KR102327054B1 - Quinoline Derivatives and Their Use as ALK and ALK L1196M Inhibitors - Google Patents

Abstract

The present invention relates to a quinoline derivative and its use as an inhibitor of ALK and mutated ALK, wherein the pharmaceutical composition comprising the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof is a disease associated with ALK and ALK L1196M, that is, abnormal There is an effect that can prevent or treat proliferative diseases resulting from cell growth and function or behavior.

Description

Quinoline Derivatives and Their Use as ALK and ALK L1196M Inhibitors

The present invention relates to quinoline derivatives and their use as inhibitors of ALK and mutated ALK, and more particularly, to treat diseases related to anaplastic lymphoma kinase (hereinafter abbreviated as 'ALK') and mutated ALK. It relates to a pharmaceutical composition comprising a quinoline derivative or a pharmaceutically acceptable salt thereof.

ALK is a kinase included in receptor tyrosine kinase (RTK), and is involved in the development of the central nervous system and peripheral nervous system in the early stages of development, and its activity is known to decrease naturally after birth. ALK is activated by binding to the domains of extracellular growth factors, midkine (MT) and pleiotrophin (PTN), which induce autophosphorylation at various tyrosine sites of ALK inside the cell membrane. From this, the subsequent signaling pathways influence cell growth and proliferation.

As a major factor that causes overexpression or dysfunction of RTK, ALK expression occurs through chromosomal rearrangements, mutations, and amplifications. Such overexpression is anaplastic large-cell lymphoma, non-small cell lung carcinoma, diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor), squamous cell carcinoma, and the like, and there are reports that it is observed in breast cancer, neuroblastoma, and the like.

Hiroshi et al. reported the development and effectiveness of the CH5424802 material (Hiroshi Sakamoto et al ., Cancer Cell 19, 679-690, 2011). The above document reports a substance that selectively inhibits ALK and mutant ALK on takinase at the enzyme level. The inhibitory effect of selectivity, ALK, and mutant ALK was confirmed through the IC _{50 measurements in Table 1.} In addition, when comparing the tumor size for 18-28 days by processing the developed material in the form of EML4-ALK fusion, increasing the amount of the drug per weight in mice having NCI-H2228 cells in which cancer has occurred (Fig. A)), it was confirmed that the effect of reducing the size of the tumor compared to the treatment concentration appeared. The same effect can be confirmed in the mouse experiment with KARPAS-299 cells, which are NPM-ALK fusion cells that generate anaplastic large cell lymphoma (Fig. 2(D)). In order to rule out the possibility that the above effect may be caused by factors other than the ALK-related effect, when treated with A549, a cell without ALK fusion, the tumor growth pattern could not be suppressed and the tumor size continued to increase. 2(A)), in the case of cancers issued by ALK fusion in non-small cell lung cancer and anaplastic large cell lymphoma, it is possible to conclude that treatment with ALK and mutant ALK inhibitors can have a therapeutic effect. can

In addition, the correlation that non-small cell lung cancer is caused by ALK fusion was also published in Nature in 2007 (Manabu Soda et al ., Nature 05945 Vol. 448, 2 August 2007). As a result of analyzing the gene obtained from a non-small cell lung cancer patient to reveal the sequence, it was confirmed that the sequence of the EML4 part and the ALK sequence lead to a fused form (FIG. 1). In the references mentioned in the above literature, it was confirmed that the fusion of ALK was first known as the form of NPM-ALK (Morris, SW et al. Science 263, 1281-1284 (1994); Shiota, M. et al. al. Oncogene 9, 1567-1574 (1994)).

In the literature reported in 2008, the frequency of EML4-ALK fusion in non-small cell lung cancer patients based on factors such as race, age, sex, and smoking habit was shown as a statistical value (Table 1). By detecting the EML4-ALK fusion in the gene, the ALK total kinase gene was identified in various fusion cases, and it was confirmed that ALK inhibition in this fusion form is possible. Based on this biological analysis, when TAE684, an ALK inhibitor, was treated, the inhibitory effect was confirmed in the remaining cancer cells except for A549 cells without EML4-ALK fusion factor (Fig. Western blot test results were presented as a result that phosphorylation of AKT, ERK, etc. contained in the was also not observed (FIGS. 3(D) and 5(D)) (Jussi P. Koivunen et al ., Clin Cancer Res 2008; 14)13) July 1, 2008)

Ruth H, Palmer et al., a document that summarizes the relationship between the signaling system of ALK and disease based on the above study results, shows the ALK form and signaling system of other species as well as human ALK, and that ALK itself in the human signaling system It was reported that JAK/STAT3, PI3K/AKT, and RAS signaling induce cell differentiation and proliferation, and it was concluded that ALK overexpression in cancer cells can inhibit cancer proliferation through inhibition (Ruth H. Palmer). et al ., biochem. J. (2009) 420, 345-351). In diseases caused by ALK fusion, cancer-related diseases including anaplastic large cell lymphoma and non-small cell lung cancer were cited as examples, and the fusion type found in each disease, its references, and sub-signaling systems were reported. In addition, the association with neuroblastoma through mutation of ALK rather than fusion form was also explained with the mutated amino acids and positions of each patient.

Accordingly, research was conducted to develop a low-molecular ATP competition inhibitor targeting ALK as an anticancer agent. C-Met, developed as a dual inhibitor of ALK and approved by the FDA, crizotinib (trade name: Xalkori) was used as the first ALK inhibitor to treat ALK-positive lung cancer patients. Although crizotinib administration showed a high therapeutic response, crizotinib resistance was observed in many patients during continuous administration. In addition, in the case of EML4-ALK fusion mutation between ALK and echinoderm microtubule-associated protein-like 4 (EML4) among various chromosomal rearrangements that cause non-small cell lung cancer, as a singular point of the factor that induces crizotinib resistance, Various point mutations in kinases have received the most attention as the cause of resistance. The EML4-ALK fusion mutation, which accounts for about 3.5% of non-small cell lung cancer, occurs in 11,300 patients every year in the United States. Based on the fact that a small molecule inhibitor in a form capable of binding can be developed, research on variants and development of inhibitors has been intensively carried out. The mutated form of ALK includes L1196M, G1269A, and G1202R, which are close to the binding site of the ligand and directly affect the binding. In addition, L1152R, C1156Y, and 1151Tins in the inserted form are reported as variants distant from the binding site. have. Based on these targets, compounds containing 2-aminopyridine, 2,4-diaminopyrimidine and benzo[b]carbazole groups were discovered as second-generation multiple mutant ALK inhibitors.

In addition, based on the above second-generation inhibitor structure, a number of mutated ALK single inhibitors are being developed, but side effects and point mutation resistance to newly developed second-generation drugs have been reported. No substances have yet been approved by the FDA as third-generation inhibitors. Therefore, there is a demand for the development of an ALK inhibitor as a new construct having an inhibitory effect on mutated ALK, rather than a similar modified substance using a similar construct of the previous generation.

