ALKNYLBENZENE COMPOSITE 3,5-DISPLACED AND SALT OF THE SAME

专利摘要:
3,5-disubstituted alkynylbenzene compound and salt thereof. the present invention relates to a compound represented by formula (i) (wherein r1, x1, x2, y and z are as defined in the specification), or a salt thereof. further refers to a fgfr inhibitor comprising the compound of formula (I) or a salt thereof as an active ingredient, a pharmaceutical composition, and an antitumor agent.
公开号:BR112014017749B1
申请号:R112014017749-0
申请日:2013-01-17
公开日:2021-08-03
发明作者:Takeshi Sagara；Satoru Ito；Sachie Otsuki；Hiroshi Sootome
申请人:Taiho Pharmaceutical Co., Ltd.；
IPC主号:

专利说明:

technical field
[001] The present invention relates to a novel 3,5-disubstituted alkynylbenzene compound and a salt thereof that have inhibitory effects on the growth factor receptor; a pharmaceutical composition, an FGFR inhibitor and an antitumor agent each comprising the 3,5-disubstituted alkynylbenzene compound or a salt thereof as an active ingredient; a method of treating a tumor; and use of the compound in treating a tumor. Previous Technique
[002] Fibroblast growth factors (FGFs) are involved in the regulation of several physiological processes such as cell proliferation, chemotaxis and differentiation. The physiological activity of FGFs is mediated by fibroblast growth factor receptors (FG-FRs), which are specific cell surface receptors. FGFRs belong to a receptor protein tyrosine kinase family and comprise an extracellular ligand binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain. Four types of FGFRs (FGFR1, FGFR2, FGFR3 and FGFR4) have been identified so far. FGFRs bind to FGFs to form dimers, and are activated by phosphorylation. Activation of receptors induces the mobilization and activation of specific downstream signal transduction molecules, thereby developing physiological functions. [003] Many reports have been made about the relationship between aberrant FGF/FGFR signaling and various human cancers (eg, NPL 1, NPL 2 and NPL 3). Aberrant activation of FGF/FGFR signaling in human cancer is considered to be attributable to an autocrine or paracrine mechanism by overexpression of FGFRs and/or gene amplification, gene mutation, chromosomal translocation or overproduction of FGFs (ligands). Furthermore, such aberrant signaling is considered to be partially responsible for therapeutic resistance to existing anticancer chemotherapeutic drugs or other receptor tyrosine kinase inhibitors in human cancer (NPL 4).
[003] In addition, aberrant signaling is known to be associated with several diseases caused by abnormal angiogenic processes, such as solid tumor, rheumatoid arthritis, psoriasis, retinopathy and age-related macular degeneration (NPL 5).
[004] In this sense, therapies targeted to FGF/FGFR signaling not only have a direct antitumor effect on tumor cells that are highly dependent on FGF/FGFR signaling, but also have an inhibitory effect on tumor angiogenesis induced by FGF signaling /FGFR; thus, such therapies are expected to be promising target therapies with sufficient antitumor effects. In addition, such therapies are expected to provide drug effect enhancers for existing anticancer chemotherapeutic drugs or other receptor tyrosine kinase inhibitors, or effective therapeutic remedies for cancer types that are resistant or unresponsive to these drugs .
[005] PTL 1 discloses a wide range of fused bicyclic compounds, having mTOR inhibitory activity; however, the specifically disclosed compounds are all imidazopyrazine compounds, and FGFR inhibitory activity is nowhere mentioned in PTL 1. PTL 2 discloses BTK inhibitor compounds with a characteristic substituent at position 3 of the pyrazolopyrimidine ring, but not mentions nothing about the inhibitory activity of FGFR. PTL 3 discloses HSP90 inhibitor compounds with a characteristic substituent at position 5 of the pyrrolopyrimidine ring, but does not mention anything about FGFR inhibitory activity. List of Citations Patent Literature PTL 1: WO 2007/087395 PTL 2: WO 2008/121742 PTL 3: WO 2010/043865 Non-Patent Literature NPL 1: J. Clin. Oncol. 24, 3664-3671 (2006) NPL 2: Mol. Cancer Res. 3, 655-667 (2005) NPL 3: Cancer Res. 70, 2085-2094 (2010) NPL 4: Clin. Cancer Res. 17, 6130-6139 (2011) NPL 5: J. Nat. Med. 1, 27-31 (1995) Invention Summary Technical problem
[006] Although FGFR inhibitors are expected to have therapeutic effects in various carcinomas, as described above, no potent and highly selective FGFR inhibitor has been found to date.
[007] Therefore, an objective of the present invention is to provide a new compound that has FGFR inhibitory activity and that is useful as an anticancer agent. Solution to Problem
[008] The present inventors carried out extensive research to achieve the above objective; and found that an alkynylbenzene compound containing a specific substituent has excellent FGFR inhibitory activity and cancer cell growth inhibitory effects, and is useful as a medicine for the treatment of cancer. The present invention was made based on this finding.
[009] The present invention provides a compound represented by Formula (I)
wherein R1 is the same or different, and each represents C1-C6 alkyl;
[0010] X1 and X2 independently represent N or CH;
[0011] Y is a group represented by Formula (A)
(wherein the divalent portion represented by
is nitrogen-containing C3-C10 heterocycloalkylene), a group represented by Formula (B)
(wherein the divalent portion represented by
is C3-C10 cycloalkylene, or a group represented by Formula (C)
(wherein the divalent portion represented by
is C6-C12 arylene);
[0012] R2 is hydrogen, C2-C6 alkynyl, - C(=O)ORx, - C(=O)N(Rx)(Ry), C1-C6 hydroxyalkyl, di(C1-C6 alkyl)aminoC1 - C6 alkyl or C2-C9 heteroaryl, optionally having R3;
[0013] R3 is C1-C6 alkyl or di(C1-C6 alkyl)aminoC1-C6 alkyl;
[0014] Z is -C(R4)=C(R5)(R6) or -C=C-R7;
[0015] R4, R5 and R6 are the same or different, and each represents hydrogen, halogen, C1-C6 alkyl optionally with R8, or a group represented by Formula (D)
(wherein the monovalent portion represented by
is C3-C10 heterocycloalkyl containing nitrogen),
[0016] R7 is hydrogen, C1-C6 alkyl or C1-C6 hydroxyalkyl;
[0017] R8 is -ORx or -N(Rx)(Ry);
[0018] R9 is C1-C6 alkyl, halogen or -ORx;
[0019] Rx and Ry are the same or different, and each represents hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, di(C1-C6 alkyl)aminoC1-C6 alkyl or C1-C6 alkoxy-C1-C6 alkyl ;
[0020] 1 is an integer from 0 to 3;
[0021] m is an integer from 1 to 3; and
[0022] n is an integer from 0 to 2; or
[0023] a salt thereof.
[0024] The present invention provides an FGFR inhibitor comprising the compound of Formula (I) or a salt thereof as an active ingredient.
The present invention further provides a pharmaceutical composition comprising the compound of Formula (I) or a salt thereof, and a pharmaceutically acceptable carrier.
[0026] The present invention provides an antitumor agent comprising the compound of Formula (I) or a salt thereof as an active ingredient.
The present invention further provides a method of treating a tumor, which comprises administering an effective amount of the compound of Formula (I), or a salt thereof, to a patient in need of such treatment.
[0028] The present invention further provides a compound of Formula (I), or a salt thereof, for use in treating a tumor.
The present invention provides the use of the compound of Formula (I) or a salt thereof in the treatment of a tumor.
[0030] Furthermore, the present invention provides the use of the compound of Formula (I) or a salt thereof in the manufacture of an antitumor agent. Advantageous Effects of the Invention
[0031] According to the present invention, a novel compound represented by Formula (I) above or a salt thereof, which is useful as an inhibitor of FGFR, can be provided.
