WO2013118817A1 - 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

Quinolylpyrrolopyrimidine compound or salt thereof

[Cross-reference of related applications]
This application claims priority based on Japanese Patent Application No. 2012-024200, the entire disclosure of which is incorporated herein by reference, filed on Feb. 7, 2012.

The present invention relates to a pyrrolopyrimidine derivative having a quinoline structure having an epidermal growth factor receptor (Epidermal Growth Factor Receptor; EGFR) inhibitory action and a pharmaceutical composition containing these as active ingredients.

EGFR is a receptor tyrosine kinase that binds to epidermal growth factor (EGF), which is a ligand in normal tissues, exerts physiological functions, and contributes to proliferation and inhibition of apoptosis in epithelial tissues ( Non-patent document 1).

EGFR is also one of oncogenes, and EGFR gene amplification and protein high expression and mutation are various cancer types such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, It is known for renal cancer, bladder cancer, skin cancer, brain tumor and the like (Non-patent Document 2). In Japan and Western countries, approximately 170 to 375 people per 100,000 population die from cancer each year, accounting for the top cause of death. (Non-Patent Document 3). Among them, the number of deaths due to lung cancer reaches about 1.4 million people a year worldwide, and non-small cell lung cancer accounts for more than 80% of lung cancers, so the development of an effective treatment method is desired (Non-Patent Document 4). ).

In recent years, causative genes for these cancers are being identified, and mutations in the EGFR gene are one of them, resulting in an active mutant EGFR protein. Examples of active mutant EGFR proteins include those in which amino acids 746-750 are deleted (EGFR (d746-750)), amino acids 858 are mutated from leucine to arginine (EGFR (L858R)), etc. For example, such mutations have been reported in 20-40% of non-small cell lung cancers, and in the West, 10-15% of non-small cell lung cancers. Non-small cell lung cancer having these mutations is highly sensitive to gefitinib (trade name Iressa (registered trademark)) and erlotinib (trade name Tarceva (registered trademark)), which are agents that inhibit the kinase activity of EGFR (EGFR inhibitor). These drugs are used as therapeutic drugs in Japan, Europe and America. However, 6-12 months after the start of use, resistance to gefitinib and erlotinib is acquired and the therapeutic effect is weakened. This acquired resistance is a serious problem in the treatment of non-small cell lung cancer having a highly sensitive mutant EGFR. It has become. About 50% of this acquired resistance is caused by a resistance mutant EGFR protein (EGFR (d746-750 / T790M) or EGFR (T790M / L858R) in which the 790th amino acid is changed from threonine to methionine as a result of the second mutation in the EGFR gene. )) Has emerged, and the development of an effective therapeutic agent for non-small cell lung cancer having this drug-resistant mutant EGFR has become an important issue (Non-patent Document 5).

On the other hand, as side effects common to EGFR inhibitors gefitinib and erlotinib currently used as therapeutic agents in clinical practice and EGFR inhibitor BIBW2992 in clinical trials, skin abnormalities and gastrointestinal disorders have been reported. These side effects are that the EGFR inhibitor inhibits not only mutant EGFR expressed in non-small cell lung cancer, but also the activity of wild-type EGFR (EGFR (WT)) expressed in the skin or digestive tract. From the viewpoint of reducing side effects, it is desirable that the inhibitory activity of normal tissue against EGFR (WT) is weak.

Accordingly, by administering a drug having a weak inhibitory activity against wild-type EGFR compared to the inhibitory activity against drug-resistant mutant EGFR in which the 790th amino acid is mutated to methionine, the drug is administered at a dose at which side effects in the skin or digestive tract do not appear strongly. It is expected to be able to suppress the growth of non-small cell lung cancer cells having resistant mutant EGFR, and is expected to contribute to cancer treatment, prolonging patient life and improving QOL. In addition to drug-resistant mutant EGFR, it has a strong inhibitory activity against highly sensitive mutant EGFR such as EGFR (d746-750) and EGFR (L858R) which are highly sensitive to gefitinib and erlotinib, and a weak inhibitory activity against wild-type EGFR. If present, it is expected that the growth of non-small cell lung cancer cells expressing high-sensitivity mutant or drug-resistant mutant EGFR can be suppressed at a dose at which side effects in the skin or gastrointestinal tract do not appear strongly, or high-sensitivity mutation Expected to reduce the frequency of drug-resistant mutant EGFR that appears as acquired resistance from non-small cell lung cancer cell carcinomas that express type EGFR, and are expected to contribute to cancer treatment and patient survival and improvement of QOL Is done. Moreover, since the expression of a highly sensitive mutant type or a drug resistant mutant type EGFR can be applied as a stratification index at the treatment site, the patient can be selected, and the ethical contribution is high.

PCI32765 ((R) -1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) 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 has high homology with EGFR in the ATP pocket, and is effective for hematological tumors such as chronic lymphoma, B cell lymphoma, and multiple myeloma However, it is not effective for epithelial tumors or solid tumors.

International Publication WO2008 / 121742 Pamphlet

As described above, an EGFR inhibitor is expected to have an effect in cancer treatment, but the clinical effect is not sufficient.

Therefore, an object of the present invention is to provide a novel compound or a salt thereof that strongly inhibits EGFR. Furthermore, it provides a novel compound or a salt thereof that inhibits EGFR (d746-750) and EGFR (L858R), and also inhibits EGFR (d746-750 / T790M) and EGFR (T790M / L858R), but does not inhibit EGFR (WT). There is.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have a pyrrolopyrimidine compound group having a quinoline structure having an excellent inhibitory activity against EGFR and a cancer cell growth inhibitory effect, thereby treating cancer. The present invention has been found to be useful as a pharmaceutical for the purpose of the present invention.

That is, the present invention relates to the general formula (I)

(In the formula, _{R 1} represents a hydrogen atom, organic halogen atom, which may have a _{R 2 C} 1 -C ₆ alkyl group, which may have a _{R 2 C} 2 -C ₆ alkenyl group or _{R 2} Optionally a C ₂ -C ₆ alkynyl group;
R _{2 is, -OR x, -N (R x} ) (R y), which may have a _{R 3 C 3 -C 10} cycloalkyl group which may have a _{R 3 C 3 -C 10} heteroaryl cycloalkyl group, which may have a good _C 6 _{-C 12} aryl group or _{R 3} have a _{R 3 C} 4 -C ₉ heteroaryl group;
R ₃ represents —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 each is a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₃ -C ₁₀ cycloalkyl group;
X represents the general formula (X ₁ ):
A group represented by — (CH ₂ ) _m —N (R ₄ ) — (X ₁ ),
General formula (X ₂ ):

A group represented by (where

Represents a C ₃ -C ₁₀ cycloalkylene group. )
Or general formula (X ₃ )

A group represented by (where

Contains at least one nitrogen atom in the ring, one of the nitrogen atoms has a bond, and further contains 0 to 2 hetero or hetero atoms selected from oxygen or sulfur atoms in the ring. And a divalent heterocycloalkylene group having 3 to 10 carbon atoms. )
Is;
m is 1 to 3;
n is 0-2;
R ₄ is a hydrogen atom or a C ₁ -C ₆ alkyl group;
R ₅ is a C ₁ -C ₆ alkyl group optionally having a hydrogen atom or a hydroxy group;
Y is

 

Is;
R ₆ , R ₇ , and R ₈ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₂ aryl group, a C ₄ -C ₉ heteroaryl group, C ₁ An aminomethyl group or a 1-pyrrolidinomethyl group optionally substituted by a —C ₆ alkyl group, and R ₆ and R ₇ together with the two carbon atoms to which they are attached, a C ₄ -C ₈ cycloalkene ring May form;
R ₉ is a C ₁ -C ₆ alkyl group which may have a hydrogen atom or a hydroxy group. Or a salt thereof.

The present invention also provides a pharmaceutical such as an EGFR inhibitor and an antitumor agent comprising the compound represented by the above general formula (I) as an active ingredient.

According to the present invention, there is provided a method for preventing or treating cancer, which comprises the step of administering to a mammal a prophylactic or therapeutically effective amount of the compound represented by the above general formula (I) or a salt thereof against cancer. .

The present invention also provides use of the compound represented by the above general formula (I) or a salt thereof for producing a preventive or therapeutic agent for cancer.

And this invention provides the compound or its salt represented with the said general formula (I) for using for the prevention or treatment of cancer.

According to the present invention, a novel compound represented by the above general formula (I) or a salt thereof useful as an EGFR inhibitor is provided.

It has been clarified that the compound of the present invention or a salt thereof has an excellent EGFR inhibitory activity and exhibits a growth inhibitory effect on cancer cell lines. Moreover, it has the advantage that there are few side effects by other kinases from the outstanding selectivity with respect to EGFR. Therefore, the compound of the present invention or a salt thereof is useful as a preventive and / or therapeutic agent for cancer.

The compound represented by the above general formula (I) of the present invention has a quinoline as a basic structure, has pyrrolopyrimidine at the 3-position thereof, and further has α and β unsaturated amides via a spacer site. It is a novel compound that is not described in any of the above prior art documents.

In the present specification, “halogen atom” specifically includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

In the present specification, the “C ₁ -C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, Examples include isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like.

In the present specification, the “C ₁ -C ₆ alkylene group” means a linear alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, an n-propylene group, an isopropylene group. , Butylene group, pentylene group, hexylene group and the like.

In the present specification, the “C ₂ -C ₆ alkenyl group” refers to a linear or branched alkenyl group having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. Examples thereof include a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.

In the present specification, the “C ₂ -C ₆ alkynyl group” refers to a linear or branched alkynyl group having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, specifically ethynyl. Group, 1-propynyl group, 1-pentynyl group, 3-methyl-1-butynyl group, 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, the “C ₄ -C ₉ heteroaryl group” means a monocyclic or bicyclic carbon containing 1 to 3 of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. A heteroaryl group having 4 to 9 carbon atoms, preferably a monocyclic or bicyclic heteroaryl group having 4 to 9 carbon atoms containing 1 to 3 nitrogen atoms, specifically a thienyl group, furyl Group, pyrrolyl group, triazolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, isobenzofuryl group, indolizinyl group, isoindolyl group, indolyl group, indazolyl group, quinolyl group Group, isoquinolyl group, phthalazinyl group, naphthyridinyl group 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, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. Cyclohexyl group, cycloheptyl group, decalyl group and the like.

In the present specification, the “C ₃ -C ₁₀ cycloalkylene group” refers to a monocyclic or polycyclic divalent cycloalkylene group having 3 to 10 carbon atoms. Examples include butylene, cyclopentylene, cyclohexylene, cycloheptylene, and decalylene.

In the present specification, the “C ₃ -C ₁₀ heterocycloalkyl group” means a carbon containing 1 to 2 hetero atoms of the same or different types selected from an oxygen atom, a sulfur atom and a nitrogen atom in a ring other than the bonding site. Represents a cycloalkyl group having a number of 3 to 10, and examples thereof include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and a tetrahydropyranyl group.

In the present specification, the “C ₃ -C ₁₀ heterocycloalkylene group” includes at least one nitrogen atom in the ring, one of the nitrogen atoms having a bond, and further selected from an oxygen atom or a sulfur atom A divalent heterocycloalkylene group having 3 to 10 carbon atoms containing 0 to 2 of the same or different heteroatoms in the ring, and examples thereof include azetidinylene, pyrrolidinylene, and piperidinylene.

In the present specification, the “C ₄ -C ₈ cycloalkene ring” refers to a cycloalkene ring having 4 to 8 carbon atoms containing one carbon-carbon double bond, specifically, cyclopropene, cyclobutene, cyclopentene. , Cyclohexene, cycloheptene, cyclooctene and the like.

General formula (X ₂ ) in the present specification:

A divalent moiety of the group represented by

And represents a C ₃ -C ₁₀ cycloalkylene group.

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

Is

One of the divalent cycloalkylene groups represented by the formula (1) is bonded to the adjacent group represented by —N (R ₄ ) —.

General formula (X ₃ ) in the present specification:

A divalent moiety of the group represented by

And represents a C ₃ -C ₁₀ heterocycloalkylene group.

In the present specification, the general formula (X ₃ )

Is

One of the nitrogen atoms on the divalent heterocycloalkylene group represented by formula ( ₁ ) has a bond, the other is bonded to the alkylene group (— (CH ₂ ) _n —), and the substituent R _{5 is present} on the ring. It has shown that.

In the present invention, X represents the general formula (X ₁ ):
— (CH ₂ ) _m —N (R ₄ ) — (X ₁ )
In the group, the — (CH ₂ ) _m — moiety is bonded to the pyrrolopyrimidine, and the —N (R ₄ ) — moiety is bonded to the carbonyl group.

In the present invention, X represents the general formula (X ₂ ):

In the case of a group represented by

The moiety is attached to the pyrrolopyrimidine and the —N (R ₄ ) — moiety is attached to the carbonyl group.

In the present invention, X represents the general formula (X ₃ )

A — (CH ₂ ) _n — moiety of the group is bonded to pyrrolopyrimidine,

One of the nitrogen atoms contained in the moiety is bonded to the carbonyl group.

As _{R 1} in the formula (I), preferably a hydrogen atom, a halogen atom, a _{R 2} may be (preferably 1) having one good _C 1 -C ₆ alkyl group or _{R 2} may have a C ₂ -C ₆ alkynyl group, more preferably having one hydrogen atom or _{R 2} is a good _C 2 -C ₆ alkynyl group, particularly preferably having one hydrogen atom, the _{R 2} Or a pentynyl group which may have one R ₂ .

As _{R 2} in the general formula (I), preferably _{-OR x, -N (R x)} (R y), which may have a _{R 3 C} 3 _{-C 10} cycloalkyl group, a _{R 3} A C ₃ -C ₁₀ heterocycloalkyl group or a C ₆ -C ₁₂ aryl group optionally having R ₃ , more preferably —OR _x , —N (R _x ) (R _y ), R ₃ A C ₃ -C ₁₀ cycloalkyl group which may have an alkyl group or a C ₆ -C ₁₂ aryl group which may have an R ₃ , particularly preferably a cyclohexane which may have a hydroxyl group, an amino group or an amino group And a phenyl group which may have an amino group.

R ₃ in the general formula (I) is preferably —OR _x , —N (R _x ) (R _y ), —N (R _x ) C (═O) R _y or —C (═O) OR _x More preferably —N (R _x ) (R _y ).

R _x , R _y and R _z in the general formula (I) are preferably the same or different and are a hydrogen atom or a C ₁ -C ₆ alkyl group, and more preferably a hydrogen atom.

X in the general formula (I) is preferably a group represented by the above general formula (X ₃ ).

As m in the general formula (I), it is preferably 2.

N in the general formula (I) is preferably 0 to 1, and more preferably 0.

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

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

Y in the general formula (I) is preferably —C (R ₆ ) ═C (R ₇ ) (R ₈ ).

R ₆ , R ₇ and R ₈ in general 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, or a C ₁ -C ₆ alkyl. An aminomethyl group or a 1-pyrrolidinomethyl group which may be substituted with a group, more preferably a hydrogen atom. R ₅ and R ₆ may also form a C ₄ -C ₈ cycloalkene ring with the two carbon atoms to which they are attached.

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

In the present invention, in the general formula (I), R ₁ is a hydrogen atom or a C ₂ -C ₆ alkynyl group which may have R ₂ ;
R ₂ may have —OR _x , —N (R _x ) (R _y ), R ₃ (preferably an amino group) or a C ₃ -C ₁₀ cycloalkyl group or R ₃ (preferably an amino group) A C ₆ -C ₁₂ aryl group optionally having:
R _x and 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 general formula (X ₃ );
n is 0 to 1;
R ₅ is a C ₁ -C ₆ alkyl group optionally having a hydrogen atom or a hydroxy group;
Y is preferably a vinyl group or a salt thereof.

Specific preferred compounds of the present invention can be exemplified as follows.

N- (2- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl) acrylamide (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 (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 ( S) -1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidin-1-yl) prop-2-ene -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 N-((1S, 2R) -2- (4-amino-5- (quinoline-3-) Yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) cyclopentyl) acrylamide 1- (4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3- d] pyrimidin-7-yl) piperidin-1-yl) prop-2-en-1-one 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 (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 (R) -1- (2-((4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine- 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) azetidin-1-yl) prop-2-en-1-one (R) -1- (2-((4-amino-5- (quinoline-3) -Yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) azetidin-1-yl) prop-2-en-1-one 1- (3- (4-amino-5- ( Quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) propa 2-En-1-one 1-((2S, 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 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- (quinoline-) 3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl) -N-methylacrylamide (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 (R) -1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine -7-yl) pyrrolidin-1-yl) -4- (pyrrolidin-1-yl) but-2-en-1-one (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- (quinoline-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- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine -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) (cyclohexenyl) methanone (R) -1- (3- (4-amino-5- (quinoline-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-Amino-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-pyrrolo) [2,3-d] pyrimidin-7-yl) methyl) azetidin-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) azetidin-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) azetidin-1-yl) -4- (ethyl (methyl) amino) but-2-en-1-one 1- (3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d]
Pyrimidin-7-yl) azetidin-1-yl) -4- (diethylamino) but-2-en-1-one 1- (3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d]
Pyrimidin-7-yl) azetidin-1-yl) -4- (isopropyl (methyl) amino) but-2-en-1-one 1- (3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d]
Pyrimidin-7-yl) azetidin-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) pyrrolidine-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] pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one (R) -tert-butyl 4-((7- (1-acryloyl) Pyrrolidin-3-yl) -4-amino-5- (quinolin-3-yl) -7H- Rolo [2,3-d] pyrimidin-6-yl) ethynyl) piperidine-1-carboxylate (R) -1- (3- (4-amino-6- (piperidin-4-ylethynyl) -5- (quinoline) -3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one tert-butyl trans-4-((7-(( R) -1-acryloylpyrrolidin-3-yl) -4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethynyl) cyclohexyl carbamate 1- ( (R) -3- (4-Amino-6-((trans-4-aminocyclohexyl) ethynyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl Pylori N-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] 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-en-1-one ( R) -1- (3- (4-Amino-6- (3-hydroxy-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) 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 ) Prop-2-yn-1-one (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 (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- ( -Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) -4-hydroxy-4-methylpent-2-yne-1- ON (R, E) -1- (3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl)- 3-chloroprop-2-en-1-one (R, Z) -1- (3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-7 -Yl) pyrrolidin-1-yl) -3-chloroprop-2-en-1-one

Furthermore, those having strong enzyme inhibitory activity against EGFR (T790M / L858R) are preferred, and those having 1 nM or less are more preferred. In addition, those having strong enzyme inhibitory activity against EGFR (d746-750 / T790M) are preferred, and those having 1 nM or less are more preferred.

Next, a method for producing the compound according to the present invention will be described.

The compound (I) of the present invention can be produced, for example, 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, and P ₁ represents an amino-protecting group contained in X: X and Y are as defined above. ]

(Process 1)
This step is a method for producing a compound represented by the general formula (III) by reacting a compound represented by the general formula (II) with SEMCl (trimethylsilylethoxymethyl chloride) in the presence of a base.

In the general formula (II), the leaving group represented by L ₁ is a bromine atom or an iodine atom. The compound represented by general formula (II) can be manufactured according to a commercial item or a well-known method.

The SEMCl used in this step is usually equimolar to excess molar relative to 1 mol of the compound represented by the general formula (II). The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, dimethylformamide, N-methylpyrrolidone, or a mixed solvent thereof is preferable. .

Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butylate, etc. Inorganic bases can be used.

The amount of the base to be used is generally 1 mol to excess mol, preferably 1 to 3 mol, per 1 mol of the compound represented by the general formula (II).
The reaction temperature is generally −78 to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time is usually 5 minutes to 7 days, preferably 5 minutes to 24 hours.
The compound represented by the general formula (III) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.

(Process 2)
This step is a method for producing a compound represented by the general formula (IV) by reacting a compound represented by the general formula (III) with ammonia or a salt thereof.

The amount of ammonia or a salt thereof used in this step is usually equimolar to excess molar with respect to 1 mol of the compound represented by the general formula (III). The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, water, methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, Dimethyl sulfoxide or the like or a mixed solvent thereof is preferable.
The reaction temperature is usually 0 to 200 ° C., preferably room temperature to 150 ° C.
The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.
The compound represented by the general formula (IV) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.

(Process 3)
This step is a method for producing a compound represented by the structural formula (V) by coupling the compound represented by the general formula (IV) with 3-quinolineboronic acid. This step can be carried out according to a generally known method (for example, Chemical Reviews, Vol. 95, p. 2457, 1995), for example, in a solvent that does not adversely influence the reaction in the presence of a transition metal catalyst and a base. Can be implemented.

The amount of 3-quinolineboronic acid used can be 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the compound represented by the general formula (IV).

Examples of the transition metal catalyst include palladium catalysts (eg, palladium acetate, palladium chloride, tetrakistriphenylphosphine palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride), nickel catalysts (eg, , Nickel chloride, etc.) are used, and if necessary, ligands (eg, triphenylphosphine, tri-tert-butylphosphine, etc.) are added, and metal oxides (eg, copper oxide, silver oxide, etc.) are added. It may be used as a cocatalyst. The amount of transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, relative to 1 mol of the compound represented by the general formula (IV). The amount of the ligand used is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, based on 1 mol of the compound represented by the general formula (IV). ) Is usually 0.0001 to 4 mol, preferably 0.01 to 2 mol, relative to 1 mol of the compound represented by).

Examples of the base include organic amine compounds (eg, trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazapicyclo [5,4,0] undec-7-ene, pyridine, N, N-dimethylaniline). Etc.), alkali metal salts (eg, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (eg, Potassium hydride, sodium hydride, etc.), alkali metal alkoxides (eg, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), alkali metal disilazides (eg, lithium disilazide, sodium disidium) Disilazide, potassium disilazide and the like) and the like. Of these, alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate and potassium phosphate, alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide, and organic amine compounds such as triethylamine and diisopropylethylamine are suitable. is there. The amount of the base to be used is generally 0.1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (IV).

Any solvent may be used as long as it does not adversely affect the reaction. For example, hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (eg, chloroform, 1,2-dichloroethane, etc.) ), Nitrile solvents (eg, acetonitrile, etc.), ether solvents (eg, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (eg, methanol, ethanol, etc.), aprotic polar solvents (eg, Dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.), water or a mixture thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 20 to 150 ° C.

The compound represented by the structural formula (V) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.

(Process 4)
This step is a method for producing the compound represented by the structural formula (VI) from the compound represented by the structural formula (V) under acidic conditions.

Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, and tosylic acid. The amount of the acid used is preferably 1 to 100 mol with respect to 1 mol of the compound represented by the structural formula (V).

The solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohol solvents (for example, methanol), hydrocarbon solvents (for example, benzene, toluene, xylene, etc.), halogenated hydrocarbons. System solvents (eg, methylene chloride, chloroform, 1,2-dichloroethane, etc.), nitrile solvents (eg, acetonitrile, etc.), ether solvents (eg, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), aprotic A polar solvent (for example, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.) or a mixture thereof is used. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.

The compound represented by the structural formula (VI) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.

(Process 5)
This step is a method for producing a compound represented by the structural formula (VII) under basic conditions from a compound represented by the structural formula (VI) or a salt thereof.

Examples of the base include alkali metal salts such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide. The amount of the base used is preferably 1 to 100 mol with respect to 1 mol of the compound represented by the structural formula (VI).

The solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water, alcohol compounds (eg, methanol, etc.), ether compounds (eg, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, etc.), An aprotic polar solvent (for example, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.) or a mixture thereof is used. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 ° C. to room temperature.

The compound represented by the structural formula (VII) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like. It can be subjected to the next step without separation and purification.

(Step 6)
This step is an alkylation reaction between a compound represented by Structural Formula (VII) and a compound represented by General Formula (VIII) in the presence of a base, and a method for obtaining a compound represented by General Formula (IX) It is.

Examples of the leaving group represented by L ₂ in the general formula (VIII) include a chlorine atom, a bromine atom, an iodine atom, a methanesulfonic acid ester, a p-toluenesulfonic acid ester, and the like. It can be produced according to the method.

In the general formula (VIII), examples of the protecting group P ₁ include tert-butyloxycarbonyl and benzyloxycarbonyl groups.

The compound represented by the general formula (VIII) can be used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the structural formula (VII).

Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride, potassium hydride and other inorganic bases, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine. And organic amine compounds such as 4- (N, N-dimethylamino) pyridine, lutidine, collidine, etc., can be used in an amount of 1 to 100 mol, preferably 2 to 10 mol.

As the solvent, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile and the like can be used singly or in combination. . The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.

The compound represented by the general formula (IX) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.

(Step 7)
This step is a method for obtaining a compound represented by the general formula (X) by deprotecting the amino group protection of the compound represented by the general formula (IX). Examples of the deprotection method include generally known methods such as Protective Groups in Organic Synthesis, T. et al. W. It can be performed by the method described in Greene, John Wiley & Sons (1981) or a method analogous thereto.

When a tert-butyloxycarbonyl group is used as the protecting group, the amount of acid used is preferably 1 to 100 mol with respect to 1 mol of the compound represented by compound IX.

The solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohol compounds (eg, methanol), hydrocarbon compounds (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons Compounds (eg, methylene chloride, chloroform, 1,2-dichloroethane, etc.), nitrile compounds (eg, acetonitrile, etc.), ether compounds (eg, dimethoxyethane, tetrahydrofuran, etc.), aprotic polar solvents (eg, N, N—) Dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.) or a mixture thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 to 100 ° C., preferably 0 to 50 ° C.

The compound represented by the general formula (X) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.

(Step 8)
In this step, a compound represented by the formula (I ′) is produced by an amidation reaction of the compound represented by the general formula (X) and a carboxylic acid (Y—CO ₂ H) or an acid chloride (Y—COCl). It is a process to do.

The carboxylic acid and acid chloride used as raw materials can be produced according to commercially available products or known methods.

When a carboxylic acid is used as the amidating reagent, the carboxylic acid is used in an amount of 0.5 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of the compound represented by the general formula (X).

Examples of the condensing agent include diphenyl phosphate azide, N, N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3,5-triazine-2- Yl) -4-methylmorpholinium chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole, 2 Examples include -chloro-1,3-dimethylimidazolinium chloride, O- (7-azabenzotriazo-1-yl) -N, N, N ', N'-tetramethylhexauronium hexafluorophosphate, etc. .

Bases include, for example, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexa Examples thereof include organic bases such as methyl disilazide, potassium hexamethyl disilazide, and butyl lithium, or inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide N-methylpyrrolidinone, dimethyl sulfoxide, etc., or a mixed solvent thereof is preferred. The reaction temperature is usually −78 to 200 ° C., preferably 0 to 50 ° C. The reaction time is usually 1 minute to 3 days, preferably 1 minute to 10 hours. When acid chloride is used as the coupling reagent, the acid chloride is used in an amount of 0.5 to 5 mol, preferably 0.9 to 1.1 mol, per 1 mol of the compound represented by the general formula (X).

Bases include, for example, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexa Examples thereof include organic bases such as methyl disilazide, potassium hexamethyl disilazide, and butyl lithium, or inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, or the like A mixed solvent or the like is preferable.
The reaction temperature is usually −78 to 200 ° C., preferably −20 to 50 ° C.
The reaction time is usually 1 minute to 3 days, preferably 1 minute to 10 hours.
The compound represented by the general formula (I ′) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. it can.
The compound represented by the general formula (IX) used for the production of the compound (I) of the present invention can also be produced, for example, by Production Method 2.

Manufacturing method 2

[Wherein, L ₁ , X, and P ₁ are as defined above. ]
(Step 9)
In this method, the compound represented by the general formula (II) and the compound represented by the general formula (XI) are produced using the Mitsunobu reaction to produce the compound represented by the general formula (XII). This step can be carried out according to a generally known method (for example, Chemical Reviews, Vol. 109, p. 2551, 2009), for example, in a solvent that does not adversely affect the reaction in the presence of Mitsunobu reagent and phosphine reagent. Can be implemented. Usually, 1 to 10 mol, preferably 1 to 5 mol of the compound represented by the general formula (XI) is used per 1 mol of the compound represented by the general formula (II).
Examples of the Mitsunobu reagent include diethyl azodicarboxylate and diisopropyl azodicarboxylate.
Examples of the phosphine reagent include triphenylphosphine and tributyphosphine.

The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, toluene, benzenetetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, or a mixed solvent thereof Is preferred.
The reaction temperature is usually −78 to 200 ° C., preferably 0 to 50 ° C.
The reaction time is usually 5 minutes to 3 days, preferably 10 minutes to 10 hours.

The compound represented by the general formula (XII) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.

(Process 10)
This step can be performed by the same method as in the second step.

(Step 11)
This step can be performed by the same method as in the third step.

Production method 3

[Wherein, X, P ₁ , Y and R ₁ are as defined above. ]

(Step 12)
This step is a method of obtaining compound (XV) by halogenating compound (IX) with, for example, a halogenating agent (XIV). Here, W in the halogenating agent (XIV) is a chlorine atom, a bromine atom or an iodine atom. As the halogenation method, it can be produced by the method described in International Publication WO2006 / 102079 pamphlet or a method according to these methods.

(Step 13)
In this step, the compound represented by the general formula (XV) is converted into a generally known method (for example, Angew Chem Int Ed, Volume, 25, P 508, 1986, Chemical Reviews, Vol. 95, p. 2457, 1995, Chemical Reviews, Vol. 107, p. 874, 2007, etc.), and a method for producing a compound represented by the general formula (XVI) by a coupling reaction under a transition metal catalyst.

In the case of alkyl chain conversion, for example, a commercially available product or tetraalkyltin that can be produced according to a known method is used.

In the case of conversion to an aryl ring, heteroaryl ring, or alkenyl group, for example, a commercially available product or a boronic acid or a boronic acid ester that can be produced according to a known method is used.

In the case of conversion of an alkynyl chain, for example, a commercially available product or a substituted acetylene that can be produced according to a known method is used.

(Step 14)
This step can be performed by the same method as in the seventh step.

(Step 15) This step can be performed by the same method as in the eighth step.

In the above production methods 1 to 3, amino groups, imino groups, hydroxyl groups, carboxyl groups, carbonyl groups and amide groups, and functional groups having active protons such as indoles are protected at appropriate steps in each production method. The protecting group can be removed after introducing a protecting group into the functional group using a conventional reagent or according to a conventional method.

The “protecting group for amino group or imino group” is not particularly limited as long as it has the function. For example, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, Aralkyl groups such as p-nitrobenzyl group, benzhydryl group, trityl group and cumyl group; for example, lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, trifluoroacetyl group and trichloroacetyl group; Benzoyl group; for example, arylalkanoyl group such as phenylacetyl group and phenoxyacetyl group; for example, lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, tert-butoxycarbonyl group; Aralkyloxycarbonyl groups such as xyloxycarbonyl and phenethyloxycarbonyl groups; for example, lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; for example tetrahydropyranyl groups; for example trimethylsilylethoxymethyl groups; for example methylsulfonyl group, ethyl A lower alkylsulfonyl group such as a sulfonyl group, a tert-butylsulfonyl group, etc .; a lower alkylsulfinyl group such as a tert-butylsulfinyl group; an arylsulfonyl group such as a benzenesulfonyl group, a toluenesulfonyl group, etc., such as a phthalimide group, etc. Imido groups, in particular trifluoroacetyl group, acetyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, trimethylsilylethoxymethyl group, Mill group and the like.

The “hydroxyl-protecting group” is not particularly limited as long as it has the function, but for example, a lower alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group; A lower alkylsilyl group such as a butyldimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydropyranyl group; a trimethylsilylethoxymethyl group; a benzyl group, a p-methoxybenzyl Aralkyl groups such as a group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; for example, acyl groups such as formyl group, acetyl group, trifluoroacetyl group, etc. Methyl group, methoxymethyl group, tetrahy Ropiraniru group, trimethylsilylethoxymethyl group, tert- butyldimethylsilyl group, such as an acetyl group.

The “carboxyl-protecting group” is not particularly limited as long as it has the function, but for example, a lower alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group; Halo lower alkyl groups such as 1,2-trichloroethyl group; for example, lower alkenyl groups such as allyl group; for example, trimethylsilylethoxymethyl group; for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group, etc. And the like, and particularly preferred are methyl group, ethyl group, tert-butyl group, allyl group, benzyl group, p-methoxybenzyl group, trimethylsilylethoxymethyl group, and the like.

The “carbonyl-protecting group” is not particularly limited as long as it has the function, and examples thereof include acetals such as ethylene ketal, trimethylene ketal and dimethyl ketal, and ketal.

The method for removing the protecting group varies depending on the type of the protecting group and the stability of the target compound (I). For example, the method described in the literature [Protective Groups Inganic Synthesis, 3rd edition, T.W. W. According to TW Greene, John Wiley & Sons (1999)] or a method analogous thereto, for example, solvolysis using, for example, an acid or base, for example, 0.01 mole to large excess of acid, preferably tri Fluoroacetic acid, formic acid, hydrochloric acid, or the like, or a method in which an equimolar to large excess base, preferably potassium hydroxide, calcium hydroxide, or the like is allowed to act; chemical reduction using a metal hydride complex or the like, palladium-carbon catalyst, Raney nickel catalyst It is carried out by catalytic reduction using etc.

The compound of the present invention can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, preparative reverse phase high performance liquid chromatography, column chromatography, preparative thin layer chromatography and the like.

When the compound of the present invention has isomers such as optical isomers, stereoisomers, positional isomers, and rotational isomers, any isomers and mixtures are included in the compound of the present invention unless otherwise specified. For example, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from a racemate is also included in the compound of the present invention. Each of these isomers can be obtained as a single compound by synthetic methods and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).

When the compound of the present invention has a tautomer, any isomer is included in the compound of the present invention.

The salt of the compound of the present invention means a conventional salt used in the field of organic chemistry. For example, when it has a carboxyl group, it has a base addition salt or an amino group or a basic heterocyclic group in the carboxyl group. And acid addition salts of the amino group or basic heterocyclic group.

Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt and ethanolamine. And organic amine salts such as salts, diethanolamine salts, triethanolamine salts, procaine salts, and N, N′-dibenzylethylenediamine salts.

Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, acetate, formate, maleate, fumarate, tartrate, citric acid Organic salts such as salts, ascorbates and trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.

The compound of the present invention or a salt thereof may be in the form of a crystal, and it is included in the compound of the present invention or a salt thereof regardless of whether the crystal form is single or polymorphic. The crystal can be produced by crystallization by applying a crystallization method known per se. The compound of the present invention or a salt thereof may be a solvate (such as a hydrate) or a non-solvate, and both are included in the compound of the present invention or a salt thereof. A compound labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) is also encompassed 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 useful as an antitumor agent. In addition, it has an excellent selectivity for EGFR, and has the advantage of fewer side effects from other kinases. The target cancer is not particularly limited, but for example, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, uterus Cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, mesothelioma, etc., preferably head and neck cancer Stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, renal cancer, prostate cancer, particularly preferably lung cancer.

When the compound of the present invention or a salt thereof is used as a medicine, a pharmaceutical carrier can be blended as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Any of injections, suppositories, ointments, patches and the like may be used, and oral preparations are preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

As the pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, binders, disintegrants, lubricants, coloring agents in solid preparations, solvents in liquid preparations, dissolution aids, It is blended as a suspending agent, isotonic agent, buffer, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.

When preparing an oral solid preparation, an excipient, if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. are added to the compound of the present invention. Tablets, coated tablets, granules, powders, capsules and the like can be produced by the method.

Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid. Examples of the binder include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of the colorant include titanium oxide and iron oxide. Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.

When preparing an oral liquid preparation, an oral solution, syrup, elixir and the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention by conventional methods.

As the flavoring / flavoring agent, those mentioned above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin. If necessary, an enteric coating or a coating can be applied to the oral preparation by a known method for the purpose of sustaining the effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.

When preparing an injection, a pH adjuster, buffer, stabilizer, tonicity agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. Can be manufactured.

Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.

When preparing a suppository, a formulation carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and an interface such as Tween 80 (registered trademark) are added to the compound of the present invention as necessary. After adding an activator etc., it can manufacture by a conventional method.

When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method.

Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.

Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method.

As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane, or a foam sheet made of cotton, suf, or chemical fiber is suitable.

The amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the compound is to be applied, or its dosage form, but generally 0 for oral dosage forms per dosage unit form. .05 to 1000 mg, 0.01 to 500 mg for injections, and 1 to 1000 mg for suppositories.

Moreover, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally. The dose may be 0.05 to 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into 2 to 3 times a day.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

The various reagents used in the examples were commercially available unless otherwise specified. For silica gel column chromatography, Moripex Prefpack (registered trademark) SI, Biotage KP-Sil (registered trademark) Silica prepacked column, or Biotage HP-Sil (registered trademark) Silica prepacked column were used. Using. For basic silica gel column chromatography, a Prepack (registered trademark) NH manufactured by Moritex Corporation or a KP-NH (registered trademark) prepacked column manufactured by Biotage was used. For preparative thin layer chromatography, Kieselgel ™ 60F254, Art. 5744 or Wako NH2 silica gel 60F254 plates were used. The NMR spectrum was measured using an AL400 (400 MHz; JEOL), Mercury 400 (400 MHz; Agilent Technology) spectrometer, or an Inova 400 (400 MHz; Agilent Technology) spectrometer equipped with an OM NMR probe (Protasis). When tetramethylsilane was included in the heavy solvent, tetramethylsilane was used as an internal standard, and in other cases, measurement was performed using an NMR solvent as an internal standard, and all δ values were shown in ppm. The microwave reaction was performed using a DiscoverS class manufactured by CEM.

The LCMS spectrum was measured using ACQUITY SQD (quadrupole type) manufactured by Waters under the following conditions.
Column: YMC YMC-Triart C18, 2.0 × 50 mm, 1.9 μm
MS detection: ESI positive
UV detection: 254 and 210 nm
Column flow rate: 0.5 mL / min
Mobile phase: water / acetonitrile (0.1% formic acid)
Injection volume: 1 μL
Gradient (table 1)
Time (min) Water Acetonitrile
0 95 5
0.1 95 5
2.1 5 95
3.0 STOP

Moreover, reverse phase preparative HPLC purification was carried out under the following conditions using a preparative system manufactured by WATERS.
Column: YMC YMC-Actus Trial C18, 30 × 50 mm, 5 μm and YMC YMC-Actus Trial C18, 20 × 10 mm, 5 μm coupled UV detection: 254 nm
MS detection: ESI positive
Column flow rate: 25 mL / min
Mobile phase: water / acetonitrile (0.1% formic acid)
Injection volume: 0.1-0.5mL
The meanings of the abbreviations are shown below.
s: singlet d: doublet t: triplet q: quartet dd: double doublet dt: double triplet td: triple doublet tt: triple triplet ddd: double double doublet ddt: double double triplet dtd: double triple doublet tdd: triple double doublet m: Multiplet br: broad brs: broad singlet DMSO-d ₆ : deuterated dimethyl sulfoxide CDCl ₃ : deuterated chloroform CD ₃ OD: deuterated methanol THF: tetrahydrofuran DMF: N, N-dimethylformamide NMP: 1-methyl-2-pyrrolidinone DMSO: dimethyl sulfoxide TFA: trifluoroacetic acid SEMCl: 2-(trimethylsilyl) 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 monohydrate HATU: O- (7-azabenzotriazo-1-yl) -N, N, N ′ , N'-tetramethylhexauronium 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) acrylamide (Step 1)
4-Chloro-5-iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine

7.01 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine synthesized by the method described in the pamphlet of International Publication No. WO2005 / 042556 was dissolved in 125 ml of anhydrous THF, and the solution was heated to 0 ° C. After cooling, 4.02 g of 60% sodium hydride was added. After stirring for 20 minutes, 13.3 ml of SEMCl was added and stirred overnight at room temperature. After cooling to 0 ° C. again, water was added to stop the reaction, and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 7.28 g of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 410.0.

(Process 2)
5-Iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

200 mg of 4-chloro-5-iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine obtained in the above step 1 was dissolved in 2.0 ml of THF, and 28 After adding 2 ml of% ammonia water, the reaction solution was stirred in a microwave reactor at 105 ° C. for 1.5 hours. The product was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 192 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 391.0.

(Process 3)
5- (Quinolin-3-yl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine

820 mg of 5-iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine obtained in Step 2 above, 545 mg of 3-quinolineboronic acid, 1.37 g of cesium carbonate was dissolved in 15 ml of 1,4-dioxane and 1.5 ml of water, 163 mg of PdCl ₂ (dppf) CH ₂ Cl ₂ was added, and the atmosphere was purged with nitrogen. Chloroform and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 545 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 392.1.

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

4-N-quinolin-3-yl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine obtained in Step 3 above Hydrochloric acid / 1,4-dioxane (20 ml) was added, and the mixture was stirred at 75 ° C. overnight. The solvent of the obtained reaction mixture was distilled off under reduced pressure. To the obtained residue, 20 ml of THF was added, 4.0 ml of 5N-NaOH aqueous solution was added, and the mixture was stirred for 1 hour. Chloroform, water and a small amount of methanol were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product. Physical property value: m / z [M + H] ⁺ 262.0.

(Process 5)
tert-Butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethylcarbamate

131 mg of 5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine obtained in the above Step 4 was dissolved in 2.0 ml of DMF, cooled to 0 ° C. and then 60% hydrogenated. Sodium 60 mg was added. After stirring for 20 minutes, 1.0 ml of a DMF solution of 167 mg of tert-butyl 2-bromoethylcarbamate was added and stirred at 50 ° C. overnight. After cooling to 0 ° C. again, water was added to stop the reaction, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 89 mg of the colorless amorphous title compound.

(Step 6)
N- (2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl) acrylamide tert-butyl 2 obtained in step 5 above To 89 mg of-(4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethylcarbamate, 2.0 ml of 4N-hydrochloric acid / 1,4-dioxane was added. And stirred at room temperature for 2 hours. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by toluene azeotropy. A portion of 17 mg of the resulting crude product of 7- (2-aminoethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine was added to 1.0 ml of chloroform. 20 μl of triethylamine was added. After cooling to 0 ° C., 100 μl of chloroform in which 4.5 μl of acryl chloride was dissolved was added and stirred at room temperature for 30 minutes. After stopping the reaction with a saturated sodium hydrogen carbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol) to obtain 7.6 mg of the colorless amorphous title compound.

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) -tert-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 methanesulfonyl chloride were added at 0 ° C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous ammonium chloride solution and water, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.1 g of the title compound as a colorless oil. Physical property value: m / z [M + H] ⁺ 266.1.

(Process 2)
(S) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate

80 mg of 5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine obtained in Example 1 (Step 4) was dissolved in 2.0 ml of DMF, and cooled to 0 ° C. 52 mg of 60% sodium hydride was added. After stirring for 20 minutes, 1.0 ml of a DMF solution of 230 mg of the mesyl obtained in the above Step 1 was added and stirred overnight at 85 ° C. After cooling to 0 ° C. again, water was added to stop the reaction, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 89 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 431.2.

(Process 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) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-7- obtained in Step 2 above Yl) To 4.0 mg of pyrrolidine-1-carboxylate, 4.0 ml of 4N-hydrochloric acid / 1,4-dioxane was added and stirred at room temperature for 1 hour. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by toluene azeotropy. 10 mg of a portion of the obtained crude product of (S) -7- (pyrrolidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine To the mixture, 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 acryl chloride was dissolved was added and stirred at room temperature for 30 minutes. After stopping the reaction with a saturated sodium hydrogen carbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol) to obtain 2.0 mg of the title compound as a white solid.

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) -tert-butyl 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 methanesulfonyl chloride were added at 0 ° C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of the title compound as a colorless oil. Physical property value: m / z [M + H] ⁺ 266.1.

(Process 2)
(R) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate

80 mg of 5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine obtained in Example 1 (Step 4) was dissolved in 2.0 ml of DMF, and cooled to 0 ° C. 71 mg of 60% sodium hydride was added. After stirring for 20 minutes, 1.0 ml of a DMF solution of 310 mg of the mesyl obtained in the above Step 1 was added and stirred at 85 ° C. overnight. After cooling to 0 ° C. again, water was added to stop the reaction, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (developing solvent: ethyl acetate / methanol) to obtain 52 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 431.2.

(Process 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) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-7- obtained in Step 2 above Yl) To 52 mg of pyrrolidine-1-carboxylate, 4.0 ml of 4N-hydrochloric acid / 1,4-dioxane was added and stirred at room temperature for 1 hour. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by toluene azeotropy. 10 mg of a portion of the obtained crude product of (R) -7- (pyrrolidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine To the mixture, 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 acryl chloride was dissolved was added and stirred at room temperature for 30 minutes. After stopping the reaction with a saturated sodium hydrogen carbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol) to obtain 2.8 mg of the title compound as a white solid.

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 According to Example 2, by using (R)-(−)-N-Boc-3-piperidinol instead of (R)-(−)-N-Boc-3-pyrrolidinol, The title compound was obtained as a white solid.

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 According to Example 2, by using (S)-(−)-N-Boc-3-piperidinol instead of (R)-(−)-N-Boc-3-pyrrolidinol, The title compound was obtained as a white solid.

Example 6
N-((1S, 2R) -2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) cyclopentyl) acrylamide according to Example 2 , (1S, 2S) -trans-N-Boc-2-aminocyclopentanol was used instead of (R)-(−)-N-Boc-3-pyrrolidinol to give the title compound as a white solid It was.

Example 7
1- (4- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidin-1-yl) prop-2-en-1- ON (process 1)
tert-butyl 4- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidine-1-carboxylate

DIAD 1 was added to a 20 ml tetrahydrofuran 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. 0.09 ml was added and the reaction 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, and the resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 1.55 g of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 463.0.

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

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

(Process 3)
tert-Butyl 4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidine-1-carboxylate

18.8 mg of tert-butyl 4- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidine-1-carboxylate obtained in Step 2 above -11 mg of quinoline boronic acid and 42 mg of cesium carbonate were dissolved in 1 ml of 1,4-dioxane and 0.1 ml of water, added with 3.3 mg of PdCl ₂ (dppf) CH ₂ Cl ₂ , purged with nitrogen, and then microwave reactor And stirred at 100 ° C. for 1 hour. Chloroform and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 14.1 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 445.1.

(Process 4)
1- (4- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidin-1-yl) prop-2-en-1- ON According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethylcarbamate Instead, tert-butyl 4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidin-1- from step 3 above was used. The title compound was obtained as a white solid by using carboxylate.

Example 8
1- (3-((4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) pyrrolidin-1-yl) prop-2-ene 1-one According to Example 2, by using N-Boc-3-hydroxymethylpyrrolidine instead of (R)-(−)-N-Boc-3-pyrrolidinol, the title compound as a white solid was obtained. It was.

Example 9
(S) -1- (2-((4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) pyrrolidin-1-yl) propaprop -2-en-1-one According to Example 2, instead of (R)-(−)-N-Boc-3-pyrrolidinol, (S)-(−)-N-Boc-2-pyrrolidinemethanol was used. By use, the title compound was obtained as a white solid.

Example 10
(R) -1- (2-((4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) pyrrolidin-1-yl) propa -2-En-1-one According to Example 2, instead of (R)-(−)-N-Boc-3-pyrrolidinol, (R)-(+)-N-Boc-2-pyrrolidinemethanol was used. By use, the title compound was obtained as a white solid.

Example 11
(S) -1- (2-((4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) azetidin-1-yl) propaprop -2-en-1-one According to Example 2, by using (S) -N-Boc-2-azetidinemethanol instead of (R)-(−)-N-Boc-3-pyrrolidinol To give the title compound as a white solid.

Example 12
(R) -1- (2-((4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) azetidin-1-yl) prop -2-en-1-one According to Example 2, by using (R) -N-Boc-2-azetidinemethanol instead of (R)-(−)-N-Boc-3-pyrrolidinol To give the title compound as a white solid.

Example 13
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) prop-2-en-1- ON (process 1)
tert-Butyl 3- (4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate

To a solution of 1.00 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine, 930 mg of N-Boc-3-hydroxyazetidine, and 1.85 g of triphenylphosphine in a 40 ml tetrahydrofuran solution, DIAD 1. 41 ml was added and the reaction was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain 1.07 g of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 435.0.

(Process 2)
tert-Butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate

To 350 mg of tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate obtained in Step 1 above, tetrahydrofuran 2. 5 ml and 2.5 ml of 28% aqueous ammonia were added, and the reaction mixture was stirred at 100 ° C. for 1.5 hours in a microwave reactor. Chloroform and water were added, the organic layer was separated, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 340 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 416.0.

(Process 3)
tert-Butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate

Tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate 30 mg obtained in Step 2 above, 3-quinolineboronic Acid 15 mg and cesium carbonate 47 mg were dissolved in 1,4-dioxane 1 ml and water 0.1 ml, PdCl ₂ (dppf) CH ₂ Cl ₂ 6 mg was added, and the atmosphere was replaced with nitrogen. Stir for hours. Chloroform and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 15 mg of the title compound as a crude product. Physical property value: m / z [M + H] ⁺ 417.0.

(Process 4)
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) prop-2-en-1- On tert-butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate obtained in step 3 above To 15 mg, 2.0 ml of 4N-hydrochloric acid / 1,4-dioxane was added and stirred at room temperature for 1 hour. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by toluene azeotropy. The obtained crude product of 7- (azetidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine was added to 11 mg of chloroform, 2.0 ml of chloroform and triethylamine. 20 μl was added. After cooling to 0 ° C., 100 μl of chloroform in which 2.0 μl of acryl chloride was dissolved was added and stirred at room temperature for 30 minutes. After stopping the reaction with a saturated sodium hydrogen carbonate solution, the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol) to obtain 3.4 mg of the title compound as a white solid.

Example 14
1-((2S, 4R) -4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxymethyl) pyrrolidine -1-yl) prop-2-en-1-one (step 1)
(2S, 4S) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4-hydroxypyrrolidine-1-carboxylate 1-N-Boc- (2S, 4S) -4-hydroxy-2- 500 mg of (hydroxymethyl) -pyrrolidine was dissolved in 4.0 ml of DMF, and 164 mg of imidazole was added. After cooling to 0 ° C., 616 μl of tert-butylchlorodiphenylsilane was added and stirred for 1 hour. 82 mg of imidazole and 300 μl of tert-butylchlorodiphenylsilane were added and stirred at 0 ° C. for 2 hours. Ethyl acetate and saturated sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 555 mg of the title compound as a colorless oil.

(Process 2)
(2S, 4R) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) Pyrrolidine-1-carboxylate

(2S, 4S) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4-hydroxypyrrolidine-1-carboxylate 555 mg, 4-chloro-5-iodo-7H obtained in Step 1 above -To a solution of pyrrolo [2,3-d] pyrimidine (340 mg) and triphenylphosphine (638 mg) in tetrahydrofuran (4 ml) was added DIAD (0.4 ml), and the reaction solution was stirred overnight. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 346 mg of the title compound as a colorless oil.

(Process 3)
(2S, 4R) -tert-butyl 4- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-((tert-butyldiphenylsilyloxy) methyl) Pyrrolidine-1-carboxylate

(2S, 4R) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] obtained in Step 2 above. ] To pyrimidine-7-yl) pyrrolidine-1-carboxylate (346 mg) were added tetrahydrofuran (2 ml) and 28% aqueous ammonia (2 ml), and the reaction mixture was stirred at 100 ° C. for 1.5 hours in a microwave reactor. Chloroform and water were added, the organic layer was separated, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 336 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 698.2.

(Process 4)
(2S, 4R) -tert-butyl 4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-((tert-butyl Diphenylsilyloxy) methyl) pyrrolidine-1-carboxylate

(2S, 4R) -tert-butyl 4- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-(( tert-butyldiphenylsilyloxy) methyl) pyrrolidine-1-carboxylate 336 mg, 3-quinolineboronic acid 124 mg, cesium carbonate 45 mg dissolved in 1,4-dioxane 5 ml, water 0.5 ml, PdCl ₂ (dppf) CH After adding ₂ Cl ₂ 31 mg and purging with nitrogen, the mixture was stirred at 100 ° C. for 1 hour in a microwave reactor. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol) to obtain 180 mg of the title compound as a colorless oil.

(Process 5)
(2S, 4R) -tert-butyl 4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxymethyl) pyrrolidine -1-carboxylate

(2S, 4R) -tert-butyl 4- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl)-obtained in Step 4 above 25 mg of 2-((tert-butyldiphenylsilyloxy) methyl) pyrrolidine-1-carboxylate was dissolved in 1.0 ml of tetrahydrofuran, and 34 mg of silica gel-supported TBAF (˜1.5 mmol / g) was added and stirred overnight. An additional 30 mg of silica gel-supported TBAF (˜1.5 mmol / g) was added, and the mixture was further stirred for 3 days. The silica gel was filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol) to obtain 12 mg of the title compound as a white solid. Physical property value: 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- (hydroxymethyl) pyrrolidine -1-yl) prop-2-en-1-one According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2, (2S, 4R) -tert-butyl 4- (4-amino-5- (quinolin-3-yl) -7H obtained in Step 5 above instead of 3-d] pyrimidin-7-yl) ethylcarbamate Using -pyrrolo [2,3-d] pyrimidin-7-yl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate gave the title compound 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- (hydroxymethyl) pyrrolidine -1-yl) prop-2-en-1-one According to Example 14, instead of 1-N-Boc- (2S, 4S) -4-hydroxy-2- (hydroxymethyl) -pyrrolidine (1 The title compound was obtained as a white solid by using -N-Boc- (2R, 4S) -4-hydroxy-2- (hydroxymethyl) -pyrrolidine.

Example 16
N- (2- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl) -N-methylacrylamide (Step 1)
tert-Butyl 2- (4-Chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl (methyl) carbamate

To a 20 ml tetrahydrofuran solution of 500 mg of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine, 470 mg of 2- (N-Boc-methylamino) ethanol and 939 mg of triphenylphosphine, 0.7 ml of DIAD was added. In addition, the reaction was stirred for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 715 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 436.9.

(Process 2)
tert-Butyl 2- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl (methyl) carbamate

368 mg of tert-butyl 2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl (methyl) carbamate obtained in Step 1 above was added to 2 ml of tetrahydrofuran and 28 ml of 2 ml of% ammonia water was added, and the reaction solution was stirred at 100 ° C. for 1.5 hours in a microwave reactor. Chloroform and water were added, the organic layer was separated, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 308 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 418.3.

(Process 3)
tert-Butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl (methyl) carbamate

Tert-Butyl 2- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl (methyl) carbamate 101 mg, 3-quinolineboro, obtained in Step 2 above. 64 mg of nic acid and 234 mg of cesium carbonate were dissolved in 2 ml of 1,4-dioxane and 0.2 ml of water, 19.6 mg of PdCl ₂ (dppf) CH ₂ Cl ₂ was added, and the atmosphere was replaced with nitrogen. Stir for 1 hour. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 14 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 419.1.

(Process 4)
N- (2- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl) -N-methylacrylamide Example 1 (Step 6) In place of tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethylcarbamate Using the resulting tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl (methyl) carbamate 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 (R) -7- (Pyrrolidin-3-yl) -5- (quinolin-3-yl) obtained as an intermediate for the preparation of Example 3 (Step 3) ) -7H-pyrrolo [2,3-d] pyrimidin-4-amine 10 mg, 4- (dimethylamino) -2-butenoic acid hydrochloride 5.9 mg, HATU 14 mg dissolved in DMF 1.0 ml, DIEA 50 μl Added and stirred overnight. Chloroform and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC purification (water / acetonitrile (0.1% formic acid)) to obtain 1.7 mg of the colorless amorphous title compound.

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-butenoic acid hydrochloride

1.79 g of 4-bromocrotonic acid methyl ester was dissolved in 40 ml of tetrahydrofuran, 1.67 ml of pyrrolidine 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 solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the obtained product, 40 ml of 3N hydrochloric acid was added and heated to reflux at 100 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of 2-isopropanol and ethyl acetate to obtain 939 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 156.0.

(Process 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 According to Example 17, instead of 4- (dimethylamino) -2-butenoic acid hydrochloride, 4- (pyrrolidin-1-yl) -2 obtained above was used. -Butenoic acid By using hydrochloride, colorless amorphous title compound was obtained.

Example 19
(R)-(3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) (cyclopentenyl) methanone ( Step 1)
According to Example 17, 1-cyclopentenecarboxylic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title compound.

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)
According to Example 17, 3- (pyridin-2-yl) -acrylic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title 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)
According to Example 17, 3- (pyridin-3-yl) -acrylic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title compound.

Example 22
Implementation of (R)-(3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) (cyclohexenyl) methanone According to Example 17, 1-cyclohexenecarboxylic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title compound.

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 According to Example 17, a colorless amorphous title compound was obtained by using 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-phenyl Prop-2-en-1-one According to Example 17, the colorless amorphous title compound was obtained by using synthetic acid instead 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 According to Example 17, a colorless amorphous title compound was obtained by 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) azetidin-1-yl)- 4- (Dimethylamino) but-2-en-1-one (Step 1) (R) -tert-butyl 2-((methylsulfonyloxy) methyl) azetidine-1-carboxylate

300 mg of (R) -1- (tert-butoxycarbonyl) -2-azetidinemethanol was dissolved in 5 ml of chloroform, and 0.33 ml of triethylamine and 150 μl of methanesulfonyl chloride were added at 0 ° C. After stirring at room temperature for 1 hour, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 444 mg of the title compound as a colorless oil. Physical property value: m / z [M + H] ⁺ 266.0.

(Process 2)
(R) -tert-butyl 2-((4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) azetidine-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 2.0 ml of DMF, and cooled to 0 ° C. 30 mg of 60% sodium hydride was added. After stirring for 20 minutes, 3.0 ml of a DMF solution of 161 mg of the mesyl obtained in the above Step 1 was added and stirred at 80 ° C. for 3 hours. After cooling to 0 ° C. again, water was added to stop the reaction, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 94 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 431.2.

(Process 3)
(R) -1- (2-((4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) azetidin-1-yl)- 4- (Dimethylamino) but-2-en-1-one (R) -tert-butyl 2-((4-amino-5- (quinolin-3-yl) -7H-pyrrolo obtained in Step 2 above) To 94 mg of [2,3-d] pyrimidin-7-yl) methyl) azetidine-1-carboxylate was added 3.0 ml of 4N-hydrochloric acid / 1,4-dioxane, and the mixture was stirred at room temperature for 1.5 hours. The solvent of the obtained reaction mixture was distilled off under reduced pressure, followed by toluene azeotropy, and (R) -7- (azetidin-2-ylmethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3 A crude product of -d] pyrimidin-4-amine was obtained.

(Process 4)
According to Example 17, instead of (R) -7- (pyrrolidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine By using (R) -7- (azetidin-2-ylmethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine obtained in Step 3, A colorless amorphous title compound was obtained.

Example 27
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- (dimethylamino) buta -2-en-1-one Preparation intermediate 7- (azetidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3- d] 6.4 mg of a crude product of pyrimidine-4-amine, 3.7 mg of 4- (dimethylamino) -2-butenoic acid hydrochloride, and 8.7 mg of HATU are dissolved in 1.0 ml of DMF, add 20 μl of triethylamine, and stir for 15 minutes. did. Chloroform and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC purification (water / acetonitrile (0.1% formic acid)) to obtain 2.6 mg of the colorless amorphous title compound.

Example 28
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-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 4-bromocrotonic acid methyl ester was dissolved in 40 ml of tetrahydrofuran, 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 solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting product, 40 ml of 3N hydrochloric acid was added and heated to reflux at 100 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of 2-isopropanol and ethyl acetate to obtain 250 mg of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 144.0.

(Process 2)
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- (ethyl (methyl) Amino) but-2-en-1-one According to Example 27, instead of 4- (dimethylamino) -2-butenoic acid hydrochloride, 4- (ethyl (methyl) amino) obtained in Step 1 above was used. By using -2-butenoic acid hydrochloride, a colorless amorphous title compound was obtained.

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

4-Bromocrotonic acid methyl ester (1.79 g) was dissolved in tetrahydrofuran (40 ml), diethylamine (2.10 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. Diethyl ether and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting product, 40 ml of 3N hydrochloric acid was added and heated to reflux at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of 2-isopropanol and ethyl acetate to obtain 1.16 g of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 158.0.

(Process 2)
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- (diethylamino) buta 2-en-1-one According to Example 27, instead of 4- (dimethylamino) -2-butenoic acid hydrochloride, 4- (diethylamino) -2-butenoic acid hydrochloride obtained in Step 1 above was used. By using this, a colorless amorphous title compound was obtained.

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

1.79 g of 4-bromocrotonic acid methyl ester was dissolved in 40 ml of tetrahydrofuran, 2.08 ml of isopropylmethylamine 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 solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting product, 40 ml of 3N hydrochloric acid was added and heated to reflux at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of 2-isopropanol and ethyl acetate to obtain 1.33 g of the title compound as a white solid. Physical property value: m / z [M + H] ⁺ 158.1.

(Process 2)
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- (isopropyl (methyl) Amino) but-2-en-1-one According to Example 27, instead of 4- (dimethylamino) -2-butenoic acid hydrochloride, 4- (isopropyl (methyl) amino) obtained in Step 1 above By using -2-butenoic acid hydrochloride, a colorless amorphous title compound was obtained.

Example 31
1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- (pyrrolidin-1- Yl) but-2-en-1-one According to Example 27, instead of 4- (dimethylamino) -2-butenoic acid hydrochloride, 4- (pyrrolidine-) obtained in Example 18 (Step 1) was used. By using 1-yl) -2-butenoic acid hydrochloride, the colorless amorphous title compound was obtained.

Example 32
(R) -1- (3- (4-Amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) Propa-2-en-1-one (Step 1)
(R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate

Production intermediate (R) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-obtained in Example 3 (Step 2) 7-yl) pyrrolidine-1-carboxylate (86 mg) was dissolved in DM2.0 ml, N-bromosuccinimide (39 mg) was added, and the mixture was stirred for 15 minutes under light shielding. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 74 mg of the title compound as a white solid substance. Physical property value: m / z [M + H] ⁺ 509.0, 511.0.

(Process 2)
(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 According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine Instead of (-7-yl) ethylcarbamate, the (R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo obtained in Step 1 above was used. By using 2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate, 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) pyrrolidin-1-yl) Propa-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) pyrrolidin-1-yl) Prop-2-en-1-one

Production intermediate (R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-] obtained in Example 32 (Step 1) d] 34 mg of pyrimidine-7-yl) pyrrolidine-1-carboxylate was dissolved in 1.0 ml of DMF, 37 μl of tetramethyltin and 5.5 mg of PdCl ₂ (dppf) CH ₂ Cl ₂ were added, and the mixture was stirred at 135 ° C. for 2 hours. . Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC purification (water / acetonitrile (0.1% formic acid)) to obtain 10 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 445.1.

(Process 2)
(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 According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine Instead of -7-yl) ethylcarbamate, (R) -1- (3- (4-amino-6-methyl-5- (quinolin-3-yl) -7H-pyrrolo [ The title compound was obtained as a white solid by using 2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one.

Example 34
(R) -1- (3- (4-Amino-6- (phenylethynyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1 -Il) prop-2-en-1-one (step 1)
(R) -tert-butyl 3- (4-amino-6- (phenylethynyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1 -Carboxylate

Production intermediate (R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-] obtained in Example 32 (Step 1) d] A suspension of 50 mg of pyrimidin-7-yl) pyrrolidine-1-carboxylate, 16 μl of phenylacetylene, 2.8 mg of copper (I) iodide in 2.0 ml of tetrahydrofuran and 0.2 ml of triethylamine was prepared to prepare PdCl ₂ (dppf ) 5.5 mg of CH ₂ Cl ₂ was added and stirred overnight at 100 ° C. under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC purification (water / acetonitrile (0.1% formic acid)) to obtain 13 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 531.3.

(Process 2)
(R) -1- (3- (4-Amino-6- (phenylethynyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1 -Yl) prop-2-en-1-one According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3- d] Instead of pyrimidin-7-yl) ethylcarbamate, (R) -tert-butyl 3- (4-amino-6- (phenylethynyl) -5- (quinolin-3-yl) obtained in Step 1 above ) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate was used to give the title compound as a white solid.

Example 35
(R) -1- (3- (4-Amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) Propa-2-en-1-one (Step 1)
(R) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -6-((trimethylsilyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine -1-carboxylate

Production intermediate (R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-] obtained in Example 32 (Step 1) d] pyrimidine-7-yl) pyrrolidine-1-carboxylate 68 mg, trimethylsilylacetylene 0.2 ml, copper (I) iodide 3.8 mg in tetrahydrofuran 2.0 ml, triethylamine 0.2 ml in suspension to prepare PdCl ₂ (Dppf) 10.9 mg of 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 solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 26 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 527.2.

(Process 2)
(R) -tert-butyl 3- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate

(R) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -6-((trimethylsilyl) ethynyl) -7H-pyrrolo [2,3-d] obtained in Step 1 above) 2 ml of a 2% potassium hydroxide methanol solution was added to 26 mg of pyrimidine-7-yl) pyrrolidine-1-carboxylate and stirred for 10 minutes. Chloroform and saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a crude product. Physical property value: m / z [M + H] ⁺ 452.2.

