KR102498531B1 - Novel pyrimidodiazepin derivatives as selective protein kinase TRKC inhibitor - Google Patents

Abstract

The present invention relates to a novel pyrimidodiazepine compound and a pharmaceutically acceptable salt thereof, a method for preparing the compound, and a pharmaceutical use of the compound as an anticancer agent or a pain treatment agent. Since the compounds have excellent activity against TRKC among the TRKS kinases, treatment and treatment of cancer treatment diseases, which are any one or more of ovarian cancer, non-small cell cancer, rectal cancer, glioma, breast cancer, esophageal cancer, lung cancer, uterine cancer, pancreatic cancer, prostate cancer and hematological cancer. It is useful in preventive medicine and pain treatment.

Description

Novel pyrimidodiazepin derivatives as selective protein kinase TRKC inhibitor

The present specification relates to pyrimidodiazepine derivative compounds having various substituents and pharmaceutically acceptable salts thereof, methods for preparing the compounds, and medical uses of the compounds.

Protein kinase is an enzyme that catalyzes the phosphorylation of hydroxy groups located on tyrosine, serine and threonine residues of proteins. It plays an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation. For this, the signal transduction system in vivo must be smoothly balanced between on and off. However, mutation or overexpression of a specific protein kinase disrupts the normal intracellular signal transduction system (mainly a state in which signal transduction continues in vivo) and causes various diseases such as cancer, inflammation, metabolic diseases, and brain diseases.

Among kinases, TRKs kinase has three isoforms: TRKA, TRKB, and TRKC, and is activated by neurotrophins growth factors. TRKC is activated by NT-3, as well as by brain-derived neurotrophic factor and NT-4/5. When TRKs are abnormal, various cancers including prostate cancer and pancreatic cancer and diseases such as pain disorders are caused. Therefore, among several protein kinases, not only efforts to develop inhibitors of Pan-TRKs, TRKA, TRKB, and TRKC, but also studies to develop selective inhibitors for each are in progress.

Universidade De vora 대학의 국제출원번호 PCT-WO 2016/207790 A1 German Patent DE2418285 A1 by PF Juby et al. Wyeth pharmaceutical company's international application patent WO2009/046416 A1

Universidade De vora International Application No. PCT-WO 2016/207790 A1

E. Z. Peter et al. Cancer, 2011, 1321-1329 W. Tao et al. Expert Opinion on Therapeutic Patents, 2009, 19(3), 305-319 Wookdeung Jin, Carcinogenesis, 2010, 31(11), 1939-1947

Accordingly, one aspect of the present invention is to provide a compound as follows to solve the above problems.

One aspect of the present invention provides a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₃ -C ₁₀ cyclyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); amino group; nitro group; amide group; carboxylic acid group; nitrile group; early childhood; sulfonamide group; sulfide group; sulfone group; or a phosphoryl group;

R ₂ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; Or a C ₃ -C ₁₀ heterocyclyl group;

The C ₁ -C ₁₃ alkyl group, C ₁ -C ₆ alkoxy group or C ₃ -C ₁₀ cyclyl group may be hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may be hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₃ R ₄ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;

The R ₃ and R ₄ are each independently hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or R ₃ together with the nitrogen or carbon atom connected to R ₄ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group and Forming a 3- to 7-membered saturated ring that may be optionally substituted with at least one of the cyano groups;

The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.

One aspect of the present invention provides a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₃ -C ₁₀ cyclyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); amino group; nitro group; amide group; carboxylic acid group; nitrile group; early childhood; sulfonamide group; sulfide group; sulfone group; or a phosphoryl group;

R ₂ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; Or a C ₃ -C ₁₀ heterocyclyl group;

The C ₁ -C ₁₃ alkyl group, C ₁ -C ₆ alkoxy group or C ₃ -C ₁₀ cyclyl group may be hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may be hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₃ R ₄ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;

The R ₃ and R ₄ are each independently hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or R ₃ together with the nitrogen or carbon atom connected to R ₄ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group and Forming a 3- to 7-membered saturated ring that may be optionally substituted with at least one of the cyano groups;

The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.

According to one aspect of the present invention, the novel pyrimidodiazepine derivative compound having various substituents represented by Formula 1, solvates thereof, or pharmaceutically acceptable salts thereof are excellent in various kinase inhibitory activities.

According to one aspect of the present invention, the novel pyrimidodiazepine derivative compound having various substituents represented by Formula 1, its solvate or its pharmaceutically acceptable salt has a highly selective kinase enzyme inhibitory activity against TRKs, particularly TRKC. showed

The novel pyrimidodiazepine derivative compound having various substituents represented by Chemical Formula 1 according to one aspect of the present invention, its solvate or its pharmaceutically acceptable salt is useful as a novel target therapeutic agent capable of treating various cancer diseases do.

A novel pyrimidodiazepine derivative compound having various substituents represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof according to an aspect of the present invention is used for treatment of diseases such as ovarian cancer, non-small cell cancer, rectal cancer, etc. , useful for prevention or improvement.

Unless otherwise specified, all numbers, values and/or expressions expressing components, reaction conditions, or amounts of components used herein are intended to indicate that such numbers, among other things, are inherently different from the measurement taken to obtain such values. Since these are approximations that reflect uncertainty, they should be understood as being qualified by the term "about" in all cases. Also, when numerical ranges are disclosed herein, such ranges are contiguous and include all values from the minimum value of such range to the maximum value inclusive, unless otherwise indicated. Furthermore, where such ranges refer to integers, all integers from the minimum value to the maximum value inclusive are included unless otherwise indicated.

In this specification, where ranges are stated for a variable, it will be understood that the variable includes all values within the stated range inclusive of the stated endpoints of the range. For example, a range of "5 to 10" includes values of 5, 6, 7, 8, 9, and 10, as well as any subrange of 6 to 10, 7 to 10, 6 to 9, 7 to 9, and the like. inclusive, as well as any value between integers that fall within the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also, for example, the range of "10% to 30%" includes values such as 10%, 11%, 12%, 13%, etc., and all integers up to and including 30%, as well as values from 10% to 15%, 12% to 12%, etc. It will be understood to include any sub-range, such as 18%, 20% to 30%, and the like, as well as any value between reasonable integers within the scope of the stated range, such as 10.5%, 15.5%, 25.5%, and the like.