[0032] It has been clarified that the compound, or a salt thereof of the present invention, has excellent FGFR inhibitory activity and has inhibitory effects on cancer cell growth. In that sense, the compound or a salt thereof of the present invention is useful to prevent and/or treat a cancer. Description of Modalities
[0033] The compound of the present invention represented by Formula (I) above is a 3,5-disubstituted alkynylbenzene compound containing a condensed heteroaryl group substituted by an α,β-unsaturated amide by means of a spacer moiety, and is not disclosed in any of the above prior art documents.
[0034] In this specification, the term "C1-C6 alkyl"refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. The C1-C6 alkyl is preferably a linear or branched alkyl group having from 1 to 4 carbon atoms (a C1-C4 alkyl group) and more preferably methyl, ethyl, isopropyl and tert-butyl.
[0035] In this specification, the term "C3-C10 cycloalkyl" refers to a monocyclic or polycyclic cycloalkyl group with 3 to 10 carbon atoms, and which is preferably a monocyclic cycloalkyl group with 3 to 6 carbon atoms ( a C3-C6 cycloalkyl group. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalyl and the like. Cyclopropyl and cyclobutyl are preferred. In this descriptive report, the divalent portion represented by
of the group represented by Formula (A)
(where R2 and l are as defined above)
[0036] is a C3-C10 heterocycloalkylene group containing at least one ring nitrogen atom and further containing from 0 to 2 identical or different heteroatoms selected from ring oxygen and sulfur atoms (containing a nitrogen-containing C3-C10 heterocycloalkylene ) and is preferably a C3-C5 heterocycloalkylene group containing 1 to 3 ring nitrogen atoms and additionally containing 0 to 1 ring oxygen atom (a nitrogen-containing C3-C5 heterocycloalkylene group). Specific examples thereof include azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, morpholinylene, octahydroquinolinylene, octahydroindolylene and the like. Among them, azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene and morpholinylene are preferred.
[0037] The group represented by Formula (A)

[0038] refers to a C3-C10 heterocycloalkylene group containing divalent nitrogen represented by
wherein the nitrogen atom has one branch, and the other branch is connected to a substituent (-(CH2)l-) and an R2 substituent is present on the ring.
[0039] In this descriptive report, the divalent portion represented by
of the group represented by Formula (B)
(where R2 and l are as defined above)
[0040] refers to a monocyclic or polycyclic divalent cycloalkylene group having from 3 to 10 carbon atoms (a C3-C10 cycloalkylene group), and preferably a monocyclic divalent cycloalkylene group having from 3 to 6 carbon atoms (a C3-C6 cycloalkylene group. Specific examples thereof include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and the like. Cyclopropylene and (1,2 or 1,3)-cyclobutylene are preferred. Formula (B)
refers to a divalent C3-C10 cycloalkylene group represented by
wherein one branch is connected to an adjacent amino group (NH) and the other branch is connected to a substituent (-(CH2)l-), and an R2 substituent is present on the ring.
[0041] In this descriptive report, the divalent portion represented by
of the group represented by Formula (C)
(where R2 and l are as defined above)
[0042] refers to a divalent arylene group having from 6 to 12 carbon atoms (a C6-C12 arylene group). Specific examples thereof include phenylene, naphthylene, biphenylene and the like. Phenylene is preferred. Formula (C)
refers to a divalent C6-C12 arylene group represented by
wherein one branch is connected to an adjacent amino group (NH) and the other branch is connected to a substituent (-(CH2)l-), and an R2 substituent is present on the ring.
[0043] In this descriptive report, the monovalent portion represented by
of the group represented by Formula (D)
(where R9, men are as defined above)
[0044] refers to a C3-C10 heterocycloalkyl group containing at least one ring nitrogen atom and additionally containing from 0 to 2 the same or different heteroatoms selected from ring oxygen and sulfur atoms (a heterocycloalkyl group - in the C3-C10 containing nitrogen) and is preferably a C3-C5 heterocycloalkylene group containing 1 to 3 ring nitrogen atoms and further containing 0 to 1 ring oxygen atom (a C3-C5 heterocycloalkylene group containing nitrogen). Specific examples thereof include azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, morpholinylene, octahydroquinolinylene, octahydroindolylene and the like. Azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene and morpholinylene are preferred. Formula (D)
denotes a nitrogen-containing C3-C10 heterocycloalkylene group represented by
wherein the nitrogen atom is attached to a substituent (-(CH2)m-) and substituents (-(R9)n) are present on the ring.
[0045] In this specification, "C2-C9 heteroaryl" refers to a monocyclic or bicyclic C2-C9 heteroaryl group containing from 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur atoms; and is preferably a C2-C5 monocyclic heteroaryl group containing 1 to 3 equal or different heteroatoms selected from nitrogen, oxygen and sulfur atoms (a C2-C5 heteroaryl group). Specific examples thereof include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, oxadizolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isobenzofuryl, indolizinyl, isoindolyl, indolyl, indazolyl, isolaquinolyl, , naphthyridinyl and the like. 1,3,4-oxadiazolyl is preferred.
[0046] In this specification, the term "C2-C6 alkynyl" refers to a linear or branched C2-C6 alkynyl group with at least one carbon-carbon triple bond. Specific examples thereof include ethynyl, 2-propynyl, 2-hexynyl and the like. Ethinyl is preferable.
[0047] In this specification, the term "C1C6 hydroxyalkyl" refers to a linear or branched C1-C6 alkyl group with a hydroxy group. Specific examples thereof include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like. Among them, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl and 2-hydroxybutyl are preferable.
[0048] In this specification, the term "di(C1-C6 alkyl C1-C6 alkyl) group" refers to a linear or branched C1-C6 alkyl group with an amino group with two linear or branched C1-C6 alkyl groups. -cadas. A linear or branched C 1 -C 4 alkyl group with an a-amino group with two linear or branched C 1 -C 4 alkyl groups (a di(C 1 -C 4 alkyl)-amino C 1 -C 4 alkyl group is preferable. Specific examples thereof include dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, diethylaminopentyl, diethylaminohexyl, dipropylaminomethyl, dibutylaminomethyl-dimethylaminomethyl, (methyl)aminomethyl and the like. Dimethylaminomethyl and diethylaminomethyl are preferred.
In this specification, the term "C1-C6 alkoxy-C1C6 alkyl" refers to a linear or branched C1-C6 alkyl group with a linear or branched C1-C6 alkoxy group. It is preferably a linear or branched C1-C4 alkyl group with a linear or branched C1-C4 alkoxy group (a C1-C4 alkoxy-C1-C4 alkyl group). Specific examples of such groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethylguanidinium, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, butoxymethyl, pentyloxymethyl and the like. Of these, 2-methoxyethyl is preferable.
[0050] In this specification, examples of "halogen" include chlorine, fluorine, bromine and iodine. Fluoride is preferable.
[0051] In Formula (I), the following combinations of X1 and X2 are preferable. (1) When X2 is N, X1 is N or CH. (2) When X2 is CH, X1 is CH.
[0052] In Formula (I), l is preferably 0 or 1.
[0053] In Formula (I), Y is preferably a group represented by Formula (A)
(wherein R2 and l are as defined above) or a group represented by Formula (C)
(where R2 and l are as defined above). More preferably, the divalent portion represented by

[0054] of a group represented by Formula (A) is pyrrolidinylene, azetidinylene or piperidinylene, or the divalent moiety represented by
of a group represented by Formula (C) is phenylene.
[0055] In Formula (I), the following combinations of Y and Z are preferable. When Y is a group represented by Formula (A)
(where R2 and l are as defined above),
[0056] Z is -C(R4)=C(R5)(Rβ) or -C=C-R7- When Y is a group represented by Formula (B) or (C):
(wherein R2 and l are as defined above), Z is -C(R4)=C(R5)(R6).
[0057] In Formula (I), R1 is preferably C1-C4 alkyl, and more preferably methyl or ethyl.
