PHTALAZINE DERIVATIVES ARE USED AS SOS1 INHIBITORS AND PHARMACEUTICALS CONTAINING THESE COMPOUNDS

Abstract

The invention relates to a phthalazine derivative compound as an SOS1 inhibitor and a pharmaceutical composition containing such compound. More specifically, the invention relates to a phthalazine derivative compound exhibiting inhibitory activity against the binding of SOS1 to RAS and / or RAC1 family proteins, their pharmacologically acceptable salts, or a pharmaceutical composition containing such compound.

Description

Novel phthalazine derivative compounds as SOS1 inhibitors and their uses

[0001] The present invention relates to a novel phthalazine derivative compound as an inhibitor of SOS1 and its use, and more particularly, to a pharmaceutical composition comprising a compound selected from a novel phthalazine derivative compound having an activity of inhibiting SOS1 binding to a RAS family protein and / or RAC1, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof.

[0002] RAS family proteins are found in 20–30% of human cancers and are known to include KRAS (Kirstin rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma viral oncogene). RAS regulates cell proliferation through the RAF / MEK / ERK pathway leading to mitogen-activated protein kinase (MAPK) activation and the PI3K / Akt / mTOR pathway via phosphatidylinositide 3-kinase (PI3K). Cancer-associated mutations in RAS family proteins inhibit their intrinsic GAP-induced GTPase (GTPase) activity, thereby increasing the population of GTP-bound / active RAS family proteins.

[0003] Meanwhile, RAS proteins function as molecular switches, with GTP and GDP existing in cells in active (GTP-bound) and inactive (GDP-bound) states. Activated GTP-bound RAS recruits other proteins through binding of their cognate RAS-binding domains (RBDs), activating effector proteins and subsequently generating downstream signals with diverse functions. The RAS activity state is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of RAS family proteins.

[0004] The binding of guanine nucleotide exchange factors (GEFs), such as Son of Sevenless 1 (SOS1), promotes GDP release from RAS family proteins, allowing them to bind GTP and become activated. Son of Sevenless (SOS) proteins exist in two isoforms, SOS1 and SOS2, and only SOS1 is phosphorylated by ERK. Growth factor-induced phosphorylation of SOS1 is largely mediated by ERK, which phosphorylates at least four serine residues in the C-terminal domain of SOS1. This suggests that SOS1 plays a crucial role in the negative feedback regulation of the KRAS pathway.

[0005] The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HD), a Dbl homology domain (DH), a pleckstrin homology domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins: a catalytic site that binds GDP-bound RAS family proteins and catalyzes guanine nucleotide exchange, and an allosteric site that binds GTP-bound RAS family proteins, resulting in further augmentation of the catalytic GEF function of SOS1. Selective pharmacological inhibition of SOS1 binding to the catalytic site of RAS family proteins is expected to prevent SOS1-mediated activation of RAS family proteins in the GTP-bound form.

[0006] These SOS1 inhibitor compounds are expected to consequently inhibit signaling downstream of RAS-family proteins (e.g., ERK phosphorylation). Therefore, novel SOS1 inhibitor compounds are being developed that bind to the SOS1 catalytic site (as confirmed by crystallography) and simultaneously prevent its binding to and activation of RAS family proteins, and have a marked inhibitory effect (low IC ) on the interaction of SOS1 with RAS family proteins, particularly KRAS. 50 ), and consequently, a substance that induces a significant decrease in ERK phosphorylation in KRAS mutant cancer cell lines is under development.

[0007] The present inventors have completed the present invention by confirming that a novel phthalazine derivative compound as an SOS1 inhibitor has an activity of inhibiting SOS1 binding to RAS family proteins and / or RAC1.

[0008] Related prior art is as follows.

[0009] 1. Simanshu D.K., et al. (2017) RAS proteins and their regulators in human disease. Cell,170, 17-33.

[0010] 2. Amy Y., et al. (2012) Oncogenic and wild type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. Cancer Discov,3(1), 112-23.

[0011] 3. Pierre S., et al., (2011) Understanding SOS (Son of Sevenless). Biochem. Pharmacol.,82(9), 1049-56.

[0012] One object of the present invention is to provide a novel phthalazine derivative compound having excellent activity in inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

[0013] Another object of the present invention is to provide a pharmaceutical composition comprising the compound in a therapeutically effective amount.

[0014] According to one embodiment of the present invention, a compound selected from the compounds of the following chemical formula 1, optical isomers thereof, diastereomers thereof, hydrates thereof, solvates thereof, and pharmaceutically acceptable salts thereof is provided:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1,

[0018] R1 is hydrogen or C 1-4 It is alkyl;

[0019] R2 is hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C2-6 Alkenyl or C 2-6 It is alkynylide;

[0020] R3 is R 3a or -L2- and;

[0021] Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo(=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a , -(CH2) r -NR a R b and R a class R b are each independently Hydrogen, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-8 Select from the group consisting of carbocyclyl, wherein the above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-4 Alkyl may be substituted with one or more halogens;

[0022] r is an integer from 0 to 1;

[0023] m is an integer from 0 to 5;

[0024] L2 is a direct bond, -O-(CH2) p , or -CH=CH-(CH2) q and;

[0025] p is an integer from 0 to 3;

[0026] q is an integer from 0 to 2;

[0027] class are each independently C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl, and in this case, C of 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl is unsubstituted or substituted with one or more R 3a can be replaced with;

[0028] X1 is -O(R4) or -N(R5)(R6);

[0029] R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, which is halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c , -NR c R d may be substituted or unsubstituted, where R c and R d are each independently hydrogen or C 1-6 It is alkyl;

[0030] R5 and R6 is each independently hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f It can be substituted with one or more functional groups selected from the group consisting of, where R e and R f are each independently hydrogen or C 1-6 It is alkyl,

[0031] Or the above -N(R5)(R6) is R5 and C in which R6 is connected to each other to form a ring with the nitrogen atom in -N(R5)(R6) 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl, wherein the above C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR gand -NR g R h It can be substituted with one or more functional groups selected from the group consisting of, where R g class R h are each independently Hydrogen, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 3-8 It is carbocyclyl;

[0032] L1 is a direct bond, -C(O)-, -O-, -NH-, -C(O)NH- or -C(O)NCH3- and;

[0033] n is an integer from 0 to 2;

[0034] is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 4-14 Heterospirocarbocyclyl, C 4-14 Fused heterocyclyl or C 4-14 Bridged heterocyclyl, and in this case, the above C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 4-14 Heterospirocarbocyclyl, C 4-14 Fused heterocyclyl or C 4-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i Rj , -C(O)OR i , -OR i , -NR i R j , C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl, wherein R i and R j are each independently hydrogen or C 1-6 It's alkyl.

[0035] According to another embodiment of the present invention, pharmaceutical compositions and pharmaceutical preparations for preventing or treating various diseases associated with inhibition of SOS1 binding to RAS family proteins and / or RAC1, comprising the above-described compound in a therapeutically effective amount, are provided.

[0036] According to another embodiment of the present invention, a method is provided for inhibiting SOS1 binding to a RAS family protein and / or RAC1 in a subject or cell, comprising administering to the subject a pharmaceutically effective amount of the compound described above.

[0037] According to another embodiment of the present invention, a method of inhibiting tyrosine kinase in a sample or cell is provided, comprising administering to the sample a pharmaceutically effective amount of the above-described compound.

[0038] According to another embodiment of the present invention, a method for preventing or treating cancer or a tumor in a subject is provided, comprising administering to the subject a pharmaceutically effective amount of the above-described compound.

[0039] According to another embodiment of the present invention, there is provided a use of the compound or a pharmacologically acceptable salt thereof for the prevention or treatment of cancer or tumor.

[0040] The phthalazine derivative compound of chemical formula 1 in the present invention has excellent activity in inhibiting SOS1 binding to RAS family proteins and / or RAC1, and thus has an anticancer effect on cancer associated with cell proliferation due to abnormal SOS1 activity, and can be usefully used as a therapeutic agent therefor.

[0041] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art in the relevant field of the present invention. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Furthermore, numerical values ​​described herein are deemed to include the meaning of "about," even if not explicitly stated. The contents of all publications cited as references herein are incorporated herein by reference in their entirety.

[0042] In the above chemical formula 1, the residues listed as R1 to R6 are used in the same meaning as generally understood by those skilled in the art.

[0043] In the present invention, unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine or iodine, specifically, but not limited to, fluorine and chlorine.

[0044] In the present invention, unless otherwise stated, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical.

[0045] As used herein, the term "alkenyl", unless otherwise stated, refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, each of which may have an E- or Z-configuration.

[0046] As used herein, the term "alkynyl" refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon triple bond, unless otherwise stated.

[0047] These alkyl, alkenyl and alkynyl groups may be linear, i.e. straight-chain, or branched. Depending on their respective definitions, the number of carbon atoms in an alkyl group may be 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4. Examples of alkyl are methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, pentyl including neopentyl and tert-pentyl, hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl. Each of the double bond and the triple bond in the alkenyl and alkynyl groups may be present at any position. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (= allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl (= propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl or hex-5-ynyl. However, the substituted alkyl, alkenyl and alkynyl groups may be substituted at any position, as long as each compound is sufficiently stable and suitable for the desired purpose, such as use as a pharmaceutical substance.

[0048] As used herein, the term "carbocyclyl" refers to a cyclic alkyl group which may be substituted or unsubstituted, unless otherwise specified, and may refer to a mono- or bicycloaliphatic group. Preferably, carbocyclyl includes, but is not limited to, aryl, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and bridged carbocyclyl. More preferably, carbocyclyl may include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohepsenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, or all possible isomers thereof.

[0049] In the present invention, unless otherwise stated, the term "heterocyclyl" may mean a monocyclic or bicyclic or more substituted or unsubstituted cyclic alkyl containing one or more, specifically one to four, heteroatoms selected from O, N, and S. Preferably, heterocyclyl includes, but is not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl. More preferably, heterocyclyl includes, but is not limited to, piperazinyl, piperidinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspiroctanyl, and similar groups. For example, C 2-10 In the case of heterocyclyl, the number of carbon atoms is indicated as C 2-10 It means a ring size of three or more members containing one or more heteroatoms.

[0050] The term "aryl" in the present invention, unless otherwise stated, represents an aromatic group which may be substituted or unsubstituted, and may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof.

[0051] In the present invention, the term "heteroaryl" means a monocyclic or bicyclic or higher aromatic group containing one or more heteroatoms selected from O, N and S, for example, 1 to 4, unless otherwise specified. Preferably, examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and similar groups. Preferably, examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl and similar groups.

[0052] In the present invention, the numerical range indicated using the term “to” refers to a range that includes the numerical values ​​described before and after the term “to” as the lower limit and the upper limit, respectively.

[0053] The term "binding of SOS1 to a RAS family protein and / or RAC1" as used in the present invention means binding of SOS1 to the catalytic site of SOS1 of a RAS family protein, and "inhibiting binding activity" means preventing SOS1-mediated activation of a RAS-family protein in a GTP-bound form.

[0054] The term "SOS1 inhibitor compound" as used in the present invention means a compound that inhibits signal transduction to downstream cells by RAS-family proteins, such as ERK phosphorylation, and specifically, "SOS1 inhibitor compound" means a compound that binds to the SOS1 catalytic site and prevents binding to and activation of RAS family proteins.

[0055] As used herein, the term "optical isomers" refers to various stereoisomers and geometric isomers that may exist for the compounds according to the present invention, unless otherwise specified. Compounds of formula 1 according to one aspect of the present invention may have an asymmetric carbon center (missing carbon), and therefore may exist as enantiomers (R or S isomers), racemates, diastereomers, or any mixtures thereof, and all of these isomers and mixtures are included in the scope of the present invention. The optically active (R)- and (S)-isomers may be resolved using conventional techniques, or may be prepared using chiral synthons or chiral reagents. When the compound contains a double bond, the substituent may be in the E or Z form. When the compound contains a disubstituted carbocyclyl, it may be in the cis- or trans form. Additionally, if the compound of the above formula 1 contains a bridged ring, it may exist as an exo or endo isomer. In addition, all tautomeric forms may also be included.

[0056] As used herein, the term "asymmetric carbon atom" refers to a carbon atom in a molecule that is bonded to four different atoms, atomic groups, or functional groups, unless otherwise specified. Compounds containing such asymmetric carbon atoms have optical rotation or optical isomers. Specifically, a compound having a structure of Chemical Formula 1 with the asymmetric carbon atom may be a compound having a structure of Chemical Formula 1a or Chemical Formula 1b below. Meanwhile, a 1:1 mixture of a pair of enantiomers is referred to as a "racemic" mixture.

[0057] [Chemical Formula 1a]

[0058]

[0059] In the above chemical formula 1a, , R1 to R3, X1, L1, , m and n are defined as in chemical formula 1.

[0060] [Chemical Formula 1b]

[0061]

[0062] The compound of formula 1, its optical isomers, and its diastereomers according to the above aspect may exist in the form of a solvate. The term "solvate" may include a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. A complex wherein the solvent molecule is water is also referred to as a "hydrate."

[0063] The compound of formula 1 according to the above aspect, its optical isomers, its diastereomers and its solvates may exist in the form of pharmaceutically acceptable salts.

[0064] The term "pharmaceutically acceptable salt" in the present invention may refer to an inorganic acid salt, an organic acid salt, or a metal salt typically used by pharmaceutical manufacturers in manufacturing pharmaceuticals. Pharmaceutically acceptable salts may include, but are not limited to, acid addition salts of pharmaceutically acceptable free acids and base compounds of formula 1, alkali metal salts (e.g., sodium salts) and alkaline earth metal salts (e.g., calcium salts), organic base addition salts of organic bases and carboxylic acid structures of formula 1, amino acid addition salts, etc.

[0065] Preferred salt forms of the compound according to the present invention include salts with inorganic acids or organic acids. In this case, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and hydrobromic acid can be used. In addition, organic acids such as acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, and glutamic acid can be used. Organic bases that can be used for preparing organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used for preparing amino acid addition salts include natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

[0066] The above salt can be prepared by a conventional method. For example, the compound of the above chemical formula 1 can be prepared by dissolving it in a solvent that can be mixed with water, such as methanol, ethanol, acetone, or 1,4-dioxane, adding a free acid or free base, and then crystallizing the resulting solution.

[0067] The details of the above preventive or therapeutic method can be applied as is to the above description of the pharmaceutical composition according to one aspect of the present invention.

[0068] In the present invention, the term “treatment” is used as a concept that includes treatment, improvement, amelioration or management of a disease.

[0069] The term "preventing" or "prevention" in the present invention refers to preventing a disease, for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or exhibit the pathology or signs of the disease.

[0070] The term "subject" or "patient" in the present invention means any animal including mammals, for example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and humans.

[0071] Hereinafter, the present invention will be described in more detail.

[0072] [Chemical Formula 1]

[0073]

[0074] In the above chemical formula 1,

[0075] R1 is hydrogen or C 1-4 It is alkyl;

[0076] R2 is hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkynylide;

[0077] R3 is R 3a or -L2- and;

[0078] Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo(=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6Alkoxy, hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and R a class R b are each independently Hydrogen, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-8 Select from the group consisting of carbocyclyl, wherein the above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-4 Alkyl may be substituted with one or more halogens;

[0079] r is an integer from 0 to 1;

[0080] m is an integer from 0 to 5;

[0081] L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and;

[0082] p is an integer from 0 to 3;

[0083] q is an integer from 0 to 2;

[0084] class are each independently C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl, and in this case, C of 6-10 Aryl, C 4-10 Heteroaryl, C3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl is unsubstituted or substituted with one or more R 3a can be replaced with;

[0085] X1 is -O(R4) or -N(R5)(R6);

[0086] R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, which is halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d may be substituted or unsubstituted, where R c and R d are each independently hydrogen or C 1-6 It is alkyl;

[0087] R5 and R6 is each independently hydrogen, C 1-6Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f It can be substituted with one or more functional groups selected from the group consisting of, where Re and R f are each independently hydrogen or C 1-6 It is alkyl,

[0088] Or the above -N(R5)(R6) is R5 and C in which R6 is connected to each other to form a ring with the nitrogen atom in -N(R5)(R6) 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl, wherein the above C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h It can be substituted with one or more functional groups selected from the group consisting of, where R g class R h are each independently Hydrogen, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy C 3-8 It is carbocyclyl;

[0089] L1 is a direct bond, -C(O)-, -O-, -NH--, -C(O)NH- or -C(O)NCH3- and;

[0090] n is an integer from 0 to 2;

[0091] is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 4-14 Fused heterocyclyl or C 4-14 Bridged heterocyclyl, and in this case, the above C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 4-14 Heterospirocarbocyclyl, C 4-14 Fused heterocyclyl or C 4-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i , -NR i R j , C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl, wherein R i and R j are each independently hydrogen or C 1-6 It's alkyl.

[0092] Preferably, a compound selected from the compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof and a pharmaceutically acceptable salt thereof class Each of them is independently C 6-10 Aryl or C 4-10 It may be heteroaryl.

[0093] Preferably, R is selected from the compounds of the present invention's formula 1, optical isomers thereof, diastereomers thereof, hydrates thereof, solvates thereof and pharmaceutically acceptable salts thereof. 3a are each independently halogen, hydroxy, cyano, amino, amine, nitro, C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and here R a and R b are each independently hydrogen, C 1-6 Alkyl, -CF3 or -CF2H, wherein the C 1-6 Alkyl may be substituted with one or more halogens.

[0094] Preferably, in a compound selected from the compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, R4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl or C 2-9 Heterocyclyl; R5 and R6 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Carbocyclyl or C 2-9 Heterocyclyl, or the above -N(R5)(R6) is C 2-9 It may be a heterocyclyl.

[0095] According to another embodiment of the present invention, the compound represented by the above chemical formula 1 may be represented by the following chemical formula 2.