Accordingly, the present inventors have found that the quinoline derivative represented by Formula 1 inhibits ALK and ALK L1196M, and as resistance to the current drug crizotinib develops, such as anaplastic large cell lymphoma and non-small cell lung cancer, which are difficult to treat. It was confirmed that it can be used to treat or prevent ALK-related diseases, and thus the present invention has been completed.

An object of the present invention is a quinoline derivative compound capable of treating ALK-related diseases such as anaplastic large cell lymphoma and non-small cell lung cancer, which are difficult to treat as resistance to the existing drug, crizotinib, develops, or a pharmaceutically An object of the present invention is to provide an acceptable salt and a method for preparing the same.

Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of ALK-related diseases comprising a quinoline derivative or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides a compound represented by Formula 1 or a pharmaceutically acceptable salt.

[Formula 1]

in formula 1

R ₁ is -NH-, -O- or -CH ₂ -;

R ₂ is aryl, wherein said aryl may be unsubstituted or substituted;

R ₃ is hydrogen or heteroaryl, wherein said heteroaryl may be unsubstituted or substituted;

R ₄ is hydrogen, C _1-6 alkyl, halogen, aryl or heteroaryl, wherein said aryl, heteroaryl may be unsubstituted or substituted,

In this case, the aryl refers to an aromatic ring having 6 to 10 carbon atoms;

The heteroaryl refers to an aromatic ring having 5 or 6 ring atoms including 1 to 4 heteroatoms selected from N, O and S.

The present invention also provides a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt comprising the steps of:

(a) reacting the compound of Formula 2 with R- ₂ -NH ₂ or R- ₂ -OH (wherein R ₂ is as defined in Formula 1) to generate a compound of Formula 3; and

(b) the compound of Formula 3 obtained in step (a) R ₃ B(OH) ₂ , R ₄ B(OH) ₂ or Suzuki coupling or Suzuki coupling with the compound of Formula 4, and then removing the tert-butyloxycarbonyl (Boc) protecting group of piperidine to produce the compound of Formula 1.

[Formula 1]

In Formula 1,

R ₁ is -NH-, -O- or -CH ₂ -;

R ₂ is aryl, wherein said aryl may be unsubstituted or substituted;

R ₃ is hydrogen or heteroaryl, wherein said heteroaryl may be unsubstituted or substituted;

R ₄ is hydrogen, C _1-6 alkyl, halogen, aryl or heteroaryl, wherein said aryl, heteroaryl may be unsubstituted or substituted,

In this case, the aryl refers to an aromatic ring having 6 to 10 carbon atoms;

The heteroaryl refers to an aromatic ring having 5 or 6 ring atoms including 1 to 4 heteroatoms selected from N, O and S.

[Formula 2]

In Formula 2, X and Y are each independently hydrogen (H) or bromo (Br).

[Formula 3]

In Formula 3, R ₁ is -NH- or -O-, and R ₂ is as defined in Formula 1.

[Formula 4]

In Formula 4, R is R ₃ or R _{4 as} defined in Formula 1, wherein _R-3 and R- ₄ are as defined in Formula 1.

The present invention also provides a method for preparing a compound of formula (5) or a pharmaceutically acceptable salt, comprising the steps of:

(a) 4-bromo-7-methoxyquinoline obtained through the bromination reaction of 7-methoxyquinolin-4-ol in Formula 4 (in this case, R is -CH ₂ -R ₂ , and R ₂ is Formula 1) generating a compound of Formula 6 below by performing Suzuki coupling with a compound of );

(b) demethylating the compound of Formula 6 obtained in step (a) to produce a compound of Formula 7;

(c) introducing trifluoromethanesulfonate (OTf) into the compound of Formula 7 obtained in step (b) to produce a compound of Formula 8; and

(d) the (c) a compound of formula (8) formula (4) obtained from step a ring compound and the Suzuki coupling of (and wherein, R is R ₄ as defined in formula (I), R ₄ is as defined in formula (I)) ( Suzuki coupling) and, if necessary, removing the tert-butyloxycarbonyl (Boc) protecting group of piperidine to prepare a compound of Formula 5.

[Formula 4]

In Formula 4, R is R ₃ or R _{4 as} defined in Formula 1, wherein _R-3 and R- ₄ are as defined in Formula 1.

[Formula 5]

In Formula 5, R ₂ and R ₄ are as defined in Formula 1.

[Formula 6]

In Formula 6, R ₂ is as defined in Formula 1.

[Formula 7]

In Formula 7, R ₂ is as defined in Formula 1.

[Formula 8]

In Formula 8, R ₂ is as defined in Formula 1.

The present invention also provides a pharmaceutical composition for treating or preventing a disease related to inhibition of ALK or ALK L1196M activity, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable carrier.

Since the compound of Formula 1 and a pharmaceutically acceptable salt thereof according to the present invention exhibit inhibitory activity against ALK kinase, diseases related to ALK and ALK mutation, such as proliferative diseases resulting from abnormal cell growth and function or behavior It can be used to treat or prevent.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is those well known and commonly used in the art.

In the present invention, as the quinoline derivative represented by Formula 1 inhibits ALK and ALK L1196M, resistance to the current drug, crizotinib, develops, so it is difficult to treat ALK and It was confirmed that it can be used to treat or prevent related diseases.

Accordingly, in one aspect, the present invention relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt.

[Formula 1]

in formula 1

R ₁ is -NH-, -O- or -CH ₂ -;

R ₂ is aryl, wherein said aryl may be unsubstituted or substituted;

R ₃ is hydrogen or heteroaryl, wherein said heteroaryl may be unsubstituted or substituted;

R ₄ is hydrogen, C _1-6 alkyl, halogen, aryl or heteroaryl, wherein said aryl, heteroaryl may be unsubstituted or substituted,

In this case, the aryl refers to an aromatic ring having 6 to 10 carbon atoms;

The heteroaryl refers to an aromatic ring having 5 or 6 ring atoms including 1 to 4 heteroatoms selected from N, O and S.

Hereinafter, the present invention will be described in more detail.

The terms used to define the compounds according to the present invention have the following meanings.

Specific examples of the term “halogen” include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), and in particular, fluorine (F) and chlorine (Cl).

The term "cyano" may be represented by -CN, and has a triple bond as an atomic group in which carbon and nitrogen are bonded one atom at a time, and another atom or functional group is bonded to a carbon atom to be hydrogen cyanide, metal cyanide or nitrile have.

The term “nitro” refers to a functional group represented _{by —NO 2 .}

The term “C _1-6 alkyl” means a monovalent linear or branched saturated hydrocarbon moiety having from 1 to 6 carbon atoms and consisting solely of carbon and hydrogen atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, and the like. Examples of "branched alkyl" include isopropyl, isobutyl, tert-butyl, and the like.