[0058] In Formula (I), R2 is preferably C2-C6 alkynyl, - C(=O)ORx C1-C4 hydroxyalkyl or C2-C9 heteroaryl optionally with R3 and more preferably, ethynyl, methoxycarbonyl, hydroxymethyl or 134- oxadiazolyl, optionally with R3.
In Formula (I), R3 is preferably C1-C4 alkyl or di-(C1-C4 alkyl)aminoC1-C4 alkyl, and more preferably methyl or dimethylaminomethyl.
[0060] In Formula (I), R4 is preferably hydrogen or halogen, more preferably hydrogen or fluorine, and even more preferably hydrogen.
[0061] In Formula (I), R5 and R6 are preferably hydrogen, C1-C4 alkyl group, optionally with R8, or a group represented by Formula (D)

[0062] (wherein R9, men are as defined above) and more preferably hydrogen, methyl with R8 or a group represented by Formula (D)
(where R9, men are as defined above)
[0063] In Formula (I), m is preferably 1.
[0064] In Formula (I), R9 is preferably C1-C4 alkyl, fluorine or hydroxy, and more preferably methyl, fluorine or hydroxy.
[0065] In Formula (I), n is preferably 0 or 1.
[0066] In Formula (I), R7 is preferably hydrogen, C1-C4 alkyl or C1-C4 hydroxyalkyl, and more preferably hydrogen, hydroxymethyl, methyl or 2-hydroxy-2-methylethyl.
[0067] In Formula (I), R8 is preferably hydroxy or -N(Rx)(Ry). In this Formula, Rx and Ry are preferably hydrogen, C1-C4 alkyl, C3-C10 cycloalkyl or C1-C4 alkoxy-C1-C4 alkyl, and more preferably hydrogen, methyl, ethyl, tert-butyl, isopropyl, cyclopropyl, cyclobutyl or 2-methoxyethyl.
[0068] Preferred compounds of the present invention are compounds represented by Formula (I), wherein R1 is C1-C4 alkyl; X1 and X2 are independently N or CH; Y is a group represented by Formula (A) or (C) below:

R2 is C2-C6 alkynyl, -C(=O)ORx, C1-C4 hydroxyalkyl or C2-C9 heteroaryl, optionally with R3; R3 is C1-C4 alkyl or di(C1-C4 alkyl)aminoC1-C4 alkyl; Z is -C(^)=C(R5)(R6) or -C=C-R7; R4 is hydrogen or halogen; R5 and R6 are the same or different and each represents hydrogen, C1-C4 alkyl optionally with R8, or a group represented by Formula (D)

[0070] R7 is hydrogen, C1-C4 alkyl or C1-C4 hydroxyalkyl; R8 is hydroxy or -N(Rx)(Ry); R9 is C1-C4 alkyl, fluorine or hydroxy; Rx and Ry are the same or different and each represents hydrogen, C1-C4 alkyl, C3-C10 cycloalkyl or C1-C4 alkoxy-C1-C4 alkyl; and l is 0 or 1, m is 1 and n is 0 or 1.
[0071] More preferable compounds of the present invention are compounds represented by Formula (I), wherein R1 is C1-C4 alkyl, X1 and X2 are such that (1) when X2 is N, X1 is N or CH, and (2 ) when X2 is CH, X1 is CH; in Y, the divalent portion represented by
of the group represented by Formula (A)
is pyrrolidinylene, azetidinylene or piperidinylene, or the divalent moiety represented by
of the group represented by Formula (C)
is phenylene; when Y is a group represented by Formula (A)
(wherein R2 is ethynyl, methoxycarbonyl, hydroxymethyl or 1,3,4-oxadiazolyl, optionally having R3; R3 is C1-C4 alkyl; and l is 0 or 1), Z is -C(R4)=C(R5) (R6) or -C=C-R7, (b) when Y is a group represented by Formula (C)
(wherein R2 is hydrogen; and l is 0 or 1), Z is -C(R4)=C(R5)(R6);
[0072] R4 is hydrogen or fluorine; R5 and R6 are the same or different and each represents hydrogen, C1-C4 alkyl optionally with R8, or a group represented by Formula (D)

[0073] R7 is hydrogen, hydroxymethyl, methyl or 2-hydroxy-2-methylethyl; R8 is -N(Rx)(Ry); R9 is C1-C4 alkyl, fluorine or hydroxy; Rx and Ry are the same or different and each represents hydrogen, C1C4 alkyl, C3-C10 cycloalkyl, or C1-C4 alkoxy-C1-C4 alkyl, m is 1 and n is 0 or 1.
[0074] Even more preferably, the compounds of the present invention are compounds represented by Formula (I), wherein R 1 is methyl or ethyl; X1 and X2 are such that (1) when X2 is N, X1 is N or CH, and (2) when X2 is CH, X1 is CH; in Y, the divalent portion represented by
is pyrrolidinylene, azetidinylene, piperidinylene or the divalent moiety represented by
is phenylene; when Y is a group represented by Formula (A)
(wherein R2 is ethynyl, methoxycarbonyl, hydroxymethyl or 1,3,4-oxadiazolyl optionally with methyl; and I is 0 or 1), Z is -C(R4)=C(R5)(R6) or -C=C -R7, (b) when Y is a group represented by Formula (C)
(where R2 is hydrogen; and l is 1),
[0075] Z is -C(R4)=C(R5)(R6); R4 is hydrogen; R5 and R6 are the same or different and each represents hydrogen, methyl having R8 the monovalent portion represented by
of the group represented by Formula (D)

[0076] is pyrrolidinyl, piperidinyl, azetidinyl, piperazinyl or morpholinyl; R7 is hydrogen, hydroxymethyl, methyl or 2-hydroxy-2-methylethyl; R8 is -N(Rx)(Ry); R9 is methyl, fluorine or hydroxy and; Rx and Ry are the same or different, and each represents hydrogen, methyl, ethyl, tert-butyl, isopropyl, cyclopropyl, cyclobutyl or 2-methoxyethyl; and m is 1 and n is 0 or 1.
Specific examples of preferred compounds of the present invention include the following: (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 2) (S)-1-(3-(4-amino-3-((3,5) -dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-yn-1-one (Compound of Example 5), (S)-1- (3-(4-amino-3-((3,5-diethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1 -one (Compound of Example 8) (4) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) azetidin-1-yl)prop-2-en-1-one (Compound of Example 9), (5) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-hydroxybut-2-en-1-one (Compound of Example 10), (6) 1-(3-( 4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en -1-one (Compound of Example 12), (7) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(cyclopropylamino)but-2-en-1-one (Compound of Example 13), (8) 1-( 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(isopropylamino)but- 2-en-1-one (Compound of Example 14), (9) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl)azetidin-1-yl)-4-(ethyl(methyl)amino)but-2-en-1-one (Compound of Example 15), (10) 1-(3-(4-amino) -3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(cyclobutylamino)but-2-en-1- one (Compound of Example 16), (11) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) azetidin-1-yl)-4-(diethylamino)but-2-en-1-one (Compound of Example 17) (12) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)) ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(tert-butylamino)but-2-en-1-one (Compound of Example 18), ( 13) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (is opropyl(methyl)amino)but-2-en-1-one (Compound of Example 19), (14) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(piperidin-1-yl)but-2-en-1-one (Compound of Example 20), (15) ( S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4 -(3-fluoropyrrolidin-1-yl)but-2-en-1-one (Compound of Example 22), (16) (R)-1-(3-(4-amino-3-((3,5) -dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-en-1-one ( Compound of Example 23), (17) 1-((2S,4S)-4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)-2-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 28), (18) 1-(2S,4S)-4-(4-amino- 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-ethynylpyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 32), (19) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) pyrrolidin-1-yl)-4-(dimethylamino o)but-2-en-1-one (Compound of Example 38), (20) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 39), (21) (S)-1-(3-(4 -amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)but- 2-en-1-one (Compound of Example 40), (22) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(4-hydroxypiperidin-1-yl)but-2-en-1-one (Compound of Example 42), (23) (S) -1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)but-2- in-1-one (Compound of Example 46), (24) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-hydroxy-4-methylpent-2-yn-1-one (Compound of Example 47), (25) 1-((S)-3-( 4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-((S)-3-fluoropyrrolidin -1-yl)but-2-en-1-one (Compound of Example 49) , (26) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1 -yl)-4-(piperidin-1-yl)but-2-en-1-one (Compound of Example 50), (27) 1-(3-(4-amino-5-((3,5-) dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)prop-2-en-1-one (Compound of Example 51), (28) 1-(3 -(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(dimethylamino)but-2 -en-1-one (Compound of Example 52), (29) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine -7-yl)azetidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en-1-one (Compound of Example 53), (30) 1-(3-(4-amino-) 5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(azetidin-1-yl)but-2-en -1-one (Compound of Example 55), (31) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)azetidin-1-yl)-4-(ethyl(methyl)amino)but-2-en-1-one (Compound of Example 56), (32) 1-(3-(4-amino-5-) ((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimi din-7-yl)azetidin-1-yl)-4-(isopropylamino)but-2-en-1-one (Compound of Example 57), (33) 1-(3-(4-amino-5-( (3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(diethylamino)but-2-en-1-one (Compound of Example 59), (34) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1- yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one (Compound of Example 60) (35) 1-(3-(4-amino-5-((3,) 5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(4-hydroxypiperidin-1-yl)but-2-en-1-one (Compound of Example 61), (36) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)azetidin-1-yl)-4-(3-hydroxypyrrolidin-1-yl)but-2-en-1-one (Compound of Example 62), (37) (R)-1-(3-( 4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(3-hydroxypyrrolidin-1-yl )but-2-en-1-one (Compound of Example 63), (38) (2S,4S)-methyl-1-acryloyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl )-7H-pyrrolo[2,3- d]pyrimidin-7-yl)pyrrolidine-2-carboxylate (Compound of Example 66), (39) 1-((2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl )-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1,3,4-oxadiazol-2-yl)pyrrolidin-1-yl)prop-2-en-1-one ( Compound of Example 68) and (40) (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 73).
