TW201336847A - Quinolyl pyrrolopyrimidine compound or salt thereof - Google Patents

Abstract

Provided is a novel compound having an inhibitory effect on EGFR and having a cytostatic effect. Also provided is a drug useful in the prevention and/or treatment of cancer based on the inhibitory effect on EGFR. A compound represented by the general formula (I) or a salt thereof.

Description

Quinoline pyrrolopyrimidine compound or salt thereof Cross-reference to related applications

The present application claims priority based on the specification of Japanese Patent Application No. 2012-024200, the entire disclosure of which is hereby incorporated by reference.

The present invention relates to a pyrrolopyrimidine derivative having a quinoline structure and a pharmaceutical composition containing the same as an active ingredient, and the pyrrolopyrimidine derivative has an epidermal growth factor receptor (EGFR) inhibitory action.

Background technique

EGFR is a receptor-type tyrosine kinase that binds to the epidermal growth factor (EGF) of the ligand and functions as a physiological function in the normal tissues, and promotes proliferation or inhibition in the epidermal tissue. Apoptosis and the like (Non-Patent Document 1).

In addition, EGFR is also one of the oncogenes. It is known that EGFR gene amplification, high protein expression and mutations are associated with various cancers, such as head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, and ovary. Cancer, kidney cancer, bladder cancer, skin cancer, brain tumor, etc. (Non-Patent Document 2). In Japan, Europe and the United States, there are about 170 to 375 people per year for every 100,000 people. Death is the upper part of the cause of death (Non-Patent Document 3). Among them, the number of deaths caused by lung cancer is the highest, and the number of deaths in the world is about 1.4 million in one year, and non-small cell lung cancer accounts for more than 80% of lung cancer. Therefore, development of an effective treatment method is expected (Non-Patent Document 4).

In recent years, the causative genes of these cancers have been gradually identified, and mutations in the EGFR gene are also one of them, which will lead to the active mutant EGFR protein. The so-called active mutant EGFR protein may be, for example, a defect 746-750 amino acid (EGFR (d746-750)) or a 858th amino acid mutated from leucine to arginine (EGFR (L858R)). Etc. For example, it has been reported that in Japan, 20-40% of non-small cell lung cancers have such mutations, and in Europe and America, 10-15% of non-small cell lung cancers also have such mutations. Since non-small cell lung cancer having such a mutation is highly sensitive to gefitinib (trade name Iressa (registered trademark)) and erlotinib (trade name Tarceva (registered trademark)) in an agent (EGFR inhibitor) that inhibits EGFR kinase activity, this is highly sensitive. The drugs are used as therapeutic drugs in Japan and Europe. However, the resistance to gefitinib and erlotinib was obtained after 6-12 months from the start of use, and the therapeutic effect was weakened. Therefore, it was severely formed in the treatment of such non-small cell lung cancer with acquired high-susceptibility mutant EGFR. Question. It is known that about 50% of this acquired drug resistance is due to a secondary mutation in the EGFR gene, resulting in the conversion of the 790th amino acid from threonine to methionine resistant mutant EGFR. Proteins (EGFR (d746-750/T790M) and EGFR (T790M/L858R)) have been an important subject for the development of therapeutic drugs that are effective against non-small cell lung cancer having such resistant mutant EGFR (Non-Patent Document 5) ).

On the other hand, the common side effects of the EGFR inhibitors gefitinib and erlotinib, which are currently used as therapeutic drugs, and the EGFR inhibitor BIBW2992 in clinical trials have been reported to have skin abnormalities and gastrointestinal disorders. These side effects are widely believed to be due to the fact that EGFR inhibitors not only inhibit mutant EGFR manifested in non-small cell lung cancer, but also inhibit the activity of wild-type EGFR (EGFR (WT)) expressed in the skin or digestive tract ( Non-patent document 1). From the viewpoint of reducing side effects, it is conceivable that the inhibitory activity against EGFR (WT) of normal tissues is weak.

Therefore, it is expected that an agent which is weak in inhibitory activity against wild-type EGFR (compared with the inhibitory activity of the 790th amino acid which has been mutated to methionine-resistant mutant EGFR) can be used without The side effects of the skin or the digestive tract strongly inhibit the proliferation of non-small cell lung cancer cells having drug-resistant mutant EGFR, and are expected to contribute to the treatment of cancer, prolonging the lifespan of patients, and increasing QOL. Furthermore, it is also potent against wild-type mutant EGFR, not only for drug-resistant mutant EGFR, but also for highly sensitive mutant EGFR such as EGFR (d746-750) and EGFR (L858R) which are highly sensitive to gefitinib and erlotinib. An agent having a weak inhibitory activity of EGFR is expected to inhibit proliferation of non-small cell lung cancer cells exhibiting high sensitivity mutant or drug resistant mutant EGFR without exerting a strong expression of side effects of skin or digestive tract. Furthermore, it is expected to reduce the frequency of drug-resistant mutant EGFR (obtained from acquired resistance to non-small cell lung cancer cell carcinoma exhibiting high-sensitivity mutant EGFR), and can be expected to treat cancer, prolong patient life and improve QOL Made a contribution. In addition, because they are applicable at the treatment site as high-sensitivity mutants Or the stratification index of the drug-resistant mutant EGFR, the choice of patients becomes possible, and the ethical benefits are also high.

PCI32765((R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine- 1-Base)prop-2-en-1-one) is known as a kinase inhibitor (Patent Document 1). In particular, it is said to selectively inhibit Bruton Tyrosin Kinase (BTK), which is highly homologous to EGFR, in ATP pocket, and is considered to be for chronic lymphocytic lymphoma, B cell lymphoma and multiple myeloma are effective tumors, but not effective for epidermal tumors and solid cancers.

Advanced technical literature Patent literature

[Patent Document 1] International Publication WO2008/121742

Non-patent literature

[Non-Patent Document 1] Nature Rev. Cancer, vol. 6, pp 803-811 (2006)

[Non-Patent Document 2] J. Clin. Oncol., vol. 19, 32s-40s (2001)

[Non-Patent Document 3] Ministry of Internal Affairs and Communications Statistics Bureau Homepage/Statistics/World Statistics "World Statistics 2011" Chapter 14 National Life and Social Security 14-1 Death Cause Death Rate

[Non-Patent Document 4] Lung Cancer, vol. 69, pp1-12 (2010)

[Non-Patent Document 5] Nature Rev. Cancer, vol. 10, pp760-774 (2010)

Summary of invention

As described above, although the effect of EGFR inhibitors on cancer treatment is expected, the current state of the art is insufficient in clinical effects.

Accordingly, it is an object of the present invention to provide a novel compound or a salt thereof which potently inhibits EGFR, and further to provide an inhibitor of EGFR (d746-750) and EGFR (L858R) or EGFR (d746-750/T790M). And EGFR (T790M/L858R) but does not inhibit the novel compound of EGFR (WT) or a salt thereof.

The inventors of the present invention have carefully studied and discussed the above problems, and as a result, it has been found that a pyrrolopyrimidine compound group having a quinoline structure has an excellent inhibitory activity against EGFR and a cancer cell proliferation inhibiting action, and is useful as a medicine for treating cancer. As for the completion of the present invention.

That is, the present invention provides a compound of the following formula (I) or a salt thereof:

(Wherein, R ₁ is a hydrogen atom, a halogen atom, R ₂ may have the C ₁ -C ₆ alkyl group which may have the R C _{2 2} -C ₆ alkenyl group or an R C ₂ of ₂ -C ₆ alkynyl group; R ₂ is _{-OR x, -N (R x)} (R y), R ₃ may have the C ₃ -C ₁₀ cycloalkyl, R ₃ can have the C ₃ -C ₁₀ heterocycloalkyl, can be R C ₃ having the ₆ -C ₁₂ aryl group or R ₃ may have the C ₄ -C ₉ heteroaryl; R ₃ is _{-OR x, -N (R x)} (R y), - N (R x ) C(=O)R _y , -N(R _x )C(=O)OR _y , -N(R _x )C(=O)N(R _y )(R _z ) or -C(=O) OR _x ; R _x , R _y , and R _z are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₃ -C ₁₀ cycloalkyl group; and X is represented by the following formula (X ₁ ); a group represented by the following formula (X ₂ ) or a group represented by the following formula (X ₃ ); formula (X ₁ ): -(CH ₂ ) _m -N(R ₄ )- ( X ₁ ) Formula (X ₂ ):

(wherein, the formula shown below represents a C ₃ -C ₁₀ cycloalkylene group);

General formula (X ₃ ):

(In the formula, the following formula represents a divalent heterocyclic alkyl group having 3 to 10 carbon atoms, which contains at least one nitrogen atom in the ring and one of the nitrogen atoms has a bond, and is contained in the ring. 0~2 homologous or heterogeneous heteroatoms selected from oxygen or sulfur atoms);

m is 1 to 3; n is 0 to 2; R ₄ is a hydrogen atom or a C ₁ -C ₆ alkyl group; R ₅ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group; Y is -C(R) ₆ )=C(R ₇ )(R ₈ ) or -C≡CR ₉ ; R ₆ , R ₇ and R _{8 are the} same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₆ - a C ₁₂ aryl group, a C ₄ -C ₉ heteroaryl group, an aminomethyl group or a 1-pyrrolidinyl group which may be substituted by a C ₁ -C ₆ alkyl group, and R ₆ and R ₇ may be bonded thereto. The two carbon atoms together form a C ₄ -C ₈ cyclic olefin ring; R ₉ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group.

Further, the present invention provides a pharmaceutical agent such as an EGFR inhibitor or an antitumor agent which comprises the compound represented by the above formula (I) as an active ingredient.

According to the present invention, there can be provided a method for preventing or treating cancer comprising the step of administering to a mammal an effective amount of the compound of the above formula (I) or a salt thereof for preventing or treating cancer.

Further, the present invention provides a use of the compound of the above formula (I) or a salt thereof for use in the manufacture of a prophylactic or therapeutic agent for cancer.

Furthermore, the present invention provides a compound of the above formula (I) or a salt thereof for use in the prevention or treatment of cancer.

According to the present invention, a novel compound of the above formula (I) or a salt thereof which is very useful as an EGFR inhibitor can be provided.

It has been found that the compound of the present invention or a salt thereof has excellent EGFR inhibitory activity and exhibits a proliferation inhibitory effect on a cancer cell line. In addition, due to its excellent selectivity for EGFR, it has the advantage of having fewer side effects caused by other kinases. Therefore, the compound of the present invention or a salt thereof is very useful as a prophylactic and/or therapeutic agent for cancer.

Form for implementing the invention

The compound of the above formula (I) of the present invention is a compound having a quinoline as a basic structure and having a pyrrolopyrimidine at the 3-position and further having an α,β-unsaturated guanamine at a spacer, and is A novel compound not described in any of the aforementioned prior art documents and the like.

In the present specification, the "halogen atom" may specifically include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present specification, the "C ₁ -C ₆ alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a positive group. Butyl, isobutyl, t-butyl, tert-butyl, pentyl and hexyl, and the like.

In the present specification, the "C ₁ -C ₆ alkylene group" means a linear alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methylene group, an ethyl group, a n-propyl group, an iso-propyl group, Stretching butyl, pentyl and hexyl groups.

In the present specification, "C ₂ -C ₆ alkenyl group" means a linear or branched alkenyl group having at least one carbon-carbon double bond and having 2 to 6 carbon atoms, and specifically, for example, a vinyl group, an allyl group, Methylvinyl, propylene, butenyl, pentenyl, hexenyl and the like.

In the present specification, "C ₂ -C ₆ alkynyl group" means a linear or branched alkynyl group having at least one carbon-carbon bond and having 2 to 6 carbon atoms, and specifically, for example, an ethynyl group or a 1-propyne group A group, a 1-pentynyl group, a 3-methyl-1-butynyl group, a 1-hexynyl group, and the like.

In the present specification, the "C ₆ -C ₁₂ aryl group" means an aryl group having 6 to 12 carbon atoms, and specific examples thereof include a phenyl group, a naphthyl group, and a biphenyl group.

In the present specification, "C ₄ -C ₉ heteroaryl group" means a carbon number of 4 to 9 which contains 1 to 3 kinds of the same or different hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom and which is monocyclic or bicyclic. An aryl group, and preferably a carbon number 4 to 9 heteroaryl group having 1 to 3 nitrogen atoms and a monocyclic or bicyclic ring, and specific examples thereof include a thienyl group, a furyl group, a pyrrolyl group, a triazolyl group, an imidazolyl group, Pyrazolyl, isothiazolyl, iso Azyl, pyridyl, pyridyl Base, pyrimidinyl, oxime Base, isobenzofuranyl, anthracene Base, isodecyl, fluorenyl, carbazolyl, quinolyl, isoquinolyl, anthracene Base and Pyridyl and the like.

In the present specification, the "C ₃ -C ₁₀ cycloalkyl group" means a monocyclic or polycyclic cycloalkyl group having 3 to 10 carbon atoms, and specifically, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, Cycloheptyl, bicyclodecyl, and the like.

In the present specification, the "C ₃ -C ₁₀ cycloalkylene group" means a monocyclic or polycyclic divalent cycloalkylene group having 3 to 10 carbon atoms, and specific examples thereof include a cyclic propyl group, a cyclobutyl group, and a ring extension. A pentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclononyl group, and the like.

In the present specification, "C ₃ -C ₁₀ heterocycloalkyl" means a carbon number of 1 to 2 of the same or different hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in a ring other than the bonding site. Examples of the 10-cycloalkyl group include a tetrahydroindolyl group, a pyrrolidinyl group, a piperidinyl group, and a tetrahydropyranyl group.

In the present specification, the "C ₃ -C ₁₀ heterocyclic alkylene group" means that at least one nitrogen atom is contained in the ring, and one of the nitrogen atoms has a bond, and further contains 0 to 2 in the ring. A divalent heterocyclic alkyl group having the same or different hetero atom of an oxygen atom or a sulfur atom and having a carbon number of 3 to 10; and examples thereof include a tetrahydroazinyl group, a pyrrolidinyl group, and a piperidinyl group.

In the present specification, the "C ₄ -C ₈ cycloalkene ring" means a C _4-8 olefin ring having one carbon-carbon double bond, and specifically, for example, cyclopropene, cyclobutene, cyclopentene, and cyclohexane. Alkene, cycloheptene, cyclooctene, and the like.

In the present specification, the group represented by the formula (X ₂ ) is as follows:

Among them, the divalent part (moiety) is as follows:

The divalent moiety represents a C ₃ -C ₁₀ cycloalkylene group.

In the present specification, the general formula (X ₂ ) is as follows:

The general formula (X ₂ ) means:

One of the bond bonds of the divalent cycloalkyl group represented by the above formula is bonded to the group of the adjacent -N(R ₄ )- group.

In the present specification, the group represented by the formula (X ₃ ) is as follows:

The two-part part (moiety) is as follows:

The divalent moiety represents a C ₃ -C ₁₀ heterocycloalkylene group.

In the present specification, the general formula (X ₃ ) is as follows:

The general formula (X ₃ ) means:

One of the nitrogen atoms on the divalent heterocyclic alkyl group represented by the above formula has a bond, and the other side is bonded to an alkyl group (-(CH ₂ ) _n -) having a substituent R ₅ on the ring.

In the present invention, when X is a group represented by the following formula (X ₁ ), the -(CH ₂ ) _m - moiety in the group is bonded to pyrrolopyrimidine, and the -N(R ₄ )- moiety is bonded to the carbonyl group. Bonding.

-(CH ₂ ) _m -N(R ₄ )- (X ₁ )

In the present invention, when X is a group represented by the following formula (X ₂ ):

The following moiety of the group is bonded to pyrrolopyrimidine;

Further, the -N(R ₄ )- moiety is bonded to a carbonyl group.

In the present invention, when X is a group represented by the following formula (X ₃ ):

a -(CH ₂ ) _n - moiety in the group is bonded to a pyrrolopyrimidine;

One of the nitrogen atoms contained in the moiety shown in the above formula is bonded to a carbonyl group.

In the formula (I), R _{1 is} preferably a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group which may have R ₂ (preferably 1) or a C ₂ -C ₆ alkynyl group which may have 1 R ₂ , more suitably a hydrogen atom or ₂ of C ₂ -C ₆ alkynyl group may have an R, particularly appropriate is a hydrogen atom, R 1 may have the ethynyl or ₂ having an R of _2-pentynyl.

In the general formula (I), R ₂ is suitably _{-OR x, -N (R x)} (R y), R ₃ may have the C ₃ -C ₁₀ cycloalkyl, R ₃ can have the C ₃ -C _{a 10} heterocycloalkyl group or a C ₆ -C ₁₂ aryl group which may have R ₃ , more preferably -OR _x , -N(R _x )(R _y ), a C ₃ -C ₁₀ cycloalkyl group which may have R ₃ Or it may have a C ₆ -C ₁₂ aryl group of R ₃ , particularly preferably a hydroxyl group, an amine group, a cyclohexane group which may have an amine group or a phenyl group which may have an amine group.

In the formula (I), R _{3 is} preferably -OR _x , -N(R _x )(R _y ), -N(R _x )C(=O)R _y or -C(=O)OR _x , It is preferably -N(R _x )(R _y ).

In the formula (I), R _x , R _y and R _{z are} preferably the same or different from each other as a hydrogen atom or a C ₁ -C ₆ alkyl group, more preferably a hydrogen atom.

In the formula (I), X is preferably a group represented by the above formula (X ₃ ).

m in the formula (I) is preferably 2.

In the formula (I), n is preferably 0 to 1, more preferably 0.

R ₄ in the formula (I) is preferably a hydrogen atom or a methyl group.

R ₅ in the formula (I) is preferably a hydrogen atom or a hydroxymethyl group.

In the formula (I), Y is preferably -C(R ₆ )=C(R ₇ )(R ₈ ).

R ₆ , R ₇ and R ₈ in the formula (I) are preferably the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₄ -C ₉ heteroaryl group, a C ₁ -C ₆ alkyl group. The substituted aminomethyl group or 1-pyrrolidinyl group is more preferably a hydrogen atom. Further, R ₅ and R ₆ may form a C ₄ -C ₈ cycloalkene ring together with the two carbon atoms to which they are bonded.

R ₉ in the formula (I) is preferably a hydrogen atom, a methyl group, a methylol group or a 1-hydroxy-1-methyl-ethyl group.

In the present invention, the following compounds or salts thereof are preferred: in the formula (I), R ₁ is a hydrogen atom or a C ₂ -C ₆ alkynyl group which may have R ₂ ; and R ₂ is -OR _x , -N ( R _x) (R _y), it may have R ₃ (as appropriate amine) of C ₃ -C ₁₀ cycloalkyl or cocoa having R ₃ (as appropriate amine) of C ₆ -C ₁₂ aryl group; R _x, R _{y is the} same or different and is a hydrogen atom or a C ₁ -C ₆ alkyl group; X is a group represented by the formula (X ₃ ); n is 0 to 1; R ₅ is a hydrogen atom or C _{1 which} may have a hydroxyl group -C ₆ alkyl; Y is a vinyl group.

Specific and desirable compounds of the invention are exemplified below.

N-(2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)propenylamine; (S)- 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)propan-2- En-1-one; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrole (S)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3) -d]pyrimidin-7-yl)piperidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-5-(quinolin-3-yl) )-7H-pyrrolo[2,3-d]pyrimidine -7-yl)piperidin-1-yl)prop-2-en-1-one; N-((1S,2R)-2-(4-amino-5-(quinolin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)propenylamine; 1-(4-(4-amino-5-(quinolin-3-yl)-7H-pyrrole And [2,3-d]pyrimidin-7-yl)piperidin-1-yl)prop-2-en-1-one; 1-(3-((4-amino-5-(quinoline-3) -yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one; (S)-1-(2- ((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidin-1-yl)prop-2-ene 1-ketone; (R)-1-(2-((4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)) () pyrrolidin-1-yl)prop-2-en-1-one; (S)-1-(2-((4-amino-5-(quinolin-3-yl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)methyl)tetrahydroazin-1-yl)prop-2-en-1-one; (R)-1-(2-((4-amino) -5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)tetrahydroazin-1-yl)prop-2-en-1-one ; 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroazin-1-yl)propane 2-en-1-one; 1-((2S,4R)-4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)-2-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one ; 1-((2R,4R)-4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-( Hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one; N-(2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)ethyl)-N-methylpropenylamine; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H- Pyrrolo[2,3-d]pyrimidine -7-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one; (R)-1-(3-(4-amino-5-() Quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)but-2-ene-1 -ketone; (R)-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl (cyclopentenyl)methanone; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)pyrrolidin-1-yl)-3-(pyridin-2-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-5-(quinoline) 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-3-(pyridin-3-yl)prop-2-en-1-one; (R)-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) (cyclic Hexenyl)methanone; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) Pyrrolidin-1-yl)-2-methylprop-2-en-1-one; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-3-phenylprop-2-en-1-one; (R)-1-(3-(4-amine) 5-((quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)but-2-en-1-one; (R) -1-(2-((4-amino-5-(quinolin-3-yl)-7H-pyridyl) And [2,3-d]pyrimidin-7-yl)methyl)tetrahydroazin-1-yl)-4-(dimethylamino)but-2-en-1-one; 1-(3 -(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroazin-1-yl)-4-(dimethyl Aminobutyryl-2-butan-1-one; 1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)tetrahydroindol-1-yl)-4-(ethyl(methyl)amino)but-2-en-1-one; 1-(3-(4-amino-5-(quinaline) Benz-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- Tetrahydroindol-1-yl-4-(2-ethylamino)but-2-en-1-one; 1-(3-(4-amino-5-(quinoline-3-) -7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroazin-1-yl)-4-(isopropyl(methyl)amino)but-2-ene-1 -ketone; 1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl -4-(pyrrolidin-1-yl)but-2-en-1-one; (R)-1-(3-(4-amino-6-bromo-5-(quinolin-3-yl) -7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino) -6-methyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (R)-1-(3-(4-Amino-6-(phenylethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-6-ethynyl-5-(quinolin-3-yl)) -7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino)- 5-(quinolin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-6-(3-amino-3-methylbut-1-ynyl)- 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine -7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-tert-butyl 4-((7-(1-propenylpyridyl)-yl)- 4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethynyl)piperidine-1-carboxylate; (R)-1 -(3-(4-Amino-6-(piperidin-4-ylethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl Pyrrolidin-1-yl)prop-2-en-1- Ketone; tert-butyl trans-4-((7-((R)-1-propenylpyridin-3-yl)-4-amino-5-(quinolin-3-yl)-7H -pyrrolo[2,3-d]pyrimidin-6-yl)ethynyl)cyclohexylamine formate; 1-((R)-3-(4-amino-6-((trans-4-) Aminocyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-ene- 1-ketone; (R)-1-(3-(4-amino-6-((1-aminocyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-6-((1- Hydroxycyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-ene-1 -ketone; (R)-1-(3-(4-amino-6-(3-hydroxy-3-methylbut-1-ynyl)-5-(quinolin-3-yl)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-6-fluoro) -5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)- 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)propan-2- Alkyn-1-one; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrole Pyridin-1- Butyr-2-yn-1-one; (R)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)pyrrolidin-1-yl)-4-hydroxybut-2-yn-1-one; (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -4-hydroxy-4-methylpent-2-yn-1-one; (R,E)-1-(3-(4-amino-5-(quinolin-3-yl)-7H-pyrrole And [2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-3-chloroprop-2-en-1-one; and (R,Z)-1-(3-(4- Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-3-chloroprop-2-en-1- ketone.

Further, it is preferred to have a strong enzyme inhibitory activity against EGFR (T790M/L858R), and more preferably 1 nM or less. Further, those having a strong enzyme inhibitory activity against EGFR (d746-750/T790M) are preferred, and those having a strong enzyme activity of 1 nM or less are more preferred.

Next, the method for producing the compound of the present invention will be described below.

For example, the compound (I) of the present invention can be produced by the following production method or the method shown in the examples. However, the production method of the compound (I) of the present invention is not limited to these reaction examples.

Manufacturing Method 1

Wherein L ₁ and L ₂ represent a leaving group, P ₁ represents a protecting group of an amine group contained in X, and X and Y are synonymous with the foregoing. ]

(step 1)

This step is a process for producing a compound of the formula (III) by reacting a compound of the formula (II) with SEMCl (trimethylsulfonylethoxymethyl chloride) in the presence of a base.

In the formula (II), the leaving group represented by L ₁ is a bromine atom or an iodine atom. The compound of the formula (II) may be a commercially available product or may be produced by a conventional method.

The SEMCl used in this step is usually equimolar to excess mol relative to the compound 1 shown in the formula (II). The reaction solvent is not particularly limited as long as it does not hinder the reaction, but for example, tetrahydrofuran, 1,4-two Alkyl, chloroform, dichloromethane, dimethylformamide, N-methylpyrrolidone or the like or a mixed solvent thereof is preferred.

As the base, an organic base such as triethylamine, diisopropylethylamine, pyridine or 4-dimethylaminopyridine or sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or sodium hydride can be used. An inorganic base such as potassium butyrate.

The base is usually used in an amount of from 1 mole to excess mol, and preferably from 1 to 3 moles, relative to the compound of the formula (II).

The reaction temperature is usually -78 to 50 ° C, and preferably 0 ° C to room temperature.

The reaction time is usually from 5 minutes to 7 days, and preferably from 5 minutes to 24 hours.

The compound of the formula (III) thus obtained can be isolated and purified by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or may be carried out without isolation. Purification and application In the next steps.

(Step 2)

This step is a method of reacting a compound of the formula (III) with ammonia or a salt thereof to produce a compound of the formula (IV).

The amount of ammonia or a salt thereof used in this step is usually equal to the molar amount of the compound 1 to the general formula (III). The reaction solvent is not particularly limited as long as it does not hinder the reaction, but is, for example, water, methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 1,4-two Alkane, dimethylformamide, N-methylpyrrolidone, dimethylhydrazine, or the like, or a mixed solvent thereof or the like is preferred.

The reaction temperature is usually from 0 to 200 ° C, and preferably from room temperature to 150 ° C.

The reaction time is usually from 5 minutes to 7 days, and preferably from 30 minutes to 24 hours.

The compound of the formula (IV) thus obtained can be isolated and purified by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or can be carried out without isolation. Purification is applied to the subsequent steps.

(Step 3)

This step is a method in which a compound of the formula (IV) is coupled with 3-quinoline boronic acid to produce a compound of the formula (V). This step can be carried out by a conventional method (for example, Chemical Reviews, Vol. 95, p. 2457, 1995), for example, in the presence of a transition metal catalyst and a base in a solvent which does not adversely affect the reaction.

The amount of the 3-quinoline boronic acid to be used is 1 to 10 moles, and preferably 1 to 3 moles, based on 1 mole of the compound of the formula (IV).

As the transition metal catalyst, for example, a palladium catalyst (for example, palladium acetate, palladium chloride, ruthenium triphenylphosphine palladium, 1,1'-bis(diphenylphosphino)palladium (II) dichloride, etc.) and a nickel catalyst can be used. (for example, nickel chloride or the like), and a ligand (for example, triphenylphosphine, tri-tert-butylphosphine, etc.) may be added as needed, and a metal oxide (for example, copper oxide, silver oxide, etc.) may be used as Cocatalyst. The amount of the transition metal catalyst used varies depending on the type of the catalyst, but it is usually 0.0001 to 1 mol, and preferably 0.01 to 0.5 mol, relative to the compound of the formula (IV); the amount of the ligand used With respect to the compound 1 of the formula (IV), the molar amount is usually 0.0001 to 4 moles, and preferably 0.01 to 2 moles; the amount of the cocatalyst used is usually relative to the compound of the formula (IV). It is 0.0001~4 moles, and should be 0.01~2 moles.

The base may, for example, be an organic amine compound (for example, trimethylamine, triethylamine, diisopropylethylamine, N-methylnorzoline, 1,8-diazabicyclo[5,4,0]undecane- 7-ene, pyridine, N,N-dimethylaniline, etc.), potassium metal salt (for example, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, hydrogen Potassium oxide, etc.), metal hydride (such as potassium hydride, sodium hydride, etc.), alkali metal alkoxide (such as sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide) And an alkali metal diammonium amide (for example, lithium-disilazide, sodium diammonium chloride, potassium dimercaptoacetate, etc.). Among them, alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate and potassium phosphate, alkali metal alkoxides such as sodium third butoxide and potassium butoxide, triethylamine and diisopropyl An organic amine compound or the like of a base amine or the like is preferred. The amount of the base used is usually 0.1 to 10 moles, and preferably 1 to 5 moles, per mole of the compound of the formula (IV).

The solvent may be any one that does not adversely affect the reaction, and examples thereof include a hydrocarbon solvent (for example, benzene, toluene, xylene, etc.), a halogenated hydrocarbon solvent (for example, chloroform, 1,2-dichloroethane, etc.), and a nitrile. a solvent (such as acetonitrile, etc.), an ether solvent (such as dimethoxyethane, tetrahydrofuran, 1,4-two) Alkane, etc.), alcoholic solvents (eg methanol, ethanol, etc.), aprotic polar solvents (eg dimethylformamide, dimethyl hydrazine, hexamethylphosphoramide, etc.), water or a mixture thereof, etc. The reaction time is from 0.1 to 100 hours, and preferably from 0.5 to 24 hours. The reaction temperature is preferably from 0 ° C to the boiling temperature of the solvent, and is preferably from 20 to 150 ° C.

The compound of the formula (V) thus obtained can be isolated and purified by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or can be carried out without isolation. Purification is applied to the subsequent steps.

(Step 4)

This step is a method of producing a compound of the formula (VI) from a compound of the formula (V) under acidic conditions.

Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosylic acid, and the like. The amount of the acid used is preferably from 1 to 100 moles per mole of the compound of the formula (V).

The solvent used for the reaction may be any one which does not adversely affect the reaction. For example, an alcohol solvent (for example, methanol), a hydrocarbon solvent (for example, benzene, toluene, xylene, etc.) or a halogenated hydrocarbon solvent may be used. For example, dichloromethane, chloroform, 1,2-dichloroethane, etc., a nitrile solvent (for example, acetonitrile, etc.), an ether solvent (for example, dimethylethane, tetrahydrofuran, 1,4-two) An alkane or the like, an aprotic polar solvent (for example, N,N-dimethylformamide, dimethylhydrazine, hexamethylphosphoric acid triamide, etc.) or a mixture thereof. The reaction time is from 0.1 to 100 hours, and preferably from 0.5 to 24 hours. The reaction temperature is from 0 ° C to the boiling temperature of the solvent, and is preferably from 0 to 100 ° C.

The compound of the formula (VI) thus obtained can be isolated and purified by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or may be isolated. Purification is applied to the subsequent steps.

(Step 5)

This step is a method of producing a compound of the formula (VII) from a compound of the formula (VI) or a salt thereof under basic conditions.

The base may, for example, be an alkali metal salt such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide or potassium hydroxide. The amount of the base used is preferably from 1 to 100 moles per mole of the compound of the formula (VI).

The solvent used for the reaction need only be used without adversely affecting the reaction. For example, water, an alcohol compound (e.g., methanol, etc.), an ether compound (e.g., dimethoxyethane, tetrahydrofuran, 1,4-two) may be used. An alkane or the like, an aprotic polar solvent (for example, N,N-dimethylformamide, dimethylhydrazine, hexamethylphosphoric acid triamide, etc.) or a mixture thereof. The reaction time is from 0.1 to 100 hours, and preferably from 0.5 to 24 hours. The reaction temperature is from 0 ° C to the boiling temperature of the solvent, and is preferably from 0 ° C to room temperature.

The compound of the formula (VII) thus obtained can be isolated and purified by a conventional method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, The reprecipitation and chromatography methods are either isolated or purified, or may be applied to the subsequent step without isolation.

(Step 6)

This step is a method in which a compound represented by the formula (VII) is alkylated with a compound of the formula (VIII) in the presence of a base, and a compound of the formula (IX) is obtained.

In the general formula (VIII), the leaving group represented by L ₂ may, for example, be a chlorine atom, a bromine atom, an iodine atom, a mesylate or a p-toluenesulfonate, and may be produced by a commercially available product or by a known method.

In the general formula (VIII), the protective group P ₁ may, for example, be a third butoxycarbonyl group or a benzyloxycarbonyl group.

The compound of the formula (VIII) may be used in an amount of from 1 to 10 moles, and preferably from 1 to 5 moles, per mole of the compound of the formula (VII).

The base may, for example, be an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride or potassium hydride, and trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N. - an organic amine compound such as methyl ortholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine or collidine, which can be used in an amount of 1 to 100 moles. And should be 2~10 moor.

The solvent may be used alone or in combination with N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl hydrazine, tetrahydrofuran, 1,4-two. Alkane, N- Pyrrolidin-2-one and acetonitrile. The reaction time is from 0.1 to 100 hours, and preferably from 0.5 to 24 hours. The reaction temperature is from 0 ° C to the boiling temperature of the solvent, and is preferably from 0 to 100 ° C.

The compound of the formula (IX) thus obtained can be used conventionally. The separation and purification methods, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, may be used for isolation, or may be applied to the subsequent step without isolation.

(Step 7)

This step is a process for obtaining a compound of the formula (X) by deprotecting an amine group of the compound of the formula (IX). The method of deprotection can be carried out by a conventional method, for example, by the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981) or the method therefor.

When the third butyloxycarbonyl group is used as the protecting group, the amount of the acid used is preferably from 1 to 100 moles per mole of the compound 1 shown by the compound IX.

The solvent used for the reaction need only be a catalyst which does not adversely affect the reaction. For example, an alcohol compound (for example, methanol or the like), a hydrocarbon compound (for example, benzene, toluene, xylene, etc.) or a halogenated hydrocarbon compound (for example, Methylene chloride, chloroform, 1,2-dichloroethane, etc., nitrile compounds (such as acetonitrile, etc.), ether compounds (such as dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents (such as N, N) a mixture of dimethylformamide, dimethylhydrazine, hexamethylphosphoric acid triamide, or the like, or the like. The reaction time is from 0.1 to 100 hours, and preferably from 0.5 to 24 hours. The reaction temperature is 0 to 100 ° C, and preferably 0 to 50 ° C.

The compound of the formula (X) thus obtained can be isolated and purified by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or may be carried out without isolation. Purification is applied to the subsequent steps.

(Step 8)

This step is a step of producing a compound of the formula (I') by amidation reaction of a compound of the formula (X) with a carboxylic acid (Y-CO ₂ H) or an acid chloride (Y-COCl). .

The carboxylic acid and acid chloride of the raw material can be produced by using a commercially available product or by a known method.

When a carboxylic acid is used as the guanamine reagent, it is carried out by using 0.5 to 10 moles (preferably 1 to 5 moles) of the carboxylic acid of the compound 1 represented by the formula (X).

The condensed oxime can be exemplified by, for example, diphenylphosphoric acid azide, N,N'-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-xamethyleneamine sulfonium salt, chlorinated 4 -(4,6-dimethoxy-1,3,5-three -2-yl)-4-methylperoxylinium, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-3-(3-di Combination of methylaminopropyl)carbodiimide with 1-hydroxybenzotriazole, 2-chloro-1,3-dimethylimidazolium chloride, O-(7-azabenzotriazole) -1-yl)-N,N,N',N'-tetramethyl six Hexafluorophosphate and the like.

The base can be exemplified by, for example, triethylamine, diisopropylethylamine, pyridine, dimethylpyridine, Colin base, 4-dimethylaminopyridine, potassium third potassium hydride, sodium butyrate, methoxy group. An organic base such as sodium, sodium ethoxide, lithium hexamethyldiamine, sodium hexamethyldiamine, potassium hexamethyldiamine or butyl lithium or sodium hydrogencarbonate or sodium carbonate. An inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide or sodium hydride.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, isopropanol, tert-butyl alcohol, toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, 1,4-two Alkyl, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylhydrazine or the like or a mixed solvent thereof is preferred. The reaction temperature is usually -78 to 200 ° C, and preferably 0 to 50 ° C. The reaction time is usually from 1 minute to 3 days, and preferably from 1 minute to 10 hours. When the acid chloride is used as the coupling agent, it is carried out with respect to the compound 1 of the formula (X), using 0.5 to 5 moles (preferably 0.9 to 1.1 moles) of the acid chloride.

The base can be exemplified by, for example, triethylamine, diisopropylethylamine, pyridine, dimethylpyridine, Colin base, 4-dimethylaminopyridine, potassium third potassium hydride, sodium butyrate, methoxy group. An organic base such as sodium, sodium ethoxide, lithium hexamethyldiamine, sodium hexamethyldiamine, potassium hexamethyldiamine or butyl lithium, or sodium hydrogencarbonate or sodium carbonate An inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide or sodium hydride.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and for example, toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, 1,4-two An alkane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or the like or a mixed solvent thereof is preferred.

The reaction temperature is usually -78 to 200 ° C, and preferably -20 to 50 ° C.

The reaction time is usually from 1 minute to 3 days, and preferably from 1 minute to 10 hours.

The compound of the formula (I') thus obtained can be subjected to isolation purification by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, and chromatography. For example, the compound of the formula (IX) used for the production of the compound (I) of the present invention can also be produced by Process 2.

Manufacturing method 2

【化19】

[wherein, L ₁ , X and P ₁ are synonymous with the aforementioned ones].

(Step 9)

This step is a method of producing a compound of the formula (XII) by using a compound represented by the formula (II) and a compound of the formula (XI) using a Mitsunobu reaction. This step can be carried out in accordance with a conventional method (for example, Chemical Reviews, Vol. 109, p. 2551, 2009), and can be carried out, for example, in the presence of a light-extending agent and a phosphine reagent in a solvent which does not adversely affect the reaction. With respect to the compound 1 mole represented by the formula (II), it is usually carried out using 1 to 10 moles (preferably 1 to 5 moles) of the compound of the formula (XI).

The photosensitizing agent may, for example, be diethyl azodicarboxylate or diisopropyl azodicarboxylate.

The phosphine reagent can be exemplified by, for example, triphenylphosphine and tributylphosphine.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction, but for example, toluene, benzenetetrahydrofuran, 1,4-two Alkyl, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylhydrazine, or the like, or a mixed solvent thereof or the like is preferred.

The reaction temperature is usually -78 to 200 ° C, and preferably 0 to 50 ° C.

The reaction time is usually from 5 minutes to 3 days, and preferably from 10 minutes to 10 hours.

The compound of the formula (XII) thus obtained can be isolated and purified by a conventional separation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or can be carried out without isolation. Purified Apply to the next steps.

(Step 10)

This step can be carried out in the same manner as in the second step.

(Step 11)

This step can be carried out in the same manner as in the third step.

Manufacturing method 3

[wherein, X, P ₁ , Y and R ₁ are synonymous with the aforementioned ones].

(Step 12)

This step is a method of producing a compound (XV) by halogenating the action of the compound (IX) by, for example, a halogenating agent (XIV). Here, W in the halogenating agent (XIV) is a chlorine atom, a bromine atom or an iodine atom. The halogenation method can be produced by the method described in the handbook of International Publication WO2006/102079 or the method according to the methods.

(Step 13)

This step is a method of the compound of the formula (XV) according to a conventional method (for example, Angew Chem Int Ed, Volume, 25, P508, 1986, Chemical). Reviews, Vol. 95, p. 2457, 1995, Chemical Reviews, Vol. 107, p. 874, 2007, etc.) A method in which a coupling reaction occurs under a transition metal catalyst to thereby produce a compound of the formula (XVI).

When the alkyl chain is converted, for example, a commercially available product or a tetraalkyltin which is produced by a conventional method can be used.

When converting to an aryl ring or a heteroaryl ring or an alkenyl group, for example, a commercially available product or a boric acid or a boric acid ester produced by a conventional method can be used.

When the alkynyl chain is converted, for example, a commercially available product or a substituted acetylene produced by a conventional method can be used.

(Step 14)

This step can be carried out in the same manner as in the seventh step.

(Step 15)

This step can be carried out in the same manner as in the eighth step.

In the above production methods 1 to 3, an amine group, an imine group, a hydroxyl group, a carboxyl group, a carbonyl group and a decylamino group, and a functional group having an active proton such as hydrazine can be used in a suitable step of each production method. The reagent or the protective group is introduced into the functional group according to a usual method, and then the protecting group is removed.

The "protecting group of an amino group or an imido group" is not particularly limited as long as it has its function, and examples thereof include a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, and an ortho An aralkyl group such as a nitrobenzyl group, a p-nitrobenzyl group, a benzhydryl group, a trityl group or a cumyl group; a mercapto group, an ethyl group, a propyl group, a lower alkyl fluorenyl group such as a butyl fluorenyl group, a trimethyl ethane group, a trifluoroethyl fluorenyl group or a trichloro ethane group; a benzyl fluorenyl group; an aryl hydrazine group such as a phenyl ethenyl group or a phenoxy acetyl group; Methoxycarbonyl, ethoxycarbonyl a lower alkoxycarbonyl group such as a propyloxycarbonyl group or a third butoxycarbonyl group; an aralkyloxycarbonyl group such as a p-nitrobenzyloxycarbonyl group or a phenethyloxycarbonyl group; a trimethylsulfonyl group and a tert-butyldimethyl group; a lower alkyl group such as a mercapto group; a tetrahydrohydropyranyl group; a trimethylsulfonylethoxymethyl group; a lower alkyl group such as a methylsulfonyl group, an ethylsulfonyl group or a t-butylsulfonyl group; a sulfonyl group or the like; a lower alkyl sulfinyl group such as a tributylsulfinyl group; an arylsulfonyl group such as a benzenesulfonyl group or a toluenesulfonyl group; Imino group. Particularly, it is preferably a trifluoroethenyl group, an ethyl fluorenyl group, a third butoxycarbonyl group, a benzyloxycarbonyl group, a trimethyldecylethoxymethyl group or a cumyl group.

The "protecting group for a hydroxyl group" is not particularly limited as long as it has its function, but may, for example, be a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a t-butyl group; a lower alkyl sulfonyl group such as a mercapto group or a tributyl dimethyl fluorenyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydropyranyl group; ; trimethyl decyl ethoxymethyl; benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, trityl, etc. An aralkyl group; a mercapto group such as a mercapto group, an ethyl fluorenyl group or a trifluoroethenyl group; and the like. In particular, a methyl group, a methoxymethyl group, a tetrahydropyranyl group, a trimethyldecylethoxymethyl group, a tert-butyldimethylmethyl group, an ethyl fluorenyl group or the like is preferred.

The "protecting group of a carboxyl group" is not particularly limited as long as it has its function, but may, for example, be a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a t-butyl group; , a lower alkyl group such as 2-trichloroethyl; a lower alkenyl group such as allyl; trimethyldecylethoxymethyl; benzyl, p-methoxybenzyl, p-nitrobenzyl Arylene such as diphenylmethyl or trityl Base. In particular, methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl, trimethyldecylethoxymethyl and the like are preferred.

The "protective group for a carbonyl group" is not particularly limited as long as it has its function, and examples thereof include a ketal such as an ethyl ketal, a trimethylene ketal, and a dimethyl ketal, and an acetal.

The removal method of the protective group varies depending on the kind of the protecting group and the stability of the objective compound (I), and the like, for example, can be described in accordance with the literature [Reference: Protective group in organic synthesis (Protective Groups in Organic Synthesis), 3rd edition, TW Greene, John Wiley & Sons, Inc. (1999), or a method based on it, for example, decomposition with an acid or a base, ie Using, for example, 0.01 mol to an excessive excess of acid (preferably trifluoroacetic acid, formic acid, hydrochloric acid, etc.) or a molar excess of excess alkali (preferably potassium hydroxide, calcium hydroxide, etc.) Method; chemical reduction using a hydrogenation metal complex or the like, or contact reduction using a palladium-carbon catalyst, a Raney nickel catalyst or the like.

The compounds of the present invention can be readily isolated and purified by conventional separation means. The means can be exemplified by solvent extraction, recrystallization, reverse phase high speed liquid chromatography for preparative separation, column chromatography, preparative separation thin layer chromatography, and the like.

When the compound of the present invention is an isomer having an optical isomer, a stereoisomer, a positional isomer, a rotamer or the like, a mixture of any of the isomers is included in the compound of the present invention. For example, when an optical isomer is present in the compound of the present invention, the optical isomer separated from the racemate is also included in the compound of the present invention. The use of such isomers is known per se The synthetic methods and separation methods (concentration, solvent extraction, column chromatography, recrystallization, etc.) are each obtained as a single compound.

When a compound of the invention has a tautomer, any of the isomers are included in the compounds of the invention.

The salt of the compound of the present invention means a substance which has been conventionally used in the field of organic chemistry, and may, for example, be a base addition salt or an amine group of the carboxyl group when having a carboxyl group, or when having a basic heterocyclic group, a salt of an acid addition salt of an amino group or a basic heterocyclic group.

The base addition salt may, for example, be an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an ammonium salt; a trimethylamine salt, a triethylamine salt or a dicyclohexylamine salt; An organic amine salt such as an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a procaine salt, or an N,N'-dibenzylethylenediamine salt.

The acid addition salt may, for example, be a mineral acid salt such as a hydrochloride, a sulfate, a nitrate, a phosphate or a perchlorate; an acetate, a formate, a maleate or a butylene; An acid salt of an acid salt, a tartrate salt, a citrate salt, an ascorbate salt, a trifluoroacetate salt or the like; a sulfonic acid salt of a methanesulfonate salt, a 2-hydroxyethanesulfonate salt, a besylate salt, a p-toluenesulfonate salt or the like Salt and so on.

The compound of the present invention or a salt thereof may also be crystalline, and is included in the compound of the present invention or a salt thereof, regardless of whether the crystal form is a single or polymorphic mixture. Crystallization can be produced by crystallization by applying a crystallization method which is conventionally known per se. The compound of the present invention or a salt thereof may be a solvate (e.g., a hydrate or the like), or may be an unsolvate, and any of them may be included in the compound of the present invention or a salt thereof. A compound identified by an isotope (e.g., ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) or the like is also included in the compound of the present invention or a salt thereof.

The compound of the present invention or a salt thereof has excellent EGFR inhibitory activity and is very useful as an antitumor agent. In addition, it has excellent selectivity for EGFR and has the advantage of having fewer side effects caused by other kinases. The target cancer is not particularly limited, and may be, for example, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, biliary/cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, Cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, sputum tumor, bone/soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor and mesothelioma, etc., and head and neck cancer, stomach cancer Colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, kidney cancer and prostate cancer are preferred, especially for lung cancer.

When the compound of the present invention or a salt thereof is used as a medicine, a pharmaceutical carrier may be blended as needed, and various administration forms may be employed depending on the purpose of prevention or treatment. For example, the form may be an oral preparation, an injection, a suppository, or an ointment. Any of the patches and the like may be used, and an oral preparation is preferred. The dosage forms can be manufactured by a formulation method conventionally used by those skilled in the art.

As the pharmaceutical carrier, various organic or inorganic carrier materials which are conventionally used can be used as a material for formulation, and can be used as an excipient, a binder, a disintegrant, a lubricant, a colorant, and a solvent in a liquid preparation in a solid preparation. , dissolution adjuvant, suspending agent, isotonic agent, buffer, painless agent, etc. are formulated. Further, a preparation additive such as a preservative, an antioxidant, a coloring agent, a sweetener, and a stabilizer may be used as needed.

When preparing a solid preparation for oral administration, it can be added to the compound of the present invention. After the excipients are added, or if necessary, excipients, binding agents, disintegrating agents, lubricants, coloring agents, flavoring agents, etc. are added, the tablet, the lozenge, the granules, and the like are prepared according to the usual method. Powder, capsules, etc.

The excipients may, for example, be lactose, white sugar, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, anhydrous citric acid or the like. The binding agent may, for example, be water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropyl Cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, and the like. Examples of the disintegrator include dried starch, sodium alginate, cold weather, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Lubricants can be enumerated, for example, as purified talc. Sodium stearate, magnesium stearate, borax, polyethylene glycol, and the like. Examples of the colorant include titanium oxide and iron oxide. The flavoring agent may, for example, be white sugar, orange peel, citric acid or tartaric acid.

When a liquid preparation for oral administration is prepared, a flavoring agent, a buffering agent, a stabilizer, a flavoring agent, and the like may be added to the compound of the present invention, and an internal liquid preparation, a syrup, an elixir, and the like may be produced by a usual method.

The flavoring agent may be the above-mentioned ones, and examples of the buffering agent include sodium citrate, and the stabilizer may, for example, be xanthan gum, gum arabic or gelatin. An enteric film coat may be applied as needed, or a coating may be applied to the oral preparation by a conventional method for the purpose of holding effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.

When the injection is prepared, pH adjustment can be added to the compound of the present invention. Agents, buffers, stabilizers, isotonic agents and local anesthetics, and subcutaneous, intramuscular and intravenous injections are prepared according to conventional methods.

Examples of the pH adjuster and the buffer include sodium citrate, sodium acetate, and sodium phosphate. The stabilizer can be listed, for example, sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. The local anesthetic may, for example, be procaine hydrochloride or lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride, glucose, D-mannitol, glycerin and the like.

When the suppository is prepared, a carrier of the formulation of the present invention may be added with a carrier such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and further, as required, an interfacial activity such as Tween 80 (registered trademark) may be added. After the agent or the like, it is produced by a usual method.

When the ointment is prepared, a base, a stabilizer, a wetting agent, a preservative, and the like which are generally used in the compound of the present invention can be blended as needed, and mixed and formulated in a usual manner.

The base may, for example, be a liquid paraffin, white petrolatum, white beeswax, octyldodecanol or paraffin.

Examples of the preservative include methyl p-oxybenzoate, ethyl p-oxybenzoate, and propyl p-benzoate.

When the patch is prepared, the ointment, cream, gel, paste, or the like may be applied to a general support by a usual method.

As the support, a woven fabric, a non-woven fabric, or a film or a foam sheet of soft vinyl chloride, polyethylene, polyurethane, or the like, which is composed of cotton, rayon or chemical fiber, is suitable.

The combination of the invention in the form of each of the above-mentioned dosage units should be formulated The amount of the substance depends on the patient's symptoms or its dosage form, but it is generally not limited. However, in general, according to the form of each administration unit, the oral preparation should be 0.05-1000 mg, and the injection should be 0.01-500 mg. It is 1~1000mg.

In addition, the daily dosage of the agent having the above-mentioned administration form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined uniformly. However, in the case of the compound of the present invention, only the average adult (body weight 50 kg) is required to be 1 day. 0.05~5000mg (preferably 0.1~1000mg) can be administered, and it should be administered once a day or divided into 2~3 times.

[Examples]

The present invention will be more specifically described by the following examples, but the present invention is not limited by the same.

Each of the various reagents used in the examples used was a commercially available product unless otherwise specified. As the cerium oxide gel column chromatography, Purif-Pack (registered trademark) SI manufactured by MORITEX Corporation, KP-Sil (registered trademark) sulphur dioxide pre-filled column (Silica prepacked column) manufactured by Biotage Co., Ltd., or HP manufactured by Biotage Co., Ltd. -Sil (registered trademark) cerium oxide pre-filled pipe column. The alkaline ceria gel column chromatography method uses a Purif-Pack (registered trademark) NH manufactured by Moritex Corporation or a KP-NH (registered trademark) pre-filled pipe column manufactured by Biotage Co., Ltd. For preparative thin layer chromatography, KieselgelTM 60F254, Art. 5744 or Kogyo NH2 cerium oxide gel 60F254 plate was used. NMR spectra were performed using AL400 (400 MHz; JEOL), Mercury 400 (400 MHz; Agilent Technologies) spectrometer or equipped with OMNMR probes (Protasis) Inova 400 (400MHz; Agilent Technologies) spectrometer, using tetramethyl decane as the internal reference when tetramethyl decane is contained in the heavy solvent, and NMR solvent as the internal reference in the case of The full δ value is shown in ppm. The microwave reaction was carried out using a Discover S class manufactured by CEM Corporation.

Further, the LCMS spectrum was measured using an ACQUITY SQD (quadrupole type) manufactured by Waters Co., Ltd. under the following conditions.

Pipe column: YMC-Triart C18 made by YMC, 2.0X50mm, 1.9μm

MS detection: ESI positive

UV detection: 254 and 210 nm

Column flow rate: 0.5mL/min

Mobile phase: water / acetonitrile (0.1% formic acid)

Injection volume: 1μL

Further, the reverse phase preparative separation HPLC purification was carried out under the following conditions using a preparative separation system manufactured by WATERS.

Column: YMC-Actus Triart C18, 30X50 mm, 5 μm and YMC-Actus Triart C18, manufactured by YMC Corporation, 20×10 mm, 5 μm.

UV detection: 254nm

MS detection: ESI positive

Column flow rate: 25mL/min

Mobile phase: water / acetonitrile (0.1% formic acid)

Injection volume: 0.1-0.5mL

The meaning of the abbreviations is shown below.

s: single peak (singlet)

d: doublet (doublet)

t: Triplet (Triplet)

q: quadruple peak (quartet)

Dd: double doublet (double doublet)

Dt: double triplet

Td: triple doublet

Tt: participate in triplet (triple triplet)

Ddd: double double doublet

Ddt: double double triplet

Dtd: double triple doublet

Tdd: double double doublet

m: multiplet (multiplet)

Br: broad peak (broad)

Brs: broad singlet

DMSO-d ₆ : heavy dimethyl hydrazine

CDCl ₃ : heavy chloroform

CD ₃ OD: heavy methanol

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

NMP: 1-methyl-2-pyrrolidone

DMSO: dimethyl hydrazine

TFA: trifluoroacetic acid

SEMCl: 2-(trimethylsulfonyl)ethoxymethyl chloride

PdCl ₂ (dppf)CH ₂ Cl ₂ :1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex

Pd(PPh ₃ ) ₂ Cl ₂ : bis(triphenylphosphine)palladium(II) dichloride

WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-hydroxybenzotriazole 1 hydrate

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-6 Hexafluorophosphate

DIAD: diisopropyl azodicarboxylate

TBAF: tetrabutylammonium fluoride

DIEA: diisopropylethylamine

Example 1 N-(2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)propenylamine (step 1) 4-chloro-5-iodo-7-((2-(trimethylmethyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

【化21】

7.01 g of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine synthesized by the method described in the handbook of International Publication WO2005/042556 was dissolved in 125 ml of anhydrous THF, and cooled to 0 ° C, and then added 60. % sodium hydride 4.02 g. After stirring for 20 minutes, 13.3 ml of SEMCl was added, and the mixture was stirred overnight at room temperature. After cooling again to 0 ° C, water was added to stop the reaction, and the product was extracted with ethyl acetate. After the organic layer was washed with saturated brine, the mixture was dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Physical property: m/z [M+H] ⁺ 410.0.

(Step 2) 5-iodo-7-((2-(trimethylsulfonyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Dissolving 200 mg of 4-chloro-5-iodo-7-((2-(trimethylsulfonyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine obtained in the above step 1 in THF After 2.0 ml of 28% aqueous ammonia was added to 2.0 ml, the reaction solution was stirred at 105 ° C for 1.5 hours in a microwave reactor. The product was extracted with ethyl acetate, and the organic layer was evaporated. Property value: m/z [M+H] ⁺ 391.0.

(Step 3) 5-(quinolin-3-yl)-7-((2-(trimethylsulfonyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-Iodo-7-((2-(trimethylsulfonyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 820 mg, 3 obtained in the above step 2 - quinoline boric acid 545 mg and cesium carbonate 1.37 g dissolved in 1,4-two To 15 ml of alkane and 1.5 ml of water, 163 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 was added} , and after nitrogen substitution, the mixture was stirred at 105 ° C for 6 hours. Chloroform and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) elute Physical property: m/z [M+H] ⁺ 392.1.

(Step 4) 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-(Quinolin-3-yl)-7-((2-(trimethylsulfonyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-amine 540mg added 4N-hydrochloric acid / 1,4-two 20 ml of alkane was stirred at 75 ° C overnight. The solvent of the obtained reaction mixture was distilled off under reduced pressure. 20 ml of THF was added to the residue, and 4.0 ml of a 5N-NaOH aqueous solution was added and stirred for 1 hour. Chloroform and water and a small amount of methanol were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. Physical property: m/z [M+H] ⁺ 262.0.

(Step 5) Tert-butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethylcarbamate

Dissolving 131 mg of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in the above step 4 in 2.0 ml of DMF, cooling to 0 ° C, then adding 60% sodium hydride 60mg. After stirring for 20 minutes, 1.0 ml of a DM solution of 167 mg of butyl 2-bromoethylcarbamate was added, and the mixture was stirred at 50 ° C overnight. After cooling again to 0 ° C, water was added to stop the reaction and the product was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

(Step 6) N-(2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)propenylamine

The third butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethylamine A obtained in the above step 5 Add 4N-hydrochloric acid/1,4-two to 89mg of acid ester 2.0 ml of alkane was stirred at room temperature for 2 hours. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by azeotropy of toluene. To a portion of 17 mg of the crude product of 7-(2-aminoethyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 1.0 ml of chloroform and 20 μl of triethylamine. After cooling to 0 ° C, 100 μl of chloroform in which 4.5 μl of acrylonitrile chloride was dissolved was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was stopped with a saturated sodium hydrogencarbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: ethyl acetate/methanol) toield

Example 2 (S)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) Prop-2-en-1-one (step 1) (R)-t-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate

935 mg of (R)-(-)-N-Boc-3-pyrrolidinol was dissolved in 15 ml of chloroform, and 1.04 ml of triethylamine and 467 μl of methanesulfonate chloride were added at 0 °C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added to separate the organic layer. The organic layer was washed with aq. Property value: m/z [M+H] ⁺ 266.1.

(Step 2)

(S)-Tertiary Butyl 3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-carboxylate Acid ester

80 mg of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Example 1 (Step 4) was dissolved in DMF 2.0 ml, cooled to 0 ° C and then added 60% sodium hydride 52 mg. After stirring for 20 minutes, 1.0 ml of a solution of 230 mg of methanesulfonate obtained in the above step 1 was added, and the mixture was stirred at 85 ° C overnight. After cooling again to 0 ° C, water was added to stop the reaction, and the product was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Physical property: m/z [M+H] ⁺ 431.2.

(Step 3) (S)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) Prop-2-en-1-one

(S)-Tertibutyl 3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrole obtained in the above step 2 Add 4N-hydrochloric acid/1,4-dimer to 89 mg of pyridine-1-carboxylate 4.0 ml of alkane was stirred at room temperature for 1 hour. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by azeotropy of toluene. Part of the crude product of (S)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine To 10 mg, 2.0 ml of chloroform and 20 μl of triethylamine were added. After cooling to 0 ° C, 100 μl of chloroform in which 2.0 μl of acrylonitrile chloride was dissolved was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was stopped with a saturated sodium hydrogencarbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Example 3 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) Prop-2-en-1-one (step 1) (S)-Tertibutyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate

935 mg of (S)-(-)-N-Boc-3-pyrrolidinol was dissolved in 15 ml of chloroform, and 1.04 ml of triethylamine and 467 μl of methanesulfonate chloride were added at 0 °C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added to separate the organic layer. The organic layer was washed with aq. Property value: m/z [M+H] ⁺ 266.1.

(Step 2) (R)-Tertiary Butyl 3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-carboxylate Acid ester

80 mg of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Example 1 (Step 4) was dissolved in DMF 2.0 ml, cooled to 0 ° C and then added 60 % sodium hydride 71 mg. After stirring for 20 minutes, 1.0 ml of a solution of the methanesulfonyl substrate obtained in the above step 1 in 310 mg of DMF was added, and stirred at 85 ° C overnight. After cooling again to 0 ° C, water was added to stop the reaction, and the product was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Physical property: m/z [M+H] ⁺ 431.2.

(Step 3) (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) Prop-2-en-1-one

(R)-Tertibutyl 3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrole obtained in the above step 2 52-mg of pyridine-1-carboxylate added 4N-hydrochloric acid/1,4-di 4.0 ml of alkane was stirred at room temperature for 1 hour. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by azeotropy of toluene. Part of the crude product of (R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 10 mg of chloroform (2.0 ml) and triethylamine (20 μl) were added. After cooling to 0 ° C, 100 μl of chloroform in which 2.0 μl of acrylonitrile chloride was dissolved was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was stopped with a saturated sodium hydrogencarbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) elute

Example 4 (S)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl) Prop-2-en-1-one

Substituting (R)-(-)-N-Boc-3-piperidinol for (R)-(-)-N-Boc-3-pyrrolidinol, as in Example 2, thereby obtaining a white solid The title compound.

Example 5 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl) Prop-2-en-1-one

Substituting (R)-(-)-N-Boc-3-piperidinol for (R)-(-)-N-Boc-3-pyrrolidinol, as in Example 2, thereby obtaining a white solid The title compound.

Example 6 N-((1S,2R)-2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)propene Guanamine

Substituting (1S,2S)-trans-N-Boc-2-aminocyclopentanol for (R)-(-)-N-Boc-3-pyrrolidinol, according to Example 2, The title compound was obtained as a white solid.

Example 7 1-(4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propan-2- En-1-one (step 1) Tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

Add DIAD 1.09 to a solution of 1.00 g of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, 1.08 g of N-Boc-4-hydroxypiperidine and 1.41 g of triphenylphosphine in tetrahydrofuran. The reaction solution was stirred for 1 hour. Further, 540 mg of N-Boc-4-hydroxypiperidine, 705 mg of triphenylphosphine and 0.55 ml of DIAD were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal Physical property: m/z [M+H] ⁺ 463.0.

(Step 2)

Tert-butyl 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

Addition of tetrabutyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate obtained in the above step 1 to 1.5 g of tetrahydrofuran And 10 ml of 28% ammonia water, and stirred at 110 ° C for 10 hours using a sealed tube reactor. Ethyl acetate and water were added, and the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol). The title compound 1.10 g was obtained as a white solid. Physical property: m/z [M+H] ⁺ 444.1.

(Step 3) Tert-butyl 4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate

The third butyl 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate obtained in the above step 2 was 18.8 mg, 3 - quinoline boric acid 11mg and cesium carbonate 42mg dissolved in 1,4-two To 1 ml of alkane and 0.1 ml of water, 3.3 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 was added} , and after nitrogen substitution, the mixture was stirred at 100 ° C for 1 hour in a microwave reactor. Chloroform and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc mjjjjjjd Physical property: m/z [M+H] ⁺ 445.1.

(Step 4) 1-(4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)propan-2- En-1-one

Based on Example 1 (Step 6), the third butyl 4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in the above Step 3 was used. Pyrimidin-7-yl)piperidine-1-carboxylate to replace tert-butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] Pyrimidine-7-yl)ethylcarbamate, whereby the title compound was obtained as a white solid.

Example 8 1-(3-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidin-1-yl) Prop-2-en-1-one

Substituting N-Boc-3-hydroxymethylpyrrolidine, (R)-(-)-N-Boc-3-pyrrolidinol, to give the title compound as a white solid.

Example 9 (S)-1-(2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine- 1-yl)prop-2-en-1-one

In the case of Example 2, (R)-(-)-N-Boc-3-pyrrolidinol was replaced with (S)-(-)-N-Boc-2-pyrrolidinemethanol, thereby producing white The title compound of the solid.

Example 10 (R)-1-(2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine- 1-yl)prop-2-en-1-one

According to the second embodiment, (R)-(+)-N-Boc-2-pyrrolidinemethanol was used instead of (R)-(-)-N-Boc-3-pyrrolidinol, thereby preparing The title compound is a white solid.

Example 11 (S)-1-(2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)tetrahydrogen唉-1-yl)prop-2-en-1-one

According to the second embodiment, (S)-N-Boc-2-tetrahydroindole methanol was used instead of (R)-(-)-N-Boc-3-pyrrolidinol, thereby obtaining a white solid. The title compound.

Example 12 (R)-1-(2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)tetrahydrogen唉-1-yl)prop-2-en-1-one

The compound of Example 2 was used, and (R)-N-Boc-2-tetrahydroindole methanol was used instead of (R)-(-)-N-Boc-3-pyrrolidinol, thereby obtaining a white solid. The title compound.

Example 13 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)propane- 2-en-1-one (step 1) Tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindole-1-carboxylate

Add DIAD to 40 ml solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 1.00 g, N-Boc-3-hydroxytetrahydroindole 930 mg and triphenylphosphine 1.85 g in tetrahydrofuran solution 1.41 ml, the reaction solution was stirred for 1 hour. The reaction mixture was concentrated and evaporated to ethylamine crystals Physical property: m/z [M+H] ⁺ 435.0.

(Step 2) Tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindole-1-carboxylate

Addition of tetrabutyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindole-1-carboxylate obtained in the above step 1 to 350 mg of tetrahydrofuran 2.5 ml and 28 ml of 28% ammonia water were allowed to stir in a microwave reactor at 100 ° C for 1.5 hours. The organic layer was separated by the addition of chloroform and water, and the organic layer was dried over anhydrous sodium sulfate. Physical property: m/z [M+H] ⁺ 416.0.

(Step 3) Tert-butyl 3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindole-1-carboxylate

The third butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindole-1-carboxylate obtained in the above step 2 was 30 mg. 15 mg of 3-quinoline boric acid and 47 mg of cesium carbonate are dissolved in 1,4-two To 1 ml of alkane and 0.1 ml of water, 6 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 was added} , and after nitrogen substitution, the mixture was stirred at 105 ° C for 1 hour in a microwave reactor. Chloroform and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by basic EtOAc (EtOAc) elute elute Physical property: m/z [M+H] ⁺ 417.0.

(Step 4) 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)propane- 2-en-1-one

The third butyl 3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindole obtained in the above step 3. 1-carboxylic acid ester 15mg added 4N-hydrochloric acid / 1,4-two 2.0 ml of alkane was stirred at room temperature for 1 hour. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by azeotropy of toluene. To the obtained crude product of 7-(tetrahydroindol-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 11 mg of chloroform was added. 20 μl of ml with triethylamine. After cooling to 0 ° C, 100 μl of chloroform in which 2.0 μl of acrylonitrile chloride was dissolved was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was stopped with a saturated sodium hydrogencarbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) elute

Example 14 1-((2S,4R)-4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxyl Methyl)pyrrolidin-1-yl)prop-2-en-1-one (step 1) (2S,4S)-Tertibutyl 2-((t-butyldiphenylphosphonyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate

500 mg of 1-N-Boc-(2S,4S)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine was dissolved in 4.0 ml of DMF, and 194 mg of imidazole was added. After cooling to 0 ° C, 616 μl of a third butyl chlorodiphenyl decane was added and stirred for 1 hour. Further, 83 mg of imidazole and 300 μl of third butyl chlorodiphenyl decane were added, and the mixture was stirred at 0 ° C for 2 hours. Ethyl acetate and a saturated sodium hydrogencarbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

(Step 2) (2S,4R)-t-butyl 2-((t-butyldiphenylphosphonyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

(2S,4S)-t-butyl 2-((t-butyldiphenylphosphonyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate 555mg, 4- To 4 ml of a solution of chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 340 mg and triphenylphosphine 638 mg in tetrahydrofuran was added 0.4 ml of DIAD, and the reaction mixture was stirred overnight. The reaction mixture was concentrated to give EtOAc m.

(Step 3) (2S,4R)-t-butyl 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((t-butyldiphenyl) Base oxime)methyl)pyrrolidine-1-carboxylate

(2S,4R)-Tertibutyl 2-((t-butyldiphenylphosphonyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrole) obtained in the above step 2 [2,3-d] Pyrimidine-7-yl)pyrrolidine-1-carboxylate 346 mg 2 ml of tetrahydrofuran and 2 ml of 28% aqueous ammonia were added, and the reaction mixture was stirred at 100 ° C for 1.5 hours in a microwave reactor. After adding chloroform and water, the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate. Property value: m/z [M+H] ⁺ 698.2.

(Step 4) (2S,4R)-Tertiary Butyl 4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-( (T-butyldiphenylphosphonyloxy)methyl)pyrrolidine-1-carboxylate

(2S,4R)-t-butyl 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(( Tributyldiphenylphosphonyloxy)methyl)pyrrolidine-1-carboxylate 336mg, 3-quinolineboronic acid 124mg, cesium carbonate 45mg dissolved in 1,4-two 5 ml of alkane and 0.5 ml of water were added, and 31 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 was added} , and after nitrogen substitution, the mixture was stirred at 100 ° C for 1 hour in a microwave reactor. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc (EtOAc) elute

(Step 5) (2S,4R)-Tertiary Butyl 4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-( Hydroxymethyl)pyrrolidine-1-carboxylate

(2S,4R)-t-butyl 4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl obtained in the above step 4 25-mg of (2-t-butyldiphenylmercaptooxy)methyl)pyrrolidine-1-carboxylate was dissolved in 1.0 ml of tetrahydrofuran, and TBAF (~) supported on cerium oxide gel was added. 1.5 mmol/g) 34 mg and stirred overnight. Further, 30 mg of TBAF (~1.5 mmol/g) supported on cerium oxide rubber was further added, and the mixture was further stirred for 3 days. After the cerium oxide gel was filtered, the residue was purified by EtOAc (EtOAc:EtOAc) Physical property: m/z [M+H] ⁺ 461.1.

(Step 6) 1-((2S,4R)-4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxyl Methyl)pyrrolidin-1-yl)prop-2-en-1-one

Based on the first embodiment (step 6), the (2S,4R)-t-butyl 4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate to replace tert-butyl 2-(4-amine 5-[(Quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethylcarbamate, whereby the title compound was obtained as a white solid.

Example 15 1-((2R,4R)-4-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxyl Methyl)pyrrolidin-1-yl)prop-2-en-1-one

Substituting Example 1 for the replacement of 1-N-Boc-(2S,4S)-4 with (1-N-Boc-(2R,4S)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine -Hydroxy-2-(hydroxymethyl)-pyrrolidine, the title compound was obtained as a white solid.

Example 16 N-(2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-N-methylpropenylamine (step 1) Third butyl 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl(methyl)urethane

Add DIAD to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 500 mg, 2-(N-Boc-methylamino)ethanol 470 mg and triphenylphosphine 939 mg in tetrahydrofuran solution 20 ml 0.7 ml, the reaction solution was stirred for 1 hour. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal Property value: m/z [M+H] ⁺ 436.9.

(Step 2) Third butyl 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl(methyl)urethane

Addition of the third butyl 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl(methyl)carbamate 368 mg obtained in the above step 1 2 ml of tetrahydrofuran and 2 ml of 28% aqueous ammonia were allowed to react in a microwave reactor at 100 ° C for 1.5 hours. After adding chloroform and water, the organic layer was separated, and the organic layer was evaporated. Physical property: m/z [M+H] ⁺ 418.3.

(Step 3) Third butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl(methyl)aminocarboxylic acid ester

The third butyl 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl(methyl)carbamate 101 mg obtained in the above step 2 was obtained. , 3-quinoline boric acid 64 mg and cesium carbonate 234 mg dissolved in 1,4-two To 2 ml of alkane and 0.2 ml of water, 19.6 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 was added} , and after nitrogen substitution, the mixture was stirred in an oil bath at 105 ° C for 1 hour. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Physical property: m/z [M+H] ⁺ 419.1.

(Step 4) N-(2-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-N-methylpropenylamine

Taking the first step (Step 6), the third butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in the above step 3 was used. Pyrimidin-7-yl)ethyl(methyl)carbamate to replace tert-butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)ethylcarbamate, whereby the title compound was obtained as a white solid.

Example 17 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -4-(dimethylamino)but-2-en-1-one

The intermediate product (R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in Example 3 (Step 3) was obtained. The crude product of pyrimidine-4-amine 10 mg, 5.9 mg of 4-(dimethylamino)-2-butanoic acid hydrochloride and 14 mg of HATU were dissolved in 1.0 ml of DMF, and 50 μl of DIEA was added thereto and stirred overnight. Chloroform and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by reverse phase preparative preparative HPLC purification (water / acetonitrile (0.1% EtOAc).

Example 18 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -4-(pyrrolidin-1-yl)but-2-en-1-one (step 1) 4-(pyrrolidin-1-yl)-2-butyric acid hydrochloride

1.79 g of methyl 4-bromocrotonate was dissolved in 40 ml of tetrahydrofuran, and 1.67 ml of pyrrolidine was added thereto at 0 ° C, followed by stirring at room temperature for 1 hour. Diethyl ether and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. 40 ml of 3N-hydrochloric acid was added to the obtained product, and the mixture was heated under reflux at 100 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. Physical property: m/z [M+H] ⁺ 156.0.

(Step 2) (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -4-(pyrrolidin-1-yl)-2-butenoic acid

In accordance with Example 17, and using the 4-(pyrrolidin-1-yl)-2-butenoic acid salt obtained above as a substitute for 4-(dimethylamino)-2-butenoic acid hydrochloride The title compound was obtained as a colorless amorphous material.

Example 19 (R)-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) (cyclic Pentenyl)methanone (step 1)

The title compound of the colorless amorphous substance was obtained by substituting 1-cyclopentene carboxylic acid to the 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 20 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -3-(pyridin-2-yl)prop-2-en-1-one (step 1)

The title of the colorless amorphous product was prepared by substituting 3-(pyridin-2-yl)-acrylic acid for 4-(dimethylamino)-2-butenoic acid hydrochloride as in the case of Example 17. Compound.

Example 21 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -3-(pyridin-3-yl)prop-2-en-1-one (step 1)

In accordance with Example 17, 3-(pyridin-3-yl)-acrylic acid was used instead of 4-( Methylamino)-2-butenoic acid hydrochloride, whereby the title compound is obtained as a colorless amorphous material.

Example 22 (R)-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) (cyclic Hexenyl) ketone

The title compound of the colorless amorphous substance was obtained by substituting 1-cyclohexene carboxylic acid for 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 23 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -2-methylprop-2-en-1-one

The title compound was obtained as a colorless amorphous material, which was obtained by using the methacrylic acid instead of 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 24 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -3-phenylprop-2-en-1-one

The title compound was obtained as a colorless amorphous material, using succinic acid in place of 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 25 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) But-2-en-1-one

The title compound was obtained as a colorless amorphous material, using crotonic acid instead of 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 26 (R)-1-(2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)tetrahydrogen唉-1-yl)-4-(dimethylamino)but-2-en-1-one (step 1) (R)-t-butyl 2-((methylsulfonyloxy)methyl)tetrahydroindole-1-carboxylate

300 mg of (R)-1-(t-butoxycarbonyl)-2-tetrahydrocarbazide methanol was dissolved in 5 ml of chloroform, and 0.33 ml of triethylamine and 150 μl of methotrexate chloride were added at 0 °C. After stirring at room temperature for 1 hour, ethyl acetate and water were added at once to separate the organic layer. The organic layer was washed with aq. Physical property: m/z [M+H] ⁺ 266.0.

(Step 2) (R)-Tertiary Butyl 2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)tetrahydrogen Nitrogen 唉-1-carboxylate

100 mg of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Example 1 (Step 4) was dissolved in DMF 2.0 ml, cooled to 0 ° C, and then added 60 % sodium hydride 30 mg. After stirring for 20 minutes, 3.0 ml of a DM solution of 161 mg of the methanesulfonyl group obtained in the above step 1 was added, and the mixture was stirred at 80 ° C for 3 hours. After cooling again to 0 ° C, water was added to stop the reaction, and the product was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by EtOAc EtOAc m. Physical property: m/z [M+H] ⁺ 431.2.

(Step 3) (R)-1-(2-((4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)tetrahydrogen唉-1-yl)-4-(dimethylamino)but-2-en-1-one

(R)-Third butyl 2-((4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) obtained in the above step 2 Methyl)tetrahydroindole-1-carboxylate 94 mg added 4N-hydrochloric acid/1,4-di 3.0 ml of alkane was stirred at room temperature for 1.5 hours. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by azeotropy of toluene to obtain (R)-7-(tetrahydroindol-2-ylmethyl)-5-(quinolin-3-yl)-7H- A crude product of pyrrolo[2,3-d]pyrimidin-4-amine.

(Step 4)

Based on Example 17, the (R)-7-(tetrahydroindol-2-ylmethyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3 obtained using the above Step 3 was obtained. -d]pyrimidine-4-amine to replace (R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Amine, whereby the title compound is obtained as a colorless amorphous material.

Example 27 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(dimethylamino)but-2-en-1-one

The intermediate 7-(tetrahydroindol-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4 obtained in Example 13 (Step 4) was obtained. - 6.4 mg of crude amine product, 3.7 mg of 4-(dimethylamino)-2-butenoic acid hydrochloride, and 8.7 mg of HATU were dissolved in 1.0 ml of DMF, and 20 μl of triethylamine was added thereto and stirred for 15 minutes. Chloroform and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc (EtOAc:EtOAc)

Example 28 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(ethyl(methyl)amino)but-2-en-1-one (step 1) 4-(ethyl(methyl)amino)-2-butenoic acid hydrochloride

1.79 g of methyl 4-bromocrotonate was dissolved in 40 ml of tetrahydrofuran, and 1.72 ml of ethylmethylamine was added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Diethyl ether and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. 40 ml of 3N-hydrochloric acid was added to the obtained product, and the mixture was heated under reflux at 100 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. Physical property: m/z [M+H] ⁺ 144.0.

(Step 2) 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(ethyl(methyl)amino)but-2-en-1-one

In accordance with Example 27, 4-(ethyl(methyl)amino)-2-butenoic acid hydrochloride obtained in the above step 1 is used in place of 4-(dimethylamino)-2-butene. The acid salt was used to prepare the title compound as a colorless amorphous material.

Example 29 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(diethylamino)but-2-en-1-one (step 1) 4-(Diethylamino)-2-butenoic acid hydrochloride

1.79 g of methyl 4-bromocrotonate was dissolved in 40 ml of tetrahydrofuran, and 2.10 ml of diethylamine was added thereto at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Diethyl ether and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. 40 ml of 3N-hydrochloric acid was added to the obtained product, and the mixture was heated under reflux at 100 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Property value: m/z [M+H] ⁺ 158.0.

(Step 2) 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(diethylamino)but-2-en-1-one

In accordance with Example 27, and using 4-(diethylamino)-2-butenoic acid hydrochloride obtained in the above step 1, substituting 4-(dimethylamino)-2-butenoic acid Salt, whereby the title compound is obtained as a colorless amorphous material.

Example 30 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(isopropyl(methyl)amino)but-2-en-1-one (step 1) 4-(isopropyl(methyl)amino)-2-butenoic acid hydrochloride

1.79 g of methyl 4-bromocrotonate was dissolved in 40 ml of tetrahydrofuran, and 2.08 ml of isopropylmethylamine was added thereto at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Diethyl ether and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. 40 ml of 3N-hydrochloric acid was added to the obtained product, and the mixture was heated under reflux at 100 ° C for 1 hour. The reaction mixture was concentrated to dryness crystals crystals crystals crystals Physical property: m/z [M+H] ⁺ 158.1.

(Step 2) 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(isopropyl(methyl)amino)but-2-en-1-one

In accordance with Example 27, the 4-(isopropyl(methyl)amino)-2-butyrate obtained in the above step 1 was used in place of 4-(dimethylamino)-2-butene. The acid salt was used to prepare the title compound as a colorless amorphous material.

Example 31 1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydroindol-1-yl)-4 -(pyrrolidin-1-yl)but-2-en-1-one

In the same manner as in Example 27, 4-(pyrrolidin-1-yl)-2-butenoic acid hydrochloride obtained in Example 18 (Step 1) was used instead of 4-(dimethylamino)-2-butane. The acid salt is obtained, whereby the title compound is obtained as a colorless amorphous material.

Example 32 (R)-1-(3-(4-Amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine- 1-yl)prop-2-en-1-one (step 1) (R)-Tertiary Butyl 3-(4-Amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine 1-carboxylic acid ester

The intermediate product (R)-tert-butyl 3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in Example 3 (Step 2) was obtained. 86 mg of pyrimidine-7-yl)pyrrolidine-1-carboxylate was dissolved in 2.0 ml of DM, and 39 mg of N-bromosuccinimide was added thereto, and the mixture was stirred under light-shielding for 15 minutes. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with a saturated sodium hydrogencarbonate solution and water, and then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate) Physical property: m/z [M+H] ⁺ 509.0, 511.0.

(Step 2) (R)-1-(3-(4-Amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine- 1-yl)prop-2-en-1-one

Based on the first step (step 6), the (R)-tert-butyl 3-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrole obtained in the above step 1 was obtained. And [2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate to replace tert-butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrole [2,3-d]pyrimidin-7-yl)ethylcarbamate, whereby the title compound was obtained as a white solid.

Example 33 (R)-1-(3-(4-Amino-6-methyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one (step 1) (R)-1-(3-(4-Amino-6-methyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one

The intermediate product (R)-t-butyl 3-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2, obtained in Example 32 (Step 1) was obtained. 34 mg of 3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate was dissolved in 1.0 ml of DMF, and 37 μl of tetramethyltin and 5.5 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 were added} , and stirred at 135 ° C. 2 hour. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with a saturated sodium hydrogencarbonate solution and water, and then dried over anhydrous sodium sulfate. The residue was purified by reverse phase preparative preparative EtOAc (EtOAc/EtOAc) Physical property: m/z [M+H] ⁺ 445.1.

(Step 2) (R)-1-(3-(4-Amino-6-methyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one

Taking Example 1 (Step 6) as the standard, and using the above Step 1, (R)-1-(3-(4-Amino-6-methyl-5-(quinolin-3-yl)-7H- Pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one to replace tert-butyl 2-(4-amino-5-(quinoline) -3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethylcarbamate, whereby the title compound was obtained as a white solid.

Example 34 (R)-1-(3-(4-Amino-6-(phenylethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- Pyrrolidin-1-yl)prop-2-en-1-one (step 1) (R)-Tertiary Butyl 3-(4-Amino-6-(phenylethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)pyrrolidine-1-carboxylate

Preparation of the intermediate product (R)-t-butyl 3-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2, obtained in Example 32 (Step 1). 3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate 50 mg, phenylacetylene ₁₆ μl, copper iodide (I) 2.8 mg of tetrahydrofuran 2.0 ml, triethylamine 0.2 ml suspension solution, PdCl ₂ added (dppf) 5.5 mg of CH ₂ Cl ₂ was stirred at 100 ° C overnight under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by reverse-purpur-purpurpurpurpurpurpurpurpurpurpurpurpurpurpurpurd Property value: m/z [M+H] ⁺ 531.3.

(Step 2) (R)-1-(3-(4-Amino-6-(phenylethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- Pyrrolidin-1-yl)prop-2-en-1-one

Taking Example 1 (Step 6) as the standard, and using the above Step 1 to obtain (R)-tert-butyl 3-(4-amino-6-(phenylethynyl)-5-(quinoline-3- -7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate to replace tert-butyl 2-(4-amino-5-(quinoline-3- The title compound was obtained as a white solid. mp </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

Example 35 (R)-1-(3-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one (step 1) (R)-Tertiary Butyl 3-(4-Amino-5-(quinolin-3-yl)-6-((trimethyldecyl)ethynyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

【化52】

Preparation of the intermediate product (R)-t-butyl 3-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2, obtained in Example 32 (Step 1). 3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate 68 mg, trimethyldecylacetylene 0.2 ml, copper iodide (I) 3.8 mg of tetrahydrofuran 2.0 ml, triethylamine 0.2 ml suspension solution Then, 10.9 mg of PdCl ₂ (dppf) CH ₂ Cl _{2 was} added, and the mixture was stirred overnight at 110 ° C under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. After the organic layer was dried over anhydrous magnesium sulfate, solvent was evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Physical property: m/z [M+H] ⁺ 527.2.

(Step 2) (R)-Tertiary Butyl 3-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrole Pyridine-1-carboxylate

(R)-Tertibutyl 3-(4-amino-5-(quinolin-3-yl)-6-((trimethyldecyl)ethynyl)-7H-pyrrole obtained in the above step 1. [2,3-d] Pyrimidine-7-yl)pyrrolidine-1-carboxylate 26 mg 2 ml of a 2% potassium hydroxide methanol solution was added, and the mixture was stirred for 10 minutes. Chloroform and a saturated ammonium chloride solution were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate. Physical property: m/z [M+H] ⁺ 452.2.

(Step 3) (R)-1-(3-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1-yl)prop-2-en-1-one

Taking Example 1 (Step 6) as the standard, and using the above Step 2, (R)-tert-butyl 3-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H -pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate to replace tert-butyl 2-(4-amino-5-(quinolin-3-yl)-7H Pyrrolo[2,3-d]pyrimidin-7-yl)ethylcarbamate, whereby the title compound is obtained as a white solid.

Example 36 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-6-((tetrahydro-2H-piperidin-4-yl)ethynyl)-7H-pyrrole [2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (step 1) (R)-Tertiary Butyl 3-(4-Amino-5-(quinolin-3-yl)-6-((tetrahydro-2H-piperidin-4-yl)ethynyl)-7H-pyrrole And [2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

【化54】

The intermediate product (R)-t-butyl 3-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2, obtained in Example 32 (Step 1) was obtained. 3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate 30.6 mg, 4-ethynyltetrahydro-2H-pyran 28.1 mg, PdCl ₂ (dppf)CH ₂ Cl ₂ 6.1 mg in acetonitrile 4 ml After mixing, 1 ml of diethylamine and 2.0 mg of copper (I) iodide were added thereto with stirring at room temperature. After the mixture was stirred at 80 ° C for 2 hours, the reaction mixture was cooled to room temperature, poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous MgSO.

(Step 2) (R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-6-((tetrahydro-2H-piperidin-4-yl)ethynyl)-7H-pyrrole [2,3-d]pyrimidine-4-amine

(R)-Tertibutyl 3-(4-Amino-5-(quinolin-3-yl)-6-((tetrahydro-2H-pyran-4-) obtained in the above step 1 at room temperature Add a solution of 58.5 μl of methanesulfonic acid to a solution of the crude purified product of acetylidyl)-7H-pyrrolo[2,3-d]pyrimidin-7-ylpyrrolidin-1-carboxylate in 4 ml of acetonitrile, and stir for 30 minutes. . After adding 0.9 ml of a 5 M aqueous sodium hydroxide solution to the reaction mixture, the mixture was neutralized, poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and evaporated.

(Step 3) (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-6-((tetrahydro-2H-piperidin-4-yl)ethynyl)-7H-pyrrole [2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

(R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-6-((tetrahydro-2H-pyran-4-yl) obtained in the above step 2 at room temperature To a solution of the crude purified product of ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine in chloroform (5 ml), 8.4 μl of triethylamine and 4.9 μl of propylene chloride. After the mixture was stirred at room temperature for 10 minutes, it was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the residue obtained was concentrated under reduced pressure to afford purified crystals (yield: ethyl acetate/methanol = 6/1). The title compound was 8.4 mg.

Example 37 (R)-1-(3-(4-Amino-6-(3-amino-3-methylbut-1-ynyl)-5-(quinolin-3-yl)-7H-pyrrole [2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

The title compound was obtained as a pale yellow solid, m.p.

Example 38 (R)-Tertiary Butyl 4-((7-(1-Propylpyridylpyrrolidin-3-yl)-4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-6-yl)ethynyl)piperidine-1-carboxylate (step 1) (R)-6-bromo-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Preparation of intermediate (R)-tert-butyl 3-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrole obtained in Example 32 (Step 1) at room temperature And [2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate 533.9 mg of methanol 4 ml solution 4N hydrochloric acid 1,4-two 5 ml of an alkane solution was stirred at 40 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc m. The extract was dried over anhydrous sodium sulfate.

(Step 2) (R)-Tertiary Butyl 4-((4-Amino-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] Pyrimidin-6-yl)ethynyl)piperidine-1-carboxylate

(R)-6-bromo-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine obtained in the above (Step 1) 41.2 mg of 4-amine, 83.8 mg of tert-butyl 4-ethynylpiperidine-1-carboxylate, 10.9 mg of Pd(PPh ₃ ) ₂ Cl ₂ in 5 ml of acetonitrile, and then added diethyl ether under stirring at room temperature. 1 ml of amine and 1.7 mg of copper (I) iodide. After the mixture was stirred at 80 ° C for 2 hours, the reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and evaporated.

(Step 3) (R)-Tertiary Butyl 4-((7-(1-Propylpyridylpyrrolidin-3-yl)-4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-6-yl)ethynyl)piperidine-1-carboxylate

(R)-Third-butyl 4-((4-amino-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrole obtained by the above (Step 2) The crude purified product of [2,3-d]pyrimidin-6-yl)ethynyl)piperidine-1-carboxylate was dissolved in 4 ml of chloroform, and 14.0 μl of triethylamine and 10.2 μl of acrylonitrile chloride were added at room temperature. After the mixture was stirred at room temperature for 10 minutes, the reaction solution was poured into saturated aqueous ammonium chloride and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate (MgSO4), EtOAc m. .

Example 39 (R)-1-(3-(4-Amino-6-(piperidin-4-ylethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] Pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

(R)-Tertibutyl 4-((7-(1-propenylpyridylpyrrolidin-3-yl)-4-amino-5-(quinoline-3-) obtained in Example 38 at room temperature 3) 7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethynyl)piperidine-1-carboxylate 35.0 mg of acetonitrile 3 ml solution was added 38.5 μl of methanesulfonic acid, and then stirred at 40 ° C 15 minutes. The reaction solution was allowed to cool to room temperature, and then added to a solution of 118.5 ml of a 5M aqueous sodium hydroxide solution, and the mixture was neutralized, and poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate.

Example 40 Third butyl trans-4-((7-((R)-1-propenylpyrrolidin-3-yl)-4-amino-5-(quinolin-3-yl)-7H-pyrrole And [2,3-d]pyrimidin-6-yl)ethynyl)cyclohexylaminoformate

The same procedure as in Example 38 was carried out, and a third butyl trans-4-ethynylcyclohexylcarbamate was used in place of the third butyl 4-ethynylpiperidine-1-carboxylate. The title compound is a pale yellow solid.

Example 41 1-((R)-3-(4-Amino-6-((trans-4-aminocyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

The same procedure as in Example 39 was used, and the obtained butyl-trans-4-((7-((R)-1-propenylpyrrolidin-3-yl)-4-yl) group of Example 40 was used. -5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethynyl)cyclohexylcarbamate to replace (R)-t-butyl 4 -((7-(1-propenylpyridylpyrrolidin-3-yl)-4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6- The title compound is obtained as a pale yellow solid.

Example 42 (R)-1-(3-(4-Amino-6-((1-aminocyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

The title compound was obtained as a pale yellow solid, m.

Example 43 (R)-1-(3-(4-Amino-6-((1-hydroxycyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d Pyrimidine-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

The title compound was obtained as a pale yellow solid, m.

Example 44 (R)-1-(3-(4-Amino-6-(3-hydroxy-3-methylbut-1-ynyl)-5-(quinolin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one

Using the same procedure as in Example 38, and using 3-methyl-1-butyn-3-ol in place of the third butyl 4-ethynylpiperidine-1-carboxylate, the title of the pale yellow solid was obtained. Compound.

Example 45 (R)-1-(3-(4-Amino-6-fluoro-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine- 1-yl)prop-2-en-1-one (step 1) (R)-Tertiary Butyl 3-(4-((Dimethylamino)methyleneamino)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] Pyrimidine-7-yl)pyrrolidine-1-carboxylate

The intermediate product (R)-tert-butyl 3-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in Example 3 (Step 2) was obtained. 150 mg of pyrimido-7-yl)pyrrolidine-1-carboxylate and 89 mg of N,N-dimethylformamide dineopentyl acetal were dissolved in DMF and stirred at 100 ° C overnight. The obtained reaction liquid was concentrated under reduced pressure, and the solvent and excess reagent was removed to give 155 mg of the title compound. Physical property: m/z [M+H] ⁺ 486.1.

(Step 2) (R)-t-butyl 3-(6-bromo-4-((dimethylamino)methyleneamino)-5-(quinolin-3-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

(R)-Tertibutyl 3-(4-((dimethylamino)methyleneamino)-5-(quinolin-3-yl)-7H-pyrrolo[(Step 1)] 155 mg of 2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate was dissolved in 4.0 ml of DMF, and 56 mg of N-bromosuccinimide was added thereto, and the mixture was stirred under light-shielding for 45 minutes. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with a saturated sodium hydrogencarbonate solution and water, and then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate) Physical property: m/z [M+H] ⁺ 564.1, 566.1.

(Step 3) (R)-Tertiary Butyl 3-(4-Amino-6-fluoro-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine 1-carboxylic acid ester

(R)-Tertibutyl 3-(6-bromo-4-((dimethylamino)methyleneamino)-5-(quinoline-3) was obtained (Step 2) under a nitrogen atmosphere. 100 mg of -7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate was dissolved in 3.0 ml of THF, and after cooling to -78 ° C, titration of 1.59 M n-butyl group Lithium 178μl. After the reaction solution was stirred for 10 minutes, 1.0 ml of a THF solution of 142 mg of N-fluorobenzenesulfonimide was added. After stirring the reaction solution for 30 minutes, ethyl acetate and water were added to separate the organic layer. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated. A 2.0 M ammonia methanol solution was added to the obtained residue, and the tube was sealed and stirred at 80 ° C for 1 hour. The obtained mixture was concentrated under reduced pressure, and the obtained residue was purified to purified crystals crystals crystals crystals crystal Physical property: m/z [M+H] ⁺ 449.1.

(Step 4) (R)-1-(3-(4-Amino-6-fluoro-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine- 1-yl)prop-2-en-1-one

Based on Example 1 (Step 6), the (R)-tert-butyl 3-(4-amino-6-fluoro-5-(quinolin-3-yl)-7H-pyrrole obtained by the above Step 3 was obtained. And [2,3-d]pyrimidine Pyridyl-7-yl)pyrrolidine-1-carboxylate to replace tert-butyl 2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] Pyrimidine-7-yl)ethylcarbamate, whereby the title compound was obtained as a white solid.

Example 46 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) Prop-2-yn-1-one (step 1)

The title compound was obtained as a colorless amorphous material.

Example 47 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) But-2-yn-1-one (step 1)

The title compound was obtained as a colorless amorphous material, which was obtained from the residue of the title compound, using 2-butynoic acid in place of 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 48 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -4-hydroxybut-2-yn-1-one (step 1)

The title compound was obtained as a colorless amorphous material, using 4-hydroxy-2-butynoic acid as the title compound of 4-(dimethylamino)-2-butenoic acid hydrochloride.

Example 49 (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl) -4-hydroxy-4-methylpent-2-yn-1-one (step 1)

Taking Example 17 as the standard, and using 4-hydroxy-4-methyl-2-pentynoic acid instead of 4-(dimethylamino)-2-butenoic acid hydrochloride, thereby obtaining a colorless non- The title compound of the crystalline substance.

Example 50 (R,E)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1- 3-chloroprop-2-en-1-one (step 1)

(R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in Example 3 (Step 3) at room temperature After adding 89.6 mg of WSC and 65.7 μl of triethylamine to a suspension of 102.1 mg of pyrimidine-4-amine in chloroform, 36.4 mg of trans-3-chloroacrylic acid was added, and the mixture was stirred at room temperature for 15 minutes.

The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, EtOAc (EtOAc m.

Example 51 (R,Z)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1- 3-chloroprop-2-en-1-one (step 1)

(R)-7-(pyrrolidin-3-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d] obtained in Example 3 (Step 3) at room temperature Pyrimidine-4-amine 254.0 mg After adding WSC 245.6 mg and 180.0 μl of triethylamine in a suspension of 20 ml of chloroform, 146.5 mg of cis-3-chloroacrylic acid was added at once, and the mixture was stirred at room temperature for 90 minutes.

The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate (MgSO4), EtOAc m.

Comparative example 1 (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Prop-2-en-1-one

The synthesis was carried out in accordance with the method described in Patent Document 1, to obtain the title compound.

The chemical structural formula and physical property values of the compounds of Examples 1 to 51 are shown in Tables 1 to 27.

Test case

The compounds of the examples of the invention were evaluated using the following test methods.

Test Example 1 Determination of various EGFR kinase activity inhibitors (in vitro)

1) Determination of EGFR (T790M/L858R) kinase inhibitory activity

The inhibitory activity of the example compounds against EGFR (T790M/L858R) kinase activity was determined.

The material was synthesized by reference to the LabChip (registered trademark) series of reagents FL-Peptide 22 of Caliper Life Sciences, Inc., and the biotinylated biotinylated material (biotin-EEPLYWSFPAKKK) was used as a matrix peptide and purchased from Carna Biosciences, Inc. The purified recombinant human EGFR (T790M/L858R) protein was used as EGFR (T790M/L858R).

The assay was carried out by stepwise dilution of the example compound with dimethyl hydrazine (DMSO). Next, EGFR (T790M/L858R) protein, matrix peptide (final concentration 250 nM), magnesium chloride (final concentration 10 mM), manganese chloride (final concentration 10 mM), and ATP (in the kinase reaction buffer (Carna Biosciences, Inc.) were added. The final concentration of 1 uM) was incubated with the DMSO solution of the example compound (final concentration of DMSO was 5%) and cultured at 25 ° C for 120 minutes for kinase reaction. EDTA was added to a final concentration of 40 mM to stop the reaction, and a test solution containing ruthenium (Eu)-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added thereto. Allow to stand at room temperature for more than 2 hours. Finally, the amount of fluorescence when irradiated with excitation light having a wavelength of 337 nm was measured using PHERAstar FS (BMG LABTECH) at two wavelengths of 620 nm and 665 nm. The phosphorylation reaction amount is determined from the fluorescence ratio of the two wavelengths, and the phosphorylation reaction can be suppressed to 50%. Concentration of the compound, ie IC50 value (nM).

2) Determination of EGFR (d746-750/T790M) kinase inhibitory activity

The inhibitory activity of the example compounds against EGFR (d746-750/T790M) kinase activity was determined.

The material was purchased from Carna Biosciences, Inc. as a purified recombinant human EGFR (d746-750/T790M) protein as EGFR (d746-750/T790M). Let the final concentration of ATP be 1.5 uM. Others used IC50 values (nM) using the same materials and assays as those used to determine EGFR (T790M/L858R) kinase inhibitory activity.

3) Determination of EGFR (L858R) kinase inhibitory activity

The inhibitory activity of the example compounds against EGFR (L858R) kinase activity was determined.

The material was purchased from Carna Biosciences, Inc. as a purified recombinant human EGFR (L858R) protein as EGFR (L858R). Let the final concentration of ATP be 4 uM. In other cases, IC50 values (nM) were obtained in the same manner as in the case of EGFR (T790M/L858R) kinase inhibitory activity assay.

4) Determination of EGFR (d746-750) kinase inhibitory activity

The inhibitory activity of the example compounds against EGFR (d746-750) kinase activity was determined.

The material was purchased from Carna Biosciences, Inc. as a purified recombinant human EGFR (d746-750) protein as EGFR (d746-750). The final concentration of ATP was 5 μM. The kinase reaction was cultured for 90 minutes. In other cases, IC50 values (nM) were obtained in the same manner as in the case of EGFR (T790M/L858R) kinase inhibitory activity assay.

5) EGFR (WT)

The inhibitory activity of the example compounds against EGFR (WT) kinase activity was determined.

The material used is EGFR (WT): the intracytoplasmic region of human EGFR (WT) having the N-terminal fused FLAG marker is expressed in insect cell Sf9 by the baculovirus expression system, and anti-FLAG antibody is used. Purified by agar (Sigma-Aldrich). The final concentration of the matrix peptide was 500 nM and the final concentration of ATP was 4.7 uM. In other cases, the IC 50 value (nM) was obtained in the same manner as in the case of the EGFR (T790M/L858R) kinase inhibitory activity assay.

The results of these and the like are shown in Table 28.

The example compounds have been confirmed to have strong inhibitory activity against EGFR (L858R), EGFR (d746-750), and even EGFR (T790M/L858R) and EGFR (d746-750/T790M). In addition, it has been confirmed that the inhibitory activity against EGFR (WT) is weak compared with the above.

Test Example 2 Test for proliferation inhibitory activity of wild-type and mutant EGFR-expressing cell lines (in vitro)

1) lung adenocarcinoma cell line exhibiting EGFR (T790M/L858R) NCI-H1975 cells, 2) lung adenocarcinoma cell line HCC827 cells expressing EGFR (d746-750), and 3) human epidermal cancer cell line A431 cells expressing EGFR (WT) were suspended in the medium recommended by ATCC. The cell suspension was sown in each well of a 384 well flat bottom microplate or a 96 well flat pan, and cultured at 37 ° C for 1 day in a 5% carbon dioxide incubator. The compound of the present invention and the comparative compound were dissolved in DMSO, and the test compound was diluted to a concentration of 200 times the final concentration using DMSO. The DMSO solution of the test compound was diluted with the medium used for suspension of each cell, and added to each well of the cell culture dish to make the final concentration of DMSO 0.5%, and then 37 ° C in an incubator containing 5% carbon dioxide. Cultivate for 3 days. Cell counts at the start of culture and after culture were carried out using Cell Titer Glo (manufactured by Promega) and using a protocol recommended by Promega. The proliferation inhibition rate was calculated by the following formula, and the concentration of the test compound (GI 50 (nM)) which was inhibited by 50% was determined.

Proliferation inhibition rate (%) = (C-T) / (C-C0) X100

T: Luminous intensity of a well to which a test compound is added

C: Luminous intensity of wells without added test compound

C0: Luminous intensity of the well measured before adding the test compound

The results are shown in Table 29.

It has been confirmed that the compound of the example has a strong proliferation inhibitory effect on cells expressing EGFR (d746-750) as well as cells expressing EGFR (T790M/L858R). Further, it has been confirmed that the proliferation inhibitory effect on EGFR (WT) expressing cells is weak compared with the above.

Claims (11)

A compound of the following formula (I) or a salt thereof: (Wherein, R ₁ is a hydrogen atom, a halogen atom, R ₂ may have the C ₁ -C ₆ alkyl group which may have the R C _{2 2} -C ₆ alkenyl group or an R C ₂ of ₂ -C ₆ alkynyl group; R ₂ is _{-OR x, -N (R x)} (R y), R ₃ may have the C ₃ -C ₁₀ cycloalkyl, R ₃ can have the C ₃ -C ₁₀ heterocycloalkyl, can be R C ₃ having the ₆ -C ₁₂ aryl group or R ₃ may have the C ₄ -C ₉ heteroaryl; R ₃ is _{-OR x, -N (R x)} (R y), - N (R x ) C(=O)R _y , -N(R _x )C(=O)OR _y , -N(R _x )C(=O)N(R _y )(R _z ) or -C(=O) OR _x ; R _x , R _y , and R _z are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₃ -C ₁₀ cycloalkyl group; and X is represented by the following formula (X ₁ ); a group represented by the following formula (X ₂ ) or a group represented by the following formula (X ₃ ); formula (X ₁ ): -(CH ₂ ) _m -N(R ₄ )- ( X ₁ ) Formula (X ₂ ): (wherein, the formula shown below represents a C ₃ -C ₁₀ cycloalkylene group); General formula (X ₃ ): (In this case, the formula represented by the following formula represents a divalent heterocyclic alkyl group having a carbon number of 3 to 10, which contains at least one nitrogen atom in the ring and one of the nitrogen atoms has a bond, and is more in the ring. Containing 0 to 2 of the same or different heteroatoms selected from oxygen or sulfur atoms); m is 1 to 3; n is 0 to 2; R ₄ is a hydrogen atom or a C ₁ -C ₆ alkyl group; R ₅ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group; Y is -C(R) ₆ )=C(R ₇ )(R ₈ ) or -C≡CR ₉ ; R ₆ , R ₇ and R _{8 are the} same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₆ - a C ₁₂ aryl group, a C ₄ -C ₉ heteroaryl group, an aminomethyl group or a 1-pyrrolidinyl group which may be substituted by a C ₁ -C ₆ alkyl group, and R ₆ and R ₇ may be bonded thereto. The two carbon atoms together form a C ₄ -C ₈ cycloalkenyl ring; R ₉ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group. The scope of the patent as item 1 or a salt thereof, wherein R ₁ is a hydrogen atom, a halogen atom, R ₂ may have the C ₁ -C ₆ alkyl group or R ₂ may have the C ₂ -C ₆ alkynyl group; R ₂ is _{-OR x, -N (R x)} (R y), R ₃ may have the C ₃ -C ₁₀ cycloalkyl, R ₃ can have the C ₃ -C ₁₀ heterocycloalkyl group, or may have R C ₃ of ₆ -C ₁₂ aryl group; R ₃ is _{-OR x, -N (R x)} (R y), - N (R x) C (= O) oR y , or -C (= O) oR _x ; R _x , R _{y are the} same or different and are a hydrogen atom or a C ₁ -C ₆ alkyl group; X is a group represented by the formula (X ₁ ), a group represented by the formula (X ₂ ) or a formula a group represented by (X ₃ ); m is 2; n is 0 to 1; R ₄ is a hydrogen atom or a C ₁ -C ₆ alkyl group; and R ₅ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group Y is -C(R ₆ )=C(R ₇ )(R ₈ ) or -C≡CR ₉ ; R ₆ , R ₇ , R _{8 are the} same or different and are a hydrogen atom, C ₁ -C ₆ alkyl a C ₄ -C ₉ heteroaryl group, an aminomethyl group or a 1-pyrrolidinyl group which may be substituted by a C ₁ -C ₆ alkyl group, and R ₆ and R ₇ may be bonded to two carbons thereof The atoms together form a C ₄ -C ₈ cycloalkenyl ring; R ₉ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group. The compound or a salt thereof according to claim 1 or 2, wherein R ₁ is a hydrogen atom or a C ₂ -C ₆ alkynyl group which may have R ₂ ; R ₂ is a hydroxyl group, an amine group, and C ₃ which may have an amine group -C ₁₀ cycloalkyl or C ₆ -C ₁₂ aryl; X is a group of the formula (X ₃ ); n is 0; R ₅ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a hydroxyl group; Y is a vinyl group. Patent application range as 1 to 3 of any one or a salt thereof, wherein R ₁ is a hydrogen atom, an ethynyl group of R ₂ may have the R or the _2-pentynyl group; R ₂ is hydroxy, amine a cyclohexane group which may have an amine group or a phenyl group which may have an amine group; X is a group represented by the formula (X ₃ ); n is 0; R ₄ is a hydrogen atom or a methylol group; Y is ethylene base. The compound or a salt thereof according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of: (R)-1-(3-(4-amino-5-(quinoline) -3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-Amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl) Prop-2-en-1-one; 1-((2R,4R)-4-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-6-(phenyl) Ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; R)-1-(3-(4-Amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine- 1-yl)prop-2-en-1-one; (R)-1-(3-(4-amino-6-(3-amino-3-methylbut-1-ynyl)-5 -(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one; (R)-1- (3-(4-Amino-6-((1-aminocyclohexyl)ethynyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7- Pyrrolidin-1-yl)prop-2-en-1-one; and (R)-1-(3-(4-amino-6-(3-hydroxy-3-methylbut-1-) Alkynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one. An EGFR inhibitor, which comprises the compound of any one of claims 1 to 5 or a salt thereof as an active ingredient. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a salt thereof. An antitumor agent, which is a compound of any one of claims 1 to 5 or a salt thereof as an active ingredient. A method for the prophylaxis or treatment of a cancer comprising the step of administering to a mammal a compound or a salt thereof according to any one of claims 1 to 5, which is a prophylactically or therapeutically effective amount for a cancer. A use of a compound or a salt thereof according to any one of claims 1 to 5, for the manufacture of a prophylactic or therapeutic agent for cancer. A compound or a salt thereof according to any one of claims 1 to 5, which is for use in the prevention or treatment of cancer.