[0096] [Chemical Formula 2]

[0097]

[0098] In the above chemical formula 2,

[0099] L1 is a direct bond, -C(O)-, -O-, -NH-, -C(O)NH- or -C(O)NCH3- and;

[0100] n is an integer from 0 to 2;

[0101] Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen;

[0102] R 4a is hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 It is a heterocyclyl;

[0103] is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein the morpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted with halogen, -C 1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

[0104] According to another embodiment of the present invention, the compound represented by the above chemical formula 1 may be represented by the following chemical formula 3.

[0105] [Chemical Formula 3]

[0106]

[0107] In the above chemical formula 3,

[0108] L3 is a direct bond, -C(O)-, -C(O)NH-, or -C(O)NCH3- and;

[0109] n is an integer from 0 to 2;

[0110] Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen;

[0111] R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl,

[0112] or the above -N(R 5a )(R 5b ) is R 5a Wow R 5b are connected to each other -N(R 5a )(R 5b ) forming a ring with the nitrogen atom in it 2-9 It is a heterocyclyl;

[0113] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted with halogen, -C1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

[0114] According to another embodiment of the present invention, the compound represented by the above chemical formula 2 may be represented by the following chemical formula 4.

[0115] [Chemical Formula 4]

[0116]

[0117] In the above chemical formula 4,

[0118] L4 is a direct bond, -C(O)-, -O-, -C(O)NH- or -C(O)NCH3-;

[0119] n is an integer from 0 to 2;

[0120] Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen;

[0121] is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl, wherein the morpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl is unsubstituted or substituted with halogen, -C 1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

[0122] According to another embodiment of the present invention, the compound represented by the above chemical formula 3 can be represented by the following chemical formula 5.

[0123] [Chemical Formula 5]

[0124]

[0125] L5 is a direct bond, -C(O)-, -C(O)NH-, or -C(O)NCH3-;

[0126] n is an integer from 0 to 2;

[0127] Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen;

[0128] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or substituted with halogen, -C 1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

[0129] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0130] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(thiomorpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0131] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(thiazolidine-3-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0132] (R)-3-(1-((6-(1,1-deoxidothiomorpholine-4-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0133] (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)-N-(tetrahydro-2H-pyran-4-yl)phthalazine-6-carboxamide;

[0134] (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-N,4-dimethyl-7-(methylamino)-N-(tetrahydro-2H-pyran-4-yl)phthalazine-6-carboxamide;

[0135] 3-((1R)-1-((6-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0136] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(4-methylpiperazine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0137] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(piperazine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0138] (R)-3-(1-((6-(4,4-difluoropiperidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0139] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0140] (R)-3-(1-((6-(4-ethylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0141] (R)-3-(1-((6-(4-cyclopropylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0142] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(pyrrolidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0143] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(piperidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0144] (R)-3-(1-((6-(azetidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0145] (R)-3-(1-((6-(3-fluoroazetidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0146] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(5-azaspiro[2.4]heptane-5-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0147] 3-((1R)-1-((6-(2-Oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0148] (R)-3-(1-((6-(4-cyclohexylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0149] (R)-3-(1-((6-(4-isopropylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0150] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(4-morpholinopiperidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0151] (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)-N-(2-morpholinoethyl)phthalazine-6-carboxamide;

[0152] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(1,4-oxazepane-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0153] (R)-(1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone;

[0154] (R)-(1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone;

[0155] (R)-(1-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone;

[0156] (R)-3-(1-((7-methoxy-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0157] (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)benzonitrile;

[0158] (R)-3-(1-((7-(cyclopentylamino)-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0159] (R)-3-(1-((7-(cyclopentylamino)-6-((4-cyclopropylpiperazin-1-yl)methyl)-4-methylphthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0160] (R)-3-(1-((7-methoxy-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile;

[0161] (R)-3-(1-((7-cyclopentylamino)-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0162]

[0163] In the present invention, the method for preparing the compound of the above chemical formula 1 is not particularly limited, but for example, it can be synthesized by the preparation method of the following reaction scheme 1, reaction scheme 2, reaction scheme 3, reaction scheme 4, reaction scheme 5, reaction scheme 6 or reaction scheme 7:

[0164]

[0165] [Reaction Formula 1]

[0166]

[0167] In the above reaction formula 1 , R1, R2, R3, R4, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0168]

[0169] [Step 1]

[0170] Dimethyl amino terephthalate (1 equivalent) was slowly added dropwise to chloroform at 20-25°C and refluxed for 4-6 minutes. N-Bromosuccinimide (1.1 equivalent) was slowly added dropwise to the reaction mixture at 20-25°C. After the addition was complete, reflux was performed at 20-25°C for 18-24 hours. After the reaction was complete, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solution was concentrated under reduced pressure to obtain the title compound.

[0171] [Step 2]

[0172] B (1 equivalent), methyl iodide (2 equivalents), and potassium carbonate (4 equivalents), prepared in the above [Step-1], were dissolved in DMF and refluxed at 100-120°C for 15-18 hours. After the reaction was completed, the solution was cooled to room temperature, and water was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0173] [Step 3]

[0174] C (1 equivalent), butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-2] were dissolved in acetonitrile and stirred under reflux at 90 to 110 °C for 15 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0175] [Step 4]

[0176] D (1 equivalent) obtained in the above [Step-3] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise at 20-25°C. After the addition was complete, the mixture was refluxed at 20-25°C for 0.5-2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and water was slowly added dropwise to the reaction mixture, which was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0177] [Step 5]

[0178] E (1 equivalent) and hydrazine hydrate (1 equivalent) obtained in the above [Step-4] were dissolved in ethanol and stirred under reflux at 85 to 105°C for 0.5 to 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound.

[0179] [Step 6]

[0180] F (1 equivalent) prepared in the above [Step-5] was dissolved in phosphoryl chloride, and the mixture was refluxed at 120-140°C for 3-4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0181] [Step 7]

[0182] G (1 equivalent), aniline (1.3 equivalents), magnesium chloride (3 equivalents), and DIPEA (6 equivalents) prepared in the above [Step-6] were dissolved in 2-butanol, and the mixture was refluxed and stirred at 110-120°C for 47-50 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0183] [Step 8]

[0184] H (1 equivalent) and sodium hydroxide (10 equivalents) obtained in the above [Step-7] were dissolved in a tetrahydrofuran: methanol: water mixture, and refluxed at 20-30°C for 2-4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with a 6N hydrochloric acid solution at low temperature until the pH reached 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0185] [Step 9]

[0186] I (1 equivalent), amine (8 equivalents), HATU (3 equivalents), and DIPEA (8 equivalents) prepared in the above [Step-8] were dissolved in DMF and stirred under reflux at room temperature for 3 to 5 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0187]

[0188] [Reaction Formula 2]

[0189]

[0190] In the above reaction formula 2 , R1, R2, R3, R5, R 6, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0191]

[0192] [Step 1]

[0193] Dimethyl amino terephthalate (1 equivalent) was slowly added dropwise to chloroform at 20-25°C and refluxed for 4-6 minutes. N-Bromosuccinimide (1.1 equivalent) was slowly added dropwise to the reaction mixture at 20-25°C. After the addition was complete, reflux was performed at 20-25°C for 18-24 hours. After the reaction was complete, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.

[0194] [Step 2]

[0195] B (1 equivalent), methyl iodide (2 equivalents), and potassium carbonate (4 equivalents) prepared in the above [Step-1] were dissolved in DMF and refluxed at 100-120°C for 15-18 hours. After the reaction was completed, the solution was cooled to room temperature, and water was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0196] [Step 3]

[0197] C (1 equivalent), butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-2] were dissolved in acetonitrile and stirred under reflux at 90 to 110 °C for 15 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0198] [Step 4]

[0199] D (1 equivalent) obtained in the above [Step-3] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise at 20-25°C. After completion of the addition, the mixture was stirred under reflux at 20-25°C for 0.5-2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and water was slowly added dropwise to the reaction mixture, which was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0200] [Step 5]

[0201] E (1 equivalent) and hydrazine hydrate (1 equivalent) obtained in the above [Step-4] were dissolved in ethanol and stirred under reflux at 85 to 105°C for 0.5 to 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound.

[0202] [Step 6]

[0203] F (1 equivalent) and sodium hydroxide (10 equivalents) prepared in the above [Step-5] were dissolved in a mixture of tetrahydrofuran: methanol: water, and refluxed at 20-30°C for 1.5-3.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with a 6N hydrochloric acid solution at low temperature until the pH reached 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0204] [Step 7]

[0205] G (1 equivalent), amine (2 equivalents), HATU (1.3 equivalents), and DIPEA (5 equivalents) prepared in the above [Step-6] were dissolved in DMF and stirred under reflux at room temperature for 2 to 3 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0206] [Step 8]

[0207] The H (1 equivalent) obtained in the above [Step-7] was dissolved in phosphoryl chloride, and the mixture was refluxed at 105-115°C for 0.5-2 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of an aqueous sodium bicarbonate solution. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0208] [Step 9]

[0209] I (1 equivalent), aniline (2.4 equivalents), cesium fluoride (3 equivalents), and DIPEA (5 equivalents) prepared in the above [Step-8] were dissolved in DMSO, and the mixture was refluxed and stirred at 120-140°C for 15-17 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0210]

[0211] [Reaction Formula 3]

[0212]

[0213]

[0214] In the above reaction formula 3 , R1, R2, R3, R4, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0215]

[0216] [Step 1]

[0217] Methyl 3-methoxy-4-methylbenzoate (1 equivalent) was mixed with acetic acid and water, and bromine (1 equivalent) was added dropwise. After the addition was complete, the mixture was refluxed and stirred at 50-60°C for 1-2 hours. After the reaction was complete, the mixture was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0218] [Step 2]

[0219] B (1 equivalent), N-bromosuccinimide (1.2 equivalent), and azobicisobutyronitrile (1 equivalent) obtained in the above [Step-1] were dissolved in chloroform and stirred under reflux at 65-70°C for 2-3 hours. After the reaction was completed, the mixture was cooled to room temperature and a saturated aqueous sodium bicarbonate solution was added dropwise. After extraction with dichloromethane, the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0220] [Step 3]

[0221] C (1 equivalent), amine (1.1 equivalent), and potassium carbonate (2 equivalent) obtained in the above [Step-2] were dissolved in acetonitrile and stirred at 20-30°C for 17-20 hours. After the reaction was completed, the mixture was cooled to room temperature and a saturated aqueous sodium bicarbonate solution was added dropwise. The mixture was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0222] [Step 4]

[0223] D (1 equivalent), butyl vinyl ether (5.0 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-3] were dissolved in acetonitrile and stirred under reflux at 90 to 110 °C for 15 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0224] [Step 5]

[0225] E (1 equivalent) obtained in the above [Step-4] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise at 25-30°C. After the addition was complete, the mixture was refluxed at 25-30°C for 0.5-2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and water was slowly added dropwise to the reaction mixture, which was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0226] [Step 6]

[0227] F (1 equivalent) and hydrazine monohydrate (1.5 equivalents) obtained in the above [Step-5] were dissolved in ethanol and stirred under reflux at 85-105°C for 0.5-2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol. The filtered solid was dried to obtain the title compound.

[0228] [Step 7]

[0229] G (1 equivalent) and phosphoryl chloride (3 equivalents) obtained in the above [Step-6] were dissolved in acetonitrile, and the mixture was refluxed and stirred at 95 to 115 °C for 0.5 to 2 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in dichloromethane, and neutralized by dropwise addition to a saturated aqueous sodium bicarbonate solution at -5 to 5 °C. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0230] [Step 8]

[0231] H (1 equivalent), aniline (1.5 equivalents), magnesium chloride (3 equivalents), and N,N-diisopropylethylamine (6 equivalents) prepared in the above [Step-7] were dissolved in 2-butanol, and the mixture was refluxed and stirred at 120-140°C for 46-50 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0232]

[0233] [Reaction Formula 4]

[0234]

[0235] In the above reaction formula 4 , R1, R2, R3, R5, R 6, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0236]

[0237] [Step 1]

[0238] Dimethyl 2-aminoterephthalate (1 equivalent) and N-bromosuccinimide (1.1 equivalent) were slowly added dropwise to chloroform at 20–30°C. After the addition was complete, the mixture was refluxed and stirred at 20–30°C for 15–18 hours. After the reaction was complete, water was slowly added dropwise, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0239] [Step 2]

[0240] B (1 equivalent), methyl iodide (2 equivalents), and potassium carbonate (1 equivalent) prepared in the above [Step-1] were dissolved in DMF and refluxed at 100-120°C for 2.5-4.5 hours. After the reaction was completed, the mixture was cooled to room temperature, and water was slowly added dropwise. The organic layer obtained by extracting with ethyl acetate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0241] [Step 3]

[0242] C (1 equivalent), butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-2] were dissolved in acetonitrile and stirred under reflux at 90 to 110 °C for 15 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0243] [Step 4]

[0244] D (1 equivalent) obtained in the above [Step-3] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise at 20-25°C. After completion of the addition, the mixture was stirred under reflux at 20-25°C for 0.5-2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and water was slowly added dropwise to the reaction mixture, which was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0245] [Step 5]

[0246] E (1 equivalent) and hydrazine hydrate (1.3 equivalent) obtained in the above [Step-4] were dissolved in ethanol and stirred under reflux at 85-105°C for 0.5-2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound.

[0247] [Step 6]

[0248] F (1 equivalent) and sodium hydroxide (12 equivalents) prepared in the above [Step-5] were dissolved in a mixture of tetrahydrofuran: methanol: water, and stirred under reflux at 20-30°C for 1.5-3.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with a 6N hydrochloric acid solution at low temperature until the pH reached 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0249] [Step 7]

[0250] G (1 equivalent), amine (8 equivalents), HATU (3 equivalents), and N,N-diisopropylethylamine (8 equivalents) prepared in the above [Step-6] were dissolved in DMF and stirred under reflux at room temperature for 15 to 18 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0251] [Step 8]

[0252] The H (1 equivalent) obtained in the above [Step-7] was dissolved in tetrahydrofuran, and borane dimethyl sulfide was slowly added dropwise. After the addition was complete, the mixture was refluxed and stirred at 20-30°C for 15-17 hours. After the reaction was complete, water was added dropwise, and the mixture was extracted with a mixed solution of dichloromethane and methanol. The resulting base layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound.

[0253] [Step 9]

[0254] The I (1 equivalent) obtained in the above [Step-8] was dissolved in phosphoryl chloride, and the mixture was stirred under reflux at 105-115°C for 1-3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of a saturated aqueous sodium bicarbonate solution. The residue was extracted with a mixed solution of dichloromethane and acetone, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound.

[0255] [Step 10]

[0256] J (1 equivalent), aniline (1.5 equivalents), magnesium chloride (3 equivalents), and N,N-diisopropylethylamine (6 equivalents) prepared in the above [Step-9] were dissolved in 2-butanol, and the mixture was stirred under reflux at 120-140°C for 45-50 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0257]

[0258] [Reaction Formula 5]

[0259]

[0260]

[0261] In the above reaction formula 5 , R1, R2, R3, R5, R 6, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0262]

[0263] [Step 1]

[0264] Dimethyl 2-aminoterephthalate (1 equivalent), ketone (2.2 equivalents), sodium triacetoxyborohydride (2 equivalents), and acetic acid (8.5 equivalents) were slowly added dropwise to dichloromethane at 25-30°C and stirred under reflux for 45-50 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0265] [Step 2]

[0266] B (1 equivalent) and N-bromosuccinimide (1.05 equivalent) prepared in the above [Step-1] were slowly added dropwise to acetonitrile at 25-30°C and stirred under reflux for 15-17 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0267] [Step 3]

[0268] C (1 equivalent), butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-2] were dissolved in acetonitrile and stirred under reflux at 90 to 110 °C for 15 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0269] [Step 4]

[0270] D (1 equivalent) obtained in the above [Step-3] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise. After completion of the addition, the mixture was stirred under reflux at 20-30°C for 1.5-3 hours. After completion of the reaction, the reaction product was concentrated under reduced pressure, and the obtained residue was slowly added dropwise to water, which was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0271] [Step 5]

[0272] D (1 equivalent) and hydrazine hydrate (1.3 equivalent) obtained in the above [Step-6] were dissolved in ethanol and stirred under reflux at 85-105°C for 0.5-2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound.

[0273] [Step 6]

[0274] E (1 equivalent) and sodium hydroxide (12 equivalents) prepared in the above [Step-5] were dissolved in a mixture of tetrahydrofuran: methanol: water, and stirred under reflux at 20-30°C for 1.5-3.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with a 6N hydrochloric acid solution at low temperature until the pH reached 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0275] [Step 7]

[0276] F (1 equivalent), amine (8 equivalents), HATU (3 equivalents), and N,N-diisopropylethylamine (8 equivalents) prepared in the above [Step-6] were dissolved in DMF and stirred under reflux at room temperature for 15 to 18 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0277] [Step 8]

[0278] The G (1 equivalent) obtained in the above [Step-7] was dissolved in tetrahydrofuran, and borane dimethyl sulfide was slowly added dropwise. After the addition was complete, the mixture was refluxed and stirred at 20-30°C for 15-17 hours. After the reaction was complete, water was added dropwise, extracted with a mixed solution of dichloromethane and methanol, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0279] [Step 9]

[0280] The H (1 equivalent) obtained in the above [Step-8] was dissolved in phosphoryl chloride, and the mixture was stirred under reflux at 105-115°C for 1-3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of a saturated aqueous sodium bicarbonate solution. The residue was extracted with a mixed solution of dichloromethane and acetone, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound.

[0281] [Step 10]

[0282] I (1 equivalent), aniline (1.5 equivalents), magnesium chloride (3 equivalents), and N,N-diisopropylethylamine (tl) prepared in the above [Step-9] were dissolved in 2-butanol, and the mixture was stirred under reflux at 120 to 140°C for 45 to 50 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0283]

[0284] [Reaction Formula 6]

[0285]

[0286] In the above reaction formula 6 , R1, R2, R3, R4, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0287]

[0288] [Step 1]

[0289] Dimethyl phenol (1 equivalent) and tetrabutylammonium tribromide (1 equivalent) were added dropwise to chloroform / water at 20–30°C and refluxed at 20–25°C for 2–4 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0290] [Step 2]

[0291] B (1 equivalent), methyl iodide (2 equivalents), and potassium hydroxide (4 equivalents) prepared in the above [Step-1] were dissolved in DMSO and stirred under reflux at 20-30°C for 0.5-2 hours. After the reaction was completed, the solution was cooled to room temperature, and water was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain the title compound.

[0292] [Step 3]

[0293] C (1 equivalent) obtained in the above [Step-2] was dissolved in water, potassium permanganate (4.4 equivalents) was slowly added dropwise at 20-30°C, and the mixture was stirred under reflux at 110-130°C for 15-17 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered under reduced pressure, and hydrochloric acid was added to the filtered organic layer, stirred under reflux at 20-30°C for 0.5-1 hour, and filtered under reduced pressure to obtain the title compound.

[0294] [Step 4]

[0295] D (1 equivalent) and sulfuric acid (1 equivalent) obtained in the above [Step-3] were dissolved in ethanol and stirred under reflux at 90-110°C for 5-7 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0296] [Step 5]

[0297] E (1 equivalent), butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-4] were dissolved in acetonitrile and stirred under reflux at 90 to 110 °C for 15 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0298] [Step 6]

[0299] F (1 equivalent) prepared in the above [Step-5] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise at 20-25°C. After the addition was complete, the mixture was refluxed at 20-25°C for 0.5-2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and water was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0300] [Step 7]

[0301] G (1 equivalent) and hydrazine hydrate (1 equivalent) prepared in the above [Step-6] were dissolved in ethanol and stirred under reflux at 85 to 105°C for 0.5 to 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound.

[0302] [Step 8]

[0303] The H (1 equivalent) obtained in the above [Step-7] was dissolved in phosphoryl chloride, and the mixture was refluxed at 120-140°C for 3-4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0304] [Step 9]

[0305] I (1 equivalent), aniline (1.3 equivalents), magnesium chloride (3 equivalents), and DIPEA (6 equivalents) prepared in the above [Step-8] were dissolved in 2-butanol, and the mixture was refluxed and stirred at 110-120°C for 47-50 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0306] [Step 10]

[0307] J (1 equivalent) and sodium hydroxide (10 equivalents) obtained in the above [Step-9] were dissolved in a mixture of tetrahydrofuran: methanol: water, and stirred under reflux for 2 to 4 hours at 20 to 30°C. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with a 6N hydrochloric acid solution at low temperature until the pH reached 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0308] [Step 11]

[0309] K (1 equivalent), amine (8 equivalents), HATU (3 equivalents), and DIPEA (8 equivalents) prepared in the above [Step-10] were dissolved in DMF and stirred under reflux at room temperature for 3 to 5 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0310]

[0311] [Reaction Formula 7]

[0312]

[0313]

[0314] In the above reaction formula 7 , R1, R2, R3, R5, R6, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0315]

[0316] [Step 1]

[0317] Dimethyl 2-aminoterephthalate (1 equivalent), ketone (2.2 equivalents), sodium triacetoxyborohydride (2 equivalents), and acetic acid (8.5 equivalents) were slowly added dropwise to dichloromethane at 25-30°C and stirred under reflux for 45-50 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0318] [Step 2]

[0319] B (1 equivalent) and N-bromosuccinimide (1.05 equivalent) prepared in the above [Step-1] were slowly added dropwise to acetonitrile at 25-30°C and stirred under reflux for 15-17 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture. The mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0320] [Step 3]

[0321] C (1 equivalent), butyl vinyl ether (5 equivalents), palladium acetate (0.1 equivalents), triphenylphosphine (0.2 equivalents), and triethylamine (1.2 equivalents) obtained in the above [Step-2] were dissolved in acetonitrile and stirred under reflux at 90-110°C for 15-20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0322] [Step 4]

[0323] D (1 equivalent) obtained in the above [Step-3] was dissolved in tetrahydrofuran, and 6N hydrochloric acid was slowly added dropwise. After the addition was completed, the mixture was stirred under reflux at 20-30°C for 1.5-3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was slowly added dropwise to water. This was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0324] [Step 5]

[0325] D (1 equivalent) and hydrazine hydrate (1.3 equivalent) obtained in the above [Step-6] were dissolved in ethanol and stirred under reflux at 85-105°C for 0.5-2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound.

[0326] [Step 6]

[0327] F (1 equivalent) prepared in the above [Step-5] was dissolved in phosphoryl chloride, and the mixture was refluxed at 100-120°C for 3-4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of an aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0328] [Step 7]

[0329] G (1 equivalent), aniline (1.6 equivalents), magnesium chloride (3 equivalents), and DIPEA (6 equivalents) prepared in the above [Step-6] were dissolved in 2-butanol, and the mixture was refluxed and stirred at 110-130°C for 16-18 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0330] [Step 8]

[0331] H (1 equivalent) and sodium hydroxide (10 equivalents) obtained in the above [Step-7] were dissolved in a tetrahydrofuran: methanol: water mixture, and refluxed at 20-30°C for 2-4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was acidified with a 6N hydrochloric acid solution at low temperature until the pH reached 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain the title compound.

[0332] [Step 9]

[0333] I (1 equivalent), amine (1.5 equivalents), HATU (1.3 equivalents), and DIPEA (3 equivalents) prepared in the above [Step-8] were dissolved in DMF and stirred under reflux at room temperature for 3 to 5 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0334]

[0335] Although the manufacturing method of the above chemical formula 1 has been described with specific examples, specific reaction conditions, such as the amount of reaction solvent, base, and reactant, are not limited to those described in this specification, and cannot be interpreted as limiting the scope of the present invention in any way.

[0336] The pharmaceutical composition of the present invention is also useful for preventing or treating various diseases related thereto, as the compound of chemical formula 1 contained therein inhibits SOS1 binding to RAS family proteins and / or RAC1.

[0337] According to another embodiment of the present invention, a pharmaceutical composition for preventing or treating a disease associated with inhibition of SOS1 binding to a RAS family protein and / or RAC1 is provided, comprising as an active ingredient a compound selected from optical isomers of the compound of the above chemical formula 1, diastereomers thereof, hydrates thereof, solvates thereof, and pharmaceutically acceptable salts thereof.

[0338] According to another embodiment of the present invention, a pharmaceutical preparation comprising the above-described pharmaceutical composition is provided.

[0339] The pharmaceutical preparation of the present invention may be in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or in parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration such as injections.

[0340] When the pharmaceutical preparation of the present invention is in the form of an injection, the carrier may include, but is not limited to, water, saline solution, glucose aqueous solution, similar sugar aqueous solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc.

[0341] For use of the compounds according to the present invention as medicaments, the latter are prepared in the form of pharmaceutical preparations, which contain, in addition to the active ingredients for oral or parenteral administration, suitable pharmaceutically organic or inorganic inert carrier substances, such as water, gelatin, gum arabic, lactose, starch, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, such as tablets, dragees, suppositories or capsules, or in liquid form, such as solutions, suspensions or emulsions. In addition, they may optionally contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers; salts or buffers for altering the osmotic pressure.

[0342] As carrier systems, surfactants, for example, bile salts or animal or plant phospholipids, or mixtures thereof, and liposomes or components thereof may also be used.

[0343] In addition, the dosage for the human body of the compound of the above chemical formula 1 according to the present invention is preferably in the range of 0.1 mg / day to 2,000 mg / day, based on an adult patient weighing 70 kg. The compound according to the present invention may be administered once or several times a day in divided doses. However, the above-mentioned dosage may vary depending on the patient's health condition, age, weight, and sex, as well as the dosage form and disease severity, and therefore, the scope of the present invention is not limited to the dosage presented above.

[0344] According to another embodiment of the present invention, a compound selected from the compound of the chemical formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, or a pharmacologically acceptable salt thereof, is provided for use in the prevention or treatment of cancer or tumor.

[0345] According to another embodiment of the present invention, a method for preventing or treating cancer or a tumor is provided, comprising administering to a subject a compound selected from the group consisting of the compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof. Preferably, the subject refers to, but is not limited to, a subject or a patient.

[0346] According to another embodiment of the present invention, there is provided a method for preventing or treating cancer or a tumor in a subject requiring administration of an inhibitor of the compound and a standard-of-care formulation, comprising administering a therapeutically effective amount of a standard-of-care formulation comprising a compound selected from the group consisting of a compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof and a pharmaceutically acceptable salt thereof.

[0347] According to another embodiment of the present invention, a method for preventing or treating cancer or a tumor in a specimen requiring administration of the composition is provided, comprising administering a therapeutically effective amount of a composition comprising a compound selected from the compound of the chemical formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof.

[0348] According to another embodiment of the present invention, a method for inhibiting SOS1 binding to a RAS family protein and / or RAC1 in a sample or cell is provided, comprising administering to the sample a compound selected from the group consisting of a compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof.

[0349] According to another embodiment of the present invention, a method for inhibiting tyrosine kinase in a sample or cell is provided, comprising administering to the sample a compound selected from the compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof.

[0350] According to another embodiment of the present invention, a method for preventing or treating cancer or a tumor in a subject is provided, comprising administering to the subject a compound selected from the compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof.

[0351] According to another embodiment of the present invention, a method for preventing or treating cancer or tumors that can be treated by inhibiting binding of SOS1 protein to RAS family proteins and / or RAC1 in a sample or cell is provided, comprising administering to the sample a compound selected from the compound of formula 1 of the present invention, an optical isomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof and a pharmaceutically acceptable salt thereof.

[0352]

[0353] Hereinafter, the present invention will be described in more detail with the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0354]

[0355] Example 1: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0356]

[0357] [Step 1] Preparation of dimethyl 2-amino-5-bromoterephthalate

[0358]

[0359] Dimethyl aminoterephthalate (20.0 g, 95.60 mmol) and N-bromosuccinimide (18.7 g, 105.16 mmol) were dissolved in 1000 mL of chloroform, and the mixture was refluxed at room temperature for 16 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 3:1 (v / v)) to obtain 15.0 g of the title compound in a 54% yield.

[0360] 1 H-NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.07 (s, 1H), 5.84 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H).

[0361]

[0362] [Step 2] Preparation of dimethyl 2-bromo-5-(methylamino) terephthalate

[0363]

[0364] Dimethyl 2-amino-5-bromoterephthalate (15.0 g, 52.06 mmol), methyl iodide (9.7 mL, 156.18 mmol), and potassium carbonate (28.8 g, 208.26 mmol) obtained in the above [Step-1] were dissolved in 150 mL of DMF, and the mixture was stirred under reflux at 110 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, and then acidified with 2N hydrochloric acid until the pH reached 3. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 9:1 (v / v)) to obtain 7.4 g of the title compound in a yield of 47%.

[0365] 1 H-NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), 7.68 (s, 1H), 7.01 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.94 (d, 3H).

[0366]

[0367] [Step 3] Preparation of dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate

[0368]

[0369] Dimethyl 2-bromo-5-(methylamino) terephthalate (7.4 g, 24.49 mmol), butyl vinyl ether (15.7 mL, 122.47 mmol), Pd(OAc)2 (550 mg, 2.45 mmol), triphenylphosphine (1.3 g, 4.90 mmol), and triethylamine (4.1 mL, 29.39 mmol) obtained in the above [Step-2] were dissolved in 80 mL of acetonitrile, and the mixture was stirred under reflux at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0370]

[0371] [Step 4] Preparation of dimethyl 2-acetyl-5-(methylamino) terephthalate

[0372]

[0373] Dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate (7.87 g, 24.49 mmol) and 6N hydrochloric acid (33 mL, 195.91 mmol) obtained in the above [Step-3] were dissolved in 80 mL of tetrahydrofuran, and the mixture was refluxed at room temperature for 1 hour. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (v / v)) to obtain 5.5 g of the title compound in a yield of 84%.

[0374] 1 H-NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.33 (s, 1H), 6.72 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.00 (d, 3H), 2.54 (s, 3H).

[0375]

[0376] [Step 5] Preparation of methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate

[0377]

[0378] Dimethyl 2-acetyl-5-(methylamino) terephthalate (5.5 g, 20.73 mmol) and hydrazine monohydrate (1.1 g, 20.73 mmol) obtained in the above [Step-4] were dissolved in 70 mL of ethanol, and the mixture was refluxed and stirred at 95°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethanol to obtain 4.8 g of the title compound in a yield of 93%.

[0379] 1 H-NMR (300 MHz, DMSO-d6): δ 12.16 (s, 1H), 8.26 (s, 1H), 7.92 (d, 1H), 7.29 (s, 1H), 3.91 (s, 3H), 2.96 (d, 3H), 2.42 (s, 3H).

[0380]

[0381] [Step 6] Preparation of methyl 1-chloro-4-methyl-7-(methylamino)phthalazine-6-carboxylate

[0382]

[0383] Methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate (1 g, 4.04 mmol) obtained in the above [Step-5] was dissolved in 20 mL of phosphoryl chloride, and the mixture was stirred under reflux at 130°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The resulting residue was neutralized by dropwise addition of saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (v / v)) to obtain 730 mg of the title compound in a yield of 68%.

[0384] 1H-NMR (300 MHz, DMSO-d6): δ 8.61 (s, 1H), 8.09 (s, 1H), 6.98 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.01 (d, 3H), 2.79 (s, 3H).

[0385]

[0386] [Step 7] Preparation of 3-bromo-N-methoxy-N,2-dimethylbenzamide

[0387]

[0388] 3-Bromo-2-methylbenzoic acid (100 g, 465.01 mmol), HATU (194.49 g, 511.51 mmol), N,O-dimethylhydroxylamine hydrochloride (50 g, 511.51 mmol), N,N-diisopropylethylamine (245.44 mL, 1395.0 mmol) were dissolved in 800 mL of DMF, and the mixture was stirred under reflux at room temperature for 16 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0389] 1 H-NMR (300 MHz, CDCl3): δ 7.60 (d, 1H), 7.21 (d, 1H), 7.09 (t, 1H), 3.42-3.31 (m, 3H), 2.38 (s, 3H), 1.48 (m, 3H).

[0390]

[0391] [Step-8] Preparation of 1-(3-bromo-2-methylphenyl)ethan-1-one

[0392]

[0393] 3-Bromo-N-methoxy-N,2-dimethylbenzamide (120 g, 464.92 mmol) obtained in the above [Step-7] was dissolved in 700 mL of tetrahydrofuran at room temperature, cooled to 0°C, and slowly added dropwise to the 3M methylmagnesium bromide (310 mL, 929.84 mmol) reactant. The mixture was stirred under reflux at 45°C for 1.5 hours. After the reaction was completed, the mixture was cooled to 0°C, and 500 mL of 6N hydrochloric acid was slowly added dropwise. The mixture was stirred under reflux at 45°C for 1 hour. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and carried out the next reaction without further purification.

[0394] 1 H-NMR (300 MHz, CD3OD): δ 7.73 (d, 1H), 7.64 (d, 1H), 7.23 (m, 1H), 2.57 (s, 3H), 2.35 (s, 3H).

[0395]

[0396] [Step-9] Preparation of (S,E)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0397]

[0398] 1-(3-Bromo-2-methylphenyl)ethan-1-one (200 g, 938.66 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (170.6 g, 1407.98 mmol), and titanium ethoxide (725 mL, 3285.4 mmol) obtained in the above [Step-8] were dissolved in 1600 mL of tetrahydrofuran at room temperature, and the mixture was stirred under reflux at 85 °C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through a filter filled with Celite, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 10:1∼3:1 (v / v)) to obtain 213 g of the title compound in a yield of 72%.

[0399] 1 H-NMR (300 MHz, CD3OD): δ 7.65 (m, 1H), 7.31-7.05 (m, 2H), 2.69 (m, 3H), 2.51-2.31 (m, 3H), 1.28 (m, 9H).

[0400]

[0401] [Step-10] Preparation of (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide

[0402]

[0403] (S,E)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (213 g, 675.08 mmol) obtained in the above [Step-9] was dissolved in 1100 mL of tetrahydrofuran, and then cooled to -78 °C. 1M L-selectride (1352 mL, 1352 mmol) was slowly added dropwise to the reaction mixture at -78 °C, stirred under reflux for 0.5 h, and stirred under reflux for 2.5 h at 0 °C. After the reaction was completed, a saturated ammonium chloride aqueous solution was added dropwise at 0 °C, and stirred under reflux for 30 minutes at room temperature. After extracting with ethyl acetate, drying with anhydrous sodium sulfate and concentrating under reduced pressure, the obtained residue was purified by column chromatography (hexane: ethyl acetate = 3:1 (v / v)) to obtain 187.5 g of the title compound in 87% yield.

[0404] 1 H-NMR (300 MHz, CDCl3): δ 7.49 (d, 1H), 7.35 (d, 1H), 7.05 (m, 1H), 4.87 (m, 1H), 3.26 (m, 1H), 2.47 (s, 3H), 1.55-1.50 (m, 3H), 1.20 (m, 9H).

[0405]

[0406] [Step-11] Preparation of (R)-1-(3-bromo-2-methylphenyl)ethan-1-amine

[0407]

[0408] (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (187.5 g, 589.12 mmol) obtained in the above [Step-11] was dissolved in 900 mL of 1,4-dioxane / 450 mL of methanol, and then hydrochloric acid (290 mL, 4 M) dissolved in dioxane was slowly added dropwise, and the mixture was stirred under reflux for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the next reaction was performed without further purification.

