KR101255566B1 - N5-(pyrimidine-4-yl)-1H-indazole-3,5-diamine Derivatives As an Inhibitor of Cell Proliferation, Enantiomers Thereof or Pharmaceutically Acceptable Salts Thereof And a Process For Preparing The Same - Google Patents

Abstract

(상기 화학식 1에서, R1은 수소; 아세틸; 페닐아세틸; 에폭시, 할로겐, 아미노, 페닐, 시아노 및 설폰아미드로 구성된 군에서 선택된 1 또는 2개의 기로 치환된 페닐아세틸; 벤조일 또는 할로겐, 아미노, 시아노 및 설폰아미드로 구성된 군에서 선택된 1 또는 2개의 기로 치환된 벤조일이고, R2는 할로겐; 히드록시; C1-C6 알킬 아민; C1-C6 알콕시, C1-C6 알킬 아미노, 히드록시, 몰포린, 피롤리딘, 피페라진, 피페리딘, C1-C6 알킬로 치환된 피페라진 및 C1-C6 알킬로 치환된 피페리딘으로 구성된 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 C1-C6 알킬 아민; C1-C6 알콕시; C1-C6 알콕시, C1-C6 알킬 아미노, 히드록시, 몰포린, 피롤리딘, 피페라진, 피페리딘, C1-C6 알킬로 치환된 피페라진 및 C1-C6 알킬로 치환된 피페리딘으로 구성된 군에서 선택된 하나 또는 그 이상의 치환기로 치환된 알콕시; 피페라진; 피페리딘 또는 몰포린이다.)The present invention relates to N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivatives represented by the following general formula (1), isomers thereof or pharmaceutically acceptable salts thereof:
[Formula 1]

(In Formula 1, R1 is hydrogen; acetyl; phenylacetyl; phenylacetyl substituted with one or two groups selected from the group consisting of epoxy, halogen, amino, phenyl, cyano and sulfonamide; benzoyl or halogen, amino, cya Benzoyl substituted with one or two groups selected from the group consisting of nos and sulfonamides, R2 is halogen; hydroxy; C1-C6 alkyl amine; C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pi C 1 -C 6 alkyl amine substituted with one or more substituents selected from the group consisting of lollidine, piperazine, piperidine, piperazine substituted with C 1 -C 6 alkyl and piperidine substituted with C 1 -C 6 alkyl; -C6 alkoxy; C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pyrrolidine, piperazine, piperidine, piperazine substituted with C1-C6 alkyl and piper substituted with C1-C6 alkyl One or more selected from the group consisting of ferridine Alkoxy substituted with a group; piperazine; is a piperidine or morpholine).

Description

N5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivatives, isomers thereof, or pharmaceutically acceptable salts thereof useful as cell proliferation inhibitors and methods for preparing the same {N5- (pyrimidine-4- yl) -1H-indazole-3,5-diamine Derivatives As an Inhibitor of Cell Proliferation, Enantiomers Thereof or Pharmaceutically Acceptable Salts Thereof And a Process For Preparing The Same}

The present invention provides a novel N ^5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, a method for preparing the same, and an abnormality containing the same as an active ingredient. A pharmaceutical composition for preventing or treating a cell proliferation related disease.

Cancer has historically been the leading cause of death for humankind, and the pattern of cancer caused by the development of industry and technology has changed. In particular, life expectancy and lifestyle changes had the greatest impact on the type and incidence of cancer. In other words, the incidence of some cancers has decreased significantly in this century, while the incidence of other cancers has increased with the aging of society. As age increases, the incidence of cancer increases and as life span increases, the likelihood of an individual becoming cancer increases (Rosemary C. Bonney, "Scrip's Guide to Cancer Therapies: A biotech revolution?" (2001)).

Cancer is the third leading cause of death worldwide after infectious and cardiovascular diseases, and in Western society the second leading cause of death after cardiovascular disease, according to WHO's World Health Report. In 2001, 7,115,000 people, 12.6% of all deaths, died of cancer. In addition, changes in eating habits, the environment, and lifespan are expected to increase the cancer population to about 30 million people annually within the next 25 years, of which 20 million people will die of cancer. In 2001, the number of cancer deaths in South Korea was the number one cause of death, with 60,086, or 24.8% of the total 242,730 deaths. Since 2000, cancer deaths have become the number one cause of death, excluding deaths from circulatory diseases. In addition, the total number of deaths does not change much compared to 10 or 20 years ago, but the number of deaths from cancer increased 1.5 times and 2.3 times, respectively.

As such, cancer is a destructive disease, but to a large extent preventable disease. It is reported that pain and burden caused by cancer can be reduced by improvements in basic research and treatment. Many studies have prevented about one-third of all cancers. In addition, about one third of cancers can be treated through effective treatments such as surgery, radiation, and chemotherapy. Therefore, identifying the cause of cancer through basic research and discovering a treatment that can effectively treat cancer will increase the possibility of preventing and treating cancer.

There are various methods of treating cancer patients, but generally surgical surgery, radiotherapy, chemotherapy, immunotherapy, and hormonal therapy are widely used. In general, surgical procedures can be applied at various stages of cancer. Early stage cancers can usually be treated with surgical procedures, but when the cancer is advanced or metastases have occurred, surgical treatment alone is difficult to treat, so other methods are used together. Radiation therapy is used to treat areas that are difficult to operate in surgery or cancers that are particularly sensitive to radiation, which may be used in combination with medication or before or after surgery. Drug therapy is a method of destroying or inhibiting DNA or related enzymes necessary for the proliferation of cancer cells by administering an anticancer agent orally or by injection. Compared to radiotherapy or surgical procedures, the advantages of drug therapy are that the drug can reach any cancer in any part of the body and can treat metastasized cancer. Currently, drug therapy is the standard therapy for treating metastatic cancer. Is being used. Of course, it is not possible to cure cancer metastasized by medication, but it plays an important role in relieving symptoms and extending lifespan.

Chemotherapeutic agents include alkylating agents, metabolic antagonists, antibiotics, plant-derived alkaloids, and hormonal agents. Biotherapeutic agents include cytokines and recombinant monoclonal antibodies. There is).

Most anticancer agents are bioactive small molecules extracted from natural products or artificially synthesized. With the development of molecular biology, the development of new drugs since the 1990s has mainly been driven by high throughput screening (HTS) for specific molecular targets. Early HTS was done in most cases by cell-free assays that measured the biochemical activity of purified proteins.

Recently, however, methods to analyze the cellular functions change or transfected change in finding new drug candidates. (Cell / phenotype-based screening ; cells / transfection-based screening) is widely used (Hart, CP Finding the target after screening the phenotype Drug Discov. Today 10: 513-519 (2005), Barberis, A. Cell-based high-throughput screens for drug discovery.Eur.Biopharm . Rev. Winter Issue (2002)). Trait-based screening does not require a separate protein purification process, it is possible to search for a function using a similar environment to physiological conditions, and has the advantage of eliminating the problems of cytotoxicity and cell permeability.

Although various chemotherapeutic agents have been developed, the research and development of drugs that can effectively cure without side effects in the treatment of diseases related to the proliferation of abnormal cells such as cancer are still insufficient. There is a need for new compounds that can inhibit abnormal cell proliferation, particularly the proliferation of abnormal cells related to cancer.

The present inventors earnestly researched to develop a compound capable of inhibiting abnormal cell proliferation based on cell growth and / or proliferation function, and as a result, effectively prevent abnormal cell proliferation such as cancer, inflammation, vascular stenosis and angiogenesis. By discovering new compounds that can be inhibited, the present invention has been completed.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

It is an object of the present invention to provide N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivatives, isomers thereof or pharmaceutically acceptable salts thereof that can effectively inhibit abnormal cell proliferation. To provide.

Another object of the present invention is to provide a method for preparing the N ^5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative.

Another object of the present invention is an abnormal cell proliferation comprising N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative, isomer thereof or pharmaceutically acceptable salt thereof as an active ingredient. To provide a pharmaceutical composition for the prevention or treatment of diseases associated with.

The present invention for achieving the above object is an N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by the following formula (1), isomers thereof or pharmaceutically acceptable salts thereof Provides:

[Formula 1]

In Formula 1, R1 is hydrogen; Acetyl; Phenylacetyl; Phenylacetyl substituted with one or two groups selected from the group consisting of epoxy, halogen, amino, phenyl, cyano and sulfonamide; Benzoyl or benzoyl substituted with one or two groups selected from the group consisting of halogen, amino, cyano and sulfonamides, R 2 is halogen; Hydroxy; C1-C6 alkyl amines; Consisting of C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pyrrolidine, piperazine, piperidine, piperazine substituted with C1-C6 alkyl and piperidine substituted with C1-C6 alkyl C1-C6 alkyl amines substituted with one or more substituents selected from the group; C1-C6 alkoxy; Consisting of C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pyrrolidine, piperazine, piperidine, piperazine substituted with C1-C6 alkyl and piperidine substituted with C1-C6 alkyl Alkoxy substituted with one or more substituents selected from the group; Piperazine; Piperidine or morpholine.

The present invention also comprises the steps of (a) reacting a compound of formula (2) and hydrazine to obtain a compound of formula (3); (b) introducing R 1 into the compound of Formula 3 to obtain a compound of Formula 4; (c) protecting the amine at position 1 indazole of the compound of formula 4 with a trityl group to obtain a compound of formula 5; (d) reducing the nitro group of the compound of formula 5 with a palladium catalyst under hydrogen air to obtain a compound of formula 6; (e) substitution of a compound of formula (6) pro-nucleophilic reactions; by introducing to the pyrimidine-2,4-dichloro-5-fluoro-through (S _N Ar reaction Nucleophilic Aromatic Substitution Reaction) to afford a compound of formula (7); (f) obtaining a compound of Formula 8 by introducing R 2 to a compound of Formula 7 through a nucleophilic substitution reaction (S _N Ar reaction); And (g) deprotecting the trityl group of the compound of Formula 8 to obtain a compound of Formula 1; N ^5- (pyrimidin-4-yl) -1H-indazole represented by the following Formula 1 Provided is a method for preparing a -3,5-diamine derivative.

The present invention also comprises the steps of (a) protecting the amino group of the compound of formula 3 with butoxycarbonyl (boc) to obtain a compound of formula (9); (b) obtaining the compound of formula 10 by reducing the nitro group of the compound of formula 9 with a palladium catalyst under hydrogen air; (c) replacing the parent compound of formula (10) nucleophilic reaction; by introducing to the pyrimidine-2,4-dichloro-5-fluoro-through (S _N Ar reaction Nucleophilic Aromatic Substitution Reaction) to afford a compound of Formula 11; (d) deprotecting the butoxycarbonyl (boc) of the compound of Formula 11 to obtain a compound of Formula 12; (e) introducing R 1 into the compound of Formula 12 to obtain a compound of Formula 13; (f) protecting the amine at the indazole 1 position of the compound of formula 13 with a trityl group to obtain a compound of formula 14; (g) obtaining a compound of Formula 15 by introducing R 2 to a compound of Formula 14 through a nucleophilic substitution reaction (S _N Ar reaction); And (h) deprotecting the trityl group of the compound of Formula 15 to obtain a compound of Formula 1; N ^5- (pyrimidin-4-yl) -1H-indazole represented by the following Formula 1 Provided is a method for preparing a -3,5-diamine derivative.

The present invention also comprises the steps of (a) protecting the amino group of the compound of formula 3 with trityl to obtain a compound of formula (16); (b) obtaining a compound of formula 17 by reducing the nitro group of the compound of formula 16 with a palladium catalyst under hydrogen air; (c) substituted striking of the compound of formula 17-nucleophilic reactions; by introducing to the pyrimidine-2,4-dichloro-5-fluoro-through (S _N Ar reaction Nucleophilic Aromatic Substitution Reaction) to afford a compound of Formula 18; (d) introducing R 2 to a compound of Formula 18 through a nucleophilic substitution reaction (S _N Ar reaction) to obtain a compound of Formula 19; (e) deprotecting the trityl group of the compound of formula 19 to obtain a compound of formula 20; And (f) introducing R 1 to the compound of Formula 20 to obtain a compound of Formula 1; N ^5- (pyrimidin-4-yl) -1H-indazol-3 represented by the following Formula 1; Provided is a method for preparing a 5-diamine derivative.

The present invention also relates to (a) a N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for the prevention or treatment of abnormal cell proliferation-related diseases comprising a pharmaceutically acceptable carrier.

N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivatives,, isomers thereof or pharmaceutically acceptable salts thereof according to the invention described above may be abnormal cells (eg, cancer). , Effectively inhibiting the proliferation of inflammation, vascular stenosis, restenosis or angiogenesis, thereby exhibiting very good efficacy in treating diseases and diseases related thereto.

According to one aspect of the present invention, the present invention provides a N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by the following Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable thereof Provide salts:

[Formula 1]

In Formula 1, R1 Is hydrogen, substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, hydroxy, substituted or unsubstituted amine, lower alkoxy or substituted lower alkoxy.

The compounds of the present invention described above are N ^5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivatives, which are effective in inhibiting the proliferation of abnormal cells, especially cancer cells.

According to a preferred embodiment of the present invention, in formula 1 R1 is hydrogen; Acetyl; Phenylacetyl; Phenylacetyl substituted with one or two groups selected from the group consisting of epoxy, halogen, amino, phenyl, cyano and sulfonamide; Benzoyl or benzoyl substituted with one or two groups selected from the group consisting of halogen, amino, cyano and sulfonamides, R 2 is halogen; Hydroxy; C1-C6 alkyl amines; Consisting of C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pyrrolidine, piperazine, piperidine, piperazine substituted with C1-C6 alkyl and piperidine substituted with C1-C6 alkyl C1-C6 alkyl amines substituted with one or more substituents selected from the group; C1-C6 alkoxy; Consisting of C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pyrrolidine, piperazine, piperidine, piperazine substituted with C1-C6 alkyl and piperidine substituted with C1-C6 alkyl Alkoxy substituted with one or more substituents selected from the group; Piperazine; Piperidine or morpholine.

In the context of the present invention, the term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, meaning that it does not contain any alkenes or alkyne moieties. The alkyl moiety may be a “unsaturated alkyl” moiety, meaning that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group of at least two carbon atoms consisting of at least one carbon-carbon double bond, and an "alkyne" moiety refers to at least two carbon atoms that represent at least one carbon-carbon triple bond. Means a group. In saturated or unsaturated the alkyl moiety can be branched, straight chain or cyclic.

Alkyl groups may have from 1 to 20 carbon atoms. The alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms, but preferably lower alkyl having 1 to 6 carbon atoms. For example, C ₁ -C ₄ alkyl is one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t- It may be selected from the group consisting of butyl.

The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O- Individually from carboxy, isocyanato, thiocyanato, isothiocyanato, amino including nitro, cyryl, trihalomethanesulfonyl, mono- and di-substituted amino groups, and protective derivatives thereof And one or more groups independently selected. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited to this.

In the context of the present invention, the term “aryl” has at least one ring having a shared pi electron field and is carbocyclic aryl (eg phenyl) and heterocyclic aryl group (eg Pyridine). The aryl includes monocyclic or fused ring polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups. In addition, the term "heteroaryl" refers to an aryl group containing at least one heterocyclic ring, and the term "heterocycle" means that the ring carbon is replaced with oxygen, nitrogen, sulfur, or the like. As a group, for example, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine , Isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine and the like, but is not limited thereto. .

The aryl group may be optionally substituted or unsubstituted. When substituted, the substituents are cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O- Individually from carboxy, isocyanato, thiocyanato, isothiocyanato, amino including nitro, cyryl, trihalomethanesulfonyl, mono- and di-substituted amino groups, and protective derivatives thereof And one or more groups independently selected. Representative aryl groups include a phenyl group derived from benzene, a naphthyl group derived from a condensed ring aromatic compound, an anthryl group, a phenanthryl group, and a biphenyl group derived from biphenyl. The compound which two aromatic rings directly bond is called biaryl.

In the context of the present invention, the expression “optionally substituted” means that the substituents are, for example, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy , Aryloxy, merceto, alkylthio, arylthio, oxo, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C Amido, N-amido, S-sulfonamido, N-sulfonamido, optionally substituted sulfonyl, C-carboxy, O-carboxy, isocyanato, thiocyanate, isothiocyane Ito, nitro, cyryl, trihalomethanesulfonyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, morpholinyl, furyl, thiazolidine, isoxazole, azetidinyl, dioxolane, pyra Genyl, thienyl, aziridine, oxazolidine, imidazole, alkanoic acid, alkanoate, mono And amino, including di-substituted amino groups, and substituted with one or more groups selected individually and independently from protective derivatives thereof. In some cases, these may also be optionally substituted.

