KR101842645B1 - Novel Hydrazinone-substituted Pyrimidine Derivatives and Use Thereof - Google Patents

Abstract

The present invention relates to a novel hydrazine-substituted pyrimidine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising these as an active ingredient, and a prophylactic or therapeutic agent for hyperproliferative disorder, ≪ / RTI >
The present invention relates to a therapeutic agent for a variety of abnormal proliferative diseases associated with excessive cell proliferation and growth due to abnormal kinase activity, for example, cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. by efficiently inhibiting the activity of c-Met tyrosine kinase Can be usefully used.

Description

Novel hydrazinone-substituted pyrimidine derivatives and their use {Novel Hydrazinone-substituted Pyrimidine Derivatives and Use Thereof}

The present invention relates to a novel hydrazine-substituted pyrimidine derivative having tyrosine kinase inhibitory activity, and a pharmaceutical composition for the prevention and treatment of various hyperproliferative disorders including an active ingredient thereof.

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The protein kinase plays an important role in growth factor signaling leading to cell growth, differentiation and proliferation, and thus the activity of protein kinase affects almost all aspects of cell life.

The abnormality of the cellular signaling system by mutation or overexpression of protein kinase has a close relationship with stroma disease ranging from relatively non-life-threatening diseases such as psoriasis to toxic (pathogenic) diseases such as cancer.

Protein kinases can be classified as tyrosine kinases (TK) and serine-threonine kinases (STK).

One of the key aspects of the activity of tyrosine kinase is that it is associated with growth factor receptors. The growth factor receptor is a cell surface protein. When bound to a growth factor ligand, the growth factor receptor is converted to an active form and interacts with proteins on the inner surface of the cell membrane to induce phosphorylation on the tyrosine residues of the receptor and other proteins , Complexes with various cytoplasmic signaling molecules inside the cells are formed, and ultimately, a number of cellular reactions such as cell growth, differentiation and proliferation, and manifest metabolic effects on the extracellular microenvironment (Schleessinger and Ullrich, Neuron 9:. 303-391 (1992) ).

The growth factor receptor with activity of tyrosine kinase is known as receptor tyrosine kinase (RTK). The receptor tyrosine kinases include a large family of transmembrane receptors that exhibit a variety of biological activities.

Subtype receptor tyrosine kinases, such as those conventionally termed 19 or more " HER RTKs, are known, and the HER RTKs include epithelial growth factor receptor (EGFR), HER2, HER3 and HER4. The receptor tyrosine kinase consists of an extracellular glycosylated ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic domain capable of phosphorylating a tyrosine residue on the protein.

In addition, the receptor tyrosine kinase family consists of the insulin receptor (IR), the insulin-like growth I receptor (IGF-1R) and the insulin receptor related receptor (IRR). IR and IGF-IR interact with insulin, IGF-I, and IGF-II to cross the cell membrane and produce a heterogeneous amount of two beta subunits containing the kinase domain and two fully extracellular glycosylated alpha subunits To form a heterotetramer.

In addition, the receptor tyrosine kinase subtype includes PDGFR [alpha], PDGFR [beta], CSFIR, c-Kit and c-Fms, which are named platelet derived growth factor receptor (PDGFR). The receptor consists of a variable number of immunoglobulin-like loops and a glycosylated extracellular domain consisting of intracellular domains. Due to the similarity with the PDGFR subtype, the fetal liver kinase (Flk) receptor subtype contained in the PDGFR group is known. The Flk subtype is derived from the kinase insert domain-receptor fetal liver kinase-1 (KDR / Flk-1), Flk-1R, Flk-1, Fms-like tyrosine kinase 1 or 3 (Flt-1 or Flt- .

As a tyrosine kinase growth factor receptor family, MET is designated c-Met and is thought to play a role in primary tumor growth and metastasis as human hepatocyte growth factor receptor tyrosine kinase (hHGFR) (Plowman et al., DN & P, 7 (6): 334-339 (1994)).

In addition to receptor tyrosine kinases, there is a complete intracellular TK of a particular family called non-receptor tyrosine kinases or cellular tyrosine kinases (CTK). The non-receptor tyrosine kinase does not contain a transmembrane domain with the extracellular domain and is composed of Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak and Ack subtypes. The Src family includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1 (Aurora-A), AUR2 (Aurora- Oncogene 8:. 2025-2031 (1993) ).

Pathogenic diseases associated with receptor tyrosine kinases and non-receptor tyrosine kinases include psoriasis, cirrhosis, diabetes, angiogenesis, restenosis, ophthalmic diseases, rheumatoid arthritis, autoimmune diseases, atherosclerosis, renal disorders and the like.

Of the PKs listed above, receptor tyrosine kinases such as Bcr-Abl, EGFR, and VEGFR have been studied as good anticancer drug targets, and anticancer drugs such as Gleevec and Iressa have been developed and marketed.

Among the RTKs that have been studied as anticancer drug targets, many anticancer drugs targeting c-Met (Hepatocyte Growth Factor Receptor: HGFR) receptor (Hepatocyte Growth Factor / Scatter Factor (HGF / Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26, WO 2004/076412, WO 2006/021881 A, WO 2006/021886, WO 2007/064797).

c-Met is overexpressed or activated in many human cancers, such as lung cancer, stomach cancer, skin cancer, renal cancer, rectal cancer, pancreatic cancer, which are accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et al., Cancer Letters , 225: 1-26 (2005); WG Jiang et al., Critical Reviews in Oncology / Hematology , 53: 35-69 (2005)). Although c-Met and its ligand, HGF, are expressed in many tissues, they are normally expressed mainly in epithelial and mesenchymal cells, respectively. c-Met and HGF / SF are required for normal mammalian development and are important in cell metastasis, cell proliferation and survival, morphogenic differentiation, and in the organization of three-dimensional tubular structures (renal tubular cells, line formation, etc.) It turned out. HGF / SF is a neovascularization factor and c-Met signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) essential for neovascularization.

It has also been found that c-Met and its ligand HGF are co-expressed at increased levels in a variety of human cancers. However, since receptors and ligands are typically expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.

In addition, gene amplification, mutation and rearrangement of c-Met have been observed in a variety of human cancers. Classes with reproductive mutations that activate c-Met kinase are susceptible to multiple renal tumors and tumors of other tissues.

Expression of c-Met and / or HGF / SF is associated with disease progression of different types of cancer (cancers such as lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin and bone) , And overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers, including lung, liver, stomach and breast. In addition, c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma, and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation with overexpression of c-Met has been reported to cause gefitinib (Gefitinib; (Irresa) (JA Engelman, K. Zejnullahu et al. Science , 316: 1039-1043 (2007)).

HGF / SF binds to the extracellular domain of c-Met to activate c-Met, and the activation of c-Met is mediated by tyrosine phosphorylation through the activation of Gab1 and Grb2 mediated PI3-kinase and Ras / MAPK, Leading to signaling, leading to cell motility and proliferation.

c-Met has been shown to interact with other proteins that lead to receptor activation, transformation and invasion, and c-Met has been shown to interact with the extracellular matrix (ECM), such as integrin: laminin, which forms focal adhesion ≪ / RTI > receptor) to promote HGF / SF-dependent invasive growth.

The present inventors have conducted studies to develop a protein kinase inhibitor, and have found that a hydrazinone-substituted morpholinopyrimidine compound having a specific structure is c-Met, Ron, KDR, Lck, Flt1, Flt3, Tie2, The inventors have experimentally observed that they have an excellent inhibitory effect on protein kinases such as TrkA, TrkB, b-Raf and Aurora-A, and thus they can be effectively used in the prevention and treatment of abnormal pheochromocytosis.

The present inventors have sought to elucidate a compound having an inhibitory activity against tyrosine kinase to develop a composition for effectively preventing or treating various hyperproliferative disorders caused by the activity of abnormal tyrosine kinases. As a result, a novel hydrazinone-substituted pyrimidine derivative of the following formula (1), which has not yet been known, binds to hepatocyte growth factor (HGF) and activates phosphorylation to increase cell proliferation, migration, infiltration, Gt; c-Met < / RTI >

SUMMARY OF THE INVENTION Accordingly, Hydrazinone substituted pyrimidine derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a novel There is provided a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity, which comprises a hydrazine-substituted pyrimidine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating hyperproliferative disorder comprising the above-mentioned hydrazine-substituted pyrimidine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient Compositions.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a hydrazinone-substituted Pyrimidine derivative or a pharmaceutically acceptable salt thereof.

Formula 1

In the above formulas,

R ₁ To R < ₃ > are each independently hydrogen; halogen; Hydroxy; Heterocycloalkyl of 5 to 6 rings; C ₁ -C ₃ alkoxy substituted by heterocycloalkyl of the five-each ring; Aldehyde, C ₁ -C ₅ alkyl substituted by heterocycloalkyl of the pentane-6 ring, C ₁ -C ₃ alkoxy substituted by heterocycloalkyl of the pentacyclic ring, or phenyl substituted with halogen; 5 -6, each heterocycloalkyl, each 5 -6, each substituted with a heterocycloalkyl ring of C ₁ -C ₃ alkoxy, C ₁ -C ₅ alkyl substituted by hydroxy or halogen, each of each ring 5 each -6 Heteroaryl of the ring; Amino-C ₁ -C ₃ alkoxy; Or 1,2,3,6-tetrahydropyridine unsubstituted or substituted with C ₁ -C ₅ alkyl or C ₁ -C ₄ alcohol, and R ₁ To at least one of R ₃ is not a hydrogen;

R ₄ is heteroaryl, each of the 5 -6, each ring substituted with unsubstituted or C ₁ -C ₅ alkyl beach; Or cyano, halogen, halo-C ₁ -C ₅ alkyl or phenyl C ₁ -C ₃ alkoxy substituted by phenyl.

The present inventors have sought to elucidate a compound having an inhibitory activity against tyrosine kinase to develop a composition for effectively preventing or treating various hyperproliferative disorders caused by the activity of abnormal tyrosine kinases. As a result, it has been found that pyrimidine derivatives substituted with the novel hydrazinone of the above formula (1), which have not been known so far, significantly inhibit the activity of c-Met kinase.

According to the present invention, the compound of formula (I) of the present invention is a compound of the formula (I) of the present invention which binds to hepatocyte growth factor (HGF) and activates phosphorylation to induce cell proliferation, migration, invasion and formation of neovascularization Significantly inhibits the activity. Accordingly, the compounds of the present invention can be usefully used for treating or preventing various abnormal proliferative diseases mediated by abnormal proliferation of cells and excessive angiogenesis.

As used herein, the term " halogen " refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, the term " heterocycloalkyl " refers to a saturated carbon ring that contains a heteroatom containing oxygen, sulfur, or nitrogen in the ring. Preferably, the heteroatom is nitrogen or oxygen. The number of heteroatoms is 1-4, preferably 1-2. "Heterocycloalkyl of 5-membered to 6-membered rings" means that the sum of the numbers of carbon and heteroatoms forming the ring is 5-6.

As used herein, the term " alkoxy " means a radical formed by removing hydrogen from an alcohol, and when C ₁ -C ₃ alkoxy is substituted, the number of carbon atoms of the substituent is not included.

As used herein, the term " alkyl " means a straight or branched saturated hydrocarbon group, including, for example, methyl, ethyl, propyl, isobutyl, pentyl or hexyl. C ₁ -C ₅ Alkyl means an alkyl group having an alkyl unit having 1 to 5 carbon atoms, and when C ₁ -C ₅ alkyl is substituted, the number of carbon atoms of the substituent is not included. In formula (1), C ₁ -C ₅ Alkyl is preferably C ₁ -C ₃ Alkyl, more preferably C ₁ -C ₂ Alkyl.

As used herein, the term " heteroaryl " means a heterocyclic aromatic group containing a hetero atom, oxygen, sulfur or nitrogen, in the ring. Preferably, the hetero atom is nitrogen or oxygen, more preferably nitrogen. The number of heteroatoms is 1-4, preferably 1-2. In heteroaryl, aryl is preferably monoaryl or biaryl.

According to a preferred embodiment of the present invention, R < 1 _> And R ₃ is hydrogen, R ₂ is halogen; Hydroxy; Morpholine; Piperidine; Piperazine; Morpholino-C ₁ -C ₃ alkoxy; Piperazinyl C ₁ -C ₃ alkoxy; Pyrrolidinyl C ₁ -C ₃ alkoxy; Piperidinyl C ₁ -C ₃ alkoxy; Phenyl substituted with aldehyde, morpholino C ₁ -C ₃ alkoxy, piperazinyl C ₁ -C ₃ alkoxy, morpholino C ₁ -C ₅ alkyl or halogen; Piperidinyl pyrazole; Pyridine substituted with halogen, piperazine or morpholino C ₁ -C ₃ alkoxy; Amino-C ₁ -C ₃ alkoxy; Or 1,2,3,6-tetrahydropyridine which is unsubstituted or substituted by C ₁ -C ₅ alkyl or C ₁ -C ₄ alcohol.

According to a preferred embodiment of the invention, R ₄ of formula (I) of the present invention is C ₁ -C ₅ alkyl substituted with pyrazole; Unsubstituted pyridine; Or cyano, halogen, halo-C ₁ -C ₅ alkyl or phenyl C ₁ -C ₃ alkoxy substituted by phenyl.

According to a more preferred embodiment of the present invention, the hydrazine-substituted pyrimidine derivative represented by the formula (1) of the present invention is selected from the group consisting of the compounds represented by the following formulas (2) to (55)

            (2)

            (4)

            (6)

            (8)

            (10)

           (12)

            (14)

            (16)

           (18)

          (20)

          (22)

          (24)

          (26)

          (28)

          (30)

          (32)

          (34)

           (36)

           (38)

         (40)

         (42)

        (44)

        (46)

Most preferably, the hydrazine substituted pyrimidine derivative of the present invention is selected from the group consisting of the compounds represented by the above formulas 6, 7, 12, 22, 23, 29, 32, 41 and 47.

According to the present invention, the nine compounds listed above have a very low IC _{50 of} less than 0.01 μM for c-Met kinase inhibitory activity Value. They can therefore be used as highly effective therapeutic compositions for a variety of atherogenic disorders.

The hydrazine-substituted pyrimidine derivatives of the present invention can be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids (free acids) are useful as salts. As the free acid, inorganic acid and organic acid can be used.

Preferably, the pharmaceutically acceptable salts of hydrazine-substituted pyrimidine derivatives of the present invention include, but are not limited to, hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, maleate, But are not limited to, those selected from the group consisting of malate, gluconate, methane sulfonate, glycinate, succinate, 4-toluenesulfonate, gluturonate, ebonate, glutamate or aspartate And salts formed using various inorganic acids and organic acids commonly used in the art.

The hydrazine-substituted pyrimidine derivative of the present invention may also exist in the form of a solvate (for example, a hydrate).

According to another aspect of the present invention, the present invention relates to a process for the preparation of There is provided a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising a pyrimidine derivative, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

According to another aspect of the present invention, there is provided a pharmaceutical composition for treating hyperproliferative disorder, comprising a hydrazine-substituted pyrimidine derivative of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, Or a pharmaceutically acceptable salt thereof.

The pyrimidine derivatives substituted with the novel hydrazinone used in the present invention have already been described above, so that they are omitted in order to avoid excessive overlapping.

As used herein, the term " hyperproliferative disorder " refers to a pathological state caused by excessive cell growth, division, and migration that is not normally regulated by the general restriction means in the growing animal. The diarrheal diseases to be prevented or treated with the composition of the present invention include, for example, cancer, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, hypoxia, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, Including, but not limited to, Crohn's disease, recurrent stenosis, atherosclerosis, intestinal adhesion, ulceration, hepatopathy, glomerulonephritis, diabetic nephropathy, malignant neuropathy, thrombotic microangiopathy, All of which are caused by abnormal proliferation of blood vessels and excessive production of new blood vessels.

More preferably, the cancer, which is one of the abnormal hyperproliferative diseases that can be prevented and treated with the composition of the present invention, is lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.

When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

The pharmaceutical composition of the present invention may be formulated into a conventional preparation using pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs May be prepared in unit dosage form or may be manufactured by intrusion into a multi-dose container. Typical formulations are, for example, oral (tablets, capsules, powders), intraoral, sublingual, rectal, vaginal, intranasal, topical or parenteral (intravenous, intracameral, intramuscular, subcutaneous And intravenous) administration formulations. For example, a compound according to the present invention may be in the form of tablets containing starch or lactose, in the form of capsules containing the active ingredient alone or in an excipient, or in the form of an elixir or suspension containing a chemical that tastes or colors For example, orally, buccally or sublingually. Liquid preparations may contain suspending agents (e. G., A mixture of a semisynthetic glyceride such as methylcellulose, witepsol or apricot kernel oil and a PEG-6 ester, or a mixture of PEG-8 and caprylic / Such as a glyceride mixture, such as a mixture of glycerides (e.g., a mixture of glycerides). It is also most preferred to use it as a sterile aqueous solution form when injected parenterally, for example, intravenously, intraperitoneally, intramuscularly, subcutaneously, and intratracheally, wherein the solution is administered in order to have isotonicity with the blood It may contain other substances (for example, salts or monosaccharides such as mannitol, glucose).

The features and advantages of the present invention are summarized as follows:

(a) The present invention relates to a novel hydrazinone-substituted pyrimidine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for inhibiting c-Met tyrosine kinase activity comprising these as an active ingredient, and a hyperproliferative disorder, Or a pharmaceutically acceptable salt thereof.

(b) The present invention relates to a method for effectively inhibiting the activity of c-Met tyrosine kinase, thereby inhibiting a variety of abnormal proliferative diseases associated with excessive cell growth and growth due to abnormal kinase activity, such as cancer, psoriasis, rheumatoid arthritis, And the like.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Method for preparing each compound

Compound 1: (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (1- methyl -1H- Pyrazole Yl) Pyridazine -3 (2H) -one

Step 1 : (S) - (4- Benzyl morpholine -2-yl) methanol

To a solution of 2 (benzylamino) ethanol (6.9 mL, 54 mmol) and ( R ) -2- (chloromethyl) oxirane (5 g, 54 mmol) in water (2 mL) / 2- And the mixture was stirred at room temperature for 13 hours. After the reaction, Et ₄ NOH (35% wt, 70 mmol) was added dropwise and further stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was adjusted to pH 9 with aqueous hydrochloric acid (1 N), extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (EtOAc / n -hexane = 6: 4) to give (S) - (4-benzylmorpholin-2-yl) methanol (5.7 g, 50%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 7.33-7.26 (m, 5H), 3.89 (dt, J = 11.2Hz, J = 2.4 Hz, 1H), 3.70 (dt, J = 11.2 Hz, J = 2.4 2H), 2.18 (dt, J = 11.2 Hz, J = 3.3 Hz, 1H), 2.04-1.97 (m, 1H), 3.67-3.53 (m,

Step 2 : (S) -morpholin-2- Monohydrate of methanol  Produce

(S) - (4- benzyl-2-yl) methanol was dissolved (5.5 g, 26 mmol) in MeOH (50ml), was added Pd / C (10% Pd, 0.55g), H 2 (gas ), And the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was filtered through celite and concentrated under reduced pressure to obtain ( S ) -morpholin-2-ylmethanol (3.1 g, 99%).

¹ H-NMR (300 MHz, CDCl ₃ )?? 3.88 (d, J = 11.2 Hz, 1H), 3.68-3.45 (m, 4H), 2.92-2.74 (m, 3H), 2.71-2.58

Step 3 : (S) - (4- (5- Bromopyrimidine Yl) morpholin-2-yl) methanol

(S) - morpholin-2-yl methanol (2.5 g, 21 mmol) was dissolved in EtOH (40ml), 5- bromo-2-chloropyrimidine (4.5 g, 23 mmol) and diisopropylethylamine ( 7.4 ml, 42 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated, extracted, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (EtOAc: hexane = 3: 7) to give 5.09 g of 87 (S) - (4- (5-bromopyrimidin- %).

¹ H-NMR (300 MHz, CDCl ₃ )?? 8.31 (s, 2H), 4.46 (d, J = 11.2 Hz, 2H), 4.02 (dd, J = 11.2 Hz, J = 2.5 Hz, 1H) 3.52 (m, 4H), 3.12-3.00 (m, 1H), 2.93-2.83 (m, 1H)

Step 4 : (S) - (4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl  4- Methylbenzenesulfonate  Produce

Yl) methanol (1.6 g, 5.8 mmol) was dissolved in CH ₂ Cl ₂ (20 ml), and TsCl (1.7 ml, g, 8.7 mmol), Et3N (1.6 ml, 11 mmol) and DMAP (0.072 g, 0.58 mmol) were added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / n -hexane = 2: 8) (S) - (4- (5-bromopyrimidin-2-yl) morpholin-2-yl) methyl 4-methylbenzenesulfonate (2.49 g, 99%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.29 (s, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.49 (d, J = 13.0 Hz, 1H), 4.37 (d , J = 13.0 Hz, 1H), 4.14 - 4.05 (m, 2H), 3.93 (dd, J = 13.4 Hz, J = 7.6 Hz, 1H), 3.74 - 3.65 (m, 1H (Dd, J = 13.4 Hz, J = 11.2 Hz, 1H), 2.45 (s, 3H), 3.50 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.08-2.9 )

Step 5: (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (1- methyl -1H- Pyrazole Yl) Pyridazine -3 (2H) -one < / RTI >

Methylbenzenesulfonate (2.5 g, 5.8 mmol) was dissolved in DMF (20 ml), and a solution of (4-methylpiperazin-1- (1.2 g, 6.9 mmol) and Cs ₂ CO ₃ (2.8 g, 8.7 mmol) were added to the solution, and the mixture was stirred at 50 ° C After the reaction was completed, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / n -hexane = 2: 8) to give (S) -2 - ((4- (5-bromopyrimidin-2- yl) morpholin- -Yl) pyridazin-3 (2H) -one (1.51 g, 60%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.29 (s, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.41 (d, J = 9.6Hz, 1H), 6.98 (d, J = 9.6 Hz, 1H), 4.55 (d, J = 14.3 Hz, 1H), 4.49 (dd, J = 13.4 Hz, J = 7.6 Hz, 1H), 4.34 (d, J = 13.4 Hz, 1H), 4.21 - 3.96 (m, 3H), 3.95 (s, 3H), 3.57 (dt, J = 11.2 Hz, J = 2.4 Hz, 1H), 3.25 - 3.10 (m, 1H), 3.01 (dd, J = 13.4 Hz, J = 11.2 Hz, 1 H)

Compound 2: (S) -2 - ((4- (5- Hydroxypyrimidine Yl) morpholin-2-yl) methyl ) -6- (1- methyl -1H- Pyrazole Yl) Pyridazine -3 (2H) -one

To a sealed tube was added a solution of (S) -2 - ((4- (5-bromopyrimidin-2-yl) morpholin- (2H) -one (200 mg, 0.46 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2' dioxaborane) (177 mg, 0.69 mmol), KOAc (182 mg, 1.9 mmol) and dppf (26 mg, 0.046 mmol) were dissolved in 1,4-dioxane , N ₂ (gas) were charged, and Pd (dppf) Cl ₂ (38 mg, 0.046 mmol) was added. Followed by stirring at 80 ° C for 12 hours. After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. After this, dissolved in _{H 2 O (1.6ml), THF} (1,6ml) into the NaBO ₃ (69mg, 0.6940mmol) was stirred for 4 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / MC = 7: 93) Yl) methyl) -6- (1-methyl-1H-pyrazol-4-yl) pyridazine-3 (2H) -one (50 mg, 30%) as a yellow solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ8.11 (s, 2H), 7.83 (s, 1H), 7.81 (s, 1H), 7.44 (d, J = 9.3 Hz, 1H), 7.49 (d, J = 9.3 Hz, 1H), 4.48-3.90 (m, 6H), 3.94 (s, 3H), 3.58 (t, J = 10.3 Hz, 1H), 3.07 (t, J = 10.3 Hz, 1H), 2.91 ( t, J = 10.3 Hz, 1H)

Compound 3: (S) -6- (1- methyl -1H- Pyrazole -4-yl) -2 - ((4- (5- (2- Morpholinoethoxy ) Pyrimidin-2-yl) morpholin-2-yl) methyl) Pyridazine -3 (2H) -one

( S ) -2 - ((4- (5-hydroxypyrimidin-2-yl) morpholin- -3 (2H) - one (12 mg, 0.032 mmol) was added to DMF (1ml), where the 4- (2-chloroethyl) morpholine hydrochloride (12 mg, 0.064 mol) and K ₂ CO ₃ (22 mg, 0.16 mmol) was added thereto, followed by stirring at 80 占 폚 for 9 hours. After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / MC = 1: 19) S) -6- (1 -methyl-1 H-pyrazol-4-yl) -2 - ((4- (5- (2-morpholinoethoxy) pyrimidin- Yl) methyl) pyridazin-3 (2H) -one (16 mg, 58%) as a yellow solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.09 (s, 2H), 7.79 (s, 1H), 7.75 (s, 1H), 7.39 (d, J = 9.4 Hz, 1H), 6.96 (d, J J = 4.4 Hz, 4H), 3.58 (dt, J = 8.4 Hz, 1H), 4.53-4.40 (m, 2H), 4.27-3.94 (m, 6H), 3.93 11.2 Hz, J = 1.9 Hz, 1H), 3.18 - 3.05 (m, 1H), 2.94 (dd, J = 13.0 Hz, J = 10.1 Hz, 1H), 2.74 (t, J = 5.4 Hz, 2H), 2.54 (t, J = 4.4 Hz, 4H)

Compound 4: (S) -6- (1- methyl -1H- Pyrazole Yl) -2 - ((4- (5- (4 - ((4- Methylpiperazine -1 day) methyl ) Phenyl ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one

Step 1 : (S) -4- (2- (2 - ((3- (1- methyl -1H- Pyrazole -4-yl) -6- Oxopyridazine -1 (6H) yl) methyl ) Morpolino ) Pyrimidin-5-yl) Of benzaldehyde  Produce

To a sealed tube was added ( S ) -2 - ((4- (5-bromopyrimidin-2-yl) morpholin- ) pyridazin -3 (2H) - one (30 mg, 0.069 mmol), (4- formylphenyl) Boro Nick acid (12 mg, 0.076 mmol), K 2 CO 3 (20 mg, 0.13 mmol) was dissolved in 1,4-dioxane (2 ml) / H ₂ O (1 ml), and then Pd (PPh ₃ ) ₄ (4 mg, 0.0035 mmol) Lt; / RTI > After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / MC = 1: 19) Yl) methyl) morpholino) pyrimidin-4-yl) - (2- (2- 5-yl) benzaldehyde (25 mg, 80%) as a brown solid.

^{1 H-NMR 300 MHz, CDCl} 3) δδ10.0 (s, 1H), 8.60 (s, 2H), 7.80 (s, 1H), 7.77 (s, 1H), 7.40 (d, J = 9.7 Hz, 1H ), 6.98 (d, J = 9.7 Hz, 1H), 4.48 (d, J = 14.3 Hz, 1H), 4.21 (dd, J = 13.4 Hz, J = 7.6 Hz, 1H) 3.60 (dt, J = 11.2 Hz , J = 2.4 Hz, 1H), 3.32-3.18 (m, 1H), 3.10 (dd, J = 13.4 Hz, J = 11.2 Hz, 1H)

Step 2 : (S) -6- (1- methyl -1H- Pyrazole Yl) -2 - ((4- (5- (4 - ((4- Methylpiperazine -1 day) methyl ) Phenyl ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one < / RTI >

(S) -4- (2- (2 - ((3- (1- methyl -1H- pyrazol-4-yl) -6-oxo-pyridazin -1 (6H) yl) methyl) morpholino) flutes 5-yl) benzaldehyde (32 mg, 0.069 mmol) was dissolved in CH ₂ Cl ₂ Was dissolved in (2ml), 1- methylpiperazine (16 u l, 0.13 mmol) , NaBH (OAc) 3 (23 mg, 0.10 mmol), AcOH was added to (5μl, 0.083 mmol), and stirred for 3 hours at room temperature Respectively. After completion of the reaction, the solution was adjusted to pH 8 with K ₂ CO ₃ (5%), and then extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. (S) -6- (1 -Methyl-1 H-pyrazol-4-yl) -2 - ((4- (5- (4- ( Yl) methyl) pyridazin-3 (2H) -one (8 mg, 21%) as a brown solid Respectively.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.55 (s, 2H), 7.82 (s, 1H), 7.78 (s, 1H), 7.45 - 7.36 (m, 5H), 6.99 (d, J = 6.9 Hz , 1H), 4.69 (d, J = 13.0 Hz, 1H), 4.53 (dd, J = 13.0 Hz, J = 8.2 Hz, 1H), 4.44 (d, J = 13.2 Hz, 1H), 4.24-4.00 (m , 4H), 3.95 (s, 3H), 3.62 (dt, J = 11.2 Hz, J = 1.9 Hz, 1H), 3.56 (s, 2H), 3.21 (m, 1H), 3.08 (dd, J = 13.2 Hz , J = 10.1 Hz, 1 H), 2.69 - 2.45 (m, 8 H), 2.36 (s,

Compound 5: (S) -3- (6-oxo-1 - ((4- (5- (1- (piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -1,6- Dihydropyridazine -3 days) Benzonitrile Hydrochloride

Step 1 : (S) - tert -Butyl 4- (4- (2- (2 - ((3- (3- Cyanophenyl ) -6- Oxopyridazine -1 (6H) -yl) methyl ) Morpolino ) Pyrimidin-5-yl) -1H- Pyrazole Yl) piperidin-l- Carboxylate  Produce

To a sealed tube was added ( S ) -2 - ((4- (5-bromopyrimidin-2-yl) morpholin- ) Pyridazin-3 (2H) -one (100 mg, 0.22 mmol), tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- (167 mg, 0.44 mol) and Cs ₂ CO ₃ (216 mg, 0.66 mmol) were dissolved in DME (3 ml) / H ₂ was added to a _{O (1ml), N 2 (} gas) after _{filling, Pd (PPh 3) 2 Cl} 2 was stirred for 3 hours at 80 ℃, insert a (16 mg, 0.022 mmol). After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / MC = 1: 19) ) - tert -butyl 4- (4- (2- (2- (3- (3-cyanophenyl) -6-oxopyridazin-1 (6H) -yl) methyl) morpholino) pyrimidine- Yl) piperidine-l-carboxylate (90 mg, 64%) as a yellow solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ8.44 (s, 2H), 8.13 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H) , 7.69 - 7.65 (m, 2H ), 7.61 - 7.55 (m, 2H), 7.09 (d, J = 9.7 Hz, 1H), 4.64 (d, J = 13.2 Hz, 1H), 4.58 (dd, J = 13.2 J = 7.9 Hz, 1H), 4.40 (d, J = 13.2 Hz, 1H), 4.29 (dd, J = 13.2 Hz, J = 4.4 Hz, 1H), 4.28-4.22 4.09 (m, 1H), 4.02 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.61 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.30-3.19 (m, 3H), 3.07 (dd, J = 13.0 Hz , J = 10.0 Hz, 1H), 2.79 (dt, J = 12.0 Hz, J = 2.0 Hz, 2H), 2.30-2.16 (m, 2H), 1.94 dt, J = 12.3 Hz , J = 3.9 Hz, 2H), 1.49 (s, 9H)

Step 2 : (S) -3- (6-Oxo-1 - ((4- (5- (1- (piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -1,6-di Hydropy Chladin-3-yl) Benzonitrile Of hydrochloride  Produce

( S ) -tert-butyl 4- (4- (2- (2- (3- (3-cyanophenyl) -6-oxopyridazin-1 (6H) -yl) methyl) morpholino) 1-carboxylate (33 mg, 0.052 mmol) was added to CH ₂ Cl ₂ and 1,4-dioxane (0.1 ml) was added, Was added 4N-HCl dissolved in dichloromethane and the mixture was stirred overnight. After completion of the reaction, CH ₂ Cl ₂ was concentrated and solidified with ether to give (S) -3- (6-oxo-1 - ((4- (5- (1- (piperidin- Yl) benzonitrile hydrochloride (22 mg, 90%) was obtained as yellow crystals in a yield of 20% It was obtained as a color solid.

^{1 H-NMR (300 MHz,} CDCl 3) δ 8.44 (s, 2H), 8.13 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.69 - 7.65 (m, 2H) , 7.61 - 7.55 (m, 2H), 7.09 (d, J = 9.7 Hz, 1H), 4.64 (d, J = 13.2 Hz, 1H), 4.58 (dd, J = 13.2 Hz J = 7.9 Hz, 1H), 4.40 (d, J = 13.2 Hz, 1H), 4.29 (dd, J = 13.2 Hz, J = 4.4 Hz, 1H), 4.28-4.22 (m, 1H), 4.02 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.61 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H) (dd, J = 13.0 Hz, J = 10.0 Hz, 1H), 2.79 (dt, J = 12.0 Hz, J = 2.0 Hz, 2H), 2.30 - 2.16 (m, 2H), 1.94 (dt, J = 12.3 Hz , ≪ / RTI > J = 3.9 Hz, 2H)

Compound 6: (S) -3- (6-Oxo-1 - ((4- (5- (1- (piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -1,6- Dihydropyridazine -3 days) Benzonitrile Hydrochloride

(S) -3- (6-oxo-1 - ((4- (5- (1- (piperidin- Yl) benzonitrile hydrochloride (57 mg, 0.0913 mmol) was dissolved in 35% HCHO (0.lml HCOOH (0.5 ml)), The mixture was stirred overnight at 95 ° C. The reaction mixture was adjusted to pH 10-11 with 2N Na ₂ CO ₃ , extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / MC = 1:15) to give (S) -3- (6-oxo-1 - ((4- (5- (1- (piperidin- Yl) benzonitrile hydrochloride (29 mg, 60%) was obtained as a yellow solid. 1H-NMR (400 MHz, CDCl3)?

^{1 H-NMR (300 MHz,} CDCl 3) δδ8.43 (s, 2H), 8.13 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H) , 7.68-7.65 (m, 2H), 7.60-7.55 (m, 2H), 7.08 (d, J = 9.7 Hz, 1H), 4.64 (d, J = 13.2 Hz, 1H), 4.58 (dd, J = 13.2 Hz, J = 7.9 Hz, 1H ), 4.29 (dd, J = 13.2 Hz, J = 8.8 Hz, 1H), 4.17-4.12 (m, 2H), 4.02 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.61 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.26-3.19 (m, 1H), 3.07 (dd, J = 13.0 Hz, J = 10.0 Hz, 1H), 3.05-2.96 ( m, 2H), 2.21-2.05 (m, 6H)

Compound 7: (S) -3- (1 - ((4- (5- (1- (2-hydroxyethyl) Tetrahydropyridine Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile

(S) -3- (6-oxo-1 - ((4- (5- (1,2,3,6-tetrahydropyridin-4-yl) pyrimidin- (0.14 ml, 1.9310 mmol), Et (3 ml) and DMF (3 ml) were added to a solution of 2- ₃ N into the (0.59ml, 4.2482mmol), K2CO3 ( 0.24g, 1.7379mmol) was stirred at 60 ^O C 3 hours. After completion of the reaction, the reaction mixture was extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / MC = 1:15) - (1 - ((4- (5- (1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4- yl) pyrimidin- Yl) methyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile (148 mg, 77%) as a yellow solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.36 (s, 2H), 8.12 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 9.7 Hz , 1H), 7.08 (d, J = 9.7 Hz, 1H), 5.97 - 5.94 (m, 1H), 4.64 (d, J = 13.0 Hz, 1H), 4.57 (dd, J = 8.0, J = 13.0 Hz, 1H), 4.40 (d, J = 13.0 Hz, 1H), 4.28 (dd, J = 4.3 Hz, J = 13.0 Hz, 1H), 4.15 - 4.09 (m, 1H), 4.02 (dt, J = 2.6 Hz, J = 11.3 Hz, 1H), 3.70 (t, J = 5.3 Hz, 1H), 3.59 (dt, J = 2.6 Hz, J = 11.3 Hz, 1H), 3.23 (d, J = 2.4 Hz, 2H), 3.22 - 3.18 (m, 1H), 3.06 (dd, J = 10.0 Hz, J = 13.0 Hz, 1H), 2.80 (t, J = 5.3 Hz, 2H), 2.69 (t, J = 5.3 Hz, 2H), 2.52-2.48 (m, 1H)

Compound 8: (S) -3- (1 - ((4- (5- (6- Fluoropyridine Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile

To a sealed tube was added a solution of (S) -3- (1 - ((4- (5-bromopyrimidin-2-yl) morpholin-2-yl) methyl) -6-oxo-1,6-dihydropyridazine (19 mg, 0.1324 mmol) and Cs ₂ CO ₃ (54 mg, 0.1655 mmol) were dissolved in DME (2 ml), and the mixture was stirred at room temperature for ₃ hours. / H ₂ was dissolved in _{O (0.5ml), N 2 (} gas) Pd (dppf) and then charged ₂ Cl ₂ (4.5mg, 0.0055mmol) were put and stirred at 80 ^O C 4 hours. After completion of the reaction, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by chromatography (MeOH / MC = 1:15) Yl) methyl) -6-oxo-1,6-di (pyridin-2-yl) Yl) benzonitrile (36 mg, 70%) as a white solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.51 (s, 2H), 8.32 (s, 1H), 8.14 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.87 (dt, J = 2.7 Hz, J = 7.8 Hz , 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 9.7 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.09 ( d, J = 9.7 Hz, 1H ), 7.02 (dd, J = 2.7 Hz, J = 8.1 Hz, 1H), 4.721 (d, J = 7.8 Hz, 1H), 7.67 Hz, 1 H), 5.3Hz, 1H ), 7.58 (t, J = 781 (d, J = 7.8 Hz, 1H), 7.3.8 H, 1 H), 7.02 (dd, J = 2.7 Hz, J = 8.17Hz, 1H), 4.721 (d, J = 7.8 Hz, 1H), 7.6 7 Hz, 1H), 5.1H), 3.62 (dt, J = 2.7 Hz, J = 11.3 Hz, 1H), 3.31 - 3.24 (m, 1H), 3.12 (dd, J = 10.0 Hz, 13.0 Hz, 1 H)

Compound 9: (S) -3- (1 - ((4- (5- (6- (4- Methylpiperazine Yl) pyridin-3-yl) pyrimidin-2-yl) morpholin- methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile

To a sealed tube was added a solution of (S) -3- (1- (4- (5- (6-fluoropyridin-3- yl) pyrimidin- Dihydropyridazin-3-yl) benzonitrile (20 mg, 0.0426 mmol) was dissolved in NMP and then 1-methylpiperazine (0.010 ml, 0.0852 mmol), diaPEA (0.023 ml, 0.1278 mmol) And the mixture was stirred overnight at 150 ° C. After the reaction was completed, the reaction mixture was extracted with water and CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by chromatography (MeOH / MC = 1:20) Yl) morpholin-2-yl) methyl) - (2-methyl-pyridin- Oxo-1,6-dihydropyridazin-3-yl) benzonitrile (10 mg, 43%) as a yellow solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ8.48 (s, 2H), 8.23 (s, 1H), 8.13 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.73-7.64 ( J = 7.7 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 4.67 (d, J = 13.0 Hz, 1H) 4.54 (dd, J = 13.0 Hz , J = 8.1 Hz, 1H), 4.43 (d, J = 13.0 Hz, 1H), 4.28 (dd, J = 13.0 Hz, J = 9.6 Hz, 1H), 4.20-4.10 ( m, 1H), 4.03 (d , J = 11.2 Hz, 1H), 3.61 (m, 5H), 3.24 (t, J = 11.2 Hz, 1H), 3.08 (t, J = 11.2 Hz, 1H), 2.55 ( m, 4 H), 2.36 (s, 3 H)

Compound 10: (S) -3- (1 - ((4- (5- (6- (2- Morpholinoethoxy ) Pyridin-3-yl) pyrimidin-2-yl) morpholin- methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile

NaH (60%, 2 mg, 0.0480 mmol) was dissolved in THF (1 ml) at 0 ° C under nitrogen charging, and then slowly added. After 20 minutes, 2-morpholinoethanol (0.005 ml, 0.0384 mol) was dissolved in THF (1 ml) and NaH (60%, 2 mg, 0.0480 mmol) was slowly added to THF (1 ml) at 0 ° C. Yl) methyl) -6- (3-fluoropyridin-3-yl) pyrimidin- Dihydro-pyridazin-3-yl) benzonitrile (15 mg, 0.0320 mmol) was dissolved in THF (1 ml), and the mixture was stirred at rt for 3 hours. After putting neutralizing NaH a NaBCO _3, water and CH ₂ Cl ₂ extracts, dried over (Na ₂ SO _4), filtered and concentrated under reduced pressure and the residue tube chromatography (MeOH / MC = 1: 20 ) To give (S) -3- (1 - ((4- (5- (6- (2-morpholinoethoxy) pyridin-3- yl) pyrimidin- ) Methyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile (9.2 mg, 50%) as a yellow solid.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.48 (s, 2H), 8.24 (s, 1H), 8.13 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.73-7.61 (m , 3H), 7.60-7.55 (m, 1H), 7.09 (d, J = 9.7 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.69 (d, J = 13.0 Hz, 1H), 4.56 (dd, J = 13.0 Hz, J = 8.2 Hz, 1H), 4.47 (t, J = 5.7 Hz, 2H), 4.46-4.42 (m, 1H), 4.29 (dd, J = 13.0 Hz, J = 9.3 Hz J = 11.2 Hz, 1H), 3.74 (t, J = 4.3 Hz, 4H), 3.61 (dt, J = 11.2 Hz, J = 1.9 Hz, , 1H), 3.09 (dd, J = 13.0 Hz, J = 10.1 Hz, 1H), 2.81 (t, J = 5.7 Hz, 2H), 2.62 - 2.56 (m, 4H)

Compound 11: (S) -3- (1 - ((4- (5- (1- (1- (2-Hydroxyethyl) piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile

(S) -3- (1 - ((4- (5- (1- (2-hydroxyethyl) -1,2,3,6-tetrahydropyridin-4-yl) pyrimidin- Morpholin-2-yl) methyl) -6-oxo-1,6-dihydropyridazin-3-yl) benzonitrile. Yellow solids (77%) were obtained.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.44 (s, 2H), 8.13 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.68 -7.64 (m, 2H ), 7.60 - 7.55 (m, 2H), 7.08 (d, J = 9.7 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.50 (dd, J = 13.2 Hz, J = 7.9 Hz, 1H ), 4.40 (d, J = 13.2 Hz, 1H), 4.29 (dd, J = 13.2 Hz, J = 4.4 Hz, 1H), 4.22 - 4.09 (m, 3H), 4.02 (dt, J = 11.2 Hz, J = 2.5 Hz, 1H), 3.26 - 3.19 (m, 1H), 3.10 - 3.04 (m, 3H), 2.60 (t, J = 5.3 Hz, 2H), 2.28 (dt, J = 11.2 Hz, J = 1.8 Hz , 2H), 2.23-2.16 (m, 2H), 2.14-2.06 (m, 2H)

_{C 25 H 28 FN 9 O 2} LCMS calculated value = 505.23, observed value: 505.8

Compound 12: (S) -6- (3-Fluorophenyl) -2 - ((4- (5- (1- (piperidin- Yl) morpholin-2-yl) methyl) pyridazin-3 (2H)

Step 1: 3- Chloro -6- (3- Fluorophenyl ) Pyridazine

Of 3,6-dichloropyridazine 100mg (0.671mmol) were dissolved in dioxane of phenyl 3-fluoro beam was dissolved in 3 ml H2O and 1ml Nick acid 115mg (0.738 mmol) and _{K 2 CO 3 140 mg (1.006} mmol), Pd (dppf) ₂ Cl ₂ 27 mg (0.033 mmol) were added to the solution, and the mixture was stirred at 90 ° C for 3 hours. After the reaction, the mixture was extracted with MC and K ₂ CO ₃ (aq), and the organic layer was dried with MgSO ₄ . The residue was separated by column chromatography (hexane: ethyl acetate = 2: 3) to obtain 114 mg (81%).

LCMS calculated for C ₁₀ H ₆ ClFN ₂ = 208.02, observed: 209.1

Step 1 -2: 3- Chloro -6- (3- Chlorophenyl ) Pyridazine

141mg (93%)

141 mg (93%)

LCMS calculated for C ₁₀ H ₆ Cl ₂ N ₂ = 223.99, observed = 224.9

Step 1 -3: 3- Chloro -6- (3- Chloro -4- Fluorophenyl ) Pyridazine

143mg (88%)

143 mg (88%)

C ₁₀ H ₆ Cl ₂ LCMS calculated value of the FN ₂ = 241.98, observed value: 242.8

Step 1 -4: 3- Chloro -6- (3- ( Trifluoromethyl ) Phenyl ) Pyridazine

131mg (76%)

131 mg (76%)

LCMS calculated for C ₁₁ H ₆ ClF ₃ N ₂ = 258.02, observed: 259.0

Step 1 -5. 3- Chloro -6- (pyridin-3-yl) Pyridazine

78mg (61%)

78 mg (61%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 9.20 (d, J = 1.8Hz, 1H), 8.76 (d, J = 3.9Hz, 1H), 8.46 (m, 1H), 7.89 (d, J = 9.0 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.49 (m,

Step 1-6. 3- Chloro -6- (pyridin-4-yl) Pyridazine

52mg (41%)

52 mg (41%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.81 (d, J = 5.5Hz, 2H), 7.95 (d, J = 5.5Hz, 2H), 7.92 (d, J = 9.0Hz, 1H), 7.67 ( d, J = 9.0 Hz, 1H)

Step 1-7. 3- Chloro -6- (3,4- Difluorophenyl ) Pyridazine

126mg (83%)

126 mg (83%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 7.96 (m, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.7Hz, 1H), 7.59 (d, J = 9.0Hz, 1H)

LCMS calculated for C ₁₀ H ₅ ClF ₂ N ₂ = 226.01, observed = 227.0

Step 1-8. 3- Chloro -6- (3,4,5- Trifluorophenyl ) Pyridazine

183mg (93%)

183 mg (93%)

¹ H-NMR (300 MHz, CDCl ₃ )?? 7.77 (m, 1H), 7.63 (d, J = 8.9 Hz,

Step 2-1. 6- (3- Fluorophenyl ) Pyridazine -3 (2H) -one

109 mg (0.522 mmol) of 3-chloro-6- (3-fluorophenyl) pyridazine was dissolved in 2 ml of acetic acid, which was then charged with nitrogen and stirred at 120 ° C for 4 hours. After the reaction, the acetic acid was concentrated under reduced pressure, and when solidified, washed with 20 ml of H 2 O (* 3) to obtain 83 mg (83%) of a pink solid.

^{1 H-NMR (300 MHz,} MeOD 4) δδ8.16 (s, 1H), 7.94 (d, J = 9.8Hz, 1H), 7.39 (dd, J = 14.1Hz, J = 8.1Hz, 1H), 7.21 (m, IH), 7.09 (m, IH), 6.96 (d, J = 9.8 Hz, IH)

Step 2-2. 6- (3- Chlorophenyl ) Pyridazine -3 (2H) -one

106mg (88%)

106 mg (88%)

^{1 H-NMR (300 MHz,} MeOD 4) δδ 8.14 (d, J = 15.7Hz, 1H), 7.94 (d, J = 9.9Hz, 1H), 7.81 (s, 1H), 7.70 (m, 1H), 7.47 (m, 1 H), 6.97 (d, J = 9.9 Hz, 1 H)

Step 2-3. 6- (3- Chloro -4- Fluorophenyl ) Pyridazine -3 (2H) -one

118mg (93%)

118 mg (93%)

^{1 H-NMR (300 MHz,} MeOD 4) δδ 8.22 (dd, J = 7.1, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.35 (t, J = 8.8, 8.8 Hz, 1H), 7.25 (t, J = 8.8, 8.8 Hz, IH), 6.96 (d, J = 9.9 Hz, IH)

Step 2-4. 6- (3- ( Trifluoromethyl ) Phenyl ) Pyridazine -3 (2H) -one

89mg (82%)

89 mg (82%)

^{1 H-NMR (300 MHz,} MeOD 4) δδ 8.40 (s, 1H), 8.30 (d, J = 7.0 Hz, 1H), 8.26 (m, 1H), 7.74 (s, 1H), 6.98 (d, J = 9.8 Hz, 1 H)

Step 2-5. 6- (4- Fluorophenyl ) Pyridazine -3 (2H) -one

90mg (99%)

90 mg (99%)

^{1 H-NMR (300 MHz,} Aceton-d 6) δδ 8.19 (m, 1H), 7.81 (m, 2H), 7.22 (t, J = 8.6Hz, 1H), 7.12 (t, J = 8.6Hz, 1H ), 6.84 (d, J = 9.9 Hz 1H)

Step 2-6. 6- (3,5- Difluorophenyl ) Pyridazine -3 (2H) -one

75mg (81%)

75 mg (81%)

^{1 H-NMR (300 MHz,} Aceton-d 6) δδ 7.92 (d, J = 9.9Hz, 1H), 7.42 (d, J = 7.2Hz, 2H), 6.99 (m, 1H), 6.88 (d, J = 10.2 Hz, 1H)

Step 2-7. 6- (pyridin-3-yl) Pyridazine -3 (2H) -one

105mg (71%)

105 mg (71%)

^{1 H-NMR (300 MHz,} D 2 O) δδ 8.98 (s, 1H), 8.58 (s, 2H), 7.94 (d, J = 9.9Hz, 1H), 7.78 (s, 1H), 7.07 (d, J = 9.9 Hz, 1H)

Step 2-8. 6- (Pyridin-4-yl) Pyridazine -3 (2H) -one

100mg (83%)

100 mg (83%)

^{1 H-NMR (300 MHz,} D 2 O) δδ 8.64 (d, J = 4.5Hz, 2H), 8.22 (d, J = 4.5Hz, 2H), 8.05 (dd, J = 9.9Hz, J = 1.9Hz , 1 H), 7.07 (dd, J = 9.9 Hz, J = 1.9 Hz, 1 H)

Step 2-9. 6- (3,4- Difluorophenyl ) Pyridazine -3 (2H) -one

95mg (86%)

95 mg (86%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 7.96 (m, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.7Hz, 2H), 7.59 (d, J = 9.0Hz, 2H)

Step 2-10. 6- (3,4,5- Trifluorophenyl ) Pyridazine -3 (2H) -one

157mg (98%)

157 mg (98%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 7.66 (d, J = 9.9 Hz, 1H), 7.44 (m, 2H), 7.10 (d, J = 9.9 Hz, 1H)

Step 3-1. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3- Fluorophenyl ) Pyridazine -3 (2H) -one

(0.116 mmol) of methyl (4-methylbenzenesulfonate) was dissolved in 1.5 ml of dimethylformamide, and a solution of 6- ( 25 mg (0.128 mmol) of Cs ₂ CO _{3 and} 45 mg (0.139 mmol) of Cs ₂ CO ₃ were added to the flask and stirred at 50 ° C for 4 hours. After the reaction, the mixture was extracted with EA and brine, and the organic layer was dried with MgSO ₄ . The residue was separated by column chromatography (hexane: ethyl acetate = 1: 2) to obtain 28 mg (54%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.30 (s, 2H), 7.66 (d, J = 9.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.43 (d, J = 6.0 2H), 4.34 (d, J = 13.2 Hz, 1H), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H) 4.10 (m, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.57 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.19 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H)

Step 3-2. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3- Chlorophenyl ) Pyridazine -3 (2H) -one

24mg (44%)

24 mg (44%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.29 (s, 2H), 7.80 (s, 1H), 7.65 (d, J = 9.6 Hz, 2H), 7.39 (d, J = 4.8 Hz, 2H), 7.05 (d, J = 9.6 Hz , 1H), 4,56 (m, 1H), 4.33 (d, J = 13.2 Hz, 1H), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H), 4.10 (m, 1H), 4.01 (d, J = 11.7 Hz, 1H), 3.58 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.20 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H)

Step 3-3. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3- Chloro -4- Fluorophenyl ) Pyridazine -3 (2H) -one

35mg (63%)

35 mg (63%)

¹ H-NMR (300 MHz, CDCl ₃ )?? 8.23 (s, 2H), 7.79 (dd, J = 6.9 Hz, J = 2.1 Hz, 1H), 7.56 6.97 (d, J = 9.9 Hz , 1H), 4,56 (m, 1H), 4.33 (d, J = 13.2 Hz, 1H), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H), 4.10 (m, 1H), 4.01 (d, J = 11.7 Hz, 1H), 3.50 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.20 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H)

Step 3-4. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3- ( Trifluoromethyl ) Phenyl ) Pyridazine -3 (2H) -one

29mg (53%)

29 mg (53%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.29 (s, 2H), 8.04 (m, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.69 (m, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 9.6 Hz, 1H), 4,55 (m, 2H), 4.34 (d, J = 13.2 Hz, 1H), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H), 4.10 (m, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.57 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.19 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H)

Step 3-5. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (4- Fluorophenyl ) Pyridazine -3 (2H) -one

48mg (93%)

48 mg (93%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.30 (s, 2H), 7.71 (dd, J = 5.1 Hz, J = 2.1 Hz, 2H), 7.66 (d, J = 9.6 Hz, 1H), 7.14 ( t, J = 8.7Hz, 2H) , 7.04 (d, J = 9.6 Hz, 1H), 4,55 (m, 2H), 4.34 (d, J = 13.2 Hz, 1H), 4.23 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H ), 4.10 (m, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.57 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.19 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H)

Step 3-6. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3,5- Difluorophenyl ) Pyridazine -3 (2H) -one

45mg (84%)

45 mg (84%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.31 (s, 2H), 7.58 (d, J = 9.6 Hz, 1H), 7.33 (dd, J = 8.4Hz, J = 2.1 Hz 2H), 7.06 (d , J = 9.6 Hz, 1H) , 6.87 (tt, J = 8.7 Hz, J = 2.4 Hz, 1H), 4,55 (m, 2H), 4.34 (d, J = 13.5 Hz, 1H), 4.25 (dd , J = 13.2 Hz, J = 4.5 Hz, 1H), 4.09 (m, 1H), 4.01 (m, 1H), 3.58 (dt, J = 11.4 Hz, J = 3.0 Hz, 1H), 3.20 (m, 1H ), 3.07 (dd, J = 13.2 Hz, J = 9.6 Hz, 1H)

Step 3-7. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (pyridin-3-yl) Pyridazine -3 (2H) -one

42mg (72%)

42 mg (72%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 9.06 (s, 1H), 8.56 (m, 1H), 8.29 (s, 2H), 7.78 (dd, J = 5.1 Hz, J = 2.1Hz, 1H), 7.66 (d, J = 9.6 Hz , 1H), 7.45 (m, 1H), 7.04 (d, J = 9.6 Hz, 1H), 4,55 (m, 2H), 4.34 (d, J = 13.2Hz, 1H ), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H), 4.10 (m, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.57 (dt, J = 11.4 Hz, J = 2.7 1H), 3.19 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H)

Step 3-8. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (pyridin-4-yl) Pyridazine -3 (2H) -one

37mg (65%)

37 mg (65%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.74 (m, 2H), 8.29 (s, 2H), 8.05 (m, 2H), 7.77 (s, 1H), 7.80 (d, J = 9.6 Hz, 1H ), 7.15 (d, J = 9.6 Hz, 1H), 4,55 (m, 2H), 4.34 (d, J = 13.2 Hz, 1H), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H ), 4.10 (m, 1H) , 4.03 (d, J = 11.4 Hz, 1H), 3.57 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.19 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1 H)

Step 3-9. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3,4- Difluorophenyl ) Pyridazine -3 (2H) -one

61mg (82%)

61 mg (82%)

¹ H-NMR (300 MHz, CDCl ₃ )?? 8.29 (s, 2H), 7.76 (s, 2H), 7.62 (d, J = 9.6 Hz, ), 7.05 (d, J = 9.6 Hz, 1H), 4,55 (m, 2H), 4.34 (d, J = 13.2 Hz, 1H), 4.24 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H ), 4.10 (m, 1H) , 4.03 (d, J = 11.4 Hz, 1H), 3.57 (dt, J = 11.4 Hz, J = 2.7 Hz, 1H), 3.19 (m, 1H), 3.04 (dd, J = 10.2 Hz, J = 3.0 Hz, 1 H)

Step 3-10. (S) -2 - ((4- (5- Bromopyrimidine Yl) morpholin-2-yl) methyl ) -6- (3,4,5- Trifluorophenyl ) Pyridazine -3 (2H) -one

80 mg (75%)

80 mg (75%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.31 (s, 2H), 7.52 (m, 1H), 7.44 (m, 2H), 7.06 (d, J = 9.6 Hz, 1H), 4,55 (m 2H), 4.34 (d, J = 13.5 Hz, 1H), 4.25 (dd, J = 13.2 Hz, J = 4.5 Hz, 1H), 4.09 , J = 11.4 Hz, J = 3.0 Hz, 1H), 3.20 (m, 1H), 3.07 (dd, J = 13.2 Hz, J = 9.6 Hz, 1H)

Step 4-1. (S) - tert -Butyl 4- (4- (2- (2 - ((3- (3- Fluorophenyl ) -6- Oxopyridazine -1 (6H) -yl) methyl ) Morpolino ) Pyrimidin-5-yl) -1H- Pyrazole Yl) piperidin-l- Carboxylate

Yl) methyl) -6- (3-fluorophenyl) pyridazin-3 (2H) -one To a solution of (S) -2 - ((4- (5- bromopyrimidin- (0.116 mmol) were dissolved in 1.5 ml of tetrahydrofuran and 1 ml of distilled water. To the mixture was added tert-butyl 4- (4- (4,4,5,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl) -1H- pyrazol-1-yl) piperidine-1-carboxylate 66mg (0.175 mmol) and _{Na 2 CO 3 46 mg (0.350} mmol), Pd (pph) 3 Cl 2 3.6 mg (0.003 mmol) were added. After charging with nitrogen, the mixture was stirred at 80 ^° C for 2 hours. After the reaction, the mixture was extracted with EA and brine, and the organic layer was dried with MgSO ₄ . The residue was separated by column chromatography (hexane: ethyl acetate = 1: 2) to obtain 86 mg (119%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.43 (s, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.58 (s, 2H), 7.54 (s, 1H), 7.43 (m, 1H ), 7.10 (m, 2H) , 4,60 (m, 2H), 4.42 (d, J = 13.8 Hz, 2H), 4.29 (d, J = 4.2 Hz, 2H), 4.25 (d, J = 4.2 Hz (D, J = 13.2 Hz, J = 10.2 Hz, 1H), 2.16 (d, , J = 11.7 Hz, 2H), 1.96 (m, 4H), 1.48 (s, 9H)

Step 5. Synthesis of (S) -6- (3- Fluorophenyl ) -2 - ((4- (5- (1- (piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) - On HCl  Salt form

(S) -tert-butyl 4- (4- (2- (2- (3- (3-fluorophenyl) -6-oxopyridazin- 1 (6H) -yl) methyl) morpholino) Yl) piperidine-1-carboxylate (30 mg, 0.048 mmol) was dissolved in 3 ml of methylene chloride, and then dissolved in 3 ml (excess) of 1,4-dioxane 4M HCl was added, and the mixture was stirred at room temperature for 18 hours. After the reaction, methylene chloride and dioxane were concentrated under reduced pressure to obtain 19 mg (72%) of a yellow solid.

LCMS calculated for C ₂₇ H ₂₉ FN ₈ O ₂ = 516.24, observed = 516.7 (free molecular weight)

Compound 13: (S) -6- (3- Chlorophenyl ) -2 - ((4- (5- (1- (piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) - On HCl  Salt form

15 mg (80%)

15 mg (80%)

LCMS calculated for C ₂₇ H ₂₉ ClN ₈ O ₂ = 532.21, observed = 532.8 (molecular weight in free form)

Compound 14: (S) -6- (3- Chloro -4- Fluorophenyl ) -2 - ((4- (5- (1- (piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) - On HCl  Salt form

31 mg (96%)

31 mg (96%)

LCMS calculated value for C ₂₇ H ₂₈ ClFN ₈ O ₂ = 550.2, observation = 550.8 (molecular weight in free form)

Compound 15: (S) -2 - ((4- (5- (1- (Piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (3- Methyl difluoromethyl ) Phenyl ) Pyridazine -3 (2H) - On HCl  Salt form

11 mg (67%)

11 mg (67%)

_{C 28 H 29 F 3 N 8} O calculated value = 566.24, observed LCMS value of ₂ = 566.8 (free form of the molecular weight)

Compound 16: S) -6- (4- Fluorophenyl ) -2 - ((4- (5- (1- (piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) - On HCl  Salt form

13mg (94%)

13 mg (94%)

LCMS value for C ₂₇ H ₂₉ FN ₈ O ₂ = 516.24, observed = 516.8 (molecular weight in free form)

Compound 17: (S) -6- (3,5- Difluorophenyl ) -2 - ((4- (5- (1- (piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) - On HCl  Salt form

18mg (55%)

18 mg (55%)

LCMS calculated for C ₂₇ H ₂₈ F ₂ N ₈ O ₂ = 534.23, observed = 534.8 (molecular weight in free form)

Compound 18: (S) -2 - ((4- (5- (1- (Piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (pyridin-3-yl) Pyridazine -3 (2H) -one HCl  Salt form

38 mg (95%)

38 mg (95%)

LCMS value of C ₂₆ H ₂₉ N ₉ O ₂ = 499.24, observed value = 499.8 (molecular weight in free form)

Compound 19: (S) -2 - ((4- (5- (1- (Piperidin-4- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (pyridin-4-yl) Pyridazine -3 (2H) -one HCl  Salt form

21 mg (79%)

21 mg (79%)

LCMS value of C ₂₆ H ₂₉ N ₉ O ₂ = 499.24, observed value = 499.7 (molecular weight in free form)

Compound 20: (S) -2 - ((4- (5- (1- (Piperidin-4-yl) Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (3,4,5-tri Reflux Phenyl) Pyridazine -3 (2H) -one HCl  Salt form

8mg (36%)

8 mg (36%)

LCMS calculated value for C ₂₇ H ₂₇ F ₃ N ₈ O ₂ = 552.22, observed value = 522.8

Compound 21: (S) -6- (3- Fluorophenyl ) -2 - ((4- (5- (1- (1- Methylpiperidine -4-yl) -1H- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one

(S) -tert-butyl 4- (4- (2- (2- (3- (3-fluorophenyl) -6-oxopyridazin- (0.090 mmol) was dissolved in 0.1 ml of 35% formaldehyde and 0.5 ml of formic acid, and after charging with nitrogen, the solution was heated to 90 [deg.] C Lt; / RTI > for 18 hours. After the reaction, the reaction mixture was cooled to about pH 10 with an NaOH solution in an ice bath, extracted with EA and brine, and dried over MgSO ₄ . The residue was separated by column chromatography (methylene chloride: methanol = 10: 1) to obtain 18 mg (36%)

C ₂₈ H ₃₁ LCMS calculated value of FN ₈ O ₂ = 530.26, observed value = 530.8

Compound 22: (S) -6- (3- Chloro -4- Fluorophenyl ) -2 - ((4- (5- (1- (1- Methylpiperidine -4-yl) -1H- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one

Compound 23: (S) -2 - ((4- (5- (1- (1- Methylpiperidine -4-yl) -1H- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (pyridin-3-yl) Pyridazine -3 (2H) -one

15 mg (32%)

15 mg (32%)

LCMS calculated value C ₂₇ H ₃₁ N ₉ O ₂ = 513.26, observed = 513.8

Compound 24: (S) -2 - ((4- (5- (1- (1- Methylpiperidine -4-yl) -1H- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (pyridin-4-yl) Pyridazine -3 (2H) -one

9 mg (22%)

9 mg (22%)

LCMS calculated for C ₂₇ H ₃₁ N ₉ O ₂ = 513.26, observed = 513.6

Compound 25: (S) -6- (3,4- Difluorophenyl ) -2 - ((4- (5- (1- (1- Methylpiperidine -4-yl) -1H- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one

2 mg (21%)

2 mg (21%)

_{C 28 H 30 F 2 N 8} O LCMS calculated value of ₂ = 548.25, observed value = 548.7

Compound 26: (S) -2 - ((4- (5- (1- (1- Methylpiperidine -4-yl) -1H- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (3,4,5-tri Reflux Orophenyl) Pyridazine -3 (2H) -one

9 mg (29%)

9 mg (29%)

^{1 H-NMR (500 MHz,} CDCl 3) δδ8.43 (s, 2H), 7.67 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 9.5 Hz, 2H) , 7.07 (d, J = 9.9 Hz, 1H), 4,65 (m, 1H), 4.58 (dd, J = 13.0 Hz, J = 7.5 Hz, 1H), 4.42 (d, J = 14.0 Hz, 1H) 1H), 3.10 (m, 1H), 3.63 (dt, J = 11.0 Hz, J = 2.5 Hz, 1H) J = 13.5 Hz, J = 10.0 Hz, 1H), 2.92 (s, 2H), 2.18 (d, J = 13.0 Hz, 2H), 1.97 (m, 2H)

_{C 28 H 29 F 3 N 8} O LCMS calculated value of ₂ = 566.24, observed value = 566.7

Compound 27: (S) -6- (3- Fluorophenyl ) -2 - ((4- (5- (1- (1- (2-hydroxyethyl) piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one

(S) -6- (3-Fluorophenyl) -2 - ((4- (5- (1- (piperidin- (0.271 mmol) of 2-bromoethanol and 75 mg (0.540 mmol) of K ₂ CO ₃ were dissolved in 5 ml of dimethylformamide, mmol) were added. After charging with nitrogen, the mixture was stirred at 60 ^° C for 4 hours. After the reaction, the dimethylformamide was concentrated under reduced pressure, extracted with EA and brine, and the organic layer was dried with MgSO ₄ . The residue was separated by column chromatography (methylene chloride: methanol = 10: 1) to obtain 56 mg (55%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.43 (s, 2H), 7.66 (d, J = 9.6 Hz, 2H), 7.57 (m, 3H), 7.42 (m, 1H), 7.13 (m, 1H ), 7.06 (d, J = 9.6 Hz, 1H), 4.60 (d, J = 13.5 Hz, 1H), 4.55 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 13.5 Hz, 1H), 4.29 (d, J = 4.2 Hz , 1H), 4.25 (d, J = 4.2 Hz, 1H), 4.17 (m, 2H), 4.03 (d, J = 11.7 Hz, 1H), 3.75 (m, 1H), 3.65 (t, J = 5.1 Hz , 2H), 3.49 (s, 2H), 3.23 (m, 1H), 3.07 (m, 3H), 2.62 (t, J = 5.1 Hz, 2H), 2.30 (m, 2H )

Compound 28: (S) -6- (3- Chloro -4- Fluorophenyl ) -2 - ((4- (5- (1- (1- (2-hydroxyethyl) piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2H) -one

7 mg (35%)

7 mg (35%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.43 (s, 2H), 7.88 (dd, J = 7.2 Hz, J = 2.4 Hz, 1H), 7.66 (d, J = 9.6 Hz, 2H), 7.60 ( d, J = 4.8 Hz, 2H ), 7.21 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 9.6 Hz, 1H), 4.60 (d, J = 13.5 Hz, 1H), 4.55 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 13.5 Hz, 1H), 4.29 (d, J = 4.2 Hz, 1H), 4.25 (d, J = 4.2 Hz, 1H), 4.17 (m, 2H) , 4.03 (d, J = 11.7 Hz, 1H), 3.75 (m, 1H), 3.65 (t, J = 5.1 Hz, 2H), 3.61 (m, 1H), 3.23 (m, 1H), 3.07 (m, 3H), 2.62 (t, J = 5.1 Hz, 2H), 2.30 (m, 2H)

Compound 29: (S) -2 - ((4- (5- (1- (1- (2-Hydroxyethyl) piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (pyridin-3-yl) Pyridazine -3 (2H) -one

5 mg (12%)

5 mg (12%)

C ₂₈ H ₃₃ N ₉ LCMS calculated value of O ₃ = 543.27, observed value = 542.9

Compound 30: (S) -2 - ((4- (5- (1- (1- (2-Hydroxyethyl) piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (pyridin-4-yl) Pyridazine -3 (2H) -one

8 mg (30%)

8 mg (30%)

C ₂₈ H ₃₃ N ₉ LCMS calculated value of O ₃ = 543.27, observed value = 542.9

Compound 31: (S) -2 - ((4- (5- (1- (1- (2-Hydroxyethyl) piperidin- Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (3,4,5- Trifluorophenyl ) Pyridazine -3 (2H) -one

8 mg (29%)

8 mg (29%)

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.43 (s, 2H), 7.67 (s, 1H), 7.58 (d, J = 9.3 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.06 (d, J = 9.6 Hz , 1H), 4.60 (d, J = 13.5 Hz, 1H), 4.55 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 13.5 Hz, 1H), 4.29 ( d, J = 4.2 Hz, 1H ), 4.25 (d, J = 4.2 Hz, 1H), 4.17 (m, 2H), 4.03 (d, J = 11.7 Hz, 1H), 3.75 (m, 1H), 3.65 ( t, J = 5.1 Hz, 2H ), 3.61 (m, 1H), 3.23 (m, 1H), 3.07 (m, 3H), 2.62 (t, J = 5.1 Hz, 2H), 2.30 (m, 2H)

Compound 32: 6- (1- methyl -One H - Pyrazole -4-yl) -2 - ((4- (5- (2- (4- Methylpiperazine -1 day) Ethoxy ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2 H ) -One

Yl) methyl) -6- (1 -methyl-1 H -pyrazol-4-yl) morpholin- 20 mg (0.0463 mmol) of pyridazin-3 (2 H ) -one was dissolved in 1 ml of DMF, and 18.5 mg (0.185 mmol) of 1-methylpiperazine and 8.5 mg (0.0509 mmol) of KI were added thereto. The mixture was stirred at 70 ° C overnight. After the reaction was completed, the reaction mixture was extracted several times with ethyl acetate and brine, and the organic layer was dried with Na ₂ SO ₄ . Separation into Prep LC under 5% MeOH / MC gave 13 mg (56%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.10 (s, 2H), 7.81 (s, 1H), 7.76 (s, 1H), 7.40 (d, J = 9.4Hz, 1H), 6.97 (d, J J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.60 (dt, J = 11.2, 2.5Hz, 1H), 3.18-3.08 (m, 1H), 2.97 (dd, J = 13.0, 10.1Hz, 1H), 2.78 (t, J = 5.4Hz, 2H), 2.62-2.52 (m, 7H ), 2.32 (s, 3H), 2.03 - 1.96 (m, 4H)

Compound 33: 2 - ((4- (5- (2- (dimethylamino) Ethoxy ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (1- methyl -One H - Pyrazole Yl) Pyridazine -3 (2 H ) -One

Yl) methyl) -6- (1 -methyl-1 H -pyrazol-4-yl) pyridazine-3 ( 2 H) - one 20 mg (0.0541 mmol) and 2- (dimethylamino) acetate hydrochloride, 23 mg (0.162 mmol), Cs 2 CO 3 22 mg (0.162 mmol), KI 9 mg (0.0541 mmol) 1 ml of DMF . After the reaction was completed at 90 ° C overnight, the reaction mixture was extracted several times with ethyl acetate and brine, and the organic layer was dried over Na ₂ SO ₄ . Separation into Prep LC under 10% MeOH / MC gave 16.6 mg (70%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.12 (s, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.40 (d, J = 9.4Hz, 1H), 6.98 (d, J (M, 3H), 4.02 (t, J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.67-3.64 1H) 3.60 (dt, J = 11.2, 2.5Hz, 1H), 3.17-3.08 (m, 1H), 2.96 (dd, J = 13.0, 10.1Hz, 1H), 2.70 (t, J = 5.4Hz, 2H) , ≪ / RTI > 2.33 (s, 6H)

Compound 34: 6- (1- methyl -One H - Pyrazole Yl) -2 - ((4- (5- (2- ( pyrroli Di-1-yl) Ethoxy ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2 H ) -One

Yl) methyl) -6- (1 -methyl-1 H -pyrazol-4-yl) morpholin- 12 mg (0.028 mmol) of pyridazin-3 (2 H ) -one was dissolved in DMF (1 ml), pyrrolidine (8 mg, 0.112 mmol) and KI (5 mg, 0.0308 mmol) were added and the mixture was stirred overnight at 70 ° C. After the reaction was completed, the reaction mixture was extracted several times with ethyl acetate and brine, and the organic layer was dried with Na ₂ SO ₄ . Separation into Prep LC under 7% MeOH / MC gave 7.5 mg (57%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.11 (s, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.40 (d, J = 9.4Hz, 1H), 6.98 (d, J J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.61 (dt, J = 11.2, 2.5Hz, 1H), 3.18-3.09 (m, 1H), 2.95 (dd, J = 13.0, 10.1Hz, 1H), 2.67 (t, J = 5.4Hz, 2H), 2.28-2.07 (m, 7H ), 1.94-1.78 (m, 4H)

Compound 35: 6- (1- methyl -One H - Pyrazole Yl) -2 - ((4- (5- (piperidin-4- Ylmethoxy ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2 H )-On

tert-butyl 4 - ((2- (2 - ((3- (1-methyl -1 H-pyrazol-4-yl) -6-oxo-pyridazin -1 (6 H) - yl) methyl) morpholino Yl) pyrimidin-5-yloxy) methyl) piperidine-1-carboxylate (5.7 mg, 0.0101 mmol) was dissolved in 1 ml of MC and 0.5 ml of trifluoroacetic acid was added. After the reaction was completed at room temperature overnight, when the reaction was completed, the solvent was removed by concentration under reduced pressure, and ether was added to drop it to the solid. The vessel was removed and the ether removed to give 3 mg (52%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.10 (s, 2H), 7.82 (s, 1H), 7.77 (s, 1H), 7.41 (d, J = 9.4Hz, 1H), 7.00 (d, J 2H), 3.95 (s, 3H), 3.63-3.55 (m, 2H), 4.03 (t, J = 2H), 3.28-3.18 (m, 4H), 3.00-2.95 (m, 1H), 2.14-2.03 (m, 8H)

Compound 36: 6- (1- methyl -One H - Pyrazole Yl) -2 - ((4- (5 - ((1- Methylpiperidine Yl) meth - Oxy ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2 H )-On

tert-butyl 4 - ((2- (2 - ((3- (1-methyl -1 H-pyrazol-4-yl) -6-oxo-pyridazin -1 (6H) - yl) methyl) morpholino ) Pyrimidin-5-yloxy) methyl) piperidine-1-carboxylate (8.6 mg, 0.0152 mmol) was dissolved in 1 ml of formic acid and 17.2 μl of formaldehyde was added. After the reaction was completed at 95 ° C overnight, the mixture was adjusted to pH 10-11 with 1N NaOH and extracted with EA. And the organic layer was Na ₂ SO ₄ and dried to obtain a 8% MeOH / MC 4.5 mg ( 61%) and separated by Prep LC in condition.

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.09 (s, 2H), 7.81 (s, 1H), 7.76 (s, 1H), 7.39 (d, J = 9.4Hz, 1H), 6.97 (d, J 2H), 3.95 (s, 3H), 3.66-3.59 (m, 2H), 4.06 (t, J = 2H), 3.18-3.09 (m, IH), 2.97 (q, J = 7.6 Hz, IH), 2.72-2.65 -1.93 (m, 5 H), 1.82 - 173 (m, 2 H)

Compound 37: 6- (4- ( Benzyloxy ) Phenyl ) -2 - ((4- (5- (1- methyl -One H - Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine-3 (2 H )-On

Yl) methyl) pyridazin-3 (2 H ) -one To a solution of 100 mg of 6- (4- (benzyloxy) phenyl) -2- 58 mg (0.281 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 201 mg (0.617 mmol) of Cs ₂ CO ₃ and PdCl ₂ (dppf) ₂ were dissolved in 3 ml of dimethoxyethane And 1 ml of distilled water. N ₂ (gas) was charged and stirred at 80 ° C for 2.5 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and brine, and the organic layer was dried with Na ₂ SO ₄ . Separation by column chromatography under 80% EA / Hex gave 50 mg (50%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.42 (s, 2H), 7.74 (d, J = 8.6Hz, 2H), 7.64 (d, J = 4.7Hz, 2H), 7.52 (s, 1H), 7.45-7.33 (m, 5H), 7.04 (d, J = 8.6Hz, 2H), 7.02 (d, J = 9.0Hz, 1H), 4.61 (dd, J = 13.2, 4.6Hz, 2H), 4.39 (d , J = 13.0Hz, 1H), 4.23 (dd, J = 13.2, 4.6Hz, 1H), 4.15-4.10 (m, 1H), 4.03 (d, J = 11.3Hz, 1H), 3.94 (s, 3H) , 3.61 (dt, J = 11.2 , 2.4Hz, 1H), 3.22 (p, J = 16.2, 6.8Hz, 1H), 3.07 (q, J = 7.7Hz, 1H)

Compound 38: (S) -3- (1 - ((4- (5- (4- (2- Morpholinoethoxy ) Phenyl ) Pyrimidin-2-yl) morpholin-2-yl) methyl ) -6-oxo-1,6-di Hydropy Chladin-3-yl) Benzonitrile

(S) -3- (1 - ((4- (5-bromopyrimidin-2-yl) morpholin-2-yl) methyl) -6-oxo-1,6-dihydropyridazin- Yl) benzonitrile (20 mg, 0.0441 mmol) and 4- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- ethyl) morpholine 29 mg (0.0882 mmol), Cs 2 CO 3 43 mg (0.132 mmol), PdCl 2 (dppf) 2 3 mg (0.00441 mmol) was added to the 1.5 ml) and distilled water (0.5 ml dimethoxyethane. After charging N ₂ (gaseous), the mixture was stirred at 80 ° C for 2 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate and brine, and the organic layer was dried with Na ₂ SO ₄ . Separation into Prep LC under 7% MeOH / MC gave 19 mg (76%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.52 (s, 2H), 8.13 (s, 1H), 8.02 (d, J = 8.6Hz, 1H), 7.68 (d, J = 9.4Hz, 1H), 7.58 (t, J = 7.7Hz, 1H), 7.46 (d, J = 8.6Hz, 1H), 7.39 (d, J = 8.6Hz, 2H), 7.09 (d, J = 9.4Hz, 1H), 6.99 ( d, J = 8.6Hz, 2H) , 4.68 (d, J = 12.5Hz, 1H), 4.60 (q, J = 8.0Hz, 1H), 4.44 (d, J = 12.5Hz, 1H), 4.30 (dd, J = 13.1, 4.1Hz, 1H) , 4.15 (t, J = 5.5Hz, 3H), 4.04 (d, J = 11.1Hz, 1H), 3.75 (t, J = 4.4Hz, 4H), 3.62 (dt, J = 11.0, 1.8Hz, 1H) , 3.21 (dt, J = 11.0, 1.8Hz, 1H), 3.09 (q, J = 8.0Hz, 1H), 2.83 (t, J = 5.5Hz, 2H), 2.61 ( t, J = 4.4 Hz, 4H)

Compound 39: (S) -3- (1 - ((4- (5- (3 -Chloro- 4- (2- morpholinoethoxy ) phenyl ) pyrimidin- ) Methyl ) -6-oxo-1,6 -dihydropyridazin- 3-yl) benzonitrile

(S) -3- (1 - ((4- (5-bromopyrimidin-2-yl) morpholin-2-yl) methyl) -6-oxo-1,6-dihydropyridazin- Yl) benzonitrile and 4- (2- (2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- ) phenoxy) ethyl) morpholine 32 mg (0.0882 mmol), Cs 2 CO 3 43 mg (0.132 mmol), PdCl 2 (dppf) 2 3 mg (0.00441 mmol) of the in 1.5 ml) and distilled water (0.5 ml dimethoxyethane do. N ₂ (gas) was charged and stirred at 80 ° C for 2 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and brine, and the organic layer was dried with Na ₂ SO ₄ . Separation into Prep LC under 7% MeOH / MC gave 18 mg (66%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.49 (s, 2H), 8.14 (s, 1H), 8.02 (d, J = 8.6Hz, 1H), 7.68 (d, J = 9.4Hz, 1H), 7.61 (t, J = 7.7Hz, 1H), 7.50 (dd, J = 11.1, 2.0Hz, 1H), 7.09 (d, J = 8.6Hz, 1H), 6.99 (t, J = 6.8Hz, 2H), 4.69 (d, J = 12.5Hz, 1H), 4.59 (q, J = 8.0Hz, 1H), 4.45 (d, J = 12.5Hz, 1H), 4.30 (dd, J = 13.1, 4.1Hz, 1H), 4.21 (t, J = 5.5Hz, 3H), 4.04 (d, J = 11.1Hz, 1H), 3.74 (t, J = 4.4Hz, 4H), 3.61 (dt, J = 11.0, 1.8Hz, 1H), J = 8.0Hz, 1H), 2.89 (t, J = 5.5Hz, 2H), 2.65 (t, J = 4.4Hz, 4H), 3.25 (dt, J =

Compound 40: (S) -3- (1 - ((4- (5- (1- (2-hydroxyethyl) -1 H - Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile Hydrochloride

3- (6-oxo -1 - (((2S) -4- (5- (1- (2- ( tetrahydro -2 H - pyran-2-yloxy) ethyl) -1 H - pyrazol -4 Yl) methyl) -1,6-dihydropyridazin-3-yl) benzonitrile (16 mg, 0.0281 mmol) was dissolved in 1 ml of MC, 4M HCl dissolved in 0.4 ml was added. After stirring at room temperature for 4 hours, the reaction was terminated, and the solvent was removed by concentration under reduced pressure. The vessel was removed and the ether removed to give 13 mg (92%).

^{1 H-NMR (300 MHz,} DMSO) δδ 8.64 (s, 2H), 8.39 (s, 1H), 8.26 (d, J = 8.6Hz, 1H), 8.17 (d, J = 9.4Hz, 1H), 8.11 (s, 1H), 7.94 ( d, J = 8.6Hz, 1H), 7.85 (s, 1H), 7.72 (t, J = 7.7Hz, 1H), 7.14 (d, J = 9.4Hz, 1H), 4.52 (d, J = 12.5Hz, 1H ), 4.47 (q, J = 8.0Hz, 1H), 4.31 (d, J = 12.5Hz, 2H), 4.23 (dd, J = 13.1, 4.1Hz, 1H), 4.04 1H), 3.93 (d, J = 12.5 Hz, 1H), 3.74-3.67 (m, 4H), 3.13-3.06

Compound 41: (S) -3- (6-Oxo-1 - ((4- (5- (1,2,3,6- Tetrahydropyridine Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -1,6- Dihydropyridazine -3 days) Benzonitrile Hydrochloride

(S) - tert-butyl 4- (2- (2 - ((3- (3-cyanophenyl) -6-oxo-pyridazin -1 (6 H) - yl) methyl)-morpho lino) pyrimidin- 5-yl) -5,6-dihydropyridine e-1 (2 H ) -carboxylate (115 mg, 0.207 mmol) was dissolved in 3 ml of MC and 4M HCl dissolved in 0.4 ml of dioxane was added. After stirring at room temperature for 4 hours, the reaction was terminated, and the solvent was removed by concentration under reduced pressure. The vessel was moved and the ether removed to yield 96 mg (94%).

^{1 H-NMR (300 MHz,} MeOD) δδ 8.54 (s, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.6Hz, 1H), 8.09 (d, J = 9.4Hz, 1H), 7.83 (d , J = 8.6Hz, 1H), 7.69 (t, J = 8.6Hz, 1H), 7.14 (d, J = 9.4Hz, 1H), 6.15 (d, J = 12.5Hz 2H), 3.46 (s, 3H), 3.46 (t, J = = 5.5 Hz, 1 H), 3.25-3.12 (m, 2H), 2.76 (brs, IH), 2.47 (brs, IH)

Compound 42: (S) -6- (l- methyl -One H - Pyrazole -4-yl) -2 - ((4- (5- (1,2,3,6- Tetrahydropyridine Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) Pyridazine -3 (2 H )-On Hydrochloride

(S) -tert -butyl 4- (2- (2- ((3- (1 -methyl-1 H -pyrazol-4-yl) -6-oxopyridazin- 1 ( 6H ) ) Morpholino) pyrimidin-5-yl) -5,6-dihydropyridin-1 (2 H ) -carboxylate was dissolved in 5 ml of MC and dissolved in 3 ml of dioxane 4M HCl was added. And the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent is removed by concentration under reduced pressure, and ether is added to drop it to a solid. The vessel was removed and the ether removed to yield 62 mg (83%).

^{1 H-NMR (300 MHz,} MeOD) δδ 8.52 (s, 2H), 8.13 (s, 1H), 7.95 (s, 1H), 7.78 (d, J = 9.4Hz, 1H), 7.03 (d, J = J = 6.6 Hz, 1 H), 4.25 (dd, J = 13.1, 4.1 Hz, 1 H), 4.62 (d, J = J = 11.0, 1.8 Hz, 2H), 3.84 (s, 2H), 3.58 (d, J = 3.10 (q, J = 6.6 Hz, 2H), 2.78-2.72 (m, 2H)

Compound 43: (S) -2 - ((4- (5- (1- methyl -1,2,3,6- Tetrahydropyridine Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6- (1- methyl -One H - Pyrazole Yl) Pyridazine -3 (2 H )-On

(S) -tert -butyl 4- (2- (2- ((3- (1 -methyl-1 H -pyrazol-4-yl) -6-oxopyridazin- 1 ( 6H ) ) Morpholino) pyrimidin-5-yl) -5,6-dihydropyridin-1 ( 2H ) -carboxylate was dissolved in 3 ml of formic acid and 0.1 ml of formaldehyde He said. After the reaction was completed at 95 ° C overnight, the mixture was adjusted to pH 10-11 with 1N NaOH and extracted with EA. The organic layer was dried over Na ₂ SO ₄ . Separation into Prep LC under 7% MeOH / MC gave 12 mg (71%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.35 (s, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.40 (d, J = 9.4Hz, 1H), 6.97 (d, J = 9.4Hz, 1H), 5.94 ( s, 1H), 4.61 (d, J = 12.5Hz, 1H), 4.51 (q, J = 6.6Hz, 1H), 4.39 (d, J = 12.5Hz, 1H), 4.17 (dd, J = 13.1, 4.1Hz, 1H), 4.11 (t, J = 5.5Hz, 1H), 4.01 (d, J = 12.5Hz, 1H), 3.95 (s, 3H), 3.59 (dt, J = 11.0, 1.8Hz, 1H), 3.19 (dt, J = 11.0, 1.8Hz, 1H), 3.10 (s, 2H), 3.02 (q, J = 6.6Hz, 1H), 2.67 (t, J = 5.5Hz , ≪ / RTI > 1H), 2.50 (s, 2H), 2.41 (s,

Compound 44: (S) -3- (1 - ((4- (5- (1 - ((1- Methylpiperidine Yl) methyl )-One H - Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -6-oxo-1,6- Dihydropyridazine -3 days) Benzonitrile

(S) - tert-butyl 4 - ((4- (2- (2 - ((3- (3-cyanophenyl) -6-oxo-pyridazin -1 (6 H) - yl) methyl) morpholino ) pyrimidin-5-yl) -1 H - pyrazol-1-yl) methyl) piperidin-1 a-carboxylate 40 mg (0.0627 mmol) as a formate mixer acid 2.5 ml and 0.5 ml 35% formaldehyde After dissolving, the mixture was stirred overnight at 95 ° C. After the reaction was completed, the mixture was adjusted to pH 10-11 with 1N NaOH and extracted with EA. The organic layer was dried over Na ₂ SO ₄ . Separation into Prep LC under 7% MeOH / MC gave 14 mg (41%).

^{1 H-NMR (300 MHz,} CDCl 3) δδ 8.44 (s, 2H), 8.14 (s, 1H), 8.02 (d, J = 8.6Hz, 1H), 7.69 (q, J = 8.0Hz, 3H), 7.59 (t, J = 7.7Hz, 1H), 7.53 (s, 1H), 7.09 (d, J = 9.4Hz, 1H), 4.65 (d, J = 12.5Hz, 1H), 4.59 (q, J = 7.1 Hz, 1H), 4.41 (d , J = 12.5Hz, 1H), 4.30 (dd, J = 13.1, 4.1Hz, 1H), 4.17-4.12 (m, 1H), 4.02 (d, J = 6.6Hz, 3H ), 3.61 (t, J = 12.0Hz, 1H), 3.23 (dt, J = 11.2, 2.5Hz, 1H), 3.07 (t, J = 12.0Hz, 1H), 2.87 (d, J = 12.5Hz, 2H ), 2.27 (s, 3H) , 1.93 (t, J = 12.0Hz, 4H), 1.62 (d, J = 12.5Hz, 2H), 1.39 (dt, J = 11.2, 2.5Hz, 1H)

Compound 45: (S) -3- (6-Oxo-1 - ((4- (5- (1- (piperidin- H - Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -1,6- Dihydropyridazine -3 days) Benzonitrile bis (2,2,2- Trifluoroacetate ) Synthesis of

(S) - tert-butyl 4- (4- (2- (2 - ((3- (3-cyanophenyl) -6-oxo-pyridazin -1 (6 H) - yl) methyl) morpholino) pyrimidin-5-yl) -1 H - pyrazol-1-yl) piperidine-1-carboxylate with 103 mg (0.165 mmol) was dissolved in trifluoroacetic MC 5 ml acetic acid is the 1 ml do. And stirred at room temperature overnight. After completion of the reaction, the solvent is removed by concentration under reduced pressure, and ether is added to drop it to a solid. The vessel was removed and the ether removed to yield 119 mg (96%).

^{1 H-NMR (500 MHz,} CDCl 3) δδ 8.45 (s, 2H), 8.15 (s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.72 (t, J = 8.6Hz, 2H), 7.68 (s, 1H), 7.63 (s, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.11 (d, J = 8.6Hz, 1H), 4.66 (d, J = 12.5Hz, 1H), 4.61 (q, J = 7.1Hz, 1H), 4.42 (d, J = 12.5Hz, 1H), 4.31 (dd, J = 13.1, 4.1Hz, 1H), 4.18-4.13 (m, 1H), 4.08-4.03 (m, 3H), 3.98 (td, J = 11.6, 4.2 Hz, 1H), 3.48 (q, J = 7.1 Hz, 1H), 3.18-3.14 J = 12.5 Hz, 2H), 1.82 (d, J = 12.5 Hz, 2H)

Compound 46: (S) -3- (6-Oxo-1 - ((4- (5- (1- (1- Tetrahydro -2H-pyran-4-yl) piperidin-4-yl) -1 H - Pyrazole Yl) pyrimidin-2-yl) morpholin-2-yl) methyl ) -1,6- Dihydropyridazine -3 days) Benzonitrile  synthesis

(S) -3- (6-oxo-1 - ((4- (5- (1- (piperidin- 2-yl) methyl) -l, 6-dihydro-pyridazin-3-yl) benzonitrile bis (2,2,2- trifluoroacetate) 119 mg (0.158 mmol) and tetrahydro -4 H - Pyran-4-one (17 mg, 0.174 mmol) was dissolved in 2 ml of MC and 9 μl of acetic acid, followed by stirring at room temperature for 0.5 hour. 67 mg (0.316 mmol) of sodium triacetoxyborohydride was gradually added and the mixture was stirred at room temperature overnight. After the reaction was completed, the organic layer was extracted with brine and dried over Na ₂ SO ₄ . Separation with Prep LC under 7% MeOH / MC gave 17 mg (18%).

^{1 H-NMR (500 MHz,} CDCl 3) δδ 8.45 (s, 2H), 8.15 (s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.72 (t, J = 8.6Hz, 2H), 7.68 (s, 1H), 7.63 (s, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.11 (d, J = 8.6Hz, 1H), 4.66 (d, J = 12.5Hz, 1H), 4.61 (q, J = 7.1Hz, 1H), 4.42 (d, J = 12.5Hz, 1H), 4.31 (dd, J = 13.1, 4.1Hz, 1H), 4.18-4.13 (m, 1H), 4.08-4.03 (m, 3H), 3.98 ( td, J = 11.6, 4.2Hz, 1H), 3.63 (dt, J = 11.2, 2.5Hz, 1H), 3.48 (q, J = 7.1Hz, 1H), 3.41 (t, J = 11.6Hz, 1H), 3.25 (dt, J = 11.2, 2.5Hz, 1H), 3.18-3.14 (m, 1H), 3.09 (q, J = 7.1Hz, 1H), 2.61 (brs, 1H), 2.41 (brs, 1H), 2.27 (brs, 1H), 2.09 (d, J = 11.5Hz, 2H), 1.92 (t, J = 12.5Hz, 2H), 1.82 (d, J = 12.5Hz, 2H), 1.67 (d, J = 11.5 Hz, 2H).

Formulation example

Formulation example  1: Tablet (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation example  2: Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation example  3: Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation example  4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water were added to prepare an injection.

Experimental Example

Experimental Example  1. c- Met Kinase  Inhibitory activity experiment

The following experiments were carried out in order to measure the cell proliferation inhibitory activity of the hydrazine-substituted pyrimidine derivatives or their pharmaceutically acceptable salts according to the present invention.

The inhibitory activity against c-Met kinase was analyzed by using Dissociation Enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), which is a kind of time-resolved fluorescence (TRF) Respectively.

10 mL of the compound prepared in Examples 4 to 6 and 8 to 12 was added as a test compound to a 96-well V-shaped bottom plate and added with tyrosine kinase buffer (20 mL) mixed with c-Met enzyme, The compounds were mixed and incubated for 15 minutes. ATP solution (10 mL) was added thereto, and the reaction was quenched at room temperature for 30 minutes. Then, 50 mM ethylenediaminetetraacetic acid solution (EDTA, 40 mL) was added to stop the reaction. The reaction was then transferred to a plate coated with streptavidin, incubated under shaking, and washed three times with PBS-T buffer (PBS 0.05% Tween 20) for 2 hours.

The anti-phosphotyrosine antibody with europium was diluted 1: 2,500, added 100 mL per well, incubated under shaking, and washed 1 hour later with PBS-T buffer (PBS 0.05% Tween 20) 5 times. An enhancement solution (100 mL) was added and incubated for 5 minutes with shaking, and then read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument. The IC ₅₀ of the test compound subjected to the above experiment was determined by two sets of data and was determined using a prism (version 5.01, GraphPad) software.

IC ₅₀ < / RTI > of the compound reducing the c-Met kinase enzyme activity to 50% The values are shown in Table 1 below.

compound c-Met IC ₅₀ ([mu] M) compound c-Met IC ₅₀ ([mu] M) 3 (Formula 4) 0.040 26 (Formula 27) 0.019 4 (Formula 5) 0.039 27 (Formula 28) 0.020 5 (Formula 6) 0.003 28 (Formula 29) 0.007 6 (Formula 7) 0.005 29 (Formula 30) 0.234 7 (Formula 8) 0.002 30 (Formula 31) 0.411 8 (Formula 9) 0.111 31 (Formula 32) 0.003 9 (Formula 10) 0.012 32 (Formula 33) 0.096 10 (Formula 11) 0.035 33 (Formula 34) 0.082 11 (Formula 12) 0.004 34 (Formula 35) 0.046 12 (Compound 13) 0.010 35 (Formula 36) 0.019 13 (Formula 14) 0.055 36 (Formula 37) 0.059 14 (Formula 15) 0.011 37 (Formula 38) 0.717 15 (Formula 16) 0.021 38 (Formula 39) 0.028 17 (Formula 18) 0.027 39 (40) 0.090 18 (Formula 19) 0.035 40 (Formula 41) 0.008 19 (Formula 20) 0.047 41 (Formula 42) 0.040 20 (Formula 21) 0.016 42 (Formula 43) 0.130 21 (Formula 22) 0.007 43 (44) 0.025 22 (Formula 23) 0.009 46 (Formula 47) 0.005 25 (Formula 26) 0.021

Compounds 5, 6, 11, 21, 22, 28, 31, 40 and 46 (formulas 6, 7, 12, 22, 23, 29, 32, 41 and 47) exhibited excellent in vitro activity against c-Met have.

Claims (9)

A hydrazinone-substituted pyrimidine derivative selected from the group consisting of compounds represented by the following formulas (2) to (47): or a pharmaceutically acceptable salt thereof:
(2)

(4)

(6)

(8)

(10)

(12)

(14)

(16)

(18)

(20)

(22)

(24)

(26)

(28)

(30)

(32)

(34)

(36)

(38)

(40)

(42)

(44)

(46)

delete delete delete The hydrazine-substituted pyrimidine derivative according to claim 1, wherein the hydrazine-substituted pyrimidine derivative is selected from the group consisting of the compounds represented by Chemical Formulas 6, 7, 12, 22, 23, 29, 32, 41, Substituted pyrimidine derivatives or pharmaceutically acceptable salts thereof.
delete A pharmaceutical composition for the prevention or treatment of a hyperproliferative disorder comprising the hydrazine-substituted pyrimidine derivative of claim 1 or 5, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
8. The method of claim 7, wherein the hyperproliferative disorder is selected from the group consisting of cancer, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, hypoxia, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, , Crohn's disease, recurrent stenosis, atherosclerosis, intestinal adhesion, ulcer, hepatopathy, glomerulonephritis, diabetic nephropathy, malignant neuropathy, thrombotic microangiopathy, organ transplant rejection, .
The composition according to claim 8, wherein the cancer is lung cancer, stomach cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell cancer, prostate cancer or brain tumor.