[0409]

[0410] [Step-12] Preparation of tert-butyl (R)-1-(3-bromo-2-methylphenyl)ethyl-carbamate

[0411]

[0412] (R)-1-(3-bromo-2-methylphenyl)ethan-1-amine (121.5 g, 484.91 mmol), di-tert-butyl dicarbonate (157.54 mL, 678.88 mmol), and N,N-diisopropylethylamine (204.75 mL, 1163.8 mmol) obtained in the above [Step-11] were dissolved in 1220 mL of dichloromethane and stirred under reflux for 1 hour at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure and the next reaction was performed without further purification.

[0413] 1 H-NMR (300 MHz, CD3OD): δ 7.46 (d, 1H), 7.34 (d, 1H), 7.10 (m, 1H), 4.96 (m, 1H), 2.47 (s, 3H), 1.53-1.25 (m, 12H).

[0414]

[0415] [Step-13] Preparation of tert-butyl (R)-1-(3-cyano-2-methylphenyl)ethyl-carbamate

[0416]

[0417] Tert-butyl (R)-1-(3-bromo-2-methylphenyl)ethyl-carbamate (150 g, 477.37 mmol), Pd(PPh3)4 (55.17 g, 47.737 mmol), and zinc cyanide (67.28 g, 572.85 mmol) obtained in the above [Step-12] were dissolved in 1500 mL of DMF, and the mixture was stirred under reflux at 130 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered through a filter filled with Celite, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 5:1∼1:1 (v / v)) to obtain 105 g of the title compound in a yield of 84%.

[0418] 1 H-NMR (300 MHz, CDCl3): δ 7.54 (m, 1H), 7.30 (m, 2H), 5.01-4.84 (m, 2H), 2.61 (s, 3H), 1.42 (m, 12H).

[0419]

[0420] [Step-14] Preparation of (R)-3-(1-aminoethyl)-2-methylbenzonitrile 2,2,2-trifluoroacetate

[0421]

[0422] Tert-butyl (R)-1-(3-cyano-2-methylphenyl)ethyl-carbamate (105 g, 401.78 mmol) obtained in the above [Step-13] was dissolved in 1000 mL of dichloromethane, and trifluoroacetic acid (153.73 mL, 20008.9 mmol) was slowly added dropwise at room temperature, followed by stirring under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 105.5 g of the title compound in a 96% yield.

[0423] 1H-NMR (300 MHz, DMSO-d6): δ 8.38 (bs, 3H), 7.83 (m, 2H), 7.55 (m, 1H), 4.70 (m, 1H), 2.49 (s, 3H), 2.95 (d, 3H).

[0424]

[0425] [Step-15] Preparation of sec-butyl 1(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino-4-methyl-7-(methylamino)phthalazine-6-carboxylate

[0426]

[0427] Methyl 1-chloro-4-methyl-7-(methylamino)phthalazine-6-carboxylate (150 mg, 0.56 mmol) obtained in the above [Step-6], (R)-3-(1-aminoethyl)-2-methylbenzonitrile 2,2,2-trifluoroacetate (201 mg, 0.73 mmol) obtained in [Step-14], magnesium chloride (161 mg, 1.69 mmol), N,N-diisopropylethylamine (0.59 mL, 3.39 mmol) were dissolved in 1.5 mL of 2-butanol, and the mixture was stirred under reflux at 120 °C for 48 hours. After completion of the reaction, it was cooled to room temperature and water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 3:1 to 1:1 (v / v)) to obtain 85 mg of the title compound in a 35% yield.

[0428] 1 H-NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.88 (m, 1H), 7.86 (d, 1H), 7.76 (d, 1H), 7.61 (m, 1H), 7.58-7.29 (m, 2H), 5.58 (m, 1H), 3.04 (d, 3H), 2.51 (s, 3H), 1.72 (m, 2H), 1.69 (m, 3H), 1.35 (m, 3H), 0.98 (m, 3H).

[0429]

[0430] [Step-16] Preparation of (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid

[0431]

[0432] In the above [Step-15], sec-butyl 1(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino-4-methyl-7-(methylamino)phthalazine-6-carboxylate (85 mg, 0.20 mmol) and sodium hydroxide (78 mg, 1.97 mmol) were dissolved in 2 mL of a solution of tetrahydrofuran: methanol: water = 2:1:1, and the mixture was stirred under reflux at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was acidified with 6N hydrochloric acid solution at low temperature until the pH became 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried in an oven dryer at 55°C to obtain 50 mg of the title compound in a yield of 68%.

[0433] 1 H-NMR (300 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.37 (m, 1H), 7.77 (d, 1H), 7.66 (d, 1H), 7.48 (s, 1H), 7.36 (t, 1H), 5.36 (m 1H), 3.12 (s, 3H), 2.71-2.67 (m, 6H), 1.62 (d, 3H).

[0434]

[0435] [Step-17] Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0436]

[0437] (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid (50 mg, 0.13 mmol), morpholine (0.1 mL, 1.07 mmol), HATU (152 mg, 0.40 mmol), N,N-diisopropylethylamine (0.2 mL, 1.07 mmol) obtained in the above [Step-16] were dissolved in 1 mL of DMF, and the mixture was stirred under reflux at room temperature for 4 hours. After the reaction was completed, it was cooled to room temperature and water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: ethyl acetate: methanol = 10:10:1 (v / v / v)) to obtain 10 mg of the title compound in 17% yield.

[0438] 1 H-NMR (300 MHz, DMSO-d6): δ 7.76 (d, 1H), 7.60 (m, 2H), 7.32 (m, 2H), 7.23 (s, 1H), 6.07 (d, 1H), 5.59 (m, 1H), 3.64 (m, 6H), 3.16 (m, 2H), 2.94 (d, 3H), 2.67 (s, 3H), 2.49 (s, 3H), 1.55 (d, 3H).

[0439] MS (ESI+, m / z): 445.2 [M+H] +

[0440]

[0441] Example 2: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(thiomorpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0442]

[0443] The procedure of Example 1 was repeated except that thiomorpholine (82 mg, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 80 mg of the title compound in a yield of 32%.

[0444] 1 H-NMR (300 MHz, DMSO-d6): δ 7.78 (m, 1H), 7.60 (m, 2H), 7.35 (m, 2H), 7.21 (s, 1H), 6.02 (m, 1H), 5.61 (m, 1H), 3.92 (m, 2H), 3.45 (m, 2H), 2.94 (m, 3H), 2.77 (m, 2H), 2.67 (s, 3H), 2.61 (m, 2H), 2.49 (s, 3H), 1.56 (m, 3H).

[0445] MS (ESI+, m / z): 461.2 [M+H] +

[0446]

[0447] Example 3: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(thiazolidine-3-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0448]

[0449] The procedure of Example 1 was repeated except that thiazolidine (72 mg, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 56 mg of the title compound in a yield of 23%.

[0450] 1 H-NMR (300 MHz, DMSO-d6): δ 7.78 (m, 1H), 7.69 (s, 1H), 7.61 (m, 1H), 7.37 (m, 2H), 7.24 (s, 1H), 6.22 (m, 1H), 5.62 (m, 1H), 4.66 (m, 2H), 3.87 (m, 2H), 3.05 (m, 2H), 2.95 (m, 3H), 2.67 (s, 3H), 2.49 (s, 3H), 1.56 (m, 3H).

[0451] MS (ESI+, m / z): 447.2 [M+H] +

[0452]

[0453] Example 4: (R)-3-(1-((6-(1,1-deoxidothiomorpholine-4-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0454]

[0455] The procedure of Example 1 was repeated except that thiomorpholine 1,1-dioxide (108 mg, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 80 mg of the title compound in a 30% yield.

[0456] 1 H-NMR (300 MHz, DMSO-d6): δ 7.77 (m, 2H), 7.61 (m, 1H), 7.37 (m, 2H), 7.23 (s, 1H), 6.10 (m, 1H), 5.62 (m, 1H), 4.06 (m, 2H), 3.59 (m, 2H), 3.43 (m, 2H), 3.26 (m, 2H), 2.95 (m, 3H), 2.67 (s, 3H), 2.49 (s, 3H), 1.56 (m, 3H).

[0457] MS (ESI+, m / z): 493.2 [M+H] +

[0458]

[0459] Example 5: (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)-N-(tetrahydro-2H-pyran-4-yl)phthalazine-6-carboxamide

[0460]

[0461] The procedure of Example 1 was repeated except that tetrahydropyran-4-amine hydrochloride (113 mg, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 14 mg of the title compound in a 6% yield.

[0462] 1H-NMR (300 MHz, DMSO-d6): δ 8.66-8.64 (m, 1H), 7.95 (s, 1H), 7.77-7.75 (m, 1H), 7.60-7.53 (m, 2H), 7.36-7.28 (m, 2H), 7.20 (s, 1H), 5.59-5.50 (m, 1H), 4.06-3.99 (m, 1H), 3.97-3.87 (m, 2H), 3.44-3.35 (m, 2H), 2.98-2.96 (m, 3H), 2.67 (s, 3H), 2.55 (s, 3H), 1.84-1.79 (m, 2H), 1.66-1.53 ​​(m, 5H).

[0463] MS (ESI+, m / z): 459.2 [M+H] +

[0464]

[0465] Example 6: (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-N,4-dimethyl-7-(methylamino)-N-(tetrahydro-2H-pyran-4-yl)phthalazine-6-carboxamide

[0466]

[0467] The procedure of Example 1 was repeated except that N-methyltetrahydropyran-4-amine (0.11 mL, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 25 mg of the title compound in a 10% yield.

[0468] 1H-NMR (300 MHz, DMSO-d6): δ 7.79-7.76 (m, 1H), 7.61-7.58 (m, 1H), 7.53 (s, 1H), 7.35-7.31 (m, 2H), 7.28-7.21 (m, 1H), 6.05-5.84 (m, 1H), 5.61- 5.52 (m, 1H), 4.04-3.82 (m, 3H), 3.79-3.37 (m, 2H), 2.93-2.91 (m, 3H), 2.67 (s, 3H), 2.47 (s, 6H), 1.85-1.80 (m, 3H), 1.78-1.74 (m, 4H).

[0469] MS (ESI+, m / z): 473.3 [M+H] +

[0470]

[0471] Example 7: 3-((1R)-1-((6-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0472]

[0473] The procedure of Example 1 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (90 mg, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 20 mg of the title compound in a yield of 7%.

[0474] 1 H-NMR (300 MHz, DMSO-d6): δ 7.78 (m, 1H), 7.64 (m, 2H), 7.35 (m, 2H), 7.22 (s, 1H), 6.16 (m, 1H), 5.62 (m, 1H), 3.61 (m, 8H), 3.14 (m, 1H), 2.95 (m, 4H), 2.68 (s, 3H), 2.51 (s, 3H), 1.57 (m, 3H).

[0475] MS (ESI+, m / z): 471.3 [M+H] +

[0476]

[0477] Example 8: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(4-methylpiperazine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0478]

[0479] The procedure of Example 1 was repeated except that 1-methylpiperazine (0.09 mL, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 25 mg of the title compound in a 10% yield.

[0480] 1 H-NMR (300 MHz, DMSO-d6): δ 7.77-7.74 (m, 1H), 7.60-7.56 (m, 2H), 7.39-7.28 (m, 2H), 7.22 (s, 1H), 6.08-6.02 (m, 1H), 5.60-5.51 (m, 1H), 3.75-3.61 (m, 2H), 3.24-3.19 (m, 2H), 2.94-2.92 (m, 3H), 2.67 (s, 3H), 2.48 (s, 3H), 2.42-2.35 (m, 2H), 2.33-2.23 (m, 5H), 1.56-1.54 (m, 3H).

[0481] MS (ESI+, m / z): 458.3 [M+H] +

[0482]

[0483] Example 9: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(piperazine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0484]

[0485] The procedure of Example 1 was repeated except that piperazine (379 mg, 1.99 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 50 mg of the title compound in a yield of 29%.

[0486] 1 H-NMR (300 MHz, DMSO-d6): δ 7.77-7.74 (m, 1H), 7.60-7.58 (m, 1H), 7.55 (s, 1H), 7.35-7.27 (m, 2H), 7.21 (s, 1H), 6.03-5.98 (m, 1H), 5.58-5.54 (m, 1H), 3.66-3.54 (m, 2H), 3.20-3.07 (m, 2H), 2.94-2.92 (m, 3H), 2.84-2.72 (m, 2H), 2.69-2.54 (m, 6H), 2.50 (s, 3H), 1.56-1.53 ​​(m, 3H).

[0487] MS (ESI+, m / z): 444.3 [M+H] +

[0488]

[0489] Example 10: (R)-3-(1-((6-(4,4-difluoropiperidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0490]

[0491] The procedure of Example 1 was repeated except that 4,4-difluoropiperidine hydrochloride (161 mg, 0.99 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 150 mg of the title compound in a yield of 47%.

[0492] 1H-NMR (300 MHz, DMSO-d6): δ 8.33 (s, 1H), 8.03 (s, 1H), 7.74-7.71 (m, 1H), 7.66-7.64 (m, 1H), 7.46 (s, 1H), 7.38-7.33 (m, 1H), 7.13-7.06 (m, 1H), 5.41-5.32 (m, 1H), 3.81-3.71 (m, 2H), 3.66-3.58 (m, 2H), 3.29-3.10 (m, 4H), 3.03-3.01 (m, 3H), 2.67 (s, 6H), 1.62-1.59 (m, 3H).

[0493] MS (ESI+, m / z): 479.2 [M+H] +

[0494]

[0495] Example 11: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0496]

[0497]

[0498]

[0499] The procedure of Example 1 was repeated except that 2-oxa-6-azaspiro[3.3]heptane (79 mg, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 60 mg of the title compound in a yield of 24%.

[0500] 1 H-NMR (300 MHz, DMSO-d6): δ 7.78 (m, 1H), 7.64 (m, 2H), 7.35 (m, 2H), 7.22 (s, 1H), 6.16 (m, 1H), 5.62 (m, 1H), 3.61 (m, 8H), 3.14 (m, 1H), 2.95 (m, 4H), 2.68 (s, 3H), 2.51 (s, 3H), 1.57 (m, 3H).

[0501] MS (ESI+, m / z): 457.2 [M+H] +

[0502]

[0503] Example 12: (R)-3-(1-((6-(4-ethylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0504]

[0505] The procedure of Example 1 was repeated except that 1-ethylpiperazine (0.10 mL, 0.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 130 mg of the title compound in a yield of 52%.

[0506] 1 H-NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 7.94 (s, 1H), 7.74-7.71 (m, 1H), 7.66-7.64 (m, 1H), 7.44 (s, 1H), 7.38-7.33 (m, 1H), 7.06-6.98 (m, 1H), 5.43-5.33 (m, 1H), 3.84-3.55 (m, 2H), 3.27-3.13 (m, 2H), 3.02-3.01 (m, 3H), 2.90-2.85 (m, 2H), 2.79-7.72 (m, 6H), 2.69-2.54(m, 2H), 2.51 (s, 3H), 1.61-1.59 (m, 3H), 1.08-1.05 (m, 3H).

[0507] MS (ESI+, m / z): 472.3 [M+H] +

[0508]

[0509] Example 13: (R)-3-(1-((6-(4-cyclopropylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0510]

[0511] The procedure of Example 1 was repeated except that 1-cyclopropylpiperazine (50 mg, 0.40 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 40 mg of the title compound in a yield of 31%.

[0512] 1 H-NMR (300 MHz, CDCl3): δ 7.70 (m, 1H), 7.64 (s, 1H), 7.51 (m, 1H), 7.24 (m, 1H), 6.60 (s, 1H), 5.77 (m, 1H), 5.55 (m, 1H), 4.96 (m, 1H), 3.74 (m, 4H), 3.00 (m, 3H), 2.74 (m, 10H), 1.71 (m, 4H), 0.51 (m, 4H).

[0513] MS (ESI+, m / z): 484.3 [M+H] +

[0514]

[0515] Example 14: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(pyrrolidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0516]

[0517] The procedure of Example 1 was repeated except that pyrrolidine (113 mg, 1.59 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 110 mg of the title compound in a yield of 24%.

[0518] 1H-NMR (300 MHz, CDCl3): δ 7.78 (s, 1H), 7.70 (m, 1H), 7.52 (m, 1H), 7.25 (m, 1H), 6.57 (s, 1H), 6.14 (m, 1H), 5.77 (m, 1H), 4.93 (m, 1H), 3.74 (m, 2H), 3.51 (m, 2H), 2.99 (m, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 2.00 (m, 4H), 1.66 (m, 3H).

[0519] MS (ESI+, m / z): 429.2 [M+H] +

[0520]

[0521]

[0522] Example 15: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(piperidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0523]

[0524] The procedure of Example 1 was repeated except that piperidine (136 mg, 1.59 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 170 mg of the title compound in a yield of 36%.

[0525] 1 H-NMR (300 MHz, CDCl3): δ 7.70 (m, 1H), 7.63 (s, 1H), 7.50 (m, 1H), 7.24 (m, 1H), 6.61 (s, 1H), 5.78 (m, 1H), 5.52 (m, 1H), 4.99 (m, 1H), 3.66 (m, 4H), 2.98 (m, 3H), 2.74 (s, 3H), 2.68 (s, 3H), 1.73 (m, 9H).

[0526] MS (ESI+, m / z): 443.3 [M+H] +

[0527]

[0528] Example 16: (R)-3-(1-((6-(azetidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0529]

[0530] The procedure of Example 1 was repeated except that azetidine hydrochloride (157 mg, 1.59 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 110 mg of the title compound in a 25% yield.

[0531] 1 H-NMR (300 MHz, DMSO-d6): δ 8.24 (s, 1H), 8.02 (s, 1H), 7.73-7.71 (m, 1H), 7.66-7.63 (m, 2H), 7.43 (s, 1H), 7.38-7.33 (m, 1H), 5.42-5.33 (m, 1H), 4.19-4.08 (m, 4H), 3.05-3.03 (m, 3H), 2.67-2.66 (m, 6H), 2.31-2.21 (m, 2H), 1.61-1.58 (m, 3H).

[0532] MS (ESI+, m / z): 415.2 [M+H] +

[0533]

[0534] Example 17: (R)-3-(1-((6-(3-fluoroazetidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0535]

[0536] The procedure of Example 1 was repeated except that 3-fluoroazetidine hydrochloride (182 mg, 1.59 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 120 mg of the title compound in a yield of 26%.

[0537] 1H-NMR (300 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.61-7.58 (m, 1H), 7.51-7.49 (m, 1H), 7.48-7.45 (m, 1H), 7.33-7.26 (m, 2H), 7.03-6.96 (m, 1H), 5.57-5.31 (m, 2H), 4.52-4.08 (m, 4H), 2.98-2.97(m, 3H), 2.66 (s, 3H), 2.53 (s, 3H), 1.56-1.54 (m, 3H).

[0538] MS (ESI+, m / z): 433.2 [M+H] +

[0539]

[0540] Example 18: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(5-azaspiro[2.4]heptane-5-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0541]

[0542] The procedure of Example 1 was repeated except that 5-azaspiro[2.4]heptane (0.18 mL, 1.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 200 mg of the title compound in a yield of 37%.

[0543] 1 H-NMR (300 MHz, DMSO-d6): δ 7.76-7.71 (m, 2H), 7.61-7.59 (m, 1H), 7.54-7.49 (m, 1H), 7.34-7.24 (m, 2H), 6.44-6.38 (m, 1H), 5.57-5.48 (m, 1H), 3.71-3.67 (m, 1H), 3.46-3.39 (m, 2H), 3.19-3.11 (m, 1H), 2.97-2.94(m, 3H), 2.67-2.66 (m, 3H), 2.54-2.52 (m, 3H), 1.87-73 (m, 2H), 1.57-1.54 (m, 3H), 0.68-0.60 (m, 4H).

[0544] MS (ESI+, m / z): 455.3 [M+H] +

[0545]

[0546] Example 19: 3-((1R)-1-((6-(2-Oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0547]

[0548] The procedure of Example 1 was repeated except that 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (248 mg, 1.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 280 mg of the title compound in a yield of 51%.

[0549] 1 H-NMR (300 MHz, DMSO-d6): δ 7.77-7.72 (m, 2H), 7.61-7.51 (m, 2H), 7.34-7.26 (m, 2H), 6.40-6.37 (m, 1H), 5.55-5.51 (m, 1H), 4.90-4.4.14(m, 2H), 4.12-3.75 (m, 2H), 3.60-3.44 (m, 2H), 2.97-2.95 (m, 3H), 2.67 (s, 3H), 2.52 (s, 3H), 2.02-1.70 (m, 2H), 1.57-1.54 (m, 3H).

[0550] MS (ESI+, m / z): 457.2 [M+H] +

[0551]

[0552] Example 20: (R)-3-(1-((6-(4-cyclohexylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0553]

[0554] The procedure of Example 1 was repeated except that 1-cyclohexylpiperazine (0.04 mL, 0.2 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 33 mg of the title compound in a yield of 47%.

[0555] 1 H-NMR (300 MHz, DMSO-d6): δ 7.78 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.35-7.28 (m, 2H), 7.21 (s, 1H), 6.00 (m, 1H), 5.59 (m, 1H), 3.65 (m, 1H), 2.94 (m, 2H), 2.89 (m, 3H), 2.73-2.40 (m, 10H), 2.25 (m, 4H), 1.74 (m, 4H), 1.17 (m, 4H).

[0556] MS (ESI+, m / z): 526.3 [M+H] +

[0557]

[0558] Example 21: (R)-3-(1-((6-(4-isopropylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0559]

[0560] The procedure of Example 1 was repeated except that 1-isopropylpiperazine (0.02 mL, 0.16 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 30 mg of the title compound in a yield of 58%.

[0561] 1H-NMR (300 MHz, DMSO-d6): δ 7.78 (d, 1H), 7.61 (d, 1H), 7.55 (s, 1H), 7.35-7.28 (m, 2H), 7.21 (s, 1H), 6.02 (m, 1H), 5.57 (m, 1H), 3.66 (m, 1H), 3.16 (m, 2H), 2.94 (m, 3H), 2.71 (m, 4H), 2.52 (m, 4H), 2.27 (m, 2H), 1.56 (m, 3H), 0.95 (m, 6H).

[0562] MS (ESI+, m / z): 486.3 [M+H] +

[0563]

[0564] Example 22: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(4-morpholinopiperidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0565]

[0566] The procedure of Example 1 was repeated except that 4-(piperidin-4-yl)-morpholine (306 mg, 1.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 35 mg of the title compound in a 5% yield.

[0567] 1 H-NMR (300 MHz, CDCl3): δ 7.70 (m, 1H), 7.62 (s, 1H), 7.51 (m, 1H), 7.22 (m, 1H), 6.61 (s, 1H), 5.79 (m, 1H), 5.53 (m, 1H), 3.77 (m, 4H), 2.99 (m, 5H), 2.75 (s, 3H), 2.68 (s, 3H), 2.59 (m, 7H), 1.98 (m, 2H), 1.67 (m, 3H), 1.48 (m, 2H).

[0568] MS (ESI+, m / z): 528.3 [M+H] +

[0569]

[0570] Example 23: (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)-N-(2-morpholinoethyl)phthalazine-6-carboxamide

[0571]

[0572] The procedure of Example 1 was repeated except that 2-morpholinoethanamine (0.24 mL, 1.79 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 500 mg of the title compound in 85% yield.

[0573] 1 H-NMR (300 MHz, MeOD-d4): δ 8.32 (s, 1H), 7.74-7.72 (m, 1H), 7.55-7.52 (m, 1H), 7.46 (s, 1H), 7.31-7.26 (m, 1H), 5.49-5.42 (m, 1H), 3.73-3.70 (m, 4H), 3.61-3.56 (m, 2H), 3.13 (s, 3H), 2.75 (s, 6H), 2.67-2.63 (m, 2H), 2.59-2.56 (m, 4H), 1.67-1.65 (m, 3H).

[0574] MS (ESI+, m / z): 488.3 [M+H] +

[0575]

[0576] Example 24: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(1,4-oxazepane-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0577]

[0578] The procedure of Example 1 was repeated except that 1,4-oxazepane (161 mg, 1.59 mmol) was used instead of morpholine in [Step-17] of the above Example 1, to obtain 170 mg of the title compound in a yield of 34%.

[0579] 1H-NMR (300 MHz, CDCl3): δ 7.70 (m, 2H), 7.51 (m, 1H), 7.25 (m, 1H), 6.62 (s, 1H), 5.80 (m, 1H), 5.42 (m, 1H), 5.00 (m, 1H), 3.93 (m, 5H), 3.54 (m, 3H), 3.00 (m, 3H), 2.74 (s, 3H), 2.69 (s, 3H), 2.09 (m, 1H), 1.84 (m, 1H), 1.67 (m, 3H).

[0580] MS (ESI+, m / z): 459.3 [M+H] +

[0581]

[0582] Example 25: (R)-(1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0583]

[0584] [Step 1] Preparation of dimethyl 2-amino-5-bromoterephthalate

[0585]

[0586] Dimethyl aminoterephthalate (20.0 g, 95.60 mmol) and N-bromosuccinimide (18.7 g, 105.16 mmol) were dissolved in 1000 mL of chloroform, and the mixture was refluxed at room temperature for 16 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 3:1 (v / v)) to obtain 15.0 g of the title compound in a 54% yield.

[0587] 1 H-NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.07 (s, 1H), 5.84 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H).

[0588]

[0589] [Step 2] Preparation of dimethyl 2-bromo-5-(methylamino) terephthalate

[0590]

[0591] Dimethyl 2-amino-5-bromoterephthalate (15.0 g, 52.06 mmol), methyl iodide (9.7 mL, 156.18 mmol), and potassium carbonate (28.8 g, 208.26 mmol) obtained in the above [Step-1] were dissolved in 150 mL of DMF, and the mixture was stirred under reflux at 110 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, and then acidified with 2N hydrochloric acid until the pH reached 3. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 9:1 (v / v)) to obtain 7.4 g of the title compound in a yield of 47%.

[0592] 1 H-NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), 7.68 (s, 1H), 7.01 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.94 (d, 3H).

[0593]

[0594] [Step 3] Preparation of dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate

[0595]

[0596] Dimethyl 2-bromo-5-(methylamino) terephthalate (7.4 g, 24.49 mmol), butyl vinyl ether (15.7 mL, 122.47 mmol), Pd(OAc)2 (550 mg, 2.45 mmol), triphenylphosphine (1.3 g, 4.90 mmol), and triethylamine (4.1 mL, 29.39 mmol) obtained in the above [Step-2] were dissolved in 80 mL of acetonitrile, and the mixture was stirred under reflux at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0597]

[0598] [Step 4] Preparation of dimethyl 2-acetyl-5-(methylamino) terephthalate

[0599]

[0600] Dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate (7.87 g, 24.49 mmol) and 6N hydrochloric acid (33 mL, 195.91 mmol) obtained in the above [Step-3] were dissolved in 80 mL of tetrahydrofuran, and the mixture was refluxed at room temperature for 1 hour. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (v / v)) to obtain 5.5 g of the title compound in a yield of 84%.

[0601] 1 H-NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.33 (s, 1H), 6.72 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.00 (d, 3H), 2.54 (s, 3H).

[0602]

[0603] [Step 5] Preparation of methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate

[0604]

[0605] Dimethyl 2-acetyl-5-(methylamino) terephthalate (5.5 g, 20.73 mmol) and hydrazine monohydrate (1.1 g, 20.73 mmol) obtained in the above [Step-4] were dissolved in 70 mL of ethanol, and the mixture was stirred under reflux at 95°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethanol to obtain 4.8 g of the title compound in a 93% yield.

[0606] 1 H-NMR (300 MHz, DMSO-d6): δ 12.16 (s, 1H), 8.26 (s, 1H), 7.92 (d, 1H), 7.29 (s, 1H), 3.91 (s, 3H), 2.96 (d, 3H), 2.42 (s, 3H).

[0607]

[0608] [Step 6] Preparation of 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid

[0609]

[0610] Methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate (4.8 g, 19.41 mmol) and sodium hydroxide (7.8 g, 194.14 mmol) obtained in the above [Step-5] were dissolved in 160 mL of a solution of tetrahydrofuran: methanol: water = 2:1:1, and the mixture was stirred under reflux at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was acidified with 6N hydrochloric acid solution at low temperature until the pH became 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried in an oven dryer at 55°C to obtain 4.8 g of the title compound in a yield of 91%.

[0611] 1 H-NMR (300 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.30 (s, 1H), 7.27 (s, 1H), 2.96 (d, 3H), 2.43 (s, 3H).

[0612]

[0613] [Step-7] Preparation of (1-hydroxy-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0614]

[0615] 1-Hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid (4.8 g, 17.80 mmol), morpholine (3.1 mL, 35.60 mmol), HATU (8.8 g, 23.14 mmol), and DIPEA (15.5 mL, 88.99 mmol) obtained in the above [Step-6] were dissolved in 100 mL of DMF and stirred under reflux at room temperature for 3 days. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 510 mg of the title compound in a yield of 9%.

[0616] 1 H-NMR (300 MHz, DMSO-d6): δ 12.12 (s, 1H), 7.56 (s, 1H), 7.18 (s, 1H), 6.20 (d, 1H), 3.64 (m, 6H), 3.16 (m, 2H), 2.84 (d, 3H), 2.41 (s, 3H).

[0617]

[0618] [Step-8] Preparation of (1-chloro-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0619]

[0620] (1-Hydroxy-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone (510 mg, 1.69 mmol) obtained in the above [Step-7] was dissolved in 10 mL of phosphoryl chloride, and the mixture was stirred under reflux at 110°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, and neutralized by dropwise addition to an aqueous sodium bicarbonate solution at 0°C. This was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 290 mg of the title compound in a yield of 53%.

[0621] 1 H-NMR (300 MHz, DMSO-d6): δ 7.94 (s, 1H), 6.87 (s, 1H), 6.67 (d, 1H), 3.64 (m, 6H), 3.16 (m, 2H), 2.90 (d, 3H), 2.77 (s, 3H).

[0622]

[0623] [Step-9] Preparation of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one

[0624]

[0625] 1-Bromo-3-nitro-5-trifluoromethylbenzene (100 g, 362.96 mmol), tributyl(1-ethylvinyl)tin (159.4 mL, 471.85 mmol), Pd(PPh3)2Cl2 (10.2 g, 14.52 mmol), and triethylamine (101 mL, 725.93 mmol) were dissolved in 500 mL of 1,4-dioxane, and the mixture was refluxed at 120 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 250 mL of tetrahydrofuran and 250 mL of 6N hydrochloric acid were added dropwise to the reaction mixture, and the mixture was refluxed at room temperature for 2 hours. 900 mL of a 1N aqueous potassium fluoride solution was added dropwise to the reaction mixture, and the mixture was refluxed at room temperature for 12 hours. After the reaction was completed, the residue was filtered through a filter filled with Celite and washed with ethyl acetate. The filtered organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 15:1-10:1 (v / v)) to obtain 66 g of the title compound in a 78% yield.

[0626] 1 H-NMR (300 MHz, CDCl3): δ 8.95 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 2.76 (s, 3H).

[0627]

[0628] [Step-10] Preparation of (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide

[0629]

[0630] 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one (66 g, 283.09 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (42.4 g, 339.71 mmol), and titanium ethoxide (71.3 mL, 339.71 mmol) obtained in the above [Step-9] were dissolved in 660 mL of tetrahydrofuran, and the mixture was stirred under reflux at 85 °C for 3 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The extracted organic layer was filtered through a filter filled with Celite and washed with ethyl acetate. The filtered organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0631] 1 H-NMR (300 MHz, CDCl3): δ 8.86 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 2.89 (s, 3H), 1.37 (s, 9H).

[0632]

[0633] [Step-11] Preparation of (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide

[0634]

[0635] (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (94 g, 279.5 mmol) obtained in the above [Step-10] was dissolved in 660 mL of tetrahydrofuran and 14 mL of water and cooled to -30 ℃. Sodium borohydride (19 g, 503.1 mmol) was slowly added dropwise to the reaction mixture and stirred under reflux for 2 hours. After the reaction was completed, water was slowly added dropwise and stirred under reflux for 1.5 hours. This was extracted with ethyl acetate, and the filtered organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 5:1 (v / v)) to obtain 35 g of the title compound in a yield of 37%.

[0636] 1 H-NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 6.08 (d, 1H), 4.74-4.64 (m, 1H), 1.47 (d, 3H), 1.14 (s, 9H).

[0637]

[0638] [Step-12] Preparation of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride

[0639]

[0640] (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (35 g, 103.5 mmol) obtained in the above [Step-11] was dissolved in 355 mL of 1,4-dioxane, and then 105 mL of 4N hydrochloric acid dissolved in 1,4-dioxane was slowly added dropwise, and the mixture was stirred under reflux for 2.5 hours at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure, and ether was added to the obtained residue to solidify. The obtained solid was filtered to obtain 27 g of the title compound in a 96% yield.

[0641] 1 H-NMR (300 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.63 (bs, 2H), 8.52 (s, 1H), 8.44 (s, 1H), 4.76 (m, 1H), 1.59 (d, 3H).

[0642]

[0643] [Step-13] Preparation of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride

[0644]

[0645] (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (27 g, 99.76 mmol) obtained in the above [Step-12] was dissolved in 405 mL of methanol, 2.7 g of Pd / C was slowly added dropwise, and the mixture was stirred under reflux for 2 hours under hydrogen gas. After completion of the reaction, the mixture was filtered through a filter filled with Celite, and the filtrate was concentrated under reduced pressure to obtain 23 g of the title compound in a yield of 96%.

[0646] 1 H-NMR (300 MHz, DMSO-d6): δ 8.46 (bs, 2H), 6.97 (s, 1H), 6.85 (s, 2H), 5.75 (s, 2H), 4.33 (m, 1H), 1.49 (d, 3H).

[0647]

[0648] [Step-14] Preparation of (R)-(1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0649]

[0650] (1-Chloro-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone (290 mg, 0.9 mmol) obtained in the above [Step-8], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (261 mg, 1.08 mmol) obtained in [Step-13], cesium fluoride (412 mg, 2.71 mmol), N,N-diisopropylethylamine (0.79 mL, 4.52 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under reflux at room temperature for 5 hours. After the reaction was completed, it was cooled to room temperature, and water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 10:1 (v / v)) to obtain 52 mg of the title compound in a 12% yield.

[0651] 1 H-NMR (300 MHz, DMSO-d6): δ 7.61 (s, 1H), 7.20 (m, 2H), 6.85 (d, 2H), 6.67 (s, 1H), 6.04 (m, 1H), 5.40 (m, 3H), 3.64 (m, 6H), 3.16 (m, 2H), 2.93 (d, 3H), 2.49 (s, 3H), 1.55 (d, 3H).

[0652] MS (ESI+, m / z): 489.2 [M+H] +

[0653]

[0654] Example 26: (R)-(1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0655]

[0656] [Step-1] Preparation of 1-bromo-3-(difluoromethyl)-2-fluorobenzene

[0657]

[0658] 3-Bromo-2-fluorobenzaldehyde (150 g, 724.1 mmol) was dissolved in 1200 mL of dichloromethane and cooled to 0 °C. Diethylaminosulfur trifluoride (150 mL, 868.92 mmol) was slowly added dropwise to the reaction mixture, the mixture was warmed to room temperature, and stirred under reflux for 4 hours. After the reaction was completed, the reaction mixture was slowly added dropwise to ice water. After extraction with dichloromethane, the obtained organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 159 g of the title compound in a yield of 97.6%.

[0659] 1 H-NMR (300 MHz, CDCl3): δ 7.79-7.67 (m, 1H), 7.59-7.54 (m, 1H), 7.19 (m, 1H), 7.16-6.72 (m, 1H).

[0660]

[0661] [Step 2] Preparation of 1-bromo-3-(difluoromethyl)-2-fluoro-5-nitrobenzene

[0662]

[0663] 1-Bromo-3-(difluoromethyl)-2-fluorobenzene (159 g, 706.64 mmol) obtained in the above [Step-1] was dissolved in 450 mL of sulfuric acid and 55 mL of nitric acid at 0°C, the mixture was heated to room temperature, and the mixture was stirred under reflux for 2 hours. After the reaction was completed, the mixture was slowly added dropwise to ice water. After extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0664]

[0665] [Step-3] Preparation of 1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethan-1-one

[0666]

[0667] The procedure of Example 25 [Step-9] was repeated except that 1-bromo-3-(difluoromethyl)-2-fluoro-5-nitrobenzene (180 g, 666.67 mmol) obtained in [Step-2] was used instead of 1-bromo-3-nitro-5-trifluoromethylbenzene used in Example 25 [Step-9], to obtain 153 g of the title compound in 98% yield without further purification.

[0668]

[0669] [Step-4] Preparation of (R,E)-N-(1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0670]

[0671] The procedure of Example 25 [Step-10] was repeated except that 1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethan-1-one (153 g, 656.3 mmol) obtained in [Step-3] was used instead of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one obtained in Example 25 [Step-9], to obtain 193 g of the title compound in 87% yield without further purification.

[0672]

[0673] [Step-5] Preparation of (R)-N-((R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide

[0674]

[0675] The procedure of Example 25 [Step-11] was repeated except that (R,E)-N-(1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (193 g, 573.8 mmol) obtained in [Step-4] was used instead of (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide obtained in Example 25 [Step-10], thereby obtaining 24.5 g of the title compound in a yield of 13%.

[0676] 1 H-NMR (300 MHz, CDCl3): δ 8.47 (m, 2H), 7.21-6.76 (m, 1H), 4.94-4.85 (m, 1H), 3.66 (m, 1H), 1.64-1.61 (m, 3H), 1.27 (m, 9H).

[0677]

[0678] [Step-6] Preparation of (R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethan-1-amine hydrochloride

[0679]

[0680] The procedure of Example 25 [Step-12] was repeated except that (R)-N-((R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide (35 g, 103.44 mmol) obtained in [Step-5] was used instead of (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide obtained in Example 25 [Step-11], thereby obtaining 28 g of the title compound in a yield of 99%.

[0681] 1 H-NMR (300 MHz, DMSO-d6): δ 8.93-8.87 (m, 3H), 8.53 (m, 1H), 7.55-7.19 (m, 1H), 4.79-4.73 (m, 1H), 1.61 (m, 3H).

[0682]

[0683] [Step-7] Preparation of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride

[0684]

[0685] The procedure of Example 25 [Step-13] was repeated except that (R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethan-1-amine hydrochloride (1.5 g, 5.54 mmol) obtained in [Step-6] was used instead of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride obtained in Example 25 [Step-12], to obtain 1.46 g of the title compound in a 99% yield without further purification.

[0686]

[0687] [Step-8] Preparation of (R)-(1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0688]

[0689] (1-Chloro-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone (60 mg, 0.19 mmol) obtained in [Step-8] of the above Example 25, (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (90 mg, 0.37 mmol) obtained in [Step-7], magnesium chloride (27 mg, 0.28 mmol), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were dissolved in 1.2 mL of 2-butanol and stirred under reflux at 110°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and then extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 7:1 (v / v)) to obtain 15 mg of the title compound in a 16% yield.

[0690] 1 H-NMR (300 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.29-6.89 (m, 2H), 6.69 (m, 1H), 6.57 (m, 1H), 6.12 (m, 1H), 5.55 (m, 1H), 5.10 (m, 2H), 3.69-3.40 (m 6H), 3.31-3.18 (m, 2H), 2.96 (m, 3H), 1.58 (m, 3H).

[0691] MS (ESI+, m / z): 489.2 [M+H] +

[0692]

[0693] Example 27: (R)-(1-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0694]

[0695] [Step-1] Preparation of ethyl 2-(3-acetylphenyl)-2,2-difluoroacetate

[0696]

[0697] 1-(3-Iodophenyl)ethanone (10 g, 40.64 mmol), ethyl 2-bromo-2,2-difluoroacetate (13 mL, 101.61 mmol), and copper (6.45 g, 101.61 mmol) were dissolved in 20 mL of DMSO and stirred under reflux at 80 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, and the mixture was filtered through a filter filled with Celite. The filtrate was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.3 g of the title compound in a yield of 53.8%.

[0698] 1 H-NMR (300 MHz, DMSO-d6): δ 8.22 (m, 1H), 8.08 (s, 1H), 7.86 (m, 1H), 4.36 (m, 2H), 2.63 (s, 3H), 1.24 (m 3H).

[0699]

[0700] [Step-2] Preparation of ethyl (R,Z)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)phenyl)-2,2-difluoroacetate

[0701]

[0702] Ethyl 2-(3-acetylphenyl)-2,2-difluoroacetate (5.3 g, 21.88 mmol), (R)-2-methylpropane-2-sulfinamide (15.6 g, 54.7 mmol), and titanium ethoxide (14.3 mL, 54.7 mmol) obtained in the above [Step-1] were dissolved in 55 mL of tetrahydrofuran, and the mixture was stirred under reflux at 80°C for 16 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The extracted organic layer was filtered through a filter filled with Celite and washed with ethyl acetate. The filtered organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 10:1-5:1 (v / v)) to obtain 5.1 g of the title compound in a yield of 67.5%.

[0703] 1 H-NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 8.11 (m, 1H), 7.74 (m, 1H), 7.55 (m, 1H), 4.36-4.29 (m, 2H), 2.81 (s, 3H), 1.35-1.27 (m, 12H).

[0704]

[0705] [Step-3] Preparation of (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0706]

[0707] Ethyl (R,Z)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)phenyl)-2,2-difluoroacetate (5.1 g, 14.77 mmol) obtained in the above [Step-2] was dissolved in 50 mL of tetrahydrofuran and 5 mL of water and cooled to -78 °C. Sodium borohydride (1.23 g, 32.48 mmol) was slowly added dropwise to the reaction mixture and stirred under reflux at room temperature for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution was slowly added dropwise, stirred under reflux for 0.5 hour, and extracted with ethyl acetate. The filtered organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 3:1 (v / v)) to obtain 1.65 g of the title compound in a yield of 37%.

[0708] 1 H-NMR (300 MHz, CDCl3): δ 7.55 (s, 1H), 7.48-7.43 (m, 3H), 4.58 (m, 1H), 3.97-3.91 (m, 2H), 3.47 (m, 1H), 2.93 (t, 1H), 1.57 (m, 3H), 1.28 (m, 9H).

[0709]

[0710] [Step-4] Preparation of (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethane-1-ol hydrochloride

[0711]

[0712] (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 1.08 mmol) obtained in the above [Step-3] was dissolved in 4 mL of 1,4-dioxane, and then 4 mL of 4N hydrochloric acid dissolved in 1,4-dioxane was slowly added dropwise, and the mixture was stirred under reflux at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 225 mg of the title compound in a yield of 87.6% without further purification.

[0713]

[0714] [Step-5] Preparation of (R)-(1-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0715]

[0716] (1-Chloro-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone (130 mg, 0.41 mmol) obtained in [Step-8] of the above Example 25, (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethan-1-ol hydrochloride (190 mg, 0.8 mmol) obtained in [Step-4], magnesium chloride (58 mg, 0.61 mmol), N,N-diisopropylethylamine (0.28 mL, 1.62 mmol) were dissolved in 1.5 mL of 2-butanol, and stirred under reflux at 110°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and then extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v / v)) to obtain 15 mg of the title compound in 8% yield.

[0717] 1 H-NMR (300 MHz, DMSO-d6): δ 7.63-7.54 (m, 3H), 7.43-7.32 (m, 3H), 7.24 (s, 1H), 6.15 (m, 1H), 5.59-5.51 (m, 2H), 3.88-3.60 (m, 8H), 3.29-3.23 (m, 2H), 3.21 (m, 2H), 3.18 (m, 3H), 1.62 (d, 3H).

[0718] MS (ESI+, m / z): 486.2 [M+H] +

[0719]

[0720] Example 28: (R)-3-(1-((7-methoxy-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0721]

[0722] [Step 1] Preparation of methyl 2-bromo-5-methoxy-methylbenzoate

[0723]

[0724] Methyl 3-methoxy-4-methylbenzoate (10 g, 55.49 mmol) was mixed with 50 mL of acetic acid and 50 mL of water, and bromine (2.84 mL, 55.49 mmol) was added dropwise. After the addition was complete, the mixture was refluxed at 60°C for 2 hours. After the reaction was complete, it was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried to obtain 13.0 g of the title compound in a 90% yield.

[0725] 1 H-NMR (300 MHz, CDCl3): δ 7.42 (s, 1H), 7.28 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.23 (s, 3H).

[0726]

[0727] [Step 2] Preparation of methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate

[0728]

[0729] Methyl 2-bromo-5-methoxy-methylbenzoate (13.0 g, 50.17 mmol), N-bromosuccinimide (10.72 g, 60.21 mmol), and azobicisobutyronitrile (8.24 g, 50.17 mmol) obtained in the above [Step-1] were dissolved in 200 mL of chloroform and stirred under reflux at 70 °C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and an aqueous sodium bicarbonate solution was added dropwise. After extraction with dichloromethane, the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 9:1 (v / v)) to obtain 13.0 g of the title compound in a yield of 76%.

[0730] 1 H-NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 7.32 (s, 1H), 4.47 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H).

[0731]

[0732] [Step 3] Preparation of methyl 2-bromo-5-methoxy-4-(morpholinomethyl)benzoate

[0733]

[0734] Methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate (13.0 g, 38.46 mmol), morpholine (3.65 mL, 42.31 mmol), and potassium carbonate (10.63 g, 76.93 mmol) obtained in the above [Step-2] were dissolved in 180 mL of acetonitrile and stirred at room temperature for 18 hours. After the reaction was completed, it was cooled to room temperature and an aqueous sodium bicarbonate solution was added dropwise. After extraction with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 11.0 g of the title compound in a yield of 83%.

[0735] 1 H-NMR (300 MHz, CDCl3): δ 7.68 (s, 1H), 7.28 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.73 (m, 4H), 3.51 (m, 2H), 2.49 (m, 4H).

[0736]

[0737] [Step 4] Preparation of methyl 2-(1-butoxyvinyl)-5-methoxy-4-(morpholinomethyl)benzoate

[0738]

[0739] Methyl 2-bromo-5-methoxy-4-(morpholinomethyl)benzoate (11.0 g, 31.96 mmol), butyl vinyl ether (20.5 mL, 159.79 mmol), Pd(OAc)2 (718 mg, 3.20 mmol), triphenylphosphine (1.68 g, 6.39 mmol), and triethylamine (5.3 mL, 38.35 mmol) obtained in the above [Step-3] were dissolved in 110 mL of acetonitrile, and the mixture was stirred under reflux at 100 °C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0740]

[0741] [Step 5] Preparation of methyl 2-acetyl-5-methoxy-4-(morpholinomethyl)benzoate

[0742]

[0743] Methyl 2-(1-butoxyvinyl)-5-methoxy-4-(morpholinomethyl)benzoate (11.6 g, 31.92 mmol) and 6N hydrochloric acid (42 mL, 255.33 mmol) obtained in the above [Step-4] were dissolved in 120 mL of tetrahydrofuran, and the mixture was refluxed and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and water was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate. The extracted organic layer was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (v / v)) to obtain 4.7 g of the title compound in a yield of 47%.

[0744] 1H-NMR (300 MHz, CDCl3): δ 7.68 (s, 1H), 7.17 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.75 (m, 4H), 3.37 (s, 2H), 2.54 (s, 3H), 2.52 (m, 4H).

[0745]

[0746] [Step 6] Preparation of 7-methoxy-4-methyl-6-(morpholinomethyl)phthalazin-1-ol

[0747]

[0748] Methyl 2-acetyl-5-methoxy-4-(morpholinomethyl)benzoate (4.7 g, 15.29 mmol) and hydrazine monohydrate (1.17 g, 22.93 mmol) obtained in the above [Step-5] were dissolved in 50 mL of ethanol, and the mixture was refluxed and stirred at 95°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethanol. The filtered solid was dried to obtain 4.1 g of the title compound in a yield of 92%.

[0749] 1 H-NMR (300 MHz, CDCl3): δ 10.29 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 4.02 (s, 3H), 3.80 (m, 4H), 3.71 (s, 2H), 2.59 (m, 7H).

[0750]

[0751]

[0752] [Step-7] Preparation of 4-((1-chloro-7-methoxy-4-methylphthalazin-6-yl)methyl)morpholine

[0753]

[0754] 7-Methoxy-4-methyl-6-(morpholinomethyl)phthalazin-1-ol (1.0 g, 3.45 mmol) and phosphoryl chloride (0.96 mL, 10.36 mmol) obtained in the above [Step-6] were dissolved in 20 mL of acetonitrile, and the mixture was stirred under reflux at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, and neutralized by dropwise addition to an aqueous sodium bicarbonate solution at 0 °C. This was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 850 mg of the title compound in a yield of 79%.

[0755] 1 H-NMR (300 MHz, CDCl3): δ 8.17 (s, 1H), 7.48 (s, 1H), 4.08 (s, 3H), 3.80 (m, 4H), 3.75 (s, 2H), 2.97 (s, 3H), 2.60 (m, 4H).

[0756]

[0757] [Step-8] Preparation of (R)-3-(1-((7-methoxy-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0758]

[0759] 4-((1-chloro-7-methoxy-4-methylphthalazin-6-yl)methyl)morpholine (350 mg, 1.13 mmol) obtained in the above [Step-7], (R)-3-(1-aminoethyl)-2-methylbenzonitrile 2,2,2-trifluoroacetate (467 mg, 1.70 mmol) obtained in [Step-14] of Example 1, magnesium chloride (324 mg, 3.41 mmol), and DIPEA (1.18 mL, 6.82 mmol) were dissolved in 7 mL of 2-butanol, and the mixture was stirred under reflux at 120°C for 48 hours. After completion of the reaction, it was cooled to room temperature and water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)), (dichloromethane: ethyl acetate: methanol = 10:1:1 (v / v / v)) to obtain 105 mg of the title compound in a yield of 21%.

[0760] 1 H-NMR (300 MHz, CDCl3): δ 8.03 (s, 1H), 7.70 (m, 1H), 7.47 (m, 1H), 7.18 (m, 1H), 7.08 (s, 1H), 5.75 (m, 1H), 5.22 (s, 1H), 4.00 (s, 3H), 3.79 (m, 4H), 3.72 (s, 2H), 2.78 (s, 3H), 2.69 (s, 3H), 2.58 (m, 4H), 1.64 (m, 3H).

[0761] MS (ESI+, m / z): 432.2 [M+H] +

[0762]

[0763] Example 29: (R)-2-Methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0764]

[0765] [Step 1] Preparation of dimethyl 2-amino-5-bromoterephthalate

[0766]

[0767] Dimethyl aminoterephthalate (135 g, 645.32 mmol) and N-bromosuccinimide (126 g, 709.85 mmol) were dissolved in 6750 mL of chloroform, and the mixture was refluxed at room temperature for 16 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 3:1 (v / v)) to obtain 102 g of the title compound in a 55% yield.

[0768] 1 H-NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.07 (s, 1H), 5.84 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H).

[0769]

[0770] [Step 2] Preparation of dimethyl 2-bromo-5-(methylamino) terephthalate

[0771]

[0772] Dimethyl 2-amino-5-bromoterephthalate (96 g, 333.22 mmol), methyl iodide (41.5 mL, 666.44 mmol), and potassium carbonate (184.2 g, 1332.90 mmol) obtained in the above [Step-1] were dissolved in 1200 mL of DMF, and the mixture was stirred under reflux at 110°C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, and the mixture was acidified with 2N hydrochloric acid until the pH reached 3. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 9:1 (v / v)) to obtain 50 g of the title compound in a 50% yield.

[0773] 1H-NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), 7.68 (s, 1H), 7.01 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.94 (d, 3H).

[0774]

[0775] [Step 3] Preparation of dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate

[0776]

[0777] Dimethyl 2-bromo-5-(methylamino) terephthalate (50 g, 165.50 mmol), butyl vinyl ether (106.3 mL, 827.49 mmol), palladium acetate obtained in the above [Step-2] (3.7 g, 16.55 mmol), triphenylphosphine (8.7 g, 33.10 mmol), and triethylamine (27.7 mL, 198.60 mmol) were dissolved in 500 mL of acetonitrile, and the mixture was refluxed at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0778]

[0779] [Step 4] Preparation of dimethyl 2-acetyl-5-(methylamino) terephthalate

[0780]

[0781] Dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate (53 g, 164.92 mmol) obtained in the above [Step-3] and 155 mL of 6N hydrochloric acid were dissolved in 530 mL of tetrahydrofuran, and the mixture was refluxed and stirred at room temperature for 1 hour. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (v / v)) to obtain 30 g of the title compound in a yield of 69%.

[0782] 1 H-NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.33 (s, 1H), 6.72 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.00 (d, 3H), 2.54 (s, 3H).

[0783]

[0784] [Step 5] Preparation of methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate

[0785]

[0786] Dimethyl 2-acetyl-5-(methylamino) terephthalate (30 g, 113.10 mmol) and hydrazine monohydrate (7.3 mL, 147.03 mmol) obtained in the above [Step-4] were dissolved in 385 mL of ethanol, and the mixture was refluxed and stirred at 95°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethanol to obtain 26 g of the title compound in a 93% yield.

[0787] 1H-NMR (300 MHz, DMSO-d6): δ 12.16 (s, 1H), 8.26 (s, 1H), 7.92 (d, 1H), 7.29 (s, 1H), 3.91 (s, 3H), 2.96 (d, 3H), 2.42 (s, 3H).

[0788]

[0789]

[0790] [Step 6] Preparation of 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid

[0791]

[0792] Methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate (10.0 g, 40.44 mmol) and sodium hydroxide (16.2 g, 404.45 mmol) obtained in the above [Step-5] were dissolved in 120 mL of a solution of tetrahydrofuran: methanol: water = 2:1:1, and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was acidified with 6N hydrochloric acid solution at low temperature until the pH became 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried in an oven dryer at 55°C to obtain 9.5 g of the title compound in a yield of 99%.

[0793] 1 H-NMR (300 MHz, DMSO-d6): δ 12.11 (s, 1H), 8.29 (s, 1H) 7.26 (s, 1H), 2.95 (s, 3H), 2.42 (s, 3H).

[0794]

[0795] [Step-7] Preparation of (1-hydroxy-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone

[0796]

[0797] 1-Hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid (9.5 g, 40.73 mmol), morpholine (28.4 mL, 325.86 mmol), HATU (46.9 g, 122.20 mmol), N,N-diisopropylethylamine (57.3 mL, 325.86 mmol) obtained in the above [Step-6] were dissolved in 100 mL of DMF and stirred at room temperature for 16 hours. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 7.3 g of the title compound in a yield of 59%.

[0798] 1 H-NMR (300 MHz, DMSO-d6): δ 12.11 (s, 1H), 7.55 (s, 1H), 7.17 (s, 1H), 6.22-6.17 (m, 1H), 3.77-3.45 (m, 6H), 3.28-3.21 (m, 2H), 2.84-2.83 (m, 3H), 2.40 (s, 3H).

[0799]

[0800] [Step 8] Preparation of 4-methyl-7-(methylamino)-6-(morpholinomethyl)phthalazin-1-ol

[0801]

[0802] (1-Hydroxy-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone (4.0 g, 13.23 mmol) obtained in the above [Step-7] was dissolved in tetrahydrofuran at 0 °C, and borane dimethylsulfide (6.27 mL, 66.15 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, water was slowly added dropwise at a low temperature, and the mixture was extracted with a mixed solution of dichloromethane and methanol, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 25:1∼10:1 (v / v)) to obtain 1.8 g of the title compound in a yield of 47%.

[0803] 1 H-NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 7.56 (s, 1H), 7.12 (s, 1H), 6.85-6.80 (m, 1H), 3.61-3.57 (m, 6H), 2.90-2.88 (m, 3H), 2.40-2.36 (m, 7H).

[0804]

[0805] [Step-9] Preparation of 4-chloro-N,1-dimethyl-7-(morpholinomethyl)phthalazin-6-amine

[0806]

[0807] 4-Methyl-7-(methylamino)-6-(morpholinomethyl)phthalazin-1-ol (1.2 g, 4.16 mmol) obtained in the above [Step-8] was dissolved in 13 mL of phosphoryl chloride, and the mixture was stirred under reflux at 110°C for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, and neutralized by dropwise addition to an aqueous sodium bicarbonate solution at 0°C. This was extracted with a mixed solution of dichloromethane and acetone, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 509 mg of the title compound in a 40% yield.

[0808] 1 H-NMR (300 MHz, CDCl3): δ 7.62 (s, 1H), 6.99 (s, 1H), 3.73-3.70 (m, 6H), 3.03-3.02 (m, 3H), 2.84 (s, 3H), 2.48-2.45 (m, 4H).

[0809]

[0810] [Step-10] Preparation of (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)benzonitrile

[0811]

[0812] 4-Chloro-N,1-dimethyl-7-(morpholinomethyl)phthalazin-6-amine (50 mg, 0.16 mmol) obtained in the above [Step-9], (R)-3-(1-aminoethyl)-2-methylbenzonitrile 2,2,2-trifluoroacetate (67 mg, 0.24 mmol) obtained in [Step-14] of Example 1, magnesium chloride (47 mg, 0.49 mmol), N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) were dissolved in 1 mL of 2-butanol, and the mixture was stirred under reflux at 130°C for 48 hours. After completion of the reaction, the mixture was cooled to room temperature and water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 32 mg of the title compound in a 33% yield.

[0813] 1 H-NMR (300 MHz, DMSO-d6): δ 7.78-7.75 (m, 1H), 7.59-7.57 (m, 2H), 7.31-7.23 (m, 2H), 7.16 (s, 1H), 6.83-6.78 (m, 1H), 5.58-5.53 (m, 1H), 3.63-3.57 (m, 6H), 3.00-2.98 (m, 3H), 2.67 (s, 3H), 2.48 (s, 3H), 2.38-2.35 (m, 4H), 1.55-1.53 ​​(m, 3H).

[0814] MS (ESI+, m / z): 431.3 [M+H] +

[0815]

[0816]

[0817] Example 30: (R)-3-(1-((7-(cyclopentylamino)-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0818]

[0819] [Step 1] Preparation of dimethyl 2-(cyclopentylamino) terephthalate

[0820]

[0821] Dimethyl 2-aminoterephthalate (26 g, 124.28 mmol), cyclopentanone (27.5 mL, 310.71 mmol), sodium triacetoxyborohydride (60 g, 283.10 mmol), and acetic acid (71 mL, 1242.80 mmol) were dissolved in 390 mL of dichloromethane at 25 °C, and the mixture was refluxed at room temperature for 48 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 50:1-20:1 (v / v)) to obtain 9.6 g of the title compound in a 28% yield.

[0822] 1 H-NMR (300 MHz, DMSO-d6): δ 7.92 (d, 1H), 7.77 (d, 1H), 7.31 (s, 1H), 7.13 (m, H), 3.94 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.03 (m, 2H), 1.70 (m, 4H) 1.64 (m, 2H).

[0823]

[0824] [Step 2] Preparation of dimethyl 2-bromo-5-(cyclopentylamino) terephthalate

[0825]

[0826] Dimethyl 2-(cyclopentylamino) terephthalate (9.6 g, 34.62 mmol) and N-bromosuccinimide (6.16 g, 34.62 mmol) obtained in the above [Step-1] were dissolved in 290 mL of acetonitrile, and the mixture was refluxed and stirred at room temperature for 16 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 50:1-25:1 (v / v)) to obtain 12 g of the title compound in a yield of 97%.

[0827] 1 H-NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.75 (d, 1H), 7.09 (s, 1H), 3.92 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.03 (m, 2H), 1.66 (m, 4H) 1.62 (m, 2H).

[0828]

[0829]

[0830] [Step 3] Preparation of dimethyl 2-(1-butoxyvinyl)-5-(cyclopentylamino) terephthalate

[0831]

[0832] Dimethyl 2-bromo-5-(cyclopentylamino) terephthalate (12 g, 33.69 mmol), butyl vinyl ether (21.63 mL, 168.44 mmol), Pd(OAc)2 (756 mg, 3.37 mmol), triphenylphosphine (1.77 g, 6.73 mmol), and triethylamine (5.63 mL, 40.42 mmol) obtained in the above [Step-2] were dissolved in 120 mL of acetonitrile, and the mixture was stirred under reflux at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. The filtered organic layer was concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0833]

[0834] [Step 4] Preparation of dimethyl 2-acetyl-5-(cyclopentylamino) terephthalate

[0835]

[0836] Dimethyl 2-(1-butoxyvinyl)-5-(cyclopentylamino) terephthalate (12.65 g, 33.69 mmol) and 6N hydrochloric acid (170 mL, 269.49 mmol) obtained in the above [Step-3] were dissolved in 130 mL of tetrahydrofuran, and the mixture was refluxed at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and water was added dropwise to the obtained residue, which was then extracted with ethyl acetate. The extracted organic layer was washed with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 20:1-5:1 (v / v)) to obtain 10 g of the title compound in a yield of 93%.

[0837] 1H-NMR (300 MHz, DMSO-d6): δ 8.37 (m, 2H), 6.86 (s, 1H), 4.04 (m, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 2.49 (s, 3H), 2.05 (m, 2H), 1.67 (m, 4H) 1.62 (m, 2H).

[0838]

[0839] [Step 5] Preparation of methyl 7-(cyclopentylamino)-1-hydroxy-4-methylphthalazine-6-carboxylate

[0840]

[0841] Dimethyl 2-acetyl-5-(cyclopentylamino) terephthalate (10 g, 31.31 mmol) and hydrazine monohydrate (1.53 mL, 31.31 mmol) obtained in the above [Step-4] were dissolved in 120 mL of ethanol, and the mixture was stirred under reflux at 100°C for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethanol to obtain 8.93 g of the title compound in a yield of 94.6%.

[0842] 1 H-NMR (300 MHz, DMSO-d6): δ 12.17 (s, 1H), 8.30 (s, 1H), 8.04 (d, 1H), 7.38 (s, 1H), 4.02 (m, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.07 (m, 2H), 1.72 (m, 4H), 1.56 (m, 2H).

[0843]

[0844] [Step 6] Preparation of 7-(cyclopentylamino)-1-hydroxy-4-methylphthalazine-6-carboxylic acid

[0845]

[0846] Methyl 7-(cyclopentylamino)-1-hydroxy-4-methylphthalazine-6-carboxylate (8.93 g, 29.63 mmol) and sodium hydroxide (14.5 g, 362.50 mmol) obtained in the above [Step-5] were dissolved in 200 mL of a solution of tetrahydrofuran: methanol: water = 2:1:1, and the mixture was stirred under reflux at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was acidified with 6N hydrochloric acid solution at low temperature until the pH became 2. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with water. The filtered solid was dried in an oven dryer at 50°C to obtain 7 g of the title compound in a yield of 82%.

[0847] 1 H-NMR (300 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.31 (s, 1H), 7.35 (s, 1H), 4.00 (m, 1H), 2.42 (s, 3H), 2.07 (m, 2H), 1.72 (m, 4H), 1.55 (m, 2H).

[0848]

[0849] [Step-7] Preparation of (7-(cyclopentylamino)-1-hydroxy-4-methylphthalazin-6-yl)(morpholino)methanone

[0850]

[0851] 7-(Cyclopentylamino)-1-hydroxy-4-methylphthalazine-6-carboxylic acid (3.5 g, 12.18 mmol), morpholine (8.5 mL, 97.45 mmol), HATU (14 g, 36.55 mmol), N,N-diisopropylethylamine (17.15 mL, 97.45 mmol) obtained in the above [Step-6] were dissolved in 13 mL of DMF and stirred under reflux for 5 hours at room temperature. After the reaction was completed, water was added dropwise, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (v / v)) to obtain 3.36 g of the title compound in a yield of 77%.

[0852] 1 H-NMR (300 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 5.86 (m, 1H), 3.65 (m, 1H), 3.63-3.16 (m, 8H), 2.40 (s, 3H), 2.01 (m, 2H), 1.69-1.63 (m, 6H).

[0853]

[0854] [Step-8] Preparation of 7-(cyclopentylamino)-4-methyl-6-(morpholinomethyl)phthalazin-1-ol

[0855]

[0856] (7-(Cyclopentylamino)-1-hydroxy-4-methylphthalazin-6-yl)(morpholino)methanone (3.26 g, 9.15 mmol) obtained in the above [Step-7] was dissolved in 65 mL of tetrahydrofuran, and borane dimethylsulfide (1.38 mL, 13.72 mmol) was slowly added dropwise. After the addition was complete, the mixture was refluxed at room temperature for 2 hours. After the reaction was complete, water was slowly added dropwise, and the mixture was extracted with a mixed solution of dichloromethane and methanol, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1:1∼9:1 (v / v)) to obtain 1 g of the title compound in a yield of 32%.

[0857] 1 H-NMR (300 MHz, DMSO-d6): δ 12.03 (s, 1H), 7.55 (s, 1H), 7.29 (m, 1H), 7.21 (s, 1H), 3.94 (m, 1H), 3.67 (s, 2H), 3.41 (m, 4H), 2.40 (s, 3H), 2.38 (m, 4H), 2.09 (m, 2H), 1.71 (m, 4H), 1.67 (m, 2H).

[0858]

[0859] [Step-9] Preparation of 4-chloro-N-cyclopentyl-1-methyl-7-(morpholinomethyl)phthalazin-6-amine

[0860]

[0861] 7-(Cyclopentylamino)-4-methyl-6-(morpholinomethyl)phthalazin-1-ol (810 mg, 2.81 mmol) obtained in the above [Step-8] was dissolved in 8.5 mL of phosphoryl chloride, and the mixture was stirred under reflux at 110°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane / acetone, and neutralized by dropwise addition to an aqueous sodium bicarbonate solution at 0°C. This was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (100% ethyl acetate) to obtain 850 mg of the title compound in a yield of 98.6%.

[0862] 1 H-NMR (300 MHz, DMSO-d6): δ 7.91 (s, 1H), 7.81 (m, 1H), 6.90 (s, 1H), 4.02 (m, 1H), 3.77 (s, 2H), 3.59 (m, 4H), 2.75 (s, 3H), 2.40 (m, 4H), 2.09 (m, 2H), 1.73 (m, 4H), 1.61 (m, 2H).

[0863]

[0864] [Step-10] Preparation of (R)-3-(1-((7-(cyclopentylamino)-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0865]

[0866] 4-Chloro-N-cyclopentyl-1-methyl-7-(morpholinomethyl)phthalazin-6-amine (60 mg, 0.17 mmol) obtained in the above [Step-9], (R)-3-(1-aminoethyl)-2-methylbenzonitrile 2,2,2-trifluoroacetate (91 mg, 0.33 mmol) obtained in [Step-14] of Example 1, magnesium chloride (47 mg, 0.50 mmol), N,N-diisopropylethylamine (0.17 mL, 1 mmol) were dissolved in 1 mL of 2-butanol, and the mixture was stirred under reflux at 120 °C for 48 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 30:1 to 10:1 (v / v)) to obtain 18 mg of the title compound in a yield of 22%.

[0867] 1 H-NMR (300 MHz, DMSO-d6): δ 7.77 (d, 1H), 7.60 (m, 2H), 7.32-7.20 (m, 4H), 5.56 (m, 1H), 4.21 (m, 1H), 3.66 (s, 2H), 3.42 (m, 4H), 2.67 (s, 3H), 2.48 (m, 3H), 2.37 (m, 4H), 2.13 (m, 2H), 1.77 (m, 4H), 1.56 (m, 5H).

[0868] MS (ESI+, m / z): 485.3 [M+H] +

[0869]

[0870] Example 31: (R)-3-(1-((7-(cyclopentylamino)-6-((4-cyclopropylpiperazin-1-yl)methyl)-4-methylphthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0871]

[0872] The procedure of Example 30 was repeated except that 1-cyclopropylpiperazine (8.9 g, 69.60 mmol) was used instead of morpholine in [Step-7] of the above Example 30, to obtain 13 mg of the title compound in a 3% yield.

[0873] 1 H-NMR (300 MHz, DMSO-d6): δ 7.76 (m, 1H), 7.62 (m, 3H), 7.43 (m, 1H), 7.34 (m, 2H), 5.56 (m, 1H), 4.27 (m, 1H), 3.66 (s, 2H), 2.67 (s, 3H), 2.54 (m, 5H), 2.34 (m, 3H), 2.18 (m, 2H), 1.74 (m, 10H), 0.40 (m, 4H).

[0874] MS (ESI+, m / z): 524.4 [M+H] +

[0875]

[0876] Example 32: (R)-3-(1-((7-methoxy-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0877]

[0878] [Step 1] Preparation of 4-bromo-2,5-dimethylphenol

[0879]

[0880] 2,5-Dimethylphenol (15 g, 122.78 mmol) and tetrabutylammonium tribromide (59 g, 122.78 mmol) were dissolved in 450 mL of chloroform / 450 mL of water at 25°C, and the mixture was refluxed at room temperature for 3 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with chloroform. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 9:1 (v / v)) to obtain 16.2 g of the title compound in a 66% yield.

[0881] 1 H-NMR (300 MHz, DMSO-d6): δ 9.44 (s, 1H), 7.26 (s, 1H), 6.73 (s, 1H), 2.06 (s, 3H), 1.99 (s, 3H).

[0882]

[0883] [Step 2] Preparation of 1-bromo-4-methoxy-2,5-dimethylbenzene

[0884]

[0885] 4-Bromo-2,5-dimethylphenol (16.2 g, 80.57 mmol), methyl iodide (10 mL, 161.15 mmol), and potassium hydroxide (18 g, 322.29 mmol) obtained in the above [Step-1] were dissolved in 120 mL of DMSO, and the mixture was refluxed and stirred at room temperature for 1 hour. After the reaction was completed, water was added dropwise, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0886]

[0887] [Step 3] Preparation of 2-bromo-5-methoxyterephthalic acid

[0888]

[0889] 1-Bromo-4-methoxy-2,5-dimethylbenzene (17.33 g, 80.57 mmol) obtained in the above [Step-2] was dissolved in 255 mL of water, potassium permanganate (56 g, 354.52 mmol) was slowly added dropwise at room temperature, and the mixture was stirred under reflux at 120°C for 16 hours. After the reaction was completed, it was cooled to room temperature and filtered. 200 mL of 2N hydrochloric acid was added to the obtained filtrate, stirred under reflux at room temperature for 30 minutes, filtered, and the obtained solid was washed with water and then proceeded with the next reaction without further purification.

[0890]

[0891] [Step 4] Preparation of diethyl 2-bromo-5-methoxyterephthalate

[0892]

[0893] 2-Bromo-5-methoxyterephthalic acid (5 g, 18.18 mmol) and sulfuric acid (3.2 mL, 18.18 mmol) obtained in the above [Step-3] were dissolved in 160 mL of ethanol, and the mixture was refluxed at 100 °C for 6 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 20:1 (v / v)) to obtain 3.2 g of the title compound in a 53% yield.

[0894] 1 H-NMR (300 MHz, DMSO-d6): δ 7.87 (s, 1H), 7.44 (s, 1H), 4.37-4.27 (m, 4H), 3.86 (s, 3H), 1.37-1.27 (m, 6H).

[0895]

[0896] [Step 5] Preparation of diethyl 2-(1-butoxyvinyl)-5-methoxyterephthalate

[0897]

[0898] The process of Example 1 [Step-3] was repeated, except that diethyl 2-bromo-5-methoxyterephthalate (3.2 g, 9.66 mmol) obtained in [Step-4] was used instead of dimethyl 2-bromo-5-(methylamino) terephthalate obtained in [Step-2] of Example 1, and the following reaction was carried out without further purification.

[0899]

[0900] [Step 6] Preparation of diethyl 2-acetyl-5-methoxyterephthalate

[0901]

[0902] The procedure of Example 1 [Step-4] was repeated except that diethyl 2-(1-butoxyvinyl)-5-methoxyterephthalate (3.4 g, 9.66 mmol) obtained in [Step-5] was used instead of dimethyl 2-(1-butoxyvinyl)-5-(methylamino) terephthalate obtained in [Step-3] of Example 1, to obtain 2.4 g of the title compound in a yield of 84%.

[0903] 1 H-NMR (300 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.32 (s, 1H), 4.32-4.27 (m, 4H), 3.93 (s, 3H), 2.53 (s, 3H), 1.33-1.26 (m, 6H).

[0904]

[0905] [Step 7] Preparation of ethyl 1-hydroxy-7-methoxy-4-methylphthalazine-6-carboxylate

[0906]

[0907] The procedure of Example 1 [Step-5] was repeated except that diethyl 2-acetyl-5-methoxyterephthalate (2.2 g, 7.48 mmol) obtained in [Step-6] was used instead of dimethyl 2-acetyl-5-(methylamino) terephthalate obtained in [Step-4] of Example 1, to obtain 1.8 g of the title compound in a yield of 92%.

[0908] 1 H-NMR (300 MHz, DMSO-d6): δ 12.48 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 4.39-4.32 (m, 2H), 4.00 (s, 3H), 2.52 (s, 3H), 1.36-1.31 (m, 3H).

[0909]

[0910] [Step 8] Preparation of ethyl 1-chloro-7-methoxy-4-methylphthalazine-6-carboxylate

[0911]

[0912] The procedure of Example 1 [Step-6] was repeated except that ethyl 1-hydroxy-7-methoxy-4-methylphthalazine-6-carboxylate (290 mg, 1.11 mmol) obtained in [Step-7] was used instead of methyl 1-hydroxy-4-methyl-7-(methylamino)phthalazine-6-carboxylate obtained in [Step-5] of Example 1, to obtain 200 mg of the title compound in a yield of 64%.

[0913] 1 H-NMR (300 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.59 (s, 1H), 4.42-4.35 (m, 2H), 4.08 (s, 3H), 2.89 (s, 3H), 1.37-1.33 (m, 3H).

[0914]

[0915] [Step-9] Preparation of ethyl (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-4-methylphthalazine-6-carboxylate

[0916]

[0917] The procedure of Example 1 [Step-15] was repeated except that ethyl 1-chloro-7-methoxy-4-methylphthalazine-6-carboxylate (180 mg, 0.64 mmol) obtained in [Step-8] was used instead of methyl 1-chloro-4-methyl-7-(methylamino)phthalazine-6-carboxylate obtained in [Step-6] of Example 1, to obtain 104 mg of the title compound in a yield of 40%.

[0918] 1H-NMR (300 MHz, DMSO-d6): δ 8.14 (s, 1H), 7.94 (s, 1H), 7.77 (d, 1H), 7.67-7.60 (m, 3H), 7.34-7.29 (m, 1H), 5.61-5.56 (m, 1H), 4.38-4.31 (m, 2H), 4.06 (s, 3H), 2.68 (s, 3H), 2.60 (s, 3H), 1.59 (d, 3H), 1.36 (m, 3H).

[0919]

[0920] [Step-10] Preparation of (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-4-methylphthalazine-6-carboxylic acid

[0921]

[0922] The procedure of Example 1 [Step-16] was repeated except that ethyl (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-4-methylphthalazine-6-carboxylate (104 mg, 0.26 mmol) obtained in [Step-9] was used instead of sec-butyl 1(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino-4-methyl-7-(methylamino)phthalazine-6-carboxylate obtained in [Step-15] of the above Example 1, to obtain 88 mg of the title compound in a yield of 91%.

[0923] 1 H-NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.50-8.45 (m, 2H), 7.93 (m, 1H), 7.66-7.64 (m, 1H), 7.38-7.33 (m, 1H), 5.45 (m, 1H), 3.99 (s, 3H), 2.81 (s, 3H), 2.69 (s, 3H), 1.68 (m, 3H).

[0924]

[0925] [Step-11] Preparation of (R)-3-(1-((7-methoxy-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0926]

[0927] The procedure of Example 1 [Step-17] was repeated except that (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-4-methylphthalazine-6-carboxylic acid (88 mg, 0.23 mmol) obtained in [Step-10] was used instead of (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazine-6-carboxylic acid obtained in [Step-16] of the above Example 1, thereby obtaining 80 mg of the title compound in a yield of 77%.

[0928] 1 H-NMR (300 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.83 (s, 1H), 7.78 (m, 1H), 7.76 (m, 2H), 7.34-7.29 (m, 1H), 5.60 (m, 1H), 4.07 (s, 3H), 3.72-3.67 (m, 4H), 3.65-3.62 (m, 2H), 3.12 (m, 2H), 2.68 (s, 3H), 2.58 (s, 3H), 1.59 (m, 3H).

[0929] MS (ESI+, m / z): 446.2 [M+H] +

[0930]

[0931] Example 33: (R)-3-(1-((7-cyclopentylamino)-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0932]

[0933] [Step 1] Preparation of dimethyl 2-(cyclopentylamino) terephthalate

[0934]

[0935] Dimethyl aminoterephthalate (2.8 g, 13.38 mmol), cyclopentanone (2.6 mL, 29.45 mmol), sodium triacetoxyborohydride (5.67 g, 26.77 mmol), and acetic acid (6.5 mL, 114.24 mmol) were dissolved in 40 mL of dichloromethane, and the mixture was refluxed at room temperature for 48 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 50:1 (v / v)) to obtain 1 g of the title compound in a 27% yield.

[0936] 1 H-NMR (300 MHz, DMSO-d6): δ 7.92 (d, 1H), 7.77 (m, 1H), 7.31 (s, 1H), 7.13-7.09 (m, 1H), 3.94-3.92 (m, 1H), 3.86-3.83 (m, 6H), 2.04-1.99 (m, 2H), 1.70-1.64 (m, 4H), 1.51-1.48 (m, 2H).

[0937]

[0938] [Step 2] Preparation of dimethyl 2-bromo-5-(cyclopentylamino) terephthalate

[0939]

[0940] Dimethyl 2-(cyclopentylamino) terephthalate (1 g, 3.61 mmol) and N-bromosuccinimide (642 mg, 3.61 mmol) obtained in the above [Step-1] were dissolved in 30 mL of acetonitrile, and the mixture was refluxed and stirred at room temperature for 16 hours. After the reaction was completed, water was added dropwise, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 50:1 (v / v)) to obtain 1.13 g of the title compound in 88% yield.

[0941] 1 H-NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.75 (m, 1H), 7.09 (s, 1H), 3.92-3.90 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.03-1.99 (m, 2H), 1.69-1.61 (m, 4H), 1.47-1.43 (m, 2H).

[0942]

[0943] [Step-3] Preparation of (R)-3-(1-((7-cyclopentylamino)-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0944]

[0945] The procedure of Example 1 was repeated except that dimethyl 2-bromo-5-(cyclopentylamino) terephthalate (1.13 g, 3.7 mmol) obtained in [Step-2] was used instead of dimethyl 2-bromo-5-(methylamino) terephthalate obtained in [Step-2] of the above Example 1, to obtain 132 mg of the title compound in a yield of 44%.

[0946] 1 H-NMR (300 MHz, DMSO-d6): δ 7.76 (m, 1H), 7.61-7.58 (m, 2H), 7.33-7.28 (m, 3H), 5.76-5.54 (m, 2H), 4.20 (m, 1H), 4.00-3.62 (m, 4H), 3.61-3.29 (m, 2H), 2.54 (s, 3H), 2.48 (m, 3H), 2.15-2.09 (m, 2H), 1.75-1.54 (m, 9H).

[0947] MS (ESI+, m / z): 499.3 [M+H] +

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956] Experimental Example 1: Testing the GTP displacement inhibition ability of SOS1.

[0957] To confirm whether the aforementioned compounds inhibit the substitution function of SOS1 binding to KRAS G12C, a homogenous time-resolved fluorescence (HTRF) assay was performed using GST-KRAS G12C (#MSC-11-538) and SOS1-Strep (#MSC-11-502) from Reaction Biology Corp. (USA, MA). The activity of the SOS1 enzyme was measured by measuring the amount of GTP bound to the KRAS G12C protein using the principle of time-resolved fluorescence energy transfer (TR-FRET). Based on the principle that Terbium bound to the antibody that binds to GST of the GST-KRAS G12C protein acts as a donor for fluorescence resonance energy transfer (FRET), and GTP bound to the KRAS G12C protein is labeled with the fluorescent agent DY-647P1 and acts as an acceptor for FRET, the more GTP is bound to the KRAS G12C protein by the substitution reaction of SOS1 according to this test, the higher the HTRF or FRET signal can be measured.

[0958] In brief, the glutathione S-transferase (GST)-labeled KRAS G12C protein (amino acid residues 2-169), streptavidin-tagged SOS1 protein (amino acid residues 564-1049, which is the catalytic domain), anti-GST antibody, labeled nucleic acid GTP-DY-647P1, and compounds required for the reaction were mixed in a buffer solution composed of 20 mM HEPES pH7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM dithiothreitol (DTT), 0.05% BSA, and 0.0025% NP40, added to a 384-well plate, and the reaction was performed at room temperature, after which the HTRF signal was measured using a PHERAstar microplate reader (BMG Labtech). At this time, the excitation signal was measured at 337 nm and the emission signal was measured at 620 / 665 nm. The fluorescence measurement value when the SOS1 protein was not included was calculated as the background signal value and was subtracted from all measured HTRF values, and the fluorescence measurement value when the synthesized compound was not included was measured as the non-inhibitory value (Control value) and this value was selected as the reference point of 100%. The fluorescence values ​​emitted at the concentrations of 0.1, 1, 10, 100, 1,000 nM (5 points, 10-fold) or 1.6, 8, 40, 200, 1,000 nM (5 points, 5-fold) of the example compounds were measured, and the 50% activity inhibition value (IC) of these compounds 50 ) was calculated using GraphPad Prism. The results of the inhibitory ability of the example compounds to suppress GTP substitution of SOS1 are shown in Table 2 below.

[0959] IC 50If the value is 50 nM or less, it is indicated as +++, if it is more than 50 nM but less than 100 nM, it is indicated as ++, and if it is more than 100 nM, it is indicated as +.

[0960]

[0961] The experimental results as described above suggest that the phthalazine derivative compound according to the present invention has excellent activity in inhibiting the binding of RAS family proteins and SOS1, and thus can be used to develop various drugs related to cancer or tumors that can be treated using the compound.

Claims

1. A compound selected from the compounds of the following chemical formula 1, optical isomers thereof, diastereomers thereof, hydrates thereof, solvates thereof, and pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is hydrogen or C 1-4 It is alkyl; R2 is hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkynylide; R3 is R 3a or -L2- and; Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo(=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and R a class R b are each independently Hydrogen, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-8 Select from the group consisting of carbocyclyl, wherein the above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, amino C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy-C 1-4 Alkyl may be substituted with one or more halogens; r is an integer from 0 to 1; m is an integer from 0 to 5; L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and; p is an integer from 0 to 3; q is an integer from 0 to 2; class are each independently C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl, and in this case, C of 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl is unsubstituted or substituted with one or more R 3a can be replaced with; X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, which is halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d may be substituted or unsubstituted, where R c and R d are each independently hydrogen or C 1-6 It is alkyl; R5 and R6 is each independently hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f It can be substituted with one or more functional groups selected from the group consisting of, where R e and R f are each independently hydrogen or C 1-6 It is alkyl, Or the above -N(R5)(R6) is R5 and C in which R6 is connected to each other to form a ring with the nitrogen atom in -N(R5)(R6) 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl, wherein the above C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h It can be substituted with one or more functional groups selected from the group consisting of, where R g class R h are each independently Hydrogen, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 3-8 It is carbocyclyl; L1 is a direct bond, -C(O)-, -O-, -NH-, -C(O)NH- or -C(O)NCH3- and; n is an integer from 0 to 2; is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 4-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 4-14 Bridged heterocyclyl, and in this case, the above C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 4-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i , -NR i R j , C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl, wherein R i and R j are each independently hydrogen or C 1-6 It's alkyl.

2. In paragraph 1, class are each independently C 6-10 Aryl or C 4-10 Heteroaryl compound.

3. In paragraph 1, R 3a are each independently halogen, hydroxy, cyano, amino, amine, nitro, C 1-6 Alkyl, haloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and here R a and R b are each independently hydrogen, C 1-6 Alkyl, -CF3 or -CF2H, wherein the C 1-6 Alkyl is a compound that can be substituted with one or more halogens.

4. In paragraph 1, R4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl; R5 and R6 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl or C 2-9 Heterocyclyl, or the above -N(R5)(R6) is C 2-9 A heterocyclyl compound.

5. In paragraph 1, The compound represented by the above chemical formula 1 is a compound represented by the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, L1 is a direct bond, -C(O)-, -O-, -NH-, -C(O)NH- or -C(O)NCH3- and; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen; R 4a is hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl; is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein the morpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted with halogen, -C 1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

6. In paragraph 1, The compound represented by the above chemical formula 1 is a compound represented by the following chemical formula 3: [Chemical Formula 3] In the above chemical formula 3, L3 is a direct bond, -C(O)-, -C(O)NH-, or -C(O)NCH3- and; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen; R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl, or the above -N(R 5a )(R 5b ) is R 5a Wow R 5b are connected to each other -N(R 5a )(R 5b ) forming a ring with the nitrogen atom in it 2-9 It is heterocyclyl; is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted with halogen, -C 1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

7. In paragraph 5, The compound represented by the above chemical formula 2 is a compound represented by the following chemical formula 4: [Chemical Formula 4] In the above chemical formula 4, L4 is a direct bond, -C(O)-, -O-, -C(O)NH- or -C(O)NCH3-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen; is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl, wherein the morpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl is unsubstituted or substituted with halogen, -C 1-3 Alkyl, C 3-10 Carbocyclyl and C 2-9 It may be substituted with one or more functional groups selected from the group consisting of heterocyclyl.

8. In paragraph 6, The compound represented by the above chemical formula 3 is a compound represented by the following chemical formula 5: [Chemical Formula 5] In the above chemical formula 5, L5 is a direct bond, -C(O)-, -C(O)NH-, or -C(O)NCH3-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -CN, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen; is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen, methyl, ethyl, cyclopropyl and cyclohexyl.

9. In paragraph 1, The compound of the above chemical formula 1 is a compound characterized in that it is selected from the group consisting of the following compounds: (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(thiomorpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(thiazolidine-3-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-3-(1-((6-(1,1-deoxidothiomorpholine-4-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)-N-(tetrahydro-2H-pyran-4-yl)phthalazine-6-carboxamide; (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-N,4-dimethyl-7-(methylamino)-N-(tetrahydro-2H-pyran-4-yl)phthalazine-6-carboxamide; 3-((1R)-1-((6-(hexahydro-1H-furo[3,4-c]pyrrole-5-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(4-methylpiperazine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(piperazine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-3-(1-((6-(4,4-difluoropiperidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-3-(1-((6-(4-ethylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((6-(4-cyclopropylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(pyrrolidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(piperidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-3-(1-((6-(azetidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((6-(3-fluoroazetidine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(5-azaspiro[2.4]heptane-5-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; 3-((1R)-1-((6-(2-Oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((6-(4-cyclohexylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((6-(4-isopropylpiperazine-1-carbonyl)-4-methyl-7-(methylamino)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(4-morpholinopiperidine-1-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)-4-methyl-7-(methylamino)-N-(2-morpholinoethyl)phthalazine-6-carboxamide; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(1,4-oxazepane-4-carbonyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-(1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone; (R)-(1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone; (R)-(1-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-4-methyl-7-(methylamino)phthalazin-6-yl)(morpholino)methanone; (R)-3-(1-((7-methoxy-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-2-methyl-3-(1-((4-methyl-7-(methylamino)-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)benzonitrile; (R)-3-(1-((7-(cyclopentylamino)-4-methyl-6-(morpholinomethyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((7-(cyclopentylamino)-6-((4-cyclopropylpiperazin-1-yl)methyl)-4-methylphthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((7-methoxy-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; (R)-3-(1-((7-cyclopentylamino)-4-methyl-6-(morpholine-4-carbonyl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

10. A pharmaceutical composition for the prevention or treatment of a disease associated with inhibition of SOS1 binding to a RAS family protein and / or RAC1, comprising as an active ingredient a compound selected from the compounds described in any one of claims 1 to 9, optical isomers thereof, diastereomers thereof, hydrates thereof, solvates thereof, and pharmaceutically acceptable salts thereof.

11. In paragraph 10, The pharmaceutical composition is a pharmaceutical composition for use in preventing or treating cancer or tumors that can be treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

12. A method for inhibiting SOS1 binding to a RAS family protein and / or RAC1 in a sample or cell, comprising administering to the sample a pharmaceutically effective amount of a compound described in claim 1.

13. A method for preventing or treating cancer in a sample, comprising administering to the sample a pharmaceutically effective amount of a compound described in paragraph 1.

14. Use of the compound described in paragraph 1 or a pharmacologically acceptable salt thereof for the prevention or treatment of cancer or tumor.