal glycine-2 residue, followed by interaction with the myristate binding site in the SH1 catalytic domain. One hallmark of Chronic Myelogenous Leukemia (CML) is that the philadelphia chromosome (Ph) is formed by the reciprocal translocation of the t (9, 22) chromosome in hematopoietic stem cells, which carries the BCR-ABL1 oncogene, which encodes a chimeric BCR-ABL1 protein lacking an N-end cap and having a constitutively active tyrosine kinase domain. Although drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via ATP-competitive mechanisms, such as imatinib, nilotinib, and dasatinib, are effective in treating CML, some patients relapse due to the occurrence of drug resistance, wherein mutations in the SH1 domain attenuate inhibition binding. Although nilotinib and dasatinib are effective against a variety of imatinib resistant mutations of BCR-ABL1, the T315I mutation is insensitive to all three drugs and can result in resistance. Thus, there remains an unmet clinical need for inhibition of BCR-ABL1 mutations (e.g., T315I). In addition to CML, BCR-ABL1 fusion proteins are responsible for a proportion of acute lymphoblastic leukemias, and drugs targeting ABL kinase activity are also therapeutic in this indication. The compounds from the present invention also have the potential to treat or prevent diseases associated with aberrant activated kinase activity of wild-type ABL1, including non-malignant diseases such as CNS diseases, in particular neurodegenerative diseases (e.g. alzheimer's disease, parkinson's disease), motor neuron diseases (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, prion diseases and the like.
The invention provides an aromatic amine compound which can be used as an inhibitor of tyrosine kinase of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric proteins, in particular BCR-ABL1, and is a compound with a general formula (I) and/or an isomer thereof:
Figure BDA0003359721260000101
wherein, the liquid crystal display device comprises a liquid crystal display device,
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 is unsubstituted or substituted with 1 to 4R 4 Group substitution;
R 2 is a 5-to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S; wherein the 5-to 6-membered heterocyclic group is substituted with 1 to 2R 5 Group substitution;
R 3 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; comprising carbon atoms and 1 to 4 atoms selected from N, O and S (O) p Is a heteroatom of (2);
p is 0, 1 or 2;
r is 0, 1 or 2;
R 4 selected from halogen, = O, OH, CN, NH 2 、NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
R 5 selected from hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropyl-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyl) oxy or amino-carbonyl;
R 6 selected from C 1-4 Alkyl or C 3-6 Cycloalkyl groups.
In some embodiments, the Y is N. In some embodiments, the Y is CH.
In some embodiments, 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 is unsubstituted or substituted with 1R 4 Group substitution;
in some embodiments, R 1 Is a 5 to 8 membered heteroaryl group containing 1 to 4N atoms; wherein the 5-to 8-membered heteroaryl is unsubstituted or substituted with 1R 4 Group substitution;
in some embodimentsIn the scheme, R 1 Is a 5 to 6 membered heteroaryl group containing 1 to 3N atoms; wherein the 5-to 6-membered heteroaryl is unsubstituted or substituted with 1R 4 Group substitution;
in some embodiments, R 1 Is a 5 to 6 membered heteroaryl group containing 1 to 2N atoms; wherein the 5-to 6-membered heteroaryl is unsubstituted or substituted with 1R 4 Group substitution;
in some embodiments, R 4 Selected from halogen, = O, OH, CN, NH 2 、NO 2 Or C 1-4 An alkyl group.
In some embodiments, R 4 Selected from halogen; = O, OH, CN, NH 2 Or C 1-4 An alkyl group.
In some embodiments, R 4 Selected from halogen, = O, OH, or C 1-4 An alkyl group.
In some embodiments, R 4 Selected from halogen or C 1-4 An alkyl group.
In some embodiments, R 1 Selected from pyrazolyl, pyridinyl, pyrimidinyl, 4-fluoro-pyrazolyl, 4-methylpyrazolyl, 3-fluoropyridyl, 4-methylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl;
in some embodiments, R 1 Selected from the group consisting of
Figure BDA0003359721260000111
Figure BDA0003359721260000121
In some embodiments, R 2 Is a 5-to 6-membered heterocyclic group containing 1 to 3N atoms; wherein the 5-to 6-membered heterocyclic group is substituted with 1 to 2R 5 Group substitution;
in some embodiments, R 2 Is a 5-to 6-membered heterocyclic group containing 1N atom; wherein the 5-to 6-membered heterocyclic group is substituted with 1 to 2R 5 Group substitution;
in some embodiments, R 2 Is a 5-to 6-membered heterocyclic group containing 1N atomThe method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-to 6-membered heterocyclic group is substituted with 1R 5 Group substitution;
in some embodiments, R 5 Selected from hydroxy, methyl, halogen, methoxy, or hydroxy-methyl;
in some embodiments, R 5 Selected from hydroxy, methoxy, or hydroxy-methyl;
in some embodiments, R 5 Selected from hydroxyl groups;
in some embodiments, R 2 Selected from 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, or 3-hydroxy-4-hydroxymethylpiperidine.
In some embodiments, R 2 Selected from the group consisting of
Figure BDA0003359721260000122
Figure BDA0003359721260000123
In some embodiments, R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or-C (O) R 6 。
In some embodiments, R 3 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or-C (O) R 6 。
In some embodiments, R 3 Selected from hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl groups.
In some embodiments, R 3 Selected from hydrogen or C 1-4 An alkyl group.
In some embodiments, R 3 Selected from hydrogen.
In some embodiments, the aromatic compound has the following formula:
Figure BDA0003359721260000131
such isomers, including enantiomers, diastereomers, cis-trans isomers, and tautomers of aromatic amine compounds having the general formula (I); any asymmetric carbon atom in the isomers may exist in the (R) -, (S) -or (R, S) -configuration, preferably the (R) -or (S) -configuration; the cis-trans isomer means that the substituents on the double bond or especially the ring can exist in cis- (=z-) or trans (=e-) form; the aromatic compounds exist in the following tautomers:
Figure BDA0003359721260000141
to illustrate the tautomerism, the following specific examples were used, (R) -2-amino-N- (4- (trifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (structure to 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 (structure to the left below), and vice versa:
Figure BDA0003359721260000142
the term "and/or a tautomer thereof and/or a (preferably pharmaceutically acceptable) salt thereof" means in particular that the compound of formula (I) may exist as such or as a tautomer (for example due to keto-enol, lactam-lactam, amide-imide or enamine-imine tautomerism) or (for example as a result of an equivalent reaction) in admixture with its tautomer or as a salt of the compound of formula (I) and/or as any one of these forms or as a mixture of two or more of said forms.
The aromatic compounds also include isotopically-labeled aromatic amine compounds identical to those recited herein, but having one or more atoms replaced by an atom 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, respectively 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, and the like.
Certain isotopically labeled aromatic amine compounds (e.g., with 3 H is H 14 C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 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 an non-isotopically-labeled reagent.
In addition, the use of heavier isotopes (such as deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium, all such forms of the compounds are included within the scope of the present application.
The aromatic amine compound may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present application may be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral 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, the active ingredient of which contains one or more of the aromatic amine compounds and the pharmaceutically acceptable salts thereof provided by the invention, and preferably also comprises pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials to be pharmaceutically acceptable comprise excipient, solvent, dispersing agent, stabilizer, emulsifier, adhesive, diluent, disintegrating agent, lubricant, glidant, sweetener and/or flavoring agent;
the excipient is an excipient prepared into a solid, semi-solid, liquid or gaseous preparation; such as tablet, pill, capsule, powder, granule, unguent, emulsion, suspension, suppository, injection, inhalant, gel, microsphere, aerosol, etc.
Typical routes of administration of the aromatic amine compound or pharmaceutically acceptable salt thereof or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical composition may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may 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, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
Therapeutic doses of the compounds of the present application may be determined, for example, according to the following: the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the present application in the pharmaceutical composition may be variable, depending on a variety of factors, including the dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. The compounds of the present application may be provided, for example, by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration. Some typical dosages range from about 1 μg/kg to about 1g/kg body weight/day. In certain embodiments, the dosage ranges from about 0.01mg/kg to about 100mg/kg body weight/day. Dosages will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health of the particular patient, the relative biological efficacy of the compound selected, the excipient formulation and its route of administration. The effective dose can be obtained by extrapolation of the dose-response curve derived from in vitro or animal model test systems.
The invention provides the use of aromatic amine compounds and prodrug derivatives thereof, and/or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease in an animal, for the manufacture of Abelson protein (ABL 1), abelson related protein (ABL 2), and related chimeric protein inhibitors; in particular to the preparation of BCR-ABL1 fusion protein inhibitors;
preferably applied to preparing medicaments for resisting diseases related to abnormal activity of the BCR-ABL1 fusion protein;
preferably, the disease associated with aberrant BCR-ABL1 fusion protein activity is a disease in which BCR-ABL1 fusion protein activity contributes to the condition and/or symptoms of the disease.
The disease related to abnormal activity of the BCR-ABL1 fusion protein is a non-malignant disease, including CNS diseases, in particular neurodegenerative diseases, motor neuron diseases, muscular dystrophy, autoimmune diseases and inflammatory diseases, virus infection, prion diseases, and the like; such as Alzheimer's disease, or Parkinson's disease; motor neuron diseases such as amyotrophic lateral sclerosis; such as diabetes and pulmonary fibrosis. .
The compounds of the present application may 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 synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is suitable for the chemical changes of the present application and the reagents and materials needed. In order to obtain the compounds of the present application, modifications or choices of synthesis steps or reaction schemes based on the existing embodiments are sometimes required by those skilled in the art.
In some embodiments, the compounds of the present application may be prepared by one skilled in the art of organic synthesis with reference to the following routes:
Figure BDA0003359721260000181
r1, R2 and R3 are defined as formula (I).
Abbreviations given in the examples below: 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-dimethylformamide); DCM (dichloromethane).
The following are examples:
example 1 (R) -2-amino-N- (4- (trifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (Compound 1)
Figure BDA0003359721260000191
1) The preparation method of the compound 1-b comprises the following steps:
to a 100ml reactor was added 1-a (2.5 g), NBS (2.7 g) and DCM (50 ml), and the mixture was reacted at room temperature for 4 hours and concentrated to dryness under reduced pressure. 50ml of water was added to the residue, stirred at room temperature for 30 minutes, filtered, and the cake was dried at 50℃for 3 hours to give 3.0 g of 1-b. ESI-MS: m/z=250.95 [ M+H ]] + 。
2) The preparation method of the compound 1-d comprises the following steps:
to a 50ml reactor were added 1-b (120 mg), 1-c (93 mg), EDCI (137 mg) and pyridine (10 ml), and the mixture was reacted at room temperature for 4 hours, followed by purification by chromatography to give 1-d (120 mg). ESI-MS: m/z=426.04 [ M+H ]] + 。
3) The preparation method of the compound 1-f comprises the following steps:
to a 50ml reactor was added 1-d (0.5 g), 1-e (1.5 g), DIPEA (0.3 g) and isopropyl alcohol (20 ml), N2-protected, reacted at 140℃for 4 hours, and purified by a column chromatography to give 1-f (0.3 g). ESI-MS: m/z=477.02 [ M+H ]] + 。
4) The preparation method of the compound 1-h comprises the following steps:
into a 50ml reactor were charged 1-f (150 mg), 1-g (130 mg), pd (dppf) Cl 2 (23mg)、K 2 CO 3 (130 mg), water (1 ml) and 1, 4-dioxane (10 ml), under nitrogen, at 95℃for 4 hours, and the reaction mixture was used directly for the next reaction. ESI-MS: m/z=549.24 [ M+H ]] + 。
5) The preparation method of the compound 1 comprises the following steps:
TFA (5 ml) was added to the reaction mixture, and the mixture was reacted at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness and purified by HPLC to give compound 1 (15 mg). 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).
EXAMPLE 2 (R) -N- (4- (trifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -2- (methylamino) -5- (1H-pyrazol-5-yl) nicotinamide (Compound 2)
Figure BDA0003359721260000211
1) The preparation method of the compound 2-b comprises the following steps:
to a 100ml reactor was added 2-a (1 g) and DMF (20 ml) and the temperature was reduced to 0 ℃. 65% sodium hydrogen (0.45 g) was slowly added and stirred for 10 minutes. Methyl iodide (0.8 g) was added dropwise thereto, and the reaction was continued with stirring after the completion of the addition for 4 hours. To the reaction system were added 100ml of water and 100ml of methylene chloride, followed by stirring and delamination. The dichloromethane layer was evaporated to dryness under reduced pressure and purified by column chromatography to give 2-b (0.4 g). ESI-MS: m/z=278.93 [ M+H ]] + 。
2) The preparation method of the compound 2-c comprises the following steps:
a100 ml reactor was charged with a solution of 2-b (0.4 g), sodium hydroxide (42 mg) and water (50 ml), and reacted at room temperature for 2 hours. PH was adjusted to 2.0 with 1M hydrochloric acid, concentrated to dryness under reduced pressure, and purified by column chromatography to give 2-c (0.2 g). ESI-MS: m/z=264.95 [ M+H ]] + 。
3) The preparation method of the compound 2-d comprises the following steps:
reference example 1, "2) preparation of Compound 1-d", wherein Compound 1-b was changed to Compound 2-c, compound 2-d was obtained. ESI-MS: m/z=440.04 [ M+H ]] + 。
4) The preparation method of the compound 2-e comprises the following steps:
reference example 1, "3) preparation of Compound 1-f", wherein Compound 1-d was changed to Compound 2-d, compound 2-e was obtained. ESI-MS: m/z=491.07 [ M+H ]] + 。
5) The preparation method of the compound 2-f comprises the following steps:
reference example 1, "4) preparation method of Compound 1-h", wherein Compound 1-f was changed to Compound 2-e, compound 2-f was obtained. ESI-MS: m/z=563.27 [ M+H ]] + 。
6) The preparation method of the compound 2 comprises the following steps:
reference to "5) Process for producing Compound 1" in example 1, "the" reaction solution in the previous step "was changed to the reaction solution in the previous step, to obtain Compound 2.ESI-MS: m/z=479.22 [ M+H ]] + 。
1 H 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).
EXAMPLE 3 (R) -N- (4- (trifluoromethoxy) phenyl) -2- (cyclopropanecarboxamido) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (Compound 3)
Figure BDA0003359721260000231
1) The preparation method of the compound 3-a comprises the following steps:
to a 50ml reactor was added 1-d (2 g), cyclopropanecarbonyl chloride (540 mg) and DCM (20 ml), and the mixture was stirred and reacted overnight at room temperature. The reaction solution was evaporated to dryness and subjected to column chromatography to give compound 3-a (860 mg), yield: 37%. ESI-MS: m/z=493.87 [ M+H ]] + 。
2) The preparation method of the compound 3-b comprises the following steps:
to a 50ml reactor were added 3-a (500 mg), 1-e (1 g), DIPEA (260 mg) and isopropyl alcohol (10 ml), and the mixture was stirred and reacted under reflux for 3 hours. The reaction solution was evaporated to dryness and subjected to column chromatography to give compound 3-b (440 mg), yield: 80%. ESI-MS: m/z=545.13 [ M+H ]] + 。
3) The preparation method of the compound 3-c comprises the following steps:
reference example 1, "4) preparation method of Compound 1-h", wherein Compound 1-f was changed to Compound 3-b, compound 3-c was obtained. ESI-MS: m/z=617.22 [ M+H ]] + 。
4) Preparation of Compound 3
Reference to "5) Process for producing Compound 1" in example 1, "the" reaction solution in the previous step "was changed to the reaction solution in the previous step, to obtain Compound 3.ESI-MS: m/z=533.24 [ M+H ]] + 。
Experimental example 1 Heat stability Effect of hABL (WT) and hABL (T315I) proteins
A solution (50 ng/. Mu.l) of hAbL (WT) or hAbL (T315I) protein was added to each well at a concentration of 16. Mu.L to each test well, and 2. Mu.L of a different compound was added thereto so that the final concentration of the compound was 5. Mu.M, and 2 multiplex wells were used together with a control well. The protein dye SYPRO Orange dye (manufacturer sigma) was added to the detection wells in an amount of 2. Mu.l per well to give a total reaction volume of 20ul, and the mixture was centrifuged and homogenized. Detecting by a fluorescence quantitative PCR instrument, wherein the operation system is 15s at 20 ℃; 30-90 ℃ of 0.02 ℃/s; 15s at 20 ℃. Analysis using software gives a melting temperature (Tm), preferably greater than 45 ℃; more preferably greater than 50 ℃. The results are shown in Table 1.
Figure BDA0003359721260000241
Experimental example 2K 562 cell proliferation inhibitory Activity assay
Taking K562 cells in good growth state, and regulating cell density to 3×10 4 Mu.l/ml, 100. Mu.l/well was inoculated into 96-well plates, the cells were incubated overnight in an incubator, 2. Mu.l of compound at different concentrations was added to each well, 2 multiplex wells were set, and control wells were set. After the cell culture is continued for 72 hours in the cell incubator, 10 mu l/hole of the detection reagent CCK-8 is added, after the cell incubator is incubated for 1.5 hours, the absorbance of the cell incubator is detected at the 450nm position by a multifunctional plate reader, and four parameters are adopted to simulate and calculate an IC (integrated circuit) 50 . The results are shown in Table 2.
Experimental example 3 determination of proliferation inhibitory Activity of Ba/F3_BCR-ABL 1T 315I cells
Taking Ba/F3_BCR-ABL 1T 315I cells in good growth state, and regulating the cell density to 3×10 4 Mu.l/ml, 100. Mu.l/well was inoculated into 96-well plates, the cells were incubated overnight in an incubator, 2. Mu.l of compound at different concentrations was added to each well, 2 multiplex wells were set, and control wells were set. After the cell culture is continued for 72 hours in the cell culture box, 10 mu l/hole of a detection reagent CCK-8 is added, after the cell culture box is incubated for 1 hour, the absorbance of the cell culture box is detected at the 450nm position by a multifunctional plate reader, and the IC50 is calculated by adopting four parameters. The results are shown in Table 2
TABLE 2 cellular Activity
Figure BDA0003359721260000251
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (10)

1. An aromatic amine compound, characterized by being a compound having the general formula (I):
Figure FDA0003359721250000011
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is a 5 to 10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S;
R 2 is a 5-to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S;
R 3 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 selected from C 1-4 Alkyl or C 3-6 Cycloalkyl;
y is N or CH.
2. The aromatic amine compound of claim 1, wherein the 5-to 10-membered heteroaryl is unsubstituted or substituted with 1 to 4R 4 Group substitution, R 4 Selected from halogen, = O, OH, CN, NH 2 、NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl; preferably said R 1 Is a 5 to 6 membered heteroaryl group containing 1 to 2N atoms; preferably said R 4 Selected from halogen, = O, OH, CN, NH 2 、NO 2 Or C 1-4 An alkyl group; preferably said R 4 Selected from halogen or C 1-4 An alkyl group;
preferably said R 1 Selected from pyrazolyl, pyridyl, pyrimidinyl, 4-fluoro-pyrazolyl, 4-methyl-pyrazolyl, 3-fluoro-pyridyl, 4-methyl-pyrazolylAn alkylpyrimidinyl, 3-cyanopyrimidinyl, or 2-methoxy-3-cyanopyrimidinyl group; or preferably said R 1 Selected from the group consisting of
Figure FDA0003359721250000021
Figure FDA0003359721250000022
3. The aromatic amine compound of claim 1, wherein the 5-to 6-membered heterocyclic group is substituted with 1 to 2R 5 Group substitution, R 5 Selected from hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropyl-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoxy or amino-carbonyl; the R is 2 Is a 5-to 6-membered heterocyclic group containing 1 to 3N atoms; wherein the 5-to 6-membered heterocyclic group is substituted with 1 to 2R 5 Group substitution; preferably said R 2 Is a 5-to 6-membered heterocyclic group containing 1N atom; preferably the 5-to 6-membered heterocyclic group is substituted with 1R 5 Group substitution; more preferably said R 5 Selected from hydroxyl groups;
preferably said R 2 Selected from 3-hydroxypyrrolidinyl, 3-hydroxymethylpyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, or 3-hydroxy-4-hydroxymethylpiperidine or preferably said R 2 Selected from the group consisting of
Figure FDA0003359721250000023
/>
Figure FDA0003359721250000024
4. The aromatic amine compound of claim 1, wherein R 3 Containing carbon atoms and 1 to 4 atoms selected from N, O and S (O) p Is a heteroatom of (2); p is 0, 1 or 2; preferably said R 3 Selected from hydrogen; c (C) 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; c (C) 3-6 Cycloalkyl radicalsor-C (O) R 6 The method comprises the steps of carrying out a first treatment on the surface of the More preferably R 3 Selected from hydrogen.
5. The aromatic amine compound of claim 1, wherein the aromatic compound has the formula:
Figure FDA0003359721250000025
/>
Figure FDA0003359721250000031
6. the aromatic amine compound according to claim 1, wherein the isomers comprise enantiomers, diastereomers, cis-trans isomers, and tautomers of the aromatic amine compound having the general formula (I); any asymmetric carbon atom in the isomers may exist in the (R) -, (S) -or (R, S) -configuration, preferably the (R) -or (S) -configuration; the cis-trans isomer means that the substituents on the double bond or especially the ring are present in cis- (=z-) or trans (=e-) form.
7. A pharmaceutical composition comprising as active ingredient a combination of one or more of the aromatic amine compounds according to any one of claims 1 to 6 and pharmaceutically acceptable salts thereof.
8. The pharmaceutical composition of claim 7, comprising a pharmaceutically acceptable adjuvant; preferably, the pharmaceutically acceptable auxiliary materials comprise excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents; preferably the excipient is an excipient formulated as a solid, semi-solid, liquid or gaseous formulation; such as tablet, pill, capsule, powder, granule, unguent, emulsion, suspension, suppository, injection, inhalant, gel, microsphere, aerosol, etc.
9. Use of an aromatic amine compound according to any one of claims 1 to 6, and a prodrug derivative thereof, a derivative thereof, and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease in an animal, for the preparation of Abelson protein (ABL 1), abelson related protein (ABL 2) and related chimeric protein inhibitors.
10. The use according to claim 9 for the preparation of BCR-ABL1 fusion protein inhibitors; preferably applied to preparing medicaments for resisting diseases related to abnormal activity of the BCR-ABL1 fusion protein; more preferably, the disease associated with aberrant BCR-ABL1 fusion protein activity is a disease in which BCR-ABL1 fusion protein activity contributes to the condition and/or symptoms of the disease; further preferably, the disease associated with abnormal activity of the BCR-ABL1 fusion protein is a non-malignant disease including CNS disease, in particular neurodegenerative disease, motor neuron disease, muscular dystrophy, autoimmune disease and inflammatory disease, viral infection, prion disease, etc.; such as Alzheimer's disease, or Parkinson's disease; motor neuron diseases such as amyotrophic lateral sclerosis; such as diabetes and pulmonary fibrosis.
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