KR102335637B1 - Novel compounds of inhibiting cdk7, and their pharmaceutically acceptable salts - Google Patents

Abstract

본 발명의 신규한 화합물은 높은 CDK7 억제 활성을 나타내므로 CDK7 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있다.The present invention relates to novel compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, or solvates of salts thereof.
<Formula (I)>

Since the novel compound of the present invention exhibits high CDK7 inhibitory activity, it can be usefully used for the treatment or prevention of CDK7-related diseases.

Description

NOVEL COMPOUNDS OF INHIBITING CDK7, AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS

The present invention relates to novel compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, or solvates of salts thereof.

<Formula (I)>

Since the novel compound of the present invention exhibits high CDK7 inhibitory activity, it can be usefully used for the treatment or prevention of CDK7-related diseases.

Protein kinase refers to a protein that plays a central role in the regulation of a wide variety of cellular processes and control of cellular functions. Kinase activity is observed in a number of disease states, including benign and malignant proliferative disorders, as well as those resulting from inappropriate activation of the immune and nervous systems. Oncogenesis is closely related to genetic modification of cyclin-dependent kinase (CDK) and its regulators, suggesting that CDK inhibitors may be useful anticancer therapeutics.

CDKs form a complex with cyclin proteins and activate them by phosphorylation of serine or threonine residues on the substrate. Among them, CDK1, CDK2, CDK4, and CDK6 regulate the entry into each phase of the cell cycle by phosphorylation of important molecules in the cell cycle. For example, CDK2/cyclin E is essential to enter the S phase, and CDK2/cyclin A is essential just before the transition from S phase to G2 phase. CDK8 and CDK9 are also involved in gene transcription.

CDK activation is completed by phosphorylation by CDK-activating kinase (CAK), and the CDK7/cyclin H complex acts as a CAK. In addition, CDK7 phosphorylates the C-terminal domain (CTD) of RNA polymerase (RNAP) II, thereby regulating the expression of oncogenic transcription factors that induce cancer cell growth and survival. That is, CDK7 is the only CDK involved in transcription and regulating the cell cycle by acting as a CAK and phosphorylating CTD at the same time.

Although cancer cells have increased genetic heterogeneity compared to normal cells, they can inhibit cancer cell growth or induce apoptosis by targeting driver mutations in major oncogenes. However, in the case of “transcriptional poisoning cancer cells” without a specific driver mutation, the growth of cancer cells can be inhibited by transcriptional regulatory kinases such as CDK7 (Yubao Wang et al., Cell 163, 174-186, September 24, 2015). Accordingly, there is a need for compounds that treat diseases and disorders associated with selective transcriptional CDKs, particularly CDK7.

Meanwhile, in order to maintain homeostasis of pharmaceuticals, it is necessary to suppress the decrease in the content of active ingredients from the manufacturing stage to the storage period of the product, and to keep the increase in impurities or related substances to a minimum.

Accordingly, the present inventors have researched and developed novel compounds that selectively inhibit CDK7, and pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts with improved physicochemical stability and solubility of the compounds. The present invention was completed.

International Publication WO 2014/063068 A1 International Publication WO 2015/058140 A1

An object of the present invention is to provide a novel compound having excellent CDK7 inhibitory activity.

Another object of the present invention is to provide pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts of the novel compounds, which have excellent physicochemical stability and solubility.

Another object of the present invention is to provide a method for preparing pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts of the novel compounds.

Another object of the present invention is to provide a pharmaceutical composition comprising the novel compound, a pharmaceutically acceptable salt, hydrate, solvate, hydrate of a salt, or a solvate of a salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating CDK7-related diseases, including the novel compound, a pharmaceutically acceptable salt, hydrate, solvate, salt hydrate, or salt solvate thereof.

The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.

<Formula (I)>

In the above formula,

_{Ra is linear C 1} -C ₃ alkyl substituted or unsubstituted with halogen;

Rb is cyano or halo, Rc is H; or

Rb and Rc together with the pyridine linked to Rb and the nitrogen linked to Rc form a fused 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) is oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemi Sulfonate, tartrate, maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, and 4-hydroxy- It may be selected from the group consisting of benzoates. In this case, the tartrate may be L-tartrate, the aspartate may be L-aspartate, the glutamate may be L-glutamate, and the camphorsulfonate may be (+)-camphorsulfonate. Preferably, it may be oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, or nicotinate, and more preferably, hydrochloride or oxalate.

In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) may be in the form of a hydrate or solvate.

In one embodiment, the solvate of the pharmaceutically acceptable salt of the compound of formula (I) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertbutyl It may be formed by one or more solvents selected from the group consisting of ether and heptane, but is not limited thereto.

The present invention provides a compound selected from the group consisting of compounds of formulas (II) to (VIII), or a pharmaceutically acceptable salt thereof.

<Formula (II)>

<Formula (III)>

<Formula (IV)>

<Formula (V)>

<Formula (VI)>

<Formula (VII)>

<Formula (VIII)>

In one embodiment, the pharmaceutically acceptable salts of the compounds of formulas (II) to (VIII) are oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, and 4 It may be selected from the group consisting of -hydroxy-benzoate. In this case, the tartrate may be L-tartrate, the aspartate may be L-aspartate, the glutamate may be L-glutamate, and the camphorsulfonate may be (+)-camphorsulfonate. Preferably, it may be oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, or nicotinate, and more preferably, hydrochloride or oxalate.

In one embodiment, the pharmaceutically acceptable salt of the compound of formulas (II) to (VIII) may be in the form of a hydrate or a solvate.

In one embodiment, the solvate of a pharmaceutically acceptable salt of a compound of Formulas (II) to (VIII) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether , methyl tertiary butyl ether, and may be formed by one or more solvents selected from the group consisting of heptane, but is not limited thereto.

The present invention provides a compound of formula (VI) or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt of the compound of formula (VI) is selected from the group consisting of oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, and nicotinate. may be selected, and preferably, hydrochloride or oxalate.

In one embodiment, the pharmaceutically acceptable salt of the compound of formula (VI) may be in the form of a hydrate or solvate.

In one embodiment, the solvate of the pharmaceutically acceptable salt of the compound of formula (VI) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertbutyl It may be formed by one or more solvents selected from the group consisting of ether and heptane, but is not limited thereto.

The present invention provides an oxalate salt of a compound of formula (VI).

The present invention provides a hydrate of the oxalate salt of the compound of formula (VI).

In one embodiment, the hydrate of the oxalate salt of the compound of formula (VI) may be amorphous.

The present invention provides solvates of the oxalates of the compounds of formula (VI).

In one embodiment, the solvate of the oxalate salt of the compound of formula (VI) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertiarybutyl ether, and heptane. It may be formed by one or more solvents selected from the group consisting of, preferably, acetone solvate of oxalate.

In one embodiment, the acetone solvate of the oxalate salt of the compound of formula (VI) may be in crystalline form, preferably 7.4°, 8.3°, 9.3°, 10.1°, 11.2°, 11.5°, 12.6°, 15.2 °, 16.5°, 16.9°, 17.4°, 17.8°, 18.6°, 19.8°, 20.3°, 21.6°, 22.1°, 22.9°, 23.6°, 24.4°, 25.5°, 26.6°, 29.0° and 31.5° It may be in a crystalline form showing an X-ray diffraction (XRD) spectrum comprising characteristic peaks at 4 or more diffraction angles 2θ ± 0.2° selected from the group consisting of, and more preferably, X-ray diffraction as shown in FIG. 1 . (XRD) spectrum.

The present invention provides anhydrides of the oxalates of compounds of formula (VI).

