KR20160002318A - Pyrimidine derivative compounds and use thereof - Google Patents

Abstract

The present invention relates to a novel pyrimidine derivative compound having inhibitory activities with respect to TAK1 kinase, and to a pharmaceutical composition comprising the same for preventing or treating cancer or tumor. According to the present invention, pyrimidine derivatives in chemical formula 1 can be usefully used as a medicine or a prevention agent of cancer or tumor, with excellent inhibitory activities with respect to TAK1 kinase. The compound is selected from the pyrimidine derivatives in the chemical formula 1, pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate thereof, and a solvate thereof.

Description

PYRIMIDINE DERIVATIVE COMPOUNDS AND USE THEREOF FIELD OF THE INVENTION [0001]

The present invention relates to a novel pyrimidine derivative compound and its use, and more particularly, to a novel pyrimidine derivative compound having an inhibitory activity against TAK1 kinase and a pharmaceutical composition for preventing or treating cancer or tumor comprising the same .

Protein kinase is an enzyme that plays an important role in intracellular signal transduction through the phosphorylation of hydroxyl groups present in the tyrosine, serine or threonine residues of proteins. It is deeply involved in cell growth, differentiation and proliferation. do.

In order for cells to maintain homeostasis, the on and off of intracellular signaling processes must be balanced. However, when the normal intracellular signal transduction process (mainly intracellular signal transduction) is induced by overexpression or mutation of a specific protein kinase, various diseases such as various cancers, inflammatory diseases, metabolic diseases or brain diseases are induced. Protein kinase is presumed to contain 518 species, which accounts for about 1.7% of total human genes, and is largely divided into tyrosine protein kinases (over 90 species) and serine / threonine protein kinases.

Medically important serine / threonine kinases include the family of mitogen-activated protein kinases (MAPKs), which act on a variety of biological processes. MAPK is activated by phosphorylation by MAPK kinase (MAPKK) at specific tyrosine and threonine residues, and MAPKK is activated by phosphorylation by MAPKK kinase (MAPKKK) at serine and serine / threonine residues. The MAPKKK group includes several including MEKK1, MEKK3, NIK and ASK1 and Raf. Several mechanisms are involved in the activation of MAPKKK by various extracellular stimuli including cytokines, proliferative factors and environmental stress.

(TGF-beta) -activated kinase 1 (TGF beta-activated kinase-1, TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) group, and the transforming growth factor- (IL-1), tumor necrosis factor-alpha (TNF-a), lipopolysaccharide, receptor activators of NF-kB ligands (e.g., regulate osteoclast differentiation and activation) Lt; RTI ID = 0.0 > -8 < / RTI > TAK1 regulates the cascade of both c-Jun N terminal kinase (JNK) and p38 MAPK, phosphorylating the MAPK kinases MKK4 and MKK3 / 6, respectively.

The NF-kB factor controls the expression of various genes involved in apoptosis, cell cycle, transformation, immune response and cell adhesion. TAK1 regulates the IκB kinase (IKK) signaling pathway, resulting in the activation of transcription factors AP-1 and NF-κB. TAK1 is also a negative regulator of the Wnt signaling pathway, and TAK1 down-regulates transcriptional regulation mediated by a complex of beta -catenin and T-cell factor / lymphoproliferative factor. The role of TAK1 in signaling by TNF- [alpha] and IL-1 [beta] induction can be confirmed from TAK1 RNAi experiments in mammalian cells, where NF- [kappa] B and MAPK Both of which were inhibited.

Overexpression of kinase dead TAK1 inhibits both JNK / p38 and NF-kB activation by IL-1 and TNK induction. Embryonic fibroblasts of TAK1 - / - mice are weak and weakly embryonic lethal by decreasing IL-1 induced signaling. TAK1 is activated after pressure overload in the myocardium of adult mice. Expression of constitutively active TAK1 in myocardium causes cardiac hypertrophy and heart failure in transgenic mice.

TAK1 is activated by association of the TAK1 binding protein (TAB1) with the N-terminal kinase domain of TAK1. It is reported that 68 amino acids of C-terminal of TAB1 are sufficient for the assembly and activation of TAK1. However, more recent studies have revealed that the minimum TAB1 segment required only includes residues 480-495. The deletion mutant of TAB1 shows that the aromatic Phe484 residue is critical for TAK1 binding. Ser192 is considered to be the most likely candidate because the autophosphorylation of the threonine / serine residue in the kinase activation loop is required for TAB1-induced TAK1 activation and the Ser192Ala mutation does not exhibit kinase activity.

Since TAK1 is a key molecule in the inflammatory NF- kappa B signaling pathway, TAK1 inhibitors are useful in the treatment of diseases associated with inflammation and tissue destruction such as rheumatoid arthritis and inflammatory growth disorders (clonal diseases), as well as cellular processes such as stress responses, apoptosis , Is effective for proliferation and differentiation.

Several inflammatory cytokines and endotoxins have been recently identified as being responsible for the kinase activity of endogenous TAK1 and that drosophila homology of TAK1 is an essential molecule for host defense signaling in Drosophila. The 5Z-7-oxozeaenol, a natural inhibitor of TAK1, was found to have an IC ₅₀ value of 8 nM. 5Z-7-oxoequinol appears to be selective for TAK1 in the MAPKKK group and alleviates the inflammation of ear edema mouse model induced by picryl chloride.

The potential mechanism of TAK1 mediated survival is driven by the ability of TAK1 to phosphorylate IKK and MKK and ultimately to activate both transcription factors NF-κB and AP-1, which play a role in cell survival.

In addition, it has been reported that the TAB1: TAK1: IKKβ: NF-κB signaling axis is abnormally formed in breast cancer cells, and as a result, carcinogenic signal transduction by TGF-β is possible.

TGF-beta signaling is also involved in extracellular angiogenesis and infiltration through a mechanism through matrix metalloproteinase 9 (MMP9), and TAK1 is involved in matrix metalloproteinase 9 (MMP9) Lt; RTI ID = 0.0 > 9 < / RTI > regulation and metastasis. In addition, it has been reported that TGF-beta signaling can induce epithelial-to-mesenchymal transition (EMT), which is involved in invasion and progression of adenoma, and that TAK1 is required for the process . Thus, it is suggested that TAK1 provides an opportunity to selectively inhibit the carcinogenic acceleration function of TGF-β.

It has also been suggested that signaling pathways leading to the production of IL-1 [beta] and TNF [alpha] by MDP-NOD2 and LPS-TLR4 converge at the level of TAK1.

Therefore, there is a growing interest in discovering selective inhibitors of TAK1 that are effective as pharmaceuticals. Nonselective inhibitors can cause unwanted side effects because there are a number of protein kinases involved in various cell responses. In this regard, the three-dimensional structure of kinase can aid in the rational design of inhibitors. By determining the amino acid residues of the binding pocket of TAK1 and the shape of their binding pocket, selective inhibitors that preferentially bind to this class of enzyme can be designed. By determining the shape of the amino acid residues of the binding pocket of TAK1 and the shape of their binding pocket, it is also possible to measure the binding of the compound to their binding pocket and design inhibitors capable of binding to, for example, TAK1.

In addition, TAK1 has been reported to play a key role in inflammatory signal transduction by activating JNK, p38 and NF-kB, suggesting that TAK1 inhibition is effective in inhibiting inflammation and tissue destruction promoted by inflammatory cytokines . Inhibitors of p38 have also been proposed for the treatment of inflammation and allergic disorders (US 2009/0124604; US 2009/0012079).

US 2009/0124604 US 2009/0012079

It is an object of the present invention to provide novel pyrimidine derivative compounds excellent in inhibitory activity against TAK1 kinase.

Another object of the present invention is to provide a pharmaceutical composition comprising said compound as an active ingredient.

According to this object, the present invention provides a compound selected from pyrimidine derivatives of formula (I), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:

In this formula,

X is CH or N;

Y is H, halogen, C _1-6 alkyl, C _3-10 cycloalkyl or haloC _1-3 alkyl;

Z is C or S = O;

R ₁ is H or C _1-6 alkyl;

R ₂ is H, C _1-6 alkyl, C _3-10 cycloalkyl, _3-10 membered heterocycloalkyl, C _6-12 aryl or _5-12 member heteroaryl, wherein said alkyl, cycloalkyl, aryl and heteroaryl is independently selected from OH, halogen, C _{1 - 6} alkyl, di-C _{1 - 6} alkylamino, C _{1 - 6} alkoxy, halo C _1-3 alkyl, (di-C _1-6 alkylamino) heterocycloalkyl , (hydroxy C _1-6 alkyl) heterocycloalkyl, heterocycloalkyl-alkyl, (C _1-6 alkyl) heterocycloalkyl, ((C _3-10 cycloalkyl) C _1-6 alkyl) heterocycloalkyl, (hetero cycloalkyl) C _1-6 alkoxy, ((C _1-6 alkyl) heterocycloalkyl) carbonyl, (di-C _1-6 alkylamino) sulfamoyl, (heterocycloalkyl) C _1-6 alkyl, ((C _1-6 alkyl) heterocycloalkyl) aminocarbonyl, ((heterocycloalkyl) C _1-6 alkyl) aminocarbonyl, and (di-C _1-6 alkylamino) C _1-6 alkyl (C _1-6 alkyl) Made of amino It may be substituted with 1 to 3 substituents selected from the group, and;

R ₃ is H, halogen, CN, C _1-6 alkyl, halo C _1-3 alkyl, C _1-6 alkoxycarbonyl or (C _1-6 alkylamino) C _1-6 alkyl,

R ₄ and R ₅ are each independently H, C _1-6 alkyl, C _6-12 aryl, C _3-6 cycloalkyl, 3-10 membered heterocycloalkyl of, amino, (amino) C _1-6 alkyl, (Amino) C _3-6 cycloalkyl, (amino) C _6-12 aryl, (amino) (3-10 membered heterocycloalkyl) or 5-12 membered heteroaryl, wherein said heterocycloalkyl and hetero Each aryl may each independently contain one or more heteroatoms selected from the group consisting of N, S and O, and each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl and CF ₃ Wherein said amino may be substituted with one or more substituents selected from the group consisting of H, halogen, CN, C _1-6 alkyl, haloC _1-3 alkyl or C _1-6 alkoxycarbonyl, said R ₄ and R ₅ may combine with each other to form a ring), wherein R ₃ and R ₄ or R ₅ may form a bond with each other;

R ₆ is H, amino or C _1-6 alkyl;

n is an integer of 0 to 3;

According to another object, there is provided a pharmaceutical composition comprising the compound of the present invention as an active ingredient.

The pyrimidine derivative of formula (I) according to the present invention is excellent in inhibitory activity against TAK1 kinase, and thus can be usefully used as a preventive or therapeutic agent for cancer or tumor.

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

The term " halogen ", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.

The term " alkyl ", as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon residues.

The term " cycloalkyl ", as used herein, unless otherwise indicated, refers to cyclic alkyl including cyclopropyl and the like.

The term " aryl ", as used herein, unless otherwise indicated, refers to an aromatic group including phenyl, naphthyl, and the like.

The term " heterocycloalkyl ", as used herein, unless otherwise indicated, refers to monocyclic or bicyclic-like cyclic aliphatic groups containing at least one, for example one to four heteroatoms selected from O, . Examples of monoheterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups no.

The term " heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic above aromatic group containing at least one, for example one to four, heteroatoms selected from O, N and S it means. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine Pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso But are not limited to, quinolinyl, purine, furopyridinyl and similar groups.

In one embodiment of the compound of general formula (I) of the present invention, Y may be a H, fluoro, chloro, bromo, methyl, cyclopropyl, or -CF _3.

In another embodiment of the compounds of formula I of the invention, R ₂ is H, cyclopropyl, cyclohexyl, phenyl, pyrazole, pyridine or thiazole, wherein said cyclopropyl, cyclohexyl, phenyl, pyrazole, pyridine or thia Each of which is independently selected from the group consisting of OH, halogen, C _1-6 alkyl, di C _1-6 alkylamino, C _1-6 alkoxy, haloC _1-3 alkyl, (C _1-6 alkylamino) heterocycloalkyl, hydroxy C _1-6 alkyl) heterocycloalkyl, heterocycloalkyl-alkyl, (C _1-6 alkyl) heterocycloalkyl, ((C _3-10 cycloalkyl) C _1-6 alkyl) heterocycloalkyl, (heterocycloalkyl ) C _1-6 alkoxy, ((C _1-6 alkyl) heterocycloalkyl) carbonyl, (di-C _1-6 alkylamino) sulfamoyl, (heterocycloalkyl) C _1-6 alkyl, ((C _{1- 6} alkyl) heterocycloalkyl) aminocarbonyl, ((heterocycloalkyl) C _1-6 alkyl) aminocarbonyl, and (di-C _1-6 alkylamino) C _1-6 Kill may be substituted with 1 to 3 substituents selected from the group consisting of (C _1-6 alkyl) amino.

In another embodiment of formula I compounds of the present invention, R ₃ is H, halogen, CN, C _1-6 alkyl, halo C _1-3 alkyl, C _1-6 alkoxycarbonyl or (di-C _1-6 Alkylamino) Ci- ₆ alkyl.

In another embodiment of the compounds of formula (I) of the invention, R ₄ and R ₅ are each independently and independently selected from the group consisting of H, methyl, methylbutyl, (dimethylamino) methyl, phenyl, (Boc) methylaminoisopropyl, methylaminoisopropyl, (Boc) methylamino isopropyl, methylaminoisopropyl, (Boc) methylaminoethyl, (Boc) amino (methyl) cyclopropyl, furanyl, methylpyrazolyl, thiazolyl, quinolinyl, pyrazinyl, dimethylaminocyclopropyl, methylpyrazolyl, Dimethylaminoisopropyl, methyloxetanyl, (Boc) pyrrolidinyl, (ethylpiperazinyl) isopropyl or methylaminoisopropyl.

In another embodiment of the compound of Formula 1 of the present invention, R ₃ and R ₄ or R ₅ may form a bond with each other, and R ₄ and R ₅ may bond to each other to form cyclohexylidene.

In another embodiment of the compounds of formula I of the present invention, R < ₆ > may be H or amino.

In another embodiment of the compounds of formula I of the present invention, n can be 0, 1 or 2.

Preferred examples of the pyrimidine derivative compounds according to the present invention are as follows:

(1) (R) -N- (1- (2-aminopyridin-4-yl) pyrrolidin-3-yl) acrylamide;

(2) (R) -N- (1- (2,6-diamino-5-chloropyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;

(3) (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;

(4) (R) -N- (1- (5-Chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;

(5) (R) -N- (1- (5-Chloro-2 - ((4-methylcyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;

(6R) -4-hydroxycyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl ) Acrylamide;

(7) (R) -N- (1- (5-Chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;

(8) Synthesis of (R) -N- (1- (2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- Amide;

(9) (R) -N- (1- (5-fluoro-2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) acrylamide;

(10) (R) -N- (1- (5-Bromo-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) acrylamide;

(11) (R) -N- (1- (5-methyl-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;

(12) (R) -N- (1- (5-Cyclopropyl-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- - yl) acrylamide;

(13) Synthesis of (R) -N- (1- (2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin- Pyrrolidin-3-yl) acrylamide;

(14) (S) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1- yl) phenyl) amino) pyridin- Yl) acrylamide;

(15) N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) azetidin-3-yl) acrylamide;

(16) (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- Yl) acrylamide;

(17) Synthesis of N- (1- (5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- ;

(18) (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- Yl) but-2-enamide;

(19) (R) -N- (1- (5-chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- Yl) -2 - ((dimethylamino) methyl) acrylamide;

(20) (R, E) -N- (1- (5-Chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- 3-yl) -4- (dimethylamino) but-2-enamide;

(21) (R, E) -N- (1- (5-Chloro-2- 3-yl) -2-phenylethenesulfonamide;

(22) (R, Z) -N- (1- (5-Chloro-2- 3-yl) -2-fluoro-3-phenylacrylamide;

(23) (R, E) -N- (1- (5-Chloro-2- Yl) -3- (pyridin-2-yl) acrylamide;

(24) Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;

(25) (R) -N- (1- (5-Chloro-2 - ((4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) < / RTI >acrylamide;

(26) (R) -N- (1- (5-Chloro-2 - ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) acrylamide;

(27) (R) -N- (1- (5-Chloro-2 - ((4- (4- (2-hydroxyethyl) piperazin- ) Pyrrolidin-3-yl) acrylamide;

(28) (R) -N- (1- (5-Chloro-2 - ((4- (1- methylpiperidin- 3-yl) acrylamide;

(29) (R) -N- (1- (5-Chloro-2 - ((4 - ((2- (dimethylamino) ethyl) 3-yl) < / RTI >acrylamide;

(30) (R) -N- (1- (5-Chloro-2 - ((4- (4- (dimethylamino) piperidin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) < / RTI >acrylamide;

(31) N - ((R) -1- (5-Chloro-2 - ((4 - ((R) -3- (dimethylamino) pyrrolidin- Yl) pyrrolidin-3-yl) acrylamide;

Pyrrolo [3,4-b] pyridin-6 (2H) -pyrrolidin-1- Yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;

(33) (R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;

(34) (R) -N- (1- (5-Chloro-2 - ((4- (2-morpholinoethoxy) phenyl) amino) pyrimidin- ) Acrylamide;

(35) (R) -N- (1- (5-Chloro-2 - ((3- (2-morpholinoethoxy) phenyl) amino) pyrimidin- ) Acrylamide;

(36) (R) -N- (1- (5-Chloro-2 - ((4-morpholinophenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;

(37) (R) -N- (1- (5-Chloro-2 - ((3-fluoro- Pyrrolidin-3-yl) acrylamide;

(38) A mixture of (R) -4 - ((4- (3-acrylamidopyrrolidin- 1 -yl) -5- chloropyrimidin- Methylpiperidin-4-yl) benzamide;

(39) (R) -N- (1- (5-Chloro-2 - ((4- (4-ethylpiperazin- 1 -carbonyl) phenyl) amino) pyrimidin- 3-yl) acrylamide;

(40) (R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazin- 1 -carbonyl) phenyl) amino) pyrimidin- 3-yl) acrylamide;

(41) Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (N, N- dimethylsulfamoyl) phenyl) amino) pyrimidin- ) Acrylamide;

(42) (R) -N- (1- (5-Chloro-2 - ((4- (4- methylpiperazin- 1 -yl) -3- (trifluoromethyl) phenyl) amino) pyrimidine- 4-yl) pyrrolidin-3-yl) acrylamide;

(43) (R) -N- (1- (5-Chloro-2 - ((1- (2-morpholinoethyl) Pyrrolidin-3-yl) acrylamide;

(44) (R) -N- (1- (5-Chloro-2 - ((1- (1- methylpiperidin- 4-yl) pyrrolidin-3-yl) acrylamide;

(45) (R) -N- (1- (5-Chloro-2 - ((5- (4-ethylpiperazin-1-yl) pyridin- 2- yl) amino) pyrimidin- 3-yl) < / RTI >acrylamide;

(46) (R) -N- (1- (5-Chloro-2 - ((6- (4- ethylpiperazin- 1 -yl) pyridin- 3-yl) < / RTI >acrylamide;

(47) A mixture of (R) -2 - ((4- (3-acrylamidopyrrolidin-1-yl) -5- chloropyrimidin- Thiazole-4-carboxamide;

(48) Synthesis of (R) -2 - ((4- (3-acrylamidopyrrolidin-1-yl) -5- chloropyrimidin- Thiazole-5-carboxamide;

(49) (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1- yl) phenyl) amino) pyrimidin- Yl) -2-cyano-5-methylhex-2-enamide;

(50) (R, E) -N- (1- (5-Chloro-2- Yl) -2-cyano-3-cyclopropyl acrylamide.

(51) (R, Z) - ethyl-2 - ((1- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) Pyrrolidin-3-yl) carbamoyl) -3-phenyl acrylate;

(52) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (pyridin-2-yl) acrylamide;

(53) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine 3-yl) -2-cyano-3-phenylacrylamide;

(54) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (1-methyl-1 H -imidazol-2-yl) acrylamide;

(55) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (4-methylthiazol-2-yl) acrylamide;

(56) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3-cyclohexyl acrylamide;

(57) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- ( m -tolyl) acrylamide;

(58) (R, E) -3- (3- bromophenyl) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin 4-ylpyrrolidin-3-yl) -2-cyanoacrylamide;

(59) (R, E) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- 3-yl) -2-cyano-3- (3-trifluoromethyl) phenyl) acrylamide;

(60) (R, E) -3- (6- bromopyridin-2-yl) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl ) Amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacrylamide;

(61) (R, E) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- 3-yl) -2-cyano (6- (trifluoromethyl) pyridin-2-yl) acrylamide;

(62) A mixture of ( R , E ) -tert-butyl- (5 - ((1- (5- Yl) pyrrolidin-3-yl) amino-4-cyano-2-methyl-5-oxopent-3-en-2-yl) (methyl) carbamate;

(63) ( R , E ) - N - (1- (5-Chloro- 3-yl) -2-cyano-4-methyl-4- (methylamino) pent-2-enamide;

(64) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- ( o -tolyl) acrylamide;

(65) ( R , E ) - N - (1- (5-Chloro- 3-yl) -2-cyano-3- ( p -tolyl) acrylamide;

(66) (R) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin -3 -Yl) -2-cyano-2-cyclohexylideneacetamide;

(67) A mixture of ( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) pyrrolidin-3-yl) amino) -2-cyano-3-oxoprop-1-en-1-yl) cyclopropyl) carbamate;

(68) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) amino) -2-cyano-5, 5-dimethylhex-2-enamide;

(69) ( R , E ) - N - (1- (5-Chloro- Yl) amino) -2-cyano-4, 4-dimethylpent-2-enamide;

(70) (R, E) -3- (1- amino-cyclopropyl) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) Pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacrylamide;

(71) A mixture of ( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) pyrrolidin-3-yl) amino) -2-cyano-3-oxo-1-en-1-yl) cyclopropyl) (methyl) carbamate;

(72) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (furan-2-yl) acrylamide;

(73) A mixture of ( R , E ) - N - (1- (5-chloro- 3-yl) -2-cyano-3- (1-methyl -1 H - pyrazol-4-yl) acrylamide;

(74) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (thiazol-2-yl) acrylamide;

(75) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (pyridin-3-yl) acrylamide;

(76) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (pyridin-4-yl) acrylamide;

(77) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (quinolin-2-yl) acrylamide;

(78) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (pyrazin-2-yl) acrylamide;

(79) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (2- (dimethylamino) phenyl) acrylamide;

(80) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine 3-yl) -2-cyano-3- (1-methyl -1 H - pyrazol-3-yl) acrylamide;

(81) (R, E) - N - (1- (5- chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano-3- ( Pyridin-2-yl) acrylamide;

(82) (R, E) - N - (1- (5- chloro-2 - ((4-diethylamino) butyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2 - cyano-3- (pyridin-2-yl) acrylamide;

(83) A solution of ( R , E ) -2-cyano- N- (1- (2- Pyridin-3-yl) -3- (pyridin-2-yl) acrylamide;

(84) A mixture of ( R , E ) -2-cyano- N- (1- (5-cyclopropyl- Pyrrolidin-3-yl) -3- (pyridin-2-yl) acrylamide;

(85) A mixture of (R) -N- (1- (5-chloro-2 - ((3- (2-morpholinoethoxy) phenyl) amino) pyrimidin- ) Acrylamide;

(86) (R, E) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-4- (dimethylamino;

(87) (R) -tert- butyl 2 - ((E) -3 - (((R) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) Phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) amino) -2-cyano-3-oxo-1- en-1-yl) pyrrolidine-1-carboxylate;

(88) (R, E) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-4- (4-ethylpiperazin-1-yl) -4-methylpent-2-enamide;

(89) (R, E) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (1- (dimethylamino) cyclopropyl) acrylamide;

(90) (R, E) - N - (1- (5- chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano-4- ( Dimethylamino) 4-methylpent-2-enamide;

(91) ( R , E ) - N- (1- (5-Chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin- 2-cyano-4-methyl-4- (methylamino) pent-2-enamide; And

(92) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano- N -methyl-3- (pyridin-2-yl) acrylamide.

The present invention also provides a pharmaceutically acceptable salt of the pyrimidine derivative represented by the above formula (1). Pharmaceutically acceptable salts should be low in toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include salts of acid addition salts, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic bases and carboxylic acid structures of formula (I) with pharmaceutically acceptable free acids and base compounds of formula Organic base addition salts, amino acid addition salts, and the like, but are not limited thereto.

Preferred salts of the compounds according to the invention include salts with inorganic or organic acids. The inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like. In addition, the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition salts are natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases besides the illustrated inorganic acids, organic acids, organic bases and amino acids may be used.

The salt can be prepared by a conventional method. For example, the compound of Formula 1 may be prepared by dissolving the compound of Formula 1 in a solvent which can be mixed with water such as methanol, ethanol, acetone, or 1,4-dioxane, and then adding a free acid or a free base followed by crystallization.

On the other hand, the compounds according to the present invention may have asymmetric carbon centers and therefore exist as R or S isomers or racemic compounds, and all these optical isomers and mixtures may be included in the scope of the present invention.

In addition, the hydrate or solvate form of the compound of formula (I) may also be included within the scope of the present invention.

The present invention also provides a pharmaceutical composition comprising, as an active ingredient, a compound selected from the pyrimidine derivative compounds of Formula 1 and pharmaceutically acceptable salts thereof.

The pharmaceutical composition inhibits the activity of TAK1 kinase, thereby preventing or treating cancer or tumor.

Specific examples of the cancer or tumor include liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer (oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, Gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, Pancreatic cancer, lung cancer, or skin cancer. However, Not limited to include also other solid tumors.

The present invention also provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical composition.

In addition to the active ingredient, the pharmaceutical preparation may be formulated according to a conventional method by adding conventional non-toxic pharmaceutically acceptable additives such as carriers, adjuvants, excipients, and the like.

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

The excipient that can be used in the pharmaceutical preparation of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, But is not limited thereto. For example, excipients such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, , Sodium alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like can be used.

When the pharmaceutical preparation of the present invention is in an oral administration form, examples of the carrier to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, , Talc, and the like, but are not limited thereto.

When the pharmaceutical preparation of the present invention is in the form of an injection, examples of the carrier include water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester and glyceride. .

The pharmaceutical preparations according to the present invention can be administered in combination with other anticancer drugs for treating cancer or tumors, thereby enhancing the therapeutic effect of the anticancer drugs administered concomitantly.

Examples of other anticancer agents for treating the above cancer or tumor include cell signaling inhibitors (imatinib, gefitinib, bortezomib, allotinib, sorafenib, sunitinib, dasatinib, borinostat, lapatinib, Such as paclitaxel, vincristine, and binomycin, such as paclitaxel, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, (Such as cisplatin, cyclophosphamide, chromosevil and camestine), anti-metabolites (such as methotrexate and 5-FU), intercalating anticancer drugs (actinomycin, anthracycline, bleomycin and mai Drugs such as topoisomerase C, topoisomerase inhibitors (such as irinotecan, topotecan and teniposide), immunotherapeutic agents (such as interleukin and interferon), and anti-hormones (such as tamoxifen and raloxifene) , And one or more agents selected therefrom may be combined with or formulated in combination with the pharmaceutical preparation of the present invention. Therefore, the pharmaceutical preparations of the present invention may further comprise these agents as an active ingredient.

The dose of the compound according to the present invention to the human body is generally in the range of 1 mg / day to 1,000 mg / day based on adult patients weighing 70 kg. The compounds according to the present invention may be administered once to several times per day. The dosage may vary depending on the patient's health condition, age, weight and sex, dosage form and disease severity, and accordingly the scope of the present invention is not limited to the above-mentioned dosage.

Hereinafter, the method for preparing the compound of formula (1) of the present invention will be described in detail.

Some of the compounds of Formula 1 of the present invention can be prepared as shown in Reaction Scheme 1 below.

[Reaction Scheme 1]

The compound of formula (A) is subjected to an amine substitution reaction with a compound of formula (A ') to prepare a compound of formula (B). The reaction may be carried out in the presence of an organic base such as triethylamine, diisopropylethylamine or pyridine; Or by adding an inorganic base such as sodium carbonate, potassium carbonate, sodium hydride or the like to the reaction solution, or by adding the base to the reaction liquid. The preferred amount of the base is 1 to 5 equivalents based on 1 equivalent of the compound of the formula (A). The solvent used in the reaction includes polar aprotic solvents such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol and 2-butanol; Or a nonpolar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may be from 0 to 150 ° C, preferably from room temperature to 100 ° C.

The compound of formula (B) is then reacted with the compound of formula (B ') to produce the compound of formula (C). The reaction may be carried out in the presence of an organic base such as triethylamine, diisopropylethylamine or pyridine; Inorganic bases such as sodium carbonate, potassium carbonate and sodium hydride; Organic acids such as trifluoroacetic acid and toluenesulfonic acid; With or without addition of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, wherein the preferred base or acid equivalent is based on 1 equivalent of the compound of formula B 0.1 to 5 equivalents. The solvent used in the reaction includes polar aprotic solvents such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol and 2-butanol; Or a nonpolar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may be from 0 ° C to 150 ° C, preferably from 50 ° C to 100 ° C.

Then, the compound of formula (D) is prepared through deprotection from the compound of formula (C). Wherein the protecting group PG can be t-butoxycarbonyl (Boc), carbobenzyloxy (CBz), and the like. As the reaction reagent for the deprotection reaction, hydrochloric acid, trifluoroacetic acid may be mixed with a solvent such as methylene chloride, tetrahydrofuran, or 1,4-dioxane, or used alone.

The compound of formula (D) is then condensed with the compound of formula (D ') or (D') to form a compound of formula (D) The reagent for condensation reaction is EDCI (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), HATU (1- [bis (dimethylamino) methylene] -1H-1,2,3- And the amount of the compound to be used is 1 to 10 equivalents, preferably 1 to 3 equivalents based on 1 equivalent of the compound of the formula (D) . The condensation reaction for preparing the compound of formula (I) may be carried out by adding an organic base such as triethylamine, diisopropylethylamine or pyridine to the reaction mixture; Or by adding an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, with or without the addition of an inorganic base, 1 to 5 equivalents. The catalyst may be reacted by adding or not adding N, N-dimethylpyridine, hydroxybenzotriazole (HOBt) or the like. The preferable amount of catalyst is 0.1 to 1 equivalent based on 1 equivalent of the compound of formula (D). The reaction solvent may be an aprotic solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, or 1,4-dioxane. The reaction temperature may be from 0 ° C to 150 ° C, preferably from 0 ° C to 50 ° C.

In addition, some of the compounds of Formula 1 of the present invention can be prepared as shown in Reaction Scheme 2 below.

[Reaction Scheme 2]

The compound of formula (E) is prepared from the compound of formula (B) by deprotection. Wherein the protecting group PG can be t-butoxycarbonyl (Boc), carbobenzyloxy (CBz), and the like. As the reaction reagent for the deprotection reaction, hydrochloric acid, trifluoroacetic acid may be mixed with a solvent such as methylene chloride, tetrahydrofuran, or 1,4-dioxane, or used alone.

The compound of formula (E) is condensed with D 'and D "to produce a compound of formula (F). When the compound of formula (D) is used, the condensation reaction reagent may be added, 4,5-b] pyridin-2-yl) -1H-1,2,3-triazolo [3, Pyridinium 3-oxide exophorophosphate). The amount of the compound to be used is 1 to 10 equivalents, preferably 1 to 3 equivalents, based on 1 equivalent of the compound of the formula (E). The condensation reaction for preparing the compound of formula (F) may be carried out in the presence of an organic base such as triethylamine, diisopropylethylamine or pyridine; Or an inorganic base such as sodium carbonate, potassium carbonate or sodium hydrogencarbonate. The preferred amount of the base is 1 to 5 equivalents based on 1 equivalent of the compound of the formula (E). The catalyst may be reacted by adding or not adding N, N-dimethylpyridine, hydroxybenzotriazole (HOBt) or the like. The preferable amount of catalyst is 0.1 to 1 equivalent based on 1 equivalent of the compound of the formula (E). The reaction solvent may be an aprotic solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, or 1,4-dioxane. The reaction temperature may be from 0 ° C to 150 ° C, preferably from 0 ° C to 50 ° C.

The compound of formula (I) is then reacted with the compound of formula (B ') shown in Scheme 1 from the compound of formula (F). An organic base such as triethylamine, diisopropylethylamine or pyridine; Inorganic bases such as sodium carbonate, potassium carbonate and sodium hydride; Organic acids such as trifluoroacetic acid and toluenesulfonic acid; Or an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., is added to or not added to the reaction solution. The preferable amount of the base or acid to be used is 0.1 to 5 equivalents based on 1 equivalent of the compound of formula (F). The solvent used in the reaction includes polar aprotic solvents such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, and tetrahydrofuran; Polar protic solvents such as methanol, ethanol, 2-propanol and 2-butanol; Or a nonpolar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may be from 0 ° C to 150 ° C, preferably from 50 ° C to 100 ° C.

Wherein X, Y, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined herein and W 1 and W 2 are preferably halogen.

Hereinafter, the present invention will be described in more detail with reference to the following Preparation Examples and Examples, but the present invention is not limited thereto.

Example

Example  1: (R) -N- (1- (2- Aminopyridine Yl) Pyrrolidine -3 days) Acrylamide  Produce

Step 1) Preparation of (R) -tert-butyl (1- (2-aminopyridin-4-yl) pyrrolidin-3-yl) carbamate

4-Chloropyridin-2-amine (0.50 g, 3.89 mmol) was dissolved in dimethylsulfoxide (7 ml) and then (R) -tert-butylpyrrolidin-3-ylcarbamate (0.72 g, 3.89 mmol ) And the mixture was stirred at 110 DEG C for 12 hours. Water was added to the reaction solution and extracted with chloroform / 2-propanol solution. The combined organic layers were dried over sodium sulfate and concentrated to give the desired compound (0.57 mg, 2.06 mmol; 53% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ 7.50 (d, 1H), 7.17 (m, 1H), 5.75 (m, 1H), 5.44 (d, 1H), 5.32 (s, 2H), 4.04 ( (m, 1H), 3.31 (m, 2H), 3.16 (m, 1H), 2.97 (m, 1H), 2.07 (m,

Step 2) Preparation of (R) -4- (3-aminopyrrolidin-1-yl) pyridin-

Yl) carbamate (2.0 g, 7.18 mmol) obtained in Step 1) was dissolved in methylene chloride (20 ml) and the mixture was stirred at < RTI ID = , Trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the desired compound (1.15 g, 6.46 mmol; 90% yield).

MS: [M + H] < ⁺ > m / z 178.2

Step 3) Preparation of (R) -N- (1- (2-aminopyridin-4-yl) pyrrolidin-3-

(50 mg, 0.28 mmol) obtained in Step 2) was dissolved in tetrahydrofuran / water (3: 1 (v / v) ), 2 ml), sodium hydrogencarbonate (118 mg, 1.40 mmol) was added and cooled to 0 < 0 > C. Acryloyl chloride (25 mg, 0.28 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction solution and extracted with chloroform / 2-propanol (3: 1) solution. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 7: 1 (v / v)) to obtain the desired compound (114 mg, 0.49 mmol; 35% yield).

MS: [M + H] < ⁺ > m / z 233.1

Example 2: Preparation of (R) -N- (1- (2,6-diamino-5-chloropyrimidin-4-yl) pyrrolidin-

Step 1) Preparation of 5,6-dichloropyrimidine-2,4-diamine

(0.30 g, 2.08 mmol) was dissolved in dimethylformamide (2 ml), and N-chlorosuccinimide (0.28 g, 2.08 mmol) was added thereto. Lt; / RTI > Ethyl acetate (50 ml) was added to the reaction solution and washed five times with water (total of 250 ml). The organic layer was dried over magnesium sulfate, filtered under reduced pressure and concentrated to give the desired compound (0.29 g, 2.0 mmol; 96% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ 6.97 (s, 1H), 6.48 (s, 2H).

Step 2) Preparation of (R) -tert-butyl (1- (2,6-diamino-5-chloropyrimidin-4- yl) pyrrolidin-

Dichloropyrimidine-2,4-diamine (0.10 g, 0.559 mmol) obtained in step 1) was dissolved in dimethylacetamide (3 ml) and then triethylamine (0.16 ml, 1.12 mmol) and (R) -tert-butylpyrrolidin-3-ylcarbamate (0.114 mg, 0.615 mmol) was added and stirred at 90 占 폚 for 12 hours. After the reaction solution was cooled to room temperature, water was added. The reaction solution was extracted three times with ethyl acetate, and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (methylene chloride: methanol = 20: 1 (v / v)) to obtain the desired compound (0.118 g, 0.40 mmol; 72% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ 7.12 (s, 1H), 5.98 (s, 2H), 5.60 (s, 2H), 3.92 (m, 1H), 3.69 (m, 2H), 3.55 ( 1H), 1.40 (m, IH), 3.40 (m, IH), 1.96 (m,

Step 3) Preparation of (R) -6- (3-aminopyrrolidin-1-yl) -5-chloropyrimidine-2,4-

Butyl) (1- (2,6-diamino-5-chloropyrimidin-4-yl) pyrrolidin-3-yl) carbamate (1.0 g, 7.18 mmol) obtained in step 2) ) Was dissolved in methylene chloride (20 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (1.15 g, 6.46 mmol; 90% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ 5.90 (s, 2H), 5.52 (s, 2H), 4.10 (s, 2H), 3.92 (m, 1H), 3.71 (m, 2H), 3.61 ( m, 2 H), 1.86 (m, 2 H).

Step 4) Preparation of (R) -N- (1- (2,6-diamino-5-chloropyrimidin-4-yl) pyrrolidin-

(R) -6- (3-aminopyrrolidin-1-yl) -5-chloropyrimidine-2,4-diamine (50 mg, 0.22 mmol) obtained in step 3) was dissolved in tetrahydrofuran / water 3: 1 (v / v), 2 ml), sodium hydrogen carbonate (92 mg, 1.09 mmol) was added and cooled to 0 ° C. Acryloyl chloride (20 mg, 0.22 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction solution and extracted with chloroform / 2-propanol (3: 1) solution. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 7: 1 (v / v)) to obtain the desired compound (17 mg, 0.06 mmol; 28% yield).

MS: [M + H] < ⁺ > m / z 283.1

Example 3: Preparation of (R) -N- (1- (5-chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) acrylamide

Step 1) Preparation of (R) -tert-butyl (1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3-yl) carbamate

2,4,5-Trichloropyrimidine (10.0 g, 54.5 Mmol) was dissolved in acetonitrile (50 ml) and then potassium carbonate (15.0 g, 109 mmol) and (R) -tert-butylpyrrolidin- 3-yl carbamate (10.0 g, 53.7 mmol) were successively added thereto, and the mixture was stirred at room temperature for 30 minutes. Water (500 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered under reduced pressure and dried at room temperature to obtain the desired compound (16.3 g, 48.9 mmol; 90% yield).

¹ H-NMR (300 MHz, DMSO-d 6)? 8.00 (s, IH), 4.65 (m, IH), 4.28 ), 3.74-3.69 (m, 1H), 2.23-2.17 (m, 1H), 1.96-1.90 (m, 1H), 1.45 (s, 9H).

Step 2) Preparation of (R) -tert-butyl (1- (5-chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino ) pyrimidin- -3-yl) carbamate

After dissolving 4- (4-methylpiperazin-1-yl) aniline (0.57 g, 3.00 mmol) in 2-butanol (10 ml), trifluoroacetic acid (0.23 ml, 3.00 mmol) The resulting (R) -tert-butyl (1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3-yl) carbamate (1.00 g, 3.00 mmol) At room temperature for 2 hours, and then cooled to room temperature. To the reaction solution was added saturated sodium bicarbonate solution (100 ml), and the mixture was stirred at room temperature for 15 hours. The resulting solid was filtered and washed with water to give the desired compound (1.2 g, 2.46 mmol; 82% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ 7.87 (s, 1H), 7.42-7.38 (m, 2H), 6.92-6.89 (m, 2H), 6.68 (bs, 1H), 4.66 (m, 1H 2H), 3.72-3.66 (m, 1H), 3.17-3.14 (m, 4H), 2.60-2.56 (m, , 4H), 2.35 (s, 3H), 2.18-2.12 (m, IH), 1.92-1.89 (m, IH), 1.45 (s, 9H).

Step 3) Synthesis of (R) -4- (3-aminopyrrolidin-1-yl) -5-chloro-N- Manufacturing

((R) -tert-butyl (1- (5-chloro-2- 3-yl) carbamate (1.00 g, 2.04 mmol) was dissolved in 1,4-dioxane (5 ml), followed by the addition of 4N hydrochloric acid dioxane solution (5 ml, 20 mmol) Lt; / RTI > The reaction solution was concentrated under reduced pressure to obtain the desired compound (0.76 g, 19.6 mmol; 96% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ 7.86 (s, 1H), 7.46-7.39 (m, 2H), 6.93-6.89 (m, 2H), 6.83 (bs, 1H), 4.05-3.96 (m 3H), 3.87 (m, IH), 3.68-3.65 (m, IH), 3.58-3.54 (m, ), 2.13-2.10 (m, 1 H), 1.80-1.72 (m, 1 H).

Step 4) Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- - yl) acrylamide

(4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-4-carboxylic acid obtained in step 3) 2-Amine (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran / water (3: 1, 2 ml) followed by sodium hydrogencarbonate (54 mg, 0.64 mmol) and cooled to 0 <0> C. Acryloyl chloride (10.5 ul, 0.13 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction solution and extracted with chloroform / 2-propanol (3: 1) solution. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 7: 1 (v / v)) to obtain the desired compound (22 mg, 0.05 mmol; 38% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 442.2

^{1 H-NMR (300 MHz,} DMSO-d6) δ 9.00 (bs, 1H), 8.39 (d, 1H), 7.89 (s, 1H), 7.52 (d, 2H), 6.83 (d, 2H), 6.22- 1H), 3.94-3.91 (m, 1H), 3.84-3.79 (m, 2H), 4.63 3H), 2.11-2. 07 (m, 1H), 1.90 (m, 1H), 3.03-2.99 (m, 4H), 2.43-2.40 (m, 4H).

Example 4: Preparation of (R) -N- (1- (5-chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-

The procedure of Example 3 was repeated, except that cyclopropylamine was used instead of 4- (4-methylpiperazin-1-yl) aniline in the step 2) of Example 3 to obtain the desired compound (15 mg, 0.05 mmol; 45% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 308.1

Example 5: Preparation of (R) -N- (1- (5-chloro-2 - ((4-methylcyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-

The procedure of Example 3 was repeated, except that 4-methylcyclohexanamide was used instead of 4- (4-methylpiperazin-1-yl) aniline in the step 2) of Example 3 to obtain the desired compound (10 mg, 0.03 mmol; 30% yield).

MS: [M + H] &lt; ⁺ &gt;

Example  6: N - ((R) -1- (5- Chloro -2 - (((1 R, 4R) -4- Hydroxycyclohexyl ) Amino) pyrimidin-4-yl) Pyrrolidine -3 days) Acrylamide  Produce

The procedure of Example 3 was repeated, except that trans-4-aminocyclohexanol was used instead of 4- (4-methylpiperazin-1-yl) aniline in the step 2) of Example 3 to obtain the desired compound 12 mg, 0.03 mmol; 33% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 7: Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin-4-yl) pyrrolidin- Manufacturing

The procedure of Example 3 was repeated except that N, N-dimethylcyclohexane-1,4-diamine was used instead of 4- (4-methylpiperazin-1-yl) aniline in step 2) of Example 3 To give the desired compound (15 mg, 0.04 mmol; 40% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 393.2

Example 8: Preparation of (R) -N- (1- (2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- Preparation of acrylamide

The procedure of Example 3 was repeated, except that 2,4-dichloropyrimidine was used instead of 2,4,5-trichloropyrimidine in the step 1) of Example 3 to obtain the desired compound (19 mg, 0.05 mmol; 50% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 408.2

Example 9: Preparation of (R) -N- (1- (5-fluoro-2 - ((4- (4-methylpiperazin- 1-yl) phenyl) amino) pyrimidin- Yl) acrylamide &lt; / RTI &gt;

The procedure of Example 3 was repeated, except that 2,4-dichloro-5-fluoropyrimidine was used instead of 2,4,5-trichloropyrimidine in the step 1) of Example 3 to obtain the desired compound 17 mg, 0.04 mmol; 40% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 10: Preparation of (R) -N- (1- (5-bromo-2 - ((4- (4-methylpiperazin- 1-yl) phenyl) amino) pyrimidin- Yl) acrylamide &lt; / RTI &gt;

The procedure of Example 3 was repeated, except that 5-bromo-2,4-dichloropyrimidine was used instead of 2,4,5-trichloropyrimidine in the step 1) of Example 3 to obtain the desired compound (16 mg, 0.03 mmol; 35% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 486.2

Example 11: (R) -N- (1- (5-Methyl-2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) acrylamide

The procedure of Example 3 was repeated except that 2,4-dichloro-5-methylpyrimidine was used instead of 2,4,5-trichloropyrimidine in the step 1) of Example 3 to obtain the desired compound (10 mg , 0.02 mmol; 25% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 422.3

Example 12: (R) -N- (1- (5-Cyclopropyl-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- 3-yl) acrylamide

The procedure of Example 3 was repeated, except that 2,4-dichloro-5-cyclopropylpyrimidine was used instead of 2,4,5-trichloropyrimidine in the step 1) of Example 3 to obtain the desired compound (9 mg, 0.02 mmol; 25% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 448.3

Example 13: Preparation of (R) -N- (1- (2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin- ) Pyrrolidin-3-yl) acrylamide

The procedure of Example 3 was repeated except that 2,4-dichloro-5- (trifluoromethyl) pyrimidine was used instead of 2,4,5-trichloropyrimidine in step 1) of Example 3 The objective compound (7 mg, 0.01 mmol; 15% yield) was obtained.

MS: [M + H] &lt; ⁺ &gt; m / z 476.2

Example 14: (S) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- - yl) acrylamide

(S) -tert-butylpyrrolidin-3-ylcarbamate was used instead of (R) -tert-butylpyrrolidin-3-ylcarbamate in step 1) of Example 3, The procedure of Step 3 was repeated to give the desired compound (12 mg, 0.03 mmol; 30% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 442.2

Example 15: Preparation of N- (1- (5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- Manufacturing

The procedure of Example 3 was repeated except that tert-butyl azetidin-3-yl carbamate was used instead of (R) -tert-butylpyrrolidin-3-ylcarbamate in step 1) of Example 3 To give the desired compound (15 mg, 0.04 mmol; 40% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 16: (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- - yl) acrylamide

(R) -tert-butylpiperidin-3-ylcarbamate was used in place of (R) -tert-butylpyrrolidin-3-ylcarbamate in step 1) of Example 3, The procedure of Step 3 was repeated to give the desired compound (10 mg, 0.02 mmol; 25% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 456.2

Example 17: Preparation of N- (l- (5-chloro-2- ((4- (4-methylpiperazin- l-yl) phenyl) amino) pyridin- Preparation of amide

The procedure of Example 3 was followed except that tert-butylpiperidin-4-ylcarbamate was used instead of (R) -tert-butylpyrrolidin-3-ylcarbamate in step 1) The objective compound (12 mg, 0.03 mmol; 35% yield) was obtained in a repeated manner.

MS: [M + H] &lt; ⁺ &gt; m / z 456.2

Example 18: (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- -Yl) -but-2-enamide &lt; / RTI &gt;

The procedure of Example 3 was repeated except that in step 4) of Example 3, but-2-ynoyl chloride was used instead of acryloyl chloride to obtain the desired compound (15 mg, 0.03 mmol; 35% yield) Respectively.

MS: [M + H] &lt; ⁺ &gt;

Example 19: (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- - yl) -2 - ((dimethylamino) methyl) acrylamide

The procedure of Example 3 was repeated, except that 2 - ((dimethylamino) methyl) acrylic acid was used instead of acryloyl chloride in step 4) of Example 3 to obtain the desired compound (10 mg, 0.04 mmol; ).

MS: [M + H] &lt; ⁺ &gt; m / z 499.3

Example 20: (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1-yl) phenyl) amino) pyridin- -3-yl) -4- (dimethylamino) but-2-enamide

The procedure of Example 3 was repeated, except that (E) -4- (dimethylamino) but-2-enoic acid was used instead of acryloyl chloride in the step 4) of Example 3 to obtain the desired compound (17 mg, 0.03 mmol; 34% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 499.3

Example 21: (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1-yl) phenyl) amino) pyridin- -3-yl) -2-phenylethene sulfonamide

The procedure of Example 3 was repeated except that (E) -2-phenylethenesulfonyl chloride was used in place of acryloyl chloride in the step 4) of Example 3 to obtain the desired compound (16 mg, 0.03 mmol; 29% Yield).

MS: [M + H] &lt; ⁺ &gt;

Example 22: (R, Z) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- 3-yl) -2-fluoro-3-phenylacrylamide

The procedure of Example 3 was repeated, except that (Z) -2-fluoro-3-phenylacrylic acid was used instead of acryloyl chloride in step 4) of Example 3 to obtain the desired compound (10 mg, 0.02 mmol; 19% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 23: (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) -3- (pyridin-2-yl) acrylamide

The procedure of Example 3 was repeated, except that (E) -3- (pyridin-2-yl) acrylic acid was used instead of acryloyl chloride in the step 4) of Example 3 to obtain the desired compound (9 mg, 0.02 mmol ; 17% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 24: (R) -N- (1- (5-Chloro-2 - ((4- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) acrylamide

Step 1) Preparation of (R) -N- (1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3- yl) acrylamide

Butyl (1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3-yl) carbamate (2.0 g, 6.0 mmol) obtained in step 1 of Example 3 After dissolving in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 1 hour, and then volatile materials were removed under reduced pressure and concentrated. The residue was dissolved in tetrahydrofuran / water (3: 1 (v / v), 40 ml) and cooled to 0 C, followed by sodium bicarbonate (5.04 g, 60.0 mmol). Acryloyl chloride (0.536 ml, 6.6 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction solution and extracted three times with methylene chloride. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (methylene chloride: methanol = 20: 1 (v / v)) to obtain the desired compound (1.09 g, 3.78 mmol; 63% yield).

^{1 H-NMR (300 MHz,} DMSO-d6) δ8.41 (d, 1H), 6.25 (m, 2H), 5.62 (m, 1H), 4.38 (m, 1H), 4.01 (m, 1H), 3.82 (m, 2H), 3.64 (m, IH), 2.14 (m, IH), 1.88 (m, IH).

Step 2) (R) -N- (1- (5-Chloro-2 - ((4- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide

Pyrrolidin-3-yl) acrylamide (0.10 g, 0.348 mmol) obtained in step 1) was dissolved in 2-butanol ( 3 ml), and then 4- (4-ethylpiperazin-1-yl) aniline (71 mg, 0.348 mmol) and trifluoroacetic acid (26 .mu.l, 0.348 mmol) Lt; / RTI &gt; After the reaction solution was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (methylene chloride: methanol = 20: 1 to 10: 1 (v / v)) to obtain the desired compound (63.5 mg, 0.14 mmol; 40% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 456.2

^{1 H-NMR (300 MHz,} DMSO-d6) δ 8.99 (s, 1H), 8.37 (s, 1H), 7.89 (d, 1H), 7.51 (d, 2H), 6.82 (d, 2H), 6.12 ( (m, 2H), 5.57 (m, 1H), 4.34 (m, 2H), 3.79 , 1 H), 1.81 (m, 1 H), 1.02 (t, 3 H).

Example 25: (R) -N- (1- (5-Chloro-2 - ((4- (4- (cyclopropylmethyl) piperazin- Pyrrolidin-3-yl) acrylamide

(4- (cyclopropylmethyl) piperazin-1-yl) aniline was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24, 24 was repeated to obtain the desired compound (12 mg, 0.02 mmol; 25% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 482.2

Example 26: (R) -N- (1- (5-Chloro-2 - ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) pyrimidin- Yl) acrylamide &lt; / RTI &gt;

The procedure of Example 24 was followed except for using 4- (4-isopropylpiperazin-1-yl) aniline in place of 4- (4-ethylpiperazin- (15 mg, 0.03 mmol; 32% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 470.2

Example 27: (R) -N- (1- (5-Chloro-2 - ((4- (4- (2-hydroxyethyl) piperazin- Yl) pyrrolidin-3-yl) acrylamide

Except that 2- (4- (4-aminophenyl) piperazin-1-yl) ethanol was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24. The procedure of Example 24 was repeated to give the desired compound (10 mg, 0.02 mmol; 21% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 472.2

Example 28: Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (1- methylpiperidin-4- yl) phenyl) amino) pyrimidin- Yl) acrylamide &lt; / RTI &gt;

The procedure of Example 24 was followed except that 4- (1-methylpiperidin-4-yl) aniline was used in place of 4- (4-ethylpiperazin- (12 mg, 0.03 mmol; 27% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 29: (R) -N- (1- (5-Chloro-2 - ((4- (2- (dimethylamino) ethyl) Pyrrolidin-3-yl) acrylamide

Except that N1- (2- (dimethylamino) ethyl) -N1-methylbenzene-1,4-diamine was used instead of 4- (4-ethylpiperazin-1-yl) aniline in Step 2) of Example 24 , And the procedure of Example 24 was repeated to give the desired compound (15 mg, 0.03 mmol; 34% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 30: (R) -N- (1- (5-Chloro-2 - ((4- (4- (dimethylamino) piperidin- 1- yl) phenyl) amino) pyrimidin- Pyrrolidin-3-yl) acrylamide

Except that 1- (4-aminophenyl) -N, N-dimethylpiperidin-4-amine was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 , The procedure of Example 24 was repeated to give the desired compound (19 mg, 0.04 mmol; 40% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 470.2

Example 31: N - ((R) -1- (5-Chloro-2 - ((4 - ((R) -3- (dimethylamino) pyrrolidin- 4-yl) pyrrolidin-3-yl) acrylamide

(R) -1- (4-aminophenyl) -N, N-dimethylpyrrolidin-3-amine instead of 4- (4-ethylpiperazin- 1 -yl) aniline in step 2) of Example 24 , The procedure of Example 24 was repeated to give the desired compound (17 mg, 0.04 mmol; 37% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 32: N - ((R) -1- (5-Chloro-2 - ((4 - ((4aR, 7aR) -hexahydro- lH-pyrrolo [3,4- b] Yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide

(4aR, 7aR) -hexahydro-lH-pyrrolo [3,4-b] pyridin-l-yl) aniline in place of 4- (4-ethylpiperazin- (2H) -yl) aniline, the procedure of Example 24 was repeated to give the desired compound (16 mg, 0.03 mmol; 34% yield).

MS: [M + H] &lt; RTI ID = 0.0 &gt; m / z &

Example 33: (R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazin- 1- yl) phenyl) amino) pyrimidin- 3-yl) acrylamide

 The procedure of Example 24 was followed except that 3- (4-ethylpiperazin-1-yl) aniline was used in place of 4- (4-ethylpiperazin- The desired compound (10 mg, 0.02 mmol; 23% yield) was obtained in a repeated manner.

MS: [M + H] &lt; ⁺ &gt; m / z 456.2

Example 34: (R) -N- (1- (5-Chloro-2 - ((4- (2-morpholinoethoxy) phenyl) amino) pyrimidin- Synthesis of acrylamide

The procedure of Example 24 was repeated, except that 4- (2-morpholinoethoxy) aniline was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 The desired compound (9 mg, 0.02 mmol; 19% yield) was obtained.

MS: [M + H] &lt; ⁺ &gt; m / z 473.2

Example 35: (R) -N- (1- (5-Chloro-2 - ((3- (2-morpholinoethoxy) phenyl) amino) pyrimidin- Synthesis of acrylamide

The procedure of Example 24 was repeated, except that 3- (2-morpholinoethoxy) aniline was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 The objective compound (7 mg, 0.01 mmol; 15% yield) was obtained.

MS: [M + H] &lt; ⁺ &gt; m / z 473.2

Example 36: Preparation of (R) -N- (1- (5-chloro-2 - ((4-morpholinophenyl) amino) pyrimidin-4-yl) pyrrolidin-

The procedure of Example 24 was repeated, except that 4-morpholinoaniline was used instead of 4- (4-ethylpiperazin-1-yl) aniline in the step 2) of Example 24 to obtain the desired compound (12 mg, 0.03 mmol; 28% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 37: (R) -N- (1- (5-Chloro-2 - ((3-fluoro- ) Pyrrolidin-3-yl) acrylamide

Except that 3-fluoro-4- (4-methylpiperazin-1-yl) aniline was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24. The procedure of Example 24 was repeated to give the desired compound (20 mg, 0.04 mmol; 43% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 460.2

Example 38: Synthesis of (R) -4 - ((4- (3-acrylamidopyrrolidin-1-yl) -5- chloropyrimidin- -Methylpiperidin-4-yl) benzamide &lt; / RTI &gt;

Amino-3-methoxy-N- (1-methylpiperidin-4-yl) benzamide instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 , The procedure of Example 24 was repeated to give the desired compound (18 mg, 0.04 mmol; 435% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 514.2

Example 39: (R) -N- (1- (5-Chloro-2 - ((4- (4-ethylpiperazine-1-carbonyl) phenyl) amino) pyrimidin- Yl) acrylamide &lt; / RTI &gt;

(4-aminophenyl) (4-ethylpiperazin-1-yl) methanone was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24. The procedure of Example 24 was repeated to give the desired compound (15 mg, 0.03 mmol; 31% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 40: (R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazin- 1 -carbonyl) phenyl) amino) pyrimidin- Yl) acrylamide &lt; / RTI &gt;

(3-aminophenyl) (4-ethylpiperazin-1-yl (13 mg, 0.03 mmol, 27% yield) was obtained as colorless crystals in step 2) of Example 24, ))) Methanone, the procedure of Example 24 was repeated to give the desired compound.

MS: [M + H] &lt; ⁺ &gt;

Example 41: (R) -N- (1- (5-Chloro-2 - ((4- (N, N- dimethylsulfamoyl) phenyl) amino) pyrimidin- Synthesis of acrylamide

(1510 mg, 0.02 mmol; 22% yield) in place of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 , The procedure of Example 24 was repeated to give the desired compound.

MS: [M + H] &lt; ⁺ &gt; m / z 451.1

Example 42: (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1 -yl) -3- (trifluoromethyl) phenyl) amino) pyrimidine Yl) pyrrolidin-3-yl) acrylamide

(4-methylpiperazin-1-yl) -3- (trifluoromethyl) aniline instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 , The procedure of Example 24 was repeated to give the desired compound (10 mg, 0.02 mmol; 20% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 510.2

Example 43: (R) -N- (1- (5-Chloro-2 - ((1- (2-morpholinoethyl) ) Pyrrolidin-3-yl) acrylamide

Except that 1- (2-morpholinoethyl) -1H-pyrazol-4-amine was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24. The procedure of Example 24 was repeated to give the desired compound (12 mg, 0.03 mmol; 27% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 447.2

Example 44: (R) -N- (1- (5-Chloro-2 - ((1- (1- methylpiperidin- Yl) pyrrolidin-3-yl) acrylamide

(1-methylpiperidin-4-yl) -1H-pyrazol-4-amine instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24 , The procedure of Example 24 was repeated to give the desired compound (13 mg, 0.03 mmol; 30% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 431.2

Example 45: (R) -N- (1- (5-Chloro-2 - ((5- (4-ethylpiperazin- Pyrrolidin-3-yl) acrylamide

(4-ethylpiperazin-1-yl) pyridin-2-amine instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24, The procedure of Step 24 was repeated to give the desired compound (9 mg, 0.02 mmol; 20% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 457.2

Example 46: (R) -N- (1- (5-Chloro-2 - ((6- (4- ethylpiperazin- Pyrrolidin-3-yl) acrylamide

(4-ethylpiperazin-l-yl) pyridin-3-amine instead of 4- (4-ethylpiperazin-l-yl) aniline in step 2) of Example 24, The procedure of Step 24 was repeated to give the desired compound (10 mg, 0.02 mmol; 22% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 457.2

Example 47: (R) -2 - ((4- (3-Acrylamidopyrrolidin-1-yl) -5-chloropyrimidin- ) Preparation of thiazole-4-carboxamide

Except that 2-amino-N- (2-morpholinoethyl) thiazole-4-carboxamide was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24. And the procedure of Example 24 was repeated to give the desired compound (8 mg, 0.02 mmol; 16% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 507.2

Example 48: (R) -2 - ((4- (3-Acrylamidopyrrolidin-1-yl) -5- chloropyrimidin- ) Preparation of thiazole-5-carboxamide

Except that 2-amino-N- (2-morpholinoethyl) thiazole-5-carboxamide was used instead of 4- (4-ethylpiperazin-1-yl) aniline in step 2) of Example 24. And the procedure of Example 24 was repeated to give the desired compound (12 mg, 0.02 mmol; 24% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 507.2

Example 49: (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- Di-3-yl) -2-cyano-5-methylhex-2-enamide

The procedure of Example 3 was repeated, except that (E) -2-cyano-5-methylhex-2-enoic acid was used instead of acryloyl chloride in the step 4) of Example 3 to obtain the desired compound (15 mg, 0.03 mmol; 29% yield).

MS: [M + H] &lt; ⁺ &gt;

Example 50: (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1-yl) phenyl) amino) pyrimidin- Pyridin-3-yl) -2-cyano-3-cyclopropylacrylamide

The procedure of Example 3 was repeated, except that (E) -2-cyano-3-cyclopropylacrylic acid was used instead of acryloyl chloride in Step 4) of Example 3 to obtain the desired compound (20 mg, 0.04 mmol ; 39% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 507.2

Example  51: ( R, Z ) -Ethyl-2 - ((1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine -3 days) Carbamoyl ) -3- Phenyl acrylate  Produce

Step 1) ( R ) Ethyl-3 - ((1- (5-chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- ) Amino) -3-oxopropanoate &lt; / RTI &gt;

(R) -4- (3- amino-pyrrolidin-1-yl) -5-chloro - N- (4- (4- methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (152 mg , 0.39 mmol) and 3-ethoxy-3-oxopropanoic acid (78 mg, 0.59 mmol) were dissolved in N , N -dimethylformamide and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (113 mg, 0.59 mmol), hydroxybenzotriazole (16 mg, 0.12 mmol) and N , N -diisopropylethylamine (205 L, 1.18 mmol) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 10: 1 (v / v)) to obtain the desired compound.

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.86 (s, 1H), 7.64-7.62 (d, 1H), 7.43-7.40 (d, 2H), 6.91-6.88 (d, 2H), 6.83 (bs 2H), 3.78-3.73 (m, 1H), 3.33 (m, IH), 4.58-4.56 (s, 2H), 3.17-3.14 (m, 4H), 2.60-2.57 (m, 4H), 2.35 -1.26 (t, 3 H).

Step 2) ( R ,  Z Phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl ) &Lt; / RTI &gt; carbamoyl) -3-phenyl acrylate

To a solution of ( R ) -ethyl-3 - ((1- (5-chloro-2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) amino) -3-oxopropanoate (100 mg, 0.20 mmol) and benzaldehyde (22 mg, 0.20 mmol) were dissolved in 2-propanol and piperidine (2-3 drops, Catalytic amount). The reaction mixture was stirred at 60 DEG C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with chloroform, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 20: 1 (v / v)) to obtain the desired compound (44 mg, 0.07 mmol; 37% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 590.3

^{1 H-NMR (300 MHz,} CDCl 3): δ 8.96 (bs, 1H), 8.77-8.74 (d, 1H), 7.88 (s, 1H), 7.59-7.49 (m, 5H), 7.37-7.31 (m (M, 3H), 3.02-2.99 (m, IH), 3.82-3. (m, 4H), 2.43-2.40 (m, 4H), 2.12 (s, 3H), 2.08 (m, 1H), 1.91 (m, 1H), 1.21-1.

Example  52: ( R , E ) - N - (1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- (pyridin-2-yl) Acrylamide  Produce

Step 1) ( R ) - N - (1- (5-chloro-2 - ((4- (4-methylpiperazin-

Pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacetamide

( R ) -4- (3-aminopyrrolidin-1-yl) -5-chloro- N- (618 mg, 1.59 mmol) and cyanoacetic acid (204 mg, 2.39 mmol) were dissolved in N , N -dimethylformamide and a solution of 1-ethyl-3- (460 mg, 2.9 mmol), hydroxybenzotriazole (65 mg, 0.48 mmol) and N , N -diisopropylethylamine (833 μL, 4.78 mmol) were added thereto and the mixture was stirred at room temperature for 5 hours Respectively. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 10: 1 (v / v)) to obtain the desired compound (514 mg, 1.13 mmol; 71% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 455.2

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.86 (s, 1H), 7.39-7.36 (m, 2H), 6.91-6.88 (m, 2H), 6.75 (bs, 1H), 6.73 (bs, 1H ), 4.52 (m, 1H), 4.03-3.97 (m, 1H), 3.92-3.87 (m, 2H), 3.79-3.74 ), 2.61-2.58 (m, 4H), 2.36 (s, 3H), 2.23-2. 17 (m, 1H), 2.03-1.99 (m, 1H).

Step 2) ( R , E ) - N - (1- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl)

Yl) pyrrolidin-3-yl) -2-cyano-3- (pyridin-2-yl) acrylamide

Obtained in step 1) (R) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Pyridinecarboxaldehyde (25 mg, 0.24 mmol) was dissolved in 2-propanol and piperidine (3.0 μL, 0.03 mmol, 0.24 mmol) ) Was added thereto, followed by stirring at 60 DEG C for 2 hours and then cooling to room temperature. The reaction mixture was diluted with chloroform, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 20: 1 (v / v)) to obtain the desired compound (53 mg, 0.10 mmol; 42% yield).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (bs, 1H), 8.82-8.80 (m, 1H), 8.75-8.74 (m, 1H), 8.08 (s, 1H), 8.00-7.94 (m, IH), 7.90 (s, IH), 7.83-7.80 (m, IH), 7.54-7.50 3H), 2.14-2.12 (m, IH), 3.03-3.00 (m, 4H), 2.43-2.41 (m, 4H) , 2.02 (m, 1 H).

Example  53: ( R , E ) - N - (1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- Of phenyl acrylamide  Produce

The procedure of Example 52 was repeated except that benzaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (58 mg, 0.11 mmol; 48% yield).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.98 (bs, 1H), 8.75-8.73 (d, 1H), 8.14 (s, 1H), 7.93-7.90 (m, 3H), 7.57-7.51 (m, 5H), 6.85-6.81 (m, 2H), 4.46-4.43 (m, IH), 4.02-3.99 (m, IH), 3.86-3.76 , 2.43-2.40 (m, 4H), 2.19 (s, 3H), 2.19-2.12 (m, 1H), 2.02-1.97 (m, 1H).

Example  54: ( R , E ) - N - (1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- (1- methyl -One H - Imidazole -2 days) Acrylamide  Produce

The procedure of Example 52 was repeated, except that 1-methyl-2-imidazole-carboxaldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (40 mg, 0.07 mmol ; 56% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 547.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (bs, 1H), 8.62-8.60 (d, 1H), 7.91-7.86 (m, 2H), 7.54-7.49 (m, 3H), 7.28 (s, 1H), 6.91-6.84 (m, 2H), 4.46-4.44 (m, 1H), 4.03 2.43-2.40 (m, 4H), 2.19 (s, 3H), 2.10 (m, 1H), 2.02 (m, 1H).

Example  55: ( R , E ) - N - (1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- (4- Methylthiazole -2 days) Acrylamide  Produce

The procedure of Example 52 was repeated except that 4-methyl-2-thiazocarboxaldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the title compound (46 mg, 0.08 mmol ; 62% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 564.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (bs, 1H), 8.83-8.81 (d, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H ), 7.54-7.51 (d, 2H), 6.84-6.81 (m, 3H), 3.03-3.00 (m, 4H), 2.45 (s, 3H), 2.43-2.40 (m, 4H), 2.19 (s, 3H), 2.15-2.13 (m,

Example 56: ( R , E ) - N - (1- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl)

Yl) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- Of cyclohexyl acrylamide  Produce

The procedure of Example 52 was repeated except that cyclohexanecarbaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (33 mg, 0.06 mmol; 55% yield) .

MS: [M + H] &lt; ⁺ &gt; m / z 549.3

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.91 (s, 1H), 7.57 (d, 1H), 7.43 (d, 2H), 6.93 (d, 2H), 6.70 (s, 1H), 6.21 ( 4H), 2.58 (m, 4H), 2.30 (m, 2H), 3.81 (m, , 3H), 2.18 (m, IH), 2.02 (m, IH), 1.75 (m, 6H), 1.32 (m, 6H).

Example  57: ( R , E ) - N - (1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- ( m - tolyl) Acrylamide  Produce

The procedure of Example 52 was repeated except that 3-methylbenzaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (58 mg, 0.10 mmol; 95% yield) Respectively.

MS: [M + H] &lt; ⁺ &gt; m / z 557.3

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.96 (s, 1H), 8.72 (d, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.72 (m, 2H), (M, 2H), 3.63 (m, 2H), 3.65 (m, 2H) (m, 4H), 2.40 (s, 3H), 2.39 (s, 3H), 2.34 (m,

Example 58: ( R , E ) -3- (3-bromophenyl) - N Amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacrylate Preparation of amide

The procedure of Example 52 was repeated except that 3-bromobenzaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (55 mg, 0.09 mmol, 80% yield) .

MS: [M + H] &lt; RTI ID = 0.0 &gt; m / z &

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.98 (s, 1H), 8.76 (d, 1H), 8.08 (d, 2H), 7.91 (d, 2H), 7.73 (d, 1H), 4H), 2.47 (m, 4H), 2.41 (m, 2H), 3.81 (m, 2H) (s, 3H), 2.38 (m, IH), 2.17 (m, IH).

Example  59: ( R , E ) - N -1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -3- (3- Trifluoromethyl ) Phenyl ) Acrylamide  Produce

The procedure of Example 52 was repeated, except that 3- (trifluoromethyl) benzaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (27 mg, 0.04 mmol; 40 % Yield).

MS: [M + H] &lt; ⁺ &gt; m / z 611.1

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (s, 1H), 8.80 (d, 1H), 8.24 (m, 3H), 7.94 (m, 2H), 7.90 (t, 1H), (M, 4H), 2.47 (m, 4H), 2.41 (m, 2H), 4.83 (s, 3H), 2.40 (m, IH), 2.17 (m, IH).

Example  60: ( R , E ) -3- (6- Bromopyridine -2 days)- N -1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Of cyanoacrylamide  Produce

The procedure of Example 52 was repeated except that 6-bromo picoline aldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (24 mg, 0.04 mmol; 35% yield) .

MS: [M + H] &lt; ⁺ &gt;

¹ H-NMR (300 MHz, DMSO-d ₆ ):? 8.98 (s, IH), 8.84 (d, IH), 8.01 4H), 2.47 (m, 4H), 2.41 (m, 2H), 4.83 (d, (s, 3H), 2.40 (m, IH), 2.17 (m, IH).

Example  61: ( R , E ) - N -1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2-cyano (6- ( Trifluoromethyl ) Pyridin-2-yl) acrylamide

The procedure of Example 52 was repeated, except that 6- (trifluoromethyl) picoline aldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (31 mg, 0.05 mmol; 46% yield).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.97 (s, 1H), 8.88 (d, 1H), 8.28 (t, 1H), 8.25 (s, 1H), 8.23 (d, 1H), 1H), 3.83 (m, 3H), 3.00 (m, 2H), 4.00 (d, (m, 4H), 2.39 (m, 4H), 2.16 (s, 3H), 2.16 (m,

Example 62: ( R , E ) - tert -butyl- (5- ((1- (5-chloro-2 - ((4- (4- methylpiperazin- 1- yl) phenyl) amino) pyrimidin- 3-yl) amino-4-cyano-2-methyl-5-oxopent-3-en-2-yl) (methyl) carbamate

Except that tert-butylmethyl (2-methyl-1-oxopropan-2-yl) carbamate (see WO2013 / 191965) was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52. [ The procedure of Example 52 was repeated to give the desired compound (22 mg, 0.03 mmol; 19% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 638.3

^{1 H-NMR (300 MHz,} CDCl 3): δ 7.92 (d, 2H), 7.87 (m, 3H), 7.33 (m, 1H), 6.93 (m, 4H), 6.29 (m, 1H), 4.70 ( (m, 3H), 2.64 (m, 4H), 1.86 (m, 2H) , 9H), 1.52 (s, 12H).

Example 63: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -4-methyl-4- (methylamino) pent-2-enamide

( R , E ) -tert-butyl- (5 - ((1- (5-chloro- Methyl-5-oxopent-3-en-2-yl) (methyl) carbamate was dissolved in dichloromethane, and tri The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (Chloroform: methanol = 8: 1 (v / v)) to give the desired compound (7.5 mg).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 10.80 (s, 1H), 8.99 (s, 1H), 7.89 (s, 1H), 7.51 (m, 3H), 6.83 (d, 2H), 4H), 2.42 (m, 4H), 2.18 (m, 4H), 1.96 (m, 2H) (m, 1 H), 1.19 (m, 9 H).

Example 64: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- ( o -Tolyl) acrylamide &lt; / RTI &gt;

The procedure of Example 52 was repeated except that 2-methylbenzaldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (76 mg, 0.14 mmol; 100% yield) Respectively.

MS: [M + H] &lt; ⁺ &gt; m / z 557.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.98 (s, 1H), 8.72 (d, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.78 (d, 1H), 1H), 3.83 (m, 3H), 3.00 (d, IH), 7.50 (d, (m, 4H), 2.41 (m, 4H), 2.39 (s, 3H), 2.16 (s, 3H), 2.16 (m,

Example 65: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- ( p -Tolyl) acrylamide &lt; / RTI &gt;

The procedure of Example 52 was repeated except that 4-methylbenzaldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (54 mg, 0.10 mmol; 88% yield) Respectively.

MS: [M + H] &lt; ⁺ &gt; m / z 557.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 9.05 (s, 1H), 8.68 (d, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.84 (d, 2H), 4H), 2.47 (m, 4H), 2.40 (m, IH), 3.40 (m, 2H) (s, 3H), 2.39 (m, IH), 2.15 (m, IH).

Example 66: ( R ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -2-cyclohexylideneacetamide &lt; / RTI &gt;

The procedure of Example 52 was repeated except that cyclohexanone was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (15 mg, 0.03 mmol; 26% yield).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.97 (s, 1H), 8.54 (d, 1H), 7.89 (s, 1H), 7.52 (d, 2H), 7.29 (d, 1H), (M, 2H), 4.01 (m, 2H), 3.80 (m, 3H), 2.99 (m, 1 H), 1.68 (m, 6 H), 1.24 (m, 5 H).

Example 67: ( R , E ) - tert -butyl- (1- (3 - ((1- (5-chloro- Yl) amino) -2-cyano-3-oxoprop-1-en-1-yl) cyclopropyl) carbamate

The procedure of Example 52 was repeated except that tert-butyl (1-formylcyclopropyl) carbamate (see WO2013 / 191965) was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 The desired compound (10 mg, 0.02 mmol; 7% yield) was obtained.

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.96 (s, 1H), 8.32 (m, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.51 (m, 2H), 4H), 2.40 (m, 4H), 2.17 (s, 3H), 2.17 (m, 3H) (m, 1 H), 1.95 (m, 1 H), 1.35 (s, 9 H), 1.28 (m, 4 H).

Example 68: ( R , E ) - N Yl) pyrrolidin-3-yl) amino) -2- (4-methylpiperazin- Preparation of cyano-5, 5-dimethylhex-2-enamide

The procedure of Example 52 was repeated except that 3,3-dimethyl butanal was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the title compound (28 mg, 0.05 mmol, 40% yield) &Lt; / RTI &gt;

MS: [M + H] &lt; ⁺ &gt; m / z 537.3

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.98 (s, 1H), 8.59 (d, 1H), 7.89 (s, 1H), 7.49 (m, 3H), 6.83 (d, 2H), 3H), 2.39 (s, 3H), 2.36 (m, IH), 3.70 (m, (m, 1 H), 1.15 (m, 9 H).

Example 69: ( R , E ) - N Yl) pyrrolidin-3-yl) amino) -2- (4-methylpiperazin- Preparation of cyano-4, 4-dimethylpent-2-enamide

The procedure of Example 52 was repeated except that pivalicdehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (17 mg, 0.03 mmol; 25% yield).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (s, 1H), 8.53 (d, 1H), 7.89 (s, 1H), 7.52 (d, 2H), 7.32 (s, 1H), 3H), 3.40 (m, 4H), 2.40 (m, 4H), 2.39 (s, 3H), 2.18 (m, 1 H), 2.06 (m, 1 H), 1.21 (s, 9 H).

Example  70: ( R , E ) -3- (1- Aminocyclopropyl ) - N - (1- (5- Chloro -2 - ((4- (4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Of cyanoacrylamide  Produce

(( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) pyrrolidin-3-yl) amino) -2-cyano-3- oxoprop-1-en-1-yl) cyclopropylcarbamate (20 mg, 0.032 mmol ) Was dissolved in dichloromethane (2 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 8: 1 (v / v)) to obtain the desired compound (5 mg).

MS: [M + H] &lt; ⁺ &gt;

Example 71: ( R , E ) - tert -butyl- (1- (3 - ((1- (5-chloro- Yl) amino) -2-cyano-3-oxop- 1-en-1-yl) cyclopropyl) (methyl) carbamate

The procedure of Example 52 was repeated, except that tert-butyl (1-formylcyclopropyl) (methyl) carbamate was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (64 mg , 0.01 mmol; 30% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 636.3

Example 72: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (furan-2-yl) acrylamide

The procedure of Example 52 was repeated except that the furan-2-carbaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (32 mg, 0.06 mmol; 46% yield) .

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.97 (bs, 1H), 8.60-8.58 (d, 1H), 2.11-8.10 (m, 1H), 7.95 (s, 1H), 7.90 (s (M, 1H), 3.84 (m, 1H), 3.84 (d, 1H), 3.75 (m, 3H), 3.03-3.00 (m, 4H), 2.44-2.40 (m, 4H), 2.19 (s, 3H), 2.12 (m, 1H), 2.00-1.97)

Example 73: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (1-methyl-1 H -Pyrazol-4-yl) acrylamide &lt; / RTI &gt;

The procedure of Example 52 was repeated, except that 1-methyl- 1H -pyrazole-4-carbaldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (54 mg, 0.10 mmol; 74% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 547.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.96 (bs, 1H), 8.51-8.49 (d, 1H), 8.11-8.10 (m, 1H), 7.95 (s, 1H), 7.90 (s (M, 1H), 3.84 (m, 1H), 3.84 (d, 3H), 2.13 (m, 1H), 2.00-1.97 (m, 1H), 3.03-3.00 (m, 4H), 2.44-2.40 (m, 4H).

Example 74: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (thiazol-2-yl) acrylamide

The procedure of Example 52 was repeated except that 2-formylthiazole was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (71 mg, 0.13 mmol, 73% yield) Respectively.

MS: [M + H] &lt; ⁺ &gt; m / z 550.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 9.00 (bs, 1H), 8.88-8.86 (d, 1H), 8.33 (s, 1H), 8.22 (s, 2H), 7.91 (s, 1H ), 7.56-7.53 (m, 2H), 6.86-6.83 (m, 2H), 4.40 (m, 2.64 (m, 4H), 2.34 (s, 3H), 2.20 (m, 1H), 2.00 (m, 1H).

Example 75: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (pyridin-3-yl) acrylamide

The procedure of Example 52 was repeated except that 3-pyridinecarboxaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (48 mg, 0.09 mmol; 67% yield) .

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (bs, 1H), 8.96 (m, 1H), 8.83-8.81 (d, 1H), 8.72-8.70 (m, 1H), 8.37-8.34 (m, IH), 8.20 (s, IH), 7.90 (s, IH), 7.62-7.57 (m, IH), 7.54-7.51 (m, 4H), 2.21 (s, 3H), 2.17 (m, 2H) -2.13 (m, 1 H), 2.05 - 2.03 (m, 1 H).

Example 76: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (pyridin-4-yl) acrylamide

The procedure of Example 52 was repeated except that 4-pyridinecarboxaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (31 mg, 0.06 mmol; 44% yield) .

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 9.00 (bs, 1H), 8.90-8.88 (d, 1H), 8.78-8.76 (m, 2H), 8.15 (s, 1H), 7.91 (s 1H), 7.76-7.74 (m, 2H), 7.55-7.51 (m, 2H), 6.85-6.82 (m, 2H), 4.46-4.45 2H), 3.78 (m, 3H), 3.03 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H), 2.20 (m,

Example 77: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (quinolin-2-yl) acrylamide

The procedure of Example 52 was repeated except that 2-quinolinecarboxaldehyde was used instead of 2-pyridinecarboxaldehyde in step 2) of Example 52 to obtain the desired compound (30 mg, 0.05 mmol, 38% yield) .

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 9.00 (bs, 1H), 8.93-8.91 (d, 1H), 8.56-8.53 (m, 1H), 8.27 (s, 1H), 8.06-8.03 (m, 2H), 7.97-7.94 (m, 1H), 7.91 (s, 1H), 7.88-7.82 2H), 4.49-4.48 (m, 1H), 4.02 (m, 1H), 3.91-3.79 (m, 3H), 3.05 (m, 4H), 2.48 , 3H), 2.20 (m, IH), 2.00 (m, IH).

Example 78: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (pyrazin-2-yl) acrylamide

The procedure of Example 52 was repeated, except that pyrazine-2-carbaldehyde (see WO2005 / 040159) was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (36 mg, 0.07 mmol; 43% yield).

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.99 (bs, 1H), 8.97 (s, 1H), 8.89-8.88 (m, 1H), 8.83 (m, 1H), 8.76-8.75 (m , 8.18 (s, IH), 7.90 (s, IH), 7.54-7.51 (m, 2H), 6.84-6.81 (m, 2H), 4.48-4.46 (M, 4H), 2.43-2.40 (m, 4H), 2.19-2.15 (m, 4H), 2.03 (m, 1H).

Example 79: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (2- (dimethylamino) phenyl) acrylamide

The procedure of Example 52 was repeated, except that 2- (dimethylamino) benzaldehyde (see WO2008 / 066151) was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (75 mg, 0.13 mmol; 83% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 586.3

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.98 (bs, 1H), 8.68-8.65 (d, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.83-7.80 (m 2H), 7.50-7.44 (t, 1H), 7.16-7.16 (m, 1H), 7.11-7.06 4H), 2.70 (s, 6H), 2.43-2.40 (m, 4H), 3.45-3.77 (m, , 2.19 (s, 3H), 2.16 - 2.11 (m, 1H), 2.05 - 2.03 (m, 1H).

Example 80: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- -3- (1-methyl-1 H -Pyrazol-3-yl) acrylamide &lt; / RTI &gt;

The procedure of Example 52 was repeated, except that 1-methyl- 1H -pyrazole-3-carbaldehyde was used instead of 2-pyridinecarboxaldehyde in the step 2) of Example 52 to obtain the desired compound (71 mg, 0.13 mmol; 84% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 547.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.97 (bs, 1H), 8.69-8.67 (d, 1H), 8.06 (s, 1H), 7.91-7.90 (m, 2H), 7.54-7.51 (m, 2H), 7.02-7.01 (d, 1H), 6.84-6.81 (m, 2H), 4.43-4.42 2H), 2.00 (m, 3H), 3.03-3.00 (m, 4H), 2.43-2.40 (m, 4H), 2.19 (s, 3H), 2.12 (m,

Example 81: ( R , E ) - N Preparation of (1- (5-chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-

The procedure of Example 52 was repeated using cyclopropylamine instead of 4- (4-methylpiperazin-1-yl) aniline in Example 3 to obtain the desired compound (72 mg, 0.18 mmol, 38% Respectively.

MS: [M + H] &lt; ⁺ &gt;

^{1 H-NMR (300 MHz,} CDCl 3): δ 8.83-8.81 (m, 1H), 8.31 (s, 1H), 7.88 (s, 1H), 7.85-7.79 (m, 1H), 7.63-7.61 (m (M, 1H), 7.44-7.39 (m, IH), 6.65-6.63 (d, IH), 5.02 (m, 2H), 3.80-3.75 (m, 1H), 2.70-2.69 (m, 1H), 2.33-2.30 (m, , 0.54-0.50 (m, 2H).

Example 82: ( R , E ) - N - (1- (5-chloro-2 - ((4-diethylamino) butyl) amino) pyrimidin-4-yl) pyrrolidin- - yl) acrylamide

The procedure of Example 52 was repeated except that N ¹ , N ¹ -diethylbutane-1,4-diamine was used instead of 4- (4-methylpiperazin-1-yl) aniline in Example 3 to obtain the desired compound 15 mg, 0.03 mmol; 20% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 497.3

¹ H-NMR (300 MHz, CDCl ₃ ):? 8.83-8.81 (m, IH), 8.31 (s, IH), 7.85-7.79 (m, 2H), 7.64-7.61 (m, 2H), 3.78 (m, IH), 6.67-6.65 (m, IH) 1H), 1.66 (m, 4H), 1.05 (m, 2H), 2.50 (m, -1.01 (t, 6H).

Example 83: ( R , E ) -2-cyano- N Pyrrolidin-3-yl) -3- (pyridin-2-yl) -pyrrolidin- ) Preparation of acrylamide

The procedure of Example 52 was repeated except that 2,4-dichloropyrimidine was used instead of 2,4,5-trichloropyrimidine in Example 3 to obtain the title compound (15 mg, 0.029 mmol; 41% yield) Respectively.

MS: [M + H] &lt; ⁺ &gt; m / z 510.3

^{1 H-NMR (300 MHz,} CDCl 3): δ 8.81 (d, 1H), 8.31 (s, 1H), 7.92 (m, 1H), 7.83 (m, 1H), 7.63 (d, 1H), 7.47 ( (d, IH), 7.40 (m, IH), 6.83 (d, IH) (m, 3H), 3.15 (s, 4H), 2.71 (s, 4H), 2.41 (m,

Example  84: ( R , E )-2- Cyano - N - (1- (5- Cyclopropyl -2 - ((4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -3- (pyridin-2-yl) Acrylamide  Produce

The procedure of Example 52 was repeated, except that 2,4-dichloro-5-cyclopyrimidine (see 2011/090760) was used instead of 2,4,5-trichloropyrimidine in Example 3 to obtain the desired compound 13 mg, 0.024 mmol; 32% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 550.3

¹ H-NMR (300 MHz, CDCl ₃ ):? 8.87 (d, IH), 8.36 (s, IH), 7.87-7.83 (m, 2H), 7.69 ), 6.99 (m, 2H), 6.94 (d, IH), 5.75 (m, IH), 4.24 4H), 2.42 (s, 3H), 2.00 (m, 1H), 0.92 (m, 2H), 0.68 (m, 2H).

Example  85: ( R , E ) - N - (1- (5- Chloro -2 - ((4- Methylpiperazine -1 day) Phenyl ) Amino) pyrimidin-4-yl) Pyrrolidine Yl) -2- Cyano -4- (dimethylamino) -4- Methylpent -2- Enamidic  Produce

Exemplary N obtained in step 1) of Example 52 (1- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine (200 mg, 0.44 mmol) and 2- (dimethylamino) -2-methylpropanal (WO2014 / 036016; 102 mg, 0.88 mmol) were dissolved in dichloromethane , Chlorotrimethylsilane (224 μL, 1.76 mmol) and pyrrolidine (217 μL, 2.64 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 20: 1 (v / v)) to obtain the desired compound (89 mg, 0.16 mmol; 37% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 552.3

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 9.00 (bs, 1H), 8.53-8.51 (d, 1H), 7.90 (s, 1H), 7.53-7.50 (d, 2H), 7.28 (s 2H), 3.74-3.73 (m, IH), 3.03-3.00 (m, IH) (m, 4H), 2.43-2.40 (m, 4H), 2.19 (s, 3H), 2.14 (s, 6H), 2.10-2.06 ).

Example 86: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-3- (4-methylpiperazin- (3-methyloxetan-3-yl) acrylamide

The procedure of Example 85 was repeated, except that 3-methyloxetane-3-carbaldehyde was used instead of 2- (dimethylamino) -2-methylpropane in Example 85 to obtain the title compound (19 mg, 0.04 mmol; 15% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 537.2

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 9.00 (bs, 1H), 8.65-8.63 (d, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.54-7.51 (d (M, 2H), 3.84 (m, 2H), 3.84-3.80 (m, 1H), 1.53 (s, 3H), 2.05 (m, 1H), 1.97 (m, 1H), 3.03-3.00 (m, 4H), 2.43-2.42

Example 87: ( R ) -tert-butyl-2 - ((E) -3 - (((R) N Yl) pyrrolidin-3-yl) amino) -2-cyano-pyrimidin- Oxo-1-en-1-yl) pyrrolidine-1-carboxylate

The procedure of Example 85 was repeated except that ( S ) -tert-butyl 2-formylpyrrolidine-1-carboxylate was used instead of 2- (dimethylamino) -2-methylpropane in Example 85 (39 mg, 0.06 mmol; 56% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 636.3

Example 88: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-4- (4-methylpiperazin- (4-ethylpiperazin-1-yl) -4-methylpent-2-enamide

The procedure of Example 85 was followed except that 2- (4-ethylpiperazin-1-yl) -2-methylpropanal was used in place of 2- (dimethylamino) The objective compound (21 mg, 0.03 mmol; 24% yield) was obtained in a repeated manner.

MS: [M + H] &lt; RTI ID = 0.0 &gt; m / z &

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.97 (s, 1H), 8.51 (d, 1H), 7.89 (s, 1H), 7.53 (d, 2H), 7.24 (s, 1H), 4H), 2.47 (m, 4H), 2.40 (m, 4H), 2.39 (m, (s, 3H), 2.18 (m, IH), 1.97 (m, IH), 1.16 (s, 6H), 0.97 (m, 3H).

Example 89: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-3- (4-methylpiperazin- (1- (dimethylamino) cyclopropyl) acrylamide

The procedure of Example 85 was repeated, except that 1- (dimethylamino) cyclopropanecarbaldehyde was used instead of 2- (dimethylamino) -2-methylpropane in Example 85 to obtain the desired compound (3.6 mg, 0.01 mmol; 6% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 550.3

^{1 H-NMR (300 MHz,} DMSO-d 6): δ 8.97 (s, 1H), 8.41 (d, 1H), 7.88 (s, 1H), 7.53 (d, 2H), 7.29 (s, 1H), 4H), 2.24 (s, 9H), 2.19 (m, 2H), 3.96 (m, 2H) (m, 1 H), 1.96 (m, 1 H), 1.13 (m, 4 H).

Example 90: ( R , E ) - N Pyridin-3-yl) -2-cyano-4- (dimethylamino) -4-methylpent-2- Preparation of enamide

The procedure of Example 85 was repeated, except that cyclopropylamine was used instead of 4- (4-methylpiperazin-1-yl) aniline in Example 3 to obtain the desired compound (43 mg, 0.01 mmol; &Lt; / RTI &gt;

MS: [M + H] &lt; ⁺ &gt; m / z 418.2

¹ H-NMR (300 MHz, CDCl 3):? 7.80 (s, 1 H), 7.00-6.90 (m, 3H), 4.54 , 2.27-2.02 (m, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 1.23 (s, ).

Example 91: ( R , E ) - N - (1- (5-chloro-2 - ((4- (dimethylamino) cyclohexyl)

Amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2- cyano-4-methyl-4- (methylamino) pent-

Step 1) tert-Butyl ( R , E ) - (5 - ((1- (5-chloro-2 - ((4- (dimethylamino)

Amino) pyrimidin-4-yl) pyrrolidin-3-yl) amino) Produce

The procedure of Example 52 was repeated except that N, N -dimethylcyclohexane-1,4-diamine was used instead of 4- (4-methylpiperazin-1-yl) aniline in Example 3 to obtain the desired compound Respectively.

Step 2) ( R , E ) - N - (1- (5-chloro-2 - ((4- (dimethylamino) cyclohexyl)

Amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2- cyano-4-methyl-4- (methylamino) pent-

( R , E ) - (5 - ((1- (5-Chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin-4-yl) piperidine obtained in step 1) 3-yl) (methyl) carbamate (5 mg, 0.01 mmol) was dissolved in 1,4-dioxane , And 4N-hydrochloric acid (1,4-dioxane solution; 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain the desired compound (4.0 mg, 89% yield).

MS: [M + H] &lt; ⁺ &gt; m / z 489.3

Example 92: ( R , E ) - N Yl) pyrrolidin-3-yl) -2-cyano-benzoyl) -piperidine- - N -Methyl-3- (pyridin-2-yl) acrylamide

Step 1) Preparation of tert-butyl (R) - (1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3-yl (methyl) carbamate

Potassium hydroxide (105 mg, 1.88 mmol) was dissolved in dimethyl sulfoxide and stirred at room temperature for 10 minutes. To the reaction mixture was added ( R ) -tert-butyl (1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3- yl) carbamate (125 mg, 0.38 mmol) obtained in Example 3, Methane (95 L, 1.52 mmol) were successively added thereto, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution and extracted with ethyl acetate solution. The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure to give the desired compound (117 mg, 0.34 mmol; 89% yield).

Step 2) ( R , E ) - N - (1- (5-chloro-2 - ((4- (4-methylpiperazin-

Pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano- N -Methyl-3- (pyridine-2-) acrylamide

Carried out in step 3 of Example 2) (R) -tert- butyl (1- (2,5-dichloro-pyrimidin-4-yl) pyrrolidin-3-yl) carbamate instead of tert- butyl (R) - ( The procedure of Example 3 was repeated except that 1- (2,5-dichloropyrimidin-4-yl) pyrrolidin-3-yl (methyl) carbamate was used to obtain the desired compound (11 mg, 0.02 mmol ; 33% yield).

MS: [M + H] &lt; ⁺ &gt;

The compounds thus prepared are summarized in Table 1 below.

number Chemical structure Compound name One

(R) -N- (1- (2-aminopyridin-4-yl) pyrrolidin-3- yl) 2

(R) -N- (1- (2,6-diamino-5-chloropyrimidin-4-yl) pyrrolidin- 3

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- Acrylamide 4

(R) -N- (1- (5-chloro-2- (cyclopropylamino) pyrimidin-4- yl) pyrrolidin- 5

(4-methylcyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide 6

Amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide (hereinafter referred to as &quot; 7

(R) -N- (1- (5-chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin-4-yl) pyrrolidin- 8

(R) -N- (1- (2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- 9

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl ) Acrylamide 10

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- ) Acrylamide 11

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- Acrylamide 12

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin- Acrylamide 13

(Trifluoromethyl) pyrimidin-4-yl) pyrrolidine &lt; / RTI &gt; Yl) acrylamide 14

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin- Amide 15

Amino) pyridin-4-yl) azetidin-3-yl) acrylamide &lt; 16

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) piperidin- Amide 17

Amino) pyridin-4-yl) piperidin-4-yl) acrylamide &lt; 18

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin- 2-enamide 19

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin- 2 - ((dimethylamino) methyl) acrylamide 20

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin- ) -4- (dimethylamino) but-2-enamide 21

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin- ) -2-phenylethenesulfonamide 22

(4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) pyrrolidin-3-yl ) -2-fluoro-3-phenylacrylamide 23

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine-3- Yl) -3- (pyridin-2-yl) acrylamide 24

(4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- Acrylamide 25

Yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine-2-carboxylic acid (2- 3-yl) acrylamide 26

(4-isopropylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl ) Acrylamide 27

(R) -N- (1- (5-chloro-2 - ((4- (4- (2- hydroxyethyl) piperazin- 1 -yl) phenyl) amino) pyrimidin- Yl) acrylamide 28

(1-methylpiperidin-4-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- ) Acrylamide 29

(Methyl) amino) phenyl) amino) pyrimidin-4-yl) pyrrolidine- 3-yl) acrylamide 30

(R) -N- (1- (5-chloro-2 - ((4- (4- (dimethylamino) piperidin- 1- yl) phenyl) amino) pyrimidin- 3-yl) acrylamide 31

Pyrrolidin-1-yl) phenyl) amino) pyrimidin-4-yl) - N - ((R) Pyrrolidin-3-yl) acrylamide 32

Pyrrolo [3,4-b] pyridin-6 (2H) -yl) - N - ((R) -1- (5-chloro- Phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) 33

(4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- Acrylamide 34

(2-morpholinoethoxy) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide 35

(2-morpholinoethoxy) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide 36

(4-morpholinophenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide 37

(3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) acrylamide 38

(R) -4 - ((4- (3-acrylamidopyrrolidin-1-yl) -5- chloropyrimidin-2- yl) amino) -3- methoxy- 4-yl) benzamide 39

(R) -N- (1- (5-chloro-2 - ((4- (4-ethylpiperazine-1-carbonyl) phenyl) amino) pyrimidin- ) Acrylamide 40

(R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazine-1-carbonyl) phenyl) amino) pyrimidin- ) Acrylamide 41

(5-chloro-2 - ((4- (N, N-dimethylsulfamoyl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- 42

(Trifluoromethyl) phenyl) amino) pyrimidin-4-yl (5-chloro-2- ) Pyrrolidin-3-yl) acrylamide 43

Pyrazol-4-yl) amino) pyrimidin-4-yl) pyrrolidine &lt; EMI ID = Yl) acrylamide 44

(1-methylpiperidin-4-yl) -lH-pyrazol-4-yl) amino) pyrimidin-4-yl ) Pyrrolidin-3-yl) acrylamide 45

Yl) amino) pyrimidin-4-yl) pyrrolidine-2-carboxylic acid (2- 3-yl) acrylamide 46

Yl) amino) pyrimidin-4-yl) pyrrolidine-2-carboxylic acid (2- 3-yl) acrylamide 47

(R) -2 - ((4- (3-acrylamidopyrrolidin-1-yl) -5-chloropyrimidin- 4-carboxamide 48

(R) -2 - ((4- (3-acrylamidopyrrolidin-1-yl) -5-chloropyrimidin- 5-carboxamide 49

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine-3- Yl) -2-cyano-5-methylhex-2-enamide 50

(4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine-3- Yl) -2-cyano-3-cyclopropylacrylamide 51

(R, Z) - ethyl-2 - ((1- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) carbamoyl) -3-phenyl acrylate 52

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (pyridin-2-yl) acrylamide 53

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3-phenylacrylamide 54

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (1-methyl- 1H -imidazol- 55

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (4-methylthiazol-2-yl) 56

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3-cyclohexyl acrylamide 57

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- ( m -tolyl) acrylamide 58

(R, E) -3- (3- bromophenyl) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin -4 Yl) pyrrolidin-3-yl) -2-cyanoacrylamide 59

( R , E ) - N -l- (5-Chloro-2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- ) -2-cyano-3- (3-trifluoromethyl) phenyl) acrylamide 60

(R, E) -3- (6- bromopyridin-2-yl) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) Pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacrylamide 61

( R , E ) - N -l- (5-Chloro-2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- ) -2-cyano (6- (trifluoromethyl) pyridin-2-yl) acrylamide 62

(R, E) -tert- butyl - (5 - ((l- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) Methyl-5-oxopent-3-en-2-yl) (methyl) carbamate 63

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-4-methyl-4- (methylamino) pent-2- 64

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- ( o -tolyl) acrylamide 65

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- ( p -tolyl) acrylamide 66

(R) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano-2-cyclohexylideneacetamide 67

( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) pyrrolidin-3-yl) amino) -2-cyano-3- oxoprop-1-en-1-yl) cyclopropyl) carbamate 68

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) amino) -2-cyano-5,5-dimethylhex-2-enamide 69

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) amino) -2-cyano-4, 4-dimethylpent-2-enamide 70

(R, E) -3- (1- amino-cyclopropyl) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- Yl) pyrrolidin-3-yl) -2-cyanoacrylamide 71

( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) amino) -2-cyano-3-oxop- 1-en-1-yl) cyclopropyl) (methyl) carbamate 72

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (furan-2-yl) acrylamide 73

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 yl) 2-cyano-3- (1-methyl -1 H - pyrazol-4-yl) acrylamide 74

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (thiazol-2-yl) acrylamide 75

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (pyridin-3-yl) acrylamide 76

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (pyridin-4-yl) acrylamide 77

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (quinolin-2-yl) acrylamide 78

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (pyrazin-2-yl) acrylamide 79

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (2- (dimethylamino) phenyl) acrylamide 80

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 yl) -2-cyano-3- (1-methyl -1 H - pyrazol-3-yl) acrylamide 81

(R, E) - N - (1- (5- chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano-3- (pyridin-2 - yl) acrylamide 82

(R, E) - N - (1- (5- chloro-2 - ((4-diethylamino) butyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano -3- (pyridin-2-yl) acrylamide 83

(R, E) -2- cyano - N - (1- (2 - ((4- (4- methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin -3 Yl) -3- (pyridin-2-yl) acrylamide 84

(R, E) -2- cyano-N - (1- (5- Cyclopropyl-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -3- (pyridin-2-yl) acrylamide 85 ( R , E ) - N - (1- (5-Chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 2-Cyano-4- (dimethylamino) -4-methylpent-2-enamide 86

( R , E ) - N - (1- (5-Chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 2-Cyano-3- (3-methyloxetan-3-yl) acrylamide 87

(R) -tert- butyl 2 - ((E) -3 - (((R) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino ) Pyrimidin-4-yl) pyrrolidin-3-yl) amino) -2-cyano-3- oxop- 88

( R , E ) - N - (1- (5-Chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 2-Cyano-4- (4-ethylpiperazin-1-yl) -4-methylpent- 89

( R , E ) - N - (1- (5-Chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 2-Cyano-3- (1- (dimethylamino) cyclopropyl) acrylamide 90

( R , E ) - N - (1- (5-chloro-2- (cyclopropylamino) pyrimidin- 4-methylpent-2-enamide 91

(R, E) - N - (1- (5- chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano Methyl-4- (methylamino) pent-2-enamide 92

(R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano- N -methyl-3- (pyridin-2-yl) acrylamide

Test Example

The results of evaluating the efficacy of the compounds prepared in the above examples were as follows.

Test Example  One: TAK1 Kinase  Evaluation of inhibitory activity

The TAK1-TAB1 protein was used to evaluate the TAK1 inhibitory activity of the compounds based on the LanthaScreen technology developed by Life Technologies. This assay is based on the binding of Alexa Fluor ^® 647-labeled, ATP-competitive kinase tracer-236 to TAK1-TAB1, in the presence of an europium-conjugated antibody The FRET (fluorescence resonance energy transfer) signal is measured. Experiments were performed in 384-well plates under conditions of 20 mM HEPES pH 7.5, 10 mM MgCl ₂ , 0.01% BSA, 0.0005% Tween-20 and 2% DMSO. After the background signal is measured in the absence of the TAK1-TAB1 protein and only the solvent (2% DMSO) is added as the non-inhibitory signal, the compound to be assayed is assayed at a set concentration (e.g., 1000 or 100 nM) to calculate the TAK1-TAB1 inhibitory activity of the compound in%.

compound % Inhibitory effect 1000 nM 100 nM Example 3 73 12 Example 13 53 18 Example 60 90 53 Example 83 71 21

As shown in Table 2, the compounds of the present invention were found to be excellent in TAK1 kinase inhibitory activity. While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (16)

Claims 1. A compound selected from the group consisting of pyrimidine derivatives of the formula (I), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Chemical Formula 1]

In this formula,
X is CH or N;
Y is H, halogen, C _1-6 alkyl, C _3-10 cycloalkyl or haloC _1-3 alkyl;
Z is C or S = O;
R ₁ is H or C _1-6 alkyl;
R ₂ is H, C _1-6 alkyl, C _3-10 cycloalkyl, _3-10 membered heterocycloalkyl, C _6-12 aryl or _5-12 member heteroaryl, wherein said alkyl, cycloalkyl, aryl And heteroaryl are each independently selected from the group consisting of OH, halogen, C _1-6 alkyl, di C _1-6 alkylamino, C _1-6 alkoxy, haloC _1-3 alkyl, (C _1-6 alkylamino) , (hydroxy C _1-6 alkyl) heterocycloalkyl, heterocycloalkyl-alkyl, (C _1-6 alkyl) heterocycloalkyl, ((C _3-10 cycloalkyl) C _1-6 alkyl) heterocycloalkyl, (hetero cycloalkyl) C _1-6 alkoxy, ((C _1-6 alkyl) heterocycloalkyl) carbonyl, (di-C _1-6 alkylamino) sulfamoyl, (heterocycloalkyl) C _1-6 alkyl, ((C _1-6 alkyl) heterocycloalkyl) aminocarbonyl, ((heterocycloalkyl) C _1-6 alkyl) aminocarbonyl, and (di-C _1-6 alkylamino) C _1-6 alkyl (C _1-6 alkyl) Group consisting of amino Which it may be substituted with 1 to 3 substituents independently selected from;
R ₃ is H, halogen, CN, C _1-6 alkyl, halo C _1-3 alkyl, C _1-6 alkoxycarbonyl or (C _1-6 alkylamino) C _1-6 alkyl,
R ₄ and R ₅ are each independently H, C _1-6 alkyl, C _6-12 aryl, C _3-6 cycloalkyl, 3-10 membered heterocycloalkyl of, amino, (amino) C _1-6 alkyl, (Amino) C _3-6 cycloalkyl, (amino) C _6-12 aryl, (amino) (3-10 membered heterocycloalkyl) or 5-12 membered heteroaryl, wherein said heterocycloalkyl and hetero Each aryl may each independently contain one or more heteroatoms selected from the group consisting of N, S and O, and each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl and CF ₃ Wherein said amino may be substituted with one or more substituents selected from the group consisting of H, halogen, CN, C _1-6 alkyl, haloC _1-3 alkyl or C _1-6 alkoxycarbonyl, said R ₄ and R ₅ may combine with each other to form a ring), wherein R ₃ and R ₄ or R ₅ may form a bond with each other;
R ₆ is H, amino or C _1-6 alkyl;
n is an integer of 0 to 3;
The method of claim 1 wherein, Y is a compound characterized in that a H, fluoro, chloro, bromo, methyl, cyclopropyl, or a -CF _3.
3. A compound according to claim 1 wherein R ₂ is H, cyclopropyl, cyclohexyl, phenyl, pyrazole, pyridine or thiazole, wherein said cyclopropyl, cyclohexyl, phenyl, pyrazole, pyridine and thiazole are each independently OH, halogen, C _{1 - 6} alkyl, di-C _{1 - 6} alkylamino, C _{1 -6} alkoxy, halo C _1-3 alkyl, (di-C _1-6 alkylamino) heterocycloalkyl, (hydroxy-C _1-6 alkyl Heterocycloalkyl, (C _1-6 alkyl) heterocycloalkyl, ((C _3-10 cycloalkyl) C _1-6 alkyl) heterocycloalkyl, (heterocycloalkyl) C _1-6 alkoxy, ((C _1-6 alkyl) heterocycloalkyl) carbonyl, (C _1-6 alkylamino) sulfamoyl, (heterocycloalkyl) C _1-6 alkyl, ((C _1-6 alkyl) aminocarbonyl, ((heterocycloalkyl) C _1-6 alkyl) aminocarbonyl, and (di-C _1-6 alkylamino) C _1-6 alkyl (C _1-6 alkyl) amino consisting of Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
The method of claim 1, wherein, R ₃ is H, halogen, CN, C _1-6 alkyl, halo C _1-3 alkyl, C _1-6 alkoxycarbonyl or (di-C _{1 - 6} alkylamino) C _{1 - 6} alkyl &Lt; / RTI &gt;
The compound of claim 1, wherein R ₄ and R ₅ are each independently selected from the group consisting of H, methyl, methylbutyl, (dimethylamino) methyl, phenyl, (dimethylamino) phenyl, pyridinyl, methylimidazolyl, methylthiazolyl, (Boc) methylaminoisopropyl, (Boc) aminocyclopropyl, methylpropyl, dimethylpropyl, dimethylbutyl, isopropyl, butylphenyl, Aminocyclopropyl, (Boc) amino (methyl) cyclopropyl, furanyl, methylpyrazolyl, thiazolyl, quinolinyl, pyrazinyl, dimethylaminocyclopropyl, methylpyrazolyl, dimethylaminoisopropyl, methyloxetanyl, (Boc) pyrrolidinyl, (ethylpiperazinyl) isopropyl or methylamino isopropyl.
The method of claim 1, wherein the compound in which the R ₃ and R ₄ or R ₅ is characterized in that it forms a bond with each other.
The compound according to claim 1, wherein R ₄ and R ₅ are bonded to each other to form cyclohexylidene.
The compound according to claim 1, wherein n is 0, 1 or 2.
2. A compound according to claim 1, wherein said compound is selected from the group consisting of:
(1) (R) -N- (1- (2-aminopyridin-4-yl) pyrrolidin-3-yl) acrylamide;
(2) (R) -N- (1- (2,6-diamino-5-chloropyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;
(3) (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;
(4) (R) -N- (1- (5-Chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;
(5) (R) -N- (1- (5-Chloro-2 - ((4-methylcyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;
(6R) -4-hydroxycyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl ) Acrylamide;
(7) (R) -N- (1- (5-Chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;
(8) Synthesis of (R) -N- (1- (2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- Amide;
(9) (R) -N- (1- (5-fluoro-2 - ((4- (4-methylpiperazin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) acrylamide;
(10) (R) -N- (1- (5-Bromo-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) acrylamide;
(11) (R) -N- (1- (5-methyl-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;
(12) (R) -N- (1- (5-Cyclopropyl-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- - yl) acrylamide;
(13) Synthesis of (R) -N- (1- (2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin- Pyrrolidin-3-yl) acrylamide;
(14) (S) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1- yl) phenyl) amino) pyridin- Yl) acrylamide;
(15) N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) azetidin-3-yl) acrylamide;
(16) (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- Yl) acrylamide;
(17) Synthesis of N- (1- (5-chloro-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- ;
(18) (R) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin- Yl) but-2-enamide;
(19) (R) -N- (1- (5-chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- Yl) -2 - ((dimethylamino) methyl) acrylamide;
(20) (R, E) -N- (1- (5-Chloro-2 - ((4- (4- methylpiperazin- 1 -yl) phenyl) amino) pyridin- 3-yl) -4- (dimethylamino) but-2-enamide;
(21) (R, E) -N- (1- (5-Chloro-2- 3-yl) -2-phenylethenesulfonamide;
(22) (R, Z) -N- (1- (5-Chloro-2- 3-yl) -2-fluoro-3-phenylacrylamide;
(23) (R, E) -N- (1- (5-Chloro-2- Yl) -3- (pyridin-2-yl) acrylamide;
(24) Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;
(25) (R) -N- (1- (5-Chloro-2 - ((4- (4- (cyclopropylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) &lt; / RTI &gt;acrylamide;
(26) (R) -N- (1- (5-Chloro-2 - ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) pyrimidin- 3-yl) acrylamide;
(27) (R) -N- (1- (5-Chloro-2 - ((4- (4- (2-hydroxyethyl) piperazin- ) Pyrrolidin-3-yl) acrylamide;
(28) (R) -N- (1- (5-Chloro-2 - ((4- (1- methylpiperidin- 3-yl) acrylamide;
(29) (R) -N- (1- (5-Chloro-2 - ((4 - ((2- (dimethylamino) ethyl) 3-yl) &lt; / RTI &gt;acrylamide;
(30) (R) -N- (1- (5-Chloro-2 - ((4- (4- (dimethylamino) piperidin- 1 -yl) phenyl) amino) pyrimidin- 3-yl) &lt; / RTI &gt;acrylamide;
(31) N - ((R) -1- (5-Chloro-2 - ((4 - ((R) -3- (dimethylamino) pyrrolidin- Yl) pyrrolidin-3-yl) acrylamide;
Pyrrolo [3,4-b] pyridin-6 (2H) -pyrrolidin-1- Yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;
(33) (R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin- - yl) acrylamide;
(34) (R) -N- (1- (5-Chloro-2 - ((4- (2-morpholinoethoxy) phenyl) amino) pyrimidin- ) Acrylamide;
(35) (R) -N- (1- (5-Chloro-2 - ((3- (2-morpholinoethoxy) phenyl) amino) pyrimidin- ) Acrylamide;
(36) (R) -N- (1- (5-Chloro-2 - ((4-morpholinophenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) acrylamide;
(37) (R) -N- (1- (5-Chloro-2 - ((3-fluoro- Pyrrolidin-3-yl) acrylamide;
(38) A mixture of (R) -4 - ((4- (3-acrylamidopyrrolidin- 1 -yl) -5- chloropyrimidin- Methylpiperidin-4-yl) benzamide;
(39) (R) -N- (1- (5-Chloro-2 - ((4- (4-ethylpiperazin- 1 -carbonyl) phenyl) amino) pyrimidin- 3-yl) acrylamide;
(40) (R) -N- (1- (5-Chloro-2 - ((3- (4-ethylpiperazin- 1 -carbonyl) phenyl) amino) pyrimidin- 3-yl) acrylamide;
(41) Synthesis of (R) -N- (1- (5-chloro-2 - ((4- (N, N- dimethylsulfamoyl) phenyl) amino) pyrimidin- ) Acrylamide;
(42) (R) -N- (1- (5-Chloro-2 - ((4- (4- methylpiperazin- 1 -yl) -3- (trifluoromethyl) phenyl) amino) pyrimidine- 4-yl) pyrrolidin-3-yl) acrylamide;
(43) (R) -N- (1- (5-Chloro-2 - ((1- (2-morpholinoethyl) Pyrrolidin-3-yl) acrylamide;
(44) (R) -N- (1- (5-Chloro-2 - ((1- (1- methylpiperidin- 4-yl) pyrrolidin-3-yl) acrylamide;
(45) (R) -N- (1- (5-Chloro-2 - ((5- (4-ethylpiperazin-1-yl) pyridin- 2- yl) amino) pyrimidin- 3-yl) &lt; / RTI &gt;acrylamide;
(46) (R) -N- (1- (5-Chloro-2 - ((6- (4- ethylpiperazin- 1 -yl) pyridin- 3-yl) &lt; / RTI &gt;acrylamide;
(47) A mixture of (R) -2 - ((4- (3-acrylamidopyrrolidin-1-yl) -5- chloropyrimidin- Thiazole-4-carboxamide;
(48) Synthesis of (R) -2 - ((4- (3-acrylamidopyrrolidin-1-yl) -5- chloropyrimidin- Thiazole-5-carboxamide;
(49) (R, E) -N- (1- (5-Chloro-2 - ((4- (4-methylpiperazin- 1- yl) phenyl) amino) pyrimidin- Yl) -2-cyano-5-methylhex-2-enamide;
(50) (R, E) -N- (1- (5-Chloro-2- Yl) -2-cyano-3-cyclopropyl acrylamide.
(51) (R, Z) - ethyl-2 - ((1- (5-chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) Pyrrolidin-3-yl) carbamoyl) -3-phenyl acrylate;
(52) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (pyridin-2-yl) acrylamide;
(53) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine 3-yl) -2-cyano-3-phenylacrylamide;
(54) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (1-methyl-1 H -imidazol-2-yl) acrylamide;
(55) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (4-methylthiazol-2-yl) acrylamide;
(56) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3-cyclohexyl acrylamide;
(57) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- ( m -tolyl) acrylamide;
(58) (R, E) -3- (3- bromophenyl) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin 4-ylpyrrolidin-3-yl) -2-cyanoacrylamide;
(59) (R, E) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- 3-yl) -2-cyano-3- (3-trifluoromethyl) phenyl) acrylamide;
(60) (R, E) -3- (6- bromopyridin-2-yl) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl ) Amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacrylamide;
(61) (R, E) - N-1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin- 3-yl) -2-cyano (6- (trifluoromethyl) pyridin-2-yl) acrylamide;
(62) A mixture of ( R , E ) -tert-butyl- (5 - ((1- (5- Yl) pyrrolidin-3-yl) amino-4-cyano-2-methyl-5-oxopent-3-en-2-yl) (methyl) carbamate;
(63) ( R , E ) - N - (1- (5-Chloro- 3-yl) -2-cyano-4-methyl-4- (methylamino) pent-2-enamide;
(64) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- ( o -tolyl) acrylamide;
(65) ( R , E ) - N - (1- (5-Chloro- 3-yl) -2-cyano-3- ( p -tolyl) acrylamide;
(66) (R) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin -3 -Yl) -2-cyano-2-cyclohexylideneacetamide;
(67) A mixture of ( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) pyrrolidin-3-yl) amino) -2-cyano-3-oxoprop-1-en-1-yl) cyclopropyl) carbamate;
(68) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) amino) -2-cyano-5, 5-dimethylhex-2-enamide;
(69) ( R , E ) - N - (1- (5-Chloro- Yl) amino) -2-cyano-4, 4-dimethylpent-2-enamide;
(70) (R, E) -3- (1- amino-cyclopropyl) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) Pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyanoacrylamide;
(71) A mixture of ( R , E ) -tert-butyl- (1- (3 - ((1- (5-chloro- Yl) pyrrolidin-3-yl) amino) -2-cyano-3-oxo-1-en-1-yl) cyclopropyl) (methyl) carbamate;
(72) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (furan-2-yl) acrylamide;
(73) A mixture of ( R , E ) - N - (1- (5-chloro- 3-yl) -2-cyano-3- (1-methyl -1 H - pyrazol-4-yl) acrylamide;
(74) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (thiazol-2-yl) acrylamide;
(75) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (pyridin-3-yl) acrylamide;
(76) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (pyridin-4-yl) acrylamide;
(77) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (quinolin-2-yl) acrylamide;
(78) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine Yl) -2-cyano-3- (pyrazin-2-yl) acrylamide;
(79) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano-3- (2- (dimethylamino) phenyl) acrylamide;
(80) (R, E) - N - (1- (5- chloro-2 - ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidine 3-yl) -2-cyano-3- (1-methyl -1 H - pyrazol-3-yl) acrylamide;
(81) (R, E) - N - (1- (5- chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano-3- ( Pyridin-2-yl) acrylamide;
(82) (R, E) - N - (1- (5- chloro-2 - ((4-diethylamino) butyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) -2 - cyano-3- (pyridin-2-yl) acrylamide;
(83) A solution of ( R , E ) -2-cyano- N- (1- (2- Pyridin-3-yl) -3- (pyridin-2-yl) acrylamide;
(84) A mixture of ( R , E ) -2-cyano- N- (1- (5-cyclopropyl- Pyrrolidin-3-yl) -3- (pyridin-2-yl) acrylamide;
(85) A mixture of (R) -N- (1- (5-chloro-2 - ((3- (2-morpholinoethoxy) phenyl) amino) pyrimidin- ) Acrylamide;
(86) (R, E) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-4- (dimethylamino;
(87) (R) -tert- butyl 2 - ((E) -3 - (((R) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) Phenyl) amino) pyrimidin-4-yl) pyrrolidin-3-yl) amino) -2-cyano-3-oxo-1- en-1-yl) pyrrolidine-1-carboxylate;
(88) (R, E) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-4- (4-ethylpiperazin-1-yl) -4-methylpent-2-enamide;
(89) (R, E) - N - (1- (5- chloro-2 - ((4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) pyrrolidin-3 Yl) -2-cyano-3- (1- (dimethylamino) cyclopropyl) acrylamide;
(90) (R, E) - N - (1- (5- chloro-2- (cyclopropylamino) pyrimidin-4-yl) pyrrolidin-3-yl) -2-cyano-4- ( Dimethylamino) 4-methylpent-2-enamide;
(91) ( R , E ) - N- (1- (5-Chloro-2 - ((4- (dimethylamino) cyclohexyl) amino) pyrimidin- 2-cyano-4-methyl-4- (methylamino) pent-2-enamide; And
(92) ( R , E ) - N - (1- (5-Chloro- Yl) -2-cyano- N -methyl-3- (pyridin-2-yl) acrylamide.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 as an active ingredient.
11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition inhibits the activity of TAK1 kinase.
11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is for preventing or treating cancer or a tumor.
13. The method of claim 12, wherein the cancer or tumor is selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, The present invention relates to a method for the treatment and prophylaxis of cancer, such as oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, Cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, Gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, A pancreatic cancer, a lung cancer, or a skin cancer. Compositions.
A pharmaceutical preparation comprising the pharmaceutical composition of claim 10.
15. The pharmaceutical preparation according to claim 14, wherein the pharmaceutical preparation is in the form of tablets, pills, powders, capsules, syrups or emulsions.
16. The method of claim 15, further comprising administering a medicament selected from the group consisting of a cell signaling inhibitor, a mitotic inhibitor, an alkylating agent, an anti-metabolite, an anti-cancer drug, a topoisomerase inhibitor, an immunotherapeutic agent, an anti-hormone agent, Or a pharmaceutically acceptable salt thereof.