In the context of the present invention, the term “O-carboxy group” is RC (═O) O—, “C-carboxy group” is —C (═O) OR, “acetyl group” is —C (═O) CH ₃ , the "trihalomethane sulfonyl" group is Y ₃ CS (= O) _2- , the "cyano group" is -CN, the "isocyanato" group is -NCO, the "thiocyanato" group is -CNS, "isothiocyanato" group is -NCS, "sulfinyl" group is -S (= O) -R, "S-sulfonamido" group is -S (= O) ₂ NR, "N -Sulfonamido "group is RS (= O) ₂ NH-," trihalomethanesulfonamido "group is Y ₃ CS (= O) ₂ NR-, and" O-carbamyl "group is -OC (= O) -NR, “N-carbamyl” group is ROC (= O) NH—, “O-thiocarbamyl” group is -OC (= S) -NR, “N-thiocarbamyl” group is ROC ( = S) NH-, "C-amido" group is -C (= O) -NR, "N-amido" group is RC (= O) NH-, "alkoxy" means -Oalkyl group, respectively In the context of the present invention, the expression “Y” means halogen and R is Kyl, cycloalkyl, aryl, heteroaryl (bonded via cyclic carbon) and heteroalicyclic (bonded via cyclic carbon) means a substituent selected from the group "halogen". And include, for example, fluoro, chloro, bromo and iodo, preferably fluoro or chloro, most preferably chloro The term “perhaloalkyl” also refers to all hydrogen atoms. Refers to an alkyl group substituted with halogen atoms, and other terms can be interpreted as meanings commonly understood in the art.

According to a preferred embodiment of the present invention, the following compounds may be mentioned as examples of the preferred compound represented by the general formula (1) of the present invention, but the present invention is not limited to these compounds:

1) N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -2- (4-ethoxyphenyl) acetamide,

2) 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (4-methylpiperazin-1-yl) pyrimidin-4-ylamino] -1 H-indazole- 3-yl} acetamide,

3) N- (5- {2-[(2-dimethylaminoethyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1H-indazol-3-yl) -2- (4- Ethoxyphenyl) acetamide,

4) N- (5- {2-[(3-dimethylaminopropyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1H-indazol-3-yl) -2- (4- Ethoxyphenyl) acetamide,

5) N- {5- [2- (3-diethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,

6) N- {5- [2- (3-dimethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl Acetamide,

7) N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,

8) N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl Acetamide,

9) N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl Acetamide,

10) N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,

11) 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (1-methylpiperidin-4-yloxy) pyrimidin-4-ylamino] -1-tri Yl-1H-indazol-3-yl} acetamide,

12) N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,

13) N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,

14) N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,

15) N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,

16) N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,

17) 2-biphenyl-4-yl-N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} Acetamide,

18) 2-biphenyl-4-yl-N- {5- [2- (2-diethylamino-ethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3- Acetamide,

19) 2-biphenyl-4-yl-N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} Acetamide,

20) 2-biphenyl-4-yl-N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl } Acetamide,

21) 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H-indazole- 3-yl} acetamide,

22) 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (1-methyl-2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H -Indazol-3-yl} acetamide,

23) 2-biphenyl-4-yl-N- (5- {5-fluoro-2- [1-methyl-2- (4-methylpiperazin-1-yl) ethoxy] pyrimidine-4- Monoamino} -1 H-indazol-3-yl) acetamide,

24) 2- (4-chlorophenyl) -N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} Acetamide,

25) 2- (4-chlorophenyl) -N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} Acetamide,

26) 2- (4-chlorophenyl) -N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl } Acetamide,

27) 2- (4-Chlorophenyl) -N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H-indazole- 3-yl} acetamide,

28) N ^5- (2- (2- (dimethylamino) ethoxy) -5-fluoropyrimidin-4-yl) -1H-indazol-3,5-diamine,

29) N ^5- (2- (2- (diethylamino) ethoxy) -5-fluoropyrimidin-4-yl) -1H-indazol-3,5-diamine,

30) 2- (4-chlorophenyl) -N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl } Acetamide,

31) 4-chloro-N- [5- (2-diethylaminomethoxy-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -benzamide,

32) N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1 H-indazol-3-yl] -benzamide,

33) N- [5 {(2-chloro-5-fluoropyrimidin-4-yl) amino} -1H-indazol-3-yl] -4- (diethylamino) benzamide,

34) N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -4-cyanobenzamide, or

35) 4-Chloro-N- [5 (5-fluoro-2-hydroxy-pyrimidin-4-ylamino) -1 H-indazol-3-yl] -benzamide

Since the compounds according to the present invention described above may have one or more chiral centers and / or geometric isomeric centers, the present invention relates to all stereoisomers represented by the formula (1), i. It may include isomers, diastereomers and geometric isomers.

Examples of specific compounds of the present invention are described in the Examples below.

According to another aspect of the present invention, the present invention provides a method for preparing a N ^5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative represented by the following Chemical Formula 1 including the following steps: It provides: (a) reacting a compound of formula 2 and hydrazine to obtain a compound of formula 3; (b) introducing R 1 into the compound of Formula 3 to obtain a compound of Formula 4; (c) protecting the amine at position 1 indazole of the compound of formula 4 with a trityl group to obtain a compound of formula 5; (d) reducing the nitro group of the compound of formula 5 with a palladium catalyst under hydrogen air to obtain a compound of formula 6; (e) obtaining the compound of formula 7 by introducing the compound of formula 6 into 2,4-dichloro-5-fluoropyrimidine via nucleophilic substitution reaction (S _N Ar reaction); (f) obtaining a compound of Formula 8 by introducing R 2 to a compound of Formula 7 through a nucleophilic substitution reaction (S _N Ar reaction); (g) deprotecting the trityl group of the compound of formula 8 to obtain a compound of formula 1. In Formula 1 to Formula 9, R 1 is substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, substituted or unsubstituted amine, lower alkoxy or substituted lower alkoxy.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

In the method for preparing N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by Formula 1, R1 is substituted or unsubstituted acetyl, or substituted or unsubstituted Benzoyl; R 2 is halogen, substituted or unsubstituted amine, lower alkoxy or substituted lower alkoxy.

Specific examples prepared by the method for preparing N ^5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative represented by Chemical Formula 1 are described in the following Examples.

As a specific example of the present invention, specific embodiments of the method for preparing N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by Chemical Formula 1 are summarized in Scheme 1 below. It is shown.

[Reaction Scheme 1]

According to another aspect of the present invention, the present invention provides a method for preparing a N5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative represented by the following Chemical Formula 1 including the following steps: It provides: (a) protecting the amino group of the compound of formula 3 with butoxycarbonyl (boc) to obtain a compound of formula (9); (b) obtaining the compound of formula 10 by reducing the nitro group of the compound of formula 9 with a palladium catalyst under hydrogen air; (c) introducing the compound of formula 10 into 2,4-dichloro-5-fluoropyrimidine via nucleophilic substitution reaction (S _N Ar reaction) to obtain a compound of formula 11; (d) deprotecting the butoxycarbonyl (boc) of the compound of Formula 11 to obtain a compound of Formula 12; (e) introducing R 1 into the compound of Formula 12 to obtain a compound of Formula 13; (f) protecting the amine at the indazole 1 position of the compound of formula 13 with a trityl group to obtain a compound of formula 14; (g) obtaining a compound of Formula 15 by introducing R 2 to a compound of Formula 14 through a nucleophilic substitution reaction (S _N Ar reaction); (h) deprotecting the trityl group of the compound of formula 15 to obtain a compound of formula 1. In Formula 1 and Formulas 9 to 15, R 1 is substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, substituted or unsubstituted amine, lower alkoxy, substituted lower alkoxy.

[Formula 1]

[Chemical Formula 9]

[Formula 10]

[Formula 11]

[Chemical Formula 12]

[Chemical Formula 13]

[Formula 14]

[Formula 15]

As another specific example of the present invention, specific embodiments of the method for preparing N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by Chemical Formula 1 are shown in Scheme 2 below. In summary.

[Reaction Scheme 2]

According to another aspect of the present invention, the present invention provides a method for preparing a N5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative represented by the following Chemical Formula 1 including the following steps: It provides: (a) protecting the amino group of the compound of formula 3 with trityl to obtain a compound of formula (16); (b) obtaining a compound of formula 17 by reducing the nitro group of the compound of formula 16 with a palladium catalyst under hydrogen air; (c) introducing the compound of formula 17 into 2,4-dichloro-5-fluoropyrimidine via nucleophilic substitution reaction (S _N Ar reaction) to obtain a compound of formula 18; (d) introducing R 2 to a compound of Formula 18 through a nucleophilic substitution reaction (S _N Ar reaction) to obtain a compound of Formula 19; (e) deprotecting the trityl group of the compound of formula 19 to obtain a compound of formula 20; (f) introducing R 1 to the compound of formula 20 to obtain a compound of formula 1. In Formula 1 and Formulas 16 to 20, R 1 is substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, substituted or unsubstituted amine, lower alkoxy or substituted lower alkoxy.

[Formula 1]

[Chemical Formula 16]

[Chemical Formula 17]

[Chemical Formula 18]

[Formula 19]

[Chemical Formula 20]

As another specific example of the present invention, specific embodiments of the method for preparing N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by Chemical Formula 1 may be represented by the following Scheme 3 It is shown in summary.

Scheme 3

According to another embodiment of the present invention, the present invention provides a N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative represented by the following formula (1), an isomer thereof, or a pharmaceutically thereof A pharmaceutical composition is provided for the prevention or treatment of a disease associated with abnormal cell proliferation, including an acceptable salt and a pharmaceutically acceptable carrier.

[Formula 1]

In Formula 1, R1 Is hydrogen, substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, hydroxy, substituted or unsubstituted amine, lower alkoxy or substituted lower alkoxy.

Since the pharmaceutical composition of the present invention uses the above-mentioned N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative of Formula 1 as an active ingredient, a common point is excessive in this specification. The description is omitted to avoid redundancy.

According to an embodiment of the present invention, specific examples of the derivative represented by Chemical Formula 1 included in the composition of the present invention include N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H -Indazol-3-yl] -2- (4-ethoxyphenyl) acetamide, 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (4-methylpiperazine -1-yl) pyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, N- (5- {2-[(2-dimethylaminoethyl) methylamino] -5-fluoro Pyrimidin-4-ylamino} -1H-indazol-3-yl) -2- (4-ethoxyphenyl) acetamide, N- (5- {2-[(3-dimethylaminopropyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1H-indazol-3-yl) -2- (4-ethoxyphenyl) acetamide, N- {5- [2- (3-diethylamino Propylamino) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl) acetamide, N- {5- [2- (3- Dimethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4 -Ethoxyphenyl) acetamide, N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} -2 -(4-ethoxyphenyl) acetamide, N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl) acetamide, N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3- Il} -2- (4-ethoxyphenyl) acetamide, N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazole -3-yl} -2- (4-ethoxyphenyl) acetamide, 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (1-methylpiperidine-4 -Yloxy) pyrimidin-4-ylamino] -1-trityl-1H-indazol-3-yl} acetamide, N- {5- [2- (3-diethylaminopropoxy) -5- Fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl) acetamide, N- {5- [2- (2-dimethylaminoethoxy)- 5-fluoropyrimidin-4-yl Mino] -1H-indazol-3-yl} acetamide, N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazole -3-yl} acetamide, N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} acetamide, N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2-biphenyl-4- Yl-N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2-biphenyl-4 -Yl-N- {5- [2- (2-diethylamino-ethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2-bi Phenyl-4-yl-N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2- Biphenyl-4-yl-N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2 -Biphenyl-4-yl-N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H-indazol-3-yl } Acetamide, 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (1-methyl-2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2-biphenyl-4-yl-N- (5- {5-fluoro-2- [1-methyl-2- (4-methylpiperazine-1 -Yl) ethoxy] pyrimidin-4-ylamino} -1H-indazol-3-yl) acetamide, 2- (4-chlorophenyl) -N- {5- [2- (2-dimethylamino Methoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2- (4-chlorophenyl) -N- {5- [2- (3-dimethylamino Propoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2- (4-chlorophenyl) -N- {5- [2- (3-di Ethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 2- (4-chlorophenyl) -N- {5- [5-fluoro -2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H-inda 3-yl} ^{acetamide, N 5 - (2- (2-} ( dimethylamino) ethoxy) -5-fluoro-pyrimidin-4-yl) -1H- indazole-3,5-diamine, N ⁵ -(2- (2- (diethylamino) ethoxy) -5-fluoropyrimidin-4-yl) -1H-indazol-3,5-diamine, 2- (4-chlorophenyl) -N- {5- [2- (2-Diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide, 4-chloro-N- [5- (2-Diethylaminomethoxy-5-fluoro-pyrimidin-4-ylamino) -1H-indazol-3-yl] -benzamide, N- [5- (2-chloro-5-fluoro -Pyrimidin-4-ylamino) -1H-indazol-3-yl] -benzamide, N- [5 [(2-chloro-5-fluoro-pyrimidin-4-ylamino) -1H-inda Zol-3-yl] -4-diethylamino-benzoamide or 4-chloro-N- [5 (5-fluoro-2-hydroxy-pyrimidin-4-ylamino) -1H-indazol-3 -Day] -benzamide.

In the composition of the present invention, not only N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative itself of Formula 1, but an isomer thereof or a pharmaceutically acceptable salt thereof is used as an active ingredient. May be included.

As used herein, the term “pharmaceutically acceptable salts” refers to formulations of compounds that do not cause serious irritation to the organism to which the compound is administered and do not impair the biological activity and properties of the compound. The term "isomer" also has the same meaning as above. The pharmaceutical salt is a compound of the present invention, such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, inorganic acids such as phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like, sulfonic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloro It can be obtained by reaction with organic carboxylic acids such as roacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. In addition, the compounds of the present invention are reacted with a base, such as alkali metal salts such as ammonium salts, sodium or potassium salts, salts such as alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, N-methyl-D-glucamine, It may be obtained by forming salts of organic bases such as tris (hydroxymethyl) methylamine and amino acid salts such as arginine or lysine.

In the context of the present invention, the term “isomer” means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but which is optically or stericly different. For example, the compound according to Formula 1 of the present invention may have an asymmetric center (asymmetric carbon atom) depending on the type of substituents, in which case the compound of Formula 1 is combined with enantiomers and diastereomers. May exist as the same optical isomer.

Unless stated otherwise, the term "compound according to the present invention" or "compound of formula 1" is used in the concept including all of the compound itself, an isomer thereof or a pharmaceutically acceptable salt thereof. have.

The compounds according to the invention are particularly effective for the treatment and prevention of diseases caused by abnormal cell growth and / or cell proliferation.

Examples of such diseases caused by abnormal cell growth and / or cell proliferation include, but are not limited to, cancer, inflammation, vascular stenosis, restenosis, angiogenesis or Kaposi's sarcoma.

The present invention therefore relates to a method of administering to a patient a pharmaceutically effective amount of a compound of formula 1 to reduce or alleviate abnormal proliferation / growth of cells. That is, the method of the present invention provides a method of treating and preventing diseases caused by abnormal cell growth and / or cell proliferation.

In the context of the present invention, the expression "abnormal cell growth (cell proliferation)" may be used interchangeably with the term "hyperproliferative disease". “Abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms, including abnormal growth of normal cells and growth of abnormal cells (eg, loss of contact inhibition).

Such abnormal cell growth includes (1) both benign and malignant tumor cells (tumors) that express activated Ras oncogenes; (2) tumor cells of both benign and malignant in which oncogene mutation in another gene results in activation of the tumor protein; (3) aberrant growth of malignant cells and benign of other proliferative diseases in which aberrations of Ras and tumor proteins are activated, but are not limited thereto. Examples of such benign proliferative diseases are psoriasis, benign prostatic hyperplasia, human papilloma virus (HPV) and retinopathy. “Abnormal cell growth” also refers to and includes abnormal growth of benign and malignant cells caused by abnormalities in cellular signaling processes.

In the context of the present invention, the phrase “treating” refers to reversing, alleviating, inhibiting or preventing the disease or condition to which the term applies, or one or more symptoms of the disease or condition, unless otherwise indicated. it means. As used herein, the term "treatment" refers to the act of treating when the expression "treating" is defined as above.

In the context of the present invention, the term “pharmaceutical composition” means a mixture of a compound of the present invention with other chemical components such as diluents or carriers.