The term “C _1-6 alkoxy” refers to a formula —OC _1-6 alkyl, including but not limited to, for example, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

The term "aryl" includes at least one ring having a shared pi electron system, including, for example, monocyclic or fused-ring polycyclic (i.e., rings that divide adjacent pairs of carbon atoms) groups. . That is, unless otherwise defined in the present specification, aryl may include phenyl, naphthyl, etc., biaryl. In an embodiment of the present invention, aryl refers to an aromatic ring having 6 to 10 carbon atoms.

The term "heteroaryl", unless otherwise defined, is an aromatic ring having 5 or 6 ring atoms including 1 to 4 hetero atoms selected from the group consisting of N, O and S, or the heteroaryl ring is a benzene ring or refers to a bicyclic ring fused to another heteroaryl ring. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl , oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Examples of bicyclic heteroaryl include indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzooxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztria zolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl and the like.

The term “heterocyclyl” denotes a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms comprising, in addition to carbon atoms, 1 to 3 heteroatoms selected from N, O and S. For example, heterocyclyl is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pipe Lidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, ho furoperazinyl, oxazepanil, dihydroindolyl, dihydrofuryl, dihydroimidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolyl, or It is benzodioxanyl.

The term "treatment" when used in a subject exhibiting symptoms of disease means stopping or delaying the progression of a disease.

The term "pharmaceutical composition" may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, as needed together with the compound of the present invention.

The term "pharmaceutically acceptable" refers to properties that do not impair the biological activity and physical properties of a compound.

The term “carrier” refers to a substance that facilitates the addition of a compound into a cell or tissue.

The term "diluent" is defined as a substance that is diluted in water which not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound.

Other terms and abbreviations used in this specification may be interpreted as meanings commonly understood by those of ordinary skill in the art to which the present invention pertains unless otherwise defined.

The present invention relates to a derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

According to a more specific embodiment of the present invention, the compound of Formula 1 may be a quinoline derivative represented by Formula 1-1, 1-2, or 1-3 below.

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

In Formulas 1-1 to 1-3, R ₂ , R ₃ and R ₄ are as defined in Formula 1 above.

According to an embodiment of the present invention, R ₂ is aryl, wherein the aryl may be unsubstituted or substituted. Specifically, the aryl is halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, -CO-C _1-6 alkyl, -CO-NH-C _1-6 alkyl, -SO ₂ - It may be substituted with 1 to 2 substituents selected from the group consisting of C _1-6 alkyl, —NH—CO—C _{1-6 alkyl and aryl.}

According to another embodiment of the present invention, when R ₂ is an aryl group, it may be phenyl.

In addition, according to another embodiment of the present invention, R ₂ may be any one selected from the group represented by the following structural formula (1).

[Structural Formula 1]

According to another embodiment of the present invention, R ₃ is hydrogen or heteroaryl, wherein the heteroaryl may be unsubstituted or substituted. Specifically, according to an embodiment of the present invention, R ₃ may be any one selected from the group represented by the following structural formula (2).

[Structural Formula 2]

According to an embodiment of the present invention, R ₄ is hydrogen, halogen, C _1-6 alkyl, aryl, heteroaryl, wherein the aryl and heteroaryl may be unsubstituted or substituted. Specifically, the aryl and heteroaryl may be substituted with 1 to 2 substituents selected from the group consisting _{of amino, C 1-6} alkyl, C _{1-6 alcohol and heterocyclyl.}

According to another embodiment of the present invention _{, when R 4} is aryl, the aryl group may be phenyl.

According to another embodiment of the present invention _{, when R 4} is heteroaryl, the heteroaryl group may be one or more substituents selected from pyridinyl, thiophenyl, furanyl, pyrazolyl, and pyrazolyl.

According to another embodiment of the present invention, when R ₄ is substituted with heterocyclyl, the heterocyclyl group may be one or more substituents selected from piperidinyl and tetrahydropyranyl.

In addition, according to another embodiment of the present invention, R ₄ may be any one selected from the group represented by the following structural formula (3).

[Structural Formula 3]

Although the scope of the present invention is not limited thereto, the quinoline derivative compound of Chemical Formula 1 according to the present invention may be any one selected from the group represented by Chemical Formulas 9 to 64 below.

According to an embodiment of the present invention, the quinoline compound may form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts in the present invention include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid, and methane; It may be an acid addition salt formed by a sulfonic acid such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., and represented by [Formula 1] according to the present invention containing a free carboxy substituent The quinoline derivative compound may be the above acid addition salts and salts of sodium, calcium and ammonium, and pharmaceutically acceptable salts are addition salts, for example, alkali metals or alkalis formed by lithium, sodium, potassium, calcium, magnesium, and the like. Earth metal salts, amino acid salts such as lysine, arginine, and guanidine, and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. It may be a salt.

The quinoline compound of Formula 1 according to the present invention can be converted into a salt thereof by a conventional method, and the preparation of the salt can be easily performed by those skilled in the art based on the structure of Formula 1 without a separate explanation.

Unless otherwise specified below, the quinoline compound of Formula 1 includes pharmaceutically acceptable salts thereof, and all of them should be construed as being included in the scope of the present invention. For convenience of description, in the present specification, they are simply expressed as a compound of Formula 1.

In another aspect, the present invention provides a step of (a) reacting a compound of Formula 2 with R- ₂ -NH ₂ or R- ₂ -OH (wherein R ₂ is as defined in Formula 1) to generate a compound of Formula 3 ; and

(b) the compound of Formula 3 obtained in step (a) R ₃ B(OH) ₂ , R ₄ B(OH) ₂ or Suzuki coupling with the compound of Formula 4, or Suzuki coupling, and then removing the tert-butyloxycarbonyl (Boc) protecting group of piperidine to generate the compound of Formula 1 It relates to a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt.

[Formula 1]

In Formula 1,

R ₁ is -NH-, -O- or -CH ₂ -;

R ₂ is aryl, wherein said aryl may be unsubstituted or substituted;

R ₃ is hydrogen or heteroaryl, wherein said heteroaryl may be unsubstituted or substituted;

R ₄ is hydrogen, C _1-6 alkyl, halogen, aryl or heteroaryl, wherein said aryl, heteroaryl may be unsubstituted or substituted,

In this case, the aryl refers to an aromatic ring having 6 to 10 carbon atoms;

The heteroaryl refers to an aromatic ring having 5 or 6 ring atoms including 1 to 4 heteroatoms selected from N, O and S.

[Formula 2]

[Formula 2]

In Formula 2, X and Y are each independently hydrogen (H) or bromo (Br).

[Formula 3]

In Formula 3, R ₁ is -NH- or -O-, and R ₂ is as defined in Formula 1.

[Formula 4]

In Formula 4, R is R ₃ or R _{4 as} defined in Formula 1, wherein _R-3 and R- ₄ are as defined in Formula 1.

According to an embodiment of the present invention, Chemical Formula 3 is the following Chemical Formula 3-1 or Chemical Formula 3-2.

[Formula 3-1]

[Formula 3-2]

In the above formula,

X and Y are as defined in Formula 2 above,

R- ₂ is as defined in Formula 1 above.