[0078] Next, the method for producing the compound according to the present invention will be explained. The compound (I) of the present invention can be produced, for example, by the following production methods or with the methods described in the Examples. However, the method for producing the compound (I) of the present invention is not limited to these reaction examples. Production Method 1
(wherein P1 is an amino group protecting group contained in Y; and R1, X1, X2, Y and Z are as defined above.)
[0079] (Step 1) In this step, the protected amino group of the compound of Formula (II) is deprotected to produce the compound of Formula (III). The method for deprotection can be carried out according to a known method, such as the method described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons (1981); or methods similar to these. An example of the protecting group is tert-butyloxycarbonyl. If a tert-butyloxycarbonyl group is used as a protecting group, deprotection is preferably carried out under acidic conditions. Examples of acids that can be used include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosic acid and the like. Such acid is preferably used in an amount of 1 to 100 moles per mole of Compound (II).
[0080] Any solvent that does not adversely affect the reaction can be used. Examples thereof include alcohols (eg methanol), hydrocarbons (eg benzene, toluene and xylene), halogenated hydrocarbons (eg methylene chloride, chloroform and 1,2-dichloroethane), nitriles (eg acetonitrile), ethers (for example dimethoxyethane and tetrahydrofuran), polar aprotic solvents (for example N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoroamide) or a mixture thereof. The reaction time is from 0.1 to 100 hours and preferably from 0.5 to 24 hours. The reaction temperature is from 0 to 120 °C, and preferably from 0 to 90 °C.
[0081] The compound of Formula (III) thus obtained can be subjected to the subsequent step after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[0082] (Step 2) In this step, the compound of Formula (III) is amide with a carboxylic acid represented by Z-COOH or with an acid halide represented by ZC(=O)-L (where L is chlorine or bromine) to produce the compound of Formula (I).
[0083] When a carboxylic acid represented by Z-COOH is used as an amidation reagent, the reaction is carried out using the carboxylic acid in an amount of 0.5 to 10 moles and preferably 1 to 3 moles per mole of compound of Formula (III) in the presence of a suitable condensing agent. The carboxylic acid can be a commercially available product, or it can be produced according to a known method.
[0084] Any reaction solvent that does not adversely affect the reaction can be used. Examples of preferred solvents include isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide and mixed solvents thereof. The reaction temperature is generally from -78 to 200 °C and preferably from 0 to 50 °C. The reaction time is typically from 5 minutes to 3 days and preferably from 5 minutes to 10 hours.
[0085] Examples of condensing agent include diphenylphosphorylazide, N,N'-dicyclohexylcarbodiimide, benzotriazol-1-yloxytrisdimethylaminophosphonium, 4-(4,6-dimethoxy-1,3,5-triazin-2 chloride) - yl)-4-methylmofolinium, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, 2-chloro chloride -1,3-dimethylimidazolinium, O-(7-azabenzotriazo-1-yl)-N,N,N',N'-tetramethylhexauronium hexafluorophosphate and the like.
[0086] A base can optionally be added to the reaction. Examples of usable bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyl lithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. Such base is added in an amount of 1 to 100 mols, and preferably 1 to 10 mols per mol of the compound of Formula (III).
[0087] When an acid halide represented by ZC(=O)-L (where L is chlorine or bromine) is used as an amidation reagent, the acid halide is used in an amount of 0.5 to 5 moles and preferably from 0.9 to 1.1 mol per mol of the compound of Formula (III). The acid halide can be a commercially available product, or it can be produced according to a known method.
[0088] Any reaction solvent that does not adversely affect the reaction can be used. Examples of preferred solvents include toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone and solvents thereof. The reaction temperature is typically -78 to 200 °C and preferably -20 to 50 °C. Reaction time is typically 5 minutes to 3 days and preferably 5 minutes to 10 hours.
[0089] A base can optionally be added to the reaction. Examples of usable bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyl lithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. Such base is added in an amount of 1 to 100 mols, preferably 1 to 10 mols per mol of the compound of Formula (III).
The thus obtained compound of Formula (I) can be isolated and purified by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[0091] Among the compounds (I) of the present invention, the compound of Formula (I') or (I") can also be produced by production method 2 using, for example, the compound (III) obtained in step 1 of production method 1 specific amine Production method 2
(where L1 and L2 are halogen; lies to a nitrogen atom; and X1, X2, Y, Rx, Ry, R1,
men are as defined above).
[0092] (Step 3) In this step, the compound of Formula (III) is amide with an acid halide represented by Formula (IV) to produce the compound of Formula (V).
[0093] Examples of hydrogen atoms represented by L1 or L2 in Formula (IV) include bromine and chlorine. The compound represented by Formula (IV) can be a commercially available product, or it can be produced according to a known method.
[0094] The compound of Formula (IV) is used in an amount of 0.5 to 5 mols and preferably 0.9 to 1.1 mol per mol of Compound (III).
[0095] A base can optionally be added to the reaction. Examples of usable bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyl lithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. Such base can be added in an amount of 1 to 100 mols and preferably 1 to 10 mols per mol of the compound of Formula (III).
[0096] Any reaction solvent that does not adversely affect the reaction can be used. Examples of preferred reaction solvents include toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone and mixed solvents thereof. The reaction temperature is typically from -78 to 200 °C and preferably from 0 to 50 °C. Reaction time is typically 5 minutes to 3 days and preferably 5 minutes to 10 hours.
[0097] The compound of Formula (V) thus obtained can be subjected to the subsequent step after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[0098] (Step 4) In this step, the compound of Formula (V) is alkylated with an amine represented by Formula (VI) or (VI') to produce the compound (I') or (I") of the present invention.
[0099] The compound of Formula (VI) or (VI') can be used in an amount of 1 to 20 mols and preferably 1 to 10 mols per mol of the compound of Formula (V).
[00100] In addition, a base can optionally be added to the reaction. Examples of such bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, he - sodium xamethyldisilazide, potassium hexamethyldisilazide and butyl lithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. Such base can be added in an amount of 1 to 100 mols and preferably 1 to 20 mol per mol of the compound of Formula (V).
