KR102163494B1 - heteroaromatic macrocyclic derivatives as protein kinase inhibitors - Google Patents

Abstract

The present invention provides a 2,7-substituted cyano[3,2- d ]pyrimidine cyclized compound having protein kinase inhibitory activity, a pharmaceutically acceptable salt thereof, and abnormal cells containing the compound as an active ingredient. It relates to a pharmaceutical composition for the prevention, alleviation or treatment of diseases caused by growth, and the novel 2,7-substituted cyano[3,2- d ]pyrimidine cyclized compound of the present invention is used for growth factor signaling Since it exhibits an excellent inhibitory effect on various protein kinases involved, it is useful as a prevention, alleviation or therapeutic agent for abnormal cell growth diseases caused by these protein kinases.

Description

Heteroaromatic macrocyclic derivatives as protein kinase inhibitors}

The present invention induces a 2,7-substituted cyano[3,2- d ]pyrimidine compound having protein kinase inhibitory activity, a pharmaceutically acceptable salt thereof, and abnormal cell growth containing the compound as an active ingredient It relates to a pharmaceutical composition for the prevention, alleviation or treatment of diseases.

Protein kinase is an enzyme that catalyzes the phosphorylation of hydroxy groups located at tyrosine, serine, and threonine residues of proteins, and plays an important role in transduction of growth factor signals that induce cell growth, differentiation and proliferation.

In order to maintain the homeostasis of the living body, the signal transmission system in the living body must be smoothly balanced on and off. However, mutation or overexpression of a specific protein kinase disrupts the normal intracellular signal transduction system, causing various diseases such as cancer, inflammation, metabolic disease, and brain disease. Representative protein kinases that cause abnormal cell growth diseases include Raf, KDR, Fms, Tie2, SAPK2a, Ret, Abl, Abl(T315I), ALK, Aurora A, Bmx, CDK/cyclinE, Kit, Src, EGFR, EphA1, FGFR3, Flt3, Fms, IGF-1R, IKKb, IR, Itk, JAK2, KDR, Met, mTOR, PDGFRa, Plk1, Ret, Syk, Tie2, TrtB, etc.

It is estimated that there are 518 species of human protein kinases, which account for about 1.7% of all human genes (Manning et al, Science, 2002, 298, 1912). Human protein kinase can be largely divided into tyrosine protein kinase (more than 90 species) and serine/threonine protein kinase. Tyrosine protein kinases can be divided into 58 receptor tyrosine kinases, divided into 20 subfamily, and 32 cytoplasmic/non-receptors, divided into 10 subfamily. Receptor tyrosine kinase has a domain capable of accepting growth factors on the cell surface and an active site capable of phosphorylating tyrosine residues in the cytoplasm. When the growth factor binds to the growth factor receptor site on the surface of the receptor tyrosine kinase cell, the receptor tyrosine kinase forms a polymer and the cytoplasmic tyrosine residue is autophosphorylated. In addition, through the sequential phosphorylation of sub-family proteins, signal transduction proceeds into the nucleus, resulting in overexpression of transcription factors that cause cancer.

Focal adhesion kinase (FAK) is a 125 kD tyrosine protein kinase present in the cytoplasm. FAK plays a critical role in cell migration, proliferation, and survival by regulating integrin and growth factor signaling systems. It has been confirmed that FAK protein and FAK mRNA are overexpressed/activated in several types of cancer cells such as squamous cell carcinoma, invasive rectal/breast cancer, metastatic prostate cancer, melanoma, and glioma. And Novartis' FAK inhibitor TAE226 (Cancer Invest. 2008, 26(2), 145) is effective in breast cancer through three animal models (HeyA8, SKOV3ip1 and HeyA8-MDR) (Cancer Res. 2007, 67(22), 10976) has been proven. In addition, Pfizer's FAK inhibitor PF-573,228 (Proc Am Assoc Cancer Res, 2006, 47, Abst 5072) is currently in clinical trials successfully. Prostate cancer (PC-3M), breast cancer (BT474), pancreatic cancer (BxPc3) ), lung cancer (H460), brain cancer (U87MG), and other animal models. Furthermore, co-administration of FAK inhibitor (TAE226) and docetaxel showed excellent (85-97% tumor reduction, P values <0.01) efficacy in animal models (Cancer Res. 2007, 67(22), 10976).

FAK is involved in the signaling of integrin cell membrane proteins. When integrin receptors cluster together in response to various external stimuli, the cytoplasmic tail of the integrin binds to the cytoskeleton and signaling proteins. FAK's FERM (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) domain and FAT (Focal Adhesion Targeting) domain independently bind to the intracellular domain of integrin, allowing FAK to be located at the local attachment point. . FAKs gathered close to each other at the local attachment point are activated by inducing intra-molecular or inter-molecular phosphorylation at the Y397 residue. The FAK/Src complex is formed by binding of the SH2 domain of the Src kinase to the phosphorylated Y397 residue of FAK. Src kinase bound to FAK performs additional phosphorylation on several tyrosine residues (Y407, Y576/577, Y861, Y925) of FAK. In addition, the FAK/Src complex performs phosphorylation by binding with various signaling proteins (P130Cas, Grb2, PI3K, Grb7). In normal cells, signaling via FAK is very tightly controlled. However, in cells that have turned into tumors, FAK is overexpressed and activated, causing several characteristics of malignancies. FAK promotes cancer cell proliferation, increases invasion, and increases cancer cell migration. In addition, FAK has been reported to inhibit cancer cell death and increase angiogenesis.

FAK is a target protein for several growth factor receptors such as epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR) as well as integrin. Overexpression of these receptors or expression of active receptors converts normal cells into tumor cells. Thus, FAK is an important phosphorylating enzyme involved in tumor-related signaling of these receptors. It has been reported that the N-terminal FERM domain of FAK binds to EGFR, and the C-terminal domain of FAK is involved in cell migration by EGF (epidermal growth factor) factor. This fact suggests that FAK plays a role in integrating signals from outside cells by recognizing signals from external EGFR receptors through the N-terminal FERM domain, and by recognizing external integrin signals through the C-terminal FAT domain of FAK. I can.

Inhibition of FAK in various ways induces cell death. Cell survival by FAK is mainly performed by PI-3 Kinase (Phosphoinositide-3 kinase). The phosphorylated Y397 of FAK binds with PI-3 kinase to synthesize the second signal substances, PI(3,4,5)P3 and PI(3,4)P2, which form protein kinase B (AKT) into the cell membrane. And phosphorylated by PDK (3'-phosphoinositide-dependent kinase). Activated PKB inhibits apoptosis by inactivating several apoptosis proteins (p21WAF, FKHR, Bad, GSK3). Another survival signal is to activate Ras by binding the SH3 domain of p130Cas to the Proline-rich motif of FAK and inducing phosphorylation of various tyrosine residues of p130Cas by FAK/Src.

The relationship between FAK and the cell cycle is explained by the binding of Grb2 (Growth factor receptor-bound protein 2) to activation of the Ras/Erk pathway when phosphorylation is induced in Y925 of FAK. FAK overexpression promotes the transition from G1 to S phase of the cell cycle, and expression of the FAK inhibitory protein FRNK (FAK Related Non-Kinase) inhibits Cyclin D1 expression and induces the expression of the Cdk inhibitor p21, resulting in the cell cycle. Impedes progress. However, overexpression of Cyclin D1 overcomes cell cycle inhibition by FRNK.

The only subtype of FAK, proline-rich tyrosine kinase 2 (PYK2), is most widely distributed in neurons, recently small cell lung cancer (Oncogene. 2008, 27(12), 1737), prostate cancer (Oncogene. 2007, 26(54), 1737). ), 7552), hepatocellular carcinoma (Br J Cancer. 2007, 97(1), 50), and glioma (Neoplasia. 2005, 7(5), 435). .

The FAK's domain organization consists of four domains. 1) FERM (band 4.1 protein, ezrin, radixin, moesin) domain; It is an amino-terminal domain that acts with integrin receptor, platelet-derived growth factor receptor (PDGFr) and epidermalgrowth factor receptor (EGFr), and inhibits kinase activity through direct interaction with the kinase domain. 2) kinase domain 3) three proline-rich (PR) regions; 4) focal adhesion targeting (FAT) domain located in the carboxyl-terminal; It works with paxillin, talin, p190RhoGEF, and a RhoA-specific GDP/GTP exchange. The FAK-related non-kinase domain (FRNK), which is an alternative splicing of FAK, is composed of the PR1, PR2 and FAT domains, and acts as an antagonistic regulator of FAK.

In order to activate FAK, autophosphorylation of Y397 located at the linkage site of the FERM and kinase domain is required. Src kinase binds to phosphorylated Y397 and phosphorylates Y576/577 in sequence, and when Y925 is phosphorylated in the end, FAK signaling system works through Grb2. FAK inhibitors currently under development have a mechanism to inhibit the autophosphorylation of Y397 by targeting the ATP binding site of the kinase domain. The degree of inhibition of autophosphorylation of Y397 is used as an important biomarker in efficacy tests using animal models.

The development of small molecule FAK inhibitors is as follows. To date, about 26 FAK inhibitors have been identified as leading substances, but only Pfizer's PF-562271 compound is being developed in phase 1 clinical trials. PF-562271 is an inhibitor of ATP-competitive FAK (IC=1.5 nM) and homology Pyk2 (13 nM). It inhibits autophosphorylation at FAK Y397 sites in fibroblasts, epithelial cells, and cancer cells. It also inhibits the migration of most cancer cells, but does not affect the growth of normal cells. Human cancer xenografts such as prostate cancer PC-3, breast cancer BT-474, colon LoVo, lung cancer NCI-H460, glioblastoma U-87 MG, and pancreatic cancer BxPC-3 in vivo experiments (25-100 mg/kg po) No toxicity was observed, and 42-90% of tumor growth inhibition or tumor regression was observed.

Vascular Endothelial Growth Factors Receptors (VEGFR) are receptor tyrosine kinase (RTK), which is an important regulator for angiogenesis. It is involved in the development and homeostasis of blood vessels and lymphatic vessels, and has an important effect on nerve cells. VEGF is mainly produced in vascular endothelial cells, hematopoietic cells, and stromal cells by hypoxia and stimulation of cell growth factors such as TGF, interleukin, and PDGF. VEGF binds to VEGF receptors (VEGFR)-1, -2, and -3, and each VEGF isoform binds to a specific receptor, inducing the formation of homozygous or heterozygous for the receptor, and then activating each signaling system. The signaling specificity of VEGFR is more finely regulated by co-receptors such as neurophilin, heparan sulfate, integrin, and cadherin.

The biological function of VEGF is mediated through type III RTK, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). VEGFR is closely related to Fms, Kit, and PDGFR. VEGF each binds to a specific receptor, VEGF-A binds to VEGFR-1, -2 and receptor heteropolymers, while VEGF-C binds to VEGF-2, -3. In addition, PIGF and VEGF-B interact exclusively with VEGFR-1 and VEGF-E only interact with VEGFR-2. The VEGF-F variant interacts with VEGFR-1 or -2. VEGF-A, -B, and PIGF are primarily required for blood vessel formation, while VEGF-C and -D are essential for lymphatic vessel formation. New blood vessels supply nutrients and oxygen to tumors and provide a pathway for cancer cell metastasis, which is essential for its proliferation and metastasis. In normal cases, angiogenesis is balanced in vivo by mutual regulation of an angiogenesis promoting substance and an angiogenesis inhibitor, but when such balance is broken, as in cancer cells, growth factor (VEGF) that has the greatest effect on vascular endothelial cells By this, the receptor, VEGFR, is activated. Among the various mechanisms of action, various inhibitors that inhibit the receptor tyrosine kinase of VEGF using a low-molecular synthetic material are being researched and developed in a variety of ways, and most of these have the potential to be commonly used in solid tumors and the formation of angiogenesis activated only in cancer cells. As it is suppressed, it has the advantage of expecting an effective drug with relatively few side effects.

Tie2 is a type of receptor tyrosine kinase, which is deeply related to angiogenesis and vasculature. The domain structure of Tie2 is highly conserved in all vertebrates (Lyons et al., 1998). The ligand of Tie2 is angiopoietins (Ang). Ang2 does not induce autophosphorylation of Tie2 and interferes with the activation of Tie2 induced by Ang1. The activation of Tie2 by Ang2 in endothelial cells triggers the activation of PI3K-Akt (Jones et al., 1999). In the mitogen-activated protein kinase (MAPK) signaling pathway, the main signaling system of Tie2, the adapter protein GRB2 and the protein tyrosine phosphatase SHP2 are in the process of dimerization through autophosphorylation of the Tie2 receptor tyrosine kinase. It plays an important role. Ang/Tie2 and vascular endothelial cell growth factor (VEGF) signaling pathways play an important role in the angiogenesis of cancer cells. Tie2 is expressed on vascular endothelial cells, especially at sites where cancer cells infiltrate. Tie2 overexpression was confirmed in breast cancer (Peters et al., 1998), and at the same time, it was also observed in uterine cancer, liver cancer, and brain cancer.

According to the literature published so far, several compounds having a thieno[3,2- d ]pyrimidine structure as a parent have been synthesized. However, thieno [3,2- d] pyrimidin-thieno [3,2- d] pyrimidine compounds have certain substituents at the same time in the 2- and 7-position of mohaek as in the present invention is not disclosed in the literature This applies to new compounds that are not. Moreover, the literature predicting that it can be used as a tumor treatment and prophylaxis by confirming the inhibitory activity of several protein kinases against thieno[3,2- d ]pyrimidine compounds substituted with specific substituents at the 2- and 7-positions It has not been announced to date.

RET (Rearranged during transfaction) kinase is a tyrosine kinase receptor associated with the development of sympathetic and parasympathetic nerves. Point mutations, chromosomal translocation, and gene amplification of abnormal RET genes have been reported to cause various types of thyroid cancer (MEN2A, MEN2B, FMTC, PTC, etc.). It has been reported that thyroid cancer MEN2A, MEN2B, and FMTC are induced by a point mutation of the RET gene, and amplification of the chromosomal shift gene causes thyroid cancer (MEN2A, MEN2B, FMTC, PTC, etc.). In addition, recently, RET kinase has been reported as an important factor inducing lung cancer in addition to the thyroid gland. It has been reported that the RET gene fuses with the KIF5B gene or the CCDC6 gene and is expressed in the form of KIF5B-RET or CCDC6-RET, causing non-small cell lung cancer (NSCLC), and in the case of non-small cell lung cancer patients, the RET gene is NCOA4 or TRIM33 ( It was reported that the presence of NCOA4-RET and TRIM33-RET fused with tripartite motif-containing 33) genes was observed. Therefore, the development of a compound capable of inhibiting RET kinase for the treatment of thyroid cancer or non-small cell lung cancer as described above is very useful. As RET tyrosine kinase inhibitors, Sorafenib, Sunitinib, XL184, Vandetanib, Ponatinib, and Cabozantinib are known, and they express KIF5B-RET. It has been reported that it has the ability to inhibit cell proliferation in such cell lines.

DDR1, a type of receptor tyrosine kinase, has a discoidin homology domain in the outer part of the cell. Through this domain, it is the only receptor tyrosine kinase that binds collagen as a ligand. When collagen binds to DDR1, DDR1 is activated and autophosphorylated, thereby regulating cell differentiation and adhesion. In addition, DDR1 induces the expression and activity of MMP, causing the degradation of the extracellular matrix, which induces cell migration and metastasis. DDR1 is expressed in various tissues such as brain, lung, kidney, and pancreas, and the degree of DDR1 expression in solid cancer is higher than that of general tissues. Changes in the level of expression of DDR1 and mutations can cause oncogenic transformation by abnormally increasing the activity of DDR1 and ultimately activating cell proliferation. In pancreatic cancer, gastric cancer, and lung cancer, it is known that the prognosis can be predicted through the expression level of DDR. For this reason, DDR1 inhibition can be a novel method that can selectively treat cancer.

FLT3 is a class III receptor tyrosine kinase mainly expressed in hematopoietic stem cells, and induces activation of PI3K, Erk, and Jak/Stat signals, which are important for blood cell growth. Normal FLT3 is activated by dimerization by a ligand (FL), opening an activation loop and autophosphorylation. The FLT3 mutation, which is always active independent of FL, induces hyperproliferation of leukemia embryonic cells. In fact, about 35% of all AML patients have the FLT3 mutation. Among them, the ITD mutation prevents the self-inhibiting function of the juxtamembrane domain and maintains its activation at all times. ITD accounts for 35% of all AML patients, and the disease prognosis is also very poor, significantly reducing the disease-free survival and overall survival period of patients. The point mutation (D835Y) in the activation loop accounts for 7% of AML patients, and this point mutation is the cause of resistance to existing FLT3 inhibitory drugs.

Janus Kinase (JAK), a tyrosine kinase, includes JAK1, JAK2, JAK3 and TYK2. JAK plays a very important role in cytokine receptor signaling. JAK is composed of FERM-SH2-JH2 (pseudokinase domain)-JH1 (kinase domain). When cytokines bind to receptors, the JAK families form heterodimers to phosphorylate each other, attract submolecules, STATs, and signal into cells. Depending on the type of cytokine, the activated JAK kinase is different, for example, IL-2 and IL-4 activate the JAK1-JAK3 heterodimer, and this complex is involved in lymphocyte proliferation, while JAK1-JAK2 Is activated by IL-6, which is associated with T-cell differentiation and inflammation, so JAK mutations are deeply associated with autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

Korean Patent Publication No. 10-2014-0019055

An object of the present invention is a novel 2,7-substituted cyano[3,2- d ]pyrimidine having specific substituents at the 2- and 7-positions of the cyano[3,2- d ]pyrimidine parent nucleus It is to provide a parental compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is the prevention and reduction of abnormal cell growth disorders containing the novel 2,7-substituted cyano[3,2- d ]pyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient. Or to provide a therapeutic pharmaceutical composition.

One aspect of the present invention provides a 2, 7-substituted cyano[3,2- d ]pyrimidine cyclized compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof do:

[Formula 1]

In Formula 1,

Q ₁ and Q ₂ are each one of -(CH ₂ ) _n -, -O(CH ₂ ) _n -, -N(CH ₂ ) _n -and -NH(CH ₂ ) _n -, and n is an integer ;

A and B are each one of a heteroaryl ring, a cyclic hydrocarbon, and an alkyl group;

M is -CHCH-, -CH ₂ CH ₂ -, -NHCO-, -CONH-, -NMe-, -NAc-, -NMs-, -NHCONHR ₁ -, -NHCOR ₁ -, -NHSONR ₁ -and -O -, wherein R ₁ is any one of an alkyl group, a cyclic hydrocarbon, a phenyl group and a substituted phenyl group.

In one aspect of the present invention, n is an integer of 0, 1, 2, 3 or 4, the heteroaryl ring is any one of phenyl, pyridine, substituted phenyl and pyrazole, and the cyclic hydrocarbon is piperazine And cyclohexane, a compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

In one aspect of the present invention, the compound is

(E)-4 ¹ H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1( 1,4)-benzenecyclotetradicarpen-9-one (Compound No. 1);

(Z)-1 ¹ H-5-oxa-3,9-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1(4,1)-pyrazolo-4( 1,4)-Benzenecyclotetradicaren-10-one (Compound No. 2);

5,15-dioxa-3,9-diaza-2(7,2)-sinao[3,2-d]pyrimidine-1(5,2)-pyridin-4(1,4)-benzene Cyclopentadicarpen-10-one (Compound No. 3);

(E)-4 ¹ H-14-oxa-3,10-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecyclotetradicarpen-9-one (Compound No. 4);

5,15-dioxa-3,11-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1,4(1,4)-dibenzenecycloventadicarene-10 -On (Compound No. 5);

(E)-4 ¹ H-8-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-5(4,1)-piperidine-4(4, 1)-pyrazolo-1(1,4)-benzenecyclooctepene (Compound No. 6);

(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecycloanedicarpene (Compound No. 7);

(E)-8-methyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 8);

(E)-8-ethyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 9);

(E)-8-propyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 10);

(E)-1-(4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo -1(1,4)-benzenecyclodicarpen-8-yl)ethen-1-one (Compound No. 11);

(E)-8-(methylsulfonyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4, 1)-pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 12);

(E)-N-methyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zola-1(1,4)-benzenecycloanedicarfen-8-carboxamide (Compound No. 13);

(E)-N-(4-chlorophenyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4 ,1)-pyrazolo-1(1,4)-benzenecycloanedicarpen-8-carbothioamide (Compound No. 14);

(E)-N-(3-acetylphenyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4 ,1)-pyrazolo-1(1,4)-benzenecycloanedicarpen-8-carboxamide (Compound No. 15);

(E)-(4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1 (1,4)-Benzenecyclodicarpene-8-yl)(phenyl)methenone (Compound No. 16);

(E)-4 ¹ H-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4) -Benzenecycloanedicarpene (Compound No. 17);

(E)-1 ³ -Fluorine-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)- Pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 18);

(4 ⁴ E,8E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1 (1,4)-Benzenecycloanedicarfen-8-ene (Compound No. 19);

(E)-4 ¹ H-10-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-8(2,3 )-Oxirana-1(1,4)-benzenecyclodicarpene (Compound No. 20); And

(E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4 )-Benzenecycloanedicarpene-8,9-diol (Compound No. 21); a compound selected from the group consisting of, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

Another aspect of the present invention provides a pharmaceutical composition comprising any one of the above compounds, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

In another aspect of the present invention, the composition provides a pharmaceutical composition for preventing, alleviating or treating diseases caused by abnormal cell growth through inhibition of protein kinase.

In another aspect of the present invention, the compound provides a pharmaceutical composition having an inhibitory ability of 90% or more at 1 uM against protein kinase.

In another aspect of the present invention, the protein kinase is ALK, ARK5, Aurora A, Aurora B, Aurora C, AXL, BLK, BMX, c-MET, c-src, CDK2, CK2a2, CLK1, CLK2, CLK4, DAPK1, DDR1, DDR2, DYRK2, DYRK3, ERk7, FER, FES, FGFR1, FGFR2, FGFR3, FGR, FLT3, FLT4, DMS, FYN, HCK, HIPK1, HIPK2, HIPK4, HPK, IGF1R, IR, IRR, JAK1, IR, IRR, JAK1 JAAK3, KDR, LCK, LOK, LRRK2, MARk4, MELK, MLK3, MYLK4, NEK1, NEK5, NEK9, p70S6K, PDGFRa, PDGFRb, PDK1, PEAK1, PIM1, PKCd, PKCeplsilon, PKCg, PKCmu, PKCg, PKCmu, PKCg, PKCmu, ROS, RSK1, RSK2, RSK3, RSK4, SIK1, SIK2, SNARK, STK16, STK38, STK38L, TRKA, TRKB, TRKC, TXK, TYK2, TYRO3, ULK1, YES, and ZIPK. .

In another aspect of the present invention, the disease caused by abnormal cell growth is a tumor disease, providing a pharmaceutical composition.

In another aspect of the present invention, the tumor disease is stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, part It is a tumor disease selected from the group consisting of thyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hochicken disease and non-Hochicken lymphoma, and fibroadenoma. , To provide a pharmaceutical composition.

In another aspect of the present invention, in a method for preparing any one of the above compounds, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,

7-(4-(2-bromoethoxy)phenyl)-N-(1-(pipenidin-4-yl)-1H-pyrazol-4-yl)cyano[3,2-d]pyrimidine -2-amine;

N-(1-(3-aminopropyl)-1H-pyrazol-4-yl)-7-(4-(2-bromoethoxy)phenyl)cyano[3,2-d]pyrimidine-2- Amine;

5-(4-(2-((1-(3-aminopropyl)-1H-pyrazol-4-yl)amino)cyano[3,2-d]pyrimidin-7-yl)phenoxy)pentene Noic acid;

5-(4-((7-(4-(3-aminoethoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pentene Noic acid;

5-((5-(2-((4-(3-aminopropoxy)phenyl)amino)cyano[3,2-d]pyrimidin-7-yl)pyrimidin-2-yl)oxy)penta Noic acid;

5-(4-((7-(4-(3-aminopropoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl)amino)phenoxy)pentanoxy acid; And

5-(4-(2-((4-(3-aminopropoxy)phenyl)amino)cyano[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)penta Noic acid; It provides a method for preparing a compound comprising the step of reacting an intermediate compound of a 2,7 substituted cyano[3,2-d]pyrimidine cyclized compound selected from among the.

The 2,7-substituted cyano[3,2- d ]pyrimidine compound represented by Formula 1 characterized by the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is ALK, ARK5, Aurora A, Aurora B, Aurora C, AXL, BLK, BMX, c-MET, c-src, CDK2, CK2a2, CLK1, CLK2, CLK4, DAPK1, DDR1, DDR2, DYRK2, DYRK3, ERk7, FER, FES, FGFR1 , FGFR2, FGFR3, FGR, FLT3, FLT4, DMS, FYN, HCK, HIPK1, HIPK2, HIPK4, HPK, IGF1R, IR, IRR, JAK1, JAK2, JAAK3, KDR, LCK, LOK, LRRK2, MARk4, MELK, MLK3 , MYLK4, NEK1, NEK5, NEK9, p70S6K, PDGFRa, PDGFRb, PDK1, PEAK1, PIM1, PKCd, PKCeplsilon, PKCg, PKCmu, PKCnu, PKD2, RET, ROS, RSK1, RSK2, RSK1, SIK3, RSK2, RSK3 , STK16, STK38, STK38L, TRKA, TRKB, TRKC, TXK, TYK2, TYRO3, ULK1, YES, and ZIPK because the ability to inhibit the activity of any one or more of the kinase is excellent, so prevent, alleviate, or It is useful as a therapeutic agent.

Abnormal cell growth diseases that can be prevented and treated from the compounds according to the present invention include gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, cervical cancer, cervical cancer, head and neck cancer. , Esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia (acute myelogenous leukemia), multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hochicken disease and non-Hochicken lymphoma, or Various tumor diseases selected from fibroadenoma and the like may be included.

1 is a result of monitoring the mass of a mouse according to Experimental Example 6 of the present invention.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a 2, 7-substituted cyano[3,2- d ]pyrimidine cyclized compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof do:

[Formula 1]

In Formula 1,

Q ₁ and Q ₂ are each one of -(CH ₂ ) _n -, -O(CH ₂ ) _n -, -N(CH ₂ ) _n -and -NH(CH ₂ ) _n -, and n is an integer ;

A and B are each one of a heteroaryl ring, a cyclic hydrocarbon, and an alkyl group;

M is -CHCH-, -CH ₂ CH ₂ -, -NHCO-, -CONH-, -NMe-, -NAc-, -NMs-, -NHCONHR ₁ -, -NHCOR ₁ -, -NHSONR ₁ -and -O -, wherein R ₁ is any one of an alkyl group, a cyclic hydrocarbon, a phenyl group and a substituted phenyl group.

In one aspect of the present invention, n is an integer of 0, 1, 2, 3 or 4, the heteroaryl ring is any one of phenyl, pyridine, substituted phenyl and pyrazole, and the cyclic hydrocarbon is piperazine And cyclohexane, a compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

In one aspect of the present invention, in Formula 1, Q1 and Q2 are each -(CH2)n-, -O(CH2)n-, -N(CH2)n-, and -NH(CH2) _n- And n is an integer; A and B are each one of a cyclic hydrocarbon having 3 to 8 carbon atoms, a heterocyclic hydrocarbon having 2 to 7 carbon atoms, a single element aromatic compound having 3 or more carbon atoms, and a heteroelement aromatic compound having 2 or more carbon atoms, and M is -CHCH -, -CH ₂ CH ₂ -, -NHCO-, -CONH-, -NMe-, -NAc-, -NMs-, -NHCONHR ₁ -, -NHCOR ₁ -, -NHSONR ₁ -and -O- In this case, R ₁ is a substituted or unsubstituted saturated hydrocarbon having 2 or more carbon atoms, a substituted or unsubstituted unsaturated hydrocarbon having 2 or more carbon atoms, a cyclic hydrocarbon having 3 to 8 carbon atoms, a heterocyclic hydrocarbon having 2 to 7 carbon atoms, and 3 carbon atoms. It may be any one of two or more single-element aromatic compounds and two or more hetero-element aromatic compounds.

A pharmaceutically acceptable salt of the 2,7-substituted cyano[3,2- d ]pyrimidine compound represented by Formula 1 according to the present invention can be prepared by a conventional method in the art. Pharmaceutically acceptable salts have low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include acid addition salts of pharmaceutically usable free acids and basic compounds of formula 1, alkali metal salts (sodium salts, etc.) and alkaline earth metal salts (calcium salts, etc.), and organic salts and carboxyls of formula 1 It is composed of an organic base addition salt of an acid and an amino acid addition salt. Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and bromic acid may be used. Organic acids include 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, glutamic acid, and the like can be used. Organic bases that can be used to prepare an organic base addition salt are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the preparation of amino acid addition salts are natural amino acids such as alanine and glycine.

The 2,7-substituted cyano[3,2- d ]pyrimidine compound represented by Formula 1 according to the present invention includes all hydrates and solvates in addition to the pharmaceutically acceptable salts described above. Hydrates and solvates are solvents in which the 2,7-substituted cyano[3,2- d ]pyrimidine compound represented by Chemical Formula 1 is mixed with water such as methanol, ethanol, acetone, and 1,4-dioxane It can be crystallized or recrystallized after dissolving in and then adding a free acid or a free base. In such cases, solvates (especially hydrates) may be formed. Accordingly, as the compound of the present invention, in addition to the compound containing various amounts of water that can be prepared by a method such as lyophilization, stoichiometric solvates including hydrates are also included.

The substituents used to define the compounds according to the present invention will be described in more detail as follows.

The term "halogen atom" in the present invention means a fluorine, chlorine, bromine, or iodine atom.

The term'alkyl group' in the present invention refers to methyl, ethyl, n -propyl, i -propyl, cyclopropyl, n -butyl, i -butyl, t -butyl, cyclobutyl, cyclopropylmethyl, n -pentyl, i- It means an aliphatic saturated hydrocarbon group having 1 to 6 carbon atoms including pentyl, neopentyl, t -pentyl, cyclopentyl, cyclobutylmethyl, n -hexyl, i -hexyl, cyclohexyl, cyclopentylmethyl, etc. .

In the present invention, the term "haloalkyl group" refers to an alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as a trifluoromethyl group.

The term'alkoxy group' in the present invention is selected from the alkyl group of CC, including methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, t -butoxy It means a hydroxy group in which a hydrogen atom is substituted by a substituent.

The term'heteroaryl group' in the present invention refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isotaiazolyl, triazolyl, oxadiazolyl , Thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, isobenzofur Ranil, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, p It refers to a monocyclic, double, or tricyclic aromatic heterohydrocarbon group containing at least one heteroatom, including talazinyl, chinolinyl, quinazolinyl, and the like.

In the present invention, the term'heterocyclic group' means a heterohydrocarbon ring group containing one or more heteroatoms, including a morpholinyl group, a piperidine group, a piperazinyl group, and an N -protected piperazinyl group. do.

The 2,7-substituted cyano[3,2- d ]pyrimidine cyclized compound represented by Chemical Formula 1 as described above will be illustrated in more detail as follows:

(E)-4 ¹ H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1( 1,4)-benzenecyclotetradicarpen-9-one (Compound No. 1);

(Z)-1 ¹ H-5-oxa-3,9-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1(4,1)-pyrazolo-4( 1,4)-Benzenecyclotetradicaren-10-one (Compound No. 2);

5,15-dioxa-3,9-diaza-2(7,2)-sinao[3,2-d]pyrimidine-1(5,2)-pyridin-4(1,4)-benzene Cyclopentadicarpen-10-one (Compound No. 3);

(E)-4 ¹ H-14-oxa-3,10-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecyclotetradicarpen-9-one (Compound No. 4);

5,15-dioxa-3,11-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1,4(1,4)-dibenzenecycloventadicarene-10 -On (Compound No. 5);

(E)-4 ¹ H-8-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-5(4,1)-piperidine-4(4, 1)-pyrazolo-1(1,4)-benzenecyclooctepene (Compound No. 6);

(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecycloanedicarpene (Compound No. 7);

(E)-8-methyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 8);

(E)-8-ethyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 9);

(E)-8-propyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 10);

(E)-1-(4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo -1(1,4)-benzenecyclodicarpen-8-yl)ethen-1-one (Compound No. 11);

(E)-8-(methylsulfonyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4, 1)-pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 12);

(E)-N-methyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zola-1(1,4)-benzenecycloanedicarfen-8-carboxamide (Compound No. 13);

(E)-N-(4-chlorophenyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4 ,1)-pyrazolo-1(1,4)-benzenecycloanedicarpen-8-carbothioamide (Compound No. 14);

(E)-N-(3-acetylphenyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4 ,1)-pyrazolo-1(1,4)-benzenecycloanedicarpen-8-carboxamide (Compound No. 15);

(E)-(4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1 (1,4)-Benzenecyclodicarpene-8-yl)(phenyl)methenone (Compound No. 16);

(E)-4 ¹ H-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4) -Benzenecycloanedicarpene (Compound No. 17);

(E)-1 ³ -Fluorine-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)- Pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 18);

(4 ⁴ E,8E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1 (1,4)-Benzenecycloanedicarfen-8-ene (Compound No. 19);

(E)-4 ¹ H-10-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-8(2,3 )-Oxirana-1(1,4)-benzenecyclodicarpene (Compound No. 20); And

(E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4 )-Benzenecycloanedicarpene-8,9-diol (Compound No. 21).

Another aspect of the present invention provides a pharmaceutical composition comprising any one of the above compounds, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

In another aspect of the present invention, the composition provides a pharmaceutical composition for preventing, alleviating or treating diseases caused by abnormal cell growth through inhibition of protein kinase.

In another aspect of the present invention, the compound provides a pharmaceutical composition having an inhibitory ability of 90% or more at 1 uM against protein kinase.

In another aspect of the present invention, the protein kinase is ALK, ARK5, Aurora A, Aurora B, Aurora C, AXL, BLK, BMX, c-MET, c-src, CDK2, CK2a2, CLK1, CLK2, CLK4, DAPK1, DDR1, DDR2, DYRK2, DYRK3, ERk7, FER, FES, FGFR1, FGFR2, FGFR3, FGR, FLT3, FLT4, DMS, FYN, HCK, HIPK1, HIPK2, HIPK4, HPK, IGF1R, IR, IRR, JAK1, IR, IRR, JAK1 JAAK3, KDR, LCK, LOK, LRRK2, MARk4, MELK, MLK3, MYLK4, NEK1, NEK5, NEK9, p70S6K, PDGFRa, PDGFRb, PDK1, PEAK1, PIM1, PKCd, PKCeplsilon, PKCg, PKCmu, PKCg, PKCmu, PKCg, PKCmu, ROS, RSK1, RSK2, RSK3, RSK4, SIK1, SIK2, SNARK, STK16, STK38, STK38L, TRKA, TRKB, TRKC, TXK, TYK2, TYRO3, ULK1, YES, and ZIPK. .

In another aspect of the present invention, the disease caused by abnormal cell growth is a tumor disease, providing a pharmaceutical composition.

In another aspect of the present invention, the tumor disease is stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, part It is a tumor disease selected from the group consisting of thyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hochicken disease and non-Hochicken lymphoma, and fibroadenoma. , To provide a pharmaceutical composition.

The pharmaceutical composition of the present invention comprises a 2,7-substituted cyano[3,2- d ]pyrimidine cyclized compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof. It is contained as an active ingredient, and conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and excipients are added thereto to provide oral preparations such as tablets, capsules, troches, solutions, and suspensions. It can be formulated as a formulation for administration or a formulation for parenteral administration.

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

In addition, the dosage of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally based on an adult patient with a weight of 70 kg. It is 0.01 to 1,000 mg/day, and according to the judgment of a doctor or pharmacist, it may be dividedly administered once or several times a day at regular time intervals.

In another aspect of the present invention, in a method for preparing any one of the above compounds, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,

7-(4-(2-bromoethoxy)phenyl)-N-(1-(pipenidin-4-yl)-1H-pyrazol-4-yl)cyano[3,2-d]pyrimidine -2-amine;

N-(1-(3-aminopropyl)-1H-pyrazol-4-yl)-7-(4-(2-bromoethoxy)phenyl)cyano[3,2-d]pyrimidine-2- Amine;

5-(4-(2-((1-(3-aminopropyl)-1H-pyrazol-4-yl)amino)cyano[3,2-d]pyrimidin-7-yl)phenoxy)pentene Noic acid;

5-(4-((7-(4-(3-aminoethoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pentene Noic acid;

5-((5-(2-((4-(3-aminopropoxy)phenyl)amino)cyano[3,2-d]pyrimidin-7-yl)pyrimidin-2-yl)oxy)penta Noic acid;

5-(4-((7-(4-(3-aminopropoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl)amino)phenoxy)pentanoxy acid; And

5-(4-(2-((4-(3-aminopropoxy)phenyl)amino)cyano[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)penta Noic acid; It provides a method for preparing a compound comprising the step of reacting an intermediate compound of a 2,7 substituted cyano[3,2-d]pyrimidine cyclized compound selected from among the.

Meanwhile, the present invention is characterized by a method for preparing a 2,7-substituted cyano[3,2- d ]pyrimidine cyclized compound represented by Chemical Formula 1, and a representative method thereof is as follows.

Compounds having the above formula are characterized by having cyano[3,2- d ]pyrimidine as a skeleton. Cyclic hydrocarbons such as a benzene ring were introduced from this skeleton through a Suzuki reaction at position 7. Then, an alkyl group having a functional group capable of cyclization was connected. Next, an alkyl group having a cyclizable functional group was connected to the second position, and the cyclic compound having an amine functional group was substituted through the Buchwald reaction. After introducing a substituent at positions 2 and 7, a cyclized compound was synthesized through reactions capable of cyclization.

The present invention as described above will be described in more detail based on the following examples, formulation examples, and experimental examples, and the following examples, formulation examples, and experimental examples are merely illustrative of the present invention and the scope of the present invention Is not limited by these.

[Example]

Example 1. (E)-4 ^One H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cyclotetradicarpen-9-one (Compound No. 1)

[Formula 2]

Step 1: 4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenol

After dissolving 7-bromo-2-chlorothieno[3,2-d]pyrimidine (5.16 g, 20.7 mmol) in dioxane (138 mL), 2.0 N sodium carbonate (62.1 mL) and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboren-2-yl)phenol (2 g, 14.61 mmol) was added. Nitrogen was flowed into the mixed solution for 10 minutes, and then Pd(PPh)Cl (1.45 g, 2.07 mmol) and t-ButylXphos (0.88 g, 2.07 mmol) were added. The reaction mixture solution was stirred at 100° C. for 6 hours and then filtered through celite. The filtrate was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (4.3 g, 81% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.52 (s, 1H), 8.65 (s, 1H), 7.82 (m, 2H), 6.89 (m, 2H). MS m/z: 263 [M+1].

Step 2: Ethyl 5-(4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenoxy)pentanoate

4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenol (1 g, 3.82 mmol) was dissolved in dimethylformamide (16 mL) and calcium carbonate (1.06 g, 7.64 mmol) ) And ethyl 5-bromopentenoate (4.2 mmol, 0.88 g) were added. The reaction mixture solution was stirred at 100° C. for 3 hours and then filtered through celite. The filtrate was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (1.12 g, 74% yield). MS m/z: 391 [M+1].

Step 3: tert-butyl (3-(4-nitro-1H-pyrazo-1-yl)propyl)carbamate

After dissolving 4-nitro-1H-pyrazole (3 g, 26.54 mmol) in acetonitrile (100 mL), calcium carbonate (7.33 g, 53.08 mmol) and tert-butyl (3-bromopropyl) carbamate (6.96 g, 29.2 mmol) was added. The reaction mixture solution was stirred at 60° C. for 3 hours and then filtered through celite. The filtrate was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated to obtain a target compound (6.81 g. 95%) without purification. MS m/z: 271 [M+1].

Step 4: tert-butyl (3-(4-nitro-1H-pyrazo-1-yl)propyl)carbamate

tert-butyl (3-(4-nitro-1H-pyrazo-1-yl)propyl)carbamate (6.81 g, 17.46 mmol) was dissolved in methanol (105 mL), and then Pd (0.7 g) was added. It was stirred at room temperature for one day under the pressure of a balloon filled with hydrogen gas. The reaction mixture solution was filtered through celite and concentrated. The target compound (5.44 g, 91% yield) was used in the next reaction without purification. MS m/z: 241 [M+1].

Step 5: ethyl 5-(4-(2-((1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)amino)cyano[3,2 -d]pyrimidin-7-yl)phenoxy)pentonate

After dissolving ethyl 5-(4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenoxy)pentanoate (1 g, 2.56 mmol) in 17 mL of sec-butanol, Calcium carbonate (1.77 g, 12.8 mmol) and tert-butyl (3-(4-nitro-1H-pyrazo-1-yl)propyl)carbamate (0.68 g, 2.82 mmol) were added. Nitrogen was flowed into the mixed solution for 10 minutes, and then Pd ₂ (dba) ₃ (0.23 g, 0.26 mmol) and Xphos (0.12 g, 0.26 mmol) were added. The reaction mixture solution was stirred at 100° C. for 2 hours and then filtered through celite. The filtrate was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain a target compound (1.26 g, 83% yield). MS m/z: 595 [M+1].

Step 6: 5-(4-(2-((1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazo-4-yl)amino)cyano[3,2- d]pyrimidin-7-yl)phenoxy)pentanoic acid

Ethyl 5-(4-(2-((1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)amino)cyano[3,2-d] Pyrimidin-7-yl)phenoxy)pentonate (1.26 g, 2.12 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL), and then LiOH-H ₂ O (0.95 g 21.2 mmol) was added. The reaction mixture solution was stirred at room temperature for one day. The reaction mixture solution was diluted with ethyl acetate and neutralized with a 2N aqueous hydrogen chloride solution to make a pH of 5, and then washed with brine. The organic layer was dried over magnesium sulfate and concentrated. The target compound (1.03 g, 86% yield) was obtained without purification. MS m/z: 567 [M+1].

Step 7: 5-(4-(2-((1-(3-aminopropyl)-1H-pyrazo-4-yl)amino)cyano[3,2-d]pyrimidin-7-yl)phenoxy City) Pentanoic Acid

5-(4-(2-((1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazo-4-yl)amino)cyano[3,2-d]pyrri Midin-7-yl)phenoxy)pentanoic acid (1.09 g, 1.93 mmol) was dissolved in dioxane (10 mL), and 4 M hydrogen chloride-dioxane (10 mL) was added. The reaction mixture solution was stirred at room temperature for 3 hours. The reaction mixture solution was diluted with ethyl acetate and neutralized with a saturated aqueous sodium bicarbonate solution to make pH 5, and then washed with brine. The organic layer was dried over magnesium sulfate and concentrated. The target compound (0.83 g, 93% yield) was obtained without purification. MS m/z: 467 [M+1].

Step 8: (E)-4 ¹ H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo -1(1,4)-benzenecyclotetradicarpen-9-one

5-(4-(2-((1-(3-aminopropyl)-1H-pyrazo-4-yl)amino)cyano[3,2-d]pyrimidin-7-yl)phenoxy)penta Noic acid (0.83 g, 1.78 mmol) was dissolved in dimethylformamide (35 mL), and TBTU (0.57 g, 1.78 mmol) and HOBt (72 mg, 0.53 mmol) were added. After stirring at room temperature for 10 minutes, triethylamine (0.49 mL, 3.56 mmol) was slowly added and stirred for one day. The reaction mixture solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate and concentrated. Purified by a romanization method to obtain a target compound (0.55 g, 72% yield). MS m/z: 449 [M+1].

Example 2. (Z)-1 ^One H-5-oxa-3,9-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1(4,1)-pyrazolo-4(1,4)-benzene Cyclotetradicarpen-10-one (Compound No. 2)

[Formula 3]

Step 1: 2-Chloro-7-(1H-pyrazol-4-yl)cyano[3,2-d]pyrimidine

4-(4,4,5,5-tetramethyl-1,3,2-dioxaboren-2-yl)phenol instead of tert-butyl 4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaboren-2-yl)-1H-pyrazole-1-carboxylate, except that the step 1 of Example 1 and the experimental method were the same.

Step 2: Ethyl 5-(4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)-1H-pyrazo-1-yl)pentonate

Step 2 of Example 1 and the experimental method are the same.

Step 3: tert-butyl (3- (4-nitrophenoxy) propyl) carbamate

After dissolving 4-nitrophenol (1 g, 7.19 mmol) in 5 mL of dimethyl formamide, calcium carbonate (1.98 g, 14.4 mmol) and tert-butyl (3-bromopropyl) carbamate (1.89 g, 7.91 mmol) were added. Added. The reaction mixture solution was stirred at 100° C. for 3 hours and then filtered through celite. The filtrate was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated to obtain a target compound (1.87 g. 88%) without purification. MS m/z: 297 [M+1].

Step 4: tert-butyl (3- (4-aminorophenoxy) propyl) carbamate

tert-butyl (3-(4-nitrophenoxy)propyl)carbamate (1.87 g, 6.33 mmol) was dissolved in methanol (20 mL), and then Pd (0.2 g) was added. It was stirred at room temperature for one day under the pressure of a balloon filled with hydrogen gas. The reaction mixture solution was filtered through celite and concentrated. The target compound (1.55 g, 91% yield) was used in the next reaction without purification. MS m/z: 267 [M+1].

Step 5: ethyl 5-(4-(2-((4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)amno)cyano[3,2-d]pyrimidine-7 -Yl)-1H-pyrazo-1-yl)pentenoate

Except that tert-butyl (3-(4-aminorophenoxy)propyl) carbamate was used instead of tert-butyl (3-(4-nitro-1H-pyrazo-1-yl)propyl) carbamate. Step 5 of Example 1 and the experimental method are the same. MS m/z: 595 [M+1].

Step 6: 5-(4-(2-((4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)amino)cyano[3,2-d]pyrimidine-7- Day)-1H-pyrazo-1-yl)pentanoic acid

Step 6 of Example 1 and the experimental method are the same. MS m/z: 567 [M+1].

Step 7: 5-(4-(2-((4-(3-aminopropoxy)phenyl)amino)cyano[3,2-d]pyrimidin-7-yl)-1H-pyrazole-1- Day) Pentanoic Acid

Step 7 of Example 1 and the experimental method are the same. MS m/z: 467 [M+1].

Step 8: (Z)-1 ¹ H-5-oxa-3,9-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1(4,1)-pyrazolo -4(1,4)-benzenecyclotetradacarpen-10-one

Step 8 of Example 1 and the experimental method are the same. MS m/z: 449 [M+1].

Example 3. 5,15-dioxa-3,9-diaza-2(7,2)-sinao[3,2-d]pyrimidine-1(5,2)-pyridin-4(1, 4)-Benzenecyclopentadicarpen-10-one (Compound No. 3)

[Formula 4]

¹ H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.12 (s, 1H), 8.93 (m, 1H), 8.40 (s, 1H), 7.94 (m, 1H), 7.55 (m , 3H), 6.91 (m, 2H), 6.50 (m, 1H), 4.00 (m, 2H), 3.87 (m, 2H), 3.27 (m, 4H), 2.11 (m, 2H), 1.88 (m, 2H), 1.55 (m, 4H). MS m/z: 476 [M+1].

Step 1: 5-(2-chlorocyano[3,2-d]pyridin-7-yl)pyridin-2-ol

5-(4,4,5,5-tetramethyl-1,3,2- instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboren-2-yl)phenol Step 1 of Example 1 and the experimental method were the same, except that dioxaborene 2-yl)pyridin-2-ol was used. MS m/z: 364 [M+1].

Step 2: Ethyl 5-((5-(2-chlorocyano [3,2-d]pyridin-7-yl)pyrimidin-2-yl)oxy)pentanoate

Step 2 of Example 1 and the experimental method are the same. MS m/z: 392 [M+1].

From the next step, it is the same as the experimental method of Steps 3-8 of Example 2.

Example 4. (E)-4 ^One H-14-oxa-3,10-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4)-benzene Cyclotetradicarpen-9-one (Compound No. 4)

[Formula 5]

Step 1: tert-butyl (3-(4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenoxy)propyl)carbamate

4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenol (1 g, 3.82 mmol) was dissolved in dimethylformamide (16 mL) and calcium carbonate (1.06 g, 7.64 mmol) ) And tert-butyl (3-bromopropyl) carbamate (1.00 g, 4.20 mmol) were added. The reaction mixture solution was stirred at 100° C. for 3 hours and then filtered through celite. The filtrate was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (1.26 g, 79% yield). MS m/z: 391 [M+1].

Step 2: Ethyl 5-(4-nitro-1H-pyrazol-1-yl)pentenoate

Step 3 of Example 1 and the experimental method were the same, except that ethyl 5-bromopentenoate was used instead of tert-butyl (3-bromopropyl) carbamate. MS m/z: 242 [M+1].

Step 3: Ethyl 5-(4-amino-1H-pyrazol-1-yl)pentenoate

The experimental method is the same as in step 4 of Example 1. MS m/z: 222 [M+1].

Step 4: Ethyl 5-(4-((7-(4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl )Amino)-1H-pyrazol-1yll)pentenoate

Except that ethyl 5-(4-amino-1H-pyrazol-1-yl)pentenoate was used instead of tert-butyl (3-(4-nitro-1H-pyrazol-1-yl)propyl)carbamate. Is the same as in Step 5 of Example 1. MS m/z: 595 [M+1].

Thereafter, the experimental method is the same as in Steps 6-8 of Example 1.

Example 5. 5,15-dioxa-3,11-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1,4(1,4)-dibenzenecycloventa Dicarpen-10-one (Compound No. 5)

[Formula 6]

Step 1: Ethyl 5-(4-nitrophenoxy)pentenoate

The experimental method is the same as in step 2 of Example 1. MS m/z: 268 [M+1].

Step 2: ethyl 5-(4-aminophenoxy)pentenoate

The experimental method is the same as in step 4 of Example 1. MS m/z: 238 [M+1].

Step 3: ethyl 4-(4-((7-(4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl )Amino)phenoxy)butenoate

Step 5 of Example 1, except that ethyl 5-(4-aminophenoxy)pentenoate was used instead of tert-butyl (3-(4-nitro-1H-pyrazo-1-yl)propyl)carbamate. And the experimental method are the same. MS m/z: 607 [M+1].

Thereafter, the experimental method is the same as in Steps 6-8 of Example 1.

Example 6. (E)-4 ^One H-8-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-5(4,1)-piperidine-4(4,1)-pyrazolo- 1(1,4)-Benzenecyclooctephene (Compound No. 6)

[Formula 7]

Step 1: 7-(4-(2-bromoethoxy)phenyl)-2-chlorothieno[3,2-d]pyrimidine

After dissolving 4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)phenol (1 g, 3.82 mmol) in tetrohydrofureran (13 mL), triphenylphosphine (1.5 g , 5.73 mmol) and 2-bromoethanol (0.54 mL, 7.64 mmol) were added. After stirring for 5 minutes, diisopropyl azoicarboxylate (1.13 mL, 5.73 mmol) was slowly added, followed by stirring at room temperature for one day. The reaction solution was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (0.97, 69% yield). MS m/z: 369 [M+1].

Step 2: tert-butyl 4-(4-((7-(4-(2-bromoethoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazole -1-yl)piperidine-1-carboxylate

The experimental method is the same as in step 5 of Example 1. MS m/z: 599 [M+1].

Step 3: 7-(4-(2-bromoethoxy)phenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)cyano[3,2-d ]Pyrimidin-2-amine

The experimental method is the same as in step 7 of Example 1. MS m/z: 499 [M+1].

Step 4: (E)-4 ¹ H-8-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-5(4,1)-piperidine-4 (4,1)-pyrazolo-1(1,4)-benzenecyclooctephene

7-(4-(2-bromoethoxy)phenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)cyano[3,2-d]pyrimidine After dissolving -2-amine (0.1 g, 0.2 mmol) in 2-ethoxymethanol (4 mL), triethylamine (0.05 mL, 0.4 mmol) was added. It was stirred at 100° C. for one day. The reaction solution was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (44 mg, 53% yield). MS m/z: 419 [M+1].

Example 7. (E)-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4)-benzene Cycloanedicarpene (Compound No. 7)

[Formula 8]

Step 1: tert-butyl (3-(4-((7-(4-(2-bromoethoxy)phenyl)cyano[3,2-d]pyrimidin-2-yl)amino)-1H-pyra Zol-1-yl)propoxy)carbamate

The experimental method is the same as in step 5 of Example 1. MS m/z: 573 [M+1].

Step 2: N-(1-(3-aminopropyl)-1H-pyrazol-4-yl)-7-(4-(2-bromoethoxy)phenyl)cyano[3,2-d]pyrimidine -2-amine

The experimental method is the same as in step 7 of Example 1.

Step 3: (E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole -1(1,4)-benzenecycloanedicarpene

The experimental method is the same as in step 4 of Example 6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.65 (s, 1H), 9.11 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.71 (m, 2H), 7.26 ( m, 3H), 4.34 (m, 2H), 4.10 (m, 2H), 2.69 (m, 2H), 2.62 (m, 2H), 1.69 (m, 2H). MS m/z: 393 [M+1].

Example 8. (E)-8-methyl-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpene (Compound No. 8)

[Formula 9]

(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-Benzenecycloanedicarpene (0.1 g, 0.26 mmol) was dissolved in dichloromethane (2.6 mL), and acetic acid (1 drop) and formaldehyde (0.03 mL, 0.78 mmol) were added. After stirring for 30 minutes, NaBH(OAc) ₃ (29 mg, 0.14 mmol) was slowly added, followed by stirring for one day. The reaction solution was diluted with dichloromethane and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (76 mg, 72% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.65 (s, 1H), 9.12 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.78 (m, 2H), 7.26 ( m, 1H), 7.20 (m, 2H), 4.40 (m, 2H), 4.10 (m, 2H), 2.42 (m, 2H), 2.21 (s, 3H), 1.73 (m, 2H). MS m/z: 406 [M+1].

Example 9. (E)-8-ethyl-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpene (Compound No. 9)

[Formula 10]

The experimental method is the same as in Example 8. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 9.11 (s, 1H), 8.31 (m, 2H), 7.80 (m, 2H), 7.25 (s, 1H), 7.18 ( m, 2H), 4.39 (m, 2H), 4.09 (m, 2H), 1.74 (m, 2H), 0.98 (m, 3H). MS m/z: 421 [M+1].

Example 10. (E)-8-propyl-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpene (Compound No. 10)

[Formula 11]

The experimental method is the same as in Example 8. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (s, 1H), 8.41 (s, 1H), 7.87 (s, 1H), 7.81 (m, 2H), 7.30 (s, 1H), 7.15 (m, 2H), 7.01 (s, 1H), 4.42 (s, 2H), 4.18 (m, 2H), 2.69 (m, 2H), 2.53 (m, 2H), 2.35 (m, 2H), 1.93 (m, 2H) ), 0.94 (m, 3H). MS m/z: 434 [M+1].

Example 11.(E)-1-(4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cyclodicarpen-8-yl)ethen-1-one (Compound No. 11)

[Formula 12]

(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-Benzenecycloanedicarpene (0.1 g, 0.26 mmol) was dissolved in dichloromethane (2.6 mL), and then acetic anhydride (0.04 mL, 0.39 mmol) was added. After adding triethylamine (0.2 mL, 0.52 mmol) at 0 °C, the mixture was stirred at room temperature for 20 minutes. The reaction solution was diluted with dichloromethane and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (85 mg, 76% yield). MS m/z: 435 [M+1].

Example 12. (E)-8-(methylsulfonyl)-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpene (Compound No. 12)

[Formula 13]

(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecycloanedicarpene (0.1 g, 0.26 mmol) was dissolved in dichloromethane (2.6 mL), and methanesulfonyl chloride (0.03 mL, 0.39 mmol) was added. Triethylamine (0.2 mL, 0.52 mmol) was added at 0° C. and then stirred at room temperature for 5 minutes. The reaction solution was diluted with dichloromethane and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (68 mg, 56% yield). MS m/z: 471 [M+1].

Example 13. (E)-N-methyl-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazola-1(1,4)-benzene Cycloanedicarpen-8-carboxamide (Compound No. 13)

[Formula 14]

(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-Benzenecycloanedicarpene (0.1 g, 0.26 mmol) was dissolved in tetrahydrofuran (2.6 mL), and then methyl isocyanate (0.03 ml, 0.52 mmol) was added. It was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (59 mg, 51% yield). MS m/z: 450 [M+1].

Example 14. (E)-N-(4-chlorophenyl)-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpen-8-carbothioamide (Compound No. 14)

[Formula 15]

The experimental method is the same as in Example 13. MS m/z: 562 [M+1].

Example 15. (E)-N-(3-acetylphenyl)-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpen-8-carboxamide (Compound No. 15)

[Formula 16]

The experimental method is the same as in Example 13. MS m/z: 554 [M+1].

Example 16. (E)-(4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cyclodicarpene-8-yl)(phenyl)methenone (Compound No. 16)

[Formula 17]

The experimental method is the same as in Example 12. MS m/z: 497 [M+1].

Example 17. (E)-4 ^One H-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 17)

[Formula 18]

MS m/z: 391 [M+1].

Step 1: 3-(4-(2-chromocyano[3,2-d]pyrimidin-7-yl)phenyl)propan-1-ol

3-(4-(4,4,5,5-tetramethyl-1,3 instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboren-2-yl)phenol) Except for the use of ,2-dioxaboren-2-yl)phenyl)propan-1-ol, step 1 and the experimental method of Example 1 are the same. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 (s, 1H), 7.98 (s, 1H), 7.71 (m, 2H), 7.18 (m, 2H), 3.65 (m, 2H), 2.67 (m, 2H), 1.86 (m, 2H). MS m/z: 305 [M+1].

Step 2: 7-(4-(3-bromopropyl)phenyl)-2-chlorocyano[3,2-d]pyrimidine

3-(4-(2-chromocyano[3,2-d]pyrimidin-7-yl)phenyl)propan-1-ol (1 g, 3.28 mmol) in dichloromethane (22 mL) After melting, PBr ₃ (0.62 mL, 6.56 mmol) was slowly added at 0 °C. It was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, and then washed with salt water. The organic layer was dried over magnesium sulfate to obtain a target compound (1.09 g, 91% yield) without stopping. MS m/z: 366 [M+1].

The subsequent experimental method is the same as in Steps 1 to 3 of Example 7.

Example 18. (E)-1 ³ -Fluorine-4 ^One H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cycloanedicarpene (Compound No. 18)

[Formula 19]

MS m/z: 411 [M+1].

Step 1: 4-(2-chlorocyano[3,2-d]pyrimidin-7-yl)-2-fluorophenol

2-fluoro-4-(4,4,5,5-teramethyl-1 instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboren-2-yl)phenol Step 1 of Example 1 and the experimental method were the same except that ,3,2-dioxaboren-2-yl)phenol was used. ¹ H NMR (400 MHz, Acetone) δ 9.42 (m, 1H), 8.61 (m, 1H), 7.92 (m, 1H), 7.74 (m, 1H), 7.12 (m, 1H), 5.60 (m, 1H) ) . MS m/z: 280 [M+1].

The subsequent experimental method is the same as the experimental method of Example 7.

Example 19. (4 ⁴ E,8E)-4 ^One H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4)-benzenecycloanedicar Pen-8-N (Compound No. 19)

[Formula 20]

Step 1: 4-nitro-1-feten-4-en-1-yl)-1H-pyrazole

Step 3 of Example 1 and the experimental method were the same except that 5-bromopenten-1-ene was used instead of tert-butyl (3-bromopropyl) carbamate. MS m/z: 182 [M+1].

Step 2: 1-(phen-4-ten-1-yl)-1H-pyrazol-4-amine

The experimental method is the same as in step 4 of Example 1. MS m/z: 152 [M+1].

Step 3: 4-(2-((1-(phen-4-ten-1-yl)-1H-pyrazol-4-yl)amino)cyano[3,2-d]pyrimidin-7-yl )phenol

tert-butyl (3-(4-nitro-1H-pyrazol-1-yl)propyl)carbamate dash 1-(phen-4-ten-1-yl)-1H-pyrazol-4-amine Except that, step 5 of Example 1 and the experimental method were the same. MS m/z: 378 [M+1].

Step 4: 7-(4-(allyroxy)phenyl)-N-(1-(phen-4-ten-1-yl)-1H-pyrazol-4-yl)cyano[3,2-d] Pyrimidine-2-amine

4-(2-((1-(phen-4-ten-1-yl)-1H-pyrazol-4-yl)amino)cyano[3,2-d]pyrimidin-7-yl)phenol ( 0.5 g, 1.33 mmol) was dissolved in dimethylformamide (13 mL), and then calcium carbonate (367 mg, 2.66 mmol) and allyl bromide (0.17 mL, 2.00 mmol) were added. It was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain a target compound (0.4 g, 72% yield). MS m/z: 418 [M+1].

Step 5: (4 ⁴ E,8E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Sol-1(1,4)-benzenecycloanedicarpene-8-ene

7-(4-(allyroxy)phenyl)-N-(1-(phen-4-ten-1-yl)-1H-pyrazol-4-yl)cyano[3,2-d]pyrimidine- 2-amine (0.3 g, 0.72 mmol) was dissolved in dichloroethane and Grubbs 2nd generation catalyst (61 mg, 0.07 mmol) was added. It was stirred at 100° C. for one day. The reaction solution was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (143 mg, 51% yield). MS m/z: 390 [M+1].

Example 20. (E)-4 ^One H-10-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-8(2,3)-oxirana-1 (1,4)-Benzenecyclodicarpene (Compound No. 20)

[Formula 21]

(4 ⁴ E,8E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1 (1,4)-Benzenecycloanedicarpene-8-ene (0.1 g, 0.26 mmol) was dissolved in dichloromethane (2.6 mL), and 3-chloroperbenzoic acid (122 mg, 0.26 mmol) was added. I did. It was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, and washed with brine. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (44 mg, 42% yield). MS m/z: 406 [M+1].

Example 21.(E)-4 ^One H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4)-benzenecycloanedicar Pen-8,9-diol (Compound No. 21)

[Formula 22]

(4 ⁴ E,8E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1 (1,4)-Benzenecycloanedicarpene-8-ene (0.1 g, 0.26 mmol) was dissolved in tetrahydrofuran (2.6 mL) and then 50% aqueous solution of N-methylmorpholine N-oxide (0.24 ml, 1.04) mmol) and OsO ₄ 4% aqueous solution (0.1 mL) were added. It was stirred at room temperature for one day. The reaction solution was diluted with ethyl acetate and washed with salt water. The organic layer was dried over magnesium sulfate and concentrated. Purified by chromatography to obtain the target compound (55 mg, 49% yield). MS m/z: 424 [M+1].

The following examples are examples of a method for preparing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the manufacturing method of the present invention. However, the present invention is not limited by the following examples.

Example 22: (E)-4 ^One H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4)-benzene Cyclotetradacarpen-9-one hydrogen chloride (Compound No. 22)

(E)-41H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1, 4)-Benzenecyclotetradacaren-9-one (300 mg, 0.589 mmol) was dissolved in tetrahydrofuran (5 mL), and then 4 M hydrogen chloride (147 μL) dissolved in dioxane was added at room temperature. The precipitate generated after 30 minutes was filtered, dried at room temperature, and the target compound, (E)-41H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine -4(4,1)-pyrazolo-1(1,4)-benzenecyclotetradacaren-9-one hydrogen chloride (305 mg) was obtained.

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

[Preparation Example]

Formulation Example 1: Tablet (direct pressure)

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

Formulation Example 2: Tablet (wet granulation)

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

Formulation Example 3: Powder and Capsule

After sieving 5.0 mg of the active ingredient, 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate were mixed together. Mixture using a suitable device to solid No. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

An injection was prepared by containing 26 mg of 12HO and 2974 mg of distilled water.

[Experimental Example]

Experimental Example 1. Measurement of enzyme activity of Example 7 and Example 1

Substrate in freshly prepared base reaction buffer (20 mM HEPES (PH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) Add solution and essential cofactors. Kinase and compound are added to the substrate solution, mixed slowly, and incubated for 20 minutes at room temperature. To initiate the reaction, 33P-ATP was added to the reaction mixture, followed by incubation at room temperature for 2 hours to react. Upon completion of the reaction, the amount of the substrate having the radiolabeled 33P-ATP was measured, the activity of the kinase was evaluated, and the IC50 value was calculated based on the value.

The experimental results were as follows. Example 7 was shown in Table 1, Example 1 was shown in Table 2. The activity value was expressed in 3 steps.

A: IC ₅₀ <100 nM,

B: 100 nM <IC ₅₀ <1 μM,

C: IC ₅₀ > 1 μM

Enzyme IC ₅₀ (μM) FLT3 A FLT3 (ITD) A FLT3 (D835Y) A FLT4 A TBK1 B c-Kit B BLK A MEK1 C ULK1 A

Enzyme IC ₅₀ (μM) FLT4 A GCN2 B

Experimental Example 2. Comparison of measuring enzyme activity of Example 1 and Comparative Example 1

Dispense 10000 cells per well of each 96 well plate. After cell stabilization, 1/3 serially diluted compound is treated to 0.5% DMSO and incubated for 72 hours. When cell titer glo is treated, luciferase decomposes luciferin only in the presence of ATP, and luminescence is released. The luminescence value was measured using Envision (perkinelmer). The GI50 value was calculated by calculating the concentration of the compound at which the cells die based on the measured luminescence value.

The following compounds were used as Comparative Example 1. (WO2014-180524). The compound of Formula 23 below is A26, which is a compound disclosed in International Publication No. WO2014-180524.

[Formula 23]

The enzyme and cell activities of Comparative Example 1 and Example 1 were compared.

The experimental results are shown in Table 3 below.

The activity value was expressed in 3 steps.

A: IC ₅₀ <100 nM,

B: 100 nM <IC ₅₀ <1 μM,

C: IC ₅₀ > 1 μM

Comparative Example 1 Example 1 rescue

FLT3 (ITD) C A BaF3 (FLT3-ITD) B A

The superior activity of the compound of Example 1 in FLT3 can be confirmed than that of the compound of Comparative Example 1 (a compound disclosed in WO2014-180524) having a similar structure.

Experimental Example 3. Measurement of enzyme activity in cells

Dispense 10000 cells per well of each 96 well plate. After cell stabilization, 1/3 serially diluted compound is treated to 0.5% DMSO and incubated for 72 hours. When cell titer glo is treated, luciferase decomposes luciferin only in the presence of ATP, and luminescence is released. The luminescence value was measured using Envision (perkinelmer). The GI50 value was calculated by calculating the concentration of the compound at which the cells die based on the measured luminescence value.

The experimental results are shown in Table 4 below.

The activity value was expressed in 3 steps.

A: IC ₅₀ <100 nM,

B: 100 nM <IC ₅₀ <1 μM,

C: IC ₅₀ > 1 μM

BaF3 Cell Cell Parental FLT (TEL) FLT3 (ITD) FLT3 (D835Y) FLT3
(ITD-D835Y) FLT3 (ITD-F691L) FLT3 (ITD-D835Y-F691L) U2OS A375 Example 7 C A A A A A A B B Example 1 B B A - - - - C C Example 2 - - B - - - - C C Example
3 - - C - - - - C C Example 5 - - B - - - - C C Example 4 - - B - - - - C C Example
8 - - - - - - B B B Example 9 - - - - - - B B B Example 10 - - - - - - A C B Example 11 - - - - - - B C C Example 12 - - - - - - B C C Example 13 - - - - - - B C C

Experimental Example 4. Comparison of measuring enzyme activity of Comparative Examples 2-3 and 7

Two commercially available drugs, Crizotinib (Comparative Example 2) and Alectinib (Comparative Example 3), were used as comparative examples, and enzyme activity with Example 7 was measured and compared.

For each cell, 10000 cells were dispensed per well of each 96 well plate. After cell stabilization, 1/3 serially diluted compound is treated to 0.5% dimethyl selphoxide and incubated for 72 hours. When cell titer glo is treated, luciferase decomposes luciferin only in the presence of ATP, and luminescence is released. The luminescence value was measured using Envision (perkinelmer). The GI ₅₀ value was calculated by calculating the concentration of the compound at which cells die based on the measured luminescence value.

The experimental results are shown in Table 5 below.

The activity value was expressed in 3 steps.

A: IC ₅₀ <100 nM,

B: 100 nM <IC ₅₀ <1 μM,

C: IC ₅₀ > 1 μM

Cmpd code Cellular activity (uM) Ba/F3 cells NSCLC Parental ALK (WT) ALK (L1196M) ALK (G1202R) SNU2535
(G1269A) Crizotinib
(Comparative Example 2) C B B B C Alectinib
(Comparative Example 3) C B B C C Example 7 C A B A C

As shown in the above experimental results, the compound of Example 7 is more active in ALK (WT) than two commercially available drugs (Comparative Example 2 and Comparative Example 3), and has similar activity in ALK (L1196M) And ALK (G1202R) has better activity.

Experimental Example 5. Inhibitory capacity at 1 uM against various protein kinases of Example 7

In Example 7, the inhibitory ability of the protein kinase described in Table 6 at a concentration of 1 uM was measured. The experimental results are shown in Table 6.

Inhibitory capacity was expressed in three stages.

A: 70 or more inhibition,

B: 30-70% inhibition

C: less than 30 inhibition

ABL A FGR A PBK C ARG A FLT1/VEGFR1 A PDGFRa A ACK A FLT3 A PDGFRb A AKT1 B FLT4 A PDK1 A AKT2 B FMS A SgK269 A AKT3 A FRK B PHKg1 A ALK A FYN A PHKg2 C ALK1 C GCK B PIM1 A ARAF B KHS2 A PIM2 B NuaK1 A RHOK B PIM3 A AurA A GPRK4 C PKA A AurB A GPRK5 C PKACb A AurC A GPRK6 C PKACg B AXL A GPRK7 B PKCa A BLK A GSK3A A PKCb A BMPR2 A GSK3B A PKCb A BMX A Haspin B PKCd A BRK A HCK A PKCe A BRSK1 A ZC1/HGK B PKCh A BRSK2 A HIPK1 A PKCg A BTK A HIPK2 A PKCi C KIT A HIPK3 A PKD1 A MER A HIPK4 A PKD3 A MET A HPK1 A PKCt A SRC A IGF1R A PKCz C CaMK1a B IKKa B PKD2 A CaMK1d B IKKb A PKG1 B CaMK1g B IKKe B PKG1 B CaMK2a A INSR A PKG2 B CaMK2b B IRAK1 A PKN1 A CaMK2d B IRAK4 A PKN2 B CaMKK1 C IRR A PKN3 B CaMKK2 C ITK B PLK1 A CDK1/cyclin A A JAK1 A PLK2 B CDK1/cyclin B A JAK2 A PLK3 C CDK1/cyclin E A JAK3 A PLK4 B CDK14/cyclin Y (PFTK1) A JNK1 B PRKX A CDK16/cyclin Y (PCTAIRE) A JNK2 B PYK2 A CDK17/cyclin Y (PCTK2) A JNK3 C RET A CDK18/cyclin Y (PCTK3) A KDR A RIPK2 B CDK11 A KHS1 B ANKRD3 B CDK2 A LATS1 A ROCK1 B CDK2 A LATS2 A ROCK2 A CDK2 A LCK A RON B CDK2 A ICK B ROS A CDK3 A LIMK1 A RSK1 A CDK4 A LIMK2 B RSK2 A CDK4 A LKB1 A RSK3 A CDK5 A LOK A RSK4 A CDK5 A LRRK2 A SBK A CDK6 A LYN A SGK A CDK6 A LYNB A SGK2 A CDK7 B MAK A SGK3 C CDK9 A MARK1 A SIK1 A CDK9 A MARK2 A QIK A CDK9 A MARK3 A Q or B CHK1 A MARK4 A SLK A CHK2 A MAP2K1 C Nuak2 A CK1d B MAP2K2 C MPSK1 A CK1e C MAP2K5 A CRIK C CK1g1 C MAP3K2 B TSSK1 A CK1g2 B MAP3K3 A YSK1 B CK1g3 C MELK A YANK2 B CK2a B ZC3/MINK B STK33 A CK2a2 A MAP2K6 C NDR1 A CLK1 A smMLCK A NDR2 A CLK2 A skMLCK A STLK3 A CLK3 B MLK1 A SYK B CLK4 A MLK2 A TAK1 B CSK B MLK3 A TAO1 A DAPK1 A MNK1 C TAO2 A DAPK2 B MNK2 B TAO3 A DCAMKL1 C MRCKa C TBK1 A DCAMKL2 B MRCKb C TEC A DDR1 A MSK1 A TIE2 B DDR2 A MSK2 C TLK1 C DLK C MST1 A TLK2 A DMPK2 A MST2 A ZC2/TNIK A DRAK1 A MST3 B TNK1 B DYRK1A B MUSK B TRKA A DYRK1B A caMLCK C TRKB A DYRK2 A SgK085 A TRKC A DYRK3 A MYO3A C TSSK2 C DYRK4 C MYO3B C TSSK3 C EGFR B NEK1 A TTBK1 C EPHA1 B NEK11 C TTBK2 C EPHA2 A NEK2 B TXK A EPHA3 C NEK3 B LTK A EPHA4 A NEK4 A TYK2 A EPHA5 B NEK5 A TYRO3 A EphA6 A NEK6 C ULK1 A EphA7 A NEK7 C ULK2 B EPHA8 C NEK8 C ULK3 A EphB1 A NEK9 A VRK1 B EphB2 B NIM1 B VRK2 C EphB3 C NLK B Wee1 B EphB4 B OSR1 C Wnk1 C HER2/ErbB2 B p38a C Wnk2 C HER4/ErbB4 B p38b C Wnk3 C Erk5 C p38d B YES A Erk7 A p38g C MAP3K8 B IRE1 A P70s6k A ZAK C IRE2 A p70S6Kb B DAPK3 A FAK A PAK1 A FER A PAK2 B FES A PAK3 A FGFR1 A PAK4 B FGFR2 A PAK5 B FGFR3 A PAK6 B FGFR4 B PASK C

Experimental Example 6. Animal efficacy of Example 7 (acute myelogenous leukemia treatment efficacy) experimental results

Animal experiments were conducted in accordance with all governmental regulations and regulations, such as the Animal Protection Act and the Experimental Animal Act, and the ethical regulations of the Laboratory Animal Laboratory of the Korea Institute of Science and Technology. (Korea Institute of Science and Technology Animal Test Approval Number: 2017-007)

Preparation of OCI-AML3 mouse xenograft model

Mice were Balb/c nude, 6-8 weeks old, female, and were used in this experiment after a week of acclimatization period after being brought into the laboratory animal room. To make an animal disease model, the OCI-AML3 cell line was used, and the cell line was subcultured at 3 day intervals using RPMI1640 containing 10% FBS and 1 x Penicillin/streptomycin. Before transplanting the cells into the mouse, wash twice with DPBS, mix 1:1 with matrigel with a cell number of 5.0 x 10e6 cells/mouse to prepare a final 100ul volume. After confirming complete anesthesia by intraperitoneal administration of Avertin at a dose of 250 mpk as an anesthetic, OCI-AML3 was implanted in the right hind limb of the mouse. The experiment was conducted using a minimum number of individuals (n=3) for statistical significance, and the control group was carried out with vehicle and GNF-7 8 mpk, and the experimental group was conducted at a dose of 30 mpk of the test compound (Example 7).

The vehicle composition for dissolving the compound for oral administration of the compound is as follows.

5% NMP / 15% solutol / 30% PEG400 / 50% 0.05M citric acid

Oral administration for in vivo efficacy study of compounds

After implantation of OCI-AML3, when the mass of the mouse reached about 150-200 mm ³ , oral administration was performed once for 3 weeks at a volume of 200 ul per mouse. The condition of the mice was observed during oral administration every day, and the body weight and mass volume were measured at 3 days intervals for 3 weeks.

Experiment result

The experimental results were as shown in FIG. 1. As can be seen in FIG. 1, in the case of the experimental group administered with the test compound, it was confirmed that the decrease in mass volume was significantly reduced.

Claims (10)

A 2,7-substituted cyano[3,2- d ]pyrimidine cyclized compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof:
[Formula 1]

In Formula 1,
Q ₁ and Q ₂ are each -(CH ₂ ) _n -, -O(CH ₂ ) _n -, -N(CH ₂ ) _n -and -NH(CH ₂ ) _n -, and n is 0, Is an integer of 1, 2, 3 or 4;
A and B are each one of phenyl, pyridine, pyrazole and piperazine,
M is -CHCH-, -CH ₂ CH ₂ -, -NHCO-, -CONH-, -NMe-, -NAc-, -NMs-, -NHCONHR ₁ -, -NHCOR ₁ -, -NHSONR ₁ -and -O -Is any one of, wherein R ₁ is a substituted or unsubstituted saturated hydrocarbon having 2 to 8 carbon atoms, a substituted or unsubstituted unsaturated hydrocarbon having 2 to 8 carbon atoms, a cyclic hydrocarbon having 3 to 8 carbon atoms, and 2 to 7 carbon atoms It is any one of heterocyclic hydrocarbon, a single element aromatic compound having 6 to 10 carbon atoms, and a heteroelement aromatic compound having 2 to 10 carbon atoms.
delete The method of claim 1,
The compound is
(E)-4 ¹ H-14-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1( 1,4)-benzenecyclotetradicarpen-9-one (Compound No. 1);
(Z)-1 ¹ H-5-oxa-3,9-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1(4,1)-pyrazolo-4( 1,4)-Benzenecyclotetradicaren-10-one (Compound No. 2);
5,15-dioxa-3,9-diaza-2(7,2)-sinao[3,2-d]pyrimidine-1(5,2)-pyridin-4(1,4)-benzene Cyclopentadicarpen-10-one (Compound No. 3);
(E)-4 ¹ H-14-oxa-3,10-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecyclotetradicarpen-9-one (Compound No. 4);
5,15-dioxa-3,11-diaza-2(7,2)-cyano[3,2-d]pyrimidine-1,4(1,4)-dibenzenecycloventadicarene-10 -On (Compound No. 5);
(E)-4 ¹ H-8-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-5(4,1)-piperidine-4(4, 1)-pyrazolo-1(1,4)-benzenecyclooctepene (Compound No. 6);
(E)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1( 1,4)-benzenecycloanedicarpene (Compound No. 7);
(E)-8-methyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 8);
(E)-8-ethyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 9);
(E)-8-propyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zolo-1(1,4)-benzenecycloanedicarpene (Compound No. 10);
(E)-1-(4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo -1(1,4)-benzenecyclodicarpen-8-yl)ethen-1-one (Compound No. 11);
(E)-8-(methylsulfonyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4, 1)-pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 12);
(E)-N-methyl-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyra Zola-1(1,4)-benzenecycloanedicarfen-8-carboxamide (Compound No. 13);
(E)-N-(4-chlorophenyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4 ,1)-pyrazolo-1(1,4)-benzenecycloanedicarpen-8-carbothioamide (Compound No. 14);
(E)-N-(3-acetylphenyl)-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4 ,1)-pyrazolo-1(1,4)-benzenecycloanedicarpen-8-carboxamide (Compound No. 15);
(E)-(4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1 (1,4)-Benzenecyclodicarpene-8-yl)(phenyl)methenone (Compound No. 16);
(E)-4 ¹ H-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazolo-1(1,4) -Benzenecycloanedicarpene (Compound No. 17);
(E)-1 ³ -Fluorine-4 ¹ H-11-oxa-3,8-diaza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)- Pyrazolo-1(1,4)-benzenecycloanedicarpene (Compound No. 18);
(4 ⁴ E,8E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1 (1,4)-Benzenecycloanedicarfen-8-ene (Compound No. 19);
(E)-4 ¹ H-10-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-8(2,3 )-Oxirana-1(1,4)-benzenecyclodicarpene (Compound No. 20); And
(E)-4 ¹ H-11-oxa-3-aza-2(7,2)-cyano[3,2-d]pyrimidine-4(4,1)-pyrazole-1(1,4 )-Benzenecycloanedicarpene-8,9-diol (Compound No. 21); a compound selected from the group consisting of, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof.
A pharmaceutical composition for preventing, reducing or treating tumor diseases comprising the compound of claim 1 or 3, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.
The method of claim 4,
The composition is a pharmaceutical composition for preventing, alleviating or treating tumor diseases caused by abnormal cell growth through inhibition of protein kinase.
The method of claim 5,
The compound has an inhibitory ability of 90% or more at 1 uM for protein kinase, a pharmaceutical composition for preventing, alleviating or treating tumor diseases.
The method of claim 5,
The protein kinases are ALK, ARK5, Aurora A, Aurora B, Aurora C, AXL, BLK, BMX, c-MET, c-src, CDK2, CK2a2, CLK1, CLK2, CLK4, DAPK1, DDR1, DDR2, DYRK2, DYRK3 , ERk7, FER, FES, FGFR1, FGFR2, FGFR3, FGR, FLT3, FLT4, DMS, FYN, HCK, HIPK1, HIPK2, HIPK4, HPK, IGF1R, IR, IRR, JAK1, JAK2, JAAK3, KDR, LCK, LOK , LRRK2, MARk4, MELK, MLK3, MYLK4, NEK1, NEK5, NEK9, p70S6K, PDGFRa, PDGFRb, PDK1, PEAK1, PIM1, PKCd, PKCeplsilon, PKCg, PKCmu, PKCnu, PKD2, RET, ROS, RSK3, RET, , RSK4, SIK1, SIK2, SNARK, STK16, STK38, STK38L, TRKA, TRKB, TRKC, TXK, TYK2, TYRO3, ULK1, YES, and any one or more of ZIPK, a pharmaceutical composition for the prevention, alleviation or treatment of tumor diseases.
delete The method of claim 4,
The tumor diseases include stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, Prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, hematologic cancer, lymphoma, and a tumor disease selected from the group consisting of fibroadenoma, a pharmaceutical composition for preventing, alleviating or treating tumor diseases. delete

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