The preparation method is summarized in a reaction scheme as follows.

[Scheme A]

The compound of Formula 2, which is the starting material of Scheme A, is, for example, any one of 4-chloroquinoline, 6-bromo-4-chloroquinoline, 7-bromo-4-chloroquinoline and 4-chloro-7-methylquinoline You can choose.

An amine is introduced at the C4 site of the starting material through a nucleophilic substitution reaction under acidic conditions to obtain a compound of Formula 3-1. Subsequently, the quinoline derivative of Formula 1-1 may be synthesized through Suzuki coupling using palladium as a catalyst at the C6 or C7 site of Formula 3-1.

More specifically, in the synthesis of the quinoline derivative of Formula 1-1 according to Scheme A, a _{nucleophilic substitution reaction using an aniline represented by R 2} -NH ₂ and hydrochloric acid of a catalytic equivalent is used as the first step in an isopropyl alcohol solution. . Then, the obtained compound of Formula 3-1, a boron compound (eg, boronic acid or boronic ester), a palladium catalyst, and potassium carbonate are used in 1,4-dioxane and water (ratio 1:1) in a solvent through Suzuki coupling. R ₃ or R ₄ may be introduced. If necessary, the Boc protecting group may be removed using trifluoroacetic acid (TFA) to obtain a final quinoline derivative.

In addition, the present invention provides a method for preparing a compound of Formula 1-2 or a pharmaceutically acceptable salt thereof, comprising the following steps.

[Scheme B]

As the starting material of Scheme B, the compound of Formula 2 may be selected from, for example, any one of 6-bromo-4-chloroquinoline and 7-bromo-4-chloroquinoline.

The compound of Formula 3-2 is obtained by introducing phenol through a nucleophilic substitution reaction using a weak base at the C4 site of the starting material. Subsequently, the quinoline derivative of Formula 1-2 may be synthesized through Suzuki coupling using palladium as a catalyst at the C6 or C7 site of Formula 3-2.

More specifically, the synthesis of the quinoline derivative of Formula 1-2 according to Scheme B is the first step of a nucleophilic substitution reaction using various phenols represented by _{R 2} -OH and potassium carbonate in a N,N -dimethylformamide solution. use it as _{Then, R 3} or R ₄ through Suzuki coupling using the obtained compound of Formula 3-2, a boron compound (eg, boronic acid or boronic ester), a palladium catalyst, and cesium carbonate in a solvent of toluene and water (ratio 2:1) can be introduced. If necessary, the Boc protecting group may be removed using trifluoroacetic acid (TFA) to obtain a final quinoline derivative.

In another aspect, the present invention provides (a) 4-bromo-7-methoxyquinoline obtained through the bromination reaction of 7-methoxyquinolin-4-ol in Formula 4 (in this case, R is -CH ₂ -R ₂ and , R ₂ is as defined in Formula 1) and Suzuki coupling (Suzuki coupling) to generate a compound of Formula 6;

(b) demethylating the compound of Formula 6 obtained in step (a) to produce a compound of Formula 7;

(c) introducing trifluoromethanesulfonate (OTf) into the compound of Formula 7 obtained in step (b) to produce a compound of Formula 8; and

(d) the (c) a compound of formula (8) formula (4) obtained from step a ring compound and the Suzuki coupling of (and wherein, R is R ₄ as defined in formula (I), R ₄ is as defined in formula (I)) ( Suzuki coupling) or Suzuki coupling followed by removal of the tert-butyloxycarbonyl (Boc) protecting group of piperidine to prepare a compound of Formula 5 or a pharmaceutically acceptable compound of Formula 5; It relates to a method for preparing a salt.

[Formula 4]

In Formula 4, R is R ₃ or R _{4 as} defined in Formula 1, wherein _R-3 and R- ₄ are as defined in Formula 1.

[Formula 5]

In Formula 5, R ₂ and R ₄ are as defined in Formula 1.

[Formula 6]

In Formula 6, R ₂ is as defined in Formula 1.

[Formula 7]

In Formula 7, R ₂ is as defined in Formula 1.

[Formula 8]

In Formula 8, R ₂ is as defined in Formula 1.

According to an embodiment of the present invention, in Formula 5, R ₂ is phenyl.

According to an embodiment of the present invention, in Formula 5, R ₄ is represented by the following Structural Formula 3-1.

[Structural Formula 3-1]

The preparation method is summarized in a reaction scheme as follows.

[Scheme C]

The starting material of Scheme C, 4-bromo-7-methoxyquinoline, can be obtained by bromination of 7-methoxyquinolin-4-ol at 110° C. using phosphoryl bromide (POBr _{3 ).}

Formula 6 is obtained through Suzuki coupling using palladium as a catalyst at the C4 site of the starting material. _{Subsequently, a demethylation reaction using boron tribromide (BBr 3} ) in addition to methoxy at the C8 position of the compound of Formula 6 is performed to synthesize a compound of Formula 7. A quinoline derivative of Chemical Formula 4 is synthesized through Suzuki coupling using palladium as a catalyst to the compound of Chemical Formula 8 obtained by treating Chemical Formula 7 with N -phenyl-bis(trifluoromethanesulfonimide) (PhNTf _{2 ).} Subsequently, the compound of formula 5 is prepared by removal of the tert-butyloxycarbonyl (Boc) protecting group of piperidine.

More specifically, the synthesis of the quinoline derivative of Formula 1-3 according to Scheme C is performed by using 4-bromo-7-methoxyquinoline as a starting material with benzylboronic ester (Bn-Bpin), a palladium catalyst, and a potassium carbonate base. The Suzuki-type coupling reaction to be used starts with a reaction of substituting an aryl group at the bromo site by heating to 120° C. under solvent conditions of 1,4-dioxane and water (ratio 4:1) and stirring. _{The synthesized compound of Chemical Formula 6 was treated with BBr 3} in a dichloromethane (DCM) solution under anhydrous conditions, followed by demethylation at room temperature to obtain the compound of Chemical Formula 7. Then, in order to introduce OTf, which is a substituent for Suzuki coupling, PhNTf ₂ and potassium carbonate are treated, and tetrahydrofuran (THF) is used as a solvent, and the mixture is heated and stirred at 120° C. using a microwave reactor. The obtained compound of Formula 8 introduces _{R 4} through Suzuki coupling using a boron compound, a palladium catalyst, and potassium carbonate in a solvent of 1,4-dioxane and water (ratio 1:1). Finally, the Boc protecting group is removed using trifluoroacetic acid (TFA) to obtain a quinoline derivative of Formula 5.

However, those of ordinary skill in the art to which the present invention pertains may prepare the compound of Formula 1 by various methods based on the structure of Formula 1, and these methods are all interpreted as being included in the scope of the present invention. should be

That is, the compound of Formula 1 may be prepared by arbitrarily combining various synthetic methods described herein or disclosed in the prior art, which is understood to be within the scope of the present invention, and the method for preparing the compound of Formula 1 is limited to those described above. it's not going to be

In another aspect, the present invention relates to a pharmaceutical composition for the treatment or prevention of diseases related to inhibition of ALK or ALK L1196M activity, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to use as an ALK kinase inhibitor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, in another aspect, the present invention inhibits ALK or ALK L1196M activity by administering a pharmaceutical composition for treatment or prevention of a disease related to inhibition of ALK or ALK L1196M activity, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof It relates to a method of treating a related disease.

Specifically, the present invention provides a method for treating or preventing a proliferative disease resulting from abnormal cell growth and function or behavior, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It relates to pharmaceutical compositions. Specifically, the compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention can be used as a therapeutic agent for ALK and proliferative diseases resulting from mutations in ALK.

The proliferative disease is, for example, cancer, and the cancer includes, but is not limited to, leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, breast cancer, lung cancer, colon cancer, liver cancer, colorectal cancer, and the like.

In one embodiment, the disease related to ALK activity may be non-small cell lung cancer among abnormal cell growth diseases.

In the present invention, the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof has an activity of inhibiting ALK and mutated ALK (L1196M) or other mutated ALK.

Numerous literatures have confirmed that in the case of non-small cell lung cancer and anaplastic large cell lymphoma, cancers generated by ALK fusion can be treated with ALK and mutated ALK inhibitors to obtain therapeutic effects. As a result of experiments at the cellular level, to prove that the quinoline derivative of the present invention is effective in suppressing non-small cell lung cancer. It can show the effect of inhibiting H2228 cells, a cell type of non-small cell lung cancer.

The ALK inhibitory activity of the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention was determined by measuring the activity of a known kinase inhibitor called Staurosporine. In addition, in order to confirm the competitive inhibitory effect on ATP, 1 μM of ATP was treated, and the reaction buffer and the compound according to the present invention were incubated together in a medium to obtain an IC ₅₀ value, which is the degree of enzymatic activity of the substance. The IC ₅₀ value is a concentration of a compound capable of inhibiting the activity of an enzyme by 50%, and the smaller the value, the greater the effect. This will be described later in the following experimental examples.

According to an embodiment of the present invention, a salt dissolved in a buffer solution is used as a diluent, and a commonly used buffer solution may be a phosphate buffered saline that mimics the salt form of a human solution. Because buffer salts can control the pH of a solution at low concentrations, the buffer diluent does not modify the biological activity of the compound.

The compounds of the present invention may be formulated for use as pharmaceutical or veterinary compositions which also contain a pharmaceutically or veterinarily acceptable carrier or diluent. The composition according to the present invention may be generally prepared according to a conventional method, and may be administered in a pharmaceutically or veterinarily appropriate form.

The pharmaceutical composition of the present invention is administered orally in the form of tablets, capsules, sugar-coated, film-coated tablets, liquid solutions or suspensions, or parenterally through subcutaneous, intramuscular or intravenous injection or infusion. can be administered.

The dosage may be determined according to various factors including the age, weight and condition of the patient and the route of administration. The daily dosage can vary within wide limits and can be adapted to the individual requirements in each individual case. However, in general, when the present compound is administered alone to adults, the dosage adopted for each route of administration is 0.0001 to 50 mg/kg of body weight, and in the range of 0.001 to 10 mg/kg of body weight, for example, 0.01 to 1 mg/kg of body weight. You can do it by weight.

Such dosages may be given, for example, from 1 to 5 times per day. For intravenous injection, a suitable daily dose is 0.0001 to 1 mg/kg body weight, preferably 0.0001 to 0.1 mg/kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

Hereinafter, the invention will be described in detail with reference to a preferred embodiment of the present invention and the effect of ALK and ALK (L1196M) inhibitory activity. However, these Examples are for explaining the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited thereby.

<Production Example>

According to the present invention, the 4-anilinoquinoline derivative represented by Formula 1-1a, the 4-phenoxyquinoline derivative represented by Formula 1-2a, or the 4-benzylquinoline derivative represented by Formula 1-3a can be prepared according to the following general preparation procedure prepared according to

<General manufacturing procedure 1>

According to Scheme A-1 below, a starting material (1 equivalent) and aniline (1.1 equivalent) were dissolved in isopropyl alcohol, 35% hydrochloric acid (1 drop) was added, and the mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the precipitate formed in the reaction solution was filtered with a solvent and moisture was removed in a vacuum to obtain an intermediate or final compound. When no precipitate was formed or a large amount was dissolved in a solvent, the solution was reduced under reduced pressure to remove the solvent, and diethyl ether (Et ₂ O) was added. The precipitate observed at this time _{was filtered with Et 2} O, washed with water, and then water was removed in a vacuum to obtain an intermediate or final compound.

<General manufacturing procedure 2>

According to Scheme A-1, the material obtained from General Procedure 1 above (1 equivalent), arylboronic acid or arylboronic ester (2-3 equivalents), potassium carbonate (3 equivalents), tetrakis(triphenyl phosphine) ) Palladium (0) (0.1 equivalent) was placed in a microwave reactor vial, and the mixture was heated and stirred at 120 °C for 1 hour under a solution in which the ratio of 1,4-dioxane to water was 1:1. After completion of the reaction, the mixture was cooled to room temperature, extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Then, a quinoline compound was obtained through column chromatography. If necessary, the Boc protecting group removal reaction is carried out by adding TFA (3 mL) to a dichloromethane (5 mL) solution of the compound, stirring at room temperature for 1 hour, drying under reduced pressure, and washing with diethyl ether to form a solid quinoline compound got 1-1.

[Scheme A-1]

<General manufacturing procedure 3>

tert-butyl-4-hydroxypiperidine-1-carboxylate (1 equivalent) or tetrahydro- 2H -pyran-4-ol (1 equivalent), methanesulfonyl chloride (MsCl) according to Scheme A-2 , 1 eq.), triethylamine (Et ₃ N, 1 eq.) and 4-dimethylaminopyridine (DMAP, 0.4 eq.) were ^{dissolved in dichloromethane at 0 o} C and stirred at room temperature for 12 hours. Water was added to the reaction solution at 0 ^{o C and extracted 3 times with dichloromethane.} The combined organic solvent layers were dried over magnesium sulfate and concentrated. This was purified through column chromatography to obtain a compound substituted with methanesulfonate. Then, 4-iodo- 1H -pyrazole (1 equivalent) was dissolved in DMF, ^{cooled to 0 o} C, 60% sodium hydride (NaH, 1.2 equivalent) was added to this solution, and the mixture was stirred at room temperature for 1 hour. The previously obtained compound (1.1 equivalents) was added to the reaction solution, and the mixture was heated and stirred at ^{100 o C.} Water was added to the reaction solution at 0 ^o C, extracted three times with ethyl acetate, and the combined organic solvent layer was dried over magnesium sulfate. The obtained organic solvent layer was concentrated and purified through column chromatography to obtain an intermediate.

<General manufacturing procedure 4>

According to Scheme A-2, the intermediate (1 equivalent) obtained in Preparation Procedure 3 was dissolved in THF under anhydrous and nitrogen substitution, and isopropylmagnesium chloride ( i PrMgCl, 1.5 equivalents) was added ^{at 0 o C and stirred for 10 minutes.} . After stirring at room temperature for an additional 1 hour, 2-methoxyboronic ester (1.55 equivalents) ^{was added at 0 o} C, followed by stirring at room temperature for 14 hours. After completion of the reaction, a saturated aqueous sodium chloride solution was added in an ice-cooled state, and an organic material was extracted three times with ethyl acetate from this solution. The combined organic solvent layers were dried over sodium sulfate and concentrated. This was passed through a silica filter to obtain a desired substituted heteroaryl-introduced boronic ester compound, concentrated and used directly in the next reaction without further purification.

[Scheme A-2]

<General manufacturing procedure 5>

The starting material (1 equivalent), phenol (1 equivalent) and potassium carbonate (2.5 equivalents) were dissolved in DMF under anhydrous conditions and nitrogen substitution according to Scheme B-1, followed by heating and stirring at ^{140 °C for 12 hours.} After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted three times with dichloromethane. The combined organic solvent layers were dried over magnesium sulfate and concentrated. This was purified through column chromatography to obtain an intermediate.

<General manufacturing procedure 6>

Intermediate (1.0 equiv.), arylboronic acid or arylboronic ester (1.2 equiv.), bis(diphenylphosphine)ferrocene-palladium () (0.05 equiv.) ) and cesium carbonate (3.3 equivalents) in a 1,4-dioxane to water ratio of 2:1 was heated and stirred at 90°C for 12 hours. After completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated. The desired 4-phenoxyquinoline derivative was obtained through column chromatography. If necessary, the Boc protecting group removal reaction is carried out by adding TFA (3 mL) to a dichloromethane (5 mL) solution of the compound, stirring at room temperature for 1 hour, drying under reduced pressure, and washing with diethyl ether to form a solid quinoline compound I got 1-2.

[Scheme B-1]

<General manufacturing procedure 7>

According to the following scheme B-2, starting material (1 equivalent), bis (pinacolato) diboron (1.1 equivalent), bis (diphenylphosphine) ferrocene-palladium () (0.05 equivalent), bis (diphenylphos Fin) ferrocene (0.05 equivalents) and potassium acetate (3 equivalents) were placed in a reaction vessel under reduced pressure to remove moisture, followed by replacement with nitrogen. This was dissolved in anhydrous 1,4-dioxane, and heated and stirred at 100 °C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered through silica-celite, and washed with a 10:1 solution of dichloromethane and methanol. The obtained organic layer was concentrated and used as it is for the next reaction.

[Scheme B-2]

<General manufacturing procedure 8>

According to Scheme C, 7-methoxyquinolin-4-ol (1 eq.) and POBr ₃ (10.4 eq.) were placed in a round bottom flask and stirred at 110 for 3 hours. After completion of the reaction, the reaction solution was slowly added to ice water and basified to pH 8 or higher with ammonia water. From this water and solution mixture, the organic layer was extracted three times with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. From the obtained mixture, 4-bromo-7-methoxyquinoline was added through column chromatography. Obtained quinoline compound (1 equivalent), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolein (1.2 equivalent), potassium carbonate (3 equivalent), tetrakis (triphenyl) Phosphine) palladium (0) (0.05 eq.) was stirred in a solution of 1,4-dioxane and water in a ratio of 4:1 at 100 °C for 6 hours. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Subsequently, a 4-benzylquinoline compound was obtained through column chromatography.

<General manufacturing procedure 9>

The quinoline compound (1 equivalent) obtained in General Preparation Procedure 8 was dissolved in anhydrous dichloromethane under nitrogen-substituted anhydrous conditions, and then BBr ₃ (10 equivalents) was added at 0°C. Then, the reaction was confirmed by stirring at room temperature for 22 hours. Ice was added to the mixture, stirred, and the organic material was extracted three times with dichloromethane, and then washed with a saturated hydrogen carbonate solution to obtain an organic layer. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. After complete drying, the organic layer was washed with dichloromethane to obtain a solid demethylated quinoline compound, which was used immediately in the next reaction. Quinoline intermediate (1 equiv), 1,1,1-trifluoro- N -phenyl- N- (trifluoromethylsulfonyl)methanesulfonamide (PhNTf ₂ ) (1 equiv) and potassium carbonate (3 equiv) It was placed in a microwave reactor vial, dissolved in anhydrous THF, and stirred at 120 °C for 20 minutes. After cooling to room temperature, it was filtered using a 10:1 solution of dichloromethane and methanol through a Celite filter, and then concentrated under reduced pressure. Then, an intermediate was obtained through column chromatography.

<General manufacturing procedure 10>

According to Scheme D, 4-benzylquinolin-7-yl trifluoromethanesulfonate (1 eq), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2) -dioxaborolan-2-yl) -1 H-pyrazol-1-reel) piperidine-1-carboxylate (3 eq.), potassium carbonate (3 equivalents), tetrakis (triphenylphosphine) palladium (0) (0.1 equivalents) was dissolved in a solvent in which the ratio of 1,4-dioxane to water was 1:1, and the mixture was stirred at 120 °C for 1 hour. After completion of the reaction, water was added to the reaction solution, and the obtained organic layer was extracted three times with ethyl acetate, dried over magnesium sulfate, and then concentrated. The desired 4-benzylquinoline derivative was obtained through column chromatography. The Boc protecting group removal reaction was carried out by adding TFA (3 mL) to a dichloromethane (5 mL) solution of the compound, stirring at room temperature for 1 hour, drying under reduced pressure, and washing with diethyl ether to form a solid quinoline compound 1-3 got

[Scheme D]

<Example 1> 7-bromo- N -phenylquinolin-4-amine

According to Scheme 1 below, 7-bromo-4-chloroquinoline (15 mg, 0.0619 mmol), aniline (6.2 μL, 0.0680 mmol) and sulfuric acid (1 drop) were reacted according to the general procedure 1 above. The obtained solid was filtered, washed with isopropyl alcohol, and then water was removed in a vacuum to obtain 7-bromo-N -phenylquinolin-4-amine. (18.5 mg, yield 99%)

[Scheme 1]

The obtained compound corresponds to the specific [Compound 10] according to the present invention, an intermediate of the quinoline compound.

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.52 (d, J = 9.1 Hz, 1H), 8.37 (d, J = 7.1 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.93 (dd, J = 9.1, 1.9 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.54 - 7.39 (m, 3H), 6.89 (d, J = 7.1 Hz, 1H).

<Example 2> N - phenyl-7- (1- (tetrahydro -2 H - Failan 4-yl) -1 H - pyrazol-4-yl) quinolin-4-amine

According to Scheme 2 below, tetrahydro- 2H -pyran-4-ol (93 μL, 0.9791 mmol), MsCl (75.8 μL, 0.9791 mmol), Et ₃ N (136.5 μL, 0.9791 mmol), DMAP (48.1 mg, 0.3916 mmol) was reacted according to General Procedure 3 above. After extraction with distilled water and dichloromethane, the mixture was concentrated, and tetrahydro- 2H -pyran-4-yl methanesulfonate was obtained through column chromatography. (169.9 mg, yield 96%)

After reacting 4-iodo- 1H -pyrazole (166.2 mg, 0.8570 mmol) and 60% NaH (41.1 mg, 1.0284 mmol) at room temperature, tetrahydro- 2H -pyran-4-yl methanesulfonate ( 169.9 mg, 0.9427 mmol) was added, followed by heating and stirring to proceed with the reaction. Through ethyl acetate extraction and column chromatography to give 4-iodo-1- (tetrahydro -2 H - Failan-4-yl) -1 H - to give the pyrazole. (196.4 mg, yield 82%)

4-iodo-1- (tetrahydro -2 H - Failan-4-yl) -1 H - pyrazole (95.5 mg, 0.3434 mmol), 2M isopropyl magnesium chloride THF solution (0.26 mL, 0.5151 mmol), 2 -Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolein (87.2 μL, 0.5323 mmol) was reacted according to General Procedure 4 above to obtain 1-(tetrahydro -2 H - Failan-4-yl) -4- (4,4,5,5-tetramethyl-1,3,2-deoxy beam Rolando 2-yl) -1 H - pyrazole mixture immediately after the used in the reaction.

According to Scheme 3 below, 7-bromo- N -phenylquinolin-4-amine (19.4 mg, 0.0649 mmol), 1-(tetrahydro- 2H -pyran-4-yl)-4-(4,4, 5,5-tetramethyl-1,3,2-deoxy beam Rolando 2-yl) -1 H - pyrazole (36.1 mg, 0.1298 mmol), potassium carbonate (27.0 mg, 0.1947 mmol), tetrakis (tri Phenyl phosphine) palladium (0) (7.5 mg, 0.0065 mmol) was reacted according to General Procedure 2 above. After the distilled water was concentrated and extracted with ethyl acetate after mukhin to, N through the column chromatography in the resulting mixture-phenyl-7- (1- (tetrahydro -2 H - Failan-4-yl) -1 H-pyrazol- 4-yl) quinolin-4-amine was obtained. (7.8 mg, yield 33%)

[Scheme 2]

[Scheme 3]

The compound obtained in Scheme 3 corresponds to the specific Chemical Formulas 1-1 and 23 according to the present invention.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.08 (s, 1H), 8.51 (s, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H) , 8.11 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H) , 7.20 - 7.11 (m, 1H), 6.85 (d, J = 5.3 Hz, 1H), 4.45 (tt, J = 10.4, 4.7 Hz, 1H), 4.05 - 3.91 (m, 2H), 3.50 (td, J) = 11.6, 2.6 Hz, 2H), 2.11 - 1.91 (m, 4H).

<Example 3> 7-bromo-4-( p -tolyloxy)quinoline

7-bromo-4-chloroquinoline (30 mg, 0.1237 mmol), p -cresol (13.4 mg, 0.1237 mmol) and potassium carbonate (42.7 mg, 0.3093 mmol) under anhydrous and nitrogen substitution with anhydrous DMF according to Scheme 4 below ) was dissolved and the reaction proceeded according to the general preparation procedure 5 above. 7-bromo-4-( p -tolyloxy)quinoline was obtained by dichloromethane extraction and column chromatography (23.9 mg, yield 61%).

[Scheme 4]

The obtained compound corresponds to an intermediate of the specific 4-phenoxyquinoline compound according to the present invention.

<Example 4> 2-(4-methyl-5-(4-( p -tolyloxy)quinolin-7-yl)cyazol-2-yl)propan-2-ol

2- (5-bromo-4-methylcyazol-2-yl) propan-2-ol (46 mg, 0.1948 mmol), bis (pinacolato) diboron (54.4 mg, 0.2143 mmol) according to Scheme 5 ), bis(diphenylphosphine)ferrocene-palladium () (8.0 mg, 0.0097 mmol), and potassium acetate (57.4 mg, 0.5844 mmol) were reacted according to General Procedure 7 to obtain a boronated compound solution. got it After silica-celite filter, reduced pressure and concentration were used immediately for the next reaction.

7-bromo-4-( p -tolyloxy)quinoline (12.8 mg, 0.0406 mmol), 2-(4-methyl-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)thiazol-2-yl)propan-2-ol (13.8 mg, 0.0487 mmol), bis(diphenylphosphine)ferrocene-palladium () (1.7 mg, 0.0020) mmol) and cesium carbonate (43.7 mg, 0.1340 mmol) according to the general procedure 6 above. Through ethyl acetate extraction and column chromatography, 2-(4-methyl-5-(4-( p -tolyloxy)quinolin-7-yl)cyazol-2-yl)propan-2-ol was obtained. (5 mg, yield 31%)

[Scheme 5]

[Scheme 6]

The obtained compound corresponds to the specific Chemical Formula 1-2 and [Formula 62] according to the present invention.

¹ H NMR (600 MHz, Methanol- d ₄ ) δ 8.63 (d, J = 5.4 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 7.5 Hz, 2H), 7.15 (d, J = 7.1 Hz, 2H), 6.62 (d, J = 5.3 Hz, 1H), 2.56 (s, 3H), 2.42 (s, 3H), 1.66 (s, 6H).

<Example 5> 4-benzyl-7-methoxyquinoline

According to Scheme 7, 7-methoxyquinolin-4-ol (100 mg, 0.5708 mmol) and POBr ₃ (1.7 g, 5.9297 mmol) were reacted according to General Procedure 8 above to 4-bromo-7 -Methoxyquinoline was obtained. (97.3 mg, yield 72%)

4-Bromo-7-methoxyquinoline (20 mg, 0.0840 mmol), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolein (22.4 μL, 0.1008 mmol) , potassium carbonate (34.8 mg, 0.2520 mmol), tetrakis (triphenyl phosphine) palladium (0) (4.9 mg, 0.0042 mmol) was reacted according to General Procedure 8 above to 4-benzyl-7-methoxy quinoline was obtained.

[Scheme 7]

The obtained compound corresponds to an intermediate of the specific quinoline compound 1-3 and [Compound 64] according to the present invention.

¹ H NMR (600 MHz, Chloroform- d ) δ 8.74 (d, J = 4.5 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.30 ( t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.20 - 7.14 (m, 3H), 7.02 (d, J = 4.5 Hz, 1H), 4.40 (s, 2H), 3.95 (s, 3H).

<Example 6> 4-benzylquinolin-7-ol

According to Scheme 8 below. 4-benzyl-7-methoxyquinoline (97.4 mg, 0.3907 mmol) and 1M BBr ₃ -dichloromethane solution (3.9 mL) were reacted according to General Procedure 9 above under anhydrous dichloromethane solvent. After that, it was washed with dichloromethane to obtain 4-benzylquinolin-7-ol. (74.9 mg, yield 81%)

[Scheme 8]

The obtained compound corresponds to an intermediate of the specific quinoline compound 1-3 and [Compound 64] according to the present invention.