Hereinafter, the present invention will be described in detail.

The compound synthesized in the present invention exhibits kinase inhibitory activity and, in particular, shows an excellent effect on TRKC.

The present invention relates to a compound having a medical effect on pain under an anticancer drug for target treatment, and exhibits such an effect through kinase inhibitory activity.

TRKC kinase (tropomyosin receptor kinase C), to which the compound of the present invention exhibits an effect, is one of the TRK receptors (TRKA, TRKB, TRKC) and is a tyrosine kinase that generally regulates synaptic strength and plasticity. TRKs receptors are known to play a role in malignant transformation, chemotaxis, metastasis and survival in human tumors (E. Z. Peter et al, Cancer, 2011, 1321-1329). appear.

TRKA has the highest affinity for the binding nerve growth factor NGF, so it plays an important role in local and nuclear actions regulating the expression, growth, motility and expression of genes encoding the biosynthesis of enzymes for neurotransmitters, especially in nociceptive sensory neurons. (W. Tao et al., Expert Opinion on Therapeutic Patents, 2009, 19(3), 305-319). TRKB expression shows aggressive tumor growth and poor prognosis in neuroblastoma tumors, and TRKC expression affects neuron survival and differentiation through several signal transduction steps. Various cancers such as renal cancer and acute myeloid leukemia occur (Jin Uk-deung, Carcinogenesis, 2010, 31(11), 1939-1947).

GNF-5837, CH7057288 and PF-06273340 are known pan-TRK inhibitors that show effects on TRKA, TRKB, and TRKC, GW441756 is known as a TRKA-selective inhibitor, and more compounds are active against various kinases including TRKs. is showing TRKC-selective kinases are not well known, and TRKC-selective kinases have not been developed at present.

vora 대학은 국제출원번호 PCT-WO 2016/207790 A1에서 하기 화학식 C로 표기되는 화합물의 합성에 대하여 설명하고 있는데, 본 발명과 유사한 구조의 화합물은 구조적으로 본 발명과는 큰 차이를 보이고 있다. On the other hand, a compound having a structure similar to that of the present invention is disclosed in German patent DE2418285 A1 by PF Juby of Germany, etc., for the synthesis of a compound represented by the following formula A, and Abbott Laboratories discloses an international application patent WO2012/045194 A1 It has been reported that a compound having the structure of Formula B has an activity as a FAK inhibitor, and Universidade De

Vora University describes the synthesis of a compound represented by the following formula C in International Application No. PCT-WO 2016/207790 A1, but a compound having a structure similar to that of the present invention is structurally different from that of the present invention.

[Formula A]

[Formula B]

[Formula C]

The present invention provides a pyrimidodiazepine derivative compound having various substituents represented by Formula 1 below, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is a hydrogen atom, alkyl, halogen, piperazine, morpholine, piperidine, hydroxy, 2-pyrrolidinylethoxy, 2-piperidinylethoxy, 2-morpholinoethoxy, 2-dialkyl can form aminoethoxy, 4-hydroxypiperinylsulfonyl;

R ₂ can form a hydrogen atom, methyl, ethyl, cycloalkyl, phenyl, methoxyphenyl, acetyl, propionyl, benzoyl, methoxybenzoyl halobenzoyl;

In addition, the present invention provides a method for preparing a pyrimidodiazepine derivative compound having various substituents represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt should have low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include acid addition salts of pharmaceutically usable free acids and basic compounds of Formula 1, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), and organic salts and carboxyl salts of Formula 1 It consists of organic base addition salts of acids and amino acid addition salts. The pharmaceutically acceptable salt in the present invention can be prepared by a conventional method in the art, for example, with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin ); , acid addition salts including salts with sulfonic acids such as benzenesulfonic acid, toluenesulfonic acid and the like. In addition, the pharmaceutically acceptable salt may be a metal salt by reaction with an alkali metal such as sodium or potassium, or a salt with ammonium ion. Among the above pharmaceutically acceptable salts, hydrochloric acid salts and sulfate salts are particularly preferred as acid addition salts.

In addition, the compound according to the present invention also includes a hydrate or solvate of the compound represented by Formula 1 above. The above hydrate or solvate may be prepared by a conventional method. For example, the base compound of formula 1 is dissolved in a solvent such as water, methanol, ethanol, acetone, or 1,4-dioxane, and then the free acid or It can be prepared by crystallization or recrystallization after adding a free base.

In addition, the compound represented by Formula 1 may have one or more asymmetric centers, and in the case of such a compound, enantiomers or diastereomers may exist. Accordingly, the compounds of the present invention include each isomer or a mixture of these isomers. Also, the different isomers can be separated or resolved by conventional methods, or any desired isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

In addition, the compound of the present invention includes a radioactive derivative of the compound represented by Formula 1, and these radioactive compounds are useful in the field of biological research.

A more detailed description of the substituent used to define the compound represented by Formula 1 is as follows.

A more detailed description of the substituent used to define the compound represented by Formula 1 is as follows.

In the present invention, 'halo' or 'halogen atom' is a term that can be used interchangeably, and means chloro, fluoro, bromo, and iodo.

In the present invention, 'alkyl' has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and refers to a linear, branched or cyclic aliphatic saturated hydrocarbon group. . Specific examples of such an alkyl group include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a normal butyl group, an isobutyl group, a tert -butyl group, a cyclobutyl group, a normal pentyl group, an iso A pentyl group, a neopentyl group, a tert -pentyl group, a cyclopentyl group, a normalhexyl group, an isohexyl group, a cyclohexyl group, a normalheptyl group, a normaloctyl group, and the like may be included.

In the present invention, the 'haloalkyl group' includes 1 to 13 halogen atoms such as fluoro, chloro, bromo, and iodo, and includes both linear and branched carbon chains having 1 to 10 carbon atoms. Specific examples of such a haloalkyl group may include a fluoromethyl group, a trifluoromethyl group, a 1,2-dichloroethyl group, a 1,1-dichloroethyl group, a pentafluoroethyl group, and the like.