[00101] Any reaction solvent that does not adversely affect the reaction can be used. For example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile and the like can be used alone or as a mixture. The reaction time is from 0.1 to 100 hours and preferably from 0.5 to 24 hours. The reaction temperature is from 0°C to the boiling temperature of the solvent and preferably is from 0 to 100°C.
[00102] The thus obtained compound of Formula (I') or (I") can be isolated and purified by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography. of Formula (II) used for the production of Compound (I) of the present invention can be produced, for example, by production method 3 or 4. Production method 3
(Where L3 and L4 are output groups; and R1, X1, X2, Y, and P1 are as defined above.)
[00103] (Step 5) In this step, the compound of Formula (VII) is subjected to a coupling reaction (Sonogashira) with the compound of Formula (VIII) to produce the compound of Formula (IX). This step can be carried out according to a generally known method (see, for example, Chemical Reviews, vol. 107, p. 874, 2007), for example, in the presence of a transition metal catalyst and a base in a solvent which does not adversely affect the reaction.
[00104] In Formula (VII), the leaving group, represented by L3, is bromine or iodine. The compound of Formula (VII) can be a commercially available product or can be produced by a known method.
[00105] In this step, the compound of Formula (VIII) can be used in an amount of 1 to 10 mols and preferably, 1 to 3 mols per mol of the compound of Formula (VII).
[00106] Examples of transition metal catalysts that can be used in this step include palladium catalysts (eg, palladium acetate, tris(dibenzylideneacetone)dipalladium and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride complex (II) dichloromethane). If necessary, a binder (eg, triphenylphosphine, triphenylphosphine and tri-tert-butylphosphine) can be added and a copper reagent (eg, copper iodide and copper acetate) can be used as a cocatalyst. The amount of transition metal catalyst used can vary depending on the type of catalyst. The transition metal catalyst is typically used in an amount of 0.0001 to 1 mol and preferably 0.01 to 0.5 mol per mol of the compound of Formula (VII). The amount of binder used is typically from 0.0001 to 4 mols and preferably from 0.01 to 2 mols per mol of the compound of Formula (VII). The amount of cocatalyst used is typically from 0.0001 to 4 moles and preferably from 0.01 to 2 moles per mole of the compound of Formula (VII).
[00107] A base can optionally be added to the reaction. Examples of usable bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and butyl lithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and sodium hydride. Among them, organic bases such as triethylamine and diisopropylethylamine are preferable. The amount of base used is typically 0.1 to 50 mols, preferably 1 to 20 mols per mol of the compound of Formula (VII).
[00108] Any reaction solvent that does not adversely affect the reaction can be used. Examples of usable solvents include hydrocarbons (eg benzene, toluene and xylene), nitriles (eg acetonitrile), ethers (eg dimethoxyethane, tetrahydrofuran and 1,4-dioxane), alcohols (eg methanol and ethanol), polar aprotic solvents (eg dimethylformamide dimethylsulfoxide and hexamethylphosphoramide), water and mixtures thereof. The reaction time is from 0.1 to 100 hours and preferably from 0.5 to 24 hours. The reaction temperature is from 0 °C to the boiling temperature of the solvent and preferably is from 0 to 150 °C.
[00109] The compound of Formula (IX) thus obtained can be subjected to the subsequent step after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[00110] (Step 6) In this step, the compound of Formula (IX) is used with the compound of Formula (X) or (XI) to produce the compound of Formula (II).
[00111] When the compound of Formula (X) is used as an alkylating reagent, the compound of Formula (II) can be produced in the presence of a base. In Formula (X), L4 can be a leaving group such as chlorine, bromine, iodine, an ester of methanesulfonic acid or an ester of p-toluenesulfonic acid. Alkylating reagents can be a commercially available product, or they can be produced according to a known method. The compound of Formula (X) can be used in an amount of 1 to 10 moles, preferably 1 to 5 moles per mole of the compound of Formula (IX).
[00112] Examples of usable bases include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride and potassium hydride; and organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and collidine. Such base can be used in an amount of 1 to 100 mols, preferably 2 to 10 mols per mol of the compound of Formula (IX).
As the solvent, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile and the like can be used alone or as a mix. The reaction time is from 0.1 to 100 hours and preferably from 0.5 to 24 hours. The reaction temperature is from 0°C to the boiling temperature of the solvent and preferably is from 0 to 100°C.
[00114] When the compound of Formula (XI) is used as an alkylating re-agent, the compound of Formula (II) can be produced using a Mitsunobu reaction. This step can be carried out according to a generally known method (see, for example, Chemical Reviews, vol. 109, p. 2551, 2009), for example, in the presence of Mitsunobu reagents and a phosphine reagent in a solvent that does not adversely affect the reaction. This step is carried out using the compound of Formula (XI) in an amount of 1 to 10 mols per mol of the compound of Formula (IX).
[00115] Examples of Mitsunobu reagents include diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like. Such Mitsunobu reagents are used in an amount of 1 to 10 mols and preferably 1 to 5 mols per mol of the compound of Formula (IX).
[00116] Examples of phosphine reagents include triphenylphosphine, tributylphosphine and the like. Such phosphine reagent is used in an amount of 1 to 10 mols and preferably 1 to 5 mols per mol of the compound of Formula (IX).
[00117] Any reaction solvent that does not adversely affect the reaction can be used. Examples of preferred reaction solvents include toluene, benzenetetraidorfuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinonedimethylsulfoxide and mixed solvents thereof.
[00118] The reaction temperature is typically from -78 to 200 °C and preferably from 0 to 50 °C. Reaction time is typically 5 minutes to 3 days and preferably 10 minutes to 10 hours.
[00119] The thus obtained compound of Formula (II) can be used after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography to produce Compound (I) of the present invention.
[00120] Production Method 4
(wherein L3, L4, R1, X1, X2, Y and P1 are as defined above.)
[00121] (Step 7) This step can be performed similarly to step 6.
[00122] (Step 8) This step can be performed similarly to step 5.
[00123] The compound of Formula (XII) used in the production of Compound (I) of the present invention can also be produced, for example, by production method 5. Production Method 5
(wherein L3, L4, X1, X2, Y and P1 are as defined above.).
[00124] (Step 9) This step can be performed similarly to step 6.
[00125] (Step 10) In this step, the compound of Formula (XIV) reacts with ammonia or a salt thereof to produce the compound of Formula (XII).
[00126] Ammonia or a salt thereof is typically used in an excess molar amount of equimolar per mole of the compound of Formula (XIII) in this step. Any reaction solvent that does not adversely affect the reaction can be used. Examples of preferred reaction solvents include water, methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and solvent mixtures thereof.
[00127] The reaction temperature is typically from 0 to 200 °C and preferably from room temperature to 150 °C. The reaction time is typically from 5 minutes to 7 days and preferably from 30 minutes to 24 hours.
[00128] The compound of Formula (XIV) thus obtained can be subjected to the subsequent step after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[00129] The compound of Formula (IX) used in the production of Compound (I) of the present invention can also be produced, for example, by the production method 6. Production Method 6
(wherein L3, X1 and X2 are as defined above, and SEM is trimethylsilylethoxymethyl).
[00130] (Step 11) In this step, the compound of Formula (XIII) is reacted with SEMCl (trimethylsilylethoxymethyl chloride) in the presence of a base to produce the compound of Formula (XV). The compound of Formula (XIII) can be a commercially available product or can be produced according to a known method.
[00131] SEMCl is typically used in an equimolar to excessive amount per mole of the compound of Formula (XIII) in this step. Any reaction solvent that does not adversely affect the reaction can be used. Examples of preferred reaction solvents include tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, dimethylformamide, N-methylpyrrolidone and mixed solvents thereof.
[00132] Examples of usable bases include organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride and potassium tert-butyrate.