The pharmaceutical composition facilitates administration of the compound into the organism. Various techniques for administering a compound exist, including but not limited to oral, injection, aerosol, parenteral or topical administration, and the like. The pharmaceutical composition may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term “therapeutically effective amount” means that the amount of the compound administered to alleviate to some extent one or more symptoms of the disorder being treated. Thus, a pharmacologically effective amount may be (1) to reverse the rate of progression of the disease or to reduce the size of the tumor in the case of cancer; (2) to prohibit further progression of the disease to some extent; Or preferably preferably an amount that has the effect of stopping tumor metastasis and / or (3) alleviating (preferably, removing) one or more symptoms associated with the disease.

The term “carrier” is defined as a compound that facilitates the addition of the compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of an organism.

The composition may further include a diluent or excipient, if necessary. The term “diluent” is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, since it mimics the salt state of the human solution. Since buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely modify the biological activity of the compounds.

The term “physiologically acceptable” is defined as a carrier or diluent that does not impair the biological activity and properties of the compound.

The compounds used herein may be administered to a human patient as such or as a pharmaceutical composition mixed with other active ingredients as in combination therapy or with a suitable carrier or excipient. Techniques for formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Ethyl acetateston, PA, 18th edition, 1990.

(a) route of administration

 Suitable routes of administration include, for example, oral, nasal, penetrating mucosa, enteral septum, direct intraventricular, intraperitoneal or intraocular injections, as well as parenteral delivery, including intramuscular, subcutaneous, intravenous or bone marrow injections. .

Also, for example, systemic administration may be by direct injection into solid tumors, often in immersion or sustained release formulations, or the compound may be administered in a local manner. It may also be administered as a targeted drug delivery system with a medicament such as a liposome coated with a tumor-specific antibody. Liposomes are targeted to and taken arbitrarily by the tumor.

(b) Compositions and Formulations

Pharmaceutical compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping and or lyophilizing processes.

Thus, a pharmaceutical composition for use according to the present invention comprises one or more pharmaceutically acceptable carriers which comprise excipients or auxiliaries which facilitate the treatment of the active compounds into formulations which can be used pharmaceutically. It may also be prepared by a conventional method using. Suitable formulations depend on the route of administration chosen. Any of the known techniques, carriers and excipients may be used as appropriate and as understood in the art, for example, Remingston's Pharmaceutical Sciences, supra.

For injection, the components of the invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution or physiological saline buffer. Noninvasive agents suitable for the barrier to pass for mucosal penetration administration are used in the formulation. Such impermeabilizers are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. Such carriers help the compounds of the invention be formulated into tablets, pills, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Pharmaceutical preparations for oral use can be prepared by mixing one or two or more compounds of the present invention with one or more excipients, optionally milling such mixture, and if necessary passing the appropriate adjuvant, then treating the mixture of granules Tablets or sugar cores can be obtained. Suitable excipients include filler corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium such as lactose, sucrose, mannitol, or sorbitol Cellulose based materials such as carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP), and the like. If necessary, a disintergrating agent may be added, such as crosslinked polyvinyl pyrrolidone, butadiene, or salts thereof such as alginic acid or sodium alginate.

Sugar cores are supplied by appropriate coating. For this purpose, optionally a concentrated sugar solution comprising arabide gum, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture This can be used. Dyestuffs or pigments may also be included in the tablets or sugars to characterize the active compound doses or to characterize other combinations thereof.

Pharmaceutical preparations which can be used orally may include soft sealing capsules made of gelatin, glycol or sorbitol, as well as pushable capsules made of gelatin. Capsules for push-fixing may also contain active ingredients, such as a filler such as lactose, a binder such as starch, and / or a mixture with talc or a lubricant such as magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may additionally be included. All formulations for oral administration should be in amounts suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated according to conventional methods.

For administration by inhalation, the compounds of use according to the invention typically use an appropriate propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Thus, it may be delivered in the form of aerosol injection provision from a pressurized pack or nebulisher. Capsules and cartridges, such as, for example, gelatin, may be formulated for use in inhalants or pulverulents, including powdered mixtures of compounds with suitable powders such as lactose or starch.

The compounds of the present invention may be formulated for parenteral administration by injection, for example by large pill injection or continuous infusion. Injectable formulations may be presented in unit dose form, for example, as ampoules or multi-dos containers, with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include components for formulation such as suspensions, stabilizers and / or dispersants.

Liquid formulations for parenteral administration include liquid solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty acids such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Liquid injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, dextran, and the like. In some cases, suspensions may contain components or stabilizers that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

The active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The compounds of the present invention may also be formulated in rectal dosage compositions such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may be formulated as deposits. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular infusion. Thus, the compounds of the invention have, for example, suitable polymers or hydrophobic materials (such as emulsions in acceptable oils), or ion exchange resins, or as low-soluble derivatives, for example low-soluble salts. It may also be formulated.

The formulation carrier for the hydrophobic compound of the present invention is a cosolvent system composed of benzyl alcohol, nonpolar surfactant, water-miscible organic polymer, and liquid phase. The cosolvent system may be a V palladium cosolvent system. The V palladium cosolvent system is a solution of benzyl alcohol 3% w / v made up to volume by anhydrous ethanol, nonpolar surfactant Polysorbate 80TM 85 w / v, and polyethylene glycol 300 65% w / v. The V palladium cosolvent system (V palladium: D5W) consists of V palladium diluted 1: 1 with 5% testrose in aqueous solution. This cosolvent system dissolves hydrophobic compounds well and provides itself with low toxicity upon systemic administration. Naturally, the proportion of cosolvent system may vary considerably without compromising its solubility and toxicological properties. Moreover, the identification of cosolvent components can be varied. For example, other low-toxic nonpolar surfactants can be used in place of Polysorbate 80, the fraction size of polyethylene glycol can be changed, and other biocompatible polymers can be substituted for polyethylene glycol such as polyvinyl pyrrolidone. can do. And other parties and polysaccharides may replace dextrose.

In addition, other delivery systems for hydrophobic drug compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles for hydrophobic agents. Usually organic solvents such as dimethylsulfoxide may be employed, even at the expense of higher toxicity. In addition, the compound may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic ingredient. Various sustained release materials have been developed and are known to those skilled in the art. Sustained release capsules can release the compound from 2 or 3 weeks to 100 days depending on its compound properties. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

Many compounds of the present invention may also be provided as salts with pharmaceutically acceptable counterions. Pharmaceutically acceptable salts may be formed with many acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to dissolve better in aqueous or proton solutions than their corresponding acid free or base forms.

(c) effective amount

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

A therapeutically effective amount for any compound used in the methods of the invention can be determined initially from cell culture assays. For example, the dose can be calculated in an animal model to obtain a range of circulating concentrations including the IC50 determined in cell culture. Such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficiency of the compounds described herein can be determined, for example, by cell culture or experimentation to determine LD50 (lethal dose for 50% of the population) and ED50 (dose with therapeutic effect for 50% of the population). Estimates can be made by surface pharmaceutical procedures in animals. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds showing high therapeutic indices are preferred. The data obtained from these cell culture assays can be used to estimate the range of doses used in humans. The dosage of such compounds is preferably in the range of circulating concentrations comprising ED50 in the absence or little toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact estimate, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (eg, Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 Reference). Typically, the dose range of the composition administered to the patient may be about 0.5 to 1000 mg / kg of the patient's body weight. Dosages may be given in a series of two or more at a time or in a day or more, depending on the extent required of the patient.

Dosages and intervals may be individually adjusted to provide plasma levels of the active site sufficient to maintain a kinase modulating effect or minimal effective concentration (MEC). The MEC depends on the individual compound, but may also be predicted from ex vivo data, such as, for example, the concentration required to achieve 50-90% inhibition of kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC or biological quantification can be used to determine plasma concentration.

Dosage intervals may be determined using MEC values. Compounds should be administered using a dosing regimen that maintains plasma levels above the MEC to be 10-90%, preferably 30-90%, most preferably 50-90% at a time.

In the case of topical administration or selective uptake, the effective local concentration of the agent may not be related to the plasma concentration.

Of course, the amount of composition to be administered will depend on the manner of administration and the judgment of the physician, depending on the subject, subject or pain severity to be treated.

According to a preferred embodiment of the present invention, the pharmaceutical composition comprising the derivative of formula 1 of the present invention has a very good efficacy in inhibiting abnormal cell proliferation related diseases, in particular, cancer, inflammation, vascular stenosis, restenosis or angiogenesis disease. Indicates.

One of the abnormal cell proliferations is acute and chronic lymphocytic leukemia, acute and chronic granulocytic leukemia, adrenal cortical tumors, bladder cancer, breast cancer, cervical cancer, cervical hyperplasia, chorionic cancer, rectal cancer, endometrial cancer, esophageal cancer, bone Congenital thrombocytopenia, genitourinary cancer, hairy cell leukemia, head and neck cancer, Hodgkin's disease (lymphoid endothelioma), Kaposi's sarcoma, lung cancer, lymphoma, malignant carcinoma, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medulla Goiter, multiple myeloma, myelosarcoma, myeloid leukemia, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, true erythrocytosis, primary brain tumor, primary macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, skin cancer Small cell lung cancer, soft tissue sarcoma, epithelial cell cancer, gastric cancer, testicular cancer, thyroid cancer and Wilm's tumor.

Examples of such inflammatory diseases include asthma, encephilitis, inflammatory enteritis, chronic obstructive pulmonary disease, allergies, pneumonia shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthrosis, arthritis, inflammatory osteolysis, and Chronic inflammation caused by chronic viral or bacterial infections, including but not limited to.

The vascular stenosis refers to a disease caused by narrowing of blood vessels, and the stenosis refers to a disease in which a vascular passage is narrowed after traumatization of a blood vessel wall. Vascular restenosis is known to be due to the proliferation, migration and secretion of extracellular matrix of vascular smooth muscle cells ( Circulation , 1997, 95, 1998-2002; J. Clin. Invest. 1997, 99, 2814-). 2816; Cardiovasc. Res. 2002, 54, 499-502).

Angiogenesis in the present invention is cancer, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, neovascular glaucoma, melanoma, proliferative retinopathy, psoriasis, hemophiliac joints, capillary proliferation in atherosclerotic plaques, keloids, Wound granulation, vascular stenosis, restenosis, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, restenosis, atherosclerosis, intestinal adhesion, cat scratch disease, ulcers, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant neurosis Thrombotic microangiopathy, organ transplant rejection, renal glomerulopathy, diabetes, inflammation or neurodegenerative diseases.

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]

In the following preparations and examples, all temperatures are in degrees Celsius unless otherwise indicated, and all parts and percentages are by weight or weight (weight / weight) parts or percent, solid / liquid unless otherwise noted Is (weight / volume) parts or%, and liquid / liquid is (volume / volume) parts or%. The reactions shown below were generally carried out in anhydrous solvent using a drying tube or under a positive pressure of argon or nitrogen at ambient temperature (unless stated otherwise), and the reaction flask was equipped with rubber for introducing substances and reagents through a scanning tube. The diaphragm was mounted. Glass articles were oven dried and / or heat dried. The reaction was analyzed by TLC and ended as judged by the consumption of starting material. Hydrogen gas reduction was carried out at the pressure mentioned in the examples or at ambient pressure. ¹ H-NMR spectra were recorded on a Bruker instrument operated at 400 Hz and ¹³ C-NMR spectra were recorded on an instrument operated at 100 Hz. NMR spectra were measured in CDCl ₃ solution (ppm) using either chloroform (7.25 ppm and 77.00 ppm) or CD3OD (3.4 and 4.8 ppm and 49.3 ppm) as references, or optionally internally tetramethylsilane (0.00 ppm). Recording). Other NMR solvents were used as needed.

The following abbreviations were used to record peak multiplicity: s (single line), d (double line), t (triple line), m (multiple line), dd (double line of double line), td (double line of double line) , qd (doublet of doublets) and coupling constants are given in hertz (Hz), if given.

Preparation Example 1 5-nitro-1H-indazol-3-ylamine

5.03 g (30.3 mmol) of 2-fluoro-5-nitrobenzonitrile and 4.4 mL (90.8 mmol) of hydrazine hydrate were added to 200 mL n-butanol, and the mixture was boiled under reflux for 4 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium carbonate solution. At this time, the undissolved compound was filtered under reduced pressure to obtain 0.78 g of the title compound, and ethyl acetate was dried over magnesium sulfate and removed by distillation under reduced pressure to obtain 4.36 g of the title compound. The two compounds were combined to give 5.14 g of the title compound in a yield of 95.2%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 12.19 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 9.2, 2.0 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H)

Preparation Example 2 4-ethoxyphenylacetyl chloride

After dissolving 10 g (60.2 mmol) of 4-ethoxyphenylacetic acid in 80 mL dichloromethane, 10 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added and stirred at room temperature for 2 hours. The solvent and remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Preparation Example 3: 2- (4-Ethoxy-phenyl) -N- (5-nitro-1H-indazol-3-yl) acetamide

4.36 g (24.5 mmol) of the compound obtained in Preparation Example 1 and the compound obtained in Preparation Example 2 were dissolved in 140 mL tetrahydrofuran, and 8 mL (60.2 mmol) of triethylamine was added thereto, and the mixture was boiled under reflux for 3 hours. 50 mL of 2N aqueous sodium hydroxide solution was added thereto, stirred at room temperature for 30 minutes, and the solvent was removed by distillation under reduced pressure. Ethyl acetate was added, followed by saturated aqueous sodium carbonate solution. The precipitated solid was filtered under reduced pressure to give 5.59 g of the title compound in a yield of 64.4%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 11.05 (s, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.14 (dd, J = 9.6 Hz, J = 2.0 Hz, 1H ), 7.69 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.00 (q, J = 6.8 Hz, 2H), 3.69 (s, 2H), 1.31 (t, J = 6.8 Hz, 3H)

Manufacturing example  4: 2- (4- Ethoxyphenyl ) -N- (5-nitro-1- Trityl -1H- Indazole -3 days) Acetamide

5.59 g (15.8 mmol) of the compound obtained in Preparation Example 3, 4.4 mL (3.16 mmol) of triethylamine and 4.4 g (1.58 mmol) of trityl chloride were added to 120 mL of acetonitrile, and stirred at room temperature for 1 hour. Boiled under reflux for 1 hour. After the solvent was removed by distillation under reduced pressure, the compound was dissolved in 40 mL of dichloromethane, and 160 mL of hexane was added to precipitate. The resulting solid was obtained by filtration under reduced pressure, and then washed with water, 5% aqueous citric acid solution and hexane to quantitatively obtain 6.95 g of the title compound.

Manufacturing example  5: N- (5-amino-1- Trityl -1H- Indazole -3-yl) -2- (4- Ethoxyphenyl ) Acetamide

2.67 g (4.58 mmol) of the compound obtained in Preparation Example 5 was dissolved in 200 mL of methanol, and a palladium catalyst was added thereto, followed by stirring at room temperature for 6 hours under hydrogen gas. Palladium was removed by filtration under reduced pressure using celite, and the solvent was removed by distillation under reduced pressure to obtain 2.78 g of the title compound.

¹ H NMR (400 MHz, CDCl ³ ): δ (ppm) 7.88 (s, 1 H), 7.21 (m, ¹⁷ H), 7.10 (d, J = 1.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H ), 6.42 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 6.15 (d, J = 8.8 Hz, 1H), 3.99 (q, J = 6.8 Hz, 2H), 2.04 (s, 2H), 1.39 (t, J = 6.8 Hz, 3H)

Manufacturing example  6: 2,4- Dichloro -5- Fluoropyrimidine

1.4 g (10.8 mmol) of 5-fluorouracil were added to 10 mL of phosphoryloxy chloride, followed by 1.6 mL (16.1 mmol) of 2-picoline, followed by stirring at 80 ° C. for 1 hour. After lowering the temperature of the reactant with an ice bath, 50 mL of 1N aqueous hydrochloric acid solution was added thereto, and the product was extracted with dichloromethane. Dichloromethane was removed by distillation under reduced pressure to obtain the title compound quantitatively.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.54 (s, 1H)

Preparation Example 7 N- [5- (2-Chloro-5-fluoropyrimidin-4-ylamino) -1-trityl-1H-indazol-3-yl] -2- (4-ethoxyphenyl Acetamide

2.59 g (4.69 mmol) of the compound obtained in Preparation Example 5, 1.4 g (8.38 mmol) of the compound 6, and 936 uL (7.03 mmol) of triethylamine were dissolved in 100 mL of N, N-dimethylformamide and stirred at room temperature for 10 hours. . N, N-dimethylformamide was removed by distillation under reduced pressure, and ethyl acetate was added thereto and washed with water. Purification by column chromatography using a hexane: ethyl acetate (1: 1) mixed solvent gave 1.57 g of the title compound in a yield of 48.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.89 (s, 1 H), 7.95 (d, J = 2.8 Hz, 1 H), 7.43 (dd, J = 9.2 Hz, J = 1.6 Hz, 1H), 7.28 (m, 17H), 6.88 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 9.6 Hz, 1H), 4.02 (q, J = 6.8 Hz, 2H), 3.68 (s, 2H), 1.41 (t, J = 7.2 Hz, 3H)

Example 1 N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -2- (4-ethoxyphenyl) acetamide

27 mg (0.039 mmol) of the compound obtained in Preparation Example 7 was dissolved in 2 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 20 minutes. 15 mL of water was added, washed with hexane, and the product was extracted with dichloromethane. Water was removed with magnesium sulfate, filtered under reduced pressure, dichloromethane was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (1: 4) mixed solvent to give 15.8 mg of the title compound in 90.7% yield. Got it.

¹ H NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ): δ (ppm) 10.22 (s, 1H), 9.65 (s, 1H), 8.03 (s, 1H), 7.98 (d, J = 2.8 Hz, 1H ), 7.58 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.01 (q, J = 6.8 Hz, 2H), 3.70 (s, 2H), 1.39 (t, J = 6.8 Hz, 3H)

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ (ppm) 207.06, 207.05, 157.72, 153.54, 152.26, 152.15, 146.91, 144.34, 140.77, 139.27, 130.60, 129.74, 128.24, 116.53, 114.64, 63.35, 41.79, 41.79 31.70, 31.21, 31.13, 30.65

Manufacturing example  8: 2- (4- Ethoxyphenyl ) -N- {5- [5- Fluoro -2- (4- Methylpiperazine -1-yl) pyrimidine-4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

86 mg (0.13 mmol) of the compound obtained in Preparation Example 7, 16.8 uL (0.151 mmol) of 1-methylpiperazine, and 20 uL (0.151 mmol) of triethylamine were added to 10 mL of chlorobenzene and boiled under reflux for 12 hours. After distillation under reduced pressure to remove chlorobenzene, ethyl acetate was added, washed with water, and distilled under reduced pressure to remove ethyl acetate. Obtained a yield of 79.8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.16 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 3.2 Hz, 1H), 7.19 (m, 17H ), 6.81 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 2.4 Hz, 1H), 6.32 (d, J = 9.2 Hz, 1H), 3.92 (q, J = 6.8 Hz, 2H), 3.72 (m, 4H), 3.53 (s, 2H), 2.41 (t, J = 4.8 Hz, 4H), 2.31 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H)

Example  2: 2- (4- Ethoxyphenyl ) -N- {5- [5- Fluoro -2- (4- Methylpiperazine -1-yl) pyrimidine-4- Amino ] -1H- Indazole -3 days} Acetamide

75.1 mg (0.101 mmol) of the compound obtained in Preparation Example 8 was dissolved in 3 mL of dichloromethane, and 0.3 mL of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 5 minutes. Water was added, washed with hexane and the product was extracted with dichloromethane. Purification by column chromatography using a hexane: ethyl acetate (1: 4) mixed solvent afforded 43 mg of the title compound in a yield of 67.4%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.01 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 3.6 Hz, 1H), 7.45 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.99 (q, J = 7.2 Hz , 2H), 3.69 (s, 2H), 3.66 (m, 4H), 3.27 (m, 3H), 2.50 (t, J = 4.4 Hz, 4H), 2.33 (s, 3H) 1.98 (m, 1H), 1.33 (t, J = 6.8 Hz, 3H), 1.25 (s, 1H)

Manufacturing example  9: N- (5- {2-[(2- Dimethylaminoethyl ) Methylamino ] -5- Fluoropyrimidine -4-yl army No} -1- Trityl -1H- Indazole -3-yl) -2- (4- Deoxyphenyl ) Acetamide

To a solution of 50 mg (0.073 mmol) of the compound obtained in Preparation Example 7 in 10 mL of chlorobenzene, 14.6 uL (0.11 mmol) of triethylamine and 14.3 uL (0.11 mmol) of N, N, N'-trimethyl ethylenediamine were added thereto. Boiled under reflux for 12 hours. 14.6 uL (0.11 mmol) of triethylamine and 14.3 uL (0.11 mmol) of N, N, N'-trimethylethylenediamine were added thereto, and the mixture was boiled under reflux for 6 hours. After distillation under reduced pressure to remove chlorobenzene, ethyl acetate was added and the organic layer was washed with a saturated aqueous sodium carbonate solution. Purification by column chromatography using a methanol: dichloromethane (10:90) mixed solvent gave 52.4 mg of the title compound in a yield of 95.5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.01 (s, 1H), 7.78 (d, J = 3.6 Hz, 1H), 7.26 (m, 17H), 6.90 (d, J = 8.4 Hz, 2H ), 6.42 (d, J = 9.2 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.67 (s, 2H), 3.64 (t, J = 6.4 Hz, 2H), 3.01 (s, 3H ), 2.82 (m, 2H), 2.34 (s, 6H), 1.41 (t, J = 6.8 Hz, 3H)

Example 3: N- (5- {2-[(2-dimethylaminoethyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1H-indazol-3-yl) -2- ( 4-ethoxyphenyl) acetamide

52.4 mg (0.070 mmol) of the compound obtained in Preparation Example 9 was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added thereto, followed by stirring for 1 minute. Water was added and washed with hexane. The aqueous layer was made to pH 13 using sodium hydroxide. The product was extracted with ethyl acetate and then the solvent was removed by distillation under reduced pressure. Purification by column chromatography using a chloroform: methanol: ammonia water (80: 10: 1) mixed solvent gave 11.5 mg of the title compound in a yield of 32.5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 11.1 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.42 (d , J = 8.4 Hz, 1H), 7.25 (d, J = 10.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 1H), 6.85 (m, 3H), 3.98 (q, J = 6.8 Hz, 2H ), 3.71 (s, 2H), 3.65 (t, J = 6.8 Hz, 2H), 3.09 (s, 3H) 2.56 (t, J = 7.2 Hz, 2H), 2.21 (s, 6H), 1.39 (t, J = 6.8 Hz, 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 171.06, 158.17, 157.63, 141.32, 139.63, 139.34, 139.15, 138.89, 131.26, 130.28, 126.63, 123.98, 116.21, 114.86, 113.70, 110.07, 110.07 63.53, 55.85, 47.27, 44.78, 42.32, 35.85, 14.56

Preparation Example 10 N- (5- {2-[(3-dimethylaminopropyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1-trityl-1H-indazol-3-yl ) -2- (4-ethoxyphenyl) acetamide

In a solution of 50 mg (0.073 mmol) of the compound obtained in Preparation Example 7 in 10 mL of chlorobenzene, 14.6 uL (0.11 mmol) of triethylamine and 16.1 uL of N, N, N'-trimethyl-1,3-propanediamine (0.11 mmol) was added thereto, and the mixture was boiled under reflux for 12 hours. 14.6 uL (0.11 mmol) of triethylamine and 16.1 uL (0.11 mmol) of N, N, N'-trimethyl-1,3-propanediamine were added thereto, and the mixture was boiled under reflux for 6 hours. Chlorobenzene was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to give 28.5 mg of the title compound in a yield of 51.0%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.08 (m, 2H), 7.83 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.23 (m, 17H ), 6.84 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 2.4 Hz, 1H), 6.32 (d, J = 9.2 Hz, 1H), 3.99 (q, J = 6.8 Hz, 2H), 3.64 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 3.03 (s, 3H) 2.28 (m, 2H), 2.18 (s, 6H), 1.73 (t, J = 7.2 Hz, 2H) , 1.39 (t, J = 7.2 Hz, 3H)

Example  4: N- (5- {2-[(3-dimethylaminopropyl) Methylamino ] -5- Fluoropyrimidine -4-yl army No} -1H- Indazole -3-yl) -2- (4- Ethoxyphenyl ) Acetamide

0.5 mL of trifluoroacetic acid was added to a solution of 28.5 mg (0.037 mmol) of the compound obtained in Preparation Example 10 in 5 mL of dichloromethane, and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous layer to make pH 13, and extracted with ethyl acetate. After distillation under reduced pressure to remove ethyl acetate, the residue was purified by column chromatography using a solvent of chloroform: methanol: ammonia (80: 10: 1) mixed solvent to obtain 10 mg of the title compound in a yield of 52.8%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.91 (s, 1 H), 7.79 (d, J = 4.0 Hz, 1H), 7.69 (dd, J = 8.8 Hz, J = 2.0 Hz , 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.03 (q, J = 6.8 Hz, 2H ), 3.73 (m, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.04 (s, 3H), 2.26 (t, J = 8.4 Hz, 2H), 2.13 (s, 6H) 1.71 (m, 2H), 1.42 (t, J = 6.8 Hz, 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 171.3, 158.1, 157.7, 139.6, 139.2, 138.9, 138.8, 138.7, 131.3, 130.3, 126.7, 123.9, 116.3, 114.7, 113.4, 110.0, 63.5, 56.7, 47.9, 44.4, 42.2, 35.6, 29.6, 24.6, 14.5

Preparation Example 11 N- {5- [2- (3-Diethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1-trityl-1H-indazol-3-yl}- 2- (4-ethoxyphenyl) acetamide

To a solution of 50 mg (0.073 mmol) of the compound obtained in Preparation Example 7 in 10 mL of chlorobenzene, 19.4 uL (0.15 mmol) of triethylamine and 23.2 uL (0.15 mmol) of 3-diethylaminopropylamine were added and refluxed for 42 hours. And boiled. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. Purification by column chromatography using a methanol: dichloromethane (10:90) mixed solvent afforded 25.6 mg of the title compound in a yield of 45.0%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.42 (s, 1H), 8.21 (s, 1H), 7.76 (d, J = 3.2 Hz, 1H), 7.25 (m, 17H), 7.05 (m , 1H), 6.85 (m, 2H), 6.78 (s, 1H), 6.32 (d, J = 9.2 Hz, 1H), 4.00 (m, 2H), 3.70 (s, 2H), 3.35 (m, 2H) , 2.92 (s, 6H) 1.99 (m, 2H), 1.40 (t, J = 6.8 Hz, 3H), 1.19 (m, 7H)

Example  5: N- {5- [2- (3- Diethylaminopropylamino ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

0.5 mL of trifluoroacetic acid was added to a solution of 25.6 mg (0.033 mmol) of the compound obtained in Preparation Example 11 in 5 mL of dichloromethane, and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous layer to make pH 13, and extracted with ethyl acetate. After distillation under reduced pressure to remove ethyl acetate, the residue was purified by column chromatography using a solvent of chloroform: methanol: ammonia (80: 10: 1) mixed solvent to obtain 9 mg of the title compound in a yield of 51.2%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.07 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.55 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H) 7.40 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.01 (q, J = 6.8 Hz, 2H), 3.71 (s, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.45 (m, 6H), 1.62 (m, 2H), 1.37 (s, 3H), 0.90 (t, J = 7.2 Hz, 6H)

Manufacturing example  12: N- {5- [2- (3- Dimethylaminopropylamino ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

50 mg (0.073 mmol) of the compound obtained in Preparation Example 7, 19.4 uL (0.15 mmol) of triethylamine, and 18.4 uL (0.15 mmol) of 3-diethylaminopropylamine were dissolved in 10 mL of chlorobenzene, and then refluxed for 42 hours. gave. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to obtain 25.6 mg of the title compound in a yield of 45.0%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.08 (s, 1 H), 7.69 (d, J = 3.6 Hz, 1 H), 7.34 (m, 1 H), 7.27 (m, 17 H) , 6.88 (d, J = 8.8 Hz, 2H), 6.37 (d, J = 9.2 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.68 (s, 2H), 3.32 (t, J = 8.0 Hz, 3H), 3.23 (t, J = 6.8 Hz, 2H), 2.18 (s, 6H), 1.68 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H)

Example 6: N- {5- [2- (3-dimethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} -2- (4-in Methoxyphenyl) acetamide

To a solution of 50.5 mg (0.067 mmol) of the compound obtained in Preparation Example 12 in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a chloroform: methanol: ammonia water (100: 10: 1) mixed solvent to give 18.9 mg of the title compound in a yield of 55.4%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.05 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.55 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.01 (q, J = 7.2 Hz , 2H), 3.72 (s, 2H), 3.22 (t, J = 6.8 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H), 2.16 (s, 6H), 1.66 (m, 2H) 1.37 ( t, J = 7.2 Hz, 3H)

Manufacturing example  13: N- {5- [2- (2- Diethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

A mixture obtained by dispersing 31.9 mg (0.73 mmol) of sodium hydride 55% in 1 mL of tetrahydrofuran in 0.5 mL of tetrahydrofuran and adding 39 uL (0.29 mmol) of N, N-diethylethanolamine to the preparation example 50 mg (0.073 mmol) of the compound obtained in 7 was added to 10 mL of chlorobenzene, and the mixture was boiled under reflux for 12 hours. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to obtain 27.2 mg of the title compound in a yield of 49.7%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.18 (m, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.90 (m, 1H), 7.26 (m, 25H), 6.87 (m , 3H), 6.36 (d, J = 9.2 Hz, 1H), 4.60 (m, 2H), 4.03 (q, J = 6.4 Hz, 2H), 3.72 (s, 2H), 3.15 (m, 2H), 2.96 (m, 4H), 1.74 (m, 4H), 1.41 (t, J = 3.8 Hz, 3H), 1.25 (m, 10H)

Example  7: N- {5- [2- (2- Diethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

To a solution of 27.2 mg (0.036 mmol) of the compound obtained in Preparation Example 13 in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a solvent of chloroform: methanol: ammonia (100: 10: 1) mixed solvent to obtain 11 mg of the title compound in a yield of 58.1%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.01 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.55 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.31 (t, J = 6.0 Hz , 2H), 4.04 (q, J = 6.8 Hz, 2H), 3.75 (s, 2H), 2.81 (t, J = 6.0 Hz, 2H), 2.60 (q, J = 7.6 Hz, 4H), 1.41 (t , J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 6H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 171.3 159.8 158.1 151.9 143.6 141.1 139.9 139.8 139.7 139.2 130.3 126.8 124.1 116.0 114.7 110.3 63.5 50.7 47.0 29.6 14.5 10.3

Preparation Example 14 N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1-trityl-1H-indazol-3-yl} -2 -(4-ethoxyphenyl) acetamide

31.9 mg (0.73 mmol) of sodium hydride 55% washed with 1 mL of tetrahydrofuran was added to 0.5 mL of tetrahydrofuran, and 34.3 uL (0.29 mmol) of 3-dimethylamino-1-propanol was added to the mixture. 50 mg (0.073 mmol) of the obtained compound was added to 10 mL of chlorobenzene, and refluxed for 12 hours to boil. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a chloroform: methanol: ammonia water (100: 10: 1) mixed solvent to obtain 19.3 mg of the title compound in a yield of 35.2%.

Example 8: N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4- Methoxyphenyl) acetamide

To a solution of 19.3 mg (0.026 mmol) of the compound obtained in Preparation Example 14 in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a solvent of chloroform: methanol: ammonia (100: 10: 1) mixed solvent to obtain 12.4 mg of the title compound in a yield of 95.1%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.04 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H) , 7.43 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.71 (s, 2H), 2.43 (m, 2H), 2.19 (s, 6H), 1.82 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 175.9, 164.1, 162.1, 147.3, 144.8, 143.7, 143.5, 143.0, 134.6, 133.8, 131.1, 127.7, 120.5, 118.2, 117.9, 113.9, 69.6, 67.0, 59.7, 47.7, 45.5, 30.1, 17.7

Manufacturing example  15: N- {5- [2- (2- Dimethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

31.9 mg (0.73 mmol) of sodium hydride 55% washed with 1 mL of tetrahydrofuran was added to 0.5 mL of tetrahydrofuran, and 29.3 uL (0.29 mmol) of 2- (dimethylamino) ethanol was added. 50 mg (0.073 mmol) of the obtained compound was added to 10 mL of chlorobenzene, refluxed for 2 hours, and boiled. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to obtain 21 mg of the title compound in a yield of 39%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.00 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.34 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 7.3 to 7.2 (m, 17H), 6.88 (d, J = 8.4 Hz, 2H), 6.39 (d, J = 9.2 Hz, 1H), 4.31 (t, J = 5.6 Hz, 2H) , 4.03 (q, J = 7.2 Hz, 2H), 3.67 (s, 2H), 2.73 (t, J = 6 Hz, 2H), 2.33 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H)

Example 9: N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} -2- (4-in Methoxyphenyl) acetamide

To a solution of 21 mg (0.029 mmol) of the compound obtained in Preparation Example 15 in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a solvent of chloroform: methanol: ammonia (100: 10: 1) mixed solvent to obtain 11 mg of the title compound in a yield of 78.2%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.99 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.54 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 6.0 Hz , 2H), 4.00 (q, J = 6.8 Hz, 2H), 3.71 (s, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.21 (s, 6H), 1.36 (t, J = 7.2 Hz , 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 175.9, 163.9, 162.1, 155.9, 147.4, 145.0, 143.7, 143.4, 143.0, 134.6, 133.8, 131.1, 127.8, 120.4, 118.2, 113.9, 69.0, 67.0, 61.2, 48.3, 45.5, 17.7

Manufacturing example  16: N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

63.9 mg (1.46 mmol) of sodium hydride 55% washed with 1 mL of tetrahydrofuran was added to 0.5 mL of tetrahydrofuran, and 87.3 uL (0.59 mmol) of 3- (diethylamino) -1-propanol was added to the mixture. 100 mg (0.15 mmol) of compound 7 was added to 10 mL of chlorobenzene, and the mixture was boiled under reflux for 2 hours. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to give 65.4 mg of the title compound in a yield of 57.6%.

Example  10: N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

To a solution of 65.4 mg (0.084 mmol) of the compound obtained in Preparation Example 16 in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a solvent of chloroform: methanol: ammonia (80: 10: 1) mixed solvent to obtain 31 mg of the title compound in a yield of 68.9%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.05 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.52 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.17 (t, J = 6.0 Hz , 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.71 (s, 2H), 2.53 (m, 6H), 1.79 (m, 2H), 1.73 (t, J = 6.8 Hz, 3H), 0.96 (t, J = 7.2 Hz, 6H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 175.8, 164.1, 162.1, 147.3, 144.8, 143.7, 143.5, 143.0, 134.6, 133.8, 131.1, 127.7, 120.4, 118.2, 118.0, 113.9, 69.9, 67.0, 52.8, 50.3, 45.5, 28.9, 17.7, 13.6

Preparation Example 17 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (1-methylpiperidin-4-yloxy) pyrimidin-4-ylamino] -1 -Trityl-1H-indazol-3-yl} acetamide

127.4 mg (2.92 mmol) of sodium hydride 55% washed with 1 mL of tetrahydrofuran was added to 0.5 mL of tetrahydrofuran and 134.5 mg (1.17 mmol) of 4-hydroxy-1-methylpiperidine were added. 100 mg (0.15 mmol) of compound 7 was added to 10 mL of chlorobenzene, and the mixture was boiled under reflux for 1 hour 30 minutes. Chlorobenzene was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed with a saturated aqueous sodium carbonate solution. The solvent was removed by distillation under reduced pressure, and then purified by column chromatography using a chloroform: methanol: ammonia water (100: 10: 1) mixed solvent to obtain 87.5 mg of the title compound in a yield of 78.7%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.89 (m, 3H), 7.23 (m, 20H), 6.80 (m, 2H), 6.36 (d, J = 9.2 Hz, 1H), 4.70 ( m, 1H), 3.93 (m, 2H), 3.60 (s, 2H), 2.64 (m, 3H), 2.26 (s, 2H), 2.21 (s, 3H), 2.14 (s, 1H), 2.01 (s , 2H), 1.87 (m, 3H), 1.69 (m, 3H), 1.32 (m, 3H)

Example 11: 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (1-methylpiperidin-4-yloxy) pyrimidin-4-ylamino] -1 H -Indazol-3-yl} acetamide

To a solution of 87.5 mg (0.12 mmol) of the compound obtained in Preparation Example 17 in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added and stirred for 1 minute. Water was added and washed with hexane. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was distilled off under reduced pressure, and then purified by column chromatography using a solvent of chloroform: methanol: ammonia (100: 10: 1) mixed solvent to obtain 54 mg of the title compound in a yield of 90.4%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.93 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 3.6 Hz, 1H), 7.52 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 9.2 Hz, 2H), 6.83 (d, J = 9.2 Hz, 2H), 4.77 (s, 1H), 3.96 (q, J = 5.2 Hz, 2H), 3.68 (s, 2H), 2.58 (m, 2H), 2.20 (m, 5H), 1.90 (m, 2H), 1.74 (m, 2H), 1.32 (t, J = 5.2 Hz, 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 175.7, 163.4, 162.1, 147.2, 144.7, 143.7, 143.6, 143.1, 134.4, 133.8, 130.9, 128.0, 120.3, 118.7, 118.2, 113.7, 75.5, 66.9, 55.9, 48.6, 45.5, 33.9, 17.8

Manufacturing example  18: 2- (4- Ethoxyphenyl ) -N- {5- [5- Fluoro -2- (2- Morpholine -4- Iethoxy ) Pyrimidin-4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

150 mg (0.22 mmol) of the compound obtained in Preparation Example 7 was dissolved in 10 mL of chlorobenzene, and then 96 mg (2.2 mmol) of sodium hydride 55% and 106.4 uL (0.878 mmol) of 4- (2-hydroxy) -morpholine were added. Was used in the same manner as in the synthesis of Compound 31. 37.1 mg of the title compound were obtained in a yield of 21.7%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.99 (d, J = 2 Hz, 1H), 7.86 (d, J = 3.2 Hz, 1H) 7.39 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.27-7.19 (m, 17H), 6.87 (d, J = 8.4 Hz, 2H), 6.38 (d, J = 9.2 Hz, 1H), 4.32 (t, J = 6.4 Hz, 2H), 4.01 (q, J = 6.8 Hz, 2H), 3.86 (m, 4H), 3.64 (s, 2H), 2.66 (t, J = 5.6 Hz, 2H), 2.49 (m, 4H), 1.40 ( t, J = 6.8 Hz, 3H)

Example  12: N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3-yl} -2- (4- Ethoxyphenyl ) Acetamide

37.1 mg (0.0477 mmol) of the compound obtained in Preparation Example 18 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 11. 20 mg of the title compound were obtained in a yield of 78.3%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.96 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 3.6 Hz, 1H), 7.60 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.36 (t, J = 5.6 Hz , 2H), 4.03 (q, J = 6.8 Hz, 2H), 3.74 (s, 2H), 3.65 (m, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.5 (m, 4H), 1.41 (t, J = 6.8 Hz, 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 170.8, 159.8, 158.0, 151.8, 143.5, 141.0, 139.8, 139.7, 139.6, 138.9, 130.2, 126.5, 123.9, 115.7, 115.0, 114.5, 110.2, 66.4, 64.5, 63.4, 56.9, 53.6, 42.2, 14.5

Manufacturing example  19: N- (5-nitro-1H- Indazole -3 days) Acetamide

To a solution of 1 g (5.61 mmol) of the compound obtained in Preparation Example 1 in 150 mL of tetrahydrofuran, 1.6 mL (22.5 mmol) of acetyl chloride and 3 mL (22.5 mmol) of triethylamine were added, followed by the same method as in Preparation Example 3. Experiment with. 1.11 g of the title compound were obtained in a yield of 89.8%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 8.99 (d, J = 2 Hz, 1H), 7.99 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 7.53 (d, J = 9.6 Hz , 1H), 2.13 (s, 3H)

Manufacturing example  20: N- (5-nitro-1- Trityl -1H- Indazole -3 days) Acetamide

1.1 g (4.99 mmol) of the compound obtained in Preparation Example 19 was dissolved in 200 mL of acetonitrile, and 997 uL (7.49 mmol) of triethylamine and 1.39 g (4.99 mmol) of trityl chloride were added thereto, followed by stirring at room temperature. After 3 hours, 997 uL (7.49 mmol) of triethylamine and 1.39 g (4.99 mmol) of trityl chloride were added, and after 24 hours, the solvent was removed by distillation under reduced pressure, dissolved in ethyl acetate, and saturated aqueous sodium bicarbonate solution and 5% citric acid. After washing with an aqueous solution, ethyl acetate was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and 1 g of the title compound was obtained in a yield of 43.3%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 9.10 (d, J = 2 Hz, 1H), 7.94 (s, 1H), 7.83 (dd, J = 5.6 Hz, J = 2 Hz, 1H), 7.31 ~ 7.16 (m, 15H), 6.41 (d, J = 9.6 Hz, 1H), 2.23 (s, 3H)

Manufacturing example  21: N- (5-amino-1- Trityl -1H- Indazole -3 days) Acetamide

1 g (2.16 mmol) of the compound obtained in Preparation Example 20 was dissolved in 30 mL of N, N-dimethylformamide and 100 mL of methanol, and the same experiment as in Preparation Example 5 was performed. The title compound was obtained quantitatively.

Manufacturing example  22: 2,4- Dichloro -5- Fluoropyrimidine

561 mg (4.32 mmol) of 5-fluorouracil was added to 3 mL phosphoryloxy chloride, followed by 642 uL of 2-picoline (6.48 mmol). The title compound was obtained quantitatively.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.54 (s, 1H)

Manufacturing example  23: N- [5- (2- Chloro -5- Fluoropyrimidine -4- Amino )-One- Trityl -1H- Indazole -3 days] Acetamide

The compound obtained in Preparation Example 21 and the compound obtained in Preparation Example 22 were dissolved in 150 mL of N, N-dimethylformamide, 863 uL (6.48 mmol) of triethylamine was added thereto, and the experiment was performed in the same manner as in Preparation Example 7. 585.8 mg of the title compound were obtained in a yield of 48.2%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.02 (d, J = 2 Hz, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.36 (dd, J = 9.6 Hz, J = 2.4 Hz, 1H), 7.28 (m, 15H), 6.44 (d, J = 9.2 Hz, 1H), 2.20 (s, 3H)

Preparation Example 24 N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1- Trityl -1H- Indazole -3 days} Acetamide

103 mg (2.36 mmol) of sodium hydride 55% washed with 1 mL of tetrahydrofuran was added to 0.5 mL of tetrahydrofuran, and 94.6 uL (0.945 mmol) of 2- (dimethylamino) ethanol was added. 133 mg (0.236 mmol) of the obtained compound were added to 10 mL of chlorobenzene, refluxed and boiled. After 1 hour, chlorobenzene was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium carbonate solution. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to give 98 mg of the title compound in a yield of 67.4%.

Example  13: N- {5- [2- (2- Dimethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3 days} Acetamide

98 mg (0.159 mmol) of the compound obtained in Preparation 24 was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added thereto, followed by stirring for 1 minute. 40 mL of 1N hydrochloric acid solution was added thereto, followed by extraction with 30 mL of hexane. Til was removed. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a solvent of chloroform: methanol: ammonia (80: 10: 1) mixed solvent to obtain 37 mg of the title compound in a yield of 62.3%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.06 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 9.2 Hz , J = 2 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 4.38 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 6 Hz, 2H), 2.33 (s, 6H ), 2.24 (s, 3H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 174.3, 163.8, 155.8, 147.5, 145.0, 143.5, 142.8, 134.5, 127.6, 120.1, 117.5, 114.2, 69.0, 61.4, 49.2, 26.5

Manufacturing example  25: N- {5- [2- (2- Diethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

133 mg (0.236 mmol) of the compound obtained in Preparation 23 was dissolved in 10 mL of chlorobenzene, and 103 mg (2.36 mmol) of sodium hydride 55% and 125.8 uL (0.945 mmol) of N, N-diethylethanolamine were prepared. The experiment was carried out in the same manner as in Example 24. 95 mg of the title compound were obtained in a yield of 62.5%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.17 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.24 (m, 15H), 7.14 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 6.39 (d, J = 9.2 Hz, 1H), 4.42 (t, J = 5.6 Hz, 2H), 3.04 (t, J = 5.6 Hz, 2H), 2.80 (q, J = 7.2 Hz, 4H), 2.16 (s, 3H), 1.07 (t, J = 7.2 Hz, 6H)

Example 14 N- {5- [2- (2-Diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} acetamide

95 mg (0.147 mmol) of the compound obtained in Preparation Example 25 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 13. 34 mg of the title compound were obtained in a yield of 57.6%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.00 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 9.2 Hz , J = 2 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 4.37 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.59 (q, J = 7.2 Hz, 4H), 2.25 (s, 3H), 1.01 (t, J = 7.2 Hz, 6H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 170.1, 159.8, 151.8, 143.4, 140.9, 139.6, 138.8, 130.3, 123.7, 116.0, 113.7, 110.2, 64.9, 50.7, 47.1, 22.6, 10.6

Manufacturing example  26: N- {5- [2- (3- Dimethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

133 mg (0.236 mmol) of compound 39 was dissolved in 10 mL of chlorobenzene, and 103 mg (2.36 mmol) of sodium hydride 55% and 110.8 uL (0.945 mmol) of 3-dimethylamino-1-propanol were used for Preparation Example 24. The experiment was conducted in the same manner. 132 mg of the title compound were obtained in a yield of 88.8%.

Example 15 N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} acetamide

132 mg (0.209 mmol) of the compound obtained in Preparation 26 was dissolved in 5 mL of dichloromethane, and the same experiment as in Example 13 was performed. 78.4 mg of the title compound were obtained in a yield of 96.5%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.16 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 3.6 Hz, 1H), 7.53 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 4.27 (t, J = 6 Hz, 2H), 2.45 (m, 2H), 2.22 (s, 3H), 2.20 (s, 6H) , 1.89 (m, 2 H)

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 170.1, 160.2, 151.9, 143.4, 140.9, 139.7, 139.6, 139.4, 138.9, 130.9, 123.5, 116.5, 113.5, 109.9, 65.8, 55.9, 44.0, 26.4 , 21.6

Preparation Example 27 N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1-trityl-1H-indazol-3-yl} acet amides

133 mg (0.236 mmol) of the compound obtained in Preparation Example 23 was dissolved in 10 mL of chlorobenzene, and then 103 mg (2.36 mmol) of sodium hydride 55% and 140.9 uL (0.945 mmol) of 3-diethylamino-1-propanol were used. Experiment was carried out in the same manner as in Preparation Example 24. 53 mg of the title compound were obtained in a yield of 34.1%.

Example 16: N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide

53 mg (0.0806 mmol) of the compound obtained in Preparation Example 27 was dissolved in 5 mL of dichloromethane, and experimented in the same manner as in Example 13. 16.5 mg of the title compound were obtained in a yield of 49.3%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.19 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.58 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 4.32 (t, J = 6 Hz, 2H), 2.69 (m, 2H), 2.63 (q, J = 5.2 Hz, 4H), 2.25 (s, 3H), 1.93 (m, 2H), 1.04 (t, J = 8.8 Hz, 6H)

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 170.7, 160.2, 151.9, 140.9, 139.7, 139.5, 138.9, 130.8, 123.6, 116.5, 113.7, 109.9, 65.9, 48.9, 46.4, 25.2, 21.6, 9.7

Preparation Example 28 bis (3-tert-butoxycarbonyl) amino-5-nitroindazole-1-carboxylic acid tert-butyl ester

1.7789 g (9.99 mmol) of the compound obtained in Preparation Example 1 was dissolved in 150 mL of tetrahydrofuran, followed by 8.72 g (39.9 mmol) of (Boc) 2 O, 5.31 mL (39.9 mmol) of triethylamine, and a small amount of 4-dimethylaminopyridine. After giving reflux to boil. After 3 hours, 2.18 g (9.99 mmol) of (Boc) 2 O and 1.32 mL (9.99 mmol) of triethylamine were added thereto, and the mixture was boiled under reflux. After 12 hours, tetrahydrofuran was removed by distillation under reduced pressure. 200 mL of ethyl acetate was added and washed with 5% aqueous citric acid solution. After drying over magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and 4.631 g of the title compound was obtained in a yield of 96.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.51 (dd, J = 2 Hz, J = 0.8 Hz, 1H), 8.42 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 8.32 ( d, J = 9.2 Hz, 1H), 1.74 (s, 9H), 1.46 (s, 18H)

Manufacturing example  29: 5-aminoo- bis (3- tert - Butoxycarbonyl Aminoindazole-1- Carboxylic acid  tert-butyl ester

4.631 g (9.68 mmol) of the compound obtained in Preparation Example 28 was dissolved in 150 mL of methanol, and tested in the same manner as in Preparation Example 5. 3.67 g of the title compound were obtained in a yield of 84.5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.92 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.69 (d, J = 2 Hz, 1H), 3.76 (s, 2H), 1.70 (s, 9H), 1.41 (s, 18H)

Preparation Example 30 bis (3-tert-butoxycarbonyl) amino-5- (2-chloro-5-fluoropyrimidine-4- Amino ) - Indazole -One- Carboxylic acid tert - butyl ester

The compound obtained in Preparation Example 29 and the compound obtained in Preparation Example 6 were dissolved in 150 mL of N, N-dimethylformamide, 2.18 mL (16.4 mmol) of triethylamine was added, and the same experiment as in Preparation Example 7 was performed. 3.297 g of the title compound were obtained in a yield of 67.7%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.14 (d, J = 8 Hz, 1H), 8.09 (d, J = 2.8 Hz, 1H), 8.01 (d, J = 2 Hz, 1H), 7.61 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 1.72 (s, 9H), 1.45 (s, 18H)

Manufacturing example  31: N5 -(2- Chloro -5- Fluoropyrimidine -4-yl) -1H- Indazole -3,5- Diamine

The compound obtained in Preparation Example 30 was dissolved in 40 mL of dichloromethane, 8 mL of trifluoroacetic acid was added thereto, followed by stirring at room temperature. After 2 hours, dichloromethane was removed by distillation under reduced pressure, dissolved in ethyl acetate, and washed with a saturated aqueous sodium carbonate solution. After drying over magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and 1.35 g of the titled compound was obtained in a yield of 87.4%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.98 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 2 Hz, 1H) 7.54 (dd, J = 8.8 Hz, J = 2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H)

Preparation Example 32 4-biphenylacetyl chloride

1.4 g (6.6 mmol) of 4-biphenylacetic acid was dissolved in 80 mL dichloromethane, and 3 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent and the remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Preparation Example 33 2-biphenyl-4-yl-N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1 H-indazol-3-yl] acetamide

735.7 mg (2.64 mmol) of the compound obtained in Preparation Example 31 was dissolved in 70 mL of tetrahydrofuran, and the compound obtained in Preparation Example 32 and 879 uL (6.6 mmol) of triethylamine were added thereto. Experiment was carried out in the same manner as in Preparation Example 3. 191 mg of the title compound were obtained in a yield of 15.3%.

Preparation 34: 2-biphenyl-4-yl-N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-trityl-1H-indazol-3-yl] Acetamide

169.3 mg (0.358 mmol) of the compound obtained in Preparation Example 33 was dissolved in 60 mL of acetonitrile, 143 uL (1.07 mmol) of triethylamine and 298.3 mg (1.07 mmol) of trityl chloride were added thereto, and the mixture was boiled under reflux. After 12 hours, 143 uL (1.07 mmol) of triethylamine and 298.3 mg (1.07 mmol) of tritylchloride were added thereto. After 2 hours, acetonitrile was removed by distillation under reduced pressure, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, and ethyl acetate was removed by distillation under reduced pressure, followed by column chromatography using dichloromethane: ethyl acetate (9: 1) mixed solvent. Purification of the compound to give 125.6 mg of the title compound in a yield of 49.1%.

Preparation Example 35 2-biphenyl-4-yl-N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1-trityl-1H- Indazol-3-yl} acetamide

103 mg (2.36 mmol) of sodium hydride 55% washed with 1 mL of tetrahydrofuran was added to 0.5 mL of tetrahydrofuran, followed by 64.2 uL (0.641 mmol) of 2- (dimethylamino) ethanol. 115 mg (0.16 mmol) of the obtained compound were added to 10 mL of chlorobenzene, refluxed and boiled. After 1 hour, chlorobenzene was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium carbonate solution. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to give 48.5 mg of the title compound in a yield of 38.5%.

Example 17 2-biphenyl-4-yl-N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3- Acetamide

48.5 mg (0.0616 mmol) of the compound obtained in Preparation Example 35 was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added thereto, followed by stirring for 1 minute. 40 mL of 1N hydrochloric acid solution was added thereto, followed by extraction with 30 mL of hexane. Til was removed. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using a chloroform: methanol: ammonia water (100: 10: 1) mixed solvent to obtain 31.2 mg of the title compound in a yield of 96.4%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.02 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 3.6 Hz, 1H) 7.58 (m, 5H), 7.50 ( d, J = 8 Hz, 2H), 7.42 (m, 3H), 7.32 (t, J = 7.6 Hz, 1H), 4.31 (t, J = 6 Hz, 2H), 3.85 (s, 2H), 2.64 ( t, J = 6 Hz, 2H), 2.23 (s, 6H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 171.3, 159.9, 152.1, 143.5, 141.1, 140.6, 139.9, 139.7, 139.5, 139.1, 134.2, 130.6, 129.5, 128.6, 127.0, 126.7, 123.9, 116.4, 114.3, 110.1, 65.0, 57.3, 44.7, 42.3

Manufacturing example  36: 2- Biphenyl -4-yl-N- {5- [2- (2- Diethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

0.115 g (0.16 mmol) of the compound obtained in Preparation 34 was dissolved in 10 mL of chlorobenzene, and 70 mg (1.6 mmol) of sodium hydride 55% and 85.4 uL (0.641 mmol) of N, N-diethylethanolamine were prepared. Experiment was carried out in the same manner as in Example 35. 18.5 mg of the title compound were obtained in a yield of 19.0%.

Example  18: 2- Biphenyl -4-yl-N- {5- [2- (2- Diethylamino - Ethoxy ) -5- Fluoropy Pyrimidin-4- Amino ] -1H- Indazole -3 days} Acetamide

18.5 mg (0.0303 mmol) of the compound obtained in Preparation Example 36 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 12.6 mg of the title compound were obtained in a yield of 75.1%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.00 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 3.6 Hz, 1H) 7.59 (d, J = 7.6 Hz, 4H), 7.53 (dd, J = 8.8 Hz, J = 2 Hz, 1H), 7.49 (d, J = 8 Hz, 2H), 7.42 (m, 3H), 7.31 (t, J = 7.6, 1H), 4.26 (t, J = 6 Hz, 2H), 3.83 (s, 2H), 2.70 (t, J = 6 Hz, 2H), 2.48 (q, J = 7.2 Hz, 4H), 0.91 (t, J = 7.2 Hz, 6H)

Manufacturing example  37: 2- Biphenyl -4-yl-N- {5- [2- (3- Dimethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

0.125 g (0.175 mmol) of the compound obtained in Preparation 34 was dissolved in 10 mL of chlorobenzene, and then 76.4 mg (1.75 mmol) of sodium hydride 55% and 82.1 uL (0.7 mmol) of 3-dimethylamino-1-propanol were used. Experiment was carried out in the same manner as in the synthesis method of 55. 52.4 mg of the title compound were obtained in a yield of 38.3%.

Example  19: 2- Biphenyl -4-yl-N- {5- [2- (3- Dimethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3 days} Acetamide

52.4 mg (0.067 mmol) of the compound obtained in Preparation Example 37 was dissolved in 5 mL of dichloromethane, and experimented in the same manner as in Example 17. 20.8 mg of the title compound were obtained in a yield of 57.5%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.06 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 3.6 Hz, 1H) 7.59 (m, 4H) 7.51 (m , 3H), 7.42 (m, 3H), 7.31 (t, J = 7.2, 1H), 4.17 (t, J = 6.4 Hz, 2H), 3.83 (s, 2H), 2.41 (m, 2H), 2.17 ( s, 6H), 1.80 (m, 2H)

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 171.4, 160.1, 143.3, 140.9, 140.6, 139.9, 139.7, 139.5, 139.1, 134.5, 130.7, 129.4, 128.5, 127.0, 126.8, 126.5, 123.8, 116.5 , 114.1, 110.0, 65.7, 55.8, 43.7, 42.0, 26.1

Manufacturing example  38: 2- Biphenyl -4-yl-N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoro Pyrimidine-4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

0.138 g (0.193 mmol) of the compound obtained in Preparation 34 was dissolved in 10 mL of chlorobenzene, and 84.2 mg (1.93 mmol) of sodium hydride 55% and 115 uL (0.72 mmol) of 3-diethylamino-1-propanol were used. Experiment was carried out in the same manner as in Preparation Example 35. 30 mg of the title compound were obtained in a yield of 19.2%.

Example  20: 2- Biphenyl -4-yl-N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3 days} Acetamide

30 mg (0.037 mmol) of the compound obtained in Preparation Example 38 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 14.4 mg of the title compound were obtained in a yield of 68.6%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.97 (m, 1H), 7.88 (m, 1H) 7.65 (m, 1H) 7.59 (m, 4H), 7.49 (d, J = 8 Hz, 2H), 7.42 (m, 3H), 7.35 (m, 1H), 4.22 (t, J = 6 Hz, 2H), 3.85 (s, 2H), 2.61 (m, 2H), 2.54 (q, J = 7.2 Hz, 4H), 1.86 (m, 2H), 1.02 (t, J = 7.2 Hz, 6H)

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 171.2, 160.1, 151.9, 143.4, 140.9, 140.6, 139.9, 139.7, 139.5, 139.1, 134.2, 130.6, 129.5, 128.6, 127.1, 126.7, 123.9, 116.4 , 114.2, 110.1, 66.0, 49.0, 46.4, 42.3, 25.1, 10.0

Preparation Example 39 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1-tri Yl-1H-indazol-3-yl} acetamide

64.3 mg (0.0899 mmol) of the compound obtained in Preparation 34 was dissolved in 10 mL of chlorobenzene, followed by 39.2 mg (0.899 mmol) of sodium hydride 55% and 43.6 uL (0.36 mmol) of 4- (2-hydroxyethyl) -morpholine. Experiment was carried out in the same manner as in Preparation Example 35 using. 20.6 mg of the title compound were obtained in a yield of 28.3%.

Example 21: 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H- Zol-3-yl} acetamide

20.6 mg (0.0254 mmol) of the compound obtained in Preparation Example 39 was dissolved in 5 mL of dichloromethane, and experimented in the same manner as in Example 17. 4.4 mg of the title compound was obtained in 30.5% yield.

¹ H NMR (400 MHz, CDCl ₃ + CD3OD): δ (ppm) 7.99 (m, 1H), 7.89 (d, J = 4 Hz, 1H), 7.60 (m, 5H), 7.49 (d, J = 8 Hz , 2H), 7.45 (t, J = 4 Hz, 2H), 7.39 (m, 1H), 7.35 (m, 1H), 4.36 (t, J = 6 Hz, 2H), 3.86 (s, 2H), 3.64 (m, 4H), 2.70 (t, J = 6 Hz, 2H), 2.49 (m, 4H)

Preparation Example 40 1-morpholin-4-ylpropan-2-ol

2 mL (28.5 mmol) of (±) -propylene oxide and 1.67 mL (19.0 mmol) of morpholine were mixed, refluxed and boiled. After 12 hours, the remaining (±) -propylene oxide was removed by distillation under reduced pressure. The title compound was obtained quantitatively.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 3.85 (m, 1H), 3.73 (m, 4H), 3.43 (s, 1H), 2.65 (m, 2H), 2.41 ~ 2.21 (m, 4H) , 1.14 (d, J = 6, 3H)

Manufacturing example  41: 2- Biphenyl -4-yl-N- {5- [5- Fluoro -2- (1- methyl -2- Morpholine -4- Iethoxy ) Pyrimidin-4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

64.3 mg (0.0899 mmol) of the compound obtained in Preparation Example 34 was dissolved in 10 mL of chlorobenzene, and then 39.2 mg (0.899 mmol) of sodium hydride 55% and 52.3 mg (0.36 mmol) of the compound obtained in Preparation Example 40 were prepared. The experiment was carried out in the same manner. 31 mg of the title compound were obtained in a yield of 41.8%.

Example 22: 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (1-methyl-2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide

31 mg (0.0376 mmol) of the compound obtained in Preparation Example 41 was dissolved in 5 mL of dichloromethane, and experimented in the same manner as in Example 17. 7.7 mg of the title compound were obtained in a yield of 35.2%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.94 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.59 (m, 5H), 7.50 ~ 7.33 (m, 6H), 5.16 (m, 1H), 3.86 (s, 2H), 3.54 (m, 4H), 2.60 (m, 1H), 2.38 (m, 5H), 1.29 (d, J = 6.4 , 3H)

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 166.4, 156.0, 147.9, 139.3, 136.8, 136.6, 136.1, 136.0, 135.8, 135.1, 129.7, 126.3, 125.6, 123.4, 123.2, 122.9, 120.3, 110.9 , 106.1, 66.8, 62.6, 59.4, 57.2, 49.8, 38.7, 14.4

Preparation Example 42 1- (4-methylpiperazin-1-yl) propan-2-ol

2 mL (28.5 mmol) of (±) -propylene oxide and 2.107 mL (19.0 mmol) of 1-methylpiperazine were mixed, refluxed and boiled. After 12 hours, the remaining (±) -propylene oxide was removed by distillation under reduced pressure. The title compound was obtained quantitatively.

Preparation Example 43 2-biphenyl-4-yl-N- (5- {5-fluoro-2- [1-methyl-2- (4-methylpiperazin-1-yl) ethoxy] pyrimidine- 4-ylamino} -1-trityl-1H-indazol-3-yl) acetamide

64.3 mg (0.0899 mmol) of the compound obtained in Preparation 34 was dissolved in 10 mL of chlorobenzene, and then 39.2 mg (0.899 mmol) of sodium hydride 55% and 57.0 mg (0.36 mmol) of the compound obtained in Preparation 42 were prepared. The experiment was carried out in the same manner. 9.4 mg of the title compound were obtained in a yield of 12.5%.

Example  23: 2- Biphenyl -4-yl-N- (5- {5- Fluoro -2- [1- methyl -2- (4- Methylpiperazine -1 day) Ethoxy ] Pyrimidin-4- Amino } -1H- Indazole -3 days) Acetamide

9.4 mg (0.0112 mmol) of the compound obtained in Preparation Example 43 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 2.5 mg of the title compound were obtained in 37.5% yield.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.91 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.60 (m, 5H), 7.51 ~ 7.33 (m, 6H), 5.12 (m, 1H), 3.86 (s, 2H), 2.66-2.31 (m, 10H), 2.22 (s, 3H), 1.28 (m, 3H)

Preparation 44: (4-chlorophenyl) acetyl chloride

2.42 g (14.2 mmol) of 4-chlorophenylacetic acid were dissolved in 70 mL dichloromethane, and 4 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent and the remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Manufacturing example  45: N- [5- (2- Chloro -5- Fluoropyrimidine -4- Amino ) -1H- Indazole -3-yl] -2- (4- Chlorophenyl ) Acetamide

1.3148 g (4.72 mmol) of the compound obtained in Preparation Example 31 were dissolved in 80 mL of tetrahydrofuran, and the compound obtained in Preparation Example 44 and 1.88 mL (14.2 mmol) of triethylamine were added thereto. Experiment was carried out in the same manner as in Preparation Example 3. 1.785 mg of the title compound were obtained in a yield of 87.8%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.97 (d, J = 3.2 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.8 Hz , J = 2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H) 7.35 (m, 4H), 3.79 (s, 2H)

Preparation Example 46 N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-trityl-1H-indazol-3-yl] -2- (4-chlorophenyl) Acetamide

1.785 g (4.14 mmol) of the compound obtained in Preparation Example 45 was dissolved in 100 mL of acetonitrile, 661 uL (4.97 mmol) of triethylamine and 1.15 mg (4.14 mmol) of trityl chloride were added, followed by stirring at room temperature. After 2 hours, 661 uL (4.97 mmol) of triethylamine and 1.15 mg (4.14 mmol) of tritylchloride were added thereto. After 2 hours, acetonitrile was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with 5% citric acid solution. Ethyl acetate was removed by distillation under reduced pressure, and purified by column chromatography using hexane: ethyl acetate (1: 1) and (2: 1) mixed solvent to obtain 1.281 g of the title compound in a yield of 45.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.09 (d, J = 1.6 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 7.31-7.19 (m, 19H) 6.40 (d, J = 9,2 Hz, 1H), 3.63 (s, 2H)

Preparation Example 47 2- (4-Chlorophenyl) -N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1-trityl-1H- Indazol-3-yl} acetamide

200 mg (0.297 mmol) of the compound obtained in Preparation 46 was dissolved in 10 mL of chlorobenzene, and 129.6 mg (2.97 mmol) of sodium hydride 55% and 119 uL (1.19 mmol) of 2- (dimethylamino) ethanol were used. Experiment was carried out in the same manner as in 35. 106.5 mg of the title compound were obtained in a yield of 49.4%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.98 (m, 1 H), 7.84 (d, J = 3.2 Hz, 1H), 7.36 (dd, J = 9.2 Hz, J = 2 Hz , 1H), 7.25 (m, 19H), 6.40 (d, J = 9.2 Hz, 1H), 4.29 (m, 2H), 3.63 (s, 2H), 2.67 (t, J = 5.2 Hz, 2H), 2.28 (s, 6H)

Example  24: 2- (4- Chlorophenyl ) -N- {5- [2- (2- Dimethylaminoethoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3 days} Acetamide

106.5 mg (0.147 mmol) of the compound obtained in Preparation Example 47 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 38.5 mg of the title compound were obtained in a yield of 54.1%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.99 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 3.2 Hz, 1H), 7.50 (dd, J = 9.2 Hz , J = 2 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.25 (t, J = 5.2 Hz, 2H), 3.70 (s, 2H), 2.65 (t, J = 5.2 Hz, 2H), 2.24 (s, 6H)

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 171.6, 170.9, 159.7, 143.7, 139.8, 139.7, 139.6, 139.2, 134.2, 132.6, 130.6, 128.3, 123.9, 116.4, 114.6, 110.1, 60.2, 53.4 , 31.4, 22.3

Preparation Example 48 2- (4-Chlorophenyl) -N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1-trityl-1H- Indazol-3-yl} acetamide

200 mg (0.297 mmol) of the compound obtained in Preparation 46 was dissolved in 10 mL of chlorobenzene, and then prepared using 129.6 mg (2.97 mmol) of 55% sodium hydride and 139.5 uL (1.19 mmol) of 3-dimethylamino-1-propanol. Experiment was carried out in the same manner as in Example 35. 48.7 mg of the title compound were obtained in a yield of 22.1%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.02 (m, 1H), 7.85 (d, J = 3.2 Hz, 1H), 7.34 ~ 7.18 (m, 20H), 6.41 (d, J = 9.6 Hz, 1H), 4.19 (t, J = 3.2 Hz, 2H), 3.67 (s, 2H), 2.67 (m, 2H), 2.39 (s, 6H), 1.92 (m, 2H)

Example 25 2- (4-Chlorophenyl) -N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3- Acetamide

48.7 mg (0.0658 mmol) of the compound obtained in Preparation 48 was dissolved in 5 mL of dichloromethane, and the same experiment as in Example 17 was performed. 13.5 mg of the title compound were obtained in a yield of 41.2%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.95 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.60 (dd, J = 9.2 Hz , J = 2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.33 (m, 4H), 4.23 (t, J = 6 Hz, 2H), 3.76 (s, 2H), 2.57 (m , 2H), 2.30 (s, 6H), 1.91 (m, 2H)

Manufacturing example  49: 2- (4- Chlorophenyl ) -N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

200 mg (0.297 mmol) of the compound obtained in Preparation 46 was dissolved in 10 mL of chlorobenzene, and 129.6 mg (2.97 mmol) of sodium hydride 55% and 177.4 uL (1.19 mmol) of 3-diethylamino-1-propanol were used. Experiment was carried out in the same manner as in Preparation Example 35. 42.9 mg of the title compound were obtained in a yield of 18.8%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.04 (m, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.32-7.20 (m, 20H), 6.41 (d, J = 9.2 Hz, 1H), 4.19 (t, J = 6 Hz, 2H), 3.68 (s, 2H), 2.76 (m, 6H), 1.91 (m, 2H), 1.12 (m, 6H)

Example  26: 2- (4- Chlorophenyl ) -N- {5- [2- (3- Diethylaminopropoxy ) -5- Fluoropyrimidine -4- Amino ] -1H- Indazole -3 days} Acetamide

42.9 mg (0.0558 mmol) of the compound obtained in Preparation Example 49 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 15.5 mg of the title compound were obtained in a yield of 52.8%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.94 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.63 (dd, J = 9.2 Hz , J = 2 Hz, 1H), 7.34 (m, 5H), 4.22 (t, J = 6 Hz, 2H), 3.76 (s, 2H), 2.58 (m, 6H), 1.87 (m, 2H), 1.01 (t, J = 7.2 Hz, 6H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 170., 160.0, 151.7, 143.3, 140.9, 139.7, 139.5, 138.9, 133.3, 132.9, 130.5, 128.6, 123.8, 123.8, 115.8, 114.1 , 110.2, 66.0, 46.4, 42.1, 25.1, 10.7, 10.4

Manufacturing example  50: 2- (4- Chlorophenyl ) -N- {5- [5- Fluoro -2- (2- Morpholine -4- Iethoxy ) Pyrimidin-4- Amino ]-One- Trityl -1H- Indazole -3 days} Acetamide

200 mg (0.297 mmol) of the compound obtained in Preparation 46 was dissolved in 10 mL of chlorobenzene, followed by 129.6 mg (2.97 mmol) of sodium hydride 55% and 144.1 uL (1.19 mmol) of 4- (2-hydroxyethyl) -morpholine. Experiment was carried out in the same manner as in Preparation Example 35 using. 115.1 mg of the title compound were obtained in a yield of 50.4%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.99 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 3.2 Hz, 1H), 7.37 (dd, J = 9.2 Hz , J = 1.6 Hz, 1H), 7.28-7.21 (m, 19H), 6.39 (d, J = 9.2 Hz, 1H), 4.31 (t, J = 5.6 Hz, 2H), 4.05 (s, 2H), 3.65 (m, 4H), 2.66 (t, J = 5.6 Hz, 2H), 2.48 (m, 4H)

Example 27: 2- (4-Chlorophenyl) -N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H- Zol-3-yl} acetamide

115.1 mg (0.15 mmol) of the compound obtained in Preparation Example 50 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 31 mg of the title compound were obtained in a yield of 39.3%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 12.73 (s, 1H), 10.70 (s, 1H), 9.58 (s, 1H), 8.09 (d, J = 3.2 Hz, 1H) , 7.97 (m, 1H), 7.56 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 7.42 (m, 5H), 4.23 (t, J = 5.6 Hz, 2H), 3.75 (s, 2H) , 3.48 (t, J = 4.4 Hz, 4H), 2.53 (m, 2H), 2.33 (m, 4H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 169.3, 160.2, 151.8, 143.8, 141.4, 141.0, 140.5, 139.0, 135.5, 131.8, 131.5, 130.6, 128.7, 124.1, 116.4, 110.4, 66.5, 64.6, 57.3, 53.9, 41.8

Preparation Example 51: (5-nitro-1-trityl-1H-indazol-3-yl) tritylamine

1 g (5.61 mmol) of the compound obtained in Preparation Example 1 was dissolved in 150 mL of acetonitrile, and 3.13 g (11.2 mmol) of trityl chloride and 1.49 mL (11.2 mmol) of triethylamine were added thereto. Stir at room temperature for 12 hours. Acetonitrile was removed by distillation under reduced pressure, and then dissolved in ethyl acetate and washed with 1N aqueous hydrochloric acid solution. After drying over magnesium sulfate, ethyl acetate was removed by distillation under reduced pressure, and 3.53 g of the title compound was obtained in a yield of 94.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.47 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 9.6 Hz, J = 2 Hz, 1H), 7.34-6.81 (m, 30H ), 6.27 (d, J = 9.6 Hz, 1H)

Preparation 52: N3,1-Ditrityl-1H-indazol-3,5-diamine

3.53 g (5.33 mmol) of the compound obtained in Preparation Example 51 was dissolved in 100 mL of N, N-dimethelformamide, and then experimented in the same manner as in Preparation Example 5. The title compound was obtained quantitatively.

Manufacturing example  53: 5- Fluoro -4- [1- Trityl -3- ( Tritylamino ) -1H- Indazole -5- Amino ] Pyrimidin-2-ol

The compound obtained in Preparation Example 52 and the compound obtained in Preparation Example 6 were dissolved in 50 mL of N, N-dimethylformamide, 709 uL (5.33 mmol) of triethylamine was added thereto, and the experiment was performed in the same manner as in Preparation Example 7. 1 g of the title compound was obtained in a yield of 24.6%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.00 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.31-6.89 (m, 31H), 6.30 (d , J = 9.2 Hz, 1H)

Manufacturing example  54: N5 -(2- (2- (dimethylamino) Ethoxy ) -5- Fluoropyrimidine -4-yl) -N3,1-ditrityl-1H- Indazole -3,5- Diamine

200 mg (0.262 mmol) of the compound obtained in Preparation Example 53 was dissolved in 10 mL of chlorobenzene, and 114.3 mg (2.62 mmol) of sodium hydride 55% and 105.2 uL (1.05 mmol) of 2- (dimethylamino) ethanol were prepared. Experiment was carried out in the same manner as in 35. 120 mg of the title compound were obtained in a yield of 56.1%.

Example 28 N5- (2- (2- (dimethylamino) ethoxy) -5-fluoropyrimidin-4-yl) -1H-indazol-3,5-diamine

120 mg (0.147 mmol) of the compound obtained in Preparation Example 54 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 35 mg of the title compound were obtained in a yield of 71.8%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 8.02 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.46 (dd, J = 8.8 Hz , J = 2 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 4.38 (t, J = 6 Hz, 2H), 2.73 (t, J = 6 Hz, 2H), 2.30 (s, 6H )

¹³ C NMR (100 MHz, CD ₃ OD): δ (ppm) 159.8, 151.6, 149.7, 143.5, 141.0, 139.4, 129.3, 123.2, 113.7, 111.8, 109.8, 64.9, 57.3, 45.2

Manufacturing example  55: N5 -(2- (2- ( Diethylamino ) Ethoxy ) -5- Fluoropyrimidine -4-yl) -N3,1-ditrityl-1H- Indazole -3,5- Diamine

200 mg (0.262 mmol) of the compound obtained in Preparation Example 53 was dissolved in 10 mL of chlorobenzene, and then prepared using 114.3 mg (2.62 mmol) of sodium hydride 55% and 139.6 uL (1.05 mmol) of N, N-diethylethanolamine. Experiment was carried out in the same manner as in Example 35. 185.5 mg of the title compound were obtained in a yield of 83.9%.

Example  29: N5 -(2- (2- ( Diethylamino ) Ethoxy ) -5- Fluoropyrimidine -4-yl) -1H-indazol-3,5- Diamine

185.5 mg (0.220 mmol) of the compound obtained in Preparation Example 55 was dissolved in 5 mL of dichloromethane, and then experimented in the same manner as in Example 17. 60 mg of the title compound were obtained in a yield of 76.0%.

¹ H NMR (400 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 7.99 (d, J = 2 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 9.2 Hz , J = 2 Hz, 1H), 7.27 (dd, J = 9.2 Hz, J = 0.8 Hz, 1H), 4.37 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.59 (q, J = 7.2 Hz, 4H), 1.05 (t, J = 7.2 Hz, 6H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ (ppm) 159.8, 151.6, 148.6, 143.4, 141.0, 139.3, 129.3, 123.3, 113.7, 111.9, 109.9, 65.0, 50.7, 47.1, 10.6

Preparation 56: (4-chlorophenyl) acetyl chloride

35.6 mg (0.209 mmol) of 4-chlorophenylacetic acid was dissolved in 6 mL dichloromethane, and 0.5 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent and the remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Example 30: 2- (4-Chlorophenyl) -N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3 Acylamide

30 mg (0.0835 mmol) of the compound obtained in Example 29 was dissolved in 8 mL of tetrahydrofuran, and the compound obtained in Preparation Example 56 and 27.8 uL (0.209 mmol) of triethylamine were added thereto. Experiment was carried out in the same manner as in Preparation Example 3. 2.9 mg of the title compound were obtained in a yield of 6.8%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.99 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 3.6 Hz, 1H), 7.53 (dd, J = 9.2 Hz, J = 2 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H) 7.41 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 6 Hz, 2H), 3.80 (s, 2H), 2.83 (t, J = 6 Hz, 2H), 2.63 (q, J = 5.2 Hz, 4H), 0.99 (t, J = 7.2 Hz, 6H)

Preparation 57: 4-chlorobenzoyl chloride

0.2389 g (1.53 mmol) of 4-chlorobenzoic acid was dissolved in 5 mL dichloromethane, and 1 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent and the remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Preparation 58: 4-Chloro-N- [5- (2-chloro-5-fluoro-pyrimidin-4-ylamino) -1 H-indazol-3-yl] -benzamide

170.1 mg (0.610 mmol) of the compound obtained in Preparation Example 31 was dissolved in 20 mL of tetrahydrofuran, and the compound obtained in Preparation Example 57 and 204 uL (1.53 mmol) of triethylamine were added and refluxed for 2 hours to boil. 20 mL of 2N aqueous sodium hydroxide solution was added thereto, stirred at room temperature for 1 hour, and then the solvent was removed by distillation under reduced pressure. Ethyl acetate was added and washed with saturated aqueous sodium bicarbonate solution. Ethyl acetate was removed by distillation under reduced pressure and purified by column chromatography using a methanol: dichloromethane (10:90) mixed solvent to give 128.9 mg of the title compound in a yield of 50.6%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 12.90 (s, 1H), 10.94 (s, 1H), 10.03 (s, 1H), 8.23 (d, J = 3.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.98-7.96 (m, 1H), 7.68-7.7.6 (m, 1H), 7.60 (d, J = 8 Hz, 2H), 7.53 (d, J = 9.2, 1H)

Manufacturing example  59: 4- Chloro -N- [5- (2- Chloro -5- Fluoro -Pyrimidine-4- Amino )-One- Trityl -1H- Indazole -3 days] Benzamide

128.9 mg (0.309 mmol) of the compound obtained in Preparation 58 was dissolved in 25 mL of acetonitrile, and 49.3 uL (0.371 mmol) of triethylamine and 103.4 mg (0.371 mmol) of trityl chloride were added thereto, and the mixture was boiled under reflux. After 1 hour, 246 uL of triethylamine (1.854 mmol) and 517.0 mg (1.854 mmol) of tritylchloride were added thereto. After 1 hour, acetonitrile was removed by distillation under reduced pressure, dissolved in ethyl acetate, washed with 5% aqueous citric acid solution, and ethyl acetate was removed by distillation under reduced pressure, followed by column chromatography using dichloromethane: ethyl acetate (9: 1) mixed solvent. Purification of the compound to give 123.6 mg of the title compound in a yield of 60.6%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.05 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.8, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.20-7.72 (m, 15H), 6.43 (d, J = 9.2 Hz, 1H)

Preparation 60: 4-Chloro-N- [5- (2-diethylaminomethoxy-5-fluoro-pyrimidin-4-ylamino) -1-trityl-1H-indazol-3-yl] Benzamide

123.6 mg (0.187 mmol) of the compound obtained in Preparation 59 was dissolved in 10 mL of chlorobenzene, followed by preparation of 81.6 mg (1.87 mmol) of sodium hydride 55% and 75.2 uL (0.75 mmol) of 2- (dimethylamino) ethanol. Experiment was carried out in the same manner as in 35. 59 mg of the title compound were obtained in a yield of 44.3%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.96 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.76 (d, J = 8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.26-7.19 (m, 17H), 6.98 (d, J = 2.8 Hz, 1H), 6.38 (d, J = 9.2, 1H) , 4.30 (t, J = 6 Hz, 2H), 2.56 (t, J = 5.6 Hz, 2H), 2.21 (s, 6H)

Example 31: 4-Chloro-N- [5- (2-diethylaminomethoxy-5-fluoro-pyrimidin-4-ylamino) -1 H-indazol-3-yl] benzamide

59 mg (0.147 mmol) of the compound obtained in Preparation 60 was dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added thereto, and stirred for 1 minute. Then, 50 mL of 1N hydrochloric acid solution was added thereto, followed by extraction with 30 mL of hexane. Til was removed. Sodium hydroxide was added to the aqueous solution to make pH 13, which was then extracted with ethyl acetate. Ethyl acetate was removed by distillation under reduced pressure, and then purified by prep TLC column chromatography using chloroform: methanol: ammonia water (80: 15: 1.5) mixed solvent to obtain 17.2 mg of the title compound in a yield of 44.2%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.32 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 3.6 Hz, 1H), 7.62 ~ 7.57 ( m, 3H), 7.52 (d, J = 9.2 Hz, 1H), 7.31 (s, 1H), 4.41 (t, J = 5.2 Hz, 2H), 2.73 (t, J = 5.2 Hz, 2H), 2.36 ( s, 6 H)

Example 32 N- [5- (2-Chloro-5-fluoro-pyrimidin-4-ylamino) -1 H-indazol-3-yl] -benzamide

Compound 89.9 obtained in Preparation Example 31. Mg (0.323 mmol) was dissolved in 25 mL of tetrahydrofuran, and 93.6 uL (0.806 mmol) of benzoyl chloride and 107 uL (0.806 mmol) of triethylamine were added to reflux and boiled. One hour later, 280.8 uL (2.418 mmol) of benzoyl chloride and 107 uL (0.806 mmol) of triethylamine were added thereto. After 2 hours, 10 mL of 2N aqueous sodium hydroxide solution was added thereto, stirred at room temperature for 1 hour, and the solvent was removed by distillation under reduced pressure. Ethyl acetate was added and washed with saturated aqueous sodium bicarbonate solution. After ethyl acetate was removed by distillation under reduced pressure, 104.9 mg of the title compound was obtained in a yield of 84.8%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 10.82 (s, 1H), 10.04 (s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.07 (d, J = 7.6 Hz, 2H) , 7.92 (s, 1H), 7.64-7.51 (m, 5H)

¹³ C NMR (100 MHz, DMSO): δ (ppm) 153.51, 152.22, 152.10, 146.92, 144.36, 141.57, 141.36, 140.65, 139.24, 134.15, 133.17, 132.32, 130.25, 130.08, 129.04, 128.92, 128.29, 123.50. , 115.37, 110.85

Manufacturing example  61: 4- Diethylaminobenzoyl  Chloride

0.1871 g (0.968 mmol) of 4-diethylaminobenzoic acid was dissolved in 10 mL dichloromethane, and 1 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent and the remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Example  33: N- [5 {(2- Chloro -5- Fluoropyrimidine -4-yl) amino} -1 H- Indazole -3-yl] -4- ( Diethylamino ) Benzamide

Compound 107.9 obtained in Preparation Example 31. Mg (0.387 mmol) was dissolved in 25 mL of tetrahydrofuran, and the compound obtained in Preparation Example 61 and 129 uL (0.968 mmol) of triethylamine were added to reflux and boiled. After 1 hour, 25 mL of 2N aqueous sodium hydroxide solution was added thereto, stirred at room temperature for 1 hour, and the solvent was removed by distillation under reduced pressure. Ethyl acetate was added and washed with saturated aqueous sodium bicarbonate solution. Ethyl acetate was removed by distillation under reduced pressure, and then purified by column chromatography using dichloromethane: methanol (10:90) mixed solvent, and then purified by column chromatography using chloroform: methanol: ammonia water (100: 10: 1) mixed solvent. Then, the resultant was purified by prep TLC column chromatography using hexane: ethyl acetate: methanol (40: 60: 1) mixed solvent to obtain 5.5 mg of the title compound in a yield of 0.33%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 12.77 (s, 1 H), 10.37 (s, 1 H), 10.03 (s, 1 H), 8.24 (d, J = 3.2 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8, 2H), 3.38 (s, 4H), 1.11 (t, J = 6.8, 6H)

Preparation 62: 4-Cyanobenzoyl Chloride

0.233 g (1.58 mmol) of 4-cyano-benzoic acid was dissolved in 20 mL dichloromethane, and 2 mL of thionyl chloride and a catalytic amount of N, N-dimethylformamide were added thereto, and the mixture was stirred at room temperature for 2 hours. The solvent and the remaining thionyl chloride were removed by distillation under reduced pressure to obtain the title compound quantitatively.

Example 34 N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -4-cyanobenzamide

Compound 176.5 obtained in Preparation Example 31. Mg (0.633 mmol) was dissolved in 20 mL of tetrahydrofuran, and the compound obtained in Preparation Example 62 and 253 uL (1.90 mmol) of triethylamine were added to reflux and boiled. After 2 hours, 20 mL of 2N aqueous sodium hydroxide solution was added thereto, stirred at room temperature for 1 hour, and the solvent was removed by distillation under reduced pressure. Ethyl acetate was added and washed with saturated aqueous sodium bicarbonate solution. Ethyl acetate was removed by distillation under reduced pressure, followed by column chromatography using hexane: ethyl acetate (1: 4) mixed solvent, followed by column chromatography using dichloromethane: methanol (10:90) mixed solvent. Then, 25.7 mg of the title compound was obtained in a yield of 9.96%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 8.25 (s, 1H), 8.25 (d, J = 3.6 Hz, 1H), 8.21 (d, J = 8 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.97 (s, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H)

Manufacturing example  63: 4- Chloro -N- [5- (5- Fluoro -2- Hydroxy -Pyrimidine-4- Amino ) -1- Lee Teal-1H- Indazole -3 days]- Benzamide

30.2 mg (0.046 mmol) of the compound obtained in Preparation Example 59 was dissolved in 5 mL of dimethyl sulfoxide, and then reacted for 10 minutes under microwave at 180 ° C. and 70 W. After further reacting for 10 minutes under the same conditions, water was added and extracted with ethyl acetate. Water was removed over magnesium sulfate, and the residue was filtered under reduced pressure, ethyl acetate was distilled off under reduced pressure, and 28.3 mg of the title compound was obtained in a yield of 96.4%.

¹ H NMR (400 MHz, DMSO): δ (ppm) 8.21 (d, J = 3.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 1.6 Hz, 1H), 7.65 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.33-7.20 (m, 15H)

Example  35: 4- Chloro -N- [5 (5- Fluoro -2- Hydroxy -Pyrimidine-4- Amino ) -1H-indazol-3-yl]- Benzamide

28.3 mg (0.044 mmol) of the compound obtained in Preparation Example 63 was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added for 1 minute, followed by stirring for 1 minute. 50 mL of 1N hydrochloric acid solution was added thereto, followed by extraction with 30 mL of hexane. Til was removed and extracted with ethyl acetate. Water was removed with magnesium sulfate, and the residue was filtered under reduced pressure, ethyl acetate was distilled off under reduced pressure, and then purified by column chromatography using a chloroform: methanol: ammonia water (100: 10: 1) mixed solvent, followed by chloroform: methanol: ammonia water (100 : 10: 1) 2 mg of the title compound was obtained in a yield of 11.4% by prep TLC column chromatography using a mixed solvent.

¹ H NMR (400 MHz, DMSO): δ (ppm) 8.09 (d, J = 1.6 Hz, 1H), 8.07 to 8.03 (m, 3H), 7.64 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H) , 7.55 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H)

Experimental Example: Cancer Cell Growth Inhibition Effect Experiment

HN3, HN4, Caki, HepG2 tumor cells and Fibroblast were found in DMEM (Dulbecco's modified Eagle's medium) containing 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin and 100 mg / ml streptomycin. ) Was cultured using a medium (Welljin, South Korea). A549, Hec-1-A, Hep-1, SNU 484 tumor cells were treated with RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin and 100 mg / ml streptomycin (Welzine, South Korea). And cultured using.

In order to measure the tumor cell growth inhibitory effect of the compound, each tumor cell was first dispensed into 3-103 cells / well in a 96-well plate and cultured for 10 hours to stabilize the cells.

Various synthesized compounds were added thereto at a final concentration of 10 μM and incubated for 24 hours or 48 hours, and the effect of the added compounds on various tumor cell growth was measured using SRB (sulforhodamine B (Sigma, USA) analysis. . Intermittently, 70 μl of SRB reagent (dissolved in 1% acetic acid solution to 0.4%) was added to each well containing cells, and left at room temperature for 20 minutes. SRB was removed and then washed 5 times with 1% acetic acid solution and dried. 200 μl of 10 mM Tris-base solution (Sigma, USA) was added and then shaken with a shaker for 10 minutes. Absorbance (OD) was measured at a wavelength of 492 nm using a 96 well plate reader. In addition, SRB analysis was performed using cells cultured under the same conditions without addition of the compound as a control, and OD was measured.

Table 1 shows the results of the growth inhibition IC50 values of the growth inhibitory capacity measured for the representative compounds of Formula 1 and their cancer cells.

* ND: No experiment

As shown in the above results, Compound 1 of the present invention was found to be very effective in inhibiting the growth of cancer cells in typical cancers of abnormal cell growth (cell proliferation) diseases.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (8)

delete N ^5- (pyrimidin-4-yl) -1H-indazole-3,5-diamine derivative represented by the following formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1, R1 is hydrogen; acetyl; phenylacetyl; phenylacetyl substituted with one or two groups selected from the group consisting of epoxy, halogen, amino, phenyl, cyano and sulfonamide; benzoyl or halogen, amino, cya Benzoyl substituted with one or two groups selected from the group consisting of nos and sulfonamides, R2 is halogen; hydroxy; C1-C6 alkyl amine; C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pi C 1 -C 6 alkyl amine substituted with one or more substituents selected from the group consisting of lollidine, piperazine, piperidine, piperazine substituted with C 1 -C 6 alkyl and piperidine substituted with C 1 -C 6 alkyl; -C6 alkoxy; C1-C6 alkoxy, C1-C6 alkyl amino, hydroxy, morpholine, pyrrolidine, piperazine, piperidine, piperazine substituted with C1-C6 alkyl and piper substituted with C1-C6 alkyl One or more selected from the group consisting of ferridine Alkoxy substituted with a group; piperazine; is a piperidine or morpholine).
The method of claim 2, wherein the derivative
1) N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -2- (4-ethoxyphenyl) acetamide,
2) 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (4-methylpiperazin-1-yl) pyrimidin-4-ylamino] -1 H-indazole- 3-yl} acetamide,
3) N- (5- {2-[(2-dimethylaminoethyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1H-indazol-3-yl) -2- (4- Ethoxyphenyl) acetamide,
4) N- (5- {2-[(3-dimethylaminopropyl) methylamino] -5-fluoropyrimidin-4-ylamino} -1H-indazol-3-yl) -2- (4- Ethoxyphenyl) acetamide,
5) N- {5- [2- (3-diethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,
6) N- {5- [2- (3-dimethylaminopropylamino) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl Acetamide,
7) N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,
8) N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl Acetamide,
9) N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxyphenyl Acetamide,
10) N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,
11) 2- (4-ethoxyphenyl) -N- {5- [5-fluoro-2- (1-methylpiperidin-4-yloxy) pyrimidin-4-ylamino] -1-tri Yl-1H-indazol-3-yl} acetamide,
12) N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} -2- (4-ethoxy Phenyl) acetamide,
13) N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,
14) N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,
15) N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,
16) N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} acetamide,
17) 2-biphenyl-4-yl-N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} Acetamide,
18) 2-biphenyl-4-yl-N- {5- [2- (2-diethylamino-ethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3- Acetamide,
19) 2-biphenyl-4-yl-N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl} Acetamide,
20) 2-biphenyl-4-yl-N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl } Acetamide,
21) 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H-indazole- 3-yl} acetamide,
22) 2-biphenyl-4-yl-N- {5- [5-fluoro-2- (1-methyl-2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H -Indazol-3-yl} acetamide,
23) 2-biphenyl-4-yl-N- (5- {5-fluoro-2- [1-methyl-2- (4-methylpiperazin-1-yl) ethoxy] pyrimidine-4- Monoamino} -1 H-indazol-3-yl) acetamide,
24) 2- (4-chlorophenyl) -N- {5- [2- (2-dimethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} Acetamide,
25) 2- (4-chlorophenyl) -N- {5- [2- (3-dimethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1H-indazol-3-yl} Acetamide,
26) 2- (4-chlorophenyl) -N- {5- [2- (3-diethylaminopropoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl } Acetamide,
27) 2- (4-Chlorophenyl) -N- {5- [5-fluoro-2- (2-morpholin-4-ylethoxy) pyrimidin-4-ylamino] -1 H-indazole- 3-yl} acetamide,
28) N ^5- (2- (2- (dimethylamino) ethoxy) -5-fluoropyrimidin-4-yl) -1H-indazol-3,5-diamine,
29) N ^5- (2- (2- (diethylamino) ethoxy) -5-fluoropyrimidin-4-yl) -1H-indazol-3,5-diamine,
30) 2- (4-chlorophenyl) -N- {5- [2- (2-diethylaminoethoxy) -5-fluoropyrimidin-4-ylamino] -1 H-indazol-3-yl } Acetamide,
31) 4-chloro-N- [5- (2-diethylaminomethoxy-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -benzamide,
32) N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1 H-indazol-3-yl] -benzamide,
33) N- [5 {(2-chloro-5-fluoropyrimidin-4-yl) amino} -1H-indazol-3-yl] -4- (diethylamino) benzamide,
34) N- [5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-indazol-3-yl] -4-cyanobenzamide, or
35) N5- (characterized in that 4-chloro-N- [5 (5-fluoro-2-hydroxy-pyrimidin-4-ylamino) -1H-indazol-3-yl] -benzamide Pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative, isomer thereof or pharmaceutically acceptable salt thereof.
(a) reacting a compound of Formula 2 and a hydrazine to obtain a compound of Formula 3;
(b) introducing R 1 into the compound of Formula 3 to obtain a compound of Formula 4;
(c) protecting the amine at position 1 indazole of the compound of formula 4 with a trityl group to obtain a compound of formula 5;
(d) reducing the nitro group of the compound of formula 5 with a palladium catalyst under hydrogen air to obtain a compound of formula 6;
(e) introducing the compound of formula 6 into 2,4-dichloro-5-fluoropyrimidine via a Nucleophilic Aromatic Substitution Reaction to obtain a compound of formula 7;
(f) obtaining a compound of Formula 8 by introducing R 2 into a compound of Formula 7 through a nucleophilic substitution reaction (SNAr reaction); And
(g) deprotecting the trityl group of the compound of Formula 8 to obtain a compound of Formula 1; N5- (pyrimidin-4-yl) -1H-indazol-3 represented by the following Formula 1 Method for preparing, 5-diamine derivative.
[Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

(Wherein R 1 is substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, substituted or unsubstituted amine, lower alkoxy or substituted lower alkoxy.)
(a) protecting the amino group of the compound of formula 3 with butoxycarbonyl (boc) to obtain a compound of formula 9;
(b) obtaining the compound of formula 10 by reducing the nitro group of the compound of formula 9 with a palladium catalyst under hydrogen air;
(c) introducing a compound of Formula 10 into 2,4-dichloro-5-fluoropyrimidine via a Nucleophilic Aromatic Substitution Reaction to obtain a compound of Formula 11;
(d) deprotecting the butoxycarbonyl (boc) of the compound of Formula 11 to obtain a compound of Formula 12;
(e) introducing R 1 into the compound of Formula 12 to obtain a compound of Formula 13;
(f) protecting the amine at the indazole 1 position of the compound of formula 13 with a trityl group to obtain a compound of formula 14;
(g) obtaining a compound of formula 15 by introducing R 2 to a compound of formula 14 through nucleophilic substitution reaction (SNAr reaction); And
(h) deprotecting the trityl group of the compound of Formula 15 to obtain a compound of Formula 1; N5- (pyrimidin-4-yl) -1H-indazol-3 represented by the following Formula 1 Method for preparing, 5-diamine derivative.
[Formula 1]

(3)

[Chemical Formula 9]

[Formula 10]

(11)

[Chemical Formula 12]

[Chemical Formula 13]

[Chemical Formula 14]

[Chemical Formula 15]

Wherein R 1 is substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, substituted or unsubstituted amine, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ Alkoxy.)
(a) protecting the amino group of the compound of formula 3 with trityl to obtain a compound of formula 16;
(b) obtaining a compound of formula 17 by reducing the nitro group of the compound of formula 16 with a palladium catalyst under hydrogen air;
(c) introducing a compound of formula 17 into 2,4-dichloro-5-fluoropyrimidine via a Nucleophilic Aromatic Substitution Reaction to obtain a compound of formula 18;
(d) introducing R 2 to a compound of Formula 18 through a nucleophilic substitution reaction (SNAr reaction) to obtain a compound of Formula 19;
(e) deprotecting the trityl group of the compound of formula 19 to obtain a compound of formula 20; And
(f) introducing R 1 to a compound of Formula 20 to obtain a compound of Formula 1; N5- (pyrimidin-4-yl) -1H-indazol-3,5- Method for preparing a diamine derivative.
[Formula 1]

(3)

[Chemical Formula 16]

[Chemical Formula 17]

[Chemical Formula 18]

[Chemical Formula 19]

[Chemical Formula 20]

Wherein R 1 is substituted or unsubstituted acetyl, or substituted or unsubstituted benzoyl; R 2 is halogen, substituted or unsubstituted amine, C ₁ -C ₆ alkoxy or substituted C ₁ -C ₆ alkoxy .)
N ^5- (pyrimidin-4-yl) -1H-indazol-3,5-diamine derivative of claim 2, an isomer thereof or a pharmaceutically acceptable salt thereof; And a pharmaceutically acceptable carrier. A pharmaceutical composition for preventing or treating one or more abnormal cell proliferation-related diseases selected from the group consisting of cancer, inflammatory disease, vascular stenosis, restenosis and angiogenesis.

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