The 'alkoxy group' in the present invention is -O-(C ₁ -C ₁₀ alkyl), and specifically exemplified, a methoxy group, an ethoxy group, a propoxy group, a tert -butoxy group, a cyclohexyloxy group, etc. may be included. there is.

In the present invention, the 'heterocyclic group' refers to a 5-membered or 6-membered aliphatic ring group containing 1 to 2 heteroatoms selected from nitrogen (N) and oxygen (O) atoms. Specific examples of these heterocycle groups include tetrahydrofuranyl group, 2,3-dihydrofuranyl group, 2,5-dihydrofuranyl group, pyrrolidinyl group, 2,3-dihydropyrrolidinyl group, 2, 5-dihydropyrrolidinyl group, tetrahydro- 2H -pyranyl group, 3,4-dihydro- 2H -pyranyl group, 4H -pyranyl group, piperidinyl group, 1,2,3,4- A tetrahydropyridinyl group, a 1,4-dihydropyridinyl group, a piperazinyl group, an N -protected piperazinyl group, a morpholino group, and the like may be included. In addition, the above heterocycle group is -OH, C ₁ -C ₁₀ alkyl group, -(C ₁ -C ₁₀ hydroxyalkyl), -O-(C ₁ -C ₁₀ alkyl), -C(O)-(C ₁ -C ₁₀ alkyl), or -C(O)NH ₂ .

In the present invention, 'aryl' means a single-ring, double-ring, or three-ring aromatic hydrocarbon group having from 6 to 15 carbon atoms. Specific examples of such an aryl group include a phenyl group and a naphthyl group.

In the present invention, 'heteroaryl' is a 5- to 14-membered monocyclic, double-cyclic, or three-cyclic aromatic ring containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms. means ring. These heteroaryls are thiophenyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, pyridinyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, indolyl group, iso An indolyl group, an indazolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzisothiazolyl group, a quinolinyl group, an isoquinolinyl group, a phthalazinyl group, a quinazolinyl group, and the like may be included.

Specific examples of the novel pyrimidodiazepine derivative compounds having various substituents represented by Chemical Formula 1 according to the present invention are as follows:

(Compound No. 1) 6-methyl-N-(4-(piperazin-1-yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2- amine;

(Compound No. 2) 6-methyl-N-(4-morpholinophenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine;

(Compound No. 3) 6-methyl-N-(4-(piperidin-1yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2- amine;

(Compound No. 4) 4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol;

(Compound No. 5) 6-methyl-N-(4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4] diazepin-2-amine;

(Compound No. 6) 6-methyl-N-(4-(2-piperidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4 ]diazepin-2-amine;

(Compound No. 7) 6-methyl-N-(4-(2-morpholinoethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2- amine;

(Compound No. 8) 6-methyl-N-(4-(2-dimethylamino)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2 -amine;

(Compound No. 9) 1-((3-((6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)aminophenyl)sulfonyl) piperidin-4-ol;

Meanwhile, the present invention provides a method for preparing a pyrimidodiazepine derivative compound having various novel substituents represented by Formula 1 above.

The method for producing a compound represented by Formula 1 as a compound according to the present invention,

Dichloropyrimidine is reacted with 2'-aminoacetophenone in the presence of a base to synthesize chloropyrimidine, and the nitro group is reduced to convert it into an amino group. Reacting the obtained compound in silica gel to synthesize an azepine derivative and reacting using a microwave reactor to prepare each desired compound; and

[Scheme 1]

(In Reaction Scheme 1, R ₁ and R ₂ are each as defined in Formula 1)

As shown in Scheme 2, the intermediate sulfone compound in Scheme 1 is reacted with benzene sulfonyl chloride and 4-hydroxypiperidine to produce sulfonamide and hydrogen reduction of the nitro group to prepare an amine compound.

[Scheme 2]

In carrying out the above preparation method, mono-, di- or tri-alkyl amine bases may be preferably used as the amine base, and specifically, monomethylamine, dimethylamine, trimethylamine, diisopropylethylamine, and the like may be included. can

In addition, a common organic solvent may be used as the reaction solvent. Preferably, alcohols may be used as the reaction solvent, specifically, aliphatic alcohols including methanol, ethanol, n-propanol, isopropanol, n-butanol, etc., and methoxymethanol, methoxyethanol, ethoxyethanol, etc. One or more selected from alkoxyalcohols may be used.

In addition, the compounds prepared through the above preparation method may be diluted and washed with an organic solvent in a general separation and purification process, for example, the organic layer may be concentrated under reduced pressure, and if necessary, may be purified by column chromatography.

On the other hand, the compound represented by Chemical Formula 1 according to the present invention is useful as a new target therapy capable of treating various human cancer diseases because it has excellent inhibitory activity selectively for TRKC. Cancer diseases that can be treated and prevented by the compound represented by Formula 1 may specifically include brain cancer, ovarian cancer, prostate cancer, and breast cancer.

Therefore, the present invention can be used as an anticancer agent containing, as an active ingredient, a pyrimidodiazepine derivative compound having various substituents represented by Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

In addition, the pharmaceutical composition of the present invention contains, as an active ingredient, a pyrimidodiazepine derivative compound having various substituents represented by Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. By adding non-toxic pharmaceutically acceptable carriers, reinforcing agents and excipients, etc., conventional preparations in the pharmaceutical field, such as tablets, capsules, troches, solutions, suspensions, etc., or preparations for parenteral administration. It can be manufactured and used for the prevention and treatment of various types of tumors.

Excipients that may be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. Examples include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, arginic acid, sodium Alginates, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

In addition, the dosage of the compound represented by Chemical Formula 1 according to the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition, and degree of disease, based on an adult patient weighing 70 kg. It is generally 0.01 mg to 5000 mg per day, and may be administered in divided doses once a day to several times at regular time intervals according to the judgment of a doctor or pharmacist.

Hereinafter, various aspects of the present invention will be described.

