HK1262235B - Condensed pyrimidine compound or salt thereof - Google Patents

Description

Condensed pyrimidine compound or its salt

Technical Field

The present invention relates to a fused pyrimidine compound or a salt thereof having RET inhibitory activity, and to a pharmaceutical composition containing the compound or salt.

Cross-reference to related patent applications

This application claims priority from Japanese Patent Application No. 2016-031919, filed on February 23, 2016, and Japanese Patent Application No. 2016-140801, filed on July 15, 2016, which are hereby incorporated by reference in their entirety. The present invention relates to a fused pyrimidine compound or a salt thereof having RET inhibitory activity, and to a pharmaceutical composition containing the compound or salt.

Background Art

There are many kinds of protein kinases in the body, and it is known that it participates in a wide range of functional regulation. RET is a receptor tyrosine kinase identified as a proto-oncogene. RET binds to the neurotrophic factor (GDNF) and GDNF receptor derived from the glial cell line to form a complex, which enables RET to perform physiological functions through intracellular phosphorylation signal conduction (non-patent literature 1). A study reported that in normal tissue, RET contributes to kidney development and nerve formation during the fetal period (non-patent literature 2). Some studies have shown that in cancers such as lung cancer, thyroid cancer, breast cancer, pancreatic cancer and prostate cancer, the transposition, mutation and overexpression of RET enhance its activation, thereby contributing to cell growth, tumor formation or tissue infiltration (non-patent literature 3,4,5,6,7 and 8). In addition, RET is known as a poor prognosis factor for cancer. As shown in some reports, the transposition of RET and its enhanced activation level are also negatively correlated with the prognosis of cancer (non-patent literature 9,10,11 and 12).

Therefore, inhibitors capable of inhibiting RET activity are considered to be useful as therapeutic agents for diseases associated with abnormal enhancement of the RET signaling pathway.

For example, it is expected that in cancers involving translocated, mutated, and overexpressed RET, administration of drugs that can specifically inhibit RET will selectively and strongly inhibit the proliferation of cancer cells and contribute to the treatment, prolongation, and improvement of the quality of life of cancer patients.

As these compounds with RET inhibitory activity, PP1 is known (non-patent document 13). In PP1, p-tolyl is bound to a fused ring pyrimidine skeleton. It is known that PP1 shows high inhibitory activity not only against RET, but also against Src (non-patent document 14), c-Kit, Bcr-Abl (non-patent documents 15 and 16), etc. For example, as a side effect, inhibition of Src may lead to abnormal increases in bone formation, while inhibition of Lck may inhibit T cells (non-patent documents 17 and 18). Since multi-kinase inhibitors not only inhibit RET, but also inhibit multiple signal transduction pathways, thereby inhibiting cell growth and other functions, the inhibitors have caused concerns about various possible side effects, which may require dose reduction and/or drug holidays, resulting in insufficient RET inhibitory activity. From the perspective of reducing side effects, it is hoped to obtain RET inhibitors with high inhibitory activity against RET and low inhibitory activity against other kinases.

Non-Patent Document 19 and Patent Document 1 disclose a substance in which a ring structure is linked to a fused pyrimidine skeleton via an amide bond. This compound is said to have Aurora kinase inhibitory activity.

Patent Document 2 discloses a pyrrolopyrimidine derivative that selectively inhibits Tie-2, TrkA, and its family member TrkB.

Patent Document 3 discloses a pyrrolopyrimidine derivative that selectively inhibits Tie-2 and its family members.

Patent Document 4 discloses a pyrrolopyrimidine derivative as a potassium channel modulator.

Patent Document 5 discloses a pyrrolopyrimidine derivative having a therapeutic effect on diabetes.

Patent Documents 6 and 7 disclose a heterocyclic substituted cyclopentane that inhibits adenosine kinase.

Patent Document 8 discloses a pyrrolopyrimidine derivative having a vinyl group or an ethynyl group.

Patent Document 9 discloses a fused pyrimidine derivative having BTK inhibitory activity.

However, none of the above patent documents specifically discloses or even suggests a RET inhibitory compound having a fused pyrimidine skeleton containing an amino group at the 4-position and a ring connected via an amide bond.

Reference List

Patent Literature

Patent Document 1: WO2007/067781 Publication

Patent Document 2: WO2004056830A1 Publication

Patent Document 3: WO2005047289A1 Publication

Patent Document 4: WO2011018894A1 Publication

Patent Document 5: WO2015078417A1 Publication

Patent Document 6: U.S. Patent No. 5,665,721

Patent Document 7: WO9640686A1 Publication

Patent Document 8: WO2014184069A1 Publication

Patent Document 9: WO2015022926A1 Publication

Non-patent literature

Non-patent document 1: Lois M. Mulligan, Nature Rev., 14(3): pp.173-186, (2014)

Non-patent document 2: Carlos F. Ibanez, Cold Spring Harb Perspect Biol., 5(2): pp. 1-10, (2013)

Non-patent document 3: Takashi Kohno, Nature Med., 18(3): pp.375-377, (2012)

Non-patent document 4: Massimo Santoro, Eur J Endocrinol., 155: pp. 645-653, (2006)

Non-patent document 5: Marjan Zarif Yeganeh, Asian Pac J Cancer Prev., 16(6): pp.2107-2117, (2015)

Non-patent document 6: Albana Gattelli, EMBO Mol Med., 5: pp. 1335-1350, (2013)

Non-patent document 7: Yoshinori Ito, Surgery, 138: pp. 788-794, (2005)

Non-patent document 8: Dawn M. Dawson, J Natl Cancer Inst., 90: pp. 519-523, (1998)

Non-patent document 9: Weijing Cai, Cancer, 119: pp. 1486-1494, (2013)

Non-patent document 10: Rossella Elisei, J Clin Endocrinol Metab., 93(3): pp.682-687, (2008)

Non-patent document 11: Albana Gattelli, EMBO Mol Med., 5: pp. 1335-1350, (2013)

Non-patent document 12: Q Zeng, J. Int. Med. Res., 36: pp. 656-664, (2008)

Non-patent document 13: Francesca Carlomagno, Cancer Res., 62(4): pp.1077-1082, (2002)

Non-patent document 14: Johannes Waltenberger, Circ Res., 85(1): pp.12-22, (1999)

Non-patent document 15: Louise Tatton, J Biol Chem., 278(7): pp.4847-4853, (2003)

Non-patent document 16: Markus Warmuth, Blood. 101(2): pp. 664-672, (2003)

Non-patent document 17: Carolyn Lowe, Proc Natl Acad Sci USA, 90(10): pp.4485-9, (1993)

Non-patent document 18: Thierry Molina, Nature, 357(6374): pp.161-4, (1992)

Non-patent document 19: McClellan WJ, Bioorganic & Medicinal Chemistry Letters 21: pp. 5620-5624 (2011)

Non-patent literature 20: Front Oncol. 2015 Dec 21; 5:278

Non-patent literature 21: Nature Reviews Clinical Oncology, vol. 9, no. 2, pp. 98-109, 2012

Summary of the Invention

Technical issues

The object of the present invention is to provide a compound or a salt thereof that selectively and potently inhibits RET, and a pharmaceutical composition comprising the same.

Solution to the problem

The inventors of the present invention conducted extensive research to achieve the above-mentioned objectives and found that the compound family represented by the following formulae (I) and (I') exhibits excellent inhibitory activity against RET and kinase selectivity and can be used as a pharmaceutical preparation for treating RET-related diseases such as malignant tumors. Thus, the present invention has been completed.

Specifically, the present invention provides a compound represented by the following formula (I) or a salt thereof:

Wherein in formula (I), A is

Where ^R1 is

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

Y is N or CH, and

n is an integer from 0 to 2,

When n is 2, the two R ^1s may be the same as or different from each other;

In formula A2, the group together with the phenyl or pyridyl group to which the group is attached forms a polycyclic C8-C14 aromatic hydrocarbon group, or an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

^R2 is

a substituted or unsubstituted C3-C10 alkyl group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C4-C12 bridged cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C3-C7 cycloalkenyl group, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

Provided that, when each group represented by R ² has a substituent, the substituent is not allowed to be a substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur and has at least one nitrogen atom; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C1-C6 alkylthio group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group,

a substituted or unsubstituted carbamoyl group,

a substituted or unsubstituted C6-C14 aromatic hydrocarbon group, or

A substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated or unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

The present invention also provides a compound represented by the following formula (I') or a salt thereof:

Wherein in formula (I'), A is

Where ^R1 is

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

Y is N or CH, and

n is an integer from 0 to 2,

When n is 2, the two R ^1s may be the same as or different from each other;

In formula A2, the group together with the phenyl or pyridyl group to which the group is attached forms a polycyclic C8-C14 aromatic hydrocarbon group, or an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

^R2 is

a substituted or unsubstituted C3-C10 alkyl group,

a substituted or unsubstituted C3-C4 cycloalkyl group,

a substituted or unsubstituted C4-C12 bridged cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

substituted or unsubstituted C3-C4 cycloalkenyl, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

Provided that, when each group represented by R ² has a substituent, the substituent is not allowed to be a substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur and has at least one nitrogen atom; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C1-C6 alkylthio group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group,

a substituted or unsubstituted carbamoyl group,

a substituted or unsubstituted C6-C14 aromatic hydrocarbon group, or

A substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated or unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

The present invention also provides medical uses, such as RET inhibitors, pharmaceutical compositions and anti-tumor agents, all of which include the compound represented by the above formula (I) or (I') or a salt thereof.

Advantageous Effects of the Invention

The present invention provides a compound represented by the above formula (I) or (I') or a salt thereof, both of which can be used as RET inhibitors.

It is disclosed that the compounds of the present invention or their salts exhibit excellent inhibitory activity and kinase selectivity against RET. Therefore, the compounds of the present invention or their salts do not cause side effects that may be caused by inhibiting kinases other than RET, such as Scr, Lck, Aurora B, EGFR, and similar kinases, and can be used as agents for preventing and/or treating RET-related diseases (e.g., cancer).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 illustrates the relative tumor volume changes observed over time in Test Case 10.

FIG2 illustrates the relative tumor volume changes observed over time in Test Case 10.

FIG3 illustrates the average weight changes observed over time in Test Case 10.

FIG4 illustrates the average weight changes observed over time in Test Case 10.

DETAILED DESCRIPTION

The compound represented by the above formula (I) or (I') of the present invention is a compound having a fused pyrimidine skeleton, having an amino group at its 4-position, and having a benzene ring, a pyridine ring, or a fused ring containing a benzene ring or a pyridine ring via an amide bond, and is a compound not disclosed in any of the above-mentioned prior art documents.

In this specification, unless otherwise indicated, * represents a binding position. For example, when A in formula (I) or (I') is the following A1:

A1 should be connected to the carbamoyl group in formula (I) or (I') at the position indicated by *.

In the present specification, the above group is also referred to as group B or B portion for short.

In the present specification, the moiety in formula A2 (wherein group B, Y and R ¹ are as defined above) (wherein group B and Y are as defined above) is a polycyclic C8-C14 aromatic hydrocarbon group containing a phenyl ring (Y is CH) or a pyridine ring (Y is N) represented by the formula, or an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. In other words, in A2, group B represents a ring having 0 to 2 nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms. Group B forms a polycyclic C8-C14 aromatic hydrocarbon group together with the phenyl or pyridine group, or an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

In the present specification, unless otherwise specified, examples of "substituents" include deuterium, halogen, hydroxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, bridged cycloalkyl, aralkyl, alkenyl, cycloalkenyl, alkynyl, haloalkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aralkyloxy, alkylthio, cycloalkyl-alkylthio, amino, mono- or dialkylamino, cycloalkylamino, cycloalkyl-alkylamino, aralkylamino, aralkylamino, aralkylamino, acylamino, alkoxycarbonylamino, aralkyloxycarbonylamino, acyl, acyloxy, alkylsiloxy, oxo, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, carbamoyl, saturated or unsaturated heterocyclic group, aralkyl, saturated heterocyclicoxy, unsaturated heterocyclicoxy, etc. When the substituents listed above are present, their number is generally 1, 2, or 3.

In the present specification, examples of "halogen" include fluorine, chlorine, bromine and iodine.

In this specification, "alkyl" refers to a linear or branched saturated hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, tert-pentyl, pent-3-yl, n-hexyl, 1,1-dimethylpropyl, 1,1,2,2-tetramethylethyl, n-heptyl, 1,1,2,2-tetramethylpropyl, n-octyl, n-nonyl, n-decyl, and the like; and specifically includes C1-C10 alkyl, C3-C10 alkyl, C1-C6 alkyl, C1-C4 alkyl, C3-C8 alkyl, C3-C6 alkyl, and the like.

In this specification, "haloalkyl" refers to an alkyl group as described above having one or more (e.g., 1-10, 1-7, or 1-5) of the halogen atoms as described above. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, 1,1,1-trifluoroethyl, monofluoro-n-propyl, perfluoro-n-propyl, perfluoroisopropyl, monofluoro-n-butyl, monofluoro-n-pentyl, monofluoro-n-hexyl, and the like; and specifically includes halogenated C1-C6 alkyl and halogenated C1-C4 alkyl.

In this specification, "hydroxyalkyl" refers to the above-mentioned alkyl group having one or more (e.g., 1-5, 1-3, or 1) hydroxyl groups. Examples include hydroxymethyl, hydroxyethyl (1-hydroxyethyl or 2-hydroxyethyl), hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like; and specifically includes hydroxy C1-C6 alkyl, hydroxy C1-C4 alkyl, and the like.

In this specification, "alkoxy" refers to an oxy group to which an alkyl group as described above is attached. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, and n-hexoxy; and specifically include C1-C6 alkoxy and C1-C4 alkoxy groups.

In this specification, "alkoxyalkyl" refers to an alkyl group as described above having one or more (e.g., 1-5, preferably 1-3, more preferably 1) alkoxy groups as described above. Examples include methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-methoxyethyl, 1-methoxy-n-propyl, 3-methoxy-n-propyl, 2-ethoxy-n-butyl, 4-methoxy-n-butyl, 5-methoxy-n-pentyl, 6-methoxy-n-hexyl, and the like; and specifically includes C1-C4 alkoxy C1-C6 alkyl and C1-C4 alkoxy C1-C4 alkyl.

In this specification, "cycloalkyl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) saturated hydrocarbon group. Examples include monocyclic cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; polycyclic cycloalkyls such as spiro[3.3]heptyl, spiro[3.4]octyl, and dispiro[5.1.7 ⁸ .2 ⁶ ]heptadecanyl; and specifically includes C3-C7 cycloalkyl, C3-C5 cycloalkyl, and the like. In the present invention, "cycloalkyl" should be specified independently of "bridged cycloalkyl" described later. Therefore, in the present invention, "bridged cycloalkyl" should be excluded from "cycloalkyl."

In this specification, "cycloalkyl-alkyl" refers to an alkyl group having one or more (e.g., 1-3, preferably 1) of the above-mentioned cycloalkyl groups. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like; and specifically includes C3-C7 cycloalkyl-substituted C1-C10 alkyl groups, C3-C7 cycloalkyl-substituted C1-C6 alkyl groups, and the like.

In the present specification, "bridged cycloalkyl" refers to a polycyclic (e.g., bicyclic or tricyclic) saturated hydrocarbon group in which at least two (e.g., 2 or 3) saturated hydrocarbon rings have at least two carbon atoms shared with adjacent rings. Examples include bicyclo[1.1.0]butyl (bicyclo[1.1.0]but-1-yl or bicyclo[1.1.0]but-2-yl), bicyclo[1.1.1]pentyl (bicyclo[1.1.1]pent-1-yl or bicyclo[1.1.1]pent-2-yl), bicyclo[3.1.0]hexyl (bicyclo[3.1.0]hex-1-yl, bicyclo[3.1.0]hex-2-yl, bicyclo[3.1.0]hex-3-yl or bicyclo[3.1.0]hex-6-yl), bicyclo[2.2.1]heptyl (bicyclo[2.2.1]hept-1-yl, bicyclo[2.2 .1]hept-2-yl or bicyclo[2.2.1]hept-7-yl), bicyclo[3.1.1]heptyl (bicyclo[3.1.1]hept-1-yl, bicyclo[3.1.1]hept-2-yl, bicyclo[3.1.1]hept-3-yl or bicyclo[3.1.1]hept-6-yl), bicyclo[4.4.0]decyl (bicyclo[4.4.0]dec-2-yl, bicyclo[4.4.0]dec-3-yl, etc.), adamantyl (adamantan-1-yl or adamantane-2-yl), etc.; and specifically include C4-C12 bridged cycloalkyl, C5-C10 bridged cycloalkyl, etc.

In this specification, "aromatic hydrocarbon group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring substituent comprising carbon and hydrogen, having an unsaturated bond and having 4e+2 electrons (e is an integer of 1 or greater) in the cyclic π electron system. Examples include phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, tetrahydronaphthyl, and the like; and specifically includes C6-C14, C6-C10, and C8-C14 aromatic hydrocarbon groups.

In this specification, "aralkyl" refers to an alkyl group as described above having one or more (e.g., 1 to 3, preferably 1) aromatic hydrocarbon groups as described above. Examples include benzyl, phenethyl, diphenylmethyl (diphenylmethyl), triphenylmethyl (trityl), naphthylmethyl, fluorenylmethyl, and the like; specifically, it includes C7-C14 aralkyl, C1-C6 alkyl groups substituted with C6-C14 aromatic hydrocarbon groups (C1-C6 alkyl groups having one or more C6-C14 aromatic hydrocarbon groups), and the like.

In this specification, "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having at least one (e.g., 1 or 2, or 1) double bond. Examples include vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2-, or 3-butenyl, 2-, 3-, or 4-pentenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 5-hexenyl, 3-methyl-3-butenyl, and the like; and specifically includes C2-C6 alkenyl, C2-C4 alkenyl, and the like.

In this specification, "cycloalkenyl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) unsaturated hydrocarbon group having at least one (e.g., 1 or 2, or 1) double bond. Examples include cyclopropenyl (e.g., 2-cyclopropen-1-yl), cyclobutenyl (e.g., 2-cyclobuten-1-yl), cyclopentenyl (e.g., 2-cyclopenten-1-yl and 3-cyclopenten-1-yl), cyclopentadienyl (e.g., 2,4-cyclopentadien-1-yl), cyclohexenyl (e.g., 3-cyclohexen-1-yl), cycloheptenyl (e.g., 3-cyclohepten-1-yl), and the like; and specifically includes C3-C7 cycloalkenyl and the like.

In this specification, "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having at least one (e.g., 1 or 2, or 1) triple bond. Examples include ethynyl, 1- or 2-propynyl, 1-, 2-, or 3-butynyl, 1-methyl-2-propynyl, and the like; and specifically includes C2-C6 alkynyl, C2-C4 alkynyl, and the like.

In this specification, "haloalkoxy" refers to the above-mentioned alkoxy group having one or more (e.g., 1-10, 1-7, or 1-5) halogen atoms. Examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, perfluoroisopropoxy, and the like; and specifically includes halogenated C1-C6 alkoxy, halogenated C1-C4 alkoxy, and the like.

In the present specification, "cycloalkoxy" refers to an oxy group to which the above-mentioned cycloalkyl group is bonded. Examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the like; and specifically includes C3-C7 cycloalkoxy.

In this specification, "cycloalkyl-alkoxy" refers to an alkoxy group having one or more (e.g., 1-3, preferably 1) of the above-mentioned cycloalkyl groups. Examples include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy, and the like; and specifically includes C3-C7 cycloalkyl-substituted C1-C4 alkoxy groups (C1-C4 alkoxy groups having one or more (e.g., 1-3, preferably 1) C3-C7 cycloalkyl groups).

In this specification, "aralkyloxy" refers to an alkoxy group having one or more (e.g., 1-3, preferably 1) aromatic hydrocarbon groups as described above. Examples include benzyloxy, phenethyloxy, naphthylmethoxy, fluorenylmethoxy, and the like; and specifically includes C7-C14 aralkyloxy groups.

In the context of the present invention, "alkylthio" refers to a mercapto group in which a hydrogen atom is replaced by an alkyl group as described above. Examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, hexylthio, and the like; and specifically includes C1-C6 alkylthio, C1-C4 alkylthio, and the like.

In this specification, "cycloalkyl-alkylthio" refers to an alkylthio group having one or more (e.g., 1-3, preferably 1) cycloalkyl groups as described above. Examples include cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio, cycloheptylmethylthio, and the like; and specifically includes C1-C4 alkylthio groups substituted with C3-C7 cycloalkyl groups (C1-C4 alkylthio groups having one or more (e.g., 1-3, preferably 1) C3-C7 cycloalkyl groups).

In this specification, "monoalkylamino" refers to an amino group having one of the above-mentioned alkyl groups. Examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, hexylamino, and the like; and specifically includes mono(C1-C6 alkyl)amino.

In this specification, "dialkylamino" refers to an amino group having two of the above-mentioned alkyl groups. Examples include dimethylamino, ethylmethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-t-butylamino, di-n-pentylamino, diisopentylamino, dihexylamino, and the like; and specifically includes di(C1-C6 alkyl)amino.

In the present specification, a single "alkylamino group" includes both a monoalkylamino group and a dialkylamino group.

In this specification, "cycloalkylamino" includes amino groups having one or two cycloalkyl groups as described above. Examples include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, dicyclobutylamino, and the like; and specifically includes amino groups substituted with C3-C7 cycloalkyl groups (amino groups having one or two C3-C7 cycloalkyl groups).

In this specification, "cycloalkyl-alkylamino" refers to an amino group having one or two cycloalkyl-alkyl groups as described above. Examples include N-cyclopropylmethylamino, N-cyclobutylmethylamino, N-cyclopentylmethylamino, N-cyclohexylmethylamino, N-cycloheptylmethylamino, and the like; and specifically includes an N-C3-C7 cycloalkyl-substituted C1-C4 alkylamino group (an amino group having one or two "C1-C4 alkyl groups having one or more (e.g., 1 to 3, preferably 1) C3-C7 cycloalkyl groups").

In the present specification, "aralkylamino" refers to an amino group having one or two of the above-mentioned aralkyl groups. Examples include benzylamino, phenethylamino, naphthylmethylamino, fluorenylmethylamino, etc., and specifically includes amino groups substituted with C7-C14 aralkyl groups.

In this specification, "aromatic amino" refers to an amino group having one or two aromatic groups as described above. Examples include phenylamino, naphthylamino, anthrylamino, phenanthrenylamino, fluorenylamino, tetrahydronaphthylamino, and the like; and specifically includes amino groups substituted with C6-C14 aromatic groups.

In the present specification, the "acyl group" refers to a formyl group, an alkylcarbonyl group, a cycloalkylcarbonyl group, an aralkylcarbonyl group or an aralkylcarbonyl group.

In this specification, "alkylcarbonyl" refers to a carbonyl group having the above-mentioned alkyl group. Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl, and the like; and specifically includes (C1-C6 alkyl)carbonyl (carbonyl group having a C1-C6 alkyl group).

In this specification, "cycloalkylcarbonyl" refers to a carbonyl group having a cycloalkyl group as described above. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, and the like; and specifically includes (C3-C7 cycloalkyl)carbonyl (a carbonyl group having a C3-C7 cycloalkyl group).

In this specification, "aralkylcarbonyl" refers to a carbonyl group having the above-mentioned aralkyl group. Examples include benzylcarbonyl, phenethylcarbonyl, naphthylmethylcarbonyl, fluorenylmethylcarbonyl, etc.; and specifically includes (C7-C14 aralkyl)carbonyl (carbonyl group having a C7-C14 aralkyl group).

In this specification, the term "aromatic hydrocarbon carbonyl group" includes carbonyl groups having the above-mentioned aromatic hydrocarbon groups. Examples include phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthracenylcarbonyl, biphenylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dioxanaphthylcarbonyl, indanylcarbonyl, phenanthrenylcarbonyl, and the like; and specifically includes (C6-C14 aromatic hydrocarbon)carbonyl.

In the present specification, "acylamino" refers to an amino group having one or two acyl groups as described above. Examples include N-formylamino, N-methylcarbonylamino, N-ethylcarbonylamino, N-n-propylcarbonylamino, N-isopropylcarbonylamino, N-n-butylcarbonylamino, N-isobutylcarbonylamino, N-tert-butylcarbonylamino, N-n-pentylcarbonylamino, N-isopentylcarbonylamino, N-hexylcarbonylamino, N,N-dimethylcarbonylamino, N-cyclopropylcarbonylamino, N-cyclobutylcarbonylamino, N-cyclopentylcarbonylamino, N-cyclohexylcarbonylamino, N-cycloheptylcarbonylamino, N-benzylcarbonylamino , N-phenethylcarbonylamino, N-naphthylmethylcarbonylamino, N-fluorenylmethylcarbonylamino, etc.; and specifically include N-formylamino, N-(C1-C6 alkyl)carbonyl-substituted amino (amino group having one or two (C1-C6 alkyl)carbonyl groups), N-(C3-C7 cycloalkyl)carbonyl-substituted amino group (amino group having one or two (C3-C7 cycloalkyl)carbonyl groups), (C7-C14 aralkyl)carbonyl-substituted amino group (amino group having one or two (C7-C14 aralkyl)carbonyl groups), etc.

In the present specification, the "acyloxy group" refers to a formyloxy group, an alkylcarbonyloxy group, a cycloalkylcarbonyloxy group, an aralkylcarbonyloxy group or an aralkylcarbonyloxy group.

In this specification, "alkylcarbonyloxy" refers to an oxy group having the above-mentioned alkylcarbonyl group. Examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonylcarbonyl, isopentylcarbonyloxy, n-hexylcarbonyloxy, and the like; and specifically includes (C1-C6 alkyl)carbonyloxy.

In this specification, "cycloalkylcarbonyloxy" refers to an oxy group having a cycloalkylcarbonyl group as described above. Examples include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, cycloheptylcarbonyloxy, and the like; specifically, it includes a carbonyloxy group substituted with a C3-C7 cycloalkyl group (a carbonyloxy group having a C3-C7 cycloalkyl group).

In this specification, "aralkylcarbonyloxy" refers to an oxy group having a cycloalkylcarbonyl group as described above. Examples include benzylcarbonyloxy, 1-phenethylcarbonyloxy, 2-phenethylcarbonyloxy, naphthylmethylcarbonyloxy, fluorenylmethylcarbonyloxy, and the like; specifically, it includes a (C7-C14 aralkyl)carbonyloxy group (a carbonyloxy group having a C7-C14 aralkyl group).

In this specification, "aromatic hydrocarbon carbonyloxy" refers to an oxy group having the above-mentioned aromatic hydrocarbon carbonyl group. Examples include phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthracenylcarbonyloxy, biphenylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthylcarbonyloxy, indanylcarbonyloxy, phenanthrenylcarbonyloxy, and the like; specifically, it includes (C6-C14 aromatic hydrocarbon)carbonyloxy.

In this specification, "alkylsilyloxy" refers to a silyloxy group having the above-mentioned alkyl group and optionally having a phenyl group. Examples include oxy groups connected to tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, etc.; and specifically include mono-C1-C6 alkylsilyloxy (silyloxy substituted with one C1-C6 alkyl group), di-C1-C6 alkylsilyloxy (silyloxy substituted with two C1-C6 alkyl groups), and tri-C1-C6 alkylsilyloxy (silyloxy substituted with three C1-C6 alkyl groups). In this specification, a single "C1-C6 alkylsilyloxy" includes all mono-C1-C6 alkylsilyloxy, di-C1-C6 alkylsilyloxy, and tri-C1-C6 alkylsilyloxy groups.

In this specification, "alkoxycarbonyl" refers to a carbonyl group having the above-mentioned alkoxy group. Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, n-hexyloxycarbonyl, and the like; and specifically includes (C1-C6 alkoxy)carbonyl.

In this specification, "alkoxycarbonylamino" refers to an amino group having one or two of the above-mentioned alkoxycarbonyl groups. Examples include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n-pentyloxycarbonylamino, isopentyloxycarbonylamino, n-hexyloxycarbonylamino, di(methoxycarbonyl)amino, and the like; and specifically includes (C1-C6 alkoxy)carbonyl-substituted amino groups (amino groups having one or two (C1-C6 alkoxy)carbonyl groups).

In this specification, "aralkyloxycarbonyl" refers to a carbonyl group having the above-mentioned aralkyloxy group. Examples include benzyloxycarbonyl, 1-phenethyloxycarbonyl, 2-phenethyloxycarbonyl, naphthylmethoxycarbonyl, fluorenylmethoxycarbonyl, and the like; and specifically includes (C7-C14 aralkyl)oxycarbonyl.

In this specification, "aralkyloxycarbonylamino" refers to an amino group having one or two of the above-mentioned aralkyloxycarbonyl groups. Examples include benzyloxycarbonylamino, 1-phenethyloxycarbonylamino, 2-phenethyloxycarbonylamino, naphthylmethoxycarbonylamino, fluorenylmethoxycarbonylamino, and the like; and specifically includes (C7-C14 aralkyl)oxycarbonyl-substituted amino groups (amino groups having one or two (C7-C14 aralkyl)oxycarbonyl groups).

In this specification, "saturated heterocyclic group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) saturated heterocyclic group having one or more (e.g., 1-3) identical or different heteroatoms selected from nitrogen, oxygen and sulfur. Examples include morpholino, 1-pyrrolidinyl, piperidino, piperazinyl, 4-methyl-1-piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, thiazolidinyl, oxazolidinyl, 7-azabicyclo[2.2.1]hept-2-yl, 2,6-dioxabicyclo[3.2.1]oct-7-yl, 7-oxabicyclo[2.2.1]heptane, etc.; and specifically includes 4- to 10-membered, 8- to 14-membered, 8- to 10-membered and 4- to 6-membered saturated heterocyclic rings.

In the present specification, "unsaturated heterocyclic group" refers to a fully or partially unsaturated heterocyclic group having one or more (e.g., 1 to 3) identical or different monocyclic or polycyclic (e.g., bicyclic or tricyclic) rings selected from nitrogen, oxygen and sulfur. Examples include imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl (pyrazyl), pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, dihydrothiazolyl, benzothienyl and the like; and specifically include 4- to 10-membered, 8- to 14-membered, 8- to 10-membered and 4- to 6-membered unsaturated heterocyclic groups.

In this specification, the term "saturated heterocyclic oxy group" refers to an oxy group having a saturated heterocyclic ring as described above. Examples include morpholinyloxy, 1-pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, tetrahydrothienyloxy, thiazolidinyloxy, and oxazolidinyloxy groups; and specifically include 4- to 10-membered, 8- to 14-membered, 8- to 10-membered, and 4- to 6-membered saturated heterocyclic oxy groups.

In this specification, the term "unsaturated heterocyclic oxy group" refers to an oxy group having the above-mentioned unsaturated heterocyclic ring. Examples include imidazolyloxy, thienyloxy, furyloxy, pyrrolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrazinyloxy, pyrimidyloxy, pyridazinyloxy, indoxyl, isoindoxyl, indazolyloxy, triazolopyridyloxy, benzimidazolyloxy, benzoxazolyloxy, benzothiazolyloxy, benzothienyloxy, benzofuranyloxy, purinyloxy, quinolyloxy, isoquinolyloxy, quinazolinyloxy, quinoxalinyloxy, methylenedioxyphenoxy, ethylenedioxyphenoxy, dihydrobenzofuranyloxy, dihydrothiazolyloxy, benzothienyloxy, and the like; and specifically include 4- to 10-membered, 8- to 14-membered, 8- to 10-membered, and 4- to 6-membered unsaturated heterocyclic oxy groups.

In the description of substituents in this specification, the term "C-C" means that the substituent has a to b carbon atoms. For example, a "C-C alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and a "C-C aryloxy" refers to an oxy group to which an aromatic hydrocarbon group having 6 to 14 carbon atoms is attached. Furthermore, the term "a- to b-membered" means that the number of atoms constituting the ring (the number of ring members) is a to b. For example, a "4- to 10-membered saturated heterocyclic group" refers to a saturated heterocyclic group having a 4- to 10-membered ring. Furthermore, the formula is "C5 bridged cycloalkane".