1H NMR (300 MHz, Methanol- d ₄ ) δ 8.82 (d, J = 5.9 Hz, 1H), 8.46 (d, J = 9.4 Hz, 1H), 7.55 (d, J = 5.9 Hz, 1H), 7.49 ( dd, J = 9.4, 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.39 - 7.23 (m, 5H), 4.72 (s, 2H).

<Example 7> 4-benzylquinolin-7-yl trifluoromethanesulfonate

According to the following Scheme 9, 4-benzylquinolin-7-ol (10 mg, 0.0425 mmol), PhNTf ₂ (15.2 mg, 0.0425 mmol) and potassium carbonate (17.6 mg, 0.1275 mmol) were prepared using a microwave reactor. The reaction was carried out according to Preparation 9. Thereafter, 4-benzylquinolin-7-yl trifluoromethanesulfonate was obtained through filtration. (7.8 mg, yield 50%)

[Scheme 9]

The obtained compound corresponds to an intermediate of the specific quinoline compound 1-3 and [Compound 64] according to the present invention.

¹ H NMR (600 MHz, Methanol- d ₄ ) δ 8.86 (d, J = 4.7 Hz, 1H), 8.36 (d, J = 9.4 Hz, 1H), 8.00 (s, 1H), 7.59 (d, J = 9.4 Hz, 1H), 7.40 (d, J = 4.7 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.27 - 7.19 (m, 3H), 4.54 (s, 2H).

<Example 8> 4-benzyl-7- (1- (piperidin-4-yl) -1 H - pyrazol-4-yl) quinoline

According to Scheme 10 below, 4-benzylquinolin-7-yl trifluoromethanesulfonate (5 mg, 0.0136 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl) -1 H - pyrazol-1-yl) piperidine-1-carboxylate (15.4 mg, 0.0408 mmol), potassium carbonate (5.6 mg, 0.0408 mmol), Tetrakis(triphenyl phosphine)palladium(0) (1.6 mg, 0.0014 mmol) was reacted according to General Procedure 10. After completion of the reaction, tert- butyl through ethyl acetate extraction and column chromatography to give 4- (4- (4-benzyl-quinoline-7-yl) -1 H - pyrazol-1-yl) piperidine-1-carboxylate got Then, TFA (0.3 mL) was slowly injected into a solution of the obtained compound in dichloromethane (0.5 mL) at 0 °C, and the Boc protecting group was removed by stirring at room temperature for 5 minutes, followed by 4-benzyl-7-(1-(piperidine-4). -yl) -1 H-pyrazol-4-yl) quinoline was obtained. (2.3 mg, yield 57%)

[Scheme 10]

The obtained compound corresponds to the specific quinoline compound 1-3 and [Compound 64] according to the present invention.

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.94 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 8.9 Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H) , 8.18 (d, J = 0.7 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.39 - 7.22 (m, 5H), 4.72 (s, 2H), 4.66 (tt, J = 9.9, 5.2 Hz, 1H), 3.66 - 3.51 (m, 2H), 3.29 - 3.19 (m, 2H), 2.45 - 2.24 (m, 4H).

Although there are differences in the structure and physical properties of the substituents depending on the type of the substituents, the reaction principles and conditions of the examples according to the present invention are the same for compounds containing substituents not described in the above examples. Therefore, it will be apparent to those of ordinary skill in the art that compounds including these substituents can be easily implemented based on the disclosure of Examples and common knowledge in the art.

In addition, with respect to the synthesis of the specific anilinoquinoline derivative, phenoxyquinoline derivative, and benzylquinoline derivative compound according to the present invention, each final compound or each intermediate is described in detail by the above Examples. It will be apparent to those skilled in the art that it can be easily carried out for the entire specific indole compound.

Anilinoquinoline, phenoxyquinoline, and benzylquinoline derivative compounds specifically disclosed by formulas 9 to 64 in the present invention are shown in [Table 1] below.

[Table 1]

<Experimental Example 1> Measurement of ALK and ALK L1196M inhibitory activity.

Measurement of ALK and ALK L1196M inhibitory activity for the specific compound represented by Formula 1 according to the present invention was carried out as follows.

In order to measure the biological and biochemical inhibitory effects of ALK and mutated ALK inhibitors according to the present invention, Reaction Biology Corp. (Malvern, PA, USA) was commissioned to measure the activity according to the concentration. The measured results are shown in the table below. 2 shows the IC ₅₀ values.

The IC ₅₀ value is the molar concentration of the compound used when the enzyme or cell activity is inhibited to 50%.

[Table 2]

As shown in <Experimental Example 1> and Table 2, it can be confirmed that the quinoline compound represented by Formula 1 according to the present invention can effectively inhibit the activities of ALK and ALK L1196M.

<Experimental Example 2> Measurement of ALK inhibitory activity

H2228 CR cells were plated in a 96-well plate at a concentration of 5000 cells/well and then cultured for 24 hours. After removal of the preservative, each concentration was treated with the material for 72 hours. After proceeding through the MTT assay (assay), the absorbance was measured at 540 nm using a microplate reader. The measured results are shown in Table 3 as IC ₅₀ values. The IC ₅₀ value is the molar concentration of the compound used when the enzyme or cell activity is inhibited to 50%.

[Table 3]

As shown in <Experimental Example 2> and Table 3, it can be confirmed that the quinoline compound represented by Formula 1 according to the present invention can effectively inhibit the activity of ALK.

As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, it is intended that the substantial scope of the invention be defined by the claims and their equivalents.

Claims (10)

A pharmaceutical composition for the prevention or treatment of cancer expressing an ALK variant having an L1196M mutation comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt.
[Formula 1]

in formula 1
R ₁ is -NH-, -O- or -CH ₂ -;
R ₂ is aryl;
R ₃ is hydrogen or heteroaryl;
R ₄ is hydrogen, C _1-6 alkyl, halogen, aryl or heteroaryl,
In this case, the aryl refers to an aromatic ring having 6 to 10 carbon atoms;
The heteroaryl refers to an aromatic ring having 5 or 6 ring atoms including 1 to 4 heteroatoms selected from N, O and S.

delete According to claim 1, wherein R ₂ Is a pharmaceutical composition, characterized in that one selected from the following formula.

According to claim 1, wherein R ₃ Is a pharmaceutical composition, characterized in that one selected from the following formula.

The pharmaceutical composition according to claim 1, wherein R ₄ is one selected from the following formulas.

The pharmaceutical composition according to claim 1, characterized in that it is one selected from Formulas 9 to 64.

delete delete delete The pharmaceutical composition according to claim 1, wherein the cancer expressing the ALK variant having the L1196M mutation is anaplastic large cell lymphoma, non-small cell lung cancer, or abnormal cell growth disease.