One aspect of the present invention provides a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₃ -C ₁₀ cyclyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heterocyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); amino group; nitro group; amide group; carboxylic acid group; nitrile group; early childhood; sulfonamide group; sulfide group; sulfone group; or a phosphoryl group;

R ₂ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; Or a C ₃ -C ₁₀ heterocyclyl group;

The C ₁ -C ₁₃ alkyl group, C ₁ -C ₆ alkoxy group or C ₃ -C ₁₀ cyclyl group may be hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may be hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₃ R ₄ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C ₁ -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;

The R ₃ and R ₄ are each independently hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or R ₃ together with the nitrogen or carbon atom connected to R ₄ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group and Forming a 3- to 7-membered saturated ring that may be optionally substituted with at least one of the cyano groups;

The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.

In one aspect of the present invention, R ₁ is a hydrogen atom, an alkyl group, a halogen, piperazine, morpholine, piperidine, hydroxy, 2-pyrrolidinylethoxy, 2-piperidinylethoxy, 2-morpholino ethoxy, 2-dialkylaminoethoxy or 4-hydroxypiperininylsulfonyl; R ₂ is a hydrogen atom, methyl, ethyl, cycloalkyl, phenyl, methoxyphenyl, acetyl, propionyl, benzoyl or methoxybenzoyl halobenzoyl, a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, and a solvent thereof A cargo, a hydrate thereof or a pharmaceutically acceptable salt thereof is provided.

,

,

,-OH,

,

,

,

, 또는

이며, R₂는 각각 독립적으로 수소원자 또는 탄소수 1 내지 3의 알킬기인, 화학식 1로 표시되는 신규 피리미딘 유도체 화합물, 이의 입체이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In one aspect of the invention, R ₁ is

,

,

,—OH,

,

,

,

, or

And, R ₂ is each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. do.

In one aspect of the present invention, the novel pyrimidine derivative compound is any one selected from the following, a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. provides:

Compound No. 1: 6-methyl-N-(4-(piperazin-1-yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine ;

Compound No. 2: 6-methyl-N-(4-morpholinophenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine;

Compound No. 3: 6-methyl-N-(4-(piperidin-1yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine ;

Compound No. 4: 4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol;

Compound No. 5: 6-methyl-N-(4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]dia zepin-2-amine;

Compound No. 6: 6-methyl-N-(4-(2-piperidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4] diazepin-2-amine;

Compound No. 7: 6-methyl-N-(4-(2-morpholinoethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine ;

Compound No. 8: 6-methyl-N-(4-(2-dimethylamino)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2- amine; and

Compound No. 9: 1-((3-((6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)aminophenyl)sulfonyl)p Peridin-4-ol.

Another aspect of the present invention provides a pharmaceutical composition for treating, preventing or mitigating cancer containing the compound of any one of the aspects of the present invention as an active ingredient.

In another aspect of the present invention, the active ingredient provides a pharmaceutical composition for inhibiting TRKC kinase activity, treating, preventing or mitigating cancer.

In another aspect of the present invention, the pharmaceutical composition provides a pharmaceutical composition for cancer treatment, prevention or reduction, which is applied to a patient group having a TRKC expression gene.

In another aspect of the present invention, the cancer is any one or more of ovarian cancer, non-small cell cancer, rectal cancer, glioma, breast cancer, esophageal cancer, lung cancer, uterine cancer, pancreatic cancer, prostate cancer, and hematological cancer. composition is provided.

Another aspect of the present invention provides a pharmaceutical composition for the treatment, prevention or alleviation of TRKC-related degenerative brain diseases, which contains the compound of any one of the aspects of the present invention as an active ingredient.

Another aspect of the present invention provides a pharmaceutical composition for the treatment, prevention or alleviation of TRKC-related inflammatory diseases, which contains the compound of any one of the aspects of the present invention as an active ingredient.

Another aspect of the present invention provides a pharmaceutical composition for pain treatment or alleviation containing the compound of any one of the aspects of the present invention as an active ingredient.

The present invention as described above will be described in more detail based on the following Examples, Preparation Examples and Experimental Examples, but the present invention is by no means limited thereto.

Example 1. 6-Methyl-N-(4-(piperazin-1-yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine manufacture of

Example 1-1. Preparation of 1-(2-((2-chloro-5-nitropyrimidin-4-yl)amino)phenyl)ethan-1-one

Acetone (20 ml), 2,4-dichloro-5-nitropyrimidine (5.0 mmol, 0.97 g), and anhydrous potassium carbonate (5.0 mmol, 0.69 g) were added to a two-necked round bottom flask and 2'-aminoacetophenone (5.0 mmol, 0.6 ml) was added and stirred at room temperature for 3 hours. After completion of the reaction, acetone was distilled off, ethyl acetate (100 ml) and water (100 ml) were added, and the organic layer was separated. The separated organic layer is dried with anhydrous sodium sulfate, filtered, and distilled, and the obtained material is solidified using a mixed solvent of dichloromethane and n-hexane to prepare a desired compound.

Yellow solid, yield: 73%, ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.49 (s, 1H, NH), 9.23 (s, 1H, ArH), 8.29 (d, J = 8.4 Hz, 1H, ArH), 8.09–8.11 (m, 1H, ArH), 7.68–7.72 (m, 1H, ArH), 7.39 (t, J = 7.6 Hz, 1H, ArH), 2.67 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO- d6 ) δ 202.18, 162.26, 158.42 _, 153.65, 136.41, 133.87, 131.91, 128.90, 127.65, 125.67, 124.25, 29.22.

Example 1-2. Preparation of 1-2-((5-amino-2-chloropyrimidin-4-yl)amino)phenyl)ethan-1-one (3)

1-(2-((2-chloro-5-nitropyrimidodiazepin-4-yl)amino)phenyl)ethane-1- Add ion (3.57 mmol, 1.04 g), iron powder (17.85 mmol, 1.0 g) and amonium chloride (1.79 mmol, 95.4 mg), respectively, and reflux while stirring for 2 hours. After completion of the reaction, the mixture is cooled to room temperature and filtered on celite to remove iron powder. Ethanol was distilled off, ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added, and the organic layer was separated. The organic layer was dried using anhydrous sodium sulfate, and the compound obtained by filtration and distillation was subjected to silica gel column chromatography (ethyl acetate: n-hexane) to prepare a desired compound.

Yellow solid, yield 43%, ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.04 (s, 1H, NH), 8.45 (d, J = 8.0 Hz, 1H, ArH), 8.06 (dd, J = 8.0 Hz, 1.2 Hz, 1H, ArH), 7.85 (s, 1H, ArH), 7.64-7.69 (m, 1H, ArH), 7.18-7.21 (m, 1H, ArH), 5.10 (s, 2H, NH ₂ ) , 2.67 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, DMSO- d6 ) δ 202.56, 151.81, 147.27 _, 141.58, 140.40, 134.52, 132.33, 129.61, 124.47, 122.40, 121.15, 29.07.

Example 1-3. 2-chloro-6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine (4)

In a 3-neck round bottom flask was added 1-2-((5-amino-2-chloropyrimidodiazepin-4-yl)amino)phenyl)ethan-1-one (1.12 mmol, 294.2 mg), p- toluenesulfonic acid - Put monohydrate (0.06 mmol, 11.4 mg) and silica gel (30 mg) and add 1,4-dioxane (20 mL) thereto. The reaction mixture is refluxed for 4 hours while stirring. After completion of the reaction, the organic solvent was distilled off, and the obtained residue was subjected to column chromatography using silica gel (ethyl acetate: n-hexane) to prepare a desired compound.

Yield 20%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H, ArH), 7.25-7.32 (m, 2H, ArH), 6.98-7.02 (m, 1H, ArH), 6.59 (d, J = 8.0 Hz, 1H, ArH), 6.26 (s, 1H, NH), 2.51 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.86. 161.33, 157.50, 156.64, 146.86, 133.14, 130.87, 130.52, 128.17, 124.01, 120.47, 28.37.

Example 1-4. Preparation of 6-methyl-N-(4-(piperazin-1-yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine

마이크로웨이브용 바이엘에 2-클로로-6-메틸-11H-벤조[e]피리미도[5,4-b][1,4]디아제핀 (0.1 mmol, 23.9 mg), 4-(피페라진-1-일)아닐린 (0.2 mmol, 35.4 mg), 아세토니트릴 (3 ml)을 넣고 5시간 동안 180 ^oC에서 마이크로웨이브 반응기에서 반응시킨다. 반응 완결 후 에틸 아세테이트와 포화 탄산수소나트륨을 넣고 추출하여 유기층을 분리한다. 유기층을 무수 탄산나트륨을 이용하여 건조, 여과, 증류하여 얻어진 화합물을 실리카겔을 사용하여 관크로마토그램 (에틸 아세테이트 : n-헥산)을 수행하여 원하는 화합물을 얻는다.

2-Chloro-6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine (0.1 mmol, 23.9 mg), 4-(piperazine-1) in a microwave vial -yl)aniline (0.2 mmol, 35.4 mg) and acetonitrile (3 ml) were added and reacted in a microwave reactor at 180 ^° C for 5 hours. After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (ethyl acetate: n-hexane) using silica gel to obtain the desired compound.

Brown solid, yield: 21%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H, ArH), 7.32 (d, J = 7.6 Hz, 1H, ArH), 7.29 (s, 1H, ArH) , 7.22-7.26 (m, 1H, ArH), 6.97 (t, J = 7.2 Hz, 1H, ArH), 6.87-6.89 (m, 2H, ArH+NH), 6.70 (d, J = 8.8 Hz, 2H, ArH), 6.61 (d, J = 8.0 Hz, 1H, ArH), 5.70 (s, 1H, NH), 3.92 (t, J = 4.8 Hz, 4H, 2CH ₂ ), 3.08 (t, J = 5.2 Hz, 4H, 2CH ₂ ), 2.49 (s, 3H, CH ₃ ), 1.72 (brs, 1H, NH). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 165.97, 159.49, 157.56, 146.98, 144.58, 140.41, 132.10, 130.06, 127.90, 123.09, 122.80, 119.69, 119.16, 116.22, 51.17, 44.19, 27.95. HRMS (ES ⁺ ): m/z calculated for C ₂₂ H ₂₃ N ₇ : 386.2093 [M+H] ⁺ . Found 386.2091.

Example 2. Preparation of 6-methyl-N-(4-morpholinophenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine

2-chloro-6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine (0.1 mmol, 23.9 mg), 4-morpholinoaniline (0.2 mmol, 35.6 mg) and acetonitrile (3 ml), and reacted in a microwave reactor at 180 ^° C. for 5 hours. After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (ethyl acetate: n-hexane) using silica gel to obtain the desired compound.

Yellow solid, yield: 26%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H, ArH), 7.33 (d, J = 8.8 Hz, 2H, ArH), 7.19-7.23 (m, 1H, ArH), 7.14 (td, J = 7.6 Hz, 1.2 Hz, 1H, ArH), 6.97 (s, 1H, NH), 6.86–6.90 (m, 1H, ArH), 6.82 (d, J = 8.8 Hz, 2H) , ArH), 6.48 (dd, J = 8.0 Hz, 0.8 Hz, 1H, ArH), 5.72 (s, 1H, NH), 3.79 (t, J = 4.8 Hz, 4H, 2CH ₂ ), 3.04 (t, J = 4.8 Hz, 4H, 2CH ₂ ), 2.40 (s, 3H, CH ₃ ). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 166.81, 159.74, 157.91, 157.57, 147.45, 146.86, 132.27, 132.02, 130.16, 127.98, 123.29, 121.61, 119.88, 116.57, 66.96, 50.03, 28.01. HRMS (ES ⁺ ): m/z calculated for C ₂₂ H ₂₂ N ₆ O: 387.1933 [M+H] ⁺ . Found 387.1935.

Example 3. 6-Methyl-N-(4-(piperidin-1yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine manufacture of

2-chloro-6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine (0.1 mmol, 23.9 mg), 4-(piperidine- 1-yl)aniline (0.2 mmol, 35.3 mg) and acetonitrile (3 ml) were added and reacted in a microwave reactor at 180 ^° C for 5 hours. After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (ethyl acetate: n-hexane) using silica gel to obtain the desired compound.