In this specification, when there are several options for the substituents possessed by the various groups defined in formula (I) and (I'), unless otherwise indicated, each group may have the same or different types of substituents. For example, unless otherwise indicated, "C1-C6 alkyl substituted by halogen or hydroxy" includes not only C1-C6 alkyl substituted by a single halogen and C1-C6 alkyl substituted by a single hydroxy, but also C1-C6 alkyl substituted by both halogen and hydroxy. Furthermore, "C1-C6 alkyl substituted by halogen or hydroxy" includes, for example, C1-C6 alkyl substituted by two or more halogen atoms (e.g., fluorine and chlorine).

A1 is preferably

More preferably

Even more preferably

A2 is preferably

Substituents such as ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R6 , and ^R7 in the chemical formula representing the compound of the present invention are explained in detail below. In the explanation of substituents, substituents such as ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^{R6 ,} and ^R7 refer to the respective substituents in formula (I) or (I') unless otherwise indicated.

R ¹ , R ^1a , R ^1b and R ^1c are each

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group, or

A substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

When the groups represented by R ¹ , R ^1a , R ^1b and R ^1c each have a substituent, examples of the “substituent” include the substituents described above, and the number thereof is usually 1, 2 or 3.

Examples of the "halogen" represented by R ¹ , R ^1a , R ^1b and R ^1c include those described above; preferably fluorine, chlorine and bromine; more preferably fluorine and chlorine; still more preferably fluorine.

Examples of the "C1-C6 alkyl group" in the "substituted or unsubstituted C1-C6 alkyl group" represented by ^R1 , ^R1a , ^R1b and ^R1c include those described above, preferably a C1-C4 alkyl group, more preferably a methyl group or n-propyl group, still more preferably a methyl group.

Examples of the “substituent” in the “substituted or unsubstituted C1-C6 alkyl group” represented by R ¹ , R ^1a , R ^1b and R ^1c include those described above;

Preferably, the hydrogen contained in the hydroxyl group or alkoxy group can be replaced by one or more deuterium atoms, a C1-C6 alkoxy group, a C1-C6 alkylthio group or a C6-C14 aromatic hydrocarbon group;

More preferably, the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or a C1-C6 alkoxy group or a C1-C6 alkylthio group;

Still more preferably a C1-C4 alkoxy group in which hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms; and

Even more preferred is a methoxy group.

The number of substituents is not particularly limited, but is preferably 0 to 3, more preferably 1.

The "substituted or unsubstituted C1-C6 alkyl group" represented by R ¹ , R ^1a , R ^1b and R ^1c is preferably a C1-C6 alkyl group which may be substituted by: a "hydroxyl group, a C1-C6 alkoxy group in which hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, a C1-C6 alkylthio group or a C6-C14 aromatic hydrocarbon group";

More preferably, it is a C1-C6 alkyl group which may be substituted by the following groups: "a C1-C6 alkoxy group in which hydrogen atoms may be replaced by one or more deuterium atoms, or a C1-C6 alkylthio group";

More preferably, it is a C1-C6 alkyl group substituted by the following groups: "a C1-C6 alkoxy group in which hydrogen atoms may be replaced by one or more deuterium atoms, or a C1-C6 alkylthio group";

Still more preferably a C1-C4 alkyl group substituted by one of the following groups: "a C1-C4 alkoxy group in which hydrogen atoms may be replaced by one or more deuterium atoms";

Still more preferably C1-C4 alkyl substituted with one C1-C4 alkoxy group; and

Even more preferred is methoxymethyl.

The "C1-C6 alkoxy group" in the "substituted or unsubstituted C1-C6 alkoxy group" represented by ^R1 , ^R1a , ^R1b and ^R1c includes those described above, preferably a C1-C4 alkoxy group, more preferably a methoxy group.

Examples of the "substituent" in ^the "substituted or unsubstituted C1-C6 alkoxy group" represented by R1, ^R1a , ^R1b and ^R1c include those described above, preferably halogen, more preferably fluorine.

When the substituent in the "substituted or unsubstituted C1-C6 alkoxy group" represented by ^R1 , ^R1a , ^R1b and ^R1c is halogen, the number thereof is not particularly limited, but is preferably 1 to 3, more preferably 3.

The "substituted or unsubstituted C1-C6 alkoxy group" represented by ^R1 , ^R1a , ^R1b and ^R1c is preferably a C1-C6 alkoxy group which may be substituted with halogen, more preferably a C1-C6 alkoxy group, still more preferably a C1-C4 alkoxy group, and still more preferably a methoxy group.

Examples of the "C2-C6 alkenyl group" in the "substituted or unsubstituted C2-C6 alkenyl group" represented by ^R1 , ^R1a , ^R1b and ^R1c include those described above, preferably C2-C4 alkenyl group, more preferably vinyl group and 1-propenyl group.

Examples of the "substituent" in the "substituted or unsubstituted C2-C6 alkenyl group" represented by R ¹ , R ^1a , R ^1b and R ^1c include those described above.

The "substituted or unsubstituted C2-C6 alkenyl group" represented by R ¹ , R ^1a , R ^1b and R ^1c is preferably a C2-C6 alkenyl group, more preferably a C2-C4 alkenyl group, still more preferably ethenyl and 1-propenyl, and most preferably 1-propenyl.

The "C2-C6 alkynyl group" in the "substituted or unsubstituted C2-C6 alkynyl group" represented by R ¹ , R ^1a , R ^1b and R ^1c includes those described above, preferably a C2-C4 alkynyl group, more preferably an ethynyl group.

Examples of the "substituent" in the "substituted or unsubstituted C2-C6 alkynyl group" represented by ^R1 , ^R1a , ^R1b and ^R1c include those described above.

The "substituted or unsubstituted C2-C6 alkynyl group" represented by R ¹ , R ^1a , R ^1b and R ^1c is preferably a C2-C6 alkynyl group, more preferably a C2-C4 alkynyl group, and even more preferably an ethynyl group.

Examples of the “substituent” in the “substituted or unsubstituted C2-C6 alkynyl group” represented by R ¹ , R ^1a , R ^1b and R ^1c include those described above;

Preferably, it is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or a C6-C14 aromatic hydrocarbon group;

More preferably, it is a 4- to 6-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or a C6-C10 aromatic hydrocarbon group;

More preferably, it is a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 nitrogen atom, or a C6-C10 aromatic hydrocarbon group; and

Even more preferred is phenyl or pyridyl.

The number of substituents is not particularly limited, but is preferably one.

The "substituted or unsubstituted amino group" represented by R ¹ , R ^1a , R ^1b and R ^1c is preferably an amino group which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; or a C6-C14 aromatic hydrocarbon group";

More preferably, it is an amino group which may be substituted by: "one or more 4- to 6-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; or a C6-C10 aromatic hydrocarbon group";

Still more preferably, it is an amino group which may be substituted with one of the following groups: a "4- to 6-membered monocyclic unsaturated heterocyclic group containing one nitrogen atom, or a C6-C10 aromatic hydrocarbon group"; and

Even more preferred is an amino group substituted with one "phenyl or pyridyl".

Examples of the "4- to 10- ^membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur" in the "substituted or unsubstituted ^4- to 10 ^- membered monocyclic or ^polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur" represented by R1, R1a, R1b, and R1c include those described above. The "4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur" is preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. Specific examples include pyrazolyl, furyl, oxazolyl, and the like. The “4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” is more preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing one oxygen atom; still more preferably a furyl group; and still more preferably a furan-2-yl group.

Examples of the "substituent" in the "substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur" represented by ^R1 , ^R1a , ^R1b and ^R1c include those mentioned above.

The “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R ¹ , R ^1a , R ^1b and R ^1c is preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; more preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing one oxygen atom; still more preferably a furyl group; and still more preferably a furan-2-yl group.

R ¹ is preferably

halogen,

cyano group,

Nitro,

C1-C6 alkyl, which may be substituted by: "hydroxy, C1-C6 alkoxy wherein the hydrogen contained in the alkoxy may be replaced by one or more deuterium atoms, C1-C6 alkylthio, or C6-C14 aromatic hydrocarbon group",

C1-C6 alkoxy, which may be substituted by halogen,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ¹ is more preferably

halogen,

cyano group,

Nitro,

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio"

C1-C6 alkoxy, which may be substituted by halogen,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ¹ is more preferably

halogen,

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio"

C1-C6 alkoxy,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C10 aromatic hydrocarbon groups", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ¹ is more preferably

halogen,

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio"

C2-C6 alkenyl,

C2-C6 alkynyl, or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ¹ is more preferably

halogen,

C1-C4 alkyl substituted by a C1-C4 alkoxy group, wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms,

C2-C6 alkenyl,

C2-C6 alkynyl, or

A 4- to 6-membered monocyclic unsaturated heterocyclic group containing one oxygen atom.

R ¹ is still more preferably a C1-C4 alkyl group substituted by one C1-C4 alkoxy group.

R ¹ is still more preferably halogen or methoxymethyl.

R ^1a is preferably

cyano group,

Nitro,

C1-C6 alkyl, which may be substituted by: "hydroxy, C1-C6 alkoxy wherein the hydrogen contained in the alkoxy may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C1-C6 alkoxy, which may be substituted by halogen,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ^1a is more preferably

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ^1a is more preferably

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C10 aromatic hydrocarbon groups", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ^1a is more preferably

C1-C6 alkyl, which is substituted by a "C1-C6 alkoxy group in which hydrogen atoms may be replaced by one or more deuterium atoms, or a C1-C6 alkylthio group",

C2-C6 alkenyl,

C2-C6 alkynyl, or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ^1a is further more preferably

C1-C4 alkyl substituted by a C1-C4 alkoxy group, wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms,

C2-C6 alkenyl,

C2-C6 alkynyl, or

A 4- to 6-membered monocyclic unsaturated heterocyclic group containing one oxygen atom.

R ^1a is still more preferably a C1-C4 alkyl group substituted by one C1-C4 alkoxy group.

R ^1a is still more preferably methoxymethyl.

R ^1b is preferably halogen, C1-C6 alkyl or C1-C6 alkoxy, more preferably halogen, and even more preferably fluorine.

R ^1c is preferably a C1-C6 alkoxy group, more preferably a C1-C4 alkoxy group, and even more preferably a methoxy group.

When each group represented by R ² has a substituent, examples of the “substituent” include those described above, and the number of substituents is generally 1, 2, or 3. However, in the present invention, the substituent possessed by each group represented by R ² is not allowed to be a “substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur, and at least one nitrogen atom”. When each group represented by R ² has a substituent, examples of substituents that may be possessed by the saturated heterocyclic group in the “substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur, and at least one nitrogen atom” excluded from the “substituent” include those described above; however, the substituents that may be possessed by the saturated heterocyclic group include at least an alkyl group. Therefore, when each group represented by R ² has a substituent, the “substituent” excludes, for example, the following:

Examples of the "C3-C10 alkyl group" in the "substituted or unsubstituted C3-C10 alkyl group" represented by ^R2 include those described above, preferably a branched C3-C8 alkyl group, more preferably a branched C3-C6 alkyl group, and even more preferably a tert-butyl group.

Examples of the "substituent" in the "substituted or unsubstituted C3-C10 alkyl group" represented by ^R2 include those described above. However, the "substituent" is preferably a halogen, a C1-C6 alkoxy group, a C3-C7 cycloalkyl group, or a "4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur";

More preferably, it is halogen, C3-C7 cycloalkyl or "a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur";

Even more preferably halogen or C3-C7 cycloalkyl;

Even more preferably halogen; and

Still more preferably, it is fluorine.

The number of the substituents is not particularly limited, but is preferably 0-3, more preferably 0 or 1.

The "substituted or unsubstituted C3-C10 alkyl group" represented by ^R2 is preferably a C3-C10 alkyl group which may be substituted by: "halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur";

More preferably, it is a C3-C10 alkyl group which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur";

Even more preferably, it is a branched C3-C8 alkyl group which may be substituted by: "halogen or C3-C7 cycloalkyl";

Even more preferably a branched C3-C6 alkyl group which may be substituted with halogen;

Still more preferably a branched C3-C6 alkyl group which may be substituted with one halogen atom; and

Still more preferably, it is a tert-butyl group which may be substituted with fluorine.

In formula (I), examples of the "C3-C7 cycloalkyl group" in the "substituted or unsubstituted C3-C7 cycloalkyl group" represented by ^R2 include those described above, more preferably a C3-C5 cycloalkyl group, more preferably a C3-C4 cycloalkyl group, and even more preferably a cyclopropyl group.

In the formula (I'), examples of the "C3-C4 cycloalkyl group" in the "substituted or unsubstituted C3-C4 cycloalkyl group" represented by ^R2 include those described above, and preferably it is a cyclopropyl group.

In formulae (I) and (I'), examples of the "substituent" in the "substituted or unsubstituted C3-C7 cycloalkyl group" and "substituted or unsubstituted C3-C4 cycloalkyl group" represented by ^R2 include those described above;

Preferably halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl;

More preferably, it is C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl;

Even more preferably C1-C4 alkyl or C3-C5 cycloalkyl;

Even more preferably methyl or cyclopropyl; and

Still more preferably, it is a methyl group.

The number of substituents is not particularly limited, but is preferably 0-3, more preferably 0-2, and even more preferably 1.

The "substituted or unsubstituted C3-C7 cycloalkyl group" represented by ^R2 in formula (I) is preferably a C3-C7 cycloalkyl group which may be substituted by "halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl";

More preferably, it is a C3-C7 cycloalkyl group which may be substituted with a C1-C6 alkyl group, a C3-C7 cycloalkyl group or a halogenated C1-C6 alkyl group;

Still more preferably a C3-C7 cycloalkyl group which may be substituted with a "C1-C4 alkyl group or a C3-C5 cycloalkyl group";

Still more preferably a C3-C5 cycloalkyl group which may be substituted with one "C1-C4 alkyl group or C3-C5 cycloalkyl group";

Still more preferably, it is a C3-C4 cycloalkyl group which may be substituted with one "C1-C4 alkyl group or C3-C5 cycloalkyl group";

Still more preferably, it is a cyclopropyl group which may be substituted with one "methyl or cyclopropyl" group;

Further more preferably

The "substituted or unsubstituted C3-C4 cycloalkyl group" represented by ^R2 in formula (I') is preferably a C3-C4 cycloalkyl group which may be substituted by "halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl";

More preferably, it is a C3-C4 cycloalkyl group which may be substituted with a C1-C6 alkyl group, a C3-C7 cycloalkyl group or a halogenated C1-C6 alkyl group;

Still more preferably a C3-C4 cycloalkyl group which may be substituted with a "C1-C4 alkyl group or a C3-C5 cycloalkyl group";

Still more preferably a C3-C4 cycloalkyl group which may be substituted with one "C1-C4 alkyl group or C3-C5 cycloalkyl group";

Still more preferably cyclopropyl which may be substituted with one "methyl or cyclopropyl"; and

Further more preferably

Examples of the "C4-C12 bridged cycloalkyl" in the "substituted or unsubstituted C4-C12 bridged cycloalkyl" represented by ^R2 include those described above, preferably a C5-C10 bridged cycloalkyl, more preferably

Examples of the "substituent" in the "substituted or unsubstituted C4-C12 bridged cycloalkyl group" represented by ^R2 include those described above.

The "substituted or unsubstituted C4-C12 bridged cycloalkyl group" represented by ^R2 is preferably a C4-C12 bridged cycloalkyl group, more preferably a C5-C10 bridged cycloalkyl group, more preferably

Examples of the "C2-C6 alkenyl group" in the "substituted or unsubstituted C2-C6 alkenyl group" represented by ^R2 include those described above, preferably a C2-C4 alkenyl group, more preferably an isopropenyl group.

Examples of the "substituent" in the "substituted or unsubstituted C2-C6 alkenyl group" represented by ^R2 include those described above, preferably halogen, more preferably fluorine.

The number of substituents is not particularly limited, but is preferably one.

The "substituted or unsubstituted C2-C6 alkenyl group" represented by ^R2 is preferably a C2-C6 alkenyl group which may be substituted by halogen, more preferably a C2-C4 alkenyl group which may be substituted by fluorine, and even more preferably a fluoroisopropenyl group.

In formula (I), examples of the "C3-C7 cycloalkenyl group" in the "substituted or unsubstituted C3-C7 cycloalkenyl group" represented by ^R2 include those described above, and preferably it is a cyclopentenyl group.

In formula (I'), examples of the "C3-C4 cycloalkenyl group" in the "substituted or unsubstituted C3-C4 cycloalkenyl group" represented by R ² include those described above.

In formulae (I) and (I'), examples of the substituent in the "substituted or unsubstituted C3-C7 cycloalkenyl group" and the "substituted or unsubstituted C3-C4 cycloalkenyl group" represented by ^R2 include those described above.

In formula (I), the "substituted or unsubstituted C3-C7 cycloalkenyl group" represented by ^R2 is preferably a C3-C7 cycloalkenyl group, more preferably a cyclopentenyl group.

In formula (I'), the "substituted or unsubstituted C3-C4 cycloalkenyl group" represented by ^R2 is preferably a C3-C4 cycloalkenyl group.

Examples of the “4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” in the “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing ¹ to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R include those described above.

The "substituent" in the "substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur" represented by ^R2 includes those described above.

R ² in formula (I) is preferably

a substituted or unsubstituted C3-C10 alkyl group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C4-C12 bridged cycloalkyl group,

substituted or unsubstituted C2-C6 alkenyl, or

a substituted or unsubstituted C3-C7 cycloalkenyl group,

The condition is that when each group represented by ^R2 has a substituent, the substituent is not allowed to be a "substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur and has at least one nitrogen atom".

R ² is more preferably

C3-C10 alkyl which may be substituted by: "halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl which may be substituted by: "halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl,

C2-C6 alkenyl which may be substituted with halogen, or

C3-C7 cycloalkenyl.

^R2 is more preferably

C3-C10 alkyl which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl group which may be substituted by: "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl, or

C3-C7 cycloalkenyl.

R ² is more preferably

C3-C10 alkyl which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl which may be substituted by "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl", or

C4-C12 bridged cycloalkyl.

^R2 is further more preferably

branched C3-C8 alkyl which may be substituted with "halogen or C3-C7 cycloalkyl",

C3-C7 cycloalkyl which may be substituted with "C1-C4 alkyl or C3-C5 cycloalkyl", or

C4-C12 bridged cycloalkyl.

^R2 is further more preferably

branched C3-C6 alkyl which may be substituted with halogen, or

C3-C7 cycloalkyl group which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group".

^R2 is further more preferably

branched C3-C6 alkyl which may be substituted with halogen, or

C3-C5 cycloalkyl group which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group".

R ² is still more preferably a C3-C5 cycloalkyl group which may be substituted with one C1-C4 alkyl group.

^R2 is further more preferably

Furthermore, R ² in formula (I') is preferably

a substituted or unsubstituted C3-C10 alkyl group,

a substituted or unsubstituted C3-C4 cycloalkyl group,

a substituted or unsubstituted C4-C12 bridged cycloalkyl group,

substituted or unsubstituted C2-C6 alkenyl, or

a substituted or unsubstituted C3-C4 cycloalkenyl group,

The condition is that when each group represented by ^R2 has a substituent, the substituent is not allowed to be a "substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur and has at least one nitrogen atom".

R ² is more preferably

C3-C10 alkyl which may be substituted by: "halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl which may be substituted by: "halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl,

C2-C6 alkenyl which may be substituted with halogen, or

C3-C4 cycloalkenyl.

^R2 is more preferably

C3-C10 alkyl which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl group which may be substituted by: "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl, or

C3-C7 cycloalkenyl.

^R2 is more preferably

C3-C10 alkyl which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl which may be substituted by "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl", or

C4-C12 bridged cycloalkyl.

^R2 is further more preferably

branched C3-C8 alkyl which may be substituted with "halogen or C3-C7 cycloalkyl",

C3-C4 cycloalkyl which may be substituted with "C1-C4 alkyl or C3-C5 cycloalkyl", or

C4-C12 bridged cycloalkyl.

^R2 is further more preferably

branched C3-C6 alkyl which may be substituted with halogen, or

C3-C4 cycloalkyl group which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group".

R ² is still more preferably a C3-C4 cycloalkyl group which may be substituted with one C1-C4 alkyl group.

^R2 is further more preferably

Preferably, ^R2 is connected to the nitrogen atom contained in the pyrrolopyrimidine or pyrazolopyrimidine skeleton in formula (I) and (I') via a carbon atom among the atoms contained in ^R2 , and the number of hydrogen atoms possessed by the carbon atom is 0 or 1. That is, preferably, in the following parts of formula (I) and (I'):

The carbon atom contained in R ² is linked to the above nitrogen atom, and the carbon atom has 0 or 1 hydrogen atom. In R ² , the number of hydrogen atoms possessed by the carbon atom is more preferably 0.

When each group represented by R ³ has a substituent, examples of the "substituent" include those described above, and the number thereof is usually 1, 2 or 3.

Examples of the "halogen" represented by R ³ include those described above; and preferably, they are fluorine, chlorine and bromine.

Examples of the "C1-C6 alkyl group" in the "substituted or unsubstituted C1-C6 alkyl group" represented by R ³ include those described above, and are preferably C1-C4 alkyl groups, more preferably methyl groups or ethyl groups, and even more preferably methyl groups.

Examples of the "substituent" in the "substituted or unsubstituted C1-C6 alkyl group" represented by R ³ include those described above, and preferably it is a hydroxyl group or an oxo group (oxo).

The number of substituents is not particularly limited, but is preferably 0 or 1, more preferably 0.

The "substituted or unsubstituted C1-C6 alkyl group" represented by ^R3 is preferably a C1-C6 alkyl group which may be substituted by a hydroxyl group or an oxo group, more preferably a C1-C4 alkyl group which may be substituted by a hydroxyl group or an oxo group, still more preferably a C1-C4 alkyl group, and still more preferably a methyl group.

The "C1-C6 alkoxy group" in the "substituted or unsubstituted C1-C6 alkoxy group" represented by R ³ includes those described above, preferably a C1-C4 alkoxy group, more preferably a methoxy group or an ethoxy group.

Examples of the "substituent" in the "substituted or unsubstituted C1-C6 alkoxy group" represented by R ³ include those described above;

Preferably, it is halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or a 4- to 10-membered monocyclic saturated heterocyclic group which may be substituted by an oxy group and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

More preferably, it is halogen, C1-C4 alkoxy, C3-C7 cycloalkyl, or a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

More preferably, it is a C1-C4 alkoxy group, a C3-C7 cycloalkyl group, or a 4- to 6-membered monocyclic saturated heterocyclic group containing one oxygen atom; and

Even more preferred is tetrahydrofuranyl.

The number of the substituents is not particularly limited, but is preferably 0 or 1, more preferably 1.

The “substituted or unsubstituted C1-C6 alkoxy group” represented by ^R3 is preferably a C1-C6 alkoxy group which may be substituted by: “halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”;

More preferably, it is a C1-C4 alkoxy group which may be substituted by: "halogen, C1-C4 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur";

Still more preferably, it is a C1-C4 alkoxy group which may be substituted by: "C1-C4 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom";

Still more preferably a C1-C4 alkoxy group which may be substituted with "one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom"; and

Still more preferably, it is ethoxy or tetrahydrofurylmethoxy.

The "C1-C6 alkylthio group" in the "substituted or unsubstituted C1-C6 alkylthio group" represented by R ³ includes those described above, is preferably a C1-C4 alkylthio group, and more preferably a methylthio group.

Examples of the "substituent" in the "substituted or unsubstituted C1-C6 alkylthio group" represented by R ³ include those described above.

The number of substituents is not particularly limited, but is preferably 0 or 1, more preferably 0.

The "substituted or unsubstituted C1-C6 alkylthio group" represented by R ³ is preferably a C1-C6 alkylthio group, more preferably a C1-C4 alkylthio group, and even more preferably a methylthio group.

The "C3-C7 cycloalkyl group" in the "substituted or unsubstituted C3-C7 cycloalkyl group" represented by R ³ includes those described above, and is preferably cyclopropyl.

The "substituent" in the "substituted or unsubstituted C3-C7 cycloalkyl group" represented by ^R3 includes those described above.

The "substituted or unsubstituted C3-C7 cycloalkyl group" represented by R ³ is preferably a C3-C7 cycloalkyl group, more preferably a C3-C5 cycloalkyl group, and even more preferably a cyclopropyl group.

Examples of the "C2-C6 alkenyl group" in the "substituted or unsubstituted C2-C6 alkenyl group" represented by R ³ include those described above, preferably a C2-C4 alkenyl group, and still more preferably a vinyl group.

Examples of the "substituent" in the "substituted or unsubstituted C2-C6 alkenyl group" represented by ^R3 include those described above, and preferably it is a hydroxyl group.

The number of substituents is not particularly limited, but is preferably 0 or 1, more preferably 0.

The "substituted or unsubstituted C2-C6 alkenyl group" represented by ^R3 is preferably a C2-C6 alkenyl group which may be substituted by a "hydroxyl group";

More preferably, it is a C2-C4 alkenyl group which may be substituted with a "hydroxyl group";

Even more preferably C2-C4 alkenyl; and

Even more preferred is a vinyl group.

Examples of the "C2-C6 alkynyl group" in the "substituted or unsubstituted C2-C6 alkynyl group" represented by R ³ include those described above, preferably a C2-C4 alkynyl group, more preferably an ethynyl group or a propynyl group.

The number of triple bonds in the "C2-C6 alkynyl group" is preferably 1, and the position of the triple bond is preferably between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom.

Examples of the "substituent" in the "substituted or unsubstituted C2-C6 alkynyl group" represented by ^R3 include those described above, and are preferably

hydroxyl groups,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ ,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by R ⁵ ,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

An unsaturated heterocyclic oxy group which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

The above-mentioned "C1-C6 alkoxy group" as an example of the substituent in the "substituted or unsubstituted C2-C6 alkynyl group" represented by R ³ is preferably a C1-C4 alkoxy group, and more preferably a methoxy group.

As an example of a substituent in the "substituted or unsubstituted C2-C6 alkynyl group" represented by ^R3 , ^R4 in the above-mentioned "amino group which may be substituted by ^R4 " is preferably a C1-C6 alkyl group, a C1-C4 alkoxy C1-C6 alkyl group or a carbamoyl group which may be substituted by a C3-C7 cycloalkyl group.

The above-mentioned “amino group which may be substituted by R ^{4 ” as an example of the substituent in the “substituted or unsubstituted C 2 -C 6 alkynyl group” represented by R 3 is} preferably an amino group which may be substituted by R ⁴ , wherein R ⁴ is a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy C 1 -C 4 alkyl group; and

More preferred is an amino group which may be substituted by R ⁴ , wherein R ⁴ is methyl or methoxyethyl.

The above-mentioned "C1-C6 alkylsilyloxy" as an example of the substituent in the "substituted or unsubstituted C2-C6 alkynyl group" represented by ^R3 is preferably a tri-C1-C6 alkylsilyloxy group, and more preferably a tert-butyldimethylsilyloxy group.

The C3-C7 cycloalkyl group which may be substituted with "hydroxyl group or oxo group" as an example of the substituent in the "substituted or unsubstituted C2-C6 alkynyl group" represented by ^R3 is preferably a C3-C7 cycloalkyl group which may be substituted with "hydroxyl group".

As an example of the substituent in the "substituted or unsubstituted C2-C6 alkynyl group" represented by ^R3 , ^R5 in the above-mentioned "C6-C14 aromatic hydrocarbon group which may be substituted by ^R5 " is preferably

halogen,

C1-C4 alkylamino which may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

C1-C6 alkoxy.

The aforementioned “C6-C14 aromatic hydrocarbon group which may be substituted by ^R5 ” as an example of a substituent in the “substituted or unsubstituted C2-C6 alkynyl group” represented by ^R3 is preferably a phenyl group which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the aforementioned methylamino group may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; and

More preferred is phenyl which may be substituted by R ⁵ , wherein R ⁵ is halogen.

In the above-mentioned “one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” as examples of substituents in the “substituted or unsubstituted C2-C6 alkynyl group” represented by R ³ , R ⁶ is preferably a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group or an oxo group.

The above-mentioned “one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” as an example of the substituent in the “substituted or unsubstituted C2-C6 alkynyl group” represented by R ³ is preferably “one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo;

More preferably, "one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy, C1-C4 alkyl or oxo;

Still more preferably, "one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy or methyl; and

Even more preferred is morpholino, tetrahydropyranyl, pyrrolidinyl, piperidinyl or oxetanyl, which may be substituted by R ⁶ , wherein R ⁶ is hydroxy or methyl.

In the above-mentioned “one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” as examples of substituents in the “substituted or unsubstituted C2-C6 alkynyl group” represented by R ³ , R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino.

“One or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” is preferably “one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino;

More preferably, "one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁷ is C1-C4 alkyl or amino; and

Even more preferred is pyrazolyl, pyrimido[1,2-b]pyridazinyl, imidazolyl, pyridyl, thiazolyl or furo[3,2-b]pyridyl, which may be substituted by R ⁷ , wherein R ⁷ is C1-C4 alkyl or amino.

The above-mentioned “unsaturated heterocyclic oxy group which may be substituted by halogen, wherein the unsaturated heterocyclic ring is a ^4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” as an example of the substituent in the “substituted or unsubstituted C2-C6 alkynyl group” represented by R3 is preferably “unsaturated heterocyclic oxy group which may be substituted by halogen, wherein the unsaturated heterocyclic ring is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, and

More preferred is "pyridyloxy group which may be substituted with halogen".

The number of substituents in the "C2-C6 alkynyl group" in the "substituted or unsubstituted C2-C6 alkynyl group" represented by R ³ is not particularly limited, but is preferably one.

The “substituted or unsubstituted C2-C6 alkynyl group” represented by R ³ is preferably a C2-C6 alkynyl group which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, and the above alkylamino may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

provided that the position of the C2-C6 alkynyl triple bond is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom;

More preferably, it is a C2-C6 alkynyl group which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the above methylamino may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

provided that the position of the C2-C6 alkynyl triple bond is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom;

Even more preferably is a C2-C6 alkynyl group which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

provided that the position of the C2-C6 alkynyl triple bond is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom;

Even more preferably is a C2-C6 alkynyl group which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl or C1-C4 alkoxy C1-C4 alkyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo, or

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino”

provided that the position of the C2-C6 alkynyl triple bond is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom; and

Still more preferably, it is a C2-C6 alkynyl group which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is methyl or methoxyethyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy or methyl, or

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is C1-C4 alkyl or amino”

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom.

Preferred specific examples include

or

Examples of the "substituent" in the "substituted or unsubstituted amino group" represented by R ³ include those described above.

Examples of the "substituent" in the "substituted or unsubstituted carbamoyl group" represented by R ³ include those described above.

Examples of the "C6-C14 aromatic hydrocarbon group" in the "substituted or unsubstituted C6-C14 aromatic hydrocarbon group" represented by R ³ include those described above, and preferably it is a phenyl group.

Examples of the “substituent” in the “substituted or unsubstituted C6-C14 aromatic hydrocarbon group” represented by R ³ include those described above;

Preferably

hydroxyl groups,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

More preferably

hydroxyl groups,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Even more preferably

hydroxyl groups,

C1-C4 alkyl, which may be substituted by hydroxyl, or

formyl group; and

Even more preferably

hydroxyl, or

C1-C4 alkyl group, which may be substituted by a hydroxy group.

The number of substituents is not particularly limited, but is preferably 0 or 1, more preferably 1.

The “substituted or unsubstituted C6-C14 aromatic hydrocarbon group” represented by R ³ is preferably a C6-C14 aromatic hydrocarbon group which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur";

More preferably, it is phenyl which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur";

Even more preferred is phenyl which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by hydroxyl, or

formyl"; and

Even more preferred is phenyl which may be substituted by:

"Hydroxy, or

C1-C4 alkyl, which may be substituted by hydroxyl group.

Examples of the “4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” in the “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing ¹ to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R include those described above.

Examples of the “substituent” in the “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R ³ include those mentioned above.

The “4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” in the “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to ³ identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R includes those described above; preferably, it is a 4- to 6-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; more preferably, it is a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 nitrogen atoms; and even more preferably, it is a pyrazolyl group.

Examples of the “substituent” in the “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R ³ include those described above;

Preferably, it is halogen, C1-C6 alkyl which may be substituted with hydroxy, or amino which may be substituted with C1-C6 alkyl (carbonyl);

More preferably, it is halogen, C1-C4 alkyl which may be substituted with hydroxy, or amino which may be substituted with C1-C4 alkyl (carbonyl); and

Still more preferred is fluorine, methyl which may be substituted with hydroxy, or acetylamino.

The number of substituents is not particularly limited, but is preferably 0 or 1, more preferably 1.

The “substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” represented by R ³ is preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group which may be substituted by “halogen, C1-C6 alkyl which may be substituted by hydroxy, or amino which may be substituted by C1-C6 alkyl(carbonyl)” and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

More preferably, it is a 4- to 6-membered monocyclic unsaturated heterocyclic group which may be substituted by: "halogen, C1-C4 alkyl which may be substituted by hydroxy, or amino which may be substituted by C1-C4 alkyl (carbonyl)", and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Still more preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Still more preferably a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 nitrogen atoms;

Still more preferably, it is pyrazolyl.

R ³ is preferably

hydrogen,

halogen,

cyano group,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C1-C6 alkylthio group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group, provided that the position of the triple bond of the C2-C6 alkynyl group is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

a substituted or unsubstituted C6-C14 aromatic hydrocarbon group, or

A substituted or unsubstituted 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ³ is more preferably

hydrogen,

halogen,

cyano group,

C1-C6 alkyl, which may be substituted by a hydroxyl group or an oxo group,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

One or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by oxo groups

and containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

C1-C6 alkylthio,

C3-C7 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, and the above alkylamino may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein

^R6 is a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group or an oxo group,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

C6-C14 aromatic hydrocarbon group, which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C6 alkyl, which may be substituted by a hydroxy group, or

amino group, which may be substituted by a C1-C6 alkyl (carbonyl) group.

R ³ is more preferably

hydrogen,

halogen,

cyano group,

C1-C4 alkyl, which may be substituted by a hydroxyl group or an oxo group,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or may be substituted by C3-C7 cycloalkyl carbamoyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, and the above alkylamino may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein

^R6 is a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group or an oxo group,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

C6-C14 aromatic hydrocarbon group, which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C6 alkyl, which may be substituted by a hydroxy group, or

amino group, which may be substituted by a C1-C6 alkyl (carbonyl) group.

R ³ is more preferably

hydrogen,

halogen,

cyano group,

C1-C4 alkyl,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C4 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the above methylamino may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C4 alkyl, which may be substituted by hydroxyl, or

amino group, which may be substituted by a C1-C4 alkyl (carbonyl) group".

R ³ is further more preferably

hydrogen,

halogen,

C1-C4 alkyl,

C1-C4 alkoxy, which may be substituted by:

"halogen,

C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by hydroxyl, or

formyl", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

R ³ is further more preferably

hydrogen,

halogen,

C1-C4 alkoxy, which may be substituted by:

C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom,

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl or C1-C4 alkoxy C1-C4 alkyl,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy, C1-C4 alkyl or oxo, or

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino”

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy, or

C1-C4 alkyl, which may be substituted by hydroxyl group", or

A 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 nitrogen atoms.

R ³ is further more preferably

C1-C4 alkoxy, which may be substituted by "one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom", or

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is methyl or methoxyethyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy or methyl, or

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, "wherein R ⁷ is C1-C4 alkyl or amino",

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom.

When A is A1, X is preferably CR ³ , and when A is A2, X is preferably N.

When A is A1 or A2, Y is preferably CH.

When A is A1, n is preferably 1 or 2, more preferably 1. When A is A2, n is preferably 0 or 1, more preferably 1.

m is an integer of 0 or 1, and is preferably 0.

l is an integer of 1-3, and preferably 2.

When A is A1 and n is 2, the attachment position of ^R1 preferably includes one para position and one ortho position or meta position, more preferably one meta position and one para position. When A is A1 and n is 1, the attachment position of ^R1 is preferably para position or meta position, most preferably para position. In this specification, unless otherwise indicated, the attachment position of ^R1 (ortho position, meta position or para position) refers to the position of the carbon atom (more specifically, the carbon atom indicated by the following arrow) among the carbon atoms contained in A1 to which the carbamoyl group in formula (I) and (I') is attached:

Even if A is

When m is 1, the binding position of R ^1b is preferably the meta position.

A1 is preferably

Where ^R1 is

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Y is N or CH, and

n is an integer of 1 or 2.

A1 is most preferred

Where ^R1 is

halogen,

cyano group,

Nitro,

C1-C6 alkyl, which may be substituted by: "hydroxy, C1-C6 alkoxy wherein the hydrogen contained in the alkoxy may be replaced by one or more deuterium atoms, C1-C6 alkylthio or C6-C14 aromatic hydrocarbon group",

C1-C6 alkoxy, which may be substituted by halogen,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Y is N or CH; and

n is an integer of 1 or 2.

A1 is more preferably

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen, C1-C6 alkyl or C1-C6 alkoxy; and

m is an integer of 0 or 1.

A1 is more preferably

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C10 aromatic hydrocarbon groups", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen, C1-C6 alkyl or C1-C6 alkoxy; and

m is an integer of 0 or 1.

A1 is further more preferably

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl, or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen; and

m is an integer of 0 or 1.

A1 is further more preferably

wherein R ^1b is halogen; and

m is an integer of 0 or 1.

A1 is further more preferably

When A is A2 and the moiety (wherein the groups B and Y are as defined above) is a polycyclic C8-C14 aromatic hydrocarbon group, examples of polycyclic C8-C14 aromatic hydrocarbon groups include those described above; preferably a bicyclic C8-C10 aromatic hydrocarbon group; more preferably

Wherein l is as defined above;

And even more preferably

When A is A2 and the moiety (wherein the groups B and Y are as defined above) is an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, examples of the 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur include those described above; preferably, it is an 8- to 10-membered bicyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; more preferably, it is an 8- to 10-membered bicyclic unsaturated heterocyclic group containing one heteroatom selected from nitrogen, oxygen and sulfur; and even more preferably,

A2 is preferably

Wherein R ¹ is a substituted or unsubstituted C1-C6 alkoxy group;

Y is CH; and

n is an integer 0 or 1.

A2 is more preferably

wherein R ^1c is a C1-C6 alkoxy group; l is an integer from 1 to 3; and n is an integer from 0 to 1; or

8- to 10-membered bicyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

A2 is more preferably

A2 is more preferably

A is more preferably A1 rather than A2.

The following [1] to [6] describe preferred embodiments of the present invention.

[1] More preferably, the compound represented by formula (I) or a salt thereof,

in

When A is A1,

^R1 is

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Y is N or CH;

n is an integer 1 or 2;

^R2 is

a substituted or unsubstituted C3-C10 alkyl group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C4-C12 bridged cycloalkyl group,

substituted or unsubstituted C2-C6 alkenyl, or

a substituted or unsubstituted C3-C7 cycloalkenyl group,

Provided that, when each group represented by R ² has a substituent, the substituent is not allowed to be a substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur and at least one nitrogen atom; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C1-C6 alkylthio group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group, provided that the position of the triple bond of the C2-C6 alkynyl group is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

a substituted or unsubstituted C6-C14 aromatic hydrocarbon group, or

a substituted or unsubstituted 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; and

When A is A2,

^R1 is a substituted or unsubstituted C1-C6 alkoxy group;

Y is CH;

n is an integer 0 or 1;

^R2 is a substituted or unsubstituted C3-C7 cycloalkyl group; and

X is N.

[1-2] More preferably, the compound represented by formula (I) or a salt thereof,

in

When A is A1,

^R1 is

halogen,

cyano group,

Nitro,

C1-C6 alkyl, which may be substituted by the following groups: "hydroxyl, C1-C6 alkoxy in which the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, C1-C6 alkylthio or C6-C14 aromatic hydrocarbon group",

C1-C6 alkoxy, which may be substituted by halogen,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Y is N or CH;

n is an integer 1 or 2;

^R2 is

C3-C10 alkyl, which may be substituted by: "hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl, which may be substituted by: "halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl,

C2-C6 alkenyl, which may be substituted by halogen, or

C3-C7 cycloalkenyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C6 alkyl, which may be substituted by a hydroxyl group or an oxo group,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C6 alkylthio,

C3-C7 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, wherein the above-mentioned alkylamino group may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 cycloalkyl or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

C6-C14 aromatic hydrocarbon group, which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C6 alkyl, which may be substituted by a hydroxy group, or

amino, which may be substituted by a C1-C6 alkyl (carbonyl) group"; and

When A is A2,

^R1 is a substituted or unsubstituted C1-C6 alkoxy group;

Y is CH;

n is an integer 0 or 1;

^R2 is a substituted or unsubstituted C3-C7 cycloalkyl group; and

X is N.

[2] More preferably, the compound represented by formula (I) or a salt thereof,

in

When A is A1,

A1 is

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen, C1-C6 alkyl or C1-C6 alkoxy; and

m is an integer 0 or 1;

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl, which may be substituted with "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl, or

C3-C7 cycloalkenyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C4 alkyl, which may be substituted by a hydroxyl group or an oxo group,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, and the above alkylamino may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

C6-C14 aromatic hydrocarbon group, which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C6 alkyl, which may be substituted by hydroxy, or amino, which may be substituted by C1-C6 alkyl (carbonyl)"; and

When A is A2,

A2 is

wherein R ^1c is a C1-C6 alkoxy group; l is an integer from 1 to 3; and n is an integer of 0 or 1.

^R2 is C3-C7 cycloalkyl; and

X is N.

[3] Still more preferably, the compound represented by formula (I) or a salt thereof, wherein

A is

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio"

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C10 aromatic hydrocarbon groups", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is hydrogen, C1-C6 alkyl or C1-C6 alkoxy;

m is an integer 0 or 1;

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl, which may be substituted with "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C4 alkyl,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C4 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the above methylamino may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C4 alkyl, which may be substituted by hydroxyl, or

amino group, which may be substituted by a C1-C4 alkyl (carbonyl) group".

[4] Still more preferably, a compound represented by formula (I) or a salt thereof,

in

A is

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio"

C2-C6 alkenyl,

C2-C6 alkynyl, or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen;

m is an integer 0 or 1;

^R2 is

branched C3-C8 alkyl group, which may be substituted with "halogen or C3-C7 cycloalkyl group",

C3-C7 cycloalkyl group, which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

C1-C4 alkyl,

C1-C4 alkoxy, which may be substituted by:

"halogen,

C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by hydroxyl, or

formyl", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

[5] Still more preferably, the compound of formula (I) or a salt thereof, wherein

A is

wherein R ^1b is halogen;

m is an integer 0 or 1;

^R2 is

branched C3-C6 alkyl, which may be substituted with halogen, or

C3-C7 cycloalkyl group, which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group";

X is CR ³ , wherein R ³ is

hydrogen,

halogen,

C1-C4 alkoxy, which may be substituted by:

"C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom",

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl or C1-C4 alkoxy C1-C4 alkyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy, C1-C4 alkyl or oxo, or

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino",

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy, or

C1-C4 alkyl, which may be substituted by hydroxyl group", or

A 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 nitrogen atoms.

[6] Still more preferably, the compound represented by formula (I) or a salt thereof, wherein

A is

^R2 is

C3-C5 cycloalkyl, which may be substituted with one C1-C4 alkyl; and

X is CR ³ , wherein R ³ is

C1-C4 alkoxy which may be substituted by "one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom", or

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is methyl or methoxyethyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by ^R6 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein ^R6 is hydroxy or methyl, or one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by ^R7 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein ^R7 is C1-C4 alkyl or amino”

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom.

Another preferred embodiment of the present invention will be described below.

Preferably, the compound represented by formula (I) or a salt thereof, wherein A is

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C7 cycloalkyl, which may be substituted with "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C4 alkyl,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the above methylamino may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C4 alkyl, which may be substituted by hydroxyl, or

amino group, which may be substituted by a C1-C4 alkyl (carbonyl) group".

More preferably, the compound represented by formula (I) or a salt thereof, wherein

A is

^R2 is

branched C3-C8 alkyl group, which may be substituted with "halogen or C3-C7 cycloalkyl group",

C3-C7 cycloalkyl group, which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

C1-C4 alkyl,

C1-C4 alkoxy, which may be substituted by:

"halogen,

C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by hydroxyl, or

formyl", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

Another preferred embodiment of the present invention will be described below.

Preferred are compounds represented by formula (I') or salts thereof, wherein

When A is A1,

^R1 is

halogen,

cyano group,

Nitro,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group,

a substituted or unsubstituted amino group, or

a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Y is N or CH;

n is an integer 1 or 2;

^R2 is

a substituted or unsubstituted C3-C10 alkyl group,

a substituted or unsubstituted C3-C4 cycloalkyl group,

a substituted or unsubstituted C4-C12 bridged cycloalkyl group,

substituted or unsubstituted C2-C6 alkenyl, or

a substituted or unsubstituted C3-C4 cycloalkenyl group,

Provided that, when each group represented by R ² has a substituent, the substituent does not allow a substituted or unsubstituted saturated heterocyclic group which may have at least one identical or different heteroatom selected from oxygen and sulfur and at least one nitrogen atom; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C1-C6 alkylthio group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group, provided that the position of the triple bond of the C2-C6 alkynyl group is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

a substituted or unsubstituted C6-C14 aromatic hydrocarbon group, or

a substituted or unsubstituted 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; and

When A is A2,

^R1 is a substituted or unsubstituted C1-C6 alkoxy group;

Y is CH;

n is an integer 0 or 1;

^R2 is a substituted or unsubstituted C3-C7 cycloalkyl group; and

X is N.

More preferably, the compound represented by formula (I') or a salt thereof, wherein

When A is A1,

^R1 is

halogen,

cyano group,

Nitro,

C1-C6 alkyl, which may be substituted by the following groups: "hydroxyl, C1-C6 alkoxy in which the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, C1-C6 alkylthio, or C6-C14 aromatic hydrocarbon group",

C1-C6 alkoxy, which may be substituted by halogen,

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

Y is N or CH;

n is an integer 1 or 2;

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl, which may be substituted with "halogen, C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl,

C2-C6 alkenyl, which may be substituted by halogen, or

C3-C4 cycloalkenyl, and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C6 alkyl, which may be substituted by a hydroxyl group or an oxo group,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C6 alkylthio,

C3-C7 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, and the above alkylamino may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

C6-C14 aromatic hydrocarbon group, which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C6 alkyl, which may be substituted by hydroxy, or amino, which may be substituted by C1-C6 alkyl (carbonyl)"; and

When A is A2,

^R1 is a substituted or unsubstituted C1-C6 alkoxy group;

Y is CH;

n is an integer 0 or 1;

^R2 is a substituted or unsubstituted C3-C7 cycloalkyl group; and

X is N.

[2] Still more preferably, the compound represented by formula (I') or a salt thereof, wherein

When A is A1,

A1 is

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen atoms contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio"

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C14 aromatic hydrocarbon groups", or

a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen, C1-C6 alkyl or C1-C6 alkoxy;

m is an integer 0 or 1;

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl, which may be substituted with "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl",

C4-C12 bridged cycloalkyl, or

C3-C4 cycloalkenyl, and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C4 alkyl, which may be substituted by a hydroxyl group or an oxo group,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, and the above alkylamino may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

C6-C14 aromatic hydrocarbon group, which may be substituted by the following groups:

"Hydroxy,

C1-C6 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C6 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C6 alkyl, which may be substituted by hydroxy, or amino, which may be substituted by C1-C6 alkyl (carbonyl)"; and

When A is A2,

A2 is

wherein R ^1c is a C1-C6 alkoxy group; l is an integer from 1 to 3; and n is an integer of 0 or 1;

^R2 is C3-C7 cycloalkyl; and

X is N.

[3] Still more preferably, the compound represented by formula (I') or a salt thereof, wherein

A is

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl,

amino group, which may be substituted by: "one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or C6-C10 aromatic hydrocarbon groups", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen, C1-C6 alkyl or C1-C6 alkoxy;

m is an integer 0 or 1;

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl, which may be substituted with "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C4 alkyl,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C4 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the above methylamino may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

an unsaturated heterocyclic oxy group which may be substituted by halogen, wherein the unsaturated heterocyclic ring is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C4 alkyl, which may be substituted by hydroxyl, or

amino group, which may be substituted by a C1-C4 alkyl (carbonyl) group".

[4] Still more preferably, the compound of formula (I') or a salt thereof, wherein

A is

Wherein R ^1a is

C1-C6 alkyl, which may be substituted by the following groups: "C1-C6 alkoxy wherein the hydrogen contained in the alkoxy group may be replaced by one or more deuterium atoms, or C1-C6 alkylthio",

C2-C6 alkenyl,

C2-C6 alkynyl, or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

R ^1b is halogen;

m is an integer 0 or 1;

^R2 is

branched C3-C8 alkyl group, which may be substituted with "halogen or C3-C7 cycloalkyl group",

C3-C4 cycloalkyl group, which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

C1-C4 alkyl,

C1-C4 alkoxy, which may be substituted by:

"halogen,

C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

an unsaturated heterocyclic oxy group which may be substituted by halogen, wherein the unsaturated heterocyclic ring is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

[5] Still more preferably, the compound represented by formula (I') or a salt thereof, wherein

A is

wherein R ^1b is halogen;

m is an integer 0 or 1;

^R2 is

branched C3-C6 alkyl, which may be substituted with halogen, or

C3-C4 cycloalkyl group, which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group";

X is CR ³ , wherein R ³ is

hydrogen,

halogen,

C1-C4 alkyl,

C1-C4 alkoxy, which may be substituted by:

"C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom",

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl or C1-C4 alkoxy C1-C4 alkyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy, C1-C4 alkyl or oxo, or

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino",

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy, or

C1-C4 alkyl group which may be substituted by hydroxy group", or a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 nitrogen atoms.

[6] Still more preferably, the compound represented by formula (I') or a salt thereof, wherein

A is

^R2 is

C3-C4 cycloalkyl, which may be substituted with one C1-C4 alkyl; and

X is CR ³ , wherein R ³ is

C1-C4 alkoxy which may be substituted by "one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom", or

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is methyl or methoxyethyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy or methyl, or

"one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁷ is C1-C4 alkoxy or amino",

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom.

Another preferred embodiment of the present invention will be described below.

Preferred are compounds represented by formula (I') or salts thereof, wherein

A is

^R2 is

C3-C10 alkyl, which may be substituted by: "halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur",

C3-C4 cycloalkyl, which may be substituted with "C1-C6 alkyl, C3-C7 cycloalkyl or halogenated C1-C6 alkyl", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

cyano group,

C1-C4 alkyl,

C1-C6 alkoxy, which may be substituted by:

"halogen,

C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl, which may be substituted with a "hydroxyl group",

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by ^R5 , wherein ^R5 is halogen, methylamino or C1-C4 alkoxy, and the above methylamino may be substituted by one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by a hydroxy group,

formyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by C1-C4 alkyl groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

4- to 6-membered monocyclic unsaturated heterocyclic group, which may be substituted by the following groups and contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur:

"halogen,

C1-C4 alkyl, which may be substituted by hydroxyl, or

amino group, which may be substituted by a C1-C4 alkyl (carbonyl) group".

More preferably, the compound represented by formula (I') or a salt thereof, wherein

A is

^R2 is

branched C3-C8 alkyl group, which may be substituted with "halogen or C3-C7 cycloalkyl group",

C3-C4 cycloalkyl group, which may be substituted with "C1-C4 alkyl group or C3-C5 cycloalkyl group", or

C4-C12 bridged cycloalkyl; and

X is

N or

CR ³ , where R ³ is

hydrogen,

halogen,

C1-C4 alkyl,

C1-C4 alkoxy, which may be substituted by:

"halogen,

C1-C4 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

C1-C4 alkylthio,

C2-C4 alkenyl,

C2-C6 alkynyl, which may be substituted by:

"Hydroxy,

C1-C4 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl group which may be substituted by C3-C5 cycloalkyl,

tri-C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

“one or more 4- to 6-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C4 alkyl, C1-C4 alkoxy or oxo,

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 6-membered monocyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

The condition is that the position of the C2-C6 alkynyl triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

Phenyl, which may be substituted by:

"Hydroxy,

C1-C4 alkyl, which may be substituted by hydroxyl, or

formyl", or

4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

Still another preferred embodiment of the present invention will be described below.

Preferred are compounds represented by formula (I) and (I') or salts thereof, wherein

A is

^R2 is

X is CR ³ , wherein R ³ is preferably

hydrogen,

halogen,

cyano group,

a substituted or unsubstituted C1-C6 alkyl group,

a substituted or unsubstituted C1-C6 alkoxy group,

a substituted or unsubstituted C1-C6 alkylthio group,

a substituted or unsubstituted C3-C7 cycloalkyl group,

a substituted or unsubstituted C2-C6 alkenyl group,

a substituted or unsubstituted C2-C6 alkynyl group, provided that the position of the triple bond of the C2-C6 alkynyl group is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom,

a substituted or unsubstituted C6-C14 aromatic hydrocarbon group, or

a substituted or unsubstituted 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur;

More preferably

hydrogen,

halogen,

Substituted or unsubstituted C1-C6 alkoxy, or

a substituted or unsubstituted C2-C6 alkynyl group, provided that the position of the triple bond of the C2-C6 alkynyl group is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom;

Even more preferably

hydrogen,

halogen,

a substituted or unsubstituted methoxy group,

a substituted or unsubstituted ethoxy group,

a substituted or unsubstituted ethynyl group, or

a substituted or unsubstituted propynyl group, provided that the position of the triple bond is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom;

Even more preferably

Methoxy or ethoxy groups which may be substituted by:

"C1-C6 alkoxy,

C3-C7 cycloalkyl, or

one or more 4- to 10-membered monocyclic saturated heterocyclic groups which may be substituted by oxo groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or

Ethynyl or propynyl groups may be substituted by:

"Hydroxy,

C1-C6 alkoxy,

amino group, which may be substituted by R ⁴ , wherein R ⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl group which may be substituted by C3-C7 cycloalkyl,

C1-C6 alkylsilyl group,

C3-C7 cycloalkyl group, which may be substituted with a hydroxyl group or an oxo group,

C6-C14 aromatic hydrocarbon group, which may be substituted by ^R5 , wherein ^R5 is halogen, C1-C4 alkylamino or C1-C6 alkoxy, the above alkylamino group may be substituted by one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups, which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy or amino, or

unsaturated heterocyclic oxy groups which may be substituted by halogen, wherein the unsaturated heterocyclic group is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur"

provided that the position of the triple bond is between the carbon atom attached to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom; and

Even more preferably

Ethynyl or propynyl groups may be substituted by:

"Hydroxy,

amino, which may be substituted by R ⁴ , wherein R ⁴ is C1-C4 alkyl or C1-C4 alkoxy C1-C4 alkyl,

C3-C7 cycloalkyl, which may be substituted by a hydroxy group,

Phenyl, which may be substituted by R ⁵ , wherein R ⁵ is halogen,

"one or more 4- to 6-membered monocyclic saturated heterocyclic groups which may be substituted by R ⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", wherein R ⁶ is hydroxy, C1-C4 alkyl or oxo, or

“one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups which may be substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur”, wherein R ⁷ is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino”

The condition is that the position of the triple bond is between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom.

Specific examples of the compounds of the present invention include, but are not limited to, the compounds produced in the Examples described below.

Preferred examples of the compounds of the present invention are as follows:

(1) 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(2) 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(3) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(4) 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(5) 4-amino-6-chloro-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(6) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(7) 4-amino-6-fluoro-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(9) 4-amino-6-(4-hydroxy-4-methylpent-1-yn-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(10) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(12) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(13) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(14) 4-amino-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(15) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(16) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(17) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(18) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(19) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(20) 4-amino-6-ethoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(21) 4-amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(22) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-thiomorpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(23) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-(tetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(24) 4-amino-6-((6-aminopyridin-3-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(25) 4-amino-6-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(26) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((1-methylpiperidin-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(27) 4-amino-6-(3-(dimethylamino)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(28) 4-amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; and

(29) 4-Amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

More preferred examples of the compounds of the present invention are as follows:

(8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(10) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(12) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; and

(13) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

The present invention also provides a RET inhibitor comprising the compound of the present invention or a salt thereof, for example, the compound or salt thereof according to any one of [1] to [6] above, as an active ingredient.

The present invention also provides a pharmaceutical composition comprising a compound of the present invention or a salt thereof, for example, a compound or a salt thereof according to any one of [1] to [6] above.

The present invention also provides a pharmaceutical composition for preventing or treating a disease that can be treated by RET inhibition, comprising a compound of the present invention or a salt thereof, such as a compound or a salt thereof according to any one of [1] to [6] above.

The present invention also provides an antitumor agent comprising the compound of the present invention or a salt thereof, for example, the compound or salt thereof according to any one of [1] to [6] above.

The present invention also provides an antitumor agent for treating malignant tumors with increased RET activation, comprising a compound of the present invention or a salt thereof, such as a compound or a salt thereof according to any one of [1] to [6] above.

The present invention also provides a compound of the present invention or a salt thereof for use in preventing or treating a malignant tumor, for example, a compound or a salt thereof according to any one of [1] to [6] above.

The present invention also provides a compound of the present invention or a salt thereof for use in preventing or treating a malignant tumor with increased RET activation, for example, a compound or a salt thereof according to any one of [1] to [6] above.

The present invention also provides use of the compound of the present invention or a salt thereof, such as the compound or a salt thereof according to any one of [1] to [6] above, for producing an antitumor agent.

The present invention also provides use of the compound of the present invention or a salt thereof, such as the compound or salt thereof according to any one of [1] to [6] above, for the manufacture of an antitumor agent for treating a malignant tumor with increased RET activation.

The present invention also provides use of the compound of the present invention or a salt thereof, such as the compound or a salt thereof according to any one of [1] to [6] above, for producing a RET inhibitor.

The present invention also provides use of the compound of the present invention or a salt thereof, such as the compound or a salt thereof according to any one of [1] to [6] above, for preventing or treating malignant tumors.

The present invention also provides use of the compound of the present invention or a salt thereof, such as the compound or a salt thereof according to any one of [1] to [6] above, for preventing or treating a malignant tumor with increased RET activation.

The present invention also provides a method for preventing or treating malignant tumors, which comprises administering a compound of the present invention or a salt thereof, such as the compound or salt thereof according to any one of [1] to [6] above, to a mammal.

The present invention also provides a method for preventing or treating a malignant tumor, comprising administering a compound of the present invention or a salt thereof, such as a compound or a salt thereof according to any one of [1] to [6] above, to a mammal, wherein the malignant tumor is a malignant tumor with increased RET activation.

The present invention also provides a method for inhibiting RET, comprising administering to a mammal a compound of the present invention or a salt thereof, for example, a compound or a salt thereof according to any one of [1] to [6] above.

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

For example, the compounds (I) and (I') of the present invention can be produced by the following production methods or the methods described in the Examples. However, the production methods of the compounds (I) and (I') of the present invention are not limited to these reaction examples.

Manufacturing method 1

wherein L ₁ is a leaving group, and R ² and R ³ are as defined above.

Step 1

This step synthesizes the compound represented by formula (BB) from the compound represented by formula (AA). The compound represented by formula (AA) can be obtained from a commercial supplier or can be produced by a known method.

Step 1 is carried out using the compound represented by formula (RE1) or a salt thereof in an amount of usually 0.5 to 5 mol, preferably 0.9 to 1.5 mol, per mol of the compound represented by formula (AA).

In this step, a base can be added as needed. Examples of bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride and potassium hydride; organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and collidine; and similar bases. The amount of base used is generally 1-100 moles, preferably 1-10 moles, per mole of the compound shown in formula (AA). Amino compounds can be obtained from commercial suppliers or manufactured by known methods. Moreover, if necessary, the reaction can be promoted by adding acid during the reaction. Examples of acids include formic acid, acetic acid, hydrochloric acid, phosphoric acid, etc. The amount of acid used is generally 1-100 moles, preferably 1-20 moles, per mole of the compound shown in formula (AA).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include alcohols (e.g., methanol and ethanol), hydrocarbons (e.g., benzene, toluene and xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform and 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane and tetrahydrofuran), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoramide), water and mixtures thereof.

The reaction time is usually in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is usually in the range of 0-120°C, preferably 50-120°C.

The compound represented by formula (BB) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Step 2

This step synthesizes the compound represented by formula (CC) from the compound represented by formula (BB).

Step 2 is carried out using a halogenating agent in an amount of usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (BB).

Examples of halogenating agents include N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, and the like. The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include toluene, benzene, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.

Examples of the leaving group represented by L ₁ include chlorine, bromine, iodine and the like.

The reaction temperature is usually in the range of -78 to 200° C., preferably 0 to 50° C. The reaction time is usually in the range of 5 minutes to 6 days, preferably 10 minutes to 3 days.

The compound represented by formula (CC) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Step 3

This step produces a compound represented by formula (DD) by reacting a compound represented by formula (CC) with ammonia or a salt thereof.

The amount of ammonia or a salt thereof used in this step is usually an equimolar to excess molar amount per mole of the compound represented by formula (CC).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include water, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, 1,2-dimethoxyethane, dimethyl sulfoxide, and mixtures thereof.

The reaction temperature is usually in the range of 0-200° C., preferably room temperature to 150° C. The reaction time is usually in the range of 5 minutes to 7 days, preferably 30 minutes to 4 days.

The compound represented by formula (DD) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Manufacturing method 2

wherein L ₁ and L ₂ are leaving groups, and R ² is as defined above.

Step 4

This step produces a compound represented by formula (FF) using a compound represented by formula (EE) and a compound represented by formula (III) or (IV). The compound represented by formula (EE) can be obtained from a commercial supplier or can be produced by a known method.

When using a compound represented by formula (III) as an alkylating agent, a compound represented by formula (FF) can be produced in the presence of a base. In formula (III), L ₂ is a leaving group, such as chlorine, bromine, iodine, mesylate or p-toluenesulfonate. The compound represented by formula (III) can be obtained from a commercial supplier, or can be manufactured by known methods. The amount of the compound represented by formula (III) is generally 1-10 moles, preferably 1-5 moles, relative to per mole of the compound represented by formula (EE).

Examples of the base include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride, and potassium hydride; organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine, and collidine; and similar bases. The amount of the base used is usually 1 to 100 moles, preferably 1 to 10 moles, per mole of the compound represented by formula (EE).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile, and the like. These solvents can be used alone or in combination.

The reaction time is usually in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is usually in the range of 0°C to the boiling point of the reaction solvent, preferably 0-100°C.

When a compound of formula (IV) is used as an alkylating agent, a compound represented by formula (FF) can be produced by a Mitsunobu reaction. This step can generally be carried out by known methods, for example, the method described in the following document: Chemical Reviews, Vol. 109, p. 2551 (2009). For example, this step can be carried out in the presence of a Mitsunobu reagent and a phosphine reagent in a solvent that does not adversely affect the reaction. This step is generally carried out using the compound represented by formula (IV) in an amount of 1-10 moles, preferably 1-5 moles, per mole of the compound represented by formula (EE).

Examples of the Mitsunobu reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc. The amount of the Mitsunobu reagent used is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (EE).

Examples of the phosphine reagent include triphenylphosphine and tributylphosphine. The amount of the phosphine reagent used is usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (EE).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include toluene, benzene, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.

The reaction temperature is usually in the range of -78 to 200° C., preferably 0 to 50° C. The reaction time is usually in the range of 5 minutes to 3 days, preferably 10 minutes to 48 hours.