[00133] Such base is typically used in an equimolar to excessive molar amount, and preferably 1 to 3 mols per mol of the compound of Formula (III).
[00134] The reaction temperature is typically from -78 to 200 °C and preferably from 0 to room temperature. The reaction time is typically 5 minutes to 7 days and preferably 10 minutes to 24 hours. The compound of Formula (XV) thus obtained can be subjected to the subsequent step after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[00135] (Step 12) This step can be carried out similarly to step 10. The compound of Formula (XVI) thus obtained can be subjected to the subsequent step after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.
[00136] (Step 13) This step can be performed similarly to step 5.
[00137] (Step 14) In this step, the compound of Formula (XVII) is deprotected under acidic conditions to produce the compound of Formula (IX). Deprotection can be carried out by a known method, such as the method described in Protective Groups in Organic Syn-thesis, T.W. Greene, John Wiley & Sons (1981); or a method similar to this one. Examples of usable acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosic acid and the like. Such acid is used in an amount of 1 to 100 mols per mol of the compound of Formula (XVII).
[00138] Any solvent that does not adversely affect the reaction can be used. Examples of usable solvents include alcohols (eg methanol), hydrocarbons (eg benzene, toluene and xylene), halogenated hydrocarbons (eg methylene chloride, chloroform and 1,2-dichloroethane), nitriles (eg ace - tonitrile), ethers (for example dimethoxyethane, tetrahydrofuran and 1,4-dioxane), polar aprotic solvents (for example N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide) and mixtures thereof. The reaction time is from 0.1 to 100 hours and preferably from 0.5 to 24 hours. The reaction temperature is from 0°C to the boiling temperature of the solvent and preferably is from 0 to 100°C.
[00139] The compound of Formula (IX) thus obtained can be used in step 6 after or without isolation and purification by known means of separation and purification, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography .
[00140] In the above production methods 1 to 6, for functional groups with an active proton, such as amino, imino, hydroxy, carboxyl, carbonyl and amide, and indole groups, protected reagents can be used or a group protecting group is introduced into such a functional group according to a usual method, and then the protecting group can be removed at an appropriate step in each production method.
[00141] The "protecting group" of an amino group, or protecting group of an imino group" is not particularly limited insofar as it has a protective function. Examples of such protecting groups include aralkyl groups such as benzyl, e.g. -methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl, trityl and cumyl; lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, pivaloyl, trifluoroacetyl and trichloroacetyl; benzoyl; arylalkanoyl groups such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and tert-butoxycarbonyl; aralkyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl; lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; tetrahydropyranyl; , ethylsulfonyl and tert-butylsulfonyl; lower alkylsulfinyl groups such as tert-butyls ulfinil; arylsulfonyl groups such as benzenesulfonyl and toluenesulfonyl; and imido groups such as phthalimido. Particularly, trifluoroacetyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxymethyl, cumyl and the like are preferable.
[00142] The "protecting group of a hydroxy group" is not particularly limited as it has a protective function. Examples of such protecting groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and tert-butyl; lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; lower alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and trityl; and acyl groups such as formyl, acetyl and trifluoroacetyl. Particularly, methyl, methoxymethyl, tert-hydropyranyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl and the like are preferable.
[00143] The "protecting group of a carboxy group" is not particularly limited as it has a protective function. Examples of such protecting groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and tert-butyl; lower haloalkyl groups such as 2,2,2-trichloroethyl; lower alkenyl groups such as allyl; trimethylsilylethoxymethyl; and aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl and trityl. Particularly, methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl, trimethylsilylethoxymethyl and the like are preferable.
[00144] The "protecting group of a carbonyl group" is not particularly limited as it has a protective function. Examples of such protecting groups include ketals and acetals, such as ethyleneketal, trimethyleneketal, dimethylketal, ethyleneacetal, trimethyleneacetal and dimethylacetal.
[00145] The method for removing such protecting group may vary depending on the type of protecting group, the stability of the desired compound (I), etc. For example, the following methods can be used: solvolysis using an acid or a base according to the method disclosed in a publication (Protective Groups in Organic Synthesis, Third Edition, TW Green, John Wiley & Sons (1999)) or a method similar thereto, i.e. a reaction method using, for example, 0.01 mol or a large excess of acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid or an equimolar amount of a large excess base, preferably potassium hydroxide or calcium hydroxide; chemical reduction using a metal hydride complex or similar; or catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst or the like.
The compound of the present invention can be isolated and purified by usual means of isolation and purification. Examples of such media include solvent extraction, recrystallization, preparative reverse phase high performance liquid chromatography, column chromatography, preparative thin layer chromatography, and the like.
[00147] When the compound of the present invention has isomers such as optical isomers, positional isomers and rotational isomers, any of the isomers and their mixtures are included in the scope of the compound of the present invention. For example, when the compound has optical isomers, optical isomers separated from a racemic mixture are also included in the scope of the compound of the present invention. Each of these isomers can be obtained as a single compound by known means of synthesis and separation (eg, concentration, solvent extraction, column chromatography and recrystallization).
[00148] The compound or a salt thereof of the present invention may be crystalline. A single crystal form thereof and a polymorphic mixture thereof are both included within the scope of the compound, or a salt thereof, of the present invention. These crystals can be produced by crystallization according to a crystallization method known per se in the art. The compound or a salt thereof of the present invention can be a solvate (e.g., a hydrate) or a non-solvate. Any such form is included within the scope of the compound or salt thereof of the present invention. Compounds labeled with an isotope (such as 3H, 14C, 35S or 125I) are also included in the scope of the compound or salt thereof of the present invention.
[00149] A prodrug of the compound of the present invention or a salt thereof refers to a compound that can be converted to the compound or salt thereof of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, a compound that can be converted to the compound or salt thereof of the present invention by enzymatic oxidation, reduction, hydrolysis or the like; or a compound which can be converted to the compound or salt thereof of the present invention by hydrolysis with gastric acid or the like. Furthermore, the prodrug of the compound or salt thereof of the present invention may comprise compounds which can be converted to the compound or salt thereof of the present invention under physiological conditions such as those described in "Iyakuhin no Kaihatsu [Development of Pharmaceuti-cals] ,” Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp. 163-198.
[00150] The salt of the compound of the present invention refers to a common salt used in the field of organic chemistry. Examples of such salts include base addition salts to carboxyl when the compound has carboxyl, and acid addition salts to a basic amino or heterocyclic group, when the compound has a basic amino or heterocyclic group.
[00151] Examples of base addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; ammonium salts; and organic amine salts, such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts and N,N'-dibenzylethylenediamine salts.
[00152] Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates and trifluoroacetates; and perfluorooctane sulfonates, such as methane sulfonates, isethionates, benzene sulfonates and p-toluene sulfonates.
[00153] The compound or a salt thereof of the present invention has excellent FGFR inhibitory activity and is useful as an antitumor agent. Furthermore, the compound, or a salt thereof of the present invention, has excellent selectivity for FGFR and advantageously has fewer side effects caused by other kinases. Although the target cancer is not particularly limited, examples of it include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, cancer of biliary tract, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma, tissue sarcoma moles, leukemia, multiple myeloma, skin cancer, brain tumor and mesothelioma. Preferably, the target cancer comprises blood cancers such as B cell lymphoma, chronic lymphocytic leukemia, peripheral T cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia and acute lymphocytic leukemia.
When the compound or salt thereof of the present invention is used as a pharmaceutical preparation, a pharmaceutical carrier can be added, if necessary, thereby forming a suitable dosage form according to the purposes of prevention and treatment. Examples of dosage forms include oral preparations, injections, suppositories, ointments, patches and the like. Of these, oral preparations are preferable. Such dosage forms can be formed by methods conventionally known to those skilled in the art.
[00155] As the pharmaceutical carrier, various conventional organic or inorganic carrier materials used as preparation materials can be mixed as an excipient, binder, disintegrant, lubricant or colorant in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonizing agent, buffer or softening agent in liquid preparations. Furthermore, pharmaceutical preparation additives such as antiseptics, antioxidants, dyes, sweeteners and stabilizers can also be used, if necessary.