Yellow solid, yield: 16%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.19-7.23 (m, 1H), 7.12-7.16 (m, 1H), 6.97 (s, 1H), 6.89 (d, J = 6.8 Hz, 3H), 6.49 (d, J = 7.6 Hz, 1H), 5.71 (s, 1H), 3.04 (t, J = 5.6 Hz, 4H), 2.40 (s, 3H), 1.67 (s, 6H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 166.52, 159.77, 158.19, 157.76, 148.65, 146.96, 132.24, 131.27, 130.12, 127.99, 124.25, 123.17, 121.80 HRMS (ES ⁺ ): m/z calculated for C ₂₃ H ₂₄ N ₆ : 385.2140 [M+H] ⁺ . Found 385.2142.

Example 4. Preparation of 4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol

2-chloro-6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine (0.33 mmol, 80.8 mg), 4-aminophenol (0.50 mmol) in a microwave vial , 54.0 mg) (0.2 mmol, 35.3 mg), ethanol (12 ml), and reacted in a microwave reactor at 180 ^° C for 5 hours. After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (ethyl acetate: n-hexane) using silica gel to obtain the desired compound.

Brown solid, yield 48%, ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 (s, 1H), 8.98 (s, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.50 ( d, J = 8.8 Hz, 2H), 7.35 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.24–7.28 (m, 1H), 6.92–6.95 (m, 2H), 6.68–6.71 (m, 2H) ), 2.34 (s, 3H). ¹³ C NMR (100 MHz, DMSO- D ₆ ) δ 166.20, 160.35, 158.31, 157.42, 152.69, 148.32, 132.65, 132.52, 130.54, 128.18, 124.06, 123.15, 121.50, 120.79, 115.36, 28.06.

Example 5. 6-Methyl-N-(4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]dia Preparation of Zepin-2-amine

디메틸포름아마이드 (11 ml)에 4-((6-메틸-11H-벤조[5,4-b][1,4]디아제핀-2-일)아미노)페놀 (0.1 mmol, 32 mg), 2-클로로에틸 피로리딘·염산염 (0.1 mmol, 17 mg)을 넣고 질소 분위기 하에서 탄산 세슘 (0.22 mmol, 71.7 mg)을 넣는다. 반응 혼합물을 저어주면서 3시간 동안 환류한다.

4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol (0.1 mmol, 32 mg), 2 in dimethylformamide (11 ml) -Add chloroethyl pyridine hydrochloride (0.1 mmol, 17 mg) and add cesium carbonate (0.22 mmol, 71.7 mg) under a nitrogen atmosphere. The reaction mixture is refluxed for 3 hours while stirring.

After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering, and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (dichloromethane: methanol) using silica gel to obtain the desired compound.

Yellow solid, yield 50%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.29-7.33 (m, 3H), 7.19-7.21 (m, 1H), 7.10-7.14 (m, 1H) ), 6.86 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.10 (t, J = 5.2 Hz, 2H), 2.95 (s, 4H), 2.38 (s, 3H), 1.90 (s, 4H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 166.93, 159.88, 157.90, 157.60, 153.91, 147.01, 133.05, 132.33, 130.13, 127.96, 124.49, 123.21, 121.86, 120.01, 114.97, 65.57 .. HRMS (ES ⁺ ): m/z calculated for C ₂₄ H ₂₆ N ₆ O: 415.2246 [M+H] ⁺ . Found 415.2246.

Example 6. 6-Methyl-N-(4-(2-piperidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4] Preparation of diazepin-2-amine

디메틸포름아마이드 (11 ml)에 4-((6-메틸-11H-벤조[5,4-b][1,4]디아제핀-2-일)아미노)페놀 (0.1 mmol, 32 mg), 2-클로로에틸 피페리딘·염산염 (0.1 mmol, 18.4 mg)을 넣고 질소 분위기 하에서 탄산 세슘 (0.22 mmol, 71.7 mg)을 넣는다. 반응 혼합물을 저어주면서 3시간 동안 환류한다.

4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol (0.1 mmol, 32 mg), 2 in dimethylformamide (11 ml) -Add chloroethyl piperidine hydrochloride (0.1 mmol, 18.4 mg) and add cesium carbonate (0.22 mmol, 71.7 mg) under a nitrogen atmosphere. The reaction mixture is refluxed for 3 hours while stirring.

After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (dichloromethane: methanol) using silica gel to obtain the desired compound.

Yellow solid, yield 61%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.19-7.21 (m, 2H), 7.10-7.14 ( m, 1H), 6.84–6.88 (m, 1H), 6.79 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.02 (t, J = 6.0 Hz, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.45 (s, 4H), 2.39 (s, 3H), 1.52-1.58 (m, 4H), 1.38-1.41 (m, 2H) . ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 166.80, 159.77, 158.05, 157.71, 154.87, 146.94, 132.41, 132.28, 130.14, 127.99, 124.44, 123.24, 122.03 , 24.16. HRMS (ES ⁺ ): m/z calculated for C ₂₅ H ₂₈ N ₆ O: 429.2403 [M+H] ⁺ . Found 429.2411.

Example 7. 6-Methyl-N-(4-(2-morpholinoethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine manufacture of

4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol (0.1 mmol, 32 mg), 2 in dimethylformamide (11 ml) -Add chloroethyl morpholine hydrochloride (0.1 mmol, 18.6 mg) and add cesium carbonate (0.22 mmol, 71.7 mg) under a nitrogen atmosphere. The reaction mixture is refluxed for 3 hours while stirring.

After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (dichloromethane: methanol) using silica gel to obtain the desired compound.

Yellow solid, yield 36%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.19-7.23 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.48 (d, J = 8.0 Hz, 1H) , 5.75 (s, 1H), 4.04 (t, J = 5.6 Hz, 2H), 3.68 (t, J = 4.8 Hz, 4H), 2.74 (t, J = 5.6 Hz, 2H), 2.53 (s, 4H) , 2.40 (s, 3H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 166.91, 159.76, 157.98, 157.69, 154.73, 146.90, 132.57, 132.29, 130.17, 127.99, 124.50, 123.29, 121.96, 119.89 . HRMS (ES ⁺ ): m/z calculated for C ₂₄ H ₂₆ N ₆ O ₂ : 431.2195 [M+H] ⁺ . Found 431.2193.

Example 8. 6-Methyl-N-(4-(2-dimethylamino)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2- Preparation of amines

디메틸포름아마이드 (11 ml)에 4-((6-메틸-11H-벤조[5,4-b][1,4]디아제핀-2-일)아미노)페놀 (0.1 mmol, 32 mg), 2-(디메틸아미노)에틸 클로라이드 (0.1 mmol, 10.8 mg)을 넣고 질소 분위기 하에서 탄산 세슘 (0.22 mmol, 71.7 mg)을 넣는다. 반응 혼합물을 저어주면서 3시간 동안 환류한다.

4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol (0.1 mmol, 32 mg), 2 in dimethylformamide (11 ml) -(Dimethylamino)ethyl chloride (0.1 mmol, 10.8 mg) was added and cesium carbonate (0.22 mmol, 71.7 mg) was added under a nitrogen atmosphere. The reaction mixture is refluxed for 3 hours while stirring.

After completion of the reaction, ethyl acetate and saturated sodium bicarbonate were added for extraction, and the organic layer was separated. The compound obtained by drying, filtering and distilling the organic layer with anhydrous sodium carbonate is subjected to column chromatography (dichloromethane: methanol) using silica gel to obtain the desired compound.

Yellow solid, yield 40%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.21 (dd, J = 8.0 Hz, 1.2 Hz, 2H ), 7.11-7.15 (m, 1H), 6.99 (s, 1H), 6.85-6.89 (m, 1H), 6.82 (d, J = 9.2 Hz, 2H), 6.48 (d, J = 8.8 Hz, 1H) , 4.00 (t, J = 5.6 Hz, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.39 (s, 3H), 2.29 (s, 6H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 166.86, 159.74, 158.00, 157.72, 154.83, 146.94, 132.48, 132.28, 130.15, 128.00, 124.49, 123.27, 121.89, 119.90 HRMS (ES ⁺ ): m/z calculated for C ₂₂ H ₂₄ N ₆ O: 389.2099 [M+H] ⁺ . Found 389.2089.

Example 9. 1-((3-((6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)aminophenyl)sulfonyl)p Preparation of peridin-4-ol

Example 9-1. Preparation of 1-((3-nitrophenylsulfonyl)piperidin-4-ol (10)

Add 3-nitrobenzenesulfonyl chloride (2.5 mmol, 546 mg), 4-hydroxypiperidine (2.7 mmol, 274.1 mg), and triethylamine (6.2 mmol, 0.86 mL) to dichloromethane (15 ml) at room temperature. Stir for 2 hours. After completion of the reaction, water was added, the organic layer was separated, dried using anhydrous magnesium sulfate, filtered, and distilled to obtain a white solid.

Yield 93%, ^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.54-8.56 (m, 1H), 8.38 (t, J = 2.0 Hz, 1H), 8.18-8.20 (m, 1H), 7.96 (t , J = 8.0 Hz, 1H), 3.52–3.57 (m, 1H), 3.21–3.26 (m, 2H), 2.80–2.85 (m, 2H), 1.73–1.79 (m, 2H), 1.40–1.48 (m , 2H). ¹³ C NMR (100 MHz, DMSO- d6 ) δ 148.57, 137.89, 133.81, 132.00, _128.15 , 122.39, 64.16, 43.67, 33.35.

Example 9-2. Preparation of 1-((3-aminophenyl)sulfonyl)piperidin-4-ol (11)

Add 1-((3-nitrophenylsulfonyl)piperidin-4-ol (6 mmol, 1.72 g) and 10% Pd/C catalyst (30 mg) in methanol (85 mL) under a nitrogen atmosphere. Here A hydrogen gas atmosphere is created using a balloon to conduct a hydrogenation reaction.

The reaction mixture was reacted at room temperature for 3 hours, and after completion of the reaction, the catalyst was removed using Celite. The filtrate is distilled and used in the next reaction.

Yield 83%, ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23 (s, 1H), 6.81-6.92 (m, 3H), 5.65 (s, 2H), 4.73 (s, 1H), 3.54 (s , 1H), 3.12 (s, 2H), 2.70 (s, 2H), 1.74 (s, 2H), 1.45 (s, 2H). ¹³ C NMR (100 MHz, DMSO- d6 ) δ 149.98, 136.33, 130.04, 118.22, _114.47 , 112.14, 64.30, 43.64, 33.38.

Example 9-3. 1-((3-((6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)aminophenyl)sulfonyl)piperidine-4 -Manufacture of wool

질소 분위기 하에서 1,4-디옥산 (10 ml)에 2-클로로-6-메틸-11H-벤조[e]피리미도[5,4-b][1,4]디아제핀 (0.23 mmol, 57.4 mg), 탄산세슘 (0.97 mmol, 316 mg), XPhos (0.12 mmol, 57.2 mg) and Pd₂(dba)₃ (0.04 mmol, 36.6 mg)을 넣고 저어주면서 1-((3-아미노페닐)술포닐)피페리딘-4-올 (0.35 mmol, 89.7 mg)을 넣어 준다. 반응 혼합물을 저어주면서 24시간 동안 환류한다. 반응 완결 후 셀라이트를 깔고 여과하여 고체물질을 제거하고 디클로로메탄 (100 ml)과 물 (100 ml)을 넣고 추출하여 유기층을 분리하고 무수 황산 나트륨으로 건조 후, 여과, 증류하여 얻어진 잔여물을 실리카겔 관 크로마토그램 (에틸 아세테이트 : n-헥산)을 수행한다.

2-chloro-6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine (0.23 mmol, 57.4 mg) in 1,4-dioxane (10 ml) under nitrogen atmosphere ), cesium carbonate (0.97 mmol, 316 mg), XPhos (0.12 mmol, 57.2 mg) and Pd ₂ (dba) ₃ (0.04 mmol, 36.6 mg) were added while stirring and 1-((3-aminophenyl)sulfonyl) Piperidin-4-ol (0.35 mmol, 89.7 mg) was added thereto. The reaction mixture is refluxed for 24 hours with stirring. After the reaction was completed, celite was spread and filtered to remove solid substances, dichloromethane (100 ml) and water (100 ml) were added and extracted, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled, and the residue obtained was silica gel A column chromatogram (ethyl acetate: n-hexane) is performed.

Yellow solid, yield 9%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.96 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.22–7.24 (m, 1H), 7.19 (s, 1H), 7.14–7.18 (m, 1H), 6.88–6.92 (m) , 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.03 (s, 1H), 3.70–3.74 (m, 1H), 3.21–3.26 (m, 2H), 2.82–2.88 (m, 2H), 2.41 (s, 3H), 1.82–1.87 (m, 2H), 1.56–1.62 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 168.27, 159.99, 156.97, 156.83, 146.71, 140.20, 136.75, 132.63, 130.32, 129.52, 127.91, 125.43, 123.55 , 28.04. HRMS (ES ⁺ ): m/z calculated for C ₂₃ H ₂₄ N ₆ O ₃ S: 465.1709 [M+H] ⁺ . Found 465.1708.

Experimental Example 1. Measurement of kinase inhibitory activity

Kinase screening was performed using the "HotSpot" assay platform method by Reaction Biology Corporation. 20 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, and 1% DMSO were used as the reaction buffer. . Necessary cofactors were added according to the kinase reaction. Freshly prepared buffer solutions and cofactors were added to the selected enzyme reaction at a concentration of 20 μM. To this solution, the test compound dissolved in dimethyl sulfoxide (DMSO) was added at an appropriate concentration. To initiate the reaction, 339-ATP (specific activity 500 μCi/μL) was added and incubated for 2 hours at room temperature. Then, the test compound was screened in 10-dose IC ₅₀ mode starting at a concentration of 20 μM. Staurosporine used as a control drug was started at a concentration of 20 μM and the IC ₅₀ value was obtained by 10-dose IC ₅₀ mode. The reaction was performed at a concentration of 10 μM ATP, and the results are summarized in Table 1 below.

Table 1 shows the inhibitory activity of representative compounds against TRKs.

Example TRKC
( _IC50 ) TRKA
( _IC50 ) TRKB
( _IC50 ) note Example 1 1 μM < 1 μM < 1 μM < Example 2 26.3 nM 1 μM < 1 μM < Example 5 21.0 nM 1 μM < 1 μM < Example 6 25.1 nM 1 μM < 1 μM < Example 7 51.1 nM 1 μM < 1 μM < Staurosporine 0.15 nM 3 nM 0.1 nM

It was confirmed that the pyrimidodiazepine compound had a very high selectivity for TRKC among TRKA, TRKB, and TRKC when compared to staurosporine used as a control substance, and compared to compounds under development such as GNF-5837, CH7057288, Entrectinib, and Repotrectinib. A large selectivity was demonstrated.

[Formulation example]

Meanwhile, the novel compound represented by Chemical Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation Example 1. Tablet (direct pressurization)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed into tablets.

Formulation Example 2. Tablet (wet granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 0.3 mg of polysorbate 80 in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation Example 3. Powder and Capsule

After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture is hardened to No. 10 using a suitable device. Filled in 5 gelatin capsules.

Formulation Example 4. Injection

An injection was prepared by containing 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ /H ₂ O, and 2974 mg of distilled water.

Although the embodiments of the present invention have been described above, those skilled in the art will understand that the present invention can be implemented in other specific forms without changing its technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (11)

A novel pyrimidine derivative compound represented by Formula 1 below, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
[Formula 1]

In Formula 1,
R ₁ is a hydroxyl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ heterocyclyl group; or a sulfonamide group;
R ₂ is hydrogen;
The C ₁ -C ₆ alkoxy group is hydrogen; hydroxy group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group;
The C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxy group; halogen group; a carbonyl group (-(C=O)R ₃ R ₄ ); a C ₁ -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; A C 1 -C ₃ alkoxy group unsubstituted or substituted with a halogen or C _{3 -C 10} heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); an amide group (-(C=O)NR ₃ R ₄ ); a carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfone group (-S(O) ₂ -); a phosphoryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; It contains one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C ₁₀ heterocyclyl group;
The R ₃ and R ₄ are each independently hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; or R ₃ together with the nitrogen or carbon atom connected to R ₄ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, or SO ₂ may optionally include at least one of hydrogen, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide group and Forming a 3- to 7-membered saturated ring that may be optionally substituted with at least one of the cyano groups;
The C ₃ -C ₁₀ heteroaryl group and C ₃ -C ₁₀ heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.
According to claim 1,
R ₁ is

,

,

,—OH,

,

,

,

, or

person
A novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The novel pyrimidine derivative compound is any one selected from the following, a novel pyrimidine derivative compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
Compound No. 1: 6-methyl-N-(4-(piperazin-1-yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine ;
Compound No. 2: 6-methyl-N-(4-morpholinophenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine;
Compound No. 3: 6-methyl-N-(4-(piperidin-1yl)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine ;
Compound No. 4: 4-((6-methyl-11H-benzo[5,4-b][1,4]diazepin-2-yl)amino)phenol;
Compound No. 5: 6-methyl-N-(4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]dia zepin-2-amine;
Compound No. 6: 6-methyl-N-(4-(2-piperidin-1-yl)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4] diazepin-2-amine;
Compound No. 7: 6-methyl-N-(4-(2-morpholinoethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-amine ;
Compound No. 8: 6-methyl-N-(4-(2-dimethylamino)ethoxy)phenyl)-11H-benzo[e]pyrimido[5,4-b][1,4]diazepine-2- amine; and
Compound No. 9: 1-((3-((6-methyl-11H-benzo[e]pyrimido[5,4-b][1,4]diazepin-2-yl)aminophenyl)sulfonyl)p peridin-4-ol;
In the pharmaceutical composition for treating, preventing or mitigating cancer containing the compound of any one of claims 1 to 3 as an active ingredient,
The cancer is any one or more of ovarian cancer, non-small cell cancer, rectal cancer, glioma, breast cancer, esophageal cancer, lung cancer, uterine cancer, pancreatic cancer, prostate cancer, and blood cancer,
A pharmaceutical composition for treating, preventing or mitigating cancer.
A pharmaceutical composition for the treatment, prevention or alleviation of TRKC-related degenerative brain diseases, which contains the compound of any one of claims 1 to 3 as an active ingredient.
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