In one embodiment, the anhydride of the oxalate salt of the compound of formula (VI) may be in crystalline form, preferably 8.3°, 13.7°, 14.9°, 15.3°, 16.0°, 16.7°, 16.9°, 17.6°, Characteristic at 4 or more diffraction angles 2θ ± 0.2° selected from the group consisting of 18.4°, 18.8°, 19.2°, 19.9°, 20.7°, 21.4°, 21.9°, 22.7°, 23.8°, 25.3°, and 25.6° It may be a crystalline form exhibiting an X-ray diffraction (XRD) spectrum including peaks, and more preferably, a crystalline form having an X-ray diffraction (XRD) spectrum as shown in FIG. 3 .

The present invention provides the hydrochloride salt of the compound of formula (VI).

In one embodiment, the hydrochloride salt of the compound of formula (VI) may be in crystalline form, preferably 7.0°, 9.1°, 10.5°, 11.0°, 13.5°, 17.1°, 19.0°, 20.8°, 21.3° , 23.2°, and 25.7° may be in a crystalline form showing an X-ray diffraction (XRD) spectrum comprising characteristic peaks at four or more diffraction angles 2θ±0.2° selected from the group consisting of, more preferably, FIG. 4 It may be in a crystalline form having an X-ray diffraction (XRD) spectrum as shown in

The present invention provides a hydrate of the hydrochloride salt of the compound of formula (VI).

The present invention provides solvates of the hydrochloride salts of compounds of formula (VI).

In one embodiment, the solvate of the hydrochloride salt of the compound of formula (VI) is acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertiarybutyl ether, and heptane. It may be formed by one or more solvents selected from the group consisting of.

The present invention provides the anhydride of the hydrochloride salt of the compound of formula (VI).

In one embodiment, the oxalate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding oxalic acid to the solution; and obtaining an oxalate salt of the compound of formula (I).

In one embodiment, the acetone solvate of the oxalate of the compound of formula (I) of the present invention is prepared by dissolving the oxalate of the compound of formula (I) in a solvent, for example, a mixture of purified water and acetone to obtain a solution; and obtaining an oxalate acetone solvate of the compound of formula (I).

In one embodiment, the hydrate of the oxalate salt of a compound of formula (I) of the present invention is prepared by impregnation with an oxalate solvate of a compound of formula (I), for example acetone solvate; and obtaining a hydrate of the oxalate salt of the compound of formula (I).

In one embodiment, the anhydride of the oxalate salt of a compound of formula (I) of the present invention is prepared by adding ethanol to the oxalate hydrate of a compound of formula (I); After stirring the mixture, vacuum drying; and obtaining an anhydride of the oxalate salt of the compound of formula (I).

In one embodiment, the hydrochloride salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, dissolving in one or more solvents selected from the group consisting of diethyl ether, methyl tertiary butyl ether, and heptane to obtain a solution; adding hydrochloric acid to the solution; and obtaining a hydrochloride salt of the compound of formula (I).

In one embodiment, the benzenesulfonate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertiary butyl ether, and heptane to obtain a solution; adding benzenesulfonic acid to the solution; and obtaining a benzenesulfonate salt of the compound of formula (I).

In one embodiment, the hemifumaric acid salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertiary butyl ether, and heptane to obtain a solution; adding fumaric acid to the solution; and obtaining a hemifumarate salt of the compound of formula (I).

In one embodiment, the succinate of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding succinic acid to the solution; and obtaining a succinate of the compound of formula (I).

In one embodiment, the hemimaleate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl dissolving in one or more solvents selected from the group consisting of acetate, diethyl ether, methyl tertiary butyl ether, and heptane to obtain a solution; adding maleic acid to the solution; and obtaining a hemmaleate salt of the compound of formula (I).

In one embodiment, the nicotinate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding nicotinic acid to the solution; and obtaining a nicotinate salt of the compound of formula (I).

In one embodiment, the glycolate salt of a compound of formula (I) of the present invention is prepared by dissolving the compound of formula (I) in a solvent such as acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate. , diethyl ether, methyl tertiary butyl ether, and dissolving in one or more solvents selected from the group consisting of heptane to obtain a solution; adding glycolic acid to the solution; and obtaining a glycolate salt of the compound of formula (I).

The present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of compounds of formulas (I) to (VIII), a pharmaceutically acceptable salt, hydrate, solvate, salt hydrate, or salt solvate thereof as an active ingredient. to provide.

The present invention relates to a CDK7-related disease comprising a compound selected from the group consisting of compounds of formulas (I) to (VIII), a pharmaceutically acceptable salt, hydrate, solvate, salt hydrate, or salt solvate as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of.

In one embodiment, the CDK7-related disease may be a proliferative disease or an infectious disease. In one embodiment, the CDK7-related disease may be cancer, specifically breast cancer, blood cancer, liver cancer, or lung cancer.

Since the novel compound according to the present invention exhibits high CDK7 inhibitory activity, it can be usefully used as a pharmaceutical composition for preventing or treating CDK7-related diseases.

1 is a graph showing the XRD pattern of Example 8.
2 is a graph showing the XRD pattern of Example 9.
3 is a graph showing the XRD pattern of Example 10.
4 is a graph showing the XRD pattern of Example 11;
5 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 8.
6 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 9.
7 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 10.
8 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 11.
9 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 12.
10 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 13.
11 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 14.
12 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 15;
13 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 16;
14 shows a hydrogen nuclear magnetic resonance spectrum analysis diagram of Example 17;

Hereinafter, embodiments and examples of the present invention will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art to which the present invention pertains can easily carry out. However, the present application may be embodied in various forms and is not limited to the embodiments and examples described herein.

Throughout this specification, when a part "includes" a component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

The term “alkyl,” as used herein, is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms, substituted or unsubstituted, and saturated, which may be straight-chain, branched, cyclic, or combinations thereof. contains aliphatic groups. For example, an alkyl group has 1 to 20 carbon atoms (ie, C ₁ -C ₂₀ alkyl), 1 to 10 carbon atoms (ie, C ₁ -C ₁₀ alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C ₁ -C ₆ alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to _{C 1} -C _{6 alkyl.} Examples of suitable alkyl groups include methyl (Me, —CH ₃ ), ethyl (Et, —CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, —CH ₂ CH ₂ CH ₃ ), 2-propyl ( i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i- Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t -Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH3)CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH3)CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH( CH ₂ CH3)(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH _{3 )} )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ ) (CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), and octyl (-(CH ₂ ) ₇ CH ₃ ). it is not going to be

Moreover, the term "alkyl" as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which includes haloalkyl groups such as trifluoromethyl, and the like; refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone.

As used herein, the term “Cx-y” or “Cx-Cy,” when used with alkyl, means containing from x to y carbons in the chain. For example, a C ₁ -C ₆ alkyl group contains 1 to 6 carbon atoms in the chain.

As used herein, the term “halo” or “halogen” includes chloro, fluoro, bromo, and iodo.

As used herein, the term “substituted” refers to a particular moiety of a compound of the present invention having one or more substituents. The term “substituted,” eg, “substituted alkyl,” with respect to alkyl and the like, means that one or more hydrogen atoms of the alkyl are each independently replaced by a non-hydrogen substituent.

As used herein, the term "pharmaceutically acceptable salt" means any acid or base addition salt, which is nontoxic and harmless to the patient and the side effects attributable to the salt do not diminish the beneficial efficacy of the compound of the present invention. . Inorganic acids that form suitable salts include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid, and organic acids that form suitable salts include glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, Fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, nicotinic acid, tosylic acid, camphorsulfonic acid, naphthoic acid, acetic acid, trifluoroacetic acid, oxalic acid, manderic acid, propionic acid, Citric acid, lactic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, carbonic acid, vanillic acid, benzenesulfonic acid, p-toluenesulfonic acid, or methanesulfonic acid, etc., preferably oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, maleate, aspartate, malate, citrate, malonate acid, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, or 4-hydroxy-benzoate, but is not limited thereto. Such salts may exist in hydrate, solvate or substantially anhydrous form. In addition, a pharmaceutically acceptable metal salt may be prepared using a base, and the metal salt includes sodium, potassium, or calcium salt, but is not limited thereto.

As used herein, the term “solvate” refers to a solid in which compound molecules and solvent molecules form a complex, and “hydrate” refers to a specific solvate in which the solvent is water.

Throughout this specification, the compounds, pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, and solvates of salts are meant to include both crystalline and amorphous forms, respectively.

The compounds of the present invention, pharmaceutically acceptable salts, hydrates, solvates, hydrates of salts, or solvates of salts thereof, can be prepared from readily available starting materials using modifications to synthetic protocols known to those skilled in the art.

Certain compounds of the present invention may have one or more stereocenters within their structure. Such stereocenters may exist in either the R or S configuration, the R and S designations being described in Pure Appl. Chem. (1976), 45, 11-30]. The present invention includes all stereoisomeric forms, such as enantiomeric and diastereomeric forms, of a compound or a pharmaceutically acceptable salt thereof, including all possible mixtures of stereoisomers.

Some of the compounds of the present invention may also exist in tautomeric forms. Such forms, although not expressly indicated in the formulas described herein, are intended to be included within the scope of the present invention.

The pharmaceutical composition of the present invention may be a pharmaceutical composition for preventing or treating a CDK7-related disease, and the CDK7-related disease includes a proliferative disease or an infectious disease. Proliferative disease means, for example, cancer, benign neoplasm, angiogenesis, inflammatory disease, auto-inflammatory disease, or autoimmune disease, and infectious disease means, for example, bacterial disease or viral disease.

The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Example 1]

(S,E)-4-(dimethylamino)-N-(3-fluoro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl) Synthesis of amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide (compound of formula (II))

Step 1) Preparation of 2-(3-bromophenyl)propanoic acid

2-(3-bromophenyl)acetic acid (21 g, 97.56 mmol) was dissolved in THF (200 ml, 0.5M), and then 1 M NaHMDS (200 ml, 200 mmol) was added dropwise at 0°C. After stirring for 30 minutes, MeI (6.07 ml, 97.56 mmol) was added and stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with 1N HCl, then the organic layer was dried (MgSO ₄ ), filtered and dried under reduced pressure. Purification of the residue using a Combi-flash column (100 % gradient in EA/Hex 10) gave 2-(3-bromophenyl)propanoic acid (19.6 g, 92 %).

Step 2) Preparation of (S)-2-(3-bromophenyl)propanoic acid

Acetonitrile (165 ml) is added to the racemic form of 2-(3-bromophenyl)propanoic acid (33.13 g, 144.63 mmol) followed by addition of (R)-1-phenylethan-1-amine, Stirred at 30-35°C. After stirring at 20-25° C. for 2 hours, the reaction is filtered, washed with 0-5° C. acetonitrile (100 ml) and dried. Acetonitrile (165 ml) was added to the dried compound and the mixture was stirred at 80-85° C. for 1 hour. After that, the mixture was cooled to 30-35° C. and stirred for 1 hour. After cooling to 20-25 °C, the mixture was stirred for 3 h, filtered and dried over acetonitrile (100 ml) cooled to 0-5 °C. This process was repeated twice. Methylene chloride (265 ml) and 1N HCl (132 ml) are added to the obtained solid, the solid is extracted, _{dried over MgSO 4} , filtered and concentrated, (S)-2-(3-bromophenyl) Propanic acid (6.6 g) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.85(br, 1H), 7.45-7.44(m, 1H), 7.43-7.40 (m, 1H), 7.23-7.20 (m, 2H), 7.05-7.04(m) , 1H), 3.76-3.71 (m, 1H), 2.00-1.94 (m, 1H), 1.60 (d, J=6.8, Hz, 3H), 1.01-0.96 (m, 2H), 0.75-0.69 (m, 2H); MS (m/z): 352.0 [M+1]; 99.6ee%

Step 3) Preparation of (S)-2-(3-bromophenyl)-N-(5-trifluoromethylthiazol-2-yl)propanamide

(S)-2-(3-bromophenyl)propanoic acid (2.6 g, 11.35 mmol) was dissolved in dichloromethane (113 ml, 0.1 M), followed by addition of oxalyl chloride (1.09 ml, 12.97 mmol) and dimethylformamide (18 ul, 0.23 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated. The concentrated mixture was dissolved in DCM (113 ml, 0.1 M) and 5-trifluoromethylthiazol-2-amine (2.06 g, 12.28 mmol) was added. DIPEA (2.1 ml, 12.28 mmol) was added slowly and stirred at room temperature for 3 h. The reaction mixture was diluted with DCM, washed with water, dried (MgSO ₄ ), filtered and dried under reduced pressure. Purify the residue by combi-flash column (EA/Hex 0 to 60 % gradient) to (S)-2-(3-bromophenyl)-N-(5-trifluoromethylthiazol-2-yl ) propanamide (3.4 g, 80 %) was provided as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.94 (brs, 1H), 8.09 (m, 1H), 7.58 (t, J = 2.0 Hz, 1H), 7.49 (dt, J = 8.0 Hz, 1,2 Hz) , 1H), 7.38 -7.30 (m, 2H), 4.07-4.00 (m, 1H), 1.47 (d, J = 7.2 Hz, 3H)

Step 4) (S)-N-(5-trifluoromethylthiazol-2-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxabo) Preparation of rolan-2-yl)phenyl)propanamide

anhydrous in (S)-2-(3-bromophenyl)-N-(5-trifluoromethylthiazol-2-yl)propanamide (3.2 g, 8.5 mmol) and KOAc (1.66 g, 16.91 mmol) 1,4-dioxane (42 ml, 0.2 M) was added and the reaction mixture was stirred and degassed. Then, bis(pinacolato)diboron (2.79 g, 10.99 mmol) and Pd(dppf)Cl ₂ .DCM (690 mg, 0.85 mmol) were added and stirred at 85° C. for 15 hours. The mixture was diluted with EtOAc, washed with water, dried (MgSO ₄ ), filtered and dried under reduced pressure. Purify the residue by combi-flash column (EA/Hex 0 to 60 % gradient) to (S)-N-(5-trifluoromethylthiazol-2-yl)-2-(3-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (2.7 g, 75%) was provided as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.90 (brs, 1H), 7.78 (td, J = 4.4 Hz, 1.2 Hz, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.67 (q, J) = 1.2 Hz, 1H), 7.41-7.39 (m, 2H), 3.84 (q, J = 7.2 Hz, 1H), 1.65 (d, J = 7.2 Hz, 3H), 1.37 (s, 12H)

Step 5) (S,E)-4-(dimethylamino)-N-(3-fluoro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazole-2) Preparation of -yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide

(S)-N-(5-trifluoromethylthiazol-2-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -yl)phenyl)propanamide (1.53 g, 3.6 mmol), (E)-N-(5-bromo-3-fluoropyridin-2-yl)-4-(dimethylamino)but-2-enamide (0.906 g, 3.0 mmol) and Cs ₂ CO ₃ (2.44 g, 7.5 mmol) were added H ₂ O (15 ml) and 1,4-dioxane (45 ml), the reaction mixture was stirred and degassed. Then, Pd(dppf)Cl ₂ .DCM (244 mg, 0.30 mmol) was added, and the mixture was stirred at 100° C. for 3 hours. The mixture was diluted with EtOAc, washed with water, further washed with brine, then dried (MgSO ₄ ), filtered and dried under reduced pressure. Purify the residue by combi-flash column (EA/Hex 50 to 100 % gradient) to (S,E)-4-(dimethylamino)-N-(3-fluoro-5-(3-(1-) Oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide (547mg, 35%) It was provided as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.60 (s, 1H), 8.11 (dd, J = 11.2 Hz, 2.0 Hz, 1H), 8.15-7.98 (m, 1H), 7.78 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.49-7.40 (m, 2H), 6.80 (dt, J = 15.6 Hz, 6.0 Hz, 1H), 6.35 (d, J = 15.6) Hz, 1H) 4.07-4.02 (m, 1H), 3.08 (d, J = 7.2 Hz, 2H), 12.19 (s, 6H), 1.53 (d, J = 6.8 Hz, 3H); MS (m/z); 522.0 [M+1]; 70ee%

[Example 2]

(S,E)-N-(3-cyano-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl Synthesis of )phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (III))

(E)-N-(5-bromo-3 instead of (E)-N-(5-bromo-3-fluoropyridin-2-yl)-4-(dimethylamino)but-2-enamide The title compound was prepared in the same manner as in Example 1, except that -cyanopyridin-2-yl)-4-(dimethylamino)but-2-enamide was used.

¹ H NMR (400 MHz, DMSO-d6) δ 12.91 (brs, 1H), 11.04 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.10 (t, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0) Hz, 1H), 6.90 (dt, J = 15.6 Hz, 6.0 Hz, 1H), 6.40 (dt, J = 15.6 Hz, 1.6 Hz, 1H), 4.13 (q, J = 6.8 Hz, 1H), 3.12 (dd , J = 6.0 Hz, 1.2 Hz, 2H), 2.22 (s, 6H), 1.57 (d, J = 6.8 Hz, 3H); MS (m/z); 529.0 [M+1]; 70ee%

[Example 3]

(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5 Synthesis of -yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide (compound of formula (IV))

(E)-N-(5-bromo-2 instead of (E)-N-(5-bromo-3-fluoropyridin-2-yl)-4-(dimethylamino)but-2-enamide In the same manner as in Example 1, except that ,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(dimethylamino)but-2-enamide was used, the title The compound was prepared.

¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.96-7.91 (m, 3H), 7.69 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.43 (t) , J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 15.6 Hz, 6.0 Hz, 1H), 4.12-4.02 (m, 3H), 3.13-3.11 (m) , 4H), 2.20 (s, 6H), 1.51 (d, J = 7.2 Hz, 3H); MS (m/z); 530.0 [M+1]; 69ee%

[Example 4]

(S,E)-N-(3-chloro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl) Synthesis of phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (V))

(E)-N-(5-bromo-3 instead of (E)-N-(5-bromo-3-fluoropyridin-2-yl)-4-(dimethylamino)but-2-enamide The title compound was prepared in the same manner as in Example 1, except that -chloropyridin-2-yl)-4-(dimethylamino)but-2-enamide was used.

¹ H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.79 (dt, J = 15.6) Hz, 6.0 Hz, 1H), 6.34 (d, J = 15.6 Hz, 1H), 4.11 (q, 5.2 Hz, 1H), 3.08 (dd, J = 6.0 Hz, 2H), 2.19 (s, 6H), 1.53 (d, J = 7.2 Hz, 3H); MS (m/z); 538.5 [M+1]; 68ee%

[Example 5]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Synthesis of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI))

Using 5-ethylthiazol-2-amine instead of 5-trifluoromethylthiazol-2-amine, (E)-N-(5-bromo-3-fluoropyridin-2-yl)- Replace 4-(dimethylamino)but-2-enamide with (E)-N-(5-bromo-3-cyanopyridin-2-yl)-4-(dimethylamino)but-2-enamide The title compound was prepared in the same manner as in Example 1, except that it was used.

¹ H NMR (400 MHz, DMSO-d6) δ 12.10 (brs, 1H), 11.03 (brs, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 7.82 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 2H), 7.14 (s, 1H), 6.89 (dt, J = 15.6 Hz, 6.0 Hz, 1H), 6.38 (d, J = 15.6 Hz, 1H), 4.05 (q, J = 6.8 Hz, 1H), 3.10 (dd, J = 5.6 Hz, 1.2 Hz, 2H), 2.72 (q, J = 7.2 Hz, 2H) , 2.20 (s, 6H), 1.52 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (m/z); 489.0 [M+1]; 75ee%

[Example 6]

(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5 Synthesis of -yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide (compound of formula (VII))

Using 5-ethylthiazol-2-amine instead of 5-trifluoromethylthiazol-2-amine, (E)-N-(5-bromo-3-fluoropyridin-2-yl)- (E)-N-(5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl) instead of 4-(dimethylamino)but-2-enamide The title compound was prepared in the same manner as in Example 1, except that -4-(dimethylamino)but-2-enamide was used.

¹ H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.96-7.92 (m, 2H), 7.70 (s, 1H), 7.58 (d , J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.12 (s, 1H), 6.87 (dd, J = 15.2 Hz, 6.4 Hz, 1H), 4.13-4.06 (m, 2H), 4.04-3.98 (m, 1H), 3.15-3.10 (m, 4H), 2.74-2.67 (m, 2H), 2.20 (s, 6H), 1.50 ( d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.6 Hz, 3H); MS (m/z); 490.0 [M+1]; 72ee%

[Example 7]

(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) Synthesis of -3-fluoropyridin-2-yl)but-2-enamide (compound of formula (VIII))

The title compound was prepared in the same manner as in Example 1, except that 5-ethylthiazol-2-amine was used instead of 5-trifluoromethylthiazol-2-amine.

¹ H NMR (400 MHz, DMSO-d6) δ 12.10 (brs, 1H), 10.48 (s, 1H), 8.59 (s, 1H), 8.10 (dd, J = 11.2 Hz, 2.0 Hz, 1H), 7.78 ( s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 6.80 ( dt, J = 15.2 Hz, 6.0 Hz, 1H), 6.35 (d, J = 15.6 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 3.07 (d, J = 5.2 Hz, 2H), 2.72 (q, J = 7.2 Hz, 2H), 2.19 (s, 6H), 1.51 (d, J = 6.8 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (m/z); 482.0 [M+1]; 65ee%

[Example 8]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) oxalate acetone solvate

± 0.2°에서 특징적인 피크를 확인하였다.(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 2-yl)-4-(dimethylamino)but-2-enamide 30 g was added to a mixture of 60 mL of methanol and 90 mL of acetone, and then the temperature was raised to 40 to 45° C. to dissolve, and 5.6 g of oxalate was added. 210 mL of acetone was slowly added to induce crystallization (30 mg of seed was added), and then crystallized for 1 to 2 hours. The temperature of the mixture was cooled to 5-10 °C, stirred for 1 hour to ripen the crystals, and the solid was filtered and washed with 150 mL of a mixture of methanol and water in a 20:1 ratio. After additional washing with 60 mL of acetone, vacuum drying at 30°C (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino) -1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide oxalate was obtained (25.5 g, 85.0%). obtained (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) 20 g of pyridin-2-yl)-4-(dimethylamino)but-2-enamide oxalate was added to a mixture of 20 mL of purified water and 100 mL of acetone, and then the temperature was raised to 40 to 45° C. to dissolve. 140 mL of acetone was slowly added to induce crystallization (seed 20 mg was added), and then crystallized for 1 to 2 hours. The temperature of the mixture was cooled slowly to 20-25° C. for 2-3 hours, stirred for 12-15 hours to ripen the crystals, and the solid was filtered and washed with 100 mL of a 40:1 mixture of acetone and water. After further washing with 40 mL of acetone, vacuum drying at 30°C (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino) -1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide oxalate acetone solvate was obtained (15 g, 75%). As a result of X-ray diffraction spectroscopy, 7.4°, 8.3°, 9.3°, 10.1°, 11.2°, 11.5°, 12.6°, 15.2°, 16.5°, 16.9°, 17.4°, 17.8°, Diffraction angles 2 of 18.6°, 19.8°, 20.3°, 21.6°, 22.1°, 22.9°, 23.6°, 24.4°, 25.5°, 26.6°, 29.0° and 31.5°

A characteristic peak was identified at ± 0.2°.

¹ H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.69 (d, J = 2.8 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.14 (s, 1H), 6.95 (dt, J = 15.2 Hz, 6.8 Hz, 1H), 6.58 (d, J = 15.6) Hz, 1H), 4.07 (q, J = 8.4 Hz, 1H), 3.85 (d, J = 6.4 Hz, 2H), 2.74 (q, J = 6.4 Hz, 2H), 2.71 (s, 6H), 2.09 ( s, 3H), 1.53 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H)

[Example 9]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) oxalate hydrate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2 prepared in Example 8 above -yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide oxalate 20 g of acetone solvate in a chamber with a humidity of 85 to 90% and a temperature of 20 to 25℃ for 2 to 4 days After vacuum drying at 30°C (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2 -yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide oxalate hydrate was obtained (18 g, 98%).

¹ H NMR (400 MHz, DMSO-d 6 ): 11.26 (s, 1H); 9.03 (d, 1H)) ; 8.68 (d, 1H), 7.83 (s, 1H) ; 7.73 (d, 1H) ; 7.52-7.44 (m, 2H) ; 7.14 (s, 1H) ; 6.90 (dt, 1H) ; 6.53 (d, 1H) ; 4.06 (q, 1H) ; 3.77 (d, 2H) ; 2.75-2.68 (m, 2H) ; 2.67 (s, 6H) ; 1.52 (d, 3H) ; 1.19 (t, 3H)

[Example 10]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) oxalate anhydride

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2 prepared in Example 9 above -yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide 50ml of ethanol was added to 2g of oxalate hydrate. While maintaining the temperature at 40 ~ 45 ℃ was stirred for 24 hours. The solid was filtered and washed with 10 mL of ethanol. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide oxalate anhydride was obtained (1.7 g, 85%). As a result of X-ray diffraction spectroscopy, as shown in FIG. 3, 8.3°, 13.7°, 14.9°, 15.3°, 16.0°, 16.7°, 16.9°, 17.6°, 18.4°, 18.8°, 19.2°, 19.9°, Characteristic peaks were identified at diffraction angles of 2θ±0.2° of 20.7°, 21.4°, 21.9°, 22.7°, 23.8°, 25.3°, and 25.6°.

¹ H NMR (400 MHz, DMSO-d6): 11.29 (s, 1H); 9.03 (d, 1H)) ; 8.69 (d, 1H), 7.83 (s, 1H); 7.74 (d, 1H) ; 7.52-7.44 (m, 2H) ; 7.14 (s, 1H) ; 6.94 (dt, 1H) ; 6.56 (d, 1H) ; 4.08 (q, 1H) ; 3.81 (d, 2H) ; 2.74-2.68 (m, 2H) ; 2.68 (s, 6H) ; 1.53 (d, 3H) ; 1.21 (t, 3H)

[Example 11]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) hydrochloride

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Dissolve 500 mg of 2-yl)-4-(dimethylamino)but-2-enamide in 10 mL of acetone, stir at 20-25°C for 10-15 minutes, and slowly add 0.9 mL of a 1.25 M hydrochloric acid solution in diethyl ether. was put in. The mixture was stirred for 6-7 hours while maintaining the temperature at 20-25°C. The solid was filtered and washed with 10 mL of acetone. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane- 2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide hydrochloride was obtained (315 mg, 58%). As a result of X-ray diffraction spectroscopy analysis, as shown in FIG. 4, the diffraction angles of 7.0°, 9.1°, 10.5°, 11.0°, 13.5°, 17.1°, 19.0°, 20.8°, 21.3°, 23.2°, and 25.7° A characteristic peak was identified at 2θ ± 0.2°.

¹ H NMR (400 MHz, DMSO-d6): 12.15 (s, 1H); 11.38 (s, 1H) ; 10.75 (s, 1H) ; 9.06 (d, 1H) ; 8.71 (d, 1H) ; 7.86 (s, 1H) ; 7.76 (dd, 1H) ; 7.54-7.47 (m, 2H) ; 7.16 (s, 1H) ; 6.97 (dt, 1H) ; 6.61 (d, 1H) ; 4.09 (q, 1H) ; 4.03-4.00 (m, 2H) ; 2.81 (d, 6H) ; 2.77-2.71 (m, 2H) ; 1.54 (d, 3H) ; 1.22 (t, 3H)

[Example 12]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) benzenesulfonate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 50 mg of 2-yl)-4-(dimethylamino)but-2-enamide was dissolved in 1 mL of methyl tertiary butyl ether, stirred at 20 to 25° C. for 10 minutes, and then 16.6 mg of benzenesulfonic acid was added. While maintaining the temperature at 20 ~ 25 ℃ stirred for 0.5 ~ 1 hour. The solid was filtered and washed with 1 mL of methyl tertiary butyl ether. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide benzenesulfonate was obtained (46 mg, 73%).

¹ H NMR (400 MHz, DMSO-d6): 12.13 (s, 1H); 11.35 (s, 1H) ; 9.69 (bs, 1H) ; 9.06 (d, 1H) ; 8.72 (d, 1H) ; 7.85 (s, 1H) ; 7.75 (dd, 1H) ; 7.63-7.61 (m, 3H) ; 7.53-7.49 (m, 2H) ; 7.36-7.33 (m, 4H) ; 7.17 (s, 1H) ; 6.90 (dt, 1H), 6.60 (d, 1H) ; 4.07 (q, 1H) ; 4.04-4.02 (m, 2H) ; 2.86 (d, 6H) ; 2.76-2.75 (m, 2H) ; 1.55 (d, 3H) ; 1.22 (t, 3H)

[Example 13]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) hemifumarate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 50 mg of 2-yl)-4-(dimethylamino)but-2-enamide was dissolved in 1 mL of methyl tertiary butyl ether, stirred at 20 to 25° C. for 10 minutes, and then 11.8 mg of fumaric acid was added. While maintaining the temperature at 20 ~ 25 ℃ stirred for 0.5 ~ 1 hour. The solid was filtered and washed with 1 mL of methyl tertiary butyl ether. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide hemifumarate was obtained (42 mg, 78 %).

¹ H NMR (400 MHz, DMSO-d6): 12.13 (bs, 1H); 11.07 (s, 1H) ; 9.03 (d, 1H) ; 8.68 (d, 1H) ; 7.85 (s, 1H) ; 7.75 (dd, 1H) ; 7.54-7.46 (m, 2H) ; 7.16 (s, 1H) ; 6.90 (dt, 1H) ; 6.63 (s, 1H) ; 6.42 (d, 1H) ; 4.07 (q, 1H) ; 3.20-3.18 (m, 2H) ; 2.77-2.71 (m, 2H) ; 2.27 (s, 6H) ; 1.55 (d, 3H) ; 1.22 (t, 3H)

[Example 14]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) succinate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 2-yl)-4-(dimethylamino)but-2-enamide 50 mg was dissolved in 1 mL of methyl tertiary butyl ether, stirred at 20 to 25° C. for 10 minutes, and then 24.16 mg of succinic acid was added. While maintaining the temperature at 20 ~ 25 ℃ stirred for 0.5 ~ 1 hour. The solid was filtered and washed with 1 mL of methyl tertiary butyl ether. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide succinate was obtained (39 mg, 73%).

¹ H NMR (400 MHz, DMSO-d6): 12.13 (bs, 1H); 11.05 (s, 1H) ; 9.03 (d, 1H) ; 8.67 (d, 1H) ; 7.85 (s, 1H) ; 7.76 (dd, 1H) ; 7.54-7.46 (m, 2H) ; 7.16 (s, 1H) ; 6.90 (dt, 1H) ; 6.41 (d, 1H); 4.07 (q, 1H) ; 3.17-3.15 (m, 2H) ; 2.77-2.71 (m, 2H) ; 2.42 (s, 2H) ; 2.25 (s, 6H) ; 1.54 (d, 3H) ; 1.21 (t, 3H)

[Example 15]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) hemimaleate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 50 mg of 2-yl)-4-(dimethylamino)but-2-enamide was dissolved in 1 mL of methyl tertiary butyl ether, and after stirring at 20 to 25° C. for 10 minutes, 12.47 mg of maleic acid was added. While maintaining the temperature at 20 ~ 25 ℃ stirred for 0.5 ~ 1 hour. The solid was filtered and washed with 1 mL of methyl tertiary butyl ether. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide hemmaleate was obtained (38 mg, 71%).

¹ H NMR (400 MHz, DMSO-d6): 12.13 (s, 1H); 11.21 (s, 1H) ; 9.75 (bs, 1H) ; 9.05 (d, 1H) ; 8.70 (d, 1H) ; 7.85 (s, 1H) ; 7.75 (dd, 1H) ; 7.54-7.46 (m, 2H) ; 7.16 (s, 1H) ; 6.90 (dt, 1H) ; 6.51 (d, 1H) ; 6.04 (s, 1H) ; 4.07 (q, 1H) ; 3.30-3.40 (m, 2H) ; 2.77-2.71 (m, 2H) ; 2.53 (s, 6H) ; 1.54 (d, 3H) ; 1.22 (t, 3H)

[Example 16]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) nicotinate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 2-yl)-4-(dimethylamino)but-2-enamide 50 mg was dissolved in 1 mL of methyl tertiary butyl ether, stirred at 20 to 25° C. for 10 minutes, and then 13.9 mg of nicotinic acid was added. While maintaining the temperature at 20 ~ 25 ℃ stirred for 0.5 ~ 1 hour. The solid was filtered and washed with 1 mL of methyl tertiary butyl ether. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide nicotinate was obtained (33 mg, 55%).

¹ H NMR (400 MHz, DMSO-d6): 12.12 (bs, 1H); 11.06 (s, 1H) ; 9.09 (d, 1H) ; 9.04 (d, 1H) ; 8.79 (dd, 1H) ; 8.68 (d, 1H) ; 8.28 (dd, 1H) ; 7.85 (s, 1H) ; 7.75 (dd, 1H) ; 7.57-7.48 (m, 3H) ; 7.17 (s, 1H) ; 6.90 (dt, 1H) ; 6.44 (d, 1H) ; 4.08 (q, 1H) ; 3.17-3.15 (m, 2H) ; 2.76-2.74 (m, 2H) ; 2.25 (s, 6H) ; 1.55 (d, 3H) ; 1.21 (t, 3H)

[Example 17]

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- Preparation of 2-yl)-4-(dimethylamino)but-2-enamide (compound of formula (VI)) glycolate

(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin- 500 mg of 2-yl)-4-(dimethylamino)but-2-enamide was dissolved in 7.5 mL of acetone, stirred at 40 to 45° C. for 10 minutes, and then 86 mg of glycolic acid was added. The mixture was stirred for 1 to 2 hours while maintaining the temperature at 20 to 25°C. The solid was filtered and washed with 5 mL of acetone. (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2- yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide glycolate was obtained (422 mg, 73%).

¹ H NMR (400 MHz, DMSO-d6): 12.12 (bs, 1H); 11.05 (s, 1H) ; 9.02 (d, 1H)) ; 8.66 (d, 1H), 7.83 (s, 1H); 7.74 (d, 1H) ; 7.52-7.43 (m, 2H) ; 7.14 (s, 1H) ; 6.89 (dt, 1H) ; 6.39 (d, 1H) ; 4.05 (q, 1H) ; 3.89 (s, 2H) ; 3.13 (d, 2H); 2.75-2.69 (m, 2H) ; 2.22 (s, 6H) ; 1.52 (d, 3H) ; 1.19 (t, 3H)

[Test Example]

The efficacy of the compound prepared in the above Example was evaluated as follows, and the results are shown below.

Test Example 1: CDK7 inhibitory activity

Compounds of the invention were assayed in vitro for CDK7 inhibitory activity using the ADP-Glo platform. Specifically, CDK7 inhibitory activity was measured using recombinant purified human CDK7 (ThermoFisher, PV3868) and ADP Glo kinase assay kit (Promega, V9102). CDK7 was diluted with IX kinase reaction buffer (40 mM Tris-Cl, pH 7.5, 20 mM MgCl ₂ , 0.1 mg/ml BSA and 50 μM DTT) and added to 96 well plates (CDK7 final concentration per reaction: 50 ng) ). The compound was finally treated to a 1% DMSO aqueous solution, and a substrate cocktail containing ATP (final concentration 90 μM) and 0.2 μg/μl MBP (myelin basic protein) in a total of 25 μl reaction mass was added to a 96-well plate. Thus, the enzymatic reaction was initiated by this. After 2 hours of incubation (30° C.), an equal volume (25 μl per reaction) of ADP Glo was added and incubated at room temperature for 60 minutes (30° C.). After that, kinase detection reagent (50 μl per reaction) was added and incubated at room temperature for 30 minutes (30° C.). The kinase activity was measured by the chemiluminescence method according to the ADP Glo Kinase Assay Kit instruction manual, and the CDK7 inhibitory activity of the compound according to the present invention was calculated. Results analysis of each compound was performed using Microsoft Excel, and IC ₅₀ values were calculated by Prism software, and the degree of CDK7 inhibition (IC ₅₀ ) is shown in Table 1 below.

Example CDK7 inhibition (IC ₅₀ nM) One 7.6 2 4.3 3 5.9 4 8.5 5 4.2 6 6.0 7 4.0

As a result, it was confirmed that the compounds of the present invention have very high CDK7 inhibitory activity.

Test Example 2: Antiproliferative effect of the compound of the present invention on cancer cells

MDA-MB-468 cells

MDA-MB-468 cells are one of the cells of triple-negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor and HER2 expression) known as a malignant tumor with a difficult initial diagnosis and high metastatic capacity, and these cells are Used to test inhibition of cell proliferation and survival.

Compounds of the present invention were tested at different concentrations (from 1000 nM to 1 nM) to assess their ability to inhibit proliferation of MDA-MB-468 cells. Cells were cultured in RPMI 1640 (Wellgene) + 10% FBS (Gibco) + 1% penicillin/streptomycin (Gibco), and incubated at 37° C. in a humidified chamber in the presence of _{5% CO 2 .}

MDA-MB-468 cells cultured in 96-well cell culture plates were treated with the compounds of the present invention and incubated for 72 hours. Then, the antiproliferative effect of the compound was analyzed by the MTT method using a tetrazolium salt, and the degree of inhibition of cell proliferation (IC ₅₀ ) is shown in Table 2 below.

Example MDA-MB-468 (IC ₅₀ nM) One 23.0 2 30.0 3 74.0 4 35.0 5 14.0 6 34.0 7 7.0

As a result, it was confirmed that the compound of the present invention has a high inhibitory activity against the proliferation of MDA-MB-468 cells.

HepG2 cells

The ability to inhibit the proliferation of HepG2 cells, which are human hepatocellular carcinoma cells, was measured through an in vitro cell viability assay. Cells were cultured at 37° C. under humidified conditions in the presence of _{5% CO 2} using a culture medium of MEM (Wellgene) + 10% FBS (Gibco) + 1% penicillin/streptomycin (Gibco). HepG2 cells cultured in 96-well cell culture plates were treated with the compound and incubated for 72 hours. Cell viability was determined by the CCK-8 method using tetrazolium salts and the ability of the compounds according to the invention to inhibit cancer cell proliferation was calculated. Analysis of the results of each compound was performed using Microsoft Excel, and IC ₅₀ values were calculated by Prism software, and the results are shown in Table 3 below.

Example HepG2 (IC ₅₀ nM) One 5.0 2 5.0 3 17.4 4 4.2 5 3.0 6 38.0 7 3.8

As a result, it was confirmed that the compound of the present invention has a high inhibitory activity against proliferation of HCC (HepG2) cells.

Test Example 3: CDK7 selectivity

The degree of inhibition of CDK2, CDK5, and CDK7 was measured using a scanMAX kinase assay panel with one set of 468 kinases including CDK2, CDK5. The compounds of the present invention were screened at 1 μM, and the results are shown in Table 4 below.

Example Inhibition rate (%) at 1uM CDK2 CDK5 CDK7 2 26 22 99 5 20 30 99

As shown in Table 4, high inhibitory activity against CDK7 and low inhibitory activity against CDK2 and CDK5 of the compound of the present invention were confirmed. From the above results, it was confirmed that the compound of the present invention highly selectively inhibited CDK7.

Test Example 4: Correlation analysis between structure and activity

Hereinafter, the correlation between the structure and activity (CDK7 inhibitory effect and antiproliferative effect on cancer cells) of the compound of the present invention was analyzed.

"thiazole" ring

In order to analyze the effect of the "thiazole" ring included in the compound of the present invention on the activity of the compound of the present invention, the compound of Example 5 and Comparative Example 1 without the "thiazole" ring The degree of inhibition of CDK7 and the degree of inhibition of cancer cell proliferation of the compounds were compared.

An experiment for confirming the degree of CDK7 inhibition was performed in the same manner as in Test Example 1. In addition, in order to confirm the degree of inhibition of cancer cell proliferation, the proliferation degree of MV-4-11 (hematologic cancer) cells, MCF-7 (breast cancer) cells, HepG2 (liver cancer) cells, and Hep3B (liver cancer) cells was measured, and the The degree of proliferation was performed in the same manner as in Experimental Example 2. The proliferation levels of MV-4-11 cells, MCF-7 cells, and Hep3B cells were IMDM (Wellgene) + 10% FBS (Gibco) + 1% penicillin/streptomycin (Gibco), RPMI (Wellgene) + 10% FBS, respectively. (Gibco) + 1% penicillin/streptomycin (Gibco), and MEM (Wellgene) + 10% FBS (Gibco) + 1% penicillin/streptomycin (Gibco) to culture the cells using a culture medium, CCK-8 Except for measuring cell viability by the method (MV-4-11 cells, Hep3B cells) and the MTT method (MCF-7 cells), it was carried out in the same manner as in Test Example 2 above. For each compound inhibiting CDK7 of about (IC ₅₀ nM) and the inhibitory degree of cancer cell proliferation (IC ₅₀ nM) it is shown in Table 5.

Example 5
(Compound of formula (VI)) Comparative Example 1

CDK7 4.0 9.7 Blood cancer MV-4-11 4.2 16.5 Breast Cancer MCF-7 22.1 417.1 Liver Cancer HepG2 3.8 128.1 Liver Cancer Hep3B 22.0 248.7

As shown in Table 5 above, as a result of comparing the compound of Example 5 including the "thiazole" ring with the compound of Comparative Example 1 not including the "thiazole" ring, the degree of CDK7 inhibition was about 2.4 times superior, It was confirmed that the degree of inhibition of proliferation for all cancer cells was excellent, and in particular, the degree of inhibition of proliferation against HepG2 cells of liver cancer was more than 33 times superior.

Therefore, it can be seen that the compound of the present invention contains a "thiazole" ring and has excellent CDK7 inhibitory and cancer cell proliferation inhibitory effects.

"4-(dimethylamino)but-2-enamide" group

In order to analyze the effect of the "4-(dimethylamino)but-2-enamide" group contained in the compound of the present invention on the activity of the compound of the present invention, the compound of Example 5 and "4-( The degree of CDK7 inhibition of the compounds of Comparative Examples 2 and 3 that did not contain a "dimethylamino)but-2-enamide" group was compared.

An experiment for confirming the degree of CDK7 inhibition was performed in the same manner as in Test Example 1, and the results are shown in Table 6 below.

Example 5 Comparative Example 2 Comparative Example 3

CDK7 (IC ₅₀ nM) 4.2 339 197

As shown in Table 6, the compound of Example 5 containing a "4-(dimethylamino)but-2-enamide" group exhibited about 80-fold and about 80-fold inhibition of CDK7 compared to the compounds of Comparative Examples 2 and 3, respectively. It was confirmed that it was 45 times superior.

Therefore, it can be seen that the compound of the present invention contains a "4-(dimethylamino)but-2-enamide" group and has an excellent CDK7 inhibitory effect.

substituted "pyridine" ring

In order to analyze the effect of the "pyridine" ring substituted with a cyano or halogen group contained in the compound of the present invention on the activity of the compound of the present invention, the compound of Example 5 including a substituted pyridine ring and unsubstituted pyridine The degree of CDK7 inhibition and the degree of inhibition of cancer cell proliferation were compared between the compound of Comparative Example 4 containing a ring and the compound of Comparative Example 5 without pyridine.

In order to confirm the degree of inhibition of cancer cell proliferation, the degree of proliferation of MV-4-11 (hematologic cancer) cells, MCF-7 (breast cancer) cells, HepG2 (liver cancer) cells, and Hep3B (liver cancer) cells was measured, and the experiment performed the above comparison. Comparative experiment with the compound of Example 1 was carried out in the same manner. For each compound inhibiting CDK7 of about (IC ₅₀ nM) and the inhibitory degree of cancer cell proliferation (IC ₅₀ nM) it is shown in Table 7.

As shown in Table 7, it was confirmed that the compound of the present invention had excellent CDK7 inhibitory activity and cancer cell proliferation inhibitory activity compared to Comparative Example 4 including the unsubstituted pyridine ring and Comparative Example 5 not including the pyridine ring. .

Therefore, it can be seen that the compound of the present invention has excellent CDK7 inhibitory and cancer cell proliferation inhibitory effects including a "pyridine" ring, and further increases the inhibitory effect when the pyridine ring is substituted.

To verify whether the compound of the present invention comprising a pyridine ring substituted with a halogen group or forming a ring fused with pyrrolidine has superior activity compared to the compound of Comparative Example 4 comprising an unsubstituted pyridine ring, The CDK7 inhibitory activity of the compound of the present invention and the compound of Comparative Example 4 was directly compared. At this time, the experiment was performed in the same manner as in Test Example 1, and the results are shown in Table 8 below.

As shown in Table 8, it was confirmed that the compounds of the present invention had more excellent CDK7 inhibitory activity compared to Comparative Example 4 including an unsubstituted pyridine ring.

Accordingly, it can be seen that the compound of the present invention has excellent CDK7 inhibitory activity when the pyridine ring is substituted with a halogen or cyano group or forms a fused ring with pyrrolidine.

Test Example 5: Salt stability test

The stability of the compound of Example 5 (compound of formula (VI)) and the compound of Example 9 (oxalate hydrate of the compound of formula (VI)) of the present invention were compared. Specifically, a stability test was performed according to the ICH guidelines, and analysis was performed using a high-performance liquid chromatography (HPLC) analysis method. After storage for 28 days in a sealed state at a temperature of 25 ± 2 °C and a relative humidity of 60 ± 5 %, the change in purity was measured, and the results are shown in Table 9 below.

As shown in Table 9 above, the compound of formula (VI) showed a purity change of at least 3% by day 28, whereas the oxalate hydrate of the compound of formula (VI) showed a change of purity of 0.5% by day 28, It was confirmed that the oxalate hydrate of the compound of (VI) has excellent storage stability.

Test Example 6: Evaluation of solubility of salts

Table 10 shows the results of solubility evaluation of the compound of Example 5 (compound of formula (VI)) and the compound of Example 9 (the oxalate hydrate of the compound of formula (VI)).

Example 5
(Compound of formula (VI)) Example 9
(Oxalate hydrate of the compound of formula (VI)) Solubility (mg/mL) 0.18 238

As shown in Table 10, it was confirmed that the oxalate hydrate of the compound of formula (VI) in purified water had a very high solubility of 1000 times or more compared to the compound of formula (VI).

Therefore, it can be seen that the oxalate hydrate of the compound of formula (VI) of the present invention has very good solubility and is advantageous for drug development by improving absorption and bioavailability of the drug.

Test Example 7: X-ray diffraction spectroscopy analysis

The salt of the compound of formula (VI), the hydrate of the salt, or the solvate of the salt prepared in Examples 8 to 11 were analyzed using an X-ray diffraction analyzer. The X-ray diffraction analyzer (XRD) measurement conditions are as follows.

1) Device: D8 Advance (Bruker)

2) Detector: Lynxeye

3) Wavelength of X-ray light source: 1.5405Å

The analysis results are shown in FIGS. 1 to 4, respectively.

Test Example 8: Hydrogen Nuclear Magnetic Resonance Spectrum (NMR) Analysis

Hydrogen nuclear magnetic resonance spectral analysis was performed on the salts, hydrates, or solvates of the compounds of Formula (VI) prepared in Examples 8 to 17. The hydrogen nuclear magnetic resonance spectrum measurement conditions were as follows, and the results are shown in FIGS. 5 to 14 .

1) Device: Bruker Model AVANCE II 400

2) Measuring range: -1 ~ 14ppm

3) Number of scans: 16

Claims (23)

A compound of formula (I): or a pharmaceutically acceptable salt thereof:
<Formula (I)>

In the above formula,
_{Ra is linear C 1} -C ₃ alkyl substituted or unsubstituted with halogen;
Rb is cyano or halo, Rc is H; or
Rb and Rc together with the pyridine linked to Rb and the nitrogen linked to Rc form a fused 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.
According to claim 1, wherein the pharmaceutically acceptable salts are oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, from the group consisting of maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, and 4-hydroxy-benzoate. A compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that selected.
A compound selected from the group consisting of compounds of formulas (II) to (VIII), or a pharmaceutically acceptable salt thereof:
<Formula (II)>

<Formula (III)>

<Formula (IV)>

<Formula (V)>

<Formula (VI)>

<Formula (VII)>

<Formula (VIII)>

4. The method of claim 3, wherein the pharmaceutically acceptable salts are oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, from the group consisting of maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphorsulfonate, 3-hydroxy-2-naphthoate, mesylate, and 4-hydroxy-benzoate. A compound or a pharmaceutically acceptable salt thereof, characterized in that selected.
5. The method of claim 4, wherein the pharmaceutically acceptable salt is selected from the group consisting of oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, and nicotinate. , a compound or a pharmaceutically acceptable salt thereof.
The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein the pharmaceutically acceptable salt is hydrochloride or oxalate.
A compound of formula (VI): or a pharmaceutically acceptable salt thereof,
The pharmaceutically acceptable salt of formula (VI), characterized in that it is selected from the group consisting of oxalate, hydrochloride, benzenesulfonate, hemifumarate, succinate, hemmaleate, glycolate, and nicotinate. A compound or a pharmaceutically acceptable salt thereof:
<Formula (VI)>

The compound of formula (VI) or a pharmaceutically acceptable salt thereof according to claim 7, wherein the pharmaceutically acceptable salt is hydrochloride or oxalate.
Characteristic at 4 or more diffraction angles 2θ ± 0.2° selected from the group consisting of 7.0°, 9.1°, 10.5°, 11.0°, 13.5°, 17.1°, 19.0°, 20.8°, 21.3°, 23.2°, and 25.7° A hydrochloride salt of a compound of formula (VI) in crystalline form, showing an X-ray diffraction (XRD) spectrum comprising peaks.
<Formula (VI)>

delete A hydrate of the hydrochloride salt of a compound of formula (VI):
<Formula (VI)>

A solvate of the hydrochloride salt of a compound of formula (VI):
<Formula (VI)>

13. The method of claim 12, wherein the solvate of the hydrochloride salt is selected from the group consisting of acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyl tertiary butyl ether, and heptane. A solvate of the hydrochloride salt of a compound of formula (VI), characterized in that it is formed with one or more solvents.
A hydrate of the oxalate salt of a compound of formula (VI):
<Formula (VI)>

15. The hydrate of the compound of formula (VI) according to claim 14, characterized in that the hydrate of the oxalate is amorphous.
Solvates of the oxalates of the compounds of formula (VI):
<Formula (VI)>

17. The method of claim 16, wherein the solvate of oxalate is selected from the group consisting of acetone, ethanol, methanol, 1-butanol, 2-butanol, 1-propanol, ethyl acetate, diethyl ether, methyltertiarybutyl ether, and heptane. A solvate of the oxalate salt of a compound of formula (VI), characterized in that it is formed with one or more solvents.
17. The solvate of the compound of formula (VI) according to claim 16, characterized in that the solvate of the oxalate is an acetone solvate of the oxalate.
19. The method of claim 18, wherein the acetone solvate of oxalate is 7.4°, 8.3°, 9.3°, 10.1°, 11.2°, 11.5°, 12.6°, 15.2°, 16.5°, 16.9°, 17.4°, 17.8°, 18.6° Characterized at 4 or more diffraction angles 2θ ± 0.2° selected from the group consisting of °, 19.8°, 20.3°, 21.6°, 22.1°, 22.9°, 23.6°, 24.4°, 25.5°, 26.6°, 29.0° and 31.5° A solvate of the oxalate salt of the compound of formula (VI), characterized in that it is in a crystalline form exhibiting an X-ray diffraction (XRD) spectrum comprising peaks.
delete Anhydride of the oxalate salt of a compound of formula (VI):
<Formula (VI)>

22. The method of claim 21, wherein the anhydride of the oxalate is 8.3°, 13.7°, 14.9°, 15.3°, 16.0°, 16.7°, 16.9°, 17.6°, 18.4°, 18.8°, 19.2°, 19.9°, 20.7°, A crystalline form exhibiting an X-ray diffraction (XRD) spectrum comprising characteristic peaks at 4 or more diffraction angles 2θ ± 0.2° selected from the group consisting of 21.4°, 21.9°, 22.7°, 23.8°, 25.3°, and 25.6° Anhydride of the oxalate of a compound of formula (VI), characterized in that delete

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