[00156] Oral solid preparations may be prepared as follows. An excipient, optionally together with a binder, disintegrant, lubricant, colorant, masking agent or flavoring agent, etc. is added to the complex of the present invention to produce tablets, coated tablets, granules, powders, capsules or the like, using a common method.
[00157] When an injection agent is prepared, a pH regulator, buffer, stabilizer, isotonizing agent, local anesthetic, etc., can be added to the compound of the present invention; and the mixture can be processed into a subcutaneous, intramuscular or intravenous injection, according to a common method.
The amount of the compound of the present invention to be contained in such a unit dosage form varies depending on the condition of the patient, the dosage form, etc. The desirable amount in unit dosage form is from 0.05 to 1000 mg in the case of an oral preparation, from 0.01 to 500 mg in the case of an injection, and from 1 to 1000 mg in the case of a suppository .
[00159] In addition, the daily dose of the drug with the dosage form described above may vary depending on the condition, body weight, age and sex of a patient, etc. and it cannot be generalized. Generally, the daily dose is preferably from 0.05 to 5000 mg per adult (body weight: 50 kg) per day and more preferably from 0.1 to 1000 mg per adult (body weight: 50 kg) per day . Such drug dose is preferably administered in one dose, or two to three divided doses, per day. Examples
[00160] The present invention is explained in detail below with reference to the Examples; however, the scope of the present invention is not limited to these Examples.
[00161] In the examples, commercially available reagents were used, unless otherwise specified. Purif-Pack (trademark), produced by Moritex Corp.; KP-Sil (trademark) prepacked silica column produced by Biotage; or HP-Sil (trademark) prepacked silica column, produced by Biotage, was used as the silica-gel column chromatography. Purif-Pack (trademark) NH, produced by Moritex Corp; or KP-NH (trademark) prepacked column, produced by Bio-tage, was used as the basic silica gel column chromatography. Kieselgel TM 60F 254, Art. 5744, produced by Merck, or a plate of NH2 silica gel 60F254, produced by Wako, was used as the preparative thin layer chromatography. The NMR spectrum was measured using AL400 (400 MHz; produced by JEOL), Mercury 400 spectrophotometer (400 MHz; produced by Agilent Technologies, Inc.) equipped with an OMNMR probe (produced by Protasis). When its deuterated solvent contains tetramethylsilane, tetramethylsilane was used as an internal reference; and when tetramethylsilane was not included, an NMR solvent was used as the reference. All delta values are shown in ppm. The microwave reaction was performed using Discover S-class, produced by CEM Corporation.
The LCMS spectrum was measured using an Acquity SQD (quadrupole), produced by Waters Corporation, under the following conditions.

Preparative reverse phase HPLC purification was performed using a preparative separation system available from Waters Corporation. Column: YMC-Actus Triart C18, 20 x 50 mm connected, 5 µm (produced by YMC) and YMC-Actus Triart C18, 20 x 10 mm, 5 µm (produced by YMC). UV detection: 254 nm MS detection: ESI positive Column flow rate: 25 mL/min Mobile phase: water and acetonitrile (0.1% formic acid) Injection volume: 0.1 to 0.5 mL
[00164] Each symbol represents the following. s: singlet d: doublet t: triplet p: quartet dd: double doublet dt: double triplet td: triple doublet tt: triple triplet ddd: double double doublet ddt: double double triplet dtd: double triplet doublet tdd: triple double doublet m: multiplet br: broad brs: broad singlet DMSO-d6: deuterated dimethylsulfoxide CDCl3: deuterated chloroform CD3OD: deuterated methanol THF: tetrahydrofuran DMF: N,N-dimethylformamide NMP: 1-methyl-2-pyrrolidone DMSO: dimethylsulfoxide TFA: trifluoroacetic acid SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride PdCl2 (dppf) CH2Cl2: 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)-dichloromethane dichloride-dichloromethane complex WSC: 1-(3-dimethylaminopropyl) hydrochloride -3-ethylcarbodiimide HOBt: 1-hydroxybenzotriazole monohydrate HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexaluronium hexafluorophosphate HBTU: O-benzotriazole hexafluorophosphate -N,N,N',N'-tetramethyluronium DIAD: diisopropyl azodicarboxylate TBAF: tetrabutylammonium fluoride DIPEA = di-isopropylethylamine Boc2O = di-tert-butyl DMAP dicarbonate: dimethylaminopyridine Example 1 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2 -en-1-one (compound of Example 1)
[00165] (Step 1) Synthesis of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
[00166] PdCl2 (dppf) CH2Cl2 (163 mg) was added to a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (520 mg) synthesized by the method disclosed in WO 2007/ 126841, 1-ethynyl-3,5-dimethoxybenzene (504 mg), copper (I) iodide (57.3 mg) and triethylamine (0.56 ml) in DMF (10 ml). After purging with nitrogen, the resulting mixture was stirred at 90°C for 6 hours. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a dark brown solid (120 mg). Physical properties: m/z [M+H]+ 296.0
[00167] (Step 2) Synthesis of tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate
N-Boc-3-pyrrolidinal (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 µL) were added thereto at 0 °C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oily compound (1.2 g). Physical properties: m/z [M+H]+ 266.1
[00169] (Step 3) Synthesis of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate of tert-butyl
[00170] A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62 mg) obtained in step 1, 3-(methylsulfonyloxy)pyrrolidine- tert-butyl 1-carboxylate (217 mg) obtained in Step 2, and potassium carbonate (221 mg) in DMF (2.0 ml) was stirred at 70°C for 1 hour. Ethyl acetate and water were added thereto to separate the organic layer. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow amorphous substance (36.2 mg). Physical properties: m/z [M+H]+ 465.1
[00171] (Step 4) Synthesis of the compound of Example 1
4N Hydrochloric acid/1,4-dioxane (4 ml) was added to 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4- tert-butyl d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (32 mg) obtained in Step 3, and the mixture was stirred at room temperature for 1.5 hour. After distilling off the solvent from the resulting reaction mixture under reduced pressure, azeotropic distillation of toluene was further carried out to obtain a crude product of 3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3- il)-1H-pyrazolo[3,4-d]pyrimidin-4-aminae (32 mg). Chloroform (2.0 mL) and triethylamine (20 µL) were added to a part of the resulting crude product (12 mg). After cooling to 0 °C, acrylic chloride (2.3 µL) dissolved in chloroform (100 µL) was added thereto, and the mixture was stirred at room temperature for 10 minutes. After quenching the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. After drying the product over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a white solid (6.5 mg). Table 1 shows its physical properties. Example 2 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )prop-2-en-1-one (Compound of Example 2)
[00173] (Step 1) Synthesis of (R)-tert-butyl 3-(methylsulfonyloxy)-pyrrolidine-1-carboxylate
[00174] (R)-N-Boc-3-pyrrolidinal (935 mg) was dissolved in chloroform (15 ml) and triethylamine (1.04 ml) and methanesulfonyl chloride (467 µL) were added thereto at 0 °C . After stirring at room temperature for 1.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the compound from title as a colorless oily compound (1.1 g). Physical properties: m/z [M+H]+ 266.1
[00175] (Step 2) Synthesis of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate of (S)-tert-butyl
A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (334 mg) obtained in Example 1 (Step 1), 3-( (R)-tert-butyl methylsulfonyloxy)pyrrolidine-1-carboxylate (379 mg) obtained in (Step 1) above and potassium carbonate (391 mg) in DMF (4.0 mL) was stirred at 70°C for 3 hours. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow amorphous substance (149 mg). Physical properties: m/z [M+H]+ 465.1
[00177] (Step 3) Synthesis of the compound of Example 2
According to Example 1 (Step 4), except that 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1- (S)-tert-butyl yl)pyrrolidine-1-carboxylate obtained in (Step 2) above was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazole tert-butyl [3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, a crude product of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3 -yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained by removing a Boc group under acidic conditions. Thereafter, amidation was carried out to obtain the title compound as a white solid. Table 1 shows its physical properties. Example 3 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)but-2 -en-1-one (Compound of Example 3)