The compound represented by formula (FF) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Step 5

This step produces a compound represented by formula (GG) by reacting a compound represented by formula (FF) with ammonia or a salt thereof.

The amount of ammonia or a salt thereof used in this step is usually an equimolar to excess molar amount per mole of the compound represented by formula (FF).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include water, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, 1,2-dimethoxyethane, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.

The reaction temperature is usually in the range of 0-200° C., preferably room temperature to 150° C. The reaction time is usually in the range of 5 minutes to 7 days, preferably 30 minutes to 4 days.

The compound represented by formula (GG) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Manufacturing method 3

wherein L ₁ and L ₂ are each a leaving group, and R ² is as defined above.

Step 6

This step uses a compound represented by formula (QQ) and a compound represented by formula (III) or (IV) to produce a compound represented by formula (WW). The compound represented by formula (QQ) can be obtained from a commercial supplier or can be manufactured by a known method. When a compound represented by formula (III) is used as an alkylating agent, a compound represented by formula (WW) can be produced in the presence of a base. In formula (III), L ₂ is a leaving group, such as chlorine, bromine, iodine, methanesulfonate or p-toluenesulfonate; it can be obtained from a commercial supplier or can be manufactured by a known method. The amount of the compound represented by formula (III) is generally 1-10 moles, preferably 1-5 moles per mole of the compound represented by formula (QQ).

Examples of bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride and potassium hydride; organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and collidine; and similar bases. The amount of the base used is generally 1-100 moles, preferably 2-10 moles, per mole of the compound represented by formula (QQ). Examples of reaction solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile, and the like. These solvents can be used alone or in combination.

The reaction time is usually in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is usually in the range of 0°C to the boiling point of the solvent, preferably 0-100°C.

When a compound of formula (IV) is used as an alkylating agent, a compound represented by formula (WW) can be produced by a Mitsunobu reaction. This step can generally be carried out by known methods, for example, the method described in the following document: Chemical Reviews, Vol. 109, p. 2551 (2009). For example, this step can be carried out in the presence of a Mitsunobu reagent and a phosphine reagent in a solvent that does not adversely affect the reaction. This step is generally carried out using the compound represented by formula (IV) in an amount of 1-10 moles, preferably 1-5 moles, per mole of the compound represented by formula (QQ).

Examples of Mitsunobu reagents include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and the like. The amount of the Mitsunobu reagent used is generally 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (QQ). Examples of phosphine reagents include triphenylphosphine and tributylphosphine. The amount of the phosphine reagent used is generally 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (QQ).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include toluene, benzene, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.

The reaction temperature is usually in the range of -78 to 200° C., preferably 0 to 50° C. The reaction time is usually in the range of 5 minutes to 3 days, preferably 10 minutes to 48 hours.

The compound represented by formula (WW) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Manufacturing Method 4

wherein L ₁ is a leaving group, R ² and X are as defined above.

Step 7

This step produces a compound represented by formula (JJ) by reacting a compound represented by formula (HH) in a solvent that does not adversely influence the reaction using, for example, a transition metal and optionally a base in the presence of an alcohol in a carbon monoxide atmosphere.

The compound represented by formula (HH) can be produced by steps 1 to 3, steps 4 and 5, or step 6 of the production method of the present application.

In this step, the pressure of carbon monoxide is generally 1 atm to 20 atm, preferably 1 atm to 10 atm.

The amount of the alcohol compound used is generally 1 to an excess mole per mole of the compound represented by formula (HH). Examples of the alcohol compound include methanol, ethanol, propanol, isopropanol, diethylaminoethanol, isobutanol, 4-(2-hydroxyethyl)morpholine, 3-morpholinopropanol, diethylaminopropanol, and the like.

Examples of transition metal catalysts that can be used in this step include palladium catalysts (e.g., palladium acetate, tris(benzylideneacetone)dipalladium, bis(triphenylphosphine)palladium(II)dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, etc.). As needed, a ligand (e.g., triphenylphosphine, xanthene, tri-tert-butylphosphine, etc.) is added. The amount of the transition metal catalyst varies depending on the type of catalyst. For example, the amount of the transition metal catalyst used is generally 0.0001-1 mole, preferably 0.001-0.5 mole, per mole of the compound represented by formula (HH). The amount of the ligand used is generally 0.0001-4 moles, preferably 0.01-2 moles, per mole of the compound represented by formula (HH).

Moreover, a base can be added during the above reaction as needed. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount of the base used is generally 0.1 to 50 moles, preferably 1 to 20 moles, per mole of the compound represented by formula (HH).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof. The reaction time is typically in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is typically in the range of 0-200° C., preferably 0-150° C.

The ester form corresponding to the alcohol used or the mixture of the ester form and the carboxylic acid compound (JJ) can be subjected to a hydrolysis reaction to convert the ester form or the mixture into a compound represented by formula (JJ). The hydrolysis is carried out using a base. Examples of the base include organic bases such as diethylamine, diisopropylethylamine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyllithium; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide.

The reaction solvent is not particularly limited, and any solvent that does not have a negative effect on the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof.

The reaction time is usually in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is usually in the range of 0°C to the boiling point of the solvent, preferably 0-150°C.

The compound represented by formula (JJ) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Manufacturing method 5

wherein L ₁ is a leaving group; E is an ester, cyano or a carboxylic acid equivalent, such as formamide; Z is a halogen; and R ² and R ³ are as defined above.

Step 8

This step is carried out by reacting a compound represented by formula (GG) in a solvent that does not adversely influence the reaction in the presence of an alcohol in a carbon monoxide atmosphere, or using a cyano compound such as copper cyanide or zinc cyanide, using, for example, a transition metal catalyst and optionally a base to produce an ester derivative or a cyano derivative represented by formula (KK).

The compound represented by formula (GG) can be produced by steps 1 to 3, and steps 4 and 5 of the production method of the present application.

In the production process of the ester derivative, the pressure of carbon monoxide is generally 1 atm to 20 atm, preferably 1 atm to 10 atm. The amount of the alcohol compound used as a reaction reagent is generally 1 to an excess mole per mole of the compound represented by formula (GG), preferably 1 to 200 moles. Examples of alcohol compounds include methanol, ethanol, propanol, isopropanol, diethylaminoethanol, isobutanol, 4-(2-hydroxyethyl)morpholine, 3-morpholinopropanol, diethylaminopropanol, etc.

In the production of cyano derivatives, examples of cyano compounds used as reaction reagents include copper cyanide, zinc cyanide, tri-n-butyltin cyanide, etc. The amount of the cyano compound used as a reaction reagent is usually 1 to 100 moles, preferably 1 to 10 moles, per mole of the compound represented by formula (GG).

Examples of transition metal catalysts that can be used in the manufacture of ester derivatives and the manufacture of cyano derivatives in this step include palladium catalysts (e.g., palladium acetate, tetrakistriphenylphosphine palladium, tris(benzylideneacetone)dipalladium, bis(triphenylphosphine)palladium(II)dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, etc.). As needed, a ligand (e.g., triphenylphosphine, xanthene, tri-tert-butylphosphine, etc.) is added. The amount of the transition metal catalyst varies depending on the type of catalyst. For example, the amount of the transition metal catalyst is typically 0.0001-1 mole, preferably 0.001-0.5 mole, relative to each mole of the compound represented by formula (GG). The amount of the ligand is typically 0.0001-4 moles, preferably 0.01-2 moles, relative to each mole of the compound represented by formula (GG).

Moreover, a base can be added during the above reaction as needed. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, coltidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyllithium; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. The amount of the base used is generally 0.1-50 moles, preferably 1-20 moles, per mole of the compound represented by formula (GG).

The reaction solvent is not specifically limited and any solvent that does not have an adverse effect on the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene and xylene), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran and 1,4-dioxane), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and hexamethylphosphoramide), water and mixtures thereof. The reaction time is generally in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is 0-200°C, preferably 0-150°C. After separation and purification from the reaction mixture by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without separation and purification, the compound represented by the formula (KK) thus obtained is subjected to subsequent steps.

Step 9

This step produces a halogenated compound (LL) by treating the compound represented by the formula (KK) with a halogenating agent.

This step is usually carried out using a halogenating agent in an amount of usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by formula (KK).

Examples of halogenating agents include 1-chloromethyl-4-fluoro-1,4-diazonia bicyclo[2.2.2]octane bis(tetrafluoroborate), N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, and the like. The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include dichloromethane, chloroform, toluene, benzene, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.

Examples of the halogen represented by Z include fluorine, chlorine, bromine, iodine and the like.

The reaction temperature is usually in the range of -78 to 200° C., preferably 0 to 50° C. The reaction time is usually in the range of 5 minutes to 6 days, preferably 10 minutes to 3 days.

The compound represented by formula (LL) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Furthermore, if necessary, E can be converted into another E by a known method such as hydrolysis or solvolysis. For example, a cyano group can be converted into formamide by hydrolysis, and a cyano group or formamide can be converted into an ester by solvolysis.

Step 10

This step is carried out by subjecting the compound represented by formula (LL) to a coupling reaction with a borate derivative, a boric acid derivative, a tin derivative, an acetylene derivative, an alkali metal salt, an alkaline earth metal salt, an alkoxide or a thioalkoxide having R ³ in a solvent that does not adversely influence the reaction, using, for example, a transition metal and, optionally, a base, to produce a compound represented by formula (MM).

The amount of borate derivatives, boric acid derivatives, tin derivatives, acetylene derivatives, alkali metal salts, alkaline earth metal salts, alkoxides or thiolates with R ³ is generally 1-100 moles, preferably 1-20 moles. The example of the transition metal catalyst that can be used for this step includes palladium catalyst (for example, palladium acetate, tetrakistriphenylphosphine palladium, tris (benzylideneacetone) dipalladium, bis (triphenylphosphine) palladium (II) dichloride, 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex etc.). As needed, add ligand (for example, triphenylphosphine, xanthene, 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine etc.). The example of copper catalyst includes copper iodide, copper bromide and copper chloride. The amount of transition metal catalyst varies depending on the type of catalyst. For example, the amount of the transition metal catalyst used is generally 0.0001 to 1 mole, preferably 0.001 to 0.5 mole, per mole of the compound represented by formula (LL). A transition metal catalyst may be used in combination as needed. The amount of the ligand used is generally 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of the compound represented by formula (LL).

Moreover, a base can be added during the above reaction as needed. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, coltidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyllithium; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide and sodium hydride. The amount of the base is generally 0.1-50 moles, preferably 1-20 moles, per mole of the compound represented by formula (LL).

The reaction solvent is not specifically limited, and any solvent that does not have a negative effect on the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol, ethanol, and ethylene glycol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof.

The reaction time is usually in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is usually in the range of 0°C to the boiling point of the solvent, preferably 0-160°C.

The compound represented by formula (MM) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Manufacturing Method 6

wherein E, R ² and R ³ are as defined above.

Step 11

This step produces a carboxylic acid compound represented by formula (NN) by hydrolyzing the compound represented by formula (MM).

Hydrolysis is carried out using a base or an acid. Examples of the base include organic bases such as diethylamine, diisopropylamine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, and the like.

The reaction solvent is not specifically limited, and any solvent that does not have a negative effect on the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol, ethanol, and ethylene glycol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof.

The reaction time is usually in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is in the range of 0°C to the boiling point of the solvent, preferably 0-160°C.

The compound represented by formula (NN) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

Manufacturing Method 7

wherein A, ^R2 and X are as defined above.

Step 12

This step involves an amidation reaction between a compound represented by formula (JJ) and a compound represented by formula (VII) to produce a compound represented by formula (RR). The compound represented by formula (VII) is used in an amount of usually 0.5 to 10 moles, preferably 1 to 3 moles, per mole of the compound represented by formula (JJ) in the presence of an appropriate condensing agent or activating agent as an amidating agent.

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of the solvent include isopropyl alcohol, tert-butyl alcohol, toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and mixtures thereof.

The reaction temperature is usually in the range of -78 to 200° C., preferably 0 to 100° C. The reaction time is in the range of 5 minutes to 7 days, preferably 5 minutes to 3 days, more preferably 5 minutes to 10 hours.

Examples of condensing agents and activators include diphenylphosphoryl azide, N,N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-tris dimethylaminophosphonium salt, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, 2-chloro-1,3-dimethylimidazolium chloride, (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate, 1,1-carbonyldiimidazole, N-hydroxysuccinimide, and the like.

Moreover, alkali can be added during the above-mentioned reaction as needed. The example of alkali includes organic base, such as triethylamine, diisopropylethylamine, pyridine, lutidine, coltidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, diazabicycloundecene, diazabicyclononene and butyllithium; and inorganic base, such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. The amount of alkali is generally 1-100 moles relative to each mole of the compound represented by formula (JJ), preferably 1-10 moles.

After the reaction is completed, a base such as sodium hydroxide solution may be added for post-treatment.

The compound represented by the formula (RR) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography.

Manufacturing method 8

wherein L ₁ is a leaving group, and A, R ² and X are as defined above.

Step 13

This step produces a compound represented by formula (RR) by reacting a compound represented by formula (HH) in the presence of compound (VII) using, for example, a transition metal and optionally a base in a solvent that does not adversely influence the reaction in a carbon monoxide atmosphere.

In this step, the pressure of carbon monoxide is generally 1 atm to 20 atm, preferably 1 atm to 10 atm.

Examples of transition metal catalysts that can be used in this step include palladium catalysts (e.g., palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium(II)dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, etc.). As needed, a ligand (e.g., triphenylphosphine, xanthene, tri-tert-butylphosphine, etc.) is added. The amount of the transition metal catalyst varies depending on the type of catalyst. For example, the amount of the transition metal catalyst used is generally 0.0001-1 mole, preferably 0.001-0.5 mole, per mole of the compound represented by formula (HH). The amount of the ligand used is generally 0.0001-4 moles, preferably 0.01-2 moles, per mole of the compound represented by formula (HH).

Moreover, a base can be added during the above reaction as needed. The example of the base includes an organic base, such as triethylamine, diisopropylethylamine, pyridine, lutidine, coltidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium hexamethyldisilazide and butyllithium; and an inorganic base, such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. The amount of the base is generally 0.1-50 moles, preferably 1-20 moles, relative to each mole of the compound represented by formula (HH).

The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof. The reaction time is generally in the range of 0.1-100 hours, preferably 0.5-24 hours. The reaction temperature is in the range of 0-250° C., preferably 0-200° C.

The compound represented by the formula (RR) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography.

Manufacturing method 9

wherein A, Z and ^R2 are as defined above.

This step produces a compound represented by formula (TT) from a compound represented by formula (OO) using an appropriate halogenating agent.

This step is usually carried out using a halogenating agent in an amount of usually 1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by the formula (OO).

Examples of halogenating agents include 1-chloromethyl-4-fluoro-1,4-diazonium bicyclo[2.2.2]octane bis(tetrafluoroborate), N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, and the like. The reaction solvent is not particularly limited, and any solvent that does not adversely affect the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), chloroform, dichloromethane, carbon tetrachloride, and mixtures thereof.

Examples of the halogen represented by Z include fluorine, chlorine, bromine, iodine and the like.

The reaction temperature is usually in the range of -78 to 200° C., preferably -10 to 50° C. The reaction time is usually in the range of 5 minutes to 6 days, preferably 10 minutes to 3 days.

The compound represented by formula (TT) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography.

Manufacturing method 10

wherein A, ^R2 and ^R3 are as defined above.

This step produces a compound represented by formula (UU) by subjecting the compound represented by formula (PP) to a coupling reaction with a borate derivative, a boronic acid derivative, a tin derivative, an acetylene derivative, an alkali metal salt, or an alkaline earth metal salt having R ³ in a solvent that does not adversely influence the reaction, using, for example, a transition metal and optionally a base.

The amount of borate derivatives, boric acid derivatives, tin derivatives, acetylene derivatives, alkali metal salts, alkaline earth metal salts, alkoxides or thiolates with R ³ is generally 1-100 moles, preferably 1-20 moles. The example of the transition metal catalyst that can be used for this step includes palladium catalyst (for example, palladium acetate, tetrakistriphenylphosphine palladium, tris (benzylideneacetone) dipalladium, bis (triphenylphosphine) palladium (II) dichloride, 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex etc.). As needed, add ligand (for example, triphenylphosphine, xanthene, 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, tricyclohexylphosphine, tri-tert-butylphosphine etc.). As needed, copper catalyst can be used. The example of copper catalyst includes copper iodide, copper bromide and copper chloride. The amount of the transition metal catalyst varies depending on the type of catalyst. For example, the amount of the transition metal catalyst used is generally 0.0001 to 1 mole, preferably 0.001 to 0.5 mole, per mole of the compound represented by formula (PP). As needed, a transition metal catalyst may be used alone or in combination. The amount of the ligand used is generally 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of the compound represented by formula (PP).

Moreover, a base can be added during the above reaction as needed. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, coltidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyllithium; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide and sodium hydride. The amount of the base used is generally 0.1-50 moles, preferably 1-20 moles, per mole of the compound represented by formula (PP).

The reaction solvent is not specifically limited, and any solvent that does not have a negative effect on the reaction can be used. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (e.g., methanol, ethanol, ethylene glycol, and isopropanol), aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof.

The reaction time ranges from 0.1 to 100 hours, preferably from 0.5 to 48 hours. The reaction temperature ranges from 0°C to the boiling point of the solvent, preferably from 0 to 160°C.

The compound represented by formula (UU) thus obtained is subjected to the subsequent steps after isolation and purification from the reaction mixture by known isolation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, recrystallization and chromatography, or without isolation and purification.

When the compounds of the present invention have isomers such as optical isomers, stereoisomers, positional isomers and rotational isomers, any mixture of isomers is included in the scope of the compounds of the present invention. For example, when the compounds of the present invention have optical isomers, the optical isomers separated by the racemic mixture are also included in the scope of the compounds of the present invention. Each of these isomers can be obtained as a separate compound by known synthesis and separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

The compound of the present invention or its salt can be in the form of crystals. Single crystals and polymorphic mixtures are both included in the scope of the compound of the present invention or its salt. These crystals can be manufactured by crystallization methods known in the art. The compound of the present invention or its salt can be a solvate (e.g., hydrate) or an ansolvate. Any of these forms is included in the scope of the compound of the present invention or its salt. Compounds labeled with isotopes (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ³⁵ S, ¹²⁵ I) are also included in the scope of the compound of the present invention or its salt.

A prodrug of a compound of the present invention or a salt thereof refers to a compound that can be converted into the compound of the present invention or a salt thereof in vivo under physiological conditions by reacting with an enzyme, gastric acid, or the like. Specifically, a compound that can be converted into the compound of the present invention or a salt thereof by enzymatic oxidation, reduction, hydrolysis, or the like; or a compound that can be converted into the compound of the present invention or a salt thereof by hydrolysis with gastric acid or the like. Furthermore, a prodrug of a compound of the present invention or a salt thereof can be a compound that can be converted into the compound of the present invention or a salt thereof under physiological conditions, such as those described in the following document: "Iyakuhin no Kaihatsu [Development of Pharmaceuticals]," Vol. 7, Molecular Design, published by Hirokawa Shoten Co. in 1990, pp. 163-198.

The salts of the compounds of the present invention refer to common salts used in the field of organic chemistry. Examples of these salts include base addition salts with carboxyl groups when the compound has a carboxyl group, and acid addition salts with amino groups or basic heterocyclic groups when the compound has an amino group or a basic heterocyclic group.

Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; organic acid salts such as acetate, formate, maleate, fumarate, tartrate, citrate, ascorbate and trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.

In this specification, "RET" refers to RET (rearranged during transfection) tyrosine kinase, including human RET and non-human mammalian RET, preferably human RET. In addition, the term "RET" includes isoforms. In addition, it is known that for RET, due to differences in carboxyl-terminal splicing, there are three types of proteins, namely, RET9, RET43 and RET51 (Trends in Genetics, 2006, Vol. 22, pp. 627-636). In addition to these three types of proteins, "RET" includes all splice variants that are now known and will be known in the future, as long as they contain the ATP-binding site of RET.

Examples of human RET include a polypeptide comprising the amino acid sequence encoded by GenBank Accession No. NM_020975 and a polypeptide comprising the amino acid sequence encoded by GenBank Accession No. NM_020630.

Furthermore, examples of the gene encoding RET include a polynucleotide comprising base sequence No. 191 to No. 3535 of the base sequence represented by GenBank Accession No. NM_020975, a polynucleotide comprising base sequence No. 191 to No. 3409 of the base sequence represented by GenBank Accession No. NM_020630, and the like.

Furthermore, the RET of the present invention may have translocation and mutation (including point mutation, deletion mutation and insertion mutation) as long as it has RET kinase activity.

In the present invention, the translocation of RET includes the following situation: the whole or part of the RET protein having RET kinase activity is fused with the whole or part of another protein (for example, KIF5B protein, CCDC6 protein, NCOA4 protein or TRIM33 protein) to form a fusion protein, preferably CCDC6-RET and KIF5B-RET (CCDC6-RET means that part of the CCDC6 protein and part of the RET protein are fused in this order; the same below) (Drilon A, Cancer Discov., 3(6), pp.630-635 (2013)).

In the present invention, the mutation of RET may be a point mutation, a deletion mutation, or an insertion mutation, as long as RET has RET kinase activity. RET mutations include polypeptides having RET kinase activity and comprising an amino acid sequence mutated by substitution, deletion, or addition of one or more amino acids, or a combination thereof, in the amino acid sequence of RET (e.g., the amino acid sequence encoded by GenBank Accession No. NM_020975 or the amino acid sequence encoded by GenBank Accession No. NM_020630).

The region to be mutated is not limited, as long as RET has RET kinase activity. Mutations can be made to the ATP-binding region or the gatekeeper region. The residue region adjacent to the hinge region where the protein kinase is connected to ATP is called the gatekeeper region. The amino acid residues in this region greatly affect the spatial conformation of the ATP-binding pocket. The amino acid in the gatekeeper region of RET is valine at position 804 of the amino acid sequence encoded by GenBank accession number NM_020975 or GenBank accession number NM_020630. Clinically, RET V804L mutations and RET V804M mutations have been reported in patients with thyroid cancer (Bolino A, Oncogene, 10, pp. 2415-2419, (1995), etc.).

In addition, it is known that continuous administration of protein kinase inhibitors often leads to spontaneous mutations of amino acid residues in the gatekeeper region (Kobayashi S, N Engl J Med., 352 (8): pp.786-792, (2005), etc.). Therefore, continuous administration of RET inhibitors can lead to mutation of valine 804 in the gatekeeper region (Cranston AN, Cancer Res., 66 (20): pp.10179-10187, (2006)). Mutations in the gatekeeper region allow the acquisition of inhibitor resistance, and thus may lead to serious treatment problems. In fact, basic research has reported that cells obtained by introducing V804L mutation or V804M mutation into RET show resistance to vandetanib, a drug with RET inhibitory activity (Carlomagno F, Oncogene, 23, pp.6056-6063, (2004)).

These resistance mutation RETs are preferably RETs having V804L, V804M, V804E, Y806C, Y806E, Y806S, Y806H or Y806N, wherein the valine at position 804 or the adjacent tyrosine at position 806 serving as the gatekeeper region is replaced by another amino acid; more preferably, RETs having V804L or V804M, wherein the valine at position 804 is replaced by leucine or methionine.

Furthermore, the RET of the present invention may have mutations in regions other than the gatekeeper region, as long as it has RET kinase activity. Examples include, but are not limited to, RET having C618S, C620R, C630R, C634R, C634W, C634Y, C691S, E768D, A883F, A883S, E884V, S891A, S891L, or M918T in the amino acid sequence encoded by GenBank Accession No. NM_020975 or GenBank Accession No. NM_020630 (for example, C618S represents RET in which cysteine at position 618 is substituted with serine; the same applies hereinafter). C634W is preferred.

The presence of RET mutations can be investigated by analyzing the RET gene sequence or the sequence of the RET gene transcript mRNA. Examples of sequence analysis methods include the dideoxynucleotide chain termination method (Sanger et al. (1977) Proc. Natl. Acad. Sci. USA 74:5463). Sequences can also be analyzed using a suitable DNA sequencer.

The presence of RET mutations can also be analyzed by, for example, in situ hybridization, Northern blot analysis, DNA microarray, RT-PCR, SSCP-PCR (single-strand conformation polymorphism-PCR), etc. These methods can be performed in a standard manner (Clinical Cancer Research, 8, 457-463, 2002).

Furthermore, the presence of RET mutations can be analyzed, for example, by immunochemical methods (eg, immunohistochemical techniques, immunoprecipitation, Western blotting, flow cytometry, ELISA, RIA, etc.) These methods can be performed in standard manner.

To analyze the presence of RET mutations by PCR, primer sequences can be designed by standard means. For example, Primer Expression (Perkin-Elmer Applied Biosystems) can be used to design primer sequences.

Due to their excellent RET inhibitory activity, the compounds of the present invention or their salts can be used as pharmaceutical preparations for preventing and treating RET-related diseases. Examples of "RET-related diseases" include diseases whose onset can be reduced and whose symptoms can be alleviated, relieved, and/or completely cured by eliminating, suppressing, and/or inhibiting RET function. Examples of these diseases include, but are not limited to, malignant tumors. Preferred examples of malignant tumors include those with increased RET activation, more preferably non-small cell lung cancer, breast cancer, colorectal cancer, or thyroid cancer with overactivation of RET.

The term "increased RET activation" means that the activation state of RET is increased due to, for example, translocation and mutation (including point mutation, deletion mutation and insertion mutation) and overexpression (including increased RET gene copy number, overexpression of RET messenger RNA, increased RET protein and constitutive activation of RET protein) of the RET gene.

The types of cancers and tumors to be treated by the compounds of the present invention or their salts are not particularly limited. Examples include epithelial cancers (respiratory cancers, digestive cancers, reproductive cancers, secretory cancers, etc.), sarcomas, hematopoietic tumors, central nervous system tumors, and peripheral nerve tumors.

Specific examples of cancer types include head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gall bladder, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), kidney cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, testicular tumor, leukemia, malignant lymphoma, multiple myeloma, osteosarcoma, soft tissue sarcoma, skin cancer, brain tumor, adrenal tumor, neuroblastoma, etc. The target cancer is preferably lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, brain tumor and leukemia; non-small cell lung cancer, breast cancer, colorectal cancer and thyroid cancer are particularly preferred.

When the compound of the present invention or a salt thereof is used as a pharmaceutical preparation, a pharmaceutical carrier may be added, if necessary, to form an appropriate dosage form according to the purpose of prevention or treatment. Examples of dosage forms include oral preparations, injections, suppositories, ointments, patches, etc.; oral preparations are preferred. These dosage forms can be formed by methods conventionally known to those skilled in the art.

As pharmaceutical carriers, a variety of conventional organic or inorganic carrier materials used as formulation materials can be mixed in solid preparations as excipients, binders, disintegrants, lubricants or coating agents; or mixed in liquid preparations as solvents, solubilizers, suspending agents, isotonic agents, pH regulators/buffers or soothing agents. In addition, if necessary, pharmaceutical formulation additives such as preservatives, antioxidants, colorants, sweeteners and stabilizers can also be used.

When preparing solid preparations for oral administration, excipients, binders, disintegrants, lubricants, colorants, sweeteners, etc. may optionally be added to the compounds of the present invention; the resulting mixture can be formulated into tablets, coated tablets, granules, powders, capsules, etc. according to general methods.

When preparing injections, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc. can be added to the compound of the present invention as needed; the resulting mixture can be formulated into subcutaneous, intramuscular and intravenous injections according to general methods.

The amount of the compound of the present invention to be incorporated into each of these unit dosage forms depends on the condition of the patient to whom the compound is to be administered, the dosage form, etc. In general, in the case of oral preparations, injections, and suppositories, the amount of the compound of the present invention is preferably 0.05-1000 mg, 0.01-500 mg, and 1-1000 mg per unit dosage form, respectively.

The daily dose of such a dosage form depends on the patient's condition, weight, age, sex, etc. and cannot be generalized. For example, the daily dose of the compound of the present invention for an adult (weight: 50 kg) can generally be 0.05-5000 mg, preferably 0.1-1000 mg; and is preferably administered in one dose or divided into two or three doses per day.

The compound of the present invention or its salt has excellent RET inhibitory activity and can be used as an anti-tumor agent. The RET described herein is preferably "activation-enhanced" RET, as defined above. Moreover, in a preferred embodiment, the compound of the present invention or its salt has very high RET selectivity and advantageously has almost no side effects caused by off-target (such as Src, Lck, EGFR and Aurora B) inhibition. Aurora B is a kinase involved in cell division. Clinical trials of agents with Aurora B inhibitory activity have reported that side effects on the blood cell system, such as neutropenia, often occur (non-patent literature 20). Moreover, inhibitors targeting EGFR are known to interact and cause side effects, such as skin diseases or gastrointestinal diseases (non-patent literature 21).

In a preferred embodiment, the compound of the present invention or a salt thereof also has an excellent cell growth inhibitory effect on cells originally harboring RET-resistance mutations, for which existing RET inhibitors are unlikely to be effective. Furthermore, the compound of the present invention or a salt thereof has an excellent cell growth inhibitory effect on cells harboring acquired RET-resistance mutations due to continuous administration of RET inhibitors, enabling long-term administration.

Furthermore, in a preferred embodiment, the compound of the present invention or a salt thereof has excellent stability in liver microsomes, and therefore can be expected to have excellent exposure in the blood without concerns about Cyp inhibition.

Furthermore, in a preferred embodiment, the compound of the present invention or a salt thereof has excellent oral absorbability. Therefore, sufficient plasma concentration is observed, and the compound of the present invention or a salt thereof can be used as an oral drug.

Example

The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to the Examples.

Unless otherwise specified, commercially available reagents were used in the experiments. For silica gel column chromatography, the following columns were used: Purif-Pack (registered trademark) SI manufactured by Moritex Corp., KP-Sil (registered trademark) silica gel pre-packed columns manufactured by Biotage, HP-Sil (registered trademark) silica gel pre-packed columns manufactured by Biotage, or HP-Sphere (registered trademark) silica gel pre-packed columns manufactured by Biotage. For alkaline silica gel column chromatography, Purif-Pack (registered trademark) NH manufactured by Moritex Corp. or KP-NH (registered trademark) pre-packed columns manufactured by Biotage were used. For preparative thin-layer chromatography, Kieselgel™ 60F 254, Art. 5744 manufactured by Merck, or NH ₂ silica gel 60F 254 plates manufactured by Wako were used. NMR spectra were measured using an AL400 (400 MHz; manufactured by JEOL), Mercury 400 (400 MHz; manufactured by Agilent Technologies, Inc.), or Inova 400 (400 MHz; manufactured by Agilent Technologies, Inc.) spectrometer equipped with an OMNMR probe (Protasis). When tetramethylsilane was contained in the deuterated solvent, tetramethylsilane was used as an internal standard; otherwise, the NMR solvent was used as the internal standard. All δ values are expressed in ppm. Microwave reactions were performed using an initiator manufactured by Biotage.

The LCMS spectrum was measured using Acquity SQD (quadrupole) manufactured by Waters Corporation under the following conditions.

Column: Acquity UPLC (registered trademark) BEH C18, 2.1 x 50 mm, 1.7 μm (manufactured by Waters Corporation)

MS detection: ESI+

UV detection: 254nm and 210nm

Column flow rate: 0.5 mL/min

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

Injection volume: 1 μL gradient (Table 1)

Reverse phase preparative HPLC purification was performed using a preparative separation system from Gilson, Inc.

Column: CombiPrep Pro C18, 50X 30mm l.D., S-5μm (manufactured by YMC)

UV detection: 254nm

Column flow rate: 40 mL/min

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

Injection volume: 0.1-1 mL

The following are the abbreviations used and their meanings.

s: single peak

d: Twin Peaks

t: Three Peaks

q: quartet

dd: double peaks

dt: double triple peak

td: triple double peaks

tt: Triple Triple Peak

ddd: double double peaks

DDT: Double Double Triple Peak

DTD: Double Triple Doublet

TDD: Triple Double Double Peaks

m: multiple peaks

br: broad peak

brs: single broad peak

brd: double broad peak

CDI: Carbonyldiimidazole

DMSO-d ₆ : deuterated dimethyl sulfoxide

CDCl ₃ : deuterated chloroform

CD ₃ OD: deuterated methanol

THF: Tetrahydrofuran

DMF: N,N-dimethylformamide

DMA: N,N-dimethylacetamide

NMP: 1-Methyl-2-pyrrolidone

DMSO: dimethyl sulfoxide

HATU: (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyleneammonium hexafluorophosphate

DIAD: diisopropyl azodicarboxylate

DIPEA: diisopropylethylamine

DME: 1,2-dimethoxyethane

Reference Example 1: Synthesis of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

Step 1: Synthesis of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-Cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A suspension of 3.0 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (synthesized according to the method described in International Publication No. WO2007/126841), 3.4 g of iodocyclopentane, and 4.8 g of potassium carbonate in 30 mL of DMF was heated to 80°C and stirred for 18 hours. The resulting mixture was cooled to room temperature, 200 mL of water was added, and the precipitate was filtered. The precipitate was washed with water and dried to yield 3.7 g of the title compound.

Physical properties: m/z[M+H] ⁺ 330.1.

Step 2: Synthesis of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

4-Amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

21 g of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Step 1, 42 ml of 2-diethylaminoethanol, and 2.24 g of Pd(PPh ₃ ) ₂ Cl ₂ were dissolved in 120 ml of NMP. The system was purged with carbon monoxide and then heated to 120°C. After stirring for 2 hours, the resulting mixture was cooled to room temperature, and 50 ml of methanol was added. 19 ml of 5N aqueous sodium hydroxide solution was then added and stirred for 30 minutes. After adding water, the aqueous layer was washed with ethyl acetate and the washed aqueous layer was adjusted to pH 3 with hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried to obtain 9.8 g of the title compound.

Physical properties: m/z[M+H] ⁺ 248.3.

Reference Example 2: Synthesis of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

Step 1: Synthesis of 1-(adamantan-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-(Adamantane-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

2.3 mL of diisopropyl azodicarboxylate was added to a solution of 1.5 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 2.6 g of 2-adamantanol, and 3.0 g of triphenylphosphine in 30 mL of THF at room temperature, followed by stirring overnight. After concentration, the residue was purified by silica gel chromatography (hexane → hexane/ethyl acetate = 1/1) to give 1.87 g of the title compound.

Physical properties: m/z[M+H] ⁺ 396.2.

Step 2: Synthesis of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

1-(Adamantane-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

1.8 g of 1-(adamantan-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Step 1, 3.0 mL of 2-diethylaminoethanol, and 160 mg of Pd(PPh ₃ ) ₂ Cl ₂ were dissolved in 5 mL of NMP. The system was purged with carbon monoxide and then heated to 120°C. After stirring for 2 hours, the resulting mixture was cooled to room temperature, and 5 mL of methanol was added. 2.3 mL of 5N aqueous sodium hydroxide solution was then added, and the mixture was stirred for 30 minutes. After adding water, the aqueous layer was washed with ethyl acetate and the washed aqueous layer was adjusted to pH 3 with hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried to yield 0.3 g of the title compound.

Physical properties: m/z[M+H] ⁺ 314.2.

Reference Example 3: Synthesis of 4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

Step 1: Synthesis of methyl 4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

4-Amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid methyl ester

3.33 g of triethylamine and 1.35 g of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added to a suspension of 4.45 g of 3-bromo-(1-tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine in 45 mL of methanol. The mixture was stirred in an autoclave at 0.5 MPa and 100°C under a carbon monoxide atmosphere for 3 hours. After cooling, the reaction solution was concentrated, dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate. The dried mixture was then filtered and concentrated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and concentrated. The resulting precipitate was suspended and washed with hexane-ethyl acetate. After filtration, the precipitate was dried under reduced pressure at 70°C to yield 2.37 g of the title compound.

Physical properties: m/z [M+H] ⁺ 250.1.

Step 2: Synthesis of 4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

4-Amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

2.23 g of methyl 4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate obtained in Step 1 was suspended in 33 mL of methanol, and 3.58 mL of 5 M aqueous sodium hydroxide solution was added. The mixture was heated under reflux with stirring for 30 minutes. After cooling, the reaction solution was neutralized with 5 M aqueous hydrochloric acid, diluted with water, and the resulting precipitate was collected by filtration. The resulting precipitate was dried under reduced pressure at 60°C to yield 2.05 g of the title compound.

Physical properties: m/z[M+H] ⁺ 236.3.

Reference Example 4: Synthesis of 4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

Step 1: Synthesis of 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

4-Chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

5.79 mL of diisopropyl azodicarboxylate was added to a solution of 4.0 g of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, 2.58 g of propan-2-ol, and 7.51 g of triphenylphosphine in 30 mL of tetrahydrofuran. The reaction solution was stirred for 18 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (hexane → hexane/ethyl acetate = 1/1) to give 4.0 g of the title compound.

Physical properties: m/z[M+H] ⁺ 322.0.

Step 2: Synthesis of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

5-Iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

30 mL of 1,2-dimethoxyethane and 30 mL of 28% aqueous ammonia were added to 3 g of 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine obtained in Step 1, and the mixture was stirred at 115°C in a stainless steel pressure tube for 18 hours. 300 mL of water was added to the reaction solution, and the resulting precipitate was washed with water to obtain 2.0 g of the title compound.

Physical properties: m/z[M+H] ⁺ 303.1.

Step 3: Synthesis of 4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

3.8 g of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, obtained in Step 2, 8.3 mL of 2-diethylaminoethanol, and 0.44 g of Pd(PPh ₃ ) ₂ Cl ₂ were dissolved in 10 mL of NMP. The system was purged with carbon monoxide and then heated to 120°C. After stirring for 2 hours, the reaction mixture was cooled to room temperature and 7 mL of methanol was added. 3.5 mL of 5N aqueous sodium hydroxide solution was then added, and the mixture was stirred for 30 minutes. After adding water, the aqueous layer was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid. The resulting precipitate was then filtered. The filtered precipitate was washed with water and dried to yield 0.670 g of the title compound.

Physical properties: m/z[M+H] ⁺ 221.2.

Reference Example 5: Synthesis of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

Step 1: Synthesis of 7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

7-(tert-Butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

A mixture solution of 29.3 g of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde, 13.4 g of tert-butylamine, and 29.7 g of N,N-diisopropylethylamine in 200 mL of ethanol was heated under reflux with stirring for 2 hours. After cooling, the reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water, and then washed with a saturated sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography to obtain 21.5 g of the title compound.

Physical properties: m/z[M+H] ⁺ 210.0.

Step 2: Synthesis of 7-(tert-butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

7-(tert-Butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

46.7 g of N-iodosuccinimide was added to a solution of 36 g of 7-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine obtained in step 1 in 360 mL of DMF, and the mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate and washed three times with water, followed by washing with a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting precipitate was suspended, washed with hexane-ethyl acetate, filtered, and then dried under reduced pressure to obtain 45.5 g of the title compound.

Physical properties: m/z[M+H] ⁺ 335.9.

Step 3: Synthesis of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

7-(tert-Butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A suspension of 52 g of 7-(tert-butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine obtained in Step 2 in 180 mL of THF and 180 mL of 28% aqueous ammonia was stirred in an autoclave at 120° C. for 14 hours. After cooling, the mixture was diluted with water, and the resulting precipitate was collected by filtration and then dried under reduced pressure at 60° C. to give 52 g of the title compound.

Physical properties: m/z[M+H] ⁺ 317.3.

Step 4: Synthesis of methyl 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

4-Amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester

A suspension of 15 g of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 3, 1.94 g of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, and 13.2 mL of triethylamine in 150 mL of methanol was stirred in an autoclave at 100°C and 0.45 MPa under a carbon monoxide atmosphere for 1.5 hours. After cooling, the reaction solution was concentrated and purified by silica gel chromatography (hexane-ethyl acetate). After concentration, the resulting precipitate was suspended, washed with hexane-ethyl acetate, filtered, and dried under reduced pressure to obtain 9.70 g of the title compound.

Physical properties: m/z[M+H] ⁺ 249.3.

Step 5: 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

4-Amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

23.4 mL of 5M aqueous sodium hydroxide solution was added to a suspension of 9.70 g of methyl 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Step 4 in 97 mL of methanol. The mixture was heated under reflux with stirring for 2 hours. After cooling, the mixture was neutralized with 5M aqueous hydrochloric acid. The resulting precipitate was diluted with water, filtered, and dried under reduced pressure at 60°C to yield 8.0 g of the title compound.

Physical properties: m/z[M+H] ⁺ 235.2.

Reference Example 6: Synthesis of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine Step 1: Synthesis of 4-chloro-7-(1-(fluoromethyl)cyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine

4-Chloro-7-(1-(fluoromethyl)cyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 1.3 g of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde, 1.0 g of 1-(fluoromethyl)cyclopropylamine hydrochloride, and 4.7 mL of N,N-diisopropylethylamine in 10 mL of ethanol was heated under reflux with stirring for 2 hours. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (hexane → hexane/ethyl acetate = 1/1) to obtain 1.1 g of the title compound.

Physical properties: m/z[M+H] ⁺ 226.0.

Step 2: Synthesis of 4-chloro-7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

4-Chloro-7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

1.2 g of N-iodosuccinimide was added to a solution of 1.0 g of 4-chloro-7-(1-(fluoromethyl)cyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine obtained in Step 1 in 10 mL of DMF, and the mixture was stirred at room temperature for 18 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction solution to terminate the reaction, and the reaction solution was diluted with water. The resulting precipitate was washed with water, filtered, and dried under reduced pressure to yield 2.5 g of the title compound.

Physical properties: m/z[M+H] ⁺ 351.9.

Step 3: Synthesis of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

7-(1-(Fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

10 mL of 1,2-dimethoxyethane and 10 mL of 28% aqueous ammonia were added to 2.5 g of 4-chloro-7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine obtained in Step 2, and the mixture was stirred at 115°C in a stainless steel pressure tube for 18 hours. 200 mL of water was added to the reaction solution, and the resulting precipitate was washed with water to obtain 1.9 g of the title compound.

Physical properties: m/z[M+H] ⁺ 333.0.

Reference Example 7: Synthesis of 7-(tert-butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Step 1: Synthesis of 1-(4,6-dichloropyrimidin-5-yl)propan-2-ol

1-(4,6-Dichloropyrimidin-5-yl)propan-2-ol

1g of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde was dissolved in 20mL of THF and the reactor was cooled to -78°C. 4.36mL of methylmagnesium bromide ether solution (3mol/L) was slowly added dropwise thereto. At the same temperature, the mixture was stirred for 1 hour, and a saturated aqueous ammonium chloride solution was slowly added thereto to terminate the reaction. The reaction mixture was stirred at room temperature for 10 minutes and placed in a separating funnel, then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate to remove the solvent. The residue was purified by basic silica gel chromatography (hexane/ethyl acetate=1/0→3/1) to obtain 446mg of the title compound.

Physical properties: m/z[M+H] ⁺ 207.0.

Step 2: Synthesis of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one

1-(4,6-Dichloropyrimidin-5-yl)propan-2-one

246 mg of 1-(4,6-dichloropyrimidin-5-yl)propan-2-ol obtained in Step 1 was dissolved in 2.5 mL of dichloromethane, 1.0 g of Dess-Martin reagent was added, and the mixture was stirred at room temperature for 1 hour. 10% aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the mixture was stirred for an additional 30 minutes. The reaction mixture was extracted with chloroform, and the organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over sodium sulfate. After removing the solvent, the residue was purified by silica gel chromatography (hexane/ethyl acetate = 1/0 → 3/1) to obtain 198 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 205.0.

Step 3: Synthesis of 1-(4-(tert-butylamino)-6-chloropyrimidin-5-yl)propan-2-one

1-(4-(tert-Butylamino)-6-chloropyrimidin-5-yl)propan-2-one

198 mg of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one obtained in Step 2, 122 μL of tert-butylamine, and 252 μL of diisopropylethylamine were dissolved in 2 mL of ethanol, and the solution was stirred at 90° C. overnight.

After the reaction mixture was concentrated, the residue was purified by silica gel chromatography (hexane/ethyl acetate=1/0→3/1) to obtain 64 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 242.1.

Step 4: Synthesis of 7-(tert-butyl)-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

7-(tert-Butyl)-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

64 mg of 1-(4-(tert-butylamino)-6-chloropyrimidin-5-yl)propan-2-one obtained in Step 3 and 42 μL of acetic acid were dissolved in 5.5 mL of ethanol, and the solution was reacted in a microwave reactor at 120° C. for 1 hour. After removing the solvent, the residue was purified by silica gel chromatography (hexane/ethyl acetate = 1/0 → 4/1) to give 54 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 224.1.

Step 5: Synthesis of 7-(tert-butyl)-4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

7-(tert-Butyl)-4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

The 7-(tert-butyl)-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine obtained in step 4 was dissolved in 1.5 mL of DMF. 64 mg of N-iodosuccinimide was added, and the mixture was stirred at room temperature overnight. A 10% aqueous sodium thiosulfate solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 1/0 → 4/1) to obtain 69 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 349.9.

Step 6: 7-(tert-Butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

7-(tert-Butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

60 mg of 7-(tert-butyl)-4-chloro-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidine, obtained in Step 5, was reacted with 600 μL of DME and 600 μL of aqueous ammonia in a pressure tube at 115°C for 12 hours. After air cooling, water was added to the reaction mixture. The resulting precipitate was filtered and dried to yield 45 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 331.0.

Reference Example 8: Synthesis of 3-fluoro-4-(methoxymethyl)aniline

3-Fluoro-4-(methoxymethyl)aniline

5.71g of cesium carbonate and 3.64mL of iodomethane are added to a mixed solution of 1.0g of (2-fluoro-4-nitrophenyl) methanol in 20mL of THF and DMF (1:1), and the mixture is stirred for 18 hours. The resulting mixture is dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue obtained is purified by silica gel column chromatography (hexane-ethyl acetate), and the reaction mixture is concentrated to obtain 0.76g of 2-fluoro-1-(methoxymethyl)-4-nitrobenzene. Subsequently, 0.76g of 2-fluoro-1-(methoxymethyl)-4-nitrobenzene is dissolved in 20mL of methanol, 400mg of palladium/charcoal (palladium 10%) is added thereto, and then stirred for 18 hours in a hydrogen atmosphere. Insoluble matter is filtered off, and the filtrate is concentrated. The residue obtained is concentrated to obtain 567mg of the title compound.

Physical properties: m/z[M+H] ⁺ 156.0.

Reference Example 9: Synthesis of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

4-Amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester Step 1: Synthesis of 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

2.5mL DMF is added to 234mg of 5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine, 131mg of zinc cyanide and 86mg of tetrakis triphenylphosphine palladium synthesized according to the method of step 1-3 in reference example 5 using 1-methylcyclopropylamine hydrochloride instead of tert-butylamine. The mixture is reacted in a microwave reactor at 150°C for 20 minutes. Insoluble matter is removed using diatomaceous earth and the filtrate is separated between toluene/ethyl acetate and water. The organic layer is washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, then filtered and concentrated. Hexane and ethyl acetate are added to the residual precipitate, and the mixture is stirred at room temperature. The resulting precipitate is filtered to obtain 100mg of the title compound.

Physical properties: m/z[M+H] ⁺ 214.2.

Step 2: Synthesis of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

100 mg of 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile obtained in step 1 was dissolved in 5 mL of DMF, 167 mg of N-bromosuccinimide was added thereto under ice cooling, and then stirred for 3.5 hours. The reaction solution was partitioned between ethyl acetate and a 10% aqueous sodium thiosulfate solution. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered and concentrated. Hexane and ethyl acetate were added to the residual precipitate, and the mixture was stirred under ice cooling. The resulting precipitate was filtered to obtain 96 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 294.0.

Step 3: 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

96 mg of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile obtained in Step 2 was dissolved in 3 mL of DMSO. 90 μL of 4N aqueous NaOH and 41 μL of 30% hydrogen peroxide were added, followed by stirring at room temperature for 1 hour. The reaction solution was partitioned between ethyl acetate and 10% aqueous sodium thiosulfate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 76 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 312.0.

Step 4: Synthesis of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

118mg of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide obtained in step 3 was dissolved in 2mL of THF, 23mg of dimethylaminopyridine and 415mg of di-tert-butyl dicarbonate were added thereto, and then stirred at room temperature overnight. After removing THF, 2mL of methanol was added thereto, and 53mg of potassium carbonate was added thereto, and then stirred at room temperature for 7 hours. The reaction solution was neutralized with 2N HCl and separated between ethyl acetate and water. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, then filtered and concentrated. 2mL of dichloromethane and 2mL of trifluoroacetic acid were added to the residue, and the mixture was stirred at room temperature for 1 hour. After removing trifluoroacetic acid, the residue was separated between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0→8/1) to give 50 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 327.0.

Reference Example 10: Synthesis of methyl 4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

Step 1: Synthesis of 1-(4,4-difluorocyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1-(4,4-difluorocyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

1.6 ml of diisopropyl azodicarboxylate was added to a solution of 1.6 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 1.0 g of 4,4-difluorocyclohexanol, and 2.1 g of triphenylphosphine in 50 ml of THF at room temperature, and the mixture was stirred overnight. After concentration, the mixture was suspended, washed with methanol, and then filtered. The resulting precipitate was dried under reduced pressure at 60°C to obtain 1.5 g of the title compound.

Physical properties: m/z[M+H] ⁺ 380.2.

Step 2: Synthesis of methyl 4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

4-Amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid methyl ester

A mixed solution of 1.5 g of 1-(4,4-difluorocyclohexyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Step 1, 330 mg of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, and 3 ml of N,N-diisopropylamine in 30 ml of methanol was stirred in an autoclave at 0.45 MPa and 100°C under a carbon monoxide atmosphere for 2 hours. After cooling, the reaction mixture was concentrated and purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate). The crude product was purified again by passing through basic silica gel (developing solvent: hexane-ethyl acetate) and concentrated. The resulting precipitate was suspended, washed with hexane-ethyl acetate, filtered, and dried to yield 650 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 312.1.

Reference Example 11: Synthesis of 4-amino-6-bromo-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

4-Amino-6-bromo-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

270 mg of 4-amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 48 was dissolved in 4 mL of DMF. 195 mg of N-bromosuccinimide was added under ice-cooling, followed by stirring at room temperature for 15 minutes. A 10% aqueous sodium thiosulfate solution was added to the reaction solution, and the resulting precipitate was filtered and washed with water to obtain 245 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 450.1.

Reference Example 12: Synthesis of 4-amino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

4-Amino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid

300 mg of 1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 453 mg of bromine were dissolved in 2 mL of water, and the solution was stirred at room temperature for 1 hour and then at 100°C for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was further washed with water to obtain 370 mg of 3-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. A solution of 370 mg of the obtained 3-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 104 mg of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, and 500 μL of triethylamine in 5 mL of methanol was stirred in an autoclave at 120°C under a carbon monoxide atmosphere for 4 hours. After cooling, the solvent was concentrated under reduced pressure. The resulting residue was dissolved in 5 mL of methanol, to which was added 0.4 mL of a 5 M aqueous sodium hydroxide solution, followed by stirring at 50° C. for 2 hours. After cooling, the solvent was concentrated under reduced pressure. The residue was neutralized with a 5 M aqueous hydrochloric acid solution, and the resulting precipitate was diluted with water, filtered, and dried under reduced pressure to obtain the title compound.

Physical properties: m/z[M+H] ⁺ 256.1.

Example 1: Synthesis of 4-amino-1-cyclopentyl-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

30 mg of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid obtained in Step 2 of Reference Example 1, 20 mg of 4-(methoxymethyl)aniline and 55 mg of HATU were dissolved in 1 mL of DMF, and 62 μL of diisopropylethylamine was added thereto. After stirring at room temperature for 18 hours, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the organic solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform → chloroform/methanol = 10/1) to obtain 36 mg of the title compound. Example 2: 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

2.43 g of HATU was added to a solution of 1.00 g of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid, 878 mg of 4-(methoxymethyl)aniline, and 2.23 mL of N,N-diisopropylethylamine in 20 mL of DMF at room temperature. The mixture was stirred at room temperature overnight, an aqueous sodium hydroxide solution was added thereto, and then extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography. After concentration, the obtained precipitate was suspended and washed with methanol, then filtered and dried under reduced pressure to obtain 1.12 g of the title compound.

Example 3: Synthesis of 4-amino-1-cyclopentyl-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (65%).

Example 4: Synthesis of 4-amino-1-cyclopentyl-N-(4-(furan-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-(furan-2-yl)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (60%).

Example 5: Synthesis of 4-amino-1-cyclopentyl-N-(4-(phenylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using N-phenylbenzene-1,4-diamine instead of 4-(methoxymethyl)aniline, the title compound was obtained (78%).

Example 6: Synthesis of 4-amino-1-cyclopentyl-N-(2-methoxy-2,3-dihydro-1H-inden-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 2-methoxy-2,3-dihydro-1H-inden-5-amine instead of 4-(methoxymethyl)aniline, the title compound was obtained (88%).

Example 7: Synthesis of 4-amino-1-cyclopentyl-N-(4-vinylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-vinylaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (69%).

Example 8: Synthesis of 4-amino-N-(3-chlorophenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 3-chloroaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (61%).

Example 9: Synthesis of (E)-4-amino-1-cyclopentyl-N-(4-(prop-1-en-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using (E)-4-(prop-1-en-1-yl)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (82%).

Example 10: Synthesis of 4-amino-1-(cyclopent-3-en-1-yl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 4-amino-1-(cyclopent-3-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid was obtained by using cyclopent-3-en-1-yl methanesulfonate instead of iodinated cyclopentane.

According to the synthesis method of Example 1, using 4-amino-1-(cyclopent-3-en-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid, the title compound was obtained (70%).

Example 11: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-1-(3-methylcyclopentyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 4-amino-1-(3-methylcyclopentyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid was obtained by using 3-methylcyclopentyl methanesulfonate instead of iodinated cyclopentane.

The reaction was carried out according to the method of Example 1, using 4-amino-1-(3-methylcyclopentyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid. The reaction solution was purified by reverse-phase preparative HPLC and concentrated. The resulting precipitate was suspended, washed with hexane-ethyl acetate, filtered, and dried under reduced pressure to obtain the title compound (55%).

Example 12: Synthesis of 4-amino-1-cyclobutyl-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid was obtained by using bromocyclobutane instead of iodocyclopentane.

The title compound was obtained by the method of Example 1 using 4-amino-1-cyclobutyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (82%).

Example 13: Synthesis of 4-amino-1-cyclobutyl-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 12, using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (65%).

Example 14: Synthesis of 4-amino-1-(3,3-dimethylcyclobutyl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 3-bromo-1,1-dimethyl-cyclobutane was used instead of iodocyclopentane to obtain 4-amino-1-(3,3-dimethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid.

The title compound was obtained by the method of Example 1 using 4-amino-1-(3,3-dimethylcyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (73%).

Example 15: Synthesis of 4-amino-1-isopropyl-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 2-bromopropane was used instead of iodocyclopentane to obtain 4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid.

The title compound (63%) was obtained by the method of Example 1, using 4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid and 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline.

Example 16: Synthesis of 4-amino-N-(4-((methylthio)methyl)phenyl)-1-(pentan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 3-bromopentane was used instead of iodocyclopentane to obtain 4-amino-1-(pentan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid.

The title compound (65%) was obtained by following the procedure of Example 1, using 4-amino-1-(pentan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid and 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline.

Example 17: 4-amino-1-cyclohexyl-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of steps 1 and 2 in Reference Example 1, 4-amino-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid was obtained by using bromocyclohexane instead of iodocyclopentane.

The title compound was obtained by the method of Example 1 using 4-amino-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (16%).

Example 18: Synthesis of 4-amino-1-cyclohexyl-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was obtained by the method of Example 17 using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline (85%).

Example 19: Synthesis of 1-(adamantan-2-yl)-4-amino-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

38 mg of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid obtained in Step 2 of Reference Example 2, 20 mg of 4-(methoxymethyl)aniline, and 55 mg of HATU were dissolved in 1 mL of DMF, and 62 μL of diisopropylethylamine was added. The mixture was stirred at room temperature for 18 hours, water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the organic solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform → chloroform/methanol = 10/1) to obtain 26 mg of the title compound.

Example 20: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-1-(trans-4-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis method of steps 1 and 2 in Reference Example 2, 4-amino-1-(trans-4-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid was obtained by using cis-4-methylcyclohexanol instead of 2-adamantanol.

The title compound was obtained by the method of Example 19 using 4-amino-1-(trans-4-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (82%).

Example 21: Synthesis of 4-amino-1-(1-fluoropropan-2-yl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis method of steps 1 and 2 in Reference Example 2, 1-fluoropropan-2-ol was used instead of 2-adamantanol to obtain 4-amino-1-(1-fluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid.

The title compound was obtained by the method of Example 19 using 4-amino-1-(1-fluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (58%).

Example 22: Synthesis of 4-amino-1-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

121 mg of HATU was added to a solution of 50 mg of 4-amino-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid obtained in step 2 of Reference Example 3, 34 mg of 4-(methoxymethyl)aniline, and 0.11 mL of N,N-diisopropylethylamine in 1 mL of DMF at room temperature. After stirring at room temperature for 1 hour, the mixture was diluted with ethyl acetate, washed with water, and then washed with a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting precipitate was suspended, washed with methanol, filtered, and dried under reduced pressure to obtain 65 mg of the title compound.

Example 23: 4-amino-1-(tert-butyl)-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was obtained by the method of Example 22 using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline (77%).

Example 24: Synthesis of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

67 mg of 4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in Step 3 of Reference Example 4, 50 mg of 4-(methoxymethyl)aniline, and 138 mg of HATU were dissolved in 1 mL of DMF, and 158 μL of diisopropylethylamine was added thereto. After stirring at room temperature for 5 hours, water was added to the reaction solution, and then extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic solution was dried under reduced pressure. The residue was purified by silica gel chromatography (chloroform → chloroform/methanol = 10/1) to obtain 76 mg of the title compound.

Example 25: Synthesis of 4-amino-7-cyclopentyl-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-3 in Reference Example 4, cyclopentanol was used instead of propan-2-ol to obtain 4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained by the method of Example 24 using 4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (69%).

Example 26: Synthesis of 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-5 in Reference Example 5, 1-fluoro-2-methylpropan-2-amine hydrochloride was used instead of tert-butylamine to obtain 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained according to the method of Example 2 using 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (67%).

Example 27: Synthesis of 4-amino-7-(tert-butyl)-N-(4-propylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 2, using 4-propylaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (48%).

Example 28: Synthesis of 4-amino-7-(tert-butyl)-N-(4-(pyridin-2-ylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained (100%) according to the method of Example 2 using N-(2-pyridyl)benzene-1,4-diamine instead of 4-(methoxymethyl)aniline.

Example 29: Synthesis of 4-amino-7-(tert-butyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained according to the method of Example 2 using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline (29%).

Example 30: Synthesis of 4-amino-7-(tert-butyl)-N-(3-fluoro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 2, using 3-fluoro-4-(methoxymethyl)aniline obtained in Reference Example 8 instead of 4-(methoxymethyl)aniline, the title compound was obtained (43%).

Example 31: Synthesis of 4-amino-7-(tert-butyl)-N-(3-chloro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained according to the method of Example 2 using 3-chloro-4-(methoxymethyl)aniline instead of 4-(methoxymethyl)aniline (27%).

Example 32: Synthesis of 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 2, the title compound (82%) was obtained by replacing 4-(methoxymethyl)aniline with 4-(methoxymethyl)3-methyl-aniline obtained by replacing (2-fluoro-4-nitrophenyl)methanol with (2-methyl-4-nitrophenyl)methanol according to Reference Example 8.

Example 33: Synthesis of 4-amino-7-(tert-butyl)-N-(2-methoxy-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 2, the title compound (60%) was obtained by replacing 4-(methoxymethyl)aniline with 2-methoxy-4-(methoxymethyl)aniline obtained by replacing (2-fluoro-4-nitrophenyl)methanol with (3-methoxy-4-nitrophenyl)methanol according to Reference Example 8.

Example 34: Synthesis of 4-amino-7-(tert-butyl)-N-(4-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained according to the method of Example 2 using 4-(ethynylphenyl)aniline instead of 4-(methoxymethyl)aniline (52%).

Example 35: 4-amino-7-(tert-butyl)-N-(4-((methoxy-d3)-methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 2, 4-((methoxy-d-3)methyl)aniline synthesized according to Reference Example 8 using (4-nitrophenyl)methanol and iodomethane (d3) was used instead of 4-(methoxymethyl)aniline to obtain the title compound (45%).

Example 36: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-5 in Reference Example 5, 1-methylcyclopropylamine hydrochloride was used instead of tert-butylamine to obtain 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound (8%) was obtained by the method of Example 2 using 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

Example 37: Synthesis of 4-amino-7-(1-methylcyclopropyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained by the method of Example 36 using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline (78%).

Example 38: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-5 in Reference Example 5, 2-methylbutan-2-amine was used instead of tert-butylamine to obtain 4-amino-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained by the method of Example 2 using 4-amino-7-(tert-pentyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (82%).

Example 39: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-5 in Reference Example 5, 1-methylcyclobutylamine hydrochloride was used instead of tert-butylamine to obtain 4-amino-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained according to the method of Example 2 using 4-amino-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (69%).

Example 40: Synthesis of 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained by the method of Example 26 using 4-((methylthio)methyl)aniline instead of 4-(methoxymethyl)aniline (55%).

Example 41: Synthesis of 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-N-(3-fluoro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 26, using 3-fluoro-4-(methoxymethyl)aniline obtained in Reference Example 8 instead of 4-(methoxymethyl)aniline, the title compound was obtained (50%).

Example 42: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-5 in Reference Example 5, 2-(thiophen-2-yl)propan-2-amine was used instead of tert-butylamine to obtain 4-amino-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained according to the method of Example 2 using 4-amino-7-(2-(thiophen-2-yl)propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (86%).

Example 43: Synthesis of 4-amino-7-(bicyclo[2.2.1]hept-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-5 in Reference Example 5, bicyclo[2.2.1]hept-2-amine was used instead of tert-butylamine to obtain 4-amino-7-(bicyclo[2.2.1]hept-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained according to the method of Example 2 using 4-amino-7-(bicyclo[2.2.1]hept-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (67%).

Example 44: 4-amino-7-(bicyclo[1.1.1.]pentan-1-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-5 in Reference Example 5, bicyclo[1.1.1]pentan-1-amine hydrochloride was used instead of tert-butylamine to obtain 4-amino-7-(bicyclo[1.1.1.]pentan-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained by the method of Example 2 using 4-amino-7-(bicyclo[1.1.1.]pentan-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (76%).

Example 45: Synthesis of 4-amino-7-(1-(fluoromethyl)cyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

A solution of 100 g of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 3 of Reference Example 6, 100 mg of 4-(methoxymethyl)aniline, 90 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 20 mg of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex in 3 mL of NMP was stirred at 100° C. under a carbon monoxide atmosphere for 4 hours. The reaction solution was concentrated and purified by silica gel chromatography (hexane-ethyl acetate-methanol) to obtain 86 mg of the title compound.

Example 46: Synthesis of 4-amino-7-(1-(difluoromethyl)cyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 1-(difluoromethyl)cyclopropylamine hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 7-(1-(difluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 7-(1-(difluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80%).

Example 47: Synthesis of 4-amino-7-(1-ethylcyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 1-ethylcyclopropylamine hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 7-(1-ethylcyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 7-(1-ethylcyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60%).

Example 48: Synthesis of 4-amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 1-methylcyclopropane hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

According to the method of Example 45, 5-iodo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was used instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine, and 3-fluoro-4-(methoxymethyl)aniline obtained in Reference Example 8 was used instead of 4-(methoxymethyl)aniline to give the title compound (80%).

Example 49: Synthesis of 7-{[1,1-di(cyclopropane)]-1-yl}-4-amino-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 1-cyclopropylcyclopropylamine hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 7-([1,1-di(cyclopropane)]-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 7-([1,1-di(cyclopropyl)]-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50%).

Example 50: Synthesis of 4-amino-7-(1,1-difluoro-2-methylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 1,1-difluoro-2-methyl-propan-2-amine hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 7-(1,1-difluoro-2-methylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained according to the method of Example 45, using 7-(1,1-difluoro-2-methylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (32%).

Example 51: Synthesis of 4-amino-7-(2,3-dimethylbutan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 2,3-dimethylbutan-2-amine hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 7-(2,3-dimethylbutan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 7-(2,3-dimethylbutan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (74%).

Example 52: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 2,3,3-trimethylbutan-2-amine was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 5-iodo-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 5-iodo-7-(2,3,3-trimethylbutan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80%).

Example 53: Synthesis of 4-amino-7-(2-cyclopropylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 2-cyclopropylpropan-2-amine hydrochloride was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 7-(2-cyclopropylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 7-(2-cyclopropylpropan-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (30%).

Example 54: Synthesis of 4-amino-7-(2-cyclopropylpropan-2-yl)-N-(3-fluoro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained according to the method of Example 53 using 3-fluoro-4-(methoxymethyl)aniline instead of 4-(methoxymethyl)aniline (40%).

Example 55: 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

3 mL of THF, 3 mL of methanol, and 0.62 mL of a 4 mol/L lithium hydroxide aqueous solution were added to 80 mg of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Reference Example 9. The mixture was stirred at room temperature overnight. 10 mL of water was added thereto, and the mixture was neutralized with a 2N HCl aqueous solution to obtain a precipitate. After removing the solvent, the residue was stirred under ice cooling for 30 minutes, and the precipitate was filtered to obtain 73 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 313.0

Step 2: Synthesis of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

10.1 mg of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in Step 1 was dissolved in 1 mL of DMF, and 5.3 mg of 4-(methoxymethyl)aniline, 17 μL of DIPEA, and 18.5 mg of HATU were added, followed by stirring at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with 1N aqueous NaOH, water, and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column (ethyl acetate/methanol = 1/0 → 8/1) to obtain 6.7 mg of the title compound.

Example 56: 4-amino-6-chloro-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

111 mg of 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester synthesized according to the method of step 1-4 in reference example 5 using 1-methylcyclopropylamine hydrochloride instead of tert-butylamine was dissolved in 4.5 mL of DMF, 90 mg of N-chlorosuccinimide was added thereto at room temperature, and then stirred overnight. The reaction solution was separated between ethyl acetate and a 10% aqueous sodium thiosulfate solution, the organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column (ethyl acetate/methanol=1/0→8/1) to obtain 45 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 281.1.

Step 2: Synthesis of 4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

According to the method in step 1 of Example 55, the title compound was obtained from 36 mg of methyl 4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1 (87%).

Physical properties: m/z[M+H] ⁺ 267.0.

Step 3: Synthesis of 4-amino-6-chloro-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Step 2 in Example 55, using 17.6 mg of 4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in Step 2, the title compound was obtained (47%).

Example 57: 4-amino-6-methoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-6-methoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

1.66g of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide obtained in step 3 of reference example 9 was dissolved in 27mL of THF, 327mg of dimethylaminopyridine and 5.84g of di-tert-butyl dicarbonate were added thereto, and then stirred at room temperature overnight. After removing THF, 25mL of methanol was added, and 5mL of 5M sodium methoxide methanol solution was added thereto, and then stirred at room temperature for 1 hour. The reaction solution was neutralized with 2N HCl and separated between ethyl acetate and water. The organic layer was separated with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated. 5mL of dichloromethane and 5mL of trifluoroacetic acid were added to the residue, and the mixture was stirred under ice cooling for 1 hour. After removing trifluoroacetic acid, the residue was separated between ethyl acetate and a sodium bicarbonate aqueous solution. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (ethyl acetate/methanol=1/0→8/1) to give 400 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 277.1.

Step 2: Synthesis of 4-amino-6-methoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 of Example 55, the title compound (50%) was obtained from methyl 4-amino-6-methoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1.

Example 58: 4-amino-6-cyano-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-6-cyano-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

77 mg of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Reference Example 9 was dissolved in 2.5 mL of DMF, 53 mg of copper cyanide was added thereto, and then stirred at 120° C. under a nitrogen atmosphere for 9 hours. The reaction solution was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate/methanol = 1/0 → 8/1) to obtain 40 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 272.1.

Step 2: Synthesis of 4-amino-6-cyano-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 of Example 55, the title compound (35%) was obtained from methyl 4-amino-6-cyano-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1.

Example 59: Synthesis of 4-amino-6-bromo-7-(1-methylcyclopropyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of step 2 of Example 55, using 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in step 1 of Example 55 and 4-((methylthio)methyl)aniline, the title compound (44%) was obtained.

Step 60: 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of 4-amino-7-(tert-butyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

According to the method of steps 4 and 5 of reference example 5, using 135 mg of 7-(tert-butyl)-5-iodo-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in reference example 7, the title compound (45%) was obtained.

Physical properties: m/z[M+H] ⁺ 249.1.

Step 2: Synthesis of 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of step 2 in Example 55, using 4-amino-7-(tert-butyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in step 1, the title compound (30%) was obtained. Example 61: 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

50 mg of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Reference Example 9, 56 mg of 3-pyridineboronic acid, 14 mg of tris(dibenzylideneacetone)dipalladium, 14 mg of 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl, and 49 mg of sodium carbonate were reacted in a mixture of 1.5 mL of 1,4-dioxane and 500 μL of water at 120° C. in a microwave reactor for 1 hour. Chloroform was added to the reaction solution, and the insoluble material was filtered, followed by concentration. The residue was purified by silica gel chromatography (ethyl acetate/methanol = 1/0 → 8/1) to obtain 27 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 324.1.

Step 2: Synthesis of 4-amino-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

26 mg of methyl 4-amino-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Step 1 was suspended in 2 mL of THF and 2 mL of methanol. 0.20 mL of a 4 mol/L aqueous lithium hydroxide solution was added, and the mixture was stirred at room temperature overnight. 10 mL of water was added, and the mixture was neutralized with a 2N aqueous HCl solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 13 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 310.1.

Step 3: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of step 2 in Example 55, using 4-amino-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in step 2, the title compound was obtained (9%).

Example 62: 4-amino-N-(4-(methoxymethyl)phenyl)-6-methyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-6-methyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

30 mg of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Reference Example 9, 55 mg of methylboronic acid, 8 mg of tris(dibenzylideneacetone)dipalladium, 5 mg of tricyclohexylphosphine, and 58 mg of tripotassium phosphate were reacted in a mixture of 1.5 mL of 1,4-dioxane and 150 μL of water in a microwave reactor at 120° C. for 1 hour. Chloroform was added to the reaction solution, and the insoluble material was filtered and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate/methanol = 1/0 → 8/1) to obtain 20 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 261.2.

Step 2: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-6-methyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 of Example 55, using methyl 4-amino-6-methyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1, the title compound (6%) was obtained.

Example 63: 4-amino-6-cyclopropyl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 in Example 62, using 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester obtained in Reference Example 9 and using cyclopropylboronic acid instead of methylboronic acid, the title compound (38%) was obtained.

Example 64: 6-Acetyl-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 6-acetyl-4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

1 mL of toluene was added to 60 mg of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Reference Example 9, 75 μL of tributyl(1-ethoxy)tin, and 21 mg of tetrakistriphenylphosphine palladium, and the mixture was reacted in a microwave reactor at 130°C for 4 hours. The reaction solution was concentrated, and the residue was purified by amino gel chromatography (hexane/ethyl acetate = 10/4 → 0/1). After the target fraction was concentrated, 1 mL of THF and 300 μL of hydrochloric acid solution (2 mol/L) were added, followed by stirring at room temperature overnight. The mixture was then allowed to react at 50°C for an additional 4 hours. The reaction solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 45 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 289.2

Step 2: Synthesis of 6-acetyl-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 of Example 55, using methyl 6-acetyl-4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1, the title compound (48%) was obtained.

Example 65: 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

1.5 mL of toluene was added to 90 mg of methyl 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in Reference Example 9, 97 μL of tributyl vinyl tin, and 32 mg of tetrakistriphenylphosphine palladium, and the mixture was reacted in a microwave reactor at 130° C. for 3 hours. After the reaction solution was concentrated, the residue was purified by amino gel chromatography (hexane/ethyl acetate = 4/1 → 3/5) to obtain 67 mg of the title compound.

Physical properties: m/z[M+H] ⁺ 273.2

Step 2: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 of Example 55, using methyl 4-amino-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1, the title compound (27%) was obtained.

Example 66: Synthesis of 4-amino-7-cyclobutyl-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of steps 1-5 in Reference Example 5, cyclobutylamine was used instead of tert-butylamine to obtain 4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

The title compound was obtained by the method of Example 2 using 4-amino-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid instead of 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (86%).

Example 67: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-1-(cis-2-methylcyclopentyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis method of steps 1 and 2 in Reference Example 2, 4-amino-1-(cis-2-methylcyclopentyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid was obtained by using trans-2-methylcyclopentanol instead of 2-adamantanol.

The title compound was obtained according to the method of Example 19 using 4-amino-1-(cis-2-methylcyclopentyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (52%).

Example 68: Synthesis of 4-amino-1-cyclopentyl-N-(4-ethynylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-ethynylaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (88%).

Example 69: Synthesis of 4-amino-6-fluoro-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

50 mg of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide obtained in Example 36 was dissolved in 1.5 mL of DMF, and 151 mg of 1-chloromethyl-4-fluoro-1,4-diazoniumbicyclo[2.2.2]octanebis(tetrafluoroborate)salt was added thereto under ice cooling. The mixture was then stirred under ice cooling, and after 1 hour, 151 mg of 1-chloromethyl-4-fluoro-1,4-diazoniumbicyclo[2.2.2]octanebis(tetrafluoroborate)salt was added thereto. The mixture was stirred for another hour, and the reaction solution was then separated between chloroform and water. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (ethyl acetate/methanol=1/0→8/1) to give 2.7 mg of the title compound.

Example 70: Synthesis of 4-amino-1-cyclopentyl-N-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-(trifluoromethoxy)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (45%).

Example 71: Synthesis of 4-amino-N-(3-benzylphenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 3-benzylaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (58%).

Example 72: Synthesis of 4-amino-1-cyclopentyl-N-(4-(oxazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-(oxazol-2-yl)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (32%).

Example 73: Synthesis of 4-amino-N-(4-cyanophenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-aminobenzonitrile instead of 4-(methoxymethyl)aniline, the title compound was obtained (69%).

Example 74: Synthesis of 4-amino-1-cyclopentyl-N-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-nitroaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (65%).

Example 75: Synthesis of 4-amino-N-(benzo[b]thiophen-5-yl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using benzo[b]thiophene-5-amine instead of 4-(methoxymethyl)aniline, the title compound was obtained (33%).

Example 76: Synthesis of 4-amino-1-cyclopentyl-N-(4-ethynyl-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-ethynyl-3-fluoroaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (34%).

Example 77: Synthesis of 4-amino-N-(4-bromo-2-methylphenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using 4-bromo-2-methylaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (51%).

Example 78: Synthesis of 4-amino-1-(3-fluoroprop-1-en-2-yl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis method of steps 1 and 2 in Reference Example 2, 1,3-difluoropropan-2-ol was used instead of 2-adamantanol to obtain 4-amino-1-(3-fluoroprop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid.

The title compound was obtained by the method of Example 19 using 4-amino-1-(3-fluoroprop-1-en-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid instead of 1-(adamantan-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (90%).

Example 79: Synthesis of 4-amino-7-(1-methoxy-2-methylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of steps 1-3 in Reference Example 6, 1-methoxy-2-methylpropan-2-amine was used instead of 1-(fluoromethyl)cyclopropylamine hydrochloride to obtain 5-iodo-7-(1-methoxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

The title compound was obtained by the method of Example 45 using 5-iodo-7-(1-methoxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine instead of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70%).

Example 80: Synthesis of N-(4-(1H-pyrazol-3-yl)phenyl)-4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of Example 2, using 4-(1H-pyrazol-3-yl)aniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (94%).

Example 81: Synthesis of 4-amino-7-(tert-butyl)-N-(5-(methoxymethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 45, using 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 3 of Reference Example 5 and 5-(methoxymethyl)pyridin-2-amine synthesized according to the method described in International Publication No. WO2010/058846, the title compound (64%) was obtained.

Example 82: Synthesis of 4-amino-1-(4,4-difluorocyclohexyl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

33 mg of 4-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid methyl ester obtained in step 2 of reference example 10 was dissolved in 2 mL of methanol. 0.05 mL of 5 M sodium hydroxide aqueous solution was added thereto at room temperature, and the mixture was stirred at 60 ° C for 1 hour. After cooling, 0.2 mL of 5 M hydrochloric acid aqueous solution was added, and the mixture was concentrated under reduced pressure. The obtained solid was suspended in 2 mL of DMF, 17 mg of 4-(methoxymethyl)aniline, 60 mg of HATU and 0.055 mL of N, N-diisopropylethylamine were added thereto at room temperature, and then stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was suspended in methanol, filtered, and then dried under reduced pressure at 60 ° C to obtain 29 mg of the title compound.

Example 83: Synthesis of 4-amino-1-cyclopentyl-N-(4-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

1 mL of trifluoroacetic acid and 50 μL of water were added to 90 mg of 4-amino-1-cyclopentyl-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide obtained in Example 1, and the mixture was stirred at 100°C for 1 hour. After cooling, the mixture was concentrated, and an ammonia-methanol solution was added to the resulting residue, followed by stirring for 30 minutes. After concentration, the resulting residue was purified by silica gel chromatography (developing solvent: chloroform/methanol) and concentrated. The resulting precipitate was suspended, washed with methanol, filtered, and then dried under reduced pressure to obtain the title compound (58%).

Example 84: Synthesis of 4-amino-1-cyclopentyl-N-(isochroman-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthetic method of Example 1, using isochroman-6-amine instead of 4-(methoxymethyl)aniline, the title compound (60%) was obtained.

Example 85: Synthesis of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

5.15 g of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Example 55 was dissolved in 50 mL of DMF. 228 mg of copper iodide, 5.24 g of 4-(prop-2-yn-1-yl)morpholine, 5.0 mL of triethylamine, and 1.38 g of tetrakistriphenylphosphine palladium were added thereto. The mixture was then stirred at 100° C. for 2 hours. The solvent was removed from the reaction solution, and the residue was purified by silica gel column (chloroform/methanol 1/0→8/1). The portion containing the by-products was then concentrated and purified again by silica gel column (ethyl acetate/methanol 1/0→4/1) to obtain 2.78 g of the title compound.

Example 86: Synthesis of 4-amino-6-(4-hydroxy-4-methylpent-1-yn-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained according to the method of Example 85 using 2-methylpent-4-yn-2-ol instead of 4-(prop-2-yn-1-yl)morpholine (36%).

Example 87: Synthesis of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained by the method of Example 85 using 4-ethynyltetrahydro-2H-pyran instead of 4-(prop-2-yn-1-yl)morpholine (66%).

Example 88: Synthesis of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained according to the method of Example 85 using 1-(prop-2-yn-1-yl)pyrrolidine instead of 4-(prop-2-yn-1-yl)morpholine (46%).

Example 89: Synthesis of (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

721 μL of (R)-(-)-tetrahydrofurfuryl alcohol was added to a suspension of 371 mg of sodium hydride (60%) in 15 mL of DMF under ice-cooling conditions with stirring. The mixture was then stirred at room temperature for 30 minutes. A solution of 800 mg of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 55 in 5 mL of DMF was added to the mixture, and the mixture was stirred at 80°C overnight. After cooling, the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 → 8/1) to yield 644 mg of the title compound.

Example 90: Synthesis of 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

1.2 g of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Example 55 was dissolved in 40 mL of DMF, and 53 mg of copper iodide, 890 mg of 4-ethynyl-1-methyl-pyrazole, 2.3 mL of triethylamine, and 320 mg of tetrakistriphenylphosphine palladium were added thereto. The mixture was then degassed and stirred at 110° C. for 1.5 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the organic solvent was then concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to obtain 700 mg of the title compound.

Example 91: Synthesis of 4-amino-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained by the method of Example 90 using 3-ethynylimidazo[1,2-b]pyridazine instead of 4-ethynyl-1-methyl-pyrazole (58%).

Example 92: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained by the method of Example 90 using 3-ethynyl-1-methyl-pyrazole instead of 4-ethynyl-1-methyl-pyrazole (28%).

Example 93: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-5-yl)vinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound was obtained by the method of Example 90 using 5-ethynyl-1-methyl-imidazole instead of 4-ethynyl-1-methyl-pyrazole (37%).

Example 94: Synthesis of 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The title compound (34%) was obtained by the method of Example 90 using 3-ethynylpyridine instead of 4-ethynyl-1-methyl-pyrazole.

Example 95: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

6.6 mg of copper iodide, 2.4 mL of propyne (1.0 mol/L DMF solution), 146 μL of triethylamine, and 24 mg of dichlorobistriphenylphosphine palladium were added to 150 mg of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Example 55. The mixture was stirred at 80°C for 5 hours. The reaction solution was separated between chloroform and water and filtered through a phase separator. The filtrate was concentrated, and the residue was purified by silica gel column (ethyl acetate/methanol = 1/0 → 8/1). Then, the portion containing the by-product was concentrated and purified again by silica gel column (chloroform/methanol = 1/0 → 8/1) to obtain 107 mg of the title compound.

According to the method of Example 89, using the compounds shown in Table 1 instead of (R)-(-)-tetrahydrofurfuryl alcohol, Example Compounds 96-102 were obtained.

Table 1

According to the synthesis method of Example 85, using the compounds shown in Table 2 instead of 4-(prop-2-yn-1-yl)morpholine, Example Compounds 103-105 were obtained.

Table 2

According to the synthesis method of Example 36, using the compounds shown in Table 3 instead of 4-(methoxymethyl)aniline, Example Compounds 106-108 were obtained.

Table 3

Example 109: Synthesis of (E)-4-amino-6-(3-hydroxyprop-1-en-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of steps 1 and 2 in Example 62, using (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane instead of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester and methylboronic acid shown in Reference Example 9, the title compound (4%) was obtained.

Example 110: Synthesis of 4-amino-6-(3-hydroxyprop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

10 mg of 4-amino-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Example 180 was dissolved in 1.5 mL of THF, 3.3 μL of acetic acid and 29 μL of tetrabutylammonium fluoride (1.0 mol/L THF solution) were added, and the mixture was stirred for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 → 8/1) to obtain 6 mg of the title compound.

According to the synthesis method of Example 90, the compounds shown in Table 4-7 were used instead of 4-ethynyl-1-methyl-pyrazole to obtain compounds 111-114, 118-126, 128-132, 134, 142-144, 151, 152, 155-163, 165, 166, 168-170, 172-178, 181-189, 191-193 and 195-200 of the examples.

Table 4

Table 5

Table 6

Table 7

According to the synthesis method of Example 115, using the compound shown in Table 8 instead of 4-((methylthio)methyl)aniline, Example Compounds 116 and 117 were obtained.

Table 8

Example 115: Synthesis of 4-amino-6-ethoxy-7-(1-methylcyclopropyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of Example 59, using 4-amino-6-ethoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid shown in Step 1 of Example 127 instead of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid, the title compound was obtained (64%).

Example 127: Synthesis of 4-amino-6-ethoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of 4-amino-6-ethoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

714 mg of methyl 4-amino-6-chloro-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate described in Step 1 of Example 56 was dissolved in 12 mL of THF, and 155 mg of dimethylaminopyridine and 1.66 g of tert-butyl diformate were added thereto, followed by stirring at 50° C. for 1 hour.

After removing the solvent, the residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. 20 mL of ethanol and 3 mL of sodium ethoxide (20% ethanol solution) were added to the residue, and the mixture was stirred overnight. 20 mL of ethanol and 12 mL of a 4N aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was stirred at 80° C. for 6 hours. After cooling, 30 mL of water was added to the reaction solution, and the ethanol was removed by an evaporator. The residue was adjusted to pH 4 with a 2N aqueous HCl solution, and the resulting precipitate was stirred under ice cooling for 1 hour and filtered to obtain 400 mg of the title compound. Step 2: Synthesis of 4-amino-6-ethoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method in step 2 of Example 55, 4-amino-6-ethoxy-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in step 1 was used instead of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid to give the title compound (56%).

Example 133: Synthesis of 4-amino-N-(4-methoxymethyl)phenyl-7-(1-methylcyclopropyl)-6-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

100 mg of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 55 was dissolved in 1 ml of DMF, and 330 μl of sodium methyl mercaptan (approximately 15% aqueous solution) was added at room temperature. After stirring for 30 minutes, the mixture was diluted with water, and the resulting solid was filtered, washed with water, and dried under reduced pressure at 60°C to obtain 87 mg of the title compound.

Example 135: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

While cooling the mixture with ice, 100 μL of tetrahydrofurfuryl alcohol was added to a suspension of 52 mg of sodium hydride (60%) in 1 mL of DMF with stirring, and the mixture was then stirred at room temperature for 30 minutes. A solution of 30 mg of 4-amino-6-chloro-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 56 in 1 mL of DMF was added, and the mixture was stirred at 80°C overnight. After cooling, the reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 → 8/1) and HPLC to yield 32.2 mg of the title compound.

According to the synthesis method of Example 135, using the compounds shown in Table 9 instead of tetrahydrofurfuryl alcohol, Example Compounds 136-141 were obtained.

Table 9

Example 145: Synthesis of 4-amino-6-(4-(hydroxymethyl)phenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

100 mg of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 55, 148 mg of potassium phosphate, 70 mg of (4-(hydroxymethyl)phenyl)boric acid, and 13 mg of tetrakis(triphenylphosphine)palladium were stirred in a microwave reactor at 130°C for 1 hour in a mixed solvent of 2 mL of dioxane and 0.2 mL of water. Ethyl acetate and water were added to the resulting reaction solution, and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: chloroform-methanol). After concentration, the resulting residue was suspended in methanol, filtered, and dried under reduced pressure to obtain 57 mg of the title compound.

Example 146: Synthesis of 4-amino-6-isopropoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

50 mg of 4-amino-6-chloro-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 56 was dissolved in 1.5 mL of DMF, 160 mg of sodium isopropoxide was added, and then the mixture was heated and stirred at 100° C. for 8 hours. The reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the residue was purified by reverse phase preparative HPLC to obtain 2.9 mg of the title compound.

According to the synthesis method of Example 145, using the compounds shown in Table 10 instead of [4-(hydroxymethyl)phenyl]boronic acid, Example Compounds 147-150 and 203 were obtained.

Table 10

Example 153: Synthesis of 4-amino-6-(4-formylphenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Refer to Example 145, but the reaction was carried out using 4-formylphenylboronic acid instead of (4-(hydroxymethyl)phenyl)boronic acid. Ethyl acetate and water were added to the resulting reaction solution, and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: chloroform-methanol). After concentration, the resulting residue was suspended in methanol, filtered, and dried under reduced pressure to obtain 23 mg of the title compound.

Example 154: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of Example 153, using phenylboronic acid instead of 4-formylphenylboronic acid, the title compound was obtained (44%).

Example 164: Synthesis of 4-amino-6-(3-(hydroxymethyl)phenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

100 mg of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Example 55, 148 mg of potassium phosphate, 70 mg of (3-(hydroxymethyl)phenyl)boric acid and 13 mg of tetrakis(triphenylphosphine)palladium were stirred in a mixed solvent of 2 mL of dioxane and 0.2 mL of water at 140 ° C. in a microwave reactor for 1 hour. Ethyl acetate and water were added to the resulting reaction solution, and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: chloroform-methanol). After concentration, the resulting residue was purified again by reverse phase preparative HPLC, alkalized with saturated sodium bicarbonate, and then extracted with chloroform. The resulting organic layer was concentrated, and the residue was suspended in methanol, filtered, and dried under reduced pressure to obtain 28 mg of the title compound.

Example 167: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of Example 164, using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate instead of [3-(hydroxymethyl)phenyl]boronic acid, 16 mg of the title compound was obtained.

Example 171: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of Example 145, using 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine instead of (4-(hydroxymethyl)phenyl)boronic acid, 84 mg of the title compound was obtained.

Example 179: Synthesis of 4-amino-6-(6-(hydroxymethyl)pyridin-3-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of Example 164, using (6-(hydroxymethyl)pyridin-3-yl)boronic acid instead of (4-(hydroxymethyl)phenyl)boronic acid, 47 mg of the title compound was obtained.

Example 180: Synthesis of 4-amino-6-(3-(tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

50 mg of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Example 55 was dissolved in 1 mL of DMF. 2 mg of copper iodide, 65 mg of 2-propyn-1-ol, 50 μL of triethylamine and 13 mg of tetrakistriphenylphosphine palladium were added thereto, degassed, and then stirred at 100 ° C for 1.5 hours. After the reaction was completed, the reaction solution was separated between chloroform and water, and the organic layer was dried over saturated sodium sulfate, filtered, and concentrated. The residue was dissolved in 2 mL of dichloromethane, and 6 mg of imidazole and 7 mg of tert-butyldimethylsilyl chloride were added thereto, and then stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column (ethyl acetate/methanol=1/0→8/1) to obtain 13 mg of the title compound.

Example 190: Synthesis of 4-amino-6-(6-fluoropyridin-3-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method of Example 164, using (6-fluoropyridin-3-yl)boronic acid instead of (4-(hydroxymethyl)phenyl)boronic acid, 47 mg of the title compound was obtained.

Example 194: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Reference Example 145: 86 mg of pyrimidin-5-ylboronic acid was used instead of (4-(hydroxymethyl)phenyl)boronic acid to carry out the reaction. Ethyl acetate and water were added to the resulting reaction solution, and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: chloroform-methanol). After concentration, the resulting residue was purified again by reverse-phase preparative HPLC. After concentration, the residue was purified again by silica gel chromatography (chloroform-methanol). The resulting residue was suspended in hexane-ethyl acetate, filtered, and dried under reduced pressure to obtain 10 mg of the title compound.

Example 201: Synthesis of 4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

Referring to the synthesis method of Step 1 in Example 56, 4-amino-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (which was synthesized according to the method of Steps 1-4 of Reference Example 5 using 1-fluoro-2-methylpropan-2-amine hydrochloride instead of tert-butylamine) was used instead of 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester to obtain the title compound (12%).

Step 2: Synthesis of 4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

According to the synthetic method of step 2 in Example 56, using 4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester obtained in step 1, the title compound (75%) was obtained.

Step 3: Synthesis of 4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of step 3 in Example 56, using 4-amino-6-chloro-7-(1-fluoro-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in step 2, the title compound (35%) was obtained.

Example 202: Synthesis of 4-amino-7-(tert-butyl)-6-chloro-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: 4-Amino-6-chloro-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester

The synthetic method of step 1 in reference example 56 was used, and 4-amino-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester obtained in step 4 of reference example 5 was used instead of 4-amino-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester to give the title compound (11%).

Step 2: Synthesis of 4-amino-6-chloro-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

According to the synthetic method of step 2 in Example 56, using methyl 4-amino-6-chloro-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate obtained in step 1, the title compound (74%) was obtained.

Step 3: Synthesis of 4-amino-7-(tert-butyl)-6-chloro-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of step 3 in Example 56, using 4-amino-6-chloro-7-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid obtained in step 2, the title compound (46%) was obtained.

Example 204: Synthesis of 4-amino-6-(1-hydroxyethyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

23 mg of 6-acetyl-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide described in Example 64 was dissolved in 2 mL of methanol. 7 mg of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol = 1/0 → 8/1) to obtain 13.6 mg of the title compound.

Example 205: Synthesis of 4-amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthesis method of Example 90, 4-amino-6-bromo-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide shown in Reference Example 11 was used instead of 4-amino-6-bromo-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, and 4-ethynyltetrahydropyran was used instead of 4-ethynyl-1-methyl-pyrazole to obtain the title compound (53%).

Example 206: Synthesis of 4-amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of Example 205, using 4-prop-2-ynylmorpholine instead of 4-ethynyltetrahydropyran, the title compound was obtained (42%).

Example 207: 4-amino-6-ethyl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of methyl 4-amino-6-ethyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

20 mg of methyl 4-amino-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate described in Step 1 of Example 65 was dissolved in 5 mL of ethyl acetate, 5 mg of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The insoluble material was filtered through Celite, and the filtrate was concentrated to obtain 20 mg of the title compound.

Step 2: Synthesis of 4-amino-6-ethyl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the method in steps 1 and 2 of Example 55, using 4-amino-6-ethyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester obtained in step 1 instead of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester, the title compound (26%) was obtained.

Comparative Example 1: Synthesis of 1-(tert-butyl)-3-(p-tolyl)pyrazolo[3,4-d]pyrimidin-4-amine

According to the synthesis method in Tetrahedron Letters, 52(44), 5761-5763; 2011, the title compound (30%) was obtained.

Comparative Example 2: Synthesis of 4-amino-7-cyclopentyl-N-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

According to the synthetic method of Example 25, using 4-phenoxyaniline instead of 4-(methoxymethyl)aniline, the title compound was obtained (79%).

Comparative Example 3: Synthesis of 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of N-[4-(methoxymethyl)phenyl]-2-nitro-benzenesulfonamide

1.9 g of 2-nitrobenzenesulfonyl chloride was added to a solution of 1.0 g of 4-(methoxymethyl)aniline and 1.5 mL of triethylamine in 10 mL of chloroform, and the mixture was stirred overnight. After concentration, the residue was purified by silica gel chromatography (developing solvent: hexane-ethyl acetate), concentrated, and dried under reduced pressure to obtain 1.89 g of the title compound.

Step 2: Synthesis of N-[4-(methoxymethyl)phenyl]-N-methyl-2-nitro-benzenesulfonamide

0.53 mL of iodomethane was added to a suspension of 1.84 g of N-[4-(methoxymethyl)phenyl]-2-nitro-benzenesulfonamide obtained in Step 1 and 1.58 g of potassium carbonate in 20 mL of DMF, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water. After extraction with ethyl acetate, the resulting organic layer was washed twice with water, then washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The resulting solution was filtered, concentrated, and dried under reduced pressure to obtain 2.04 g of the title compound.

Step 3: Synthesis of 4-(methoxymethyl)-N-methyl-aniline

1.59 mL of 3-methylbenzenethiol was added to a suspension of 2.51 g of N-[4-(methoxymethyl)phenyl]-N-methyl-2-nitrobenzenesulfonamide obtained in Step 2 and 2.51 g of potassium carbonate in 10 mL of DMF, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate-water and extracted with ethyl acetate. The resulting organic layer was washed twice with water, then washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated, and the resulting residue was purified by silica gel chromatography, concentrated, and dried under reduced pressure to obtain 0.81 g of the title compound.

Step 4: Synthesis of 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

A solution of 59 mg of 4-(methoxymethyl)-N-methyl-aniline, 48 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene, 12 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, and 50 mg of 7-(tert-butyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine described in Step 3 of Reference Example 5 in 1 mL of DMA was stirred at 110°C under a carbon monoxide atmosphere for 1.5 hours. The reaction solution was purified by silica gel chromatography (developing solvent: chloroform-methanol), concentrated, and further purified using a reverse-phase preparative system. After concentration, the resulting residue was suspended, washed with hexane-ethyl acetate, filtered, and dried under reduced pressure at 60°C to obtain 3.5 mg of the title compound.

Comparative Example 4: Synthesis of 7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Step 1: Synthesis of 7-(tert-butyl)-5-iodo-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

400 mg of 7-(tert-butyl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine described in Step 2 of Reference Example 5 was added to 10 mL of a solution of methylamine in THF, and the mixture was stirred in a microwave reactor at 120° C. for 12 hours. The resulting reaction solution was concentrated, purified by basic silica gel chromatography (developing solvent: hexane-ethyl acetate), and then concentrated to obtain 400 mg of the title compound.

Step 2: Synthesis of 7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

7-(tert-Butyl)-5-iodo-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 1, 103 mg of 4-(methoxymethyl)aniline, 90 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 24 mg of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added to 1 mL of DMA, and the mixture was stirred at 110°C under a carbon monoxide atmosphere for 2 hours. The resulting reaction solution was purified by silica gel chromatography (developing solvent: hexane-ethyl acetate), concentrated, and further purified by basic silica gel chromatography, followed by concentration to obtain 52 mg of the title compound.

Comparative Example 5: Synthesis of 4-amino-N-(4-(methoxymethyl)phenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

According to the synthesis method of Example 1, using 4-amino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid shown in Reference Example 12 instead of 4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid, the title compound was obtained (33%).

Tables 11 to 34 show the structural formulas and physical properties of the compounds obtained in Examples and Comparative Examples.

Table 11

Table 12 (continued)

Table 13 (continued)

Table 14 (continued)

Table 15 (continued)

Table 16 (continued)

Table 17 (continued)

Table 18 (continued)

Table 19 (continued)

Table 20 (continued)

Table 21 (continued)

Table 22 (continued)

Table 23 (continued)

Table 24 (continued)

Table 25 (continued)

Table 26 (continued)

Table 27 (continued)

Table 28 (continued)

Table 29 (continued)

Table 30 (continued)

Table 31 (continued)

Table 32 (continued)

Table 33 (continued)

Table 34 (continued)

Test Example 1: Measuring inhibitory activity against RET (in vitro)

Regarding the measurement conditions for the in vitro inhibitory activity of compounds against RET kinase activity, the AnaSpec website states that Srctide (GEEPLYWSFPAKKK) corresponds to the substrate peptide used in the reaction to measure RET kinase activity. Therefore, the amino acid sequence was partially modified and biotinylated to prepare a biotinylated peptide (biotin-EEPLYWSFPAKKK). The purified recombinant human RET protein used in the test was purchased from Carna Biosciences, Inc.

To measure the inhibitory activity, first, the compounds of the present invention were each independently diluted stepwise with dimethyl sulfoxide (DMSO). Subsequently, RET protein, substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 10 mM), ATP (final concentration: 10 μM) and a DMSO solution of the compound of the present invention (final DMSO concentration: 2.5%) were added to a buffer for kinase reaction (13.5 mM Tris, pH 7.5, 2 mM dithiothreitol, 0.009% Tween-20). Each mixture was incubated at 25° C. for 100 minutes to perform the kinase reaction. EDTA was then added thereto to a final concentration of 24 mM to terminate the reaction. A detection solution containing Eu-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added thereto, and each mixture was allowed to stand at room temperature for 2 hours or longer. Finally, fluorescence intensity was measured at 620 nm and 665 nm using a PHERAstar FS (BMG Labtech) under excitation light of 337 nm. The phosphorylation level was calculated based on the ratio of the fluorescence intensities at the two wavelengths, and the compound concentration at which phosphorylation was inhibited by 50% was defined as the _IC50 value (nM).

Tables 35 and 36 show the RET inhibitory activity IC ₅₀ (nM) of vandetanib, the compounds of Examples, and Compounds 2-5 of Comparative Examples.

Vandetanib is known to have high inhibitory activity against RET (Carlomagno F. Cancer Res. 2002 Dec 15; 62(24): 7284-90). It was found that the compounds of the present invention, represented by the compounds of the Examples, or their salts, exhibited in vitro RET inhibitory activity comparable to or higher than that of vandetanib. In contrast, the compounds of Comparative Examples 2-5 exhibited significantly lower inhibitory activity against RET.

Table 35

Table 36 (continued)

Test Example 2: Selectivity for RET relative to other kinases (in vitro)

Because multikinase inhibitors inhibit not only RET but also numerous signaling pathways, thereby inhibiting cell growth and other functions, they raise concerns about potential side effects, which may require dose reductions or drug holidays, leading to insufficient RET inhibitory activity. The following discusses the selectivity of the compounds of the present invention or their salts for RET relative to other kinases.

1) RET inhibitory activity measurement

The inhibitory activity against RET was measured in the same manner as in Test Example 1.

2) Measurement of SRC inhibitory activity

Regarding the conditions for measuring the in vitro inhibitory activity of compounds against SRC kinase activity, the PerkinElmer LabChip series consumable reagent price list indicates that FL-Peptide 4 corresponds to the substrate peptide used to measure SRC kinase activity. Therefore, FL-Peptide 4 was used as the substrate. The purified recombinant human SRC protein used in the test was purchased from CarnaBiosciences, Inc.

To measure inhibitory activity, the test compound was first diluted individually with dimethyl sulfoxide (DMSO). Subsequently, SRC protein, FL-Peptide 4 (final concentration: 1.5 μM), magnesium chloride (final concentration: 10 mM), ATP (final concentration: 15 μM), and a DMSO solution of the test compound (final DMSO concentration: 5%) were added to a reaction buffer (100 mM HEPES, pH 7.0, 1 mM dithiothreitol, 0.003% Brij35, 0.04% Tween-20) containing a phosphatase inhibitor cocktail (PhosSTOP, Roche) and a protease inhibitor cocktail (cOmplete Mini, EDTA-free, Roche) at recommended concentrations. Each mixture was incubated at 30°C for 90 minutes to allow the kinase reaction to proceed. EDTA (final concentration: 30 mM) diluted in separation buffer purchased from PerkinElmer was then added. Finally, the non-phosphorylated substrate peptide (S) and phosphorylated peptide (P) were separated and detected by microchannel capillary electrophoresis using a LabChip EZ Reader II (PerkinElmer). The phosphorylation level was calculated based on the peak heights of S and P, and the compound concentration that inhibited phosphorylation by 50% was defined as the _IC50 value (nM).

3) LCK inhibitory activity measurement

Regarding the measurement conditions for the in vitro inhibitory activity of compounds against LCK kinase activity, the AnaSpec website states that Srctide (GEEPLYWSFPAKKK) corresponds to a substrate peptide used in the reaction to measure LCK kinase activity. Therefore, the amino acid sequence was partially modified and biotinylated to prepare a biotinylated peptide (biotin-EEPLYWSFPAKKK). The purified recombinant human LCK protein used in the test was purchased from Carna Biosciences, Inc.

To measure inhibitory activity, first, the test compound is diluted stepwise with dimethyl sulfoxide (DMSO) independently of each other. Subsequently, LCK protein, substrate peptide (final concentration: 250nM), magnesium chloride (final concentration: 10mM), ATP (final concentration: 50μM) and a DMSO solution of the test compound (final DMSO concentration: 5%) are added to a buffer solution (13.5mMTris, pH 7.5, 2mM dithiothreitol, 0.009% Tween-20) for kinase reaction. Each mixture is incubated at 25°C for 60 minutes to carry out the kinase reaction. EDTA is then added thereto to obtain a final concentration of 40mM to terminate the reaction. A detection solution containing Eu-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) is added thereto, and each mixture is allowed to stand at room temperature for 2 hours or longer. Finally, fluorescence intensity was measured at 620 nm and 665 nm using a PHERAstar FS (BMG Labtech) under excitation light at a wavelength of 337 nm. The phosphorylation level was calculated based on the ratio of the fluorescence intensities at the two wavelengths, and the compound concentration that inhibited phosphorylation by 50% was defined as the _IC50 value (nM).

4) Measurement of AURB (Aurora B) inhibitory activity

The in vitro inhibitory activity of the compounds against AURB kinase was measured with reference to the method described in JP2008-81492A. The purified recombinant human AURB protein used in the test was purchased from Carna Biosciences, Inc.

To measure inhibitory activity, the test compounds were first diluted individually with dimethyl sulfoxide (DMSO). AURB protein, FL-Peptide 21 (caliper Life Sciences, final concentration: 100 nM), magnesium chloride (final concentration: 1 mM), ATP (final concentration: 40 μM), and a DMSO solution of the test compound (final DMSO concentration: 5%) were then added to a kinase reaction buffer (20 mM HEPES, pH 7.4, 2 mM dithiothreitol, 0.01% Tween-20). Each mixture was incubated at 25°C for 60 minutes to allow for the kinase reaction. The kinase reaction was terminated by adding IMAP Progressive Binding Reagent diluted in IMAP Progressive Binding Buffer A (1:500 dilution, Molecular Devices, LLC). The reaction solution was allowed to stand in the dark at room temperature for 120 minutes, and the phosphorylation level was calculated based on the fluorescence polarization measured using PHERAstar (BMG LABTECH, excitation wavelength: 485 nm, detection wavelength: 520 nm). The compound concentration at which phosphorylation was inhibited by 50% was defined as the _IC50 value (nM).

5) Measuring inhibitory activity against EGFR

Regarding the measurement conditions for the in vitro inhibitory activity of compounds against EGFR kinase activity, the price list for PerkinElmer's LabChip (trademark) series of consumable reagents indicates that FL-Peptide 22 corresponds to the substrate peptide used to measure EGFR kinase activity. Therefore, a biotinylated peptide (biotin-EEPLYWSFPAKKK) was prepared with reference to the amino acid sequence. The purified recombinant human EGFR protein used in the test was purchased from Carna Biosciences, Inc.

To measure inhibitory activity, the test compound was first diluted stepwise with dimethyl sulfoxide (DMSO) independently. Subsequently, EGFR protein, substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 10 mM), manganese chloride (final concentration: 10 mM), ATP (final concentration: 1.5 μM) and a DMSO solution of the test compound (final DMSO concentration: 2.5%) were added to a buffer solution for kinase reaction (Carna Biosciences, Inc.). Each mixture was incubated at 25°C for 120 minutes to perform the kinase reaction. EDTA was then added to a final concentration of 24 mM to terminate the reaction. A detection solution containing Eu-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added thereto, and each mixture was allowed to stand at room temperature for 2 hours or longer. Finally, fluorescence intensity was measured at 620 nm and 665 nm using a PHERAstar FS (BMG Labtech) under excitation light of 337 nm. The phosphorylation level was calculated based on the ratio of the fluorescence intensities at the two wavelengths, and the compound concentration at which phosphorylation was inhibited by 50% was defined as the _IC50 value (nM).

6) Selectivity for RET inhibition

Based on the values obtained in sections 1) to 5) above, the SRC inhibitory activity _IC50 (nM)/RET inhibitory activity _IC50 (nM), LCK inhibitory activity _IC50 (nM)/RET inhibitory activity _IC50 (nM), AURB inhibitory activity _IC50 (nM)/RET inhibitory activity _IC50 (nM), and EGFR inhibitory activity _IC50 (nM)/RET inhibitory activity _IC50 (nM) were calculated, and the selectivity of the test compound for RET inhibition was investigated.

Tables 37-44 show the results. Tables 37-44 illustrate that, compared to Compound 1 of the Comparative Example, the compounds of the present invention or their salts represented by the Example compounds exhibit higher RET inhibitory selectivity relative to SRC, LCK, Aurora BB, and EGFR. The compounds of the present invention or their salts also exhibit excellent RET inhibitory selectivity relative to other kinases (PI3K, TrkB). Therefore, the results show that the compounds of the present invention or their salts are less likely to cause side effects due to inhibition of kinases other than RET.

Table 37

Table 38 (continued)

Table 39 (continued)

Table 40 (continued)

Table 41 (continued)

Table 42 (continued)

Table 43 (continued)

Table 44 (continued)

Test 3: Inhibitory activity against RET resistance mutations (in vitro)

1) Measurement of inhibitory activity against RET(V804L)

Regarding the measurement conditions for the in vitro inhibitory activity of compounds against RET (V804L) (i.e., RET with the V804L mutation) kinase activity, the AnaSpec website states that Srctide (GEEPLYWSFPAKKK) corresponds to the substrate peptide used in the reaction to measure RET kinase activity. Therefore, the amino acid sequence was partially modified and biotinylated to prepare a biotinylated peptide (biotin-EEPLYWSFPAKKK). The purified recombinant human RET (V804L) protein used in the test was purchased from Eurofins.

To measure inhibitory activity, the test compound was first diluted stepwise with dimethyl sulfoxide (DMSO). Subsequently, RET (V804L) protein, substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 10 mM), ATP (final concentration: 10 μM), and a DMSO solution of the test compound (final DMSO concentration: 5%) were added to a kinase reaction buffer (13.5 mM Tris, pH 7.5, 2 mM dithiothreitol, 0.009% Tween-20). Each mixture was incubated at 25°C for 120 minutes to allow the kinase reaction to proceed. EDTA was then added to a final concentration of 40 mM to terminate the reaction. A detection solution containing Eu-labeled anti-phosphotyrosine antibody PT66 (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added, and each mixture was allowed to stand at room temperature for 2 hours or longer. Finally, fluorescence intensity was measured at 620 nm and 665 nm using a PHERAstar FS (BMG Labtech) under excitation light of 337 nm. The phosphorylation level was calculated based on the ratio of the fluorescence intensities at the two wavelengths, and the compound concentration at which phosphorylation was inhibited by 50% was defined as the _IC50 value (nM).

2) Measuring inhibitory activity against RET(V804M)

Purified recombinant human RET (V804M) protein purchased from Eurofins was used, the final ATP concentration in the kinase reaction system was 13 μM, and the other parts followed method 1) to measure the RET (V804M) (ie, RET with V804M mutation) kinase activity.

Tables 45 to 48 show the inhibitory activities IC ₅₀ (nM) of Example compounds, vandetanib, and Comparative Example compounds 1 to 4 against RET having resistance mutations.

Vandetanib is known to have high inhibitory activity against RET (Carlomagno F. Cancer Res. 2002 Dec 15; 62(24): 7284-90). However, vandetanib exhibits significantly low inhibitory activity against RET(V804L) and RET(V804M).

Comparative Example compounds 1-4 also exhibited significantly low inhibitory activity against RET(V804L) and RET(V804M).

It is reported that Alectinib exhibits an inhibitory effect on RET (V804L) with an in vitro IC ₅₀ (nM) of 32 (Mol Cancer Ther. 2014 Dec; 13 (12): 2910-8). The compounds of the present invention represented by the Example compounds or their salts exhibit excellent inhibitory activity against RET (V804L) at a level comparable to or higher than that of Alectinib. The compounds of the present invention represented by the Example compounds or their salts also exhibit high inhibitory activity against (V804M). The results indicate that the compounds of the present invention or their salts have antitumor effects on cancers and tumors expressing RET with mutations in its gatekeeper site (e.g., V804L and V804M).

Table 45

Table 46 (continued)

Table 47 (continued)

Table 48 (continued)

Test Example 4: Evaluation of stability in liver microsomes

A solution of the test compound in DMSO/acetonitrile (each test compound at a final concentration of 1 μM, DMSO at a final concentration of 0.01%, and acetonitrile at a final concentration of 1%) was independently added to a liver microsomal mixture solution (mouse liver microsomes at a final concentration of 0.25 mg/mL, potassium phosphate buffer at a final concentration of 100 mM, and magnesium chloride at a final concentration of 3 mM). Each mixture was pre-incubated at 37°C for 5 minutes. An NADPH-generating system (glucose-6-phosphate at a final concentration of 10 mM, oxidized phosphoamido adenine dinucleotide at a final concentration of 1 mM, and glucose-6-phosphate dehydrogenase at a final concentration of 1 unit/mL) was added to a portion of each mixture solution to initiate the metabolic reaction. After incubation at 37°C for 30 minutes, a double amount of ethanol was added to terminate the reaction, thereby obtaining a post-reaction sample. A double amount of ethanol was added to each residual mixture solution, and the NADPH-generating system was further added to obtain a pre-reaction sample. Pre-reaction and post-reaction samples were centrifuged at 2000×g, and the supernatants were filtered through a glass filter. Each filtrate was then introduced into an LC-MS/MS system to detect the MS/MS peak of the test compound. The percentage of residual test compound (residual %) was calculated based on the ratio of the post-reaction MS/MS peak of the test compound to the pre-reaction MS/MS peak.

Table 49 shows the results. Although the residual percentages of Comparative Example Compounds 1 and 2 were 0% in each case, the compounds of the present invention or their salts represented by the Example compounds had very high residual percentages. This indicates that the compounds of the present invention or their salts have significantly higher stability in mouse liver microsomes than the compounds of the Comparative Examples.

Table 49

Test Example 5: Evaluation of oral absorbability

The compounds of the present invention were suspended or dissolved in 0.5% HPMC and 0.1N hydrochloric acid and orally administered to BALB/cA mice. Blood was collected from the fundus of the mice at 0.5, 1, 2, 4, and 6 hours after oral administration to obtain plasma. The concentration of the compound in the obtained plasma was measured by LC-MS/MS, and oral absorption was evaluated.

The results showed that the compound of the present invention had a sufficient concentration in plasma, indicating excellent oral absorption.

Test Example 6: Evaluation of cell growth inhibition effect (1)

In vitro cytotoxicity assays were performed on TT cells, a human thyroid cancer cell line harboring a RET activating mutation (C634W).

A TT cell suspension prepared in Ham's F12K (Kaighn's) medium (Life Technologies Japan) containing 10% FBS was seeded at 5× ¹⁰ cells/well (0.15 mL) per well of a 96-well flat-bottom microplate and cultured overnight at 37°C in an incubator containing 5% carbon dioxide (Day 0). The compounds of the present invention were each dissolved in dimethyl sulfoxide to a concentration of 10 mM and further diluted in RPMI1640 medium (manufactured by Wako Pure Chemical Industries, Ltd.) containing 10% FBS to achieve final concentrations of 40, 12, 4, 1.2, 0.4, 0.12, 0.04, and 0.012 μM, respectively. The compounds of varying concentrations were each added at 0.05 mL/well to the wells of the culture plates containing the TT cells (Day 1) and cultured at 37°C in an incubator containing 5% carbon dioxide for 7 days. After incubation (day 8), 0.1 mL of culture medium was taken from each well, 0.1 mL of CellTiter Glo 2.0 reagent (Promega Corporation), a luminescent detection reagent for intracellular ATP, was added thereto, and then shaken for 1 minute. After shaking, each culture was allowed to stand at room temperature for 15 minutes, and chemiluminescence was measured using a photometer to use it as an indicator of the number of viable cells. Based on the values of T _{day 8 and} C _{day 1} , the growth rate from day 1 at different compound concentrations was calculated by the following formula to determine the concentration at which the test compound can inhibit cell growth by 50% (GI ₅₀ (nM)).

1) T _{day 8} ≥ C _{day 1}

Growth rate (%) = (T _{day 8} - C _{day 1} ) / (C _{day 8} - C _{day 1} ) × 100

2) T _{Day 8} < C _{Day 1}

Growth rate (%) = (T _{day 8} - C _{day 1} ) / C _{day 1} × 100

T: absorbance of the wells to which the test compound was added.

C: absorbance of wells to which no test compound was added.

Day 1: The day on which the test compounds are added.

Day 8: Evaluation day.

The results are shown in Table 50. The compounds of the present invention exhibited a high growth inhibitory effect on TT cells.

Table 50

Test Example 7: Evaluation of cell growth inhibitory effect (2)

In vitro cytotoxicity assays were performed on LC-2/ad cells (a human lung adenocarcinoma cell line harboring the CCDC6-RET fusion gene).

A LC-2/ad cell suspension prepared in RPMI1640 medium containing 10% FBS was seeded at 5×10 ³ cells/well (0.15 mL) in each well of a 96-well flat-bottom microplate and cultured overnight at 37°C in an incubator containing 5% carbon dioxide (Day 0). The compounds of the present invention were each independently dissolved in dimethyl sulfoxide to a concentration of 10 mM and further diluted with RPMI1640 medium containing 10% FBS to achieve final concentrations of 40, 12, 4, 1.2, 0.4, 0.12, 0.04, and 0.012 μM, respectively. Compounds of varying concentrations were each independently added to each well of the above-mentioned culture plate containing LC-2/ad cells at 0.05 mL/well (Day 1) and cultured at 37°C in an incubator containing 5% carbon dioxide for 7 days. After culture (day 8), 0.1 mL of culture medium was taken from each well, 0.1 mL of CellTiter Glo 2.0 reagent (Promega Corporation), a luminescent detection reagent for intracellular ATP, was added thereto, and then shaken for 5 minutes. After shaking, each culture was allowed to stand at room temperature for 15 minutes, and chemiluminescence was measured using a photometer to use as an indicator of the number of viable cells. Based on the values of T _{day 8 and} C _{day 1} , the concentration (GI ₅₀ (nM)) was determined in the same manner as in Test Example 6.

The results are shown in Table 51. The compounds of the present invention showed a high growth inhibitory effect.

Table 51

Test Example 8: Evaluation of cell growth inhibition effect (3)

In vitro cytotoxicity assays were performed on Ba/F3_TEL-RET V804L cells (Ba/F3 cells introduced with the TEL-RET fusion gene having the gatekeeper mutation V804L).

Plasmid DNA prepared by introducing the V804L mutation into the RET gene of the TEL-RET fusion gene was introduced into Ba/F3 cells using standard techniques to produce Ba/F3_TEL-RET V804L. A Ba/F3_TEL-RET V804L cell suspension prepared in RPMI1640 medium containing 10% FBS was seeded at 1× ¹⁰ cells/well (0.075 mL) per well of a 96-well flat-bottom microplate. The compounds of the present invention were each independently dissolved in dimethyl sulfoxide to a concentration of 10 mM and further diluted in RPMI1640 medium containing 10% FBS to achieve final concentrations of 40, 12, 4, 1.2, 0.4, 0.12, 0.04, and 0.012 μM, respectively. The compound of different concentrations was added to each well of the culture plate containing Ba/F3_TEL-RET V804L cells at 0.025 mL/well (Day 1) and cultured at 37°C in an incubator containing 5% carbon dioxide for 4 days. After culture (Day 4), 0.1 mL of CellTiter Glo 2.0 reagent (Promega Corporation), a luminescent detection reagent for intracellular ATP, was added thereto, followed by shaking for 5 minutes. After shaking, each culture was allowed to stand at room temperature for 15 minutes, and chemiluminescence was measured using a photometer to use it as an indicator of the number of viable cells. Evaluation was performed on Day 4, and the concentration (GI ₅₀ (nM)) was determined in the same manner as in Test Example 6, depending on the values of T _{Day 8} and C _{Day 1} .

The results are shown in Table 52. Alectinib, known for its inhibitory effect against the RET V804L mutation, has a GI ₅₀ of 206 (nM). In comparison, the compounds of the present invention exhibited far superior growth inhibitory effects against Ba/F3_TEL-RET V804L cells.

Table 52

Test Example 9: Evaluation of cell growth inhibition effect (4)

In vitro cell growth inhibition assays were performed on Ba/F3_BCR-RET V804M cells (Ba/F3 cells introduced with the BCR-RET fusion gene having the gatekeeper mutation V804M).

A Ba/F3_BCR-RET V804M cell suspension prepared in RPMI1640 medium containing 10% FCS and 2 ng/mL IL3 (interleukin-3) was seeded into each well of a 384-well plate at 5×10 ³ cells/well (0.05 mL). The compounds of the present invention were each independently dissolved in dimethyl sulfoxide to a concentration of 10 mM and further diluted with culture medium to achieve final concentrations of 1000, 300, 100, 30, 10, 3, 1, and 0.3 μM, respectively. Compounds of varying concentrations were each independently added at 50 nL/well to each well of the above-described culture plate containing Ba/F3_BCR-RET V804M cells (Day 1) and cultured at 37°C in an incubator containing 5% carbon dioxide for 2 days. After incubation (day 3), 0.015 mL of CellTiter Glo (Promega Corporation), a luminescent detection reagent for intracellular ATP, was added, and chemiluminescence was measured using a luminometer as an indicator of viable cell count. The compound concentration that inhibited cell viability by 50% on day 3 (IC ₅₀ (nM)) was determined by the following formula.

Survival rate (%) = (T _{day 3)} / (C _{day 3} ) × 100

T: absorbance of the wells to which the test compound was added.

C: absorbance of wells to which no test compound was added.

Day 1: The day on which the test compounds are added.

Day 3: The day of the evaluation.

The results are shown in Table 53. The compounds of the present invention exhibited a high growth inhibitory effect on Ba/F3_BCR-RET V804M cells.

Table 53

Test Example 10: Evaluation of in vivo anti-tumor effects using a mouse model with subcutaneous implantation of TT cells (a human thyroid cancer cell line with a RET activating mutation)

Human thyroid cancer cell lines (TT) were subcutaneously implanted into the right flank of 6- to 7-week-old BALB/cA Jcl-nu/nu male mice. Approximately 2-3 weeks after cell implantation, the length (mm) and width (mm) of the tumors found in the mice were measured. After calculating the tumor volume (TV), the mice were grouped (n=5 or 6) so that each group had a substantially equal average TV. The day the mice were grouped was designated "grouping day" (Day 0 or Day 1).

Test solutions containing the present compound were prepared at a dose of 50, 100 or 150 mg/kg/day and orally administered to mice for 14 consecutive days (the first administration day was day 1). A control group was administered with a solvent (0.5% HPMC/0.1N HCl).

In order to determine the antitumor effect index, the TV of each administration group was measured on the 15th day, and the tumor volume (relative tumor volume: RTV) and T/C (%) on the 15th day relative to the tumor volume on the grouping day (day 0 or day 1) were calculated by the following formula, and the antitumor effect was evaluated. When the group (test compound treatment group) administered with any compound of the present invention showed a statistically significantly smaller average RTV than the average RTV of the control group (Dunnett test, p < 0.05), it was determined that there was an antitumor effect. Figures 1 and 2 and Tables 54 and 55 show the results. In the figures, the symbol "*" indicates a statistically significant difference.

TV (mm ³ ) = (length × width ² )/2

RTV = (TV on day 15) / (TV on day 0 or day 1)

T/C (%) = (average RTV of the test compound-treated group) / (average RTV of the control group) × 100

To determine the toxicity index, the body weight of the mice was measured over time (body weight: BW (g)), and the average body weight change (body weight change: BWC (%)) from the day of grouping (day 0 or day 1) to day 15 was calculated by the following formula (n: the day on which body weight was measured twice a week, with the last measurement day being day 15 for the final evaluation). Figures 3 and 4 show the results.

BWC (%) = [(BW on day n) - (BW on day 0 or day 1)] / (BW on day 0 or day 1) × 100

The compounds of the present invention have a significant antitumor effect on the human thyroid cancer line TT having a RET-activating mutation implanted subcutaneously into nude mice. No toxicity such as weight loss was observed.

Table 54

Table 55

Attached text:

Figure 1

Horizontal axis: day

Vertical axis: relative tumor volume (RTV)

comparison

Example 85 100 mg/kg/day

Figure 2

Horizontal axis: day

Vertical axis: relative tumor volume (RTV)

comparison

Example 90 50 mg/kg/day

Example 89 150 mg/kg/day

Example 87 50 mg/kg/day

Figure 3

Horizontal axis: day

Vertical axis: Body weight change (% from day 0)

comparison

Example 85 100 mg/kg/day

Figure 4

Horizontal axis: day

Vertical axis: Body weight change (% from day 1)

comparison

Example 90 50 mg/kg/day

Example 89 150 mg/kg/day

Example 87 50 mg/kg/day

Claims (19)

1. The use of the compound represented by formula (I) or a salt thereof for the manufacture of RET inhibitors: In equation (I), A is... When A is A1 Where ^R1 is halogen, C1-C6 alkyl groups, which are unsubstituted or substituted with the following groups: C1-C6 alkoxy or C1-C6 alkylthio, hydroxyl, wherein the hydrogen atom in the C1-C6 alkoxy group can be replaced by one or more deuterium atoms. C1-C6 alkoxy groups, Halogen-substituted or unsubstituted C2-C6 alkenyl groups, or Unsubstituted C2-C6 ynyl group, Y is N or CH, and n is an integer between 0 and 2. When n is 2, the two ^R1s can be the same or different from each other; When A is A2 Y is CH, and When n is 0, In formula A2, the group together with the phenyl group to which the group is attached forms a 9- to 10-membered bicyclic unsaturated heterocyclic group containing a heteroatom selected from oxygen or sulfur; ^R2 is C3-C10 alkyl groups, which are unsubstituted or substituted by one or more substituents selected from: halogens, C1-C6 alkoxy groups, C3-C7 cycloalkyl groups, and 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C7 cycloalkyl groups, which are unsubstituted or substituted by one or more substituents selected from: C1-C6 alkyl groups, C3-C7 cycloalkyl groups, halo-C1-C6 alkyl groups, and halogens. C4-C10 bridged cycloalkyl groups, or C3-C7 cycloalkenyl, and X is N or CR ³ , where R ³ is (i)Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) Unsubstituted C1-C4 alkyl groups, (v) C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following groups: (v-1) halogens, (v-2)C1-C6 alkoxy group, (v-3)C3-C7 cycloalkyl groups, and (v-4) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (vi) Unsubstituted C1-C6 alkylthio groups, (vii) Unsubstituted C3-C7 cycloalkyl groups, (viii) C2-C6 alkenyl groups, which are either unsubstituted or substituted with hydroxyl groups. (ix) C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following groups: (ix-1)hydroxyl group, (ix-2)C1-C6 alkoxy group, (ix-3)amino, which is unsubstituted or substituted with an ^R4 group, wherein ^R4 is at least one group selected from: C1-C6 alkyl and C1-C4 alkoxy, C1-C6 alkyl and unsubstituted or substituted with a C3-C7 cycloalkyl carbamoyl group. (ix-4)C1-C6 alkylsiloxy, (ix-5)C3-C7 cycloalkyl groups, which are either unsubstituted or substituted with hydroxyl or oxo groups. (ix-6)C6 aromatic group, which is unsubstituted or substituted with ^R5 , wherein ^R5 is halogen, unsubstituted or substituted with one or more C1-C4 alkylamino or C1-C6 alkoxy groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (ix-7) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 groups, and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. Where ^R6 is a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or an oxo group. (ix-8) One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which are the same or different from each other, wherein ^R7 is a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or amino group, and (ix-9) Unsaturated heterocyclic oxygen groups, which are unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 10-membered monocyclic or bicyclic unsaturated heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be the same or different from each other. The condition is that the C2-C6 ynyl triple bond is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom; (x)C6 aromatic group, which is unsubstituted or substituted with the following groups: (x-1)hydroxyl group, (x-2) Unsubstituted or hydroxyl-substituted C1-C6 alkyl groups, (x-3)formyl group, or (x-4) One or more 4- to 10-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with C1-C6 alkyl groups, and contain 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be the same as or different from each other. or (xi)4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with the following groups: (xi-2) Unsubstituted or hydroxyl-substituted C1-C6 alkyl groups, or (xi-3)amino, which is either unsubstituted or substituted with a C1-C6 alkyl carbonyl group, It also contains 1-3 heteroatoms, which are the same or different from each other, selected from nitrogen, oxygen and sulfur. 2. The use of the compound represented by formula (I) or a salt thereof in the manufacture of antitumor agents: In equation (I), A is... When A is A1 Where ^R1 is halogen, C1-C6 alkyl groups, which are unsubstituted or substituted with the following groups: C1-C6 alkoxy or C1-C6 alkylthio, hydroxyl, wherein the hydrogen atom in the C1-C6 alkoxy group can be replaced by one or more deuterium atoms. C1-C6 alkoxy groups, halogen-substituted or unsubstituted C2-C6 alkenyl groups, or Unsubstituted C2-C6 ynyl group, Y is N or CH, and n is an integer between 0 and 2. When n is 2, the two ^R1s can be the same or different from each other; When A is A2 Y is CH, and When n is 0, In formula A2, the group together with the phenyl group to which the group is attached forms a 9- to 10-membered bicyclic unsaturated heterocyclic group containing a heteroatom selected from oxygen or sulfur; ^R2 is a C3-C10 alkyl group that is unsubstituted or substituted with one or more substituents selected from the following: halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, and 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C7 cycloalkyl groups, which are unsubstituted or substituted by one or more substituents selected from: C1-C6 alkyl groups, C3-C7 cycloalkyl groups, halo-C1-C6 alkyl groups, and halogens. C4-C10 bridged cycloalkyl groups, or C3-C7 cycloalkenyl, and X is N or CR ³ , where R ³ is (i)Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) Unsubstituted C1-C4 alkyl groups, (v) C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following groups: (v-1) halogens, (v-2)C1-C6 alkoxy, (v-3)C3-C7 cycloalkyl, and (v-4) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (vi) Unsubstituted C1-C6 alkylthio groups, (vii) Unsubstituted C3-C7 cycloalkyl groups, (viii) C2-C6 alkenyl groups, which are either unsubstituted or substituted with hydroxyl groups. (ix) C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following groups: (ix-1)hydroxyl group, (ix-2)C1-C6 alkoxy group, (ix-3)amino, which is unsubstituted or substituted with an ^R4 group, wherein ^R4 is at least one group selected from: C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkyl, and unsubstituted or substituted with a C3-C7 cycloalkyl carbamoyl group. (ix-4)C1-C6 alkylsiloxy, (ix-5)C3-C7 cycloalkyl groups, which are either unsubstituted or substituted with hydroxyl or oxo groups. (ix-6)C6 aromatic group, which is unsubstituted or substituted with ^R5 , wherein ^R5 is halogen, unsubstituted or substituted with one or more C1-C4 alkylamino or C1-C6 alkoxy groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (ix-7) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 groups, and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. Where ^R6 is a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or an oxo group. (ix-8) One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which are the same or different from each other, wherein ^R7 is a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or amino group, and (ix-9) Unsaturated heterocyclic oxygen groups, which are unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 10-membered monocyclic or bicyclic unsaturated heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be the same or different from each other. The condition is that the C2-C6 ynyl triple bond is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom; (x)C6 aromatic group, which is unsubstituted or substituted with the following groups: (x-1)hydroxyl group, (x-2) Unsubstituted or hydroxyl-substituted C1-C6 alkyl groups, (x-3)formyl group, or (x-4) One or more 4- to 10-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with C1-C6 alkyl groups, and contain 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be the same as or different from each other. or (xi)4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with the following groups: (xi-2) an unsubstituted or hydroxyl-substituted C1-C6 alkyl group, or (xi-3) an amino group that is unsubstituted or substituted with a C1-C6 alkyl carbonyl group. It also contains 1-3 heteroatoms, which are the same or different from each other, selected from nitrogen, oxygen and sulfur. 3. The use according to claim 1 or 2, wherein when A is A1, A1 is Where R ^1a is C1-C6 alkyl groups, which are unsubstituted or substituted with C1-C6 alkoxy or C1-C6 alkylthio groups, wherein the hydrogen atoms contained in the C1-C6 alkoxy group may be replaced by one or more deuterium atoms. C2-C6 alkenyl, or C2-C6 acetylene group, R ^1b is a halogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group; and m is an integer, either 0 or 1. 4. The use according to claim 1 or 2, wherein ^R2 is a C3-C10 alkyl group that is unsubstituted or substituted by one or more substituents selected from: halogens, C3-C7 cycloalkyl groups, and one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C7 cycloalkyl groups, which are either unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl groups, C3-C7 cycloalkyl groups, and halogenated C1-C6 alkyl groups. C4-C10 bridged cycloalkyl groups, or C3-C7 cycloalkenyl. 5. The use according to claim 1 or 2, wherein when X is CR ³ , R ³ is (i)Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) Unsubstituted C1-C4 alkyl groups, (v) C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following: (v-1) halogens, (v-2)C1-C6 alkoxy, (v-3)C3-C7 cycloalkyl, and (v-4) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; (vi) C1-C4 alkylthio groups. (vii)C3-C5 cycloalkyl groups, (viii) C2-C6 alkenyl groups, which are either unsubstituted or substituted with hydroxyl groups. (ix) C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following: (ix-1)hydroxyl group, (ix-2)C1-C6 alkoxy group, (ix-3)amino, which is unsubstituted or substituted with ^R4 , wherein ^R4 is at least one group selected from: C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkyl, and unsubstituted or substituted with C3-C7 cycloalkyl carbamoyl. (ix-4)C1-C6 alkylsiloxy, (ix-5)C3-C7 cycloalkyl groups, which are either unsubstituted or substituted with hydroxyl or oxo groups. (ix-6)C6 aromatic group, which is unsubstituted or substituted with ^R5 , wherein ^R5 is halogen, unsubstituted or substituted with one or more C1-C4 alkylamino or C1-C6 alkoxy groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (ix-7) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 , and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R6 is a hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or oxo group. (ix-8) One or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R7 is a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or amino group, and (ix-9) Unsaturated heterocyclic oxygen groups, which are unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocycle containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. The condition is that the triple bond of the C2-C6 ynyl group is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom. (x)C6 aromatic group, which is unsubstituted or substituted with the following groups: (x-1)hydroxyl group, (x-2)C1-C6 alkyl groups, which are either unsubstituted or substituted with hydroxyl groups. (x-3)formyl group, or (x-4) A 4- to 10-membered monocyclic saturated heterocyclic group, which is unsubstituted or substituted with a C1-C6 alkyl group and contains 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or (xi)4- to 6-membered monocyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with the following groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur: (xi-2)C1-C6 alkyl groups, which are either unsubstituted or substituted with hydroxyl groups, or (xi-3)amino, which is either unsubstituted or substituted with a C1-C6 alkyl carbonyl group. 6. The use according to claim 1 or 2, wherein A is Where R ^1a is C1-C6 alkyl groups, which are unsubstituted or substituted with C1-C6 alkoxy or C1-C6 alkylthio groups, wherein the hydrogen atoms in the C1-C6 alkoxy group can be replaced by one or more deuterium atoms. C2-C6 alkenyl, or C2-C6 acetylene group, R ^1b is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy; m is an integer, either 0 or 1; ^R2 is C3-C10 alkyl groups, which are unsubstituted or substituted by one or more substituents selected from: halogens, C3-C7 cycloalkyl groups, and one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C7 cycloalkyl, which is unsubstituted or substituted by one or more substituents selected from C1-C6 alkyl, C3-C7 cycloalkyl and halogenated C1-C6 alkyl, or C4-C10 bridged cycloalkyl groups; and X is N or CR ³ , where R ³ is (i’) Hydrogen, (ii’) Halogen (iii’) Cyano group, (iv’)C1-C4 alkyl, (v’)C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following: (v-1’)halogen, (v-2’)C1-C6 alkoxy group, (v-3’)C3-C7 cycloalkyl, and (v-4’) one or more 4- to 6-membered monocyclic saturated heterocyclic groups It is unsubstituted and contains 1-3 identical or different atoms selected from nitrogen, heteroatoms of oxygen and sulfur (vi’)C1-C4 alkylthio group, (vii’)C3-C5 cycloalkyl, (viii’)C2-C4 alkenyl group, which is either unsubstituted or substituted with a hydroxyl group. (ix’)C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following: (ix-1’)hydroxyl group, (ix-2’)C1-C4 alkoxy group, (ix-3')amino, which is unsubstituted or substituted with ^R4 , wherein ^R4 is at least one group selected from: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl, and unsubstituted or substituted with C3-C5 cycloalkyl carbamoyl. (ix-4’)tri-C1-C6 alkylsiloxy, (ix-5’)C3-C7 cycloalkyl, which is either unsubstituted or substituted with hydroxyl or oxo groups. (ix-6')phenyl, which is unsubstituted or substituted with ^R5 , wherein ^R5 is a halogen, unsubstituted or substituted with one or more methylamino or C1-C4 alkoxy groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (ix-7') One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 , and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R6 is a hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or oxo group. (ix-8') One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R7 is a halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, or amino group, and (ix-9’)unsaturated heterocyclic oxygen group, which is unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 6-membered monocyclic unsaturated heterocycle containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. The condition is that the triple bond of the C2-C6 ynyl group is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom. (x’)phenyl, which is unsubstituted or substituted with the following groups: (x-1’)hydroxyl group, (x-2’)C1-C4 alkyl groups, which are either unsubstituted or substituted with hydroxyl groups. (x-3’)formyl group, or (x-4’) one or more 4- to 6-membered monocyclic saturated heterocyclic groups It is either unsubstituted or substituted with C1-C4 alkyl groups and contains 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, or (xi’)4- to 6-membered monocyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with the following groups and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur: (xi-2’)C1-C4 alkyl, which is either unsubstituted or substituted with a hydroxyl group, or (xi-3’)amino, which is either unsubstituted or substituted with a C1-C4 alkyl carbonyl group. 7. The use according to any one of claims 1 or 2, wherein A is R ^1b is a halogen; m is an integer, either 0 or 1; ^R2 is Branched C3-C6 alkyl groups, which are either unsubstituted or substituted with halogens, or C3-C7 cycloalkyl groups, which are either unsubstituted or substituted with C1-C4 or C3-C5 cycloalkyl groups; and X is ^CR3 , where ^R3 is (i”) hydrogen. (ii”) Halogens, (v’)C1-C4 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following: (v-2”)C1-C4 alkoxy group, (v-3”)C3-C7 cycloalkyl, and (v-4”) One or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom (vi”)C1-C4 alkylthio group, (viii’)C2-C4 alkenyl, (ix’)C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following: (ix-1”)hydroxyl group, (ix-2”)amino, which is unsubstituted or substituted with ^R4 , wherein ^R4 is a C1-C4 alkyl or a C1-C4 alkoxy-C1-C4 alkyl. (ix-5”)C3-C7 cycloalkyl, which is either unsubstituted or substituted with a hydroxyl group. (ix-6”)phenyl, which is either unsubstituted or substituted with ^R5 , where ^R5 is a halogen. (ix-7”) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 , and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R6 is a hydroxyl, C1-C4 alkyl, or oxo group, and (ix-8”) One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R7 is a halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, or amino group. The condition is that the triple bond of the C2-C6 ynyl group is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom. (x”)phenyl, which is unsubstituted, or substituted with a hydroxyl group or an unsubstituted or hydroxylated C1-C4 alkyl group, or (xi”)4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 or 2 nitrogen atoms. 8. A compound or a salt thereof represented by the following formula (I’): In equation (I’), A is When A is A1 Where ^R1 is halogen, C1-C6 alkyl groups, which are unsubstituted or substituted with the following groups: C1-C6 alkoxy or C1-C6 alkylthio, hydroxyl, wherein the hydrogen atom in the C1-C6 alkoxy group can be replaced by one or more deuterium atoms. C1-C6 alkoxy groups, halogen-substituted or unsubstituted C2-C6 alkenyl groups, or Unsubstituted C2-C6 ynyl group, Y is N or CH, and n is an integer between 0 and 2. When n is 2, the two ^R1s can be the same or different from each other; When A is A2 Y is CH, and When n is 0, In formula A2, the group together with the phenyl group to which the group is attached forms a 9- to 10-membered bicyclic unsaturated heterocyclic group containing a heteroatom selected from oxygen or sulfur; ^R2 is a C3-C10 alkyl group that is unsubstituted or substituted with one or more substituents selected from the following: halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, and 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C4 cycloalkyl groups, which are unsubstituted or substituted by one or more substituents selected from: C1-C6 alkyl groups, C3-C7 cycloalkyl groups, halogenated C1-C6 alkyl groups, and halogens. C4-C10 bridged cycloalkyl groups, or C3-C4 cycloalkenyl, and X is N or CR ³ , where R ³ is (i)Hydrogen, (ii) Halogens, (iii) Cyano group, (iv) Unsubstituted C1-C4 alkyl groups, (v) C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following groups: (v-1) halogens, (v-2)C1-C6 alkoxy, (v-3)C3-C7 cycloalkyl, and (v-4) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (vi) Unsubstituted C1-C6 alkylthio groups, (vii) Unsubstituted C3-C7 cycloalkyl groups, (viii) C2-C6 alkenyl groups, which are either unsubstituted or substituted with hydroxyl groups. (ix) C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following groups: (ix-1)hydroxyl group, (ix-2)C1-C6 alkoxy group, (ix-3)amino, which is unsubstituted or substituted with an ^R4 group, wherein ^R4 is at least one group selected from: C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkyl, and unsubstituted or substituted with a C3-C7 cycloalkyl carbamoyl group. (ix-4)C1-C6 alkylsiloxy, (ix-5)C3-C7 cycloalkyl groups, which are either unsubstituted or substituted with hydroxyl or oxo groups. (ix-6)C6 aromatic group, which is unsubstituted or substituted with ^R5 , wherein ^R5 is halogen, unsubstituted or substituted with one or more C1-C4 alkylamino or C1-C6 alkoxy groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. (ix-7) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 groups, and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. Where ^R6 is a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or an oxo group. (ix-8) One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which are the same or different from each other, wherein ^R7 is a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or amino group. (ix-9) Unsaturated heterocyclic oxygen groups, which are unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 10-membered monocyclic or bicyclic unsaturated heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be the same or different from each other. The condition is that the C2-C6 ynyl triple bond is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to said carbon atom; (x)C6 aromatic group, which is unsubstituted or substituted with the following groups: (x-1)hydroxyl group, (x-2) Unsubstituted or hydroxyl-substituted C1-C6 alkyl groups, (x-3)formyl group, or (x-4) A 4- to 10-membered monocyclic saturated heterocyclic group, which is unsubstituted or substituted with a C1-C6 alkyl group, and contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be the same or different from each other. or (xi)4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with the following groups: (xi-2) an unsubstituted or hydroxyl-substituted C1-C6 alkyl group, or (xi-3) an amino group that is unsubstituted or substituted with a C1-C6 alkyl carbonyl group. It also contains 1-3 heteroatoms, which are the same or different from each other, selected from nitrogen, oxygen and sulfur. 9. The compound or a salt thereof according to claim 8, wherein when A is Al, Al is Where R ^1a is C1-C6 alkyl groups, which are unsubstituted or substituted with C1-C6 alkoxy or C1-C6 alkylthio groups, wherein the hydrogen atoms in the alkoxy group may be replaced by one or more deuterium atoms. C2-C6 alkenyl, or C2-C6 acetylene group, R ^1b is a halogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group; and m is an integer, either 0 or 1. 10. The compound of claim 8 or a salt thereof, wherein ^R2 is selected from: C3-C10 alkyl groups, which are unsubstituted or substituted by one or more substituents selected from: halogens, C3-C7 cycloalkyl groups, and one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C4 cycloalkyl groups, which are either unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl, C3-C7 cycloalkyl, and halogenated C1-C6 alkyl groups. C4-C10 bridged cycloalkyl groups, and C3-C4 cycloalkenyl. 11. The compound of claim 8 or a salt thereof, wherein when X is ^CR3 , ^R3 is selected from: (i)Hydrogen; (ii) Halogens; (iii) Cyano group; (iv) Unsubstituted C1-C4 alkyl groups; (v) C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following: (v-1) halogens, (v-2)C1-C6 alkoxy group, (v-3)C3-C7 cycloalkyl groups, and (v-4) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; (vi)C1-C4 alkylthio groups; (vii)C3-C5 cycloalkyl; (viii) C2-C6 alkenyl groups, which are either unsubstituted or substituted with hydroxyl groups; (ix) C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following: (ix-1)hydroxyl group; (ix-2)C1-C6 alkoxy group; (ix-3)amino, which is unsubstituted or substituted with ^R4 , wherein ^R4 is at least one group selected from the following: C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, and unsubstituted or substituted with C3-C7 cycloalkyl carbamoyl. (ix-4)C1-C6 alkylsiloxy; (ix-5)C3-C7 cycloalkyl, which is unsubstituted or substituted with hydroxyl or oxo groups; (ix-6)C6 aromatic group, which is either unsubstituted or substituted with ^R5 , wherein R ⁵ is selected from halogens; unsubstituted C1-C4 alkylamino groups or C1-C6 alkylamino groups substituted with one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; and C1-C6 alkoxy groups. (ix-7) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted by ^R6 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein ^R6 is selected from hydroxyl, C1-C6 alkyl, C1-C6 alkoxy and oxo groups; (ix-8) One or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R7 is selected from halogens, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and amino groups; and (ix-9) Unsaturated heterocyclic oxygen, which is unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocycle containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. In this configuration, the triple bond of the C2-C6 ynyl group is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the adjacent carbon atom. (x)C6 aromatic group, which is unsubstituted or substituted with the following groups: (x-1)hydroxyl group, (x-2)C1-C6 alkyl groups, which are either unsubstituted or substituted with hydroxyl groups. (x-3)formyl group, or (x-4) A 4- to 10-membered monocyclic saturated heterocyclic group, which is unsubstituted or substituted with a C1-C6 alkyl group and contains 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, or (xi)4- to 6-membered monocyclic unsaturated heterocyclic groups, which are unsubstituted or substituted by one or more substituents selected from the following: (xi-2)C1-C6 alkyl groups, which are either unsubstituted or substituted with hydroxyl groups, or The (xi-3)amino, which is either unsubstituted or substituted with a C1-C6 alkyl carbonyl group, The 4- to 6-membered monocyclic unsaturated heterocyclic group contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. 12. The compound or a salt thereof according to claim 8, wherein A is... R ^1a is selected from: C1-C6 alkyl groups, which are unsubstituted or substituted with C1-C6 alkoxy or C1-C6 alkylthio groups, wherein the hydrogen atoms in the alkoxy group may be replaced by one or more deuterium atoms. C2-C6 alkenyl, or C2-C6 acetylene group, R ^1b is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy; m is an integer, either 0 or 1; R ² is selected from: C3-C10 alkyl groups, which are unsubstituted or substituted by one or more substituents selected from: halogens, C3-C7 cycloalkyl groups, and one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. C3-C4 cycloalkyl, which is unsubstituted or substituted by one or more substituents selected from C1-C6 alkyl, C3-C7 cycloalkyl and halogenated C1-C6 alkyl, or C4-C10 bridged cycloalkyl groups; and X is N or CR ³ , where R ³ is selected from: (i’) Hydrogen, (ii’) Halogen (iii’) Cyano group, (iv’)C1-C4 alkyl, (v’)C1-C6 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following: (v-1’)halogen, (v-2’)C1-C6 alkoxy group, (v-3’)C3-C7 cycloalkyl, and (v-4’) one or more 4- to 6-membered monocyclic saturated heterocyclic groups It is unsubstituted and contains 1-3 identical or different atoms selected from nitrogen, heteroatoms of oxygen and sulfur (vi’)C1-C4 alkylthio group, (vii’)C3-C5 cycloalkyl, (viii’)C2-C4 alkenyl group, which is either unsubstituted or substituted with a hydroxyl group. (ix’)C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following: (ix-1’)hydroxyl group, (ix-2’)C1-C4 alkoxy group, (ix-3')amino, which is unsubstituted or substituted with ^R4 , wherein ^R4 is at least one group selected from: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl, and unsubstituted or substituted with C3-C5 cycloalkyl carbamoyl. (ix-4’)tri-C1-C6 alkylsiloxy, (ix-5’)C3-C7 cycloalkyl, which is either unsubstituted or substituted with hydroxyl or oxo groups. (ix-6')phenyl, which is unsubstituted or substituted with ^R5 , wherein ^R5 is selected from halogens; an unsubstituted or substituted methylamino group containing one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups selected from nitrogen, oxygen, and sulfur; and a C1-C4 alkoxy group. (ix-7') One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 , and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R6 is a hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or oxo group. (ix-8') One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with ^R7 , and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R7 is selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, and amino groups, and (ix-9’)unsaturated heterocyclic oxygen group, which is unsubstituted or halogenated, wherein the unsaturated heterocycle is a 4- to 6-membered monocyclic unsaturated heterocycle containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. The triple bond of the C2-C6 ynyl group is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to that carbon atom. (x’)phenyl, which is unsubstituted or substituted by one or more substituents selected from the following: (x-1’)hydroxyl group, (x-2’)C1-C4 alkyl groups, which are either unsubstituted or substituted with hydroxyl groups. (x-3’)formyl group, or (x-4’) one or more 4- to 6-membered monocyclic saturated heterocyclic groups It is either unsubstituted or substituted with C1-C4 alkyl groups and contains 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, or (xi’)4- to 6-membered monocyclic unsaturated heterocyclic groups, which are unsubstituted or substituted with the following groups: (xi-2’)C1-C4 alkyl, which is either unsubstituted or substituted with a hydroxyl group, or (xi-3’)amino group, which is either unsubstituted or substituted with a C1-C4 alkyl carbonyl group. The 4- to 6-membered monocyclic unsaturated heterocyclic group contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. 13. The compound or a salt thereof according to claim 8, wherein A is... R ^1b is a halogen; m is an integer, either 0 or 1; ^R2 is Branched C3-C6 alkyl groups, which are either unsubstituted or substituted with halogens, or C3-C4 cycloalkyl groups, which are either unsubstituted or substituted with C1-C4 or C3-C5 cycloalkyl groups; and X is ^CR3 , where ^R3 is (i”) hydrogen; (ii”) Halogens; (v’)C1-C4 alkoxy group, which is unsubstituted or substituted by one or more substituents selected from the following: (v-2”)C1-C4 alkoxy group, (v-3”)C3-C7 cycloalkyl, and (v-4”) One or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom; (vi”)C1-C4 alkylthio group, (viii’)C2-C4 alkenyl, (ix’)C2-C6 ynyl group, which is unsubstituted or substituted by one or more substituents selected from the following: (ix-1”)hydroxyl group; (ix-2”)amino, which is unsubstituted or substituted with ^R4 , wherein ^R4 is a C1-C4 alkyl or a C1-C4 alkoxy-C1-C4 alkyl; (ix-5”)C3-C7 cycloalkyl, which is either unsubstituted or substituted with hydroxyl groups; (ix-6”)phenyl, which is either unsubstituted or substituted with ^R5 , where ^R5 is a halogen; (ix-7”) One or more 4- to 6-membered monocyclic saturated heterocyclic groups, which are unsubstituted or substituted with ^R6 , and contain 1-3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein ^R6 is a hydroxyl, C1-C4 alkyl, or oxo group; and (ix-8”) One or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups, which are unsubstituted or substituted by R ⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, wherein R ⁷ is a halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or amino group; The triple bond of the C2-C6 ynyl group is located between the carbon atom connected to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to the carbon atom. (x”)phenyl, which is unsubstituted or substituted by one or more substituents selected from: hydroxyl and unsubstituted or hydroxylated C1-C4 alkyl; or (xi”)4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 or 2 nitrogen atoms. 14. The compound according to claim 8, wherein the compound is selected from: (1) 4-amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2) 4-amino-7-(1-fluoro-2-methylpropyl-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (3) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (4) 4-Amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (5) 4-Amino-6-chloro-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (6) 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (7) 4-Amino-6-fluoro-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (8) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (9) 4-Amino-6-(4-hydroxy-4-methylpent-1-yn-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (10) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (11) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolid-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (12)(R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (13) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (14) 4-Amino-6-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (15) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-pyrazol-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (16) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (17) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (18) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (19) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (20) 4-Amino-6-ethoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (21) 4-Amino-6-((1-hydroxycyclopentyl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (22) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-thiomorpholinopropyl-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (23) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-(tetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (24) 4-amino-6-((6-aminopyridin-3-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (25) 4-Amino-6-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (26) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((1-methylpiperidin-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (27) 4-amino-6-(3-(dimethylamino)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (28) 4-Amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (29) 4-Amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (30) 4-Amino-1-cyclopentyl-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (31) 4-Amino-N-(3-chlorophenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (32) 4-amino-1-(cyclopent-3-en-1-yl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (33) 4-amino-N-(4-((methylthio)methyl)phenyl)-1-(pent-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (34) 4-Amino-1-cyclohexyl-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (35) 1-(adamantane-2-yl)-4-amino-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (36) 4-amino-N-(4-(methoxymethyl)phenyl)-1-(trans-4-methylcyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (37) 4-Amino-1-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (38) 4-Amino-1-(tert-butyl)-N-(4-((methylthio)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (39) 4-Amino-7-(tert-butyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (40) 4-Amino-7-(tert-butyl)-N-(3-fluoro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (41) 4-Amino-7-(tert-butyl)-N-(2-methoxy-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (42) 4-Amino-7-(tert-butyl)-N-(4-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (43) 4-Amino-7-(tert-butyl)-N-(4-((methoxy-d3)-methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (44) 4-Amino-7-(1-methylcyclopropyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (45) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(tert-amyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (46) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclobutyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (47) 4-Amino-7-(1-fluoro-2-methylpropyl-2-yl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (48) 4-Amino-7-(1-fluoro-2-methylpropyl-2-yl)-N-(3-fluoro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (49) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(2-(thiophen-2-yl)propyl-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (50) 4-amino-7-(bicyclo[2.2.1]hept-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (51) 4-amino-7-(bicyclo[1.1.1.]pent-1-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (52) 4-Amino-7-(1-(fluoromethyl)cyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (53) 4-Amino-7-(1-(difluoromethyl)cyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (54) 4-Amino-7-(1-ethylcyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (55) 4-Amino-N-(3-fluoro-4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (56) 7-{[1,1-bis(cyclopropane)]-1-yl}-4-amino-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (57) 4-Amino-7-(1,1-difluoro-2-methylpropyl-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (58) 4-Amino-7-(2,3-dimethylbut-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (59) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(2,3,3-trimethylbut-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (60) 4-Amino-7-(2-cyclopropylpropyl-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (61) 4-Amino-7-(2-cyclopropylpropyl-2-yl)-N-(3-fluoro-4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (62) 4-Amino-6-methoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (63) 4-Amino-6-cyano-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (64) 4-Amino-6-bromo-7-(1-methylcyclopropyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (65) 4-Amino-7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (66) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (67) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-methyl-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (68) 4-Amino-6-cyclopropyl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (69) 4-Amino-1-cyclopentyl-N-(4-ethynylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (70) 4-Amino-7-(1-methoxy-2-methylpropyl-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (71) 4-Amino-1-cyclopentyl-N-(4-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (72) 4-Amino-1-cyclopentyl-N-(isochroman-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (73)(R)-4-amino-N-(4-(methoxymethyl)phenyl)-6-(2-methoxypropoxy)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (74) 4-Amino-6-(2-fluoroethoxy)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (75) 4-Amino-6-isobutoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (76) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-(2-methoxypropoxy)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (77) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-3-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (78) 4-Amino-6-(3-cyclopropyl-3-hydroxypropyl-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (79) 4-Amino-N-(4-ethynylphenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (80)(E)-4-amino-6-(3-hydroxypropyl-1-en-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (81) 4-Amino-6-(3-hydroxyprop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (82) 4-Amino-6-(3-hydroxy-3-(pyridin-3-yl)but-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (83) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((4-oxocyclohexyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (84) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-((2-methoxyphenyl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (85) 4-Amino-6-((1-ethyl-1H-pyrazol-5-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (86) 4-Amino-6-ethoxy-7-(1-methylcyclopropyl)-N-(4-((methylthio)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (87)(E)-4-amino-6-ethoxy-7-(1-methylcyclopropyl)-N-(4-(prop-1-en-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (88) 4-Amino-6-((1-ethyl-1H-pyrazol-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (89) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(thiophen-2-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (90) 4-Amino-6-((6-chloropyridin-3-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (91)6-((1H-indol-3-ylethynyl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (92) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((3-((pyridine-4-methyl)amino)phenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (93) 4-Amino-6-(imidazo[1,2-a]pyridin-3-ylethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (94) 4-Amino-6-(3-hydroxybut-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (95) 4-Amino-6-(3-(3-hydroxyoxetane-3-yl)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (96) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((2-methylthiazo-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (97) 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-4-amino-N-(4-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (98)6-((1H-pyrazol-5-yl)ethynyl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (99) 4-Amino-6-((3-fluorophenyl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (100)4-Amino-N-(4-methoxymethyl)phenyl-7-(1-methylcyclopropyl)-6-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (101) 4-amino-6-(3-amino-3-methylbut-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (102) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (103) 4-Amino-6-(2-methoxy-2-methylpropoxy)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (104) 4-Amino-6-(2-methoxyethoxy)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (105) 4-Amino-6-(3-methoxy-3-methylbutoxy)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (106) 4-Amino-6-(cyclopentylmethoxy)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (107) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (108) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-(3-methyl-3-morpholinobut-1-yn-1-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (109) 4-Amino-6-(3-(4-hydroxytetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (110) 4-Amino-6-((1-isopropyl-1H-pyrazol-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (111) 4-Amino-6-(4-(hydroxymethyl)phenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (112) 4-Amino-6-isopropoxy-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (113)6-(6-acetamidopyridin-3-yl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (114) 4-Amino-6-(4-hydroxyphenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (115) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (116) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (117) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-thiomorpholinopropyl-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (118) 4-Amino-6-(4-formylphenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (119) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (120)4-Amino-6-(3-(2,5-dioxoimidazolidine-4-yl)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (121) 4-Amino-6-(4-hydroxyhex-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (122) 4-Amino-6-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (123) 4-Amino-6-(furano[3,2-b]pyridin-6-ylethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (124)6-((1H-pyrazol-4-yl)ethynyl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (125)6-((1H-pyrrolo-2-yl)ethynyl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (126) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(phenylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (127) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-(3-methyl-3-(1H-pyrrolo-1-yl)but-1-yn-1-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (128) 4-Amino-6-(3-(hydroxymethyl)phenyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (129) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-((4-methoxyphenyl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (130) 4-Amino-6-((1-hydroxycyclopropyl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (131) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (132) 4-Amino-6-(3-(3-cyclopropylureo)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (133)6-(3-(1H-pyrrolo-1-yl)prop-1-yn-1-yl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (134) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-2-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (135) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (136) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-2-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (137) 4-Amino-6-(5-(((2-fluoropyridin-3-yl)oxy)pent-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (138) 4-Amino-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (139) 4-Amino-6-((5-fluoropyridin-3-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (140) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(thiophen-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (141) 4-Amino-6-((3-hydroxytetrahydrofuran-3-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (142) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(3-(1-oxomorpholino)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (143) 4-Amino-6-(6-(hydroxymethyl)pyridin-3-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (144) 4-Amino-6-(3-(tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (145) 4-Amino-6-((1,5-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (146) 4-Amino-6-((3,5-dimethylisoxazol-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (147) 4-Amino-6-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (148) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-4-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (149) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(4-morpholinobut-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (150) 4-Amino-6-(4-hydroxypent-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (151) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-(3-(4-methoxypiperidin-1-yl)prop-1-yn-1-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (152)6-((1H-imidazol-5-yl)ethynyl)-4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (153) 4-Amino-N-(4-(methoxymethyl)phenyl)-6-((6-methoxypyridin-3-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (154) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(thiazolyl-5-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (155) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide; (156) 4-Amino-6-((5-cyanopyridin-3-yl)ethynyl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (157) 4-Amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6-(pyrimidin-5-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide; (158) 4-Amino-6-(3-((2-methoxyethyl)(methyl)amino)prop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (159) 4-Amino-6-(3-cyclohexylprop-1-yn-1-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (160)4-Amino-N-(4-(methoxymethyl)phenyl)-6-(3-methoxypropyl-1-yn-1-yl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (161) 4-Amino-6-chloro-7-(1-fluoro-2-methylpropyl-2-yl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (162) 4-Amino-7-(tert-butyl)-6-chloro-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (163) 4-Amino-6-(3,6-dihydro-2H-pyran-4-yl)-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (164) 4-amino-6-ethyl-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; and Salts of these compounds. 15. A RET inhibitor comprising, as an active ingredient, a compound or a salt thereof according to any one of claims 8-14. 16. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 8-14. 17. An antitumor agent comprising a compound or a salt thereof according to any one of claims 8-14. 18. Use of the compound or a salt thereof according to any one of claims 8-14 for the manufacture of a RET inhibitor. 19. Use of the compound or salt thereof according to any one of claims 8-14 in the manufacture of an antitumor agent.