(Process 3)
(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 According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine Instead of -7-yl) ethylcarbamate, (R) -tert-butyl 3- (4-amino-6-ethynyl-5- (quinolin-3-yl) -7H-pyrrolo obtained in Step 2 above [ By using 2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate, the title compound was obtained as a white solid.

Example 36
(R) -1- (3- (4-Amino-5- (quinolin-3-yl) -6-((tetrahydro-2H-pyran-4-yl) ethynyl) -7H-pyrrolo [2,3-d Pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one (Step 1)
(R) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -6-((tetrahydro-2H-pyran-4-yl) ethynyl) -7H-pyrrolo [2,3-d ] Pyrimidin-7-yl) pyrrolidine-1-carboxylate

Production intermediate (R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-] obtained in Example 32 (Step 1) 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 were mixed in 4 ml of acetonitrile, 1 ml of diethylamine and 2.0 mg of copper (I) iodide were added with stirring at room temperature. After the mixture was stirred at 80 ° C. for 2 hours, the reaction solution was allowed to cool to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title compound.

(Process 2)
(R) -7- (Pyrrolidin-3-yl) -5- (quinolin-3-yl) -6-((tetrahydro-2H-pyran-4-yl) ethynyl) -7H-pyrrolo [2,3-d ] Pyrimidin-4-amine (R) -tert-butyl 3- (4-amino-5- (quinolin-3-yl) -6-((tetrahydro-2H-pyran-4-yl) obtained in Step 1 above ) Ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate crude product in 4 ml of acetonitrile was added 58.5 μl of methanesulfonic acid at room temperature, then 30 Stir for minutes. The reaction solution was neutralized by adding 0.9 ml of 5M aqueous sodium hydroxide solution, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound.

(Process 3)
(R) -1- (3- (4-Amino-5- (quinolin-3-yl) -6-((tetrahydro-2H-pyran-4-yl) ethynyl) -7H-pyrrolo [2,3-d ] Pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one (R) -7- (Pyrrolidin-3-yl) -5- (quinoline-3-) obtained in Step 2 above Yl) -6-((tetrahydro-2H-pyran-4-yl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine in a 5 ml chloroform solution with 8.4 μl triethylamine and 4.9 μl of acrylic chloride was added at room temperature. The mixture was stirred at room temperature for 10 minutes, poured into a saturated aqueous ammonium chloride solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer silica gel chromatography (developing solution: ethyl acetate / methanol = 6/1) to give the title compound as a pale yellow solid. 4 mg was obtained.

Example 37
(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 In the same manner as in Example 35, 1,1-dimethylpropargylamine was used instead of 4-ethynyltetrahydro-2H-pyran. Used to give the title compound as a pale yellow solid.

Example 38
(R) -tert-butyl 4-((7- (1-acryloylpyrrolidin-3-yl) -4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine- 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

Production intermediate (R) -tert-butyl 3- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-] obtained in Example 32 (Step 1) d] To a solution of 533.9 mg of pyrimidine-7-yl) pyrrolidine-1-carboxylate in 4 ml of methanol was added 5 ml of 4N hydrochloric acid 1,4-dioxane solution at room temperature, and the mixture was stirred at 40 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 1 ml of methanol, added to a saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 423 mg of the title compound as a pale yellow solid.

(Process 2)
(R) -tert-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 obtained in (Step 1) above 2,3-d] pyrimidin-4-amine (41.2 mg), tert-butyl 4-ethynylpiperidine-1-carboxylate (83.8 mg), and Pd (PPh ₃ ) ₂ Cl _{2 (} 10.9 mg) were mixed in acetonitrile (5 ml). 1 ml of diethylamine and 1.7 mg of copper (I) iodide were added with stirring at room temperature. After the mixture was stirred at 80 ° C. for 2 hours, the reaction solution was allowed to cool 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 concentrated under reduced pressure to give the crude title compound.

(Process 3)
(R) -tert-butyl 4-((7- (1-acryloylpyrrolidin-3-yl) -4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine- 6-yl) ethynyl) piperidine-1-carboxylate (R) -tert-butyl 4-((4-amino-7- (pyrrolidin-3-yl) -5- (quinoline) obtained in (Step 2) above The crude product of -3-yl) -7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethynyl) piperidine-1-carboxylate is dissolved in 4 ml of chloroform, 14.0 μl of triethylamine and 10. 2 μl was added at room temperature. After stirring the mixture at room temperature for 10 minutes, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution: ethyl acetate / methanol) to obtain 45.8 mg of the title compound as a pale yellow solid.

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) -tert-butyl 4-((7- (1-acryloylpyrrolidin-3-yl) -4-amino- obtained in Example 38 5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethynyl) piperidine-1-carboxylate 35.0 mg in acetonitrile 3 ml at room temperature with methanesulfonic acid 38. After adding 5 μl, the mixture was stirred at 40 ° C. for 15 minutes. The reaction solution was allowed to cool to room temperature, neutralized by adding 118.5 ml of 5M aqueous sodium hydroxide solution, poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 30.2 mg of the title compound as a pale yellow solid.

Example 40
tert-butyl trans-4-((7-((R) -1-acryloylpyrrolidin-3-yl) -4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] Pyrimidin-6-yl) ethynyl) cyclohexyl carbamate Using the same procedure as in Example 38, using tert-butyl trans-4-ethynylcyclohexyl carbamate instead of tert-butyl 4-ethynylpiperidine-1-carboxylate The title compound was obtained as a yellow solid.

Example 41
1-((R) -3- (4-amino-6-((trans-4-aminocyclohexyl) ethynyl) -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-acryloylpyrrolidin-3- Yl) -4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethynyl) piperidine-1-carboxylate instead of obtained in Example 40 Tert-butyl trans-4-((7-((R) -1-acryloylpyrrolidin-3-yl) -4-amino-5 · BR> | (quinolin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-6-yl) With sulfonyl) cyclohexyl carbamate, the title compound was 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] pyrimidine-7- Yl) pyrrolidin-1-yl) prop-2-en-1-one Using a procedure similar to Example 38, substituting 1-ethynylcyclohexaneamine for tert-butyl 4-ethynylpiperidine-1-carboxylate To give the title compound as a pale yellow solid.

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 Using a procedure similar to that in Example 38, substituting 1-ethynylcyclohexanol for tert-butyl 4-ethynylpiperidine-1-carboxylate To give the title compound as a pale yellow solid.

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 a procedure similar to that in Example 38, instead of tert-butyl 4-ethynylpiperidine-1-carboxylate, 3-methyl- The title compound was obtained as a pale yellow solid using 1-butyn-3-ol.

Example 45
(R) -1- (3- (4-Amino-6-fluoro-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) Propa-2-en-1-one (Step 1)
(R) -tert-butyl 3- (4-((dimethylamino) methyleneamino) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1 -Carboxylate

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

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

(R) -tert-butyl 3- (4-((dimethylamino) methyleneamino) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine obtained in (Step 1) -7-yl) pyrrolidine-1-carboxylate (155 mg) was dissolved in DMF (4.0 ml), N-bromosuccinimide (56 mg) was added, and the mixture was stirred for 45 minutes under light shielding. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to obtain 138 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 564.1, 566.1.

(Process 3)
(R) -tert-butyl 3- (4-amino-6-fluoro-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate

(R) -tert-butyl 3- (6-bromo-4-((dimethylamino) methyleneamino) -5- (quinolin-3-yl) -7H-pyrrolo [2,3] obtained in (Step 2) -D] Pyrimidin-7-yl) pyrrolidine-1-carboxylate (100 mg) was dissolved in 3.0 ml of THF under a nitrogen atmosphere, cooled to -78 ° C., and 178 μl of 1.59 M n-butyllithium was added dropwise. After stirring the reaction solution for 10 minutes, 1.0 ml of a THF solution containing 142 mg of N-fluorobenzenesulfonimide was added. After stirring the reaction solution for 30 minutes, ethyl acetate and water were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue was added 2.0M ammonia methanol solution, and the mixture was stirred at 80 ° C. for 1 hour after sealing. The obtained mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative HPLC purification (water / acetonitrile (0.1% formic acid)) to obtain 24 mg of the colorless amorphous title compound. Physical property value: m / z [M + H] ⁺ 449.1.

(Process 4)
(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 According to Example 1 (Step 6), tert-butyl 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine Instead of (-7-yl) ethylcarbamate, the (R) -tert-butyl 3- (4-amino-6-fluoro-5- (quinolin-3-yl) -7H-pyrrolo obtained in Step 3 above was used. By using 2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate, 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- In-1-on (process 1)
The colorless amorphous title compound was obtained according to Example 17 by using propionic acid instead of 4- (dimethylamino) -2-butenoic acid hydrochloride.

Example 47
(R) -1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) but-2- In-1-on (process 1)
According to Example 17, 2-butinoic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title compound.

Example 48
(R) -1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) -4-hydroxy But-2-yne-1-one (Step 1)
According to Example 17, 4-hydroxy-2-butynoic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title compound.

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)
According to Example 17, 4-hydroxy-4-methyl-2-pentynoic acid was used in place of 4- (dimethylamino) -2-butenoic acid hydrochloride to obtain a colorless amorphous title compound.

Example 50 (R, E) -1- (3- (4-Amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl ) -3-Chloroprop-2-en-1-one (Step 1)
(R) -7- (Pyrrolidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-4-obtained in Example 3 (Step 3) 89.6 mg of WSC and 65.7 μl of triethylamine were added to a suspension of 92.1 ml of amine in 102.1 mg of chloroform at room temperature, and 36.4 mg of trans-3-chloroacrylic acid was added thereto, followed by stirring at room temperature for 15 minutes.

The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound as a colorless solid.

Example 51 (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-one (Step 1)
(R) -7- (Pyrrolidin-3-yl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine-4-obtained in Example 3 (Step 3) To a suspension of amine 254.0 mg in chloroform 20 ml, WSC 245.6 mg and triethylamine 180.0 μl were added at room temperature, cis-3-chloroacrylic acid 146.5 mg was added, and the mixture was stirred at room temperature for 90 minutes.

The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound as a pale yellow solid.

Comparative Example 1
(R) -1- (3- (4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-ene -1-On

The title compound was obtained by synthesis according to the method described in Patent Document 1.

Tables 1 to 27 show chemical structural formulas and physical property values of the compounds of Examples 1 to 51.

 

Test Examples The example compounds of the present invention were evaluated using the following test methods.

Test Example 1 Measurement of Various EGFR Kinase Activity Inhibitory Actions (In Vitro) 1) Measurement of EGFR (T790M / L858R) Kinase Inhibitory Activity The inhibitory activities of Example compounds on the EGFR (T790M / L858R) kinase activity were measured.

The material was a biotinylated amino acid described in reference to Caliper Life Science LabChip (registered trademark) series reagent FL-Peptide 22 (biotin-EEPLYWSFPAKKK) as a substrate peptide, and EGFR (T790M / L858R) Purified recombinant human EGFR (T790M / L858R) protein from Carna Biosciences was purchased.

In the measurement method, the example compounds were serially diluted with dimethyl sulfoxide (DMSO). Next, in the buffer for kinase reaction (Karna Biosciences), EGFR (T790M / L858R) protein, substrate peptide (final concentration is 250 nM), magnesium chloride (final concentration is 10 mM), manganese chloride (final concentration is 10 mM), ATP (final concentration is 1 uM) and DMSO solution of the example compound (final concentration of DMSO is 5%), and incubated at 25 ° C. for 120 minutes to perform a kinase reaction. The reaction was stopped by adding EDTA to a final concentration of 40 mM, and a detection solution containing europium (Eu) -labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added, It was allowed to stand at room temperature for 2 hours or more. Finally, the amount of fluorescence when irradiated with excitation light with a wavelength of 337 nm was measured with PHERAstar FS (BMG LABTECH) at two wavelengths of 620 nm and 665 nm. The amount of phosphorylation reaction was determined from the fluorescence amount ratio of the two wavelengths, and an IC50 value (nM), which is a compound concentration capable of suppressing the phosphorylation reaction by 50%, was obtained.

2) Measurement of EGFR (d746-750 / T790M) kinase inhibitory activity The inhibitory activity of Example compounds on EGFR (d746-750 / T790M) kinase activity was measured.

As the material, purified recombinant human EGFR (d746-750 / T790M) protein from Carna Biosciences Inc. was purchased as EGFR (d746-750 / T790M). The final concentration of ATP was 1.5 uM. Other than that, IC50 values (nM) were obtained by the same materials and measurement methods as in the measurement of EGFR (T790M / L858R) kinase inhibitory activity.

3) Measurement of EGFR (L858R) kinase inhibitory activity The inhibitory activity of Example compounds on EGFR (L858R) kinase activity was measured.

As the material, purified recombinant human EGFR (L858R) protein from Carna Biosciences Inc. was purchased as EGFR (L858R). The final concentration of ATP was 4 uM. Other than that, IC50 values (nM) were obtained by the same materials and measurement methods as in the measurement of EGFR (T790M / L858R) kinase inhibitory activity.

4) Measurement of EGFR (d746-750) kinase inhibitory activity The inhibitory activity of the example compounds on EGFR (d746-750) kinase activity was measured.

As the material, purified recombinant human EGFR (d746-750) protein from Carna Biosciences Inc. was purchased as EGFR (d746-750). The final concentration of ATP was 5 μM. The incubation for the kinase reaction was 90 minutes. Other than that, IC50 values (nM) were obtained by the same materials and measurement methods as in the measurement of EGFR (T790M / L858R) kinase inhibitory activity.

5) EGFR (WT)
The inhibitory activity on the EGFR (WT) kinase activity of the Example compounds was measured.

The material is human EGFR (WT) in which FLAG (WT) is fused with a FLAG tag at the N-terminal, and the cytoplasmic domain of human EGFR (WT) is expressed in insect cells Sf9 by a baculovirus expression system, and anti-FLAG antibody agarose (Sigma Aldrich) ) Was used. The final concentration of the substrate peptide was 500 nM, and the final concentration of ATP was 4.7 uM. Other than that, IC50 values (nM) were obtained by the same materials and measurement methods as in the measurement of EGFR (T790M / L858R) kinase inhibitory activity.

These results are shown in Table 28.

Example compounds were confirmed to have potent inhibitory activity not only against EGFR (L858R) and EGFR (d746-750), but also against EGFR (T790M / L858R) and EGFR (d746-750 / T790M). . Moreover, compared with these, it was confirmed that EGFR (WT) has weak inhibitory activity.

Test Example 2 Growth Inhibitory Activity Measurement Test for Wild Type and Mutant EGFR-expressing Cell Lines (In Vitro)
1) NCI-H1975 cell, a lung adenocarcinoma cell line expressing EGFR (T790M / L858R), 2) HCC827 cell, a lung adenocarcinoma cell line expressing EGFR (d746-750), 3) A431 cells, which are human epithelioid cancer cell lines expressing EGFR (WT), were each suspended in a medium recommended by ATCC. The cell suspension was seeded in each well of a 384 well flat bottom microplate or a 96 well flat bottom plate and cultured at 37 ° C. in an incubator containing 5% carbon dioxide gas for 1 day. The compound of the present invention and the comparative compound were dissolved in DMSO, and the test compound was diluted with DMSO to a concentration 200 times the final concentration. A DMSO solution of the test compound is diluted with the medium used for suspending each cell, and this is added to each well of the cell culture plate so that the final concentration of DMSO is 0.5%. For 3 days at 37 ° C. The number of cells at the start of culture and after culture was measured using Cell titergro (manufactured by Promega) based on the protocol recommended by Promega. The growth inhibition rate was calculated from the following formula, and the concentration of the test compound that inhibited 50% (GI50 (nM)) was determined.

Growth inhibition rate (%) = (C−T) / (C−C0) X 100
T: Luminescence intensity of well to which test compound was added C: Luminescence intensity of well to which test compound was not added C0: Luminescence intensity of well measured before addition of test compound Table 29 shows the results.

Example compounds were confirmed to have a strong growth inhibitory effect not only on EGFR (d746-750) -expressing cells but also on EGFR (T790M / L858R) -expressing cells. Moreover, compared with these, it was confirmed that the growth inhibitory effect is weak with respect to the EGFR (WT) expression cell.

Claims (11)

1. The following general formula (I)
   

   

   (Where
   R ₁ represents a hydrogen atom, a halogen atom, which may have a _{R 2 C} 1 -C ₆ alkyl group may have a may have a _{R 2 C} 2 -C ₆ alkenyl group or _{R 2} A C ₂ -C ₆ alkynyl group;
   R _{2 is, -OR x, -N (R x} ) (R y), which may have a _{R 3 C 3 -C 10} cycloalkyl group which may have a _{R 3 C 3 -C 10} heteroaryl cycloalkyl group, which may have a good _C 6 _{-C 12} aryl group or _{R 3} have a _{R 3 C} 4 -C ₉ heteroaryl group;
   R ₃ represents —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 each is a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₃ -C ₁₀ cycloalkyl group;
   X is
   General formula (X ₁ ):
   — (CH ₂ ) _m —N (R ₄ ) — (X ₁ )
   A group represented by
   General formula (X ₂ ):
   

   

   A group represented by (where
   

   

   Represents a C ₃ -C ₁₀ cycloalkylene group. )
   Or general formula (X ₃ )
   

   

   A group represented by (where
   

   

   Contains at least one nitrogen atom in the ring, one of the nitrogen atoms has a bond, and further contains 0 to 2 hetero or hetero atoms selected from oxygen or sulfur atoms in the ring. And a divalent heterocycloalkylene group having 3 to 10 carbon atoms. )
   Is;
   m is 1 to 3;
   n is 0-2;
   R ₄ is a hydrogen atom or a C ₁ -C ₆ alkyl group;
   R ₅ is a C ₁ -C ₆ alkyl group optionally having a hydrogen atom or a hydroxy group;
   Y is
   

   

    
   Is;
   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 -C ₁₂ aryl group, a C ₄ -C ₉ heteroaryl group, a C _1- An aminomethyl group or a 1-pyrrolidinomethyl group optionally substituted by a C ₆ alkyl group, and R ₆ and R ₇ together with the two carbon atoms to which they are attached, a C ₄ -C ₈ cycloalkene ring; May form;
   R ₉ is a C ₁ -C ₆ alkyl group which may have a hydrogen atom or a hydroxy group. Or a salt thereof.
2. R ₁ is a hydrogen atom, a halogen atom, which may have a good _C 1 -C ₆ alkyl group or _{R 2} may have a _{R 2 C} 2 -C ₆ alkynyl group;
   R _{2 is, -OR x, -N (R x} ) (R y), which may have a _{R 3 C 3 -C 10} cycloalkyl group, an _C 3 _-C have a _{R 3 10} heteroatoms A cycloalkyl group or a C ₆ -C ₁₂ aryl group optionally having R ₃ ;
   R ₃ is —OR _x , —N (R _x ) (R _y ), —N (R _x ) C (═O) OR _y or —C (═O) OR _x ;
   R _x and 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 general formula (X ₁ ), a group represented by the general formula (X ₂ ), or a group represented by the general formula (X ₃ );
   m is 2;
   n is 0 to 1;
   R ₄ is a hydrogen atom or a C ₁ -C ₆ alkyl group;
   R ₅ is a C ₁ -C ₆ alkyl group optionally having a hydrogen atom or a hydroxy group;
   Y is
   

   

   
   Is;
   R ₆ , R ₇ and R ₈ may be the same or different and may be substituted with a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₄ -C ₉ heteroaryl group, or a C ₁ -C ₆ alkyl group. An aminomethyl group or a 1-pyrrolidinomethyl group, and R ₆ and R ₇ together with the two carbon atoms to which they are attached may form a C ₄ -C ₈ cycloalkene ring;
   The compound or a salt thereof according to claim 1, wherein R ₉ is a C ₁ -C ₆ alkyl group which may have a hydrogen atom or a hydroxy group.
3. R ₁ is a hydrogen atom or a C ₂ -C ₆ alkynyl group optionally having R ₂ ;
   R ₂ is a hydroxyl group, an amino group, a C ₃ -C ₁₀ cycloalkyl group or a C ₆ -C ₁₂ aryl group which may have an amino group;
   X is a group represented by the general formula (X ₃ );
   n is 0;
   R ₅ is a C ₁ -C ₆ alkyl group optionally having a hydrogen atom or a hydroxy group;
   The compound or salt thereof according to claim 1 or 2, wherein Y is a vinyl group.
4. R ₁ is a hydrogen atom, be a good pentynyl group which may have a good ethynyl group, or R ₂ may have a R _2;
   R ₂ is a hydroxyl group, an amino group, a cyclohexane group that may have an amino group, or a phenyl group that may have an amino group;
   X is a group represented by the general formula (X ₃ );
   n is 0;
   R ₄ is a hydrogen atom or a hydroxymethyl group;
   The compound or a salt thereof according to claim 1, wherein Y is a vinyl group.
5. The compound or a salt thereof according to any one of claims 1 to 4, wherein the compound is selected from the following group of compounds.
   (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) -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- (phenylethynyl) -5- (quinoline-) 3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) propa 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-6- (3-amino-3-methylbut-1-ynyl) -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 -6-((1-aminocyclohexyl) ethynyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-ene -1-one (R) -1- (3- (4-amino-6- (3-hydroxy-3-methylbuta) 1-ynyl) -5- (quinolin-3-yl)-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) prop-2-en-1-one
6. An EGFR inhibitor comprising the compound according to any one of claims 1 to 5 or a salt thereof as an active ingredient.
7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a salt thereof.
8. An antitumor agent comprising the compound or salt thereof according to any one of claims 1 to 5 as an active ingredient.
9. A method for preventing or treating cancer comprising the step of administering to a mammal a prophylactic or therapeutically effective amount of the compound or salt thereof according to any one of claims 1 to 5 for cancer.
10. Use of the compound or a salt thereof according to any one of claims 1 to 5 for producing a preventive or therapeutic agent for cancer.
11. The compound or a salt thereof according to any one of claims 1 to 5, for use in the prevention or treatment of cancer.