[00179] According to Example 1 (Step 4), except that crotyl chloride was used in place of acrylic chloride, the title compound was obtained as a white solid. Table 1 shows its physical properties. Example 4 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )-4-(dimethylamino)but-2-en-1-one (Compound of Example 4)
[00180] The crude product (5.6 mg) of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d] pyrimidin-4-amine obtained in Example 2 as an intermediate, 4-(dimethylamino)but-2-enoic acid hydrochloride (6.3 mg) and HATU (15 mg) were dissolved in DMF (1.0 ml). DIPEA (50 µl) was added to this, followed by stirring overnight. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by preparative reverse phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (2.3 mg). Table 1 shows its physical properties. Example 5 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )prop-2-in-1-one (Compound of Example 5)
[00181] The crude product (16 mg) of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine obtained in Example 2 as an intermediate, 3-(trimethylsilyl)propionic acid (10 mg) and HA-TU (28 mg) were dissolved in DMF (0.5 ml). DIPEA (31 µl) was added to this, followed by stirring overnight. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a white solid (0.7 mg). Table 1 shows its physical properties. Example 6 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )-2-fluoroprop-2-en-1-one (Compound of Example 6)
[00182] According to Example 4, except that 2-fluoroacrylic acid was used in place of 4-(dimethylamino)but-2-enoic acid hydrochloride, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 7 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )-2-(pyrrolidin-1-ylmethyl)prop-2-en-1-one (compound of Example 7)
According to Example 4, except that 2-(pyrrolidin-1-ylmethyl)acetic acid (Synth. Commun. 1995, 641) was used in place of 4-(dimethylamino)but-2 acid hydrochloride -enoic, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 8 Synthesis of (S)-1-(3-(4-amino-3-((3,5-diethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )prop-2-en-1-one (Compound of Example 8)
[00184] (Step 1) Synthesis of 1,3-diethoxy-5-ethynylbenzene
Carbon tetrabromide (4.78 g) was dissolved in dichloroethane (14 ml) and triphenylphosphine (7.56 g) was added thereto at 0°C. After stirring at 0°C for 5 minutes, a solution of 3,5-diethoxybenzaldehyde (1.40 g) in dichloromethane (7 ml) was added, followed by stirring for 20 minutes. Without carrying out further treatment, the reaction mixture was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate) to obtain 1-(2,2-dibromovinyl)-3,5-diethoxybenzene. The compound obtained was used for the subsequent reaction without further purification. The compound obtained above was dissolved in THF (30 ml). A 1.63 M solution of n-butyl lithium in hexane (10.5 ml) was added thereto at -78°C. The resulting mixture was stirred at -78°C for 30 minutes. After adding a saturated aqueous ammonium chloride solution, the reaction mixture was subjected to extraction using ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, and the organic layer was then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless oily substance (1.31 g). Physical properties: m/z [M+H]+ 191.0.
[00186] (Step 2) According to Example 1, except that the 1,3-diethoxy-5-ethynylbenzene obtained in Step 1 was used in place of 1-ethynyl-3,5-dimethoxybenzene, the title compound was obtained as a colorless amorphous substance. Table 1 shows its physical properties. Example 9 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)prop-2 -en-1-one (compounded from Example 9)
[00187] (Step 1) Synthesis of tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate
[00188] N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 µL) were added thereto at 0 °C. After stirring at room temperature for 0.5 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless oily compound (2.32 g). Physical properties: m/z [M+H]+ 252.0
[00189] (Step 2) Synthesis of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate
[00190] A suspension of tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.32 g) obtained in Step 1 above, 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4- amine (1.37g) and cesium carbonate (3.47g) in DMF (10ml) was stirred at 90°C for 10 hours. Ethyl acetate and water were added thereto to separate the organic layer. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow amorphous substance (482 mg). Physical properties: m/z [M+H]+ 417.0
[00191] (Step 3) Synthesis of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate of tert-butyl
[00192] PdCl2 (dppf) CH2Cl2 (39 mg) was added to a mixture of 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate of tert-butyl (200 mg) obtained in Step 2 above, 1-ethynyl-3,5-dimethoxybenzene (117 mg), copper (I) iodide (14 mg) and triethylamine (0.5 ml) in THF (5 ml). After purging with nitrogen, the resulting mixture was stirred at 80°C for 1.5 hour. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (185 mg). Physical properties: m/z [M+H]+ 451.1
[00193] (Step 4) Synthesis of the compound of Example 9
[00194] According to Example 1 (Step 4), except that tert 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate -butyl obtained in Step 3 above was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine- tert-butyl 1-carboxylate, a crude product of 1-(azetidin-3-i)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained by removing a Boc group under acidic conditions. Thereafter, amidation was carried out to obtain the title compound as a white solid. Table 1 shows its physical properties. Example 10 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- hydroxybut-2-in-1-one(Compound of Example 10)
[00195] A crude product (6.0 mg) of 1-(azetidin-3-yl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4- amine obtained in Example 9 as an intermediate, 4-hydroxybut-2-yn acid (3.7 mg) and HATU (11 mg) were dissolved in DMF (1.0 ml). DIPEA (30 µL) was added to this, followed by stirring overnight.
[00196] Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative reverse phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (1.4 mg). Table 1 shows its physical properties. Example 11 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- hydroxy-4-methylpent-2-yn-1-one (Compound of Example 11)
[00197] According to Example 10, except that 4-hydroxy-4-methylpent-2-ynoic acid was used in place of 4-hydroxybut-2-ynoic acid, the title compound was obtained as a colorless, amorphous substance. . Table 1 shows its physical properties. Example 12 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (dimethylamino)but-2-en-1-one (compound of Example 12)
[00198] According to Example 10, except that 4-(dimethylamino)but-2-enoic acid hydrochloride was used in place of 4-hydroxybut-2-in acid, the title compound was obtained as a colorless substance, amorphous. Table 1 shows its physical properties. Example 13 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)- 4-(cyclopropylamino)but-2-en-1-one (compound of Example 13)
[00199] (Step 1) Synthesis of 4-bromobut-2-enoyl chloride
[00200] Thionyl chloride (3.0 ml) was added to 4-bromocrotonic acid (329 mg) and the mixture was stirred at 80°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and azeotropic distillation of toluene was further carried out to obtain the title compound as a crude product (394 mg).
[00201] (Step 2) Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin- 1-yl)-4-bromobut-2-en-1-one
A crude product (140 mg) of 1-(azetidin-3-yl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, obtained in E-example 9 as an intermediate, was suspended in THF (4.5 mL), DI-PEA (178 µL) was added thereto and the mixture was cooled to 0 °C. A solution of 4-bromobut-2-enoyl chloride (66 mg) obtained in Step 1 above in THF (0.5 ml) was added to the mixture dropwise and stirred at room temperature for 15 minutes. After quenching the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. After drying the result on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (160 mg). Physical properties: m/z [M+H]+ 497.0, 499.0
[00203] (Step 3) Synthesis of the compound of Example 13
The crude product (12 mg) of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) azetidin-1-yl)-4-bromobut-2-en-1-one obtained in Step 2 above was dissolved in DMF (0.5 ml). Cyclopropylamine (5 µL) and DIPEA (10 µL) were added thereto, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the resulting residue was purified by purification by preparative reverse phase HPLC (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless substance, amorphous (3.4 mg). Table 1 shows its physical properties. Example 14 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (isopropylamino)but-2-en-1-one (Compound of Example 14)
[00205] According to Example 13 (Step 3), except that isopropylamine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 15 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (ethyl(methyl)amino)but-2-en-1-one (compound of Example 15)
[00206] According to Example 13 (Step 3), except that ethyl-methylamine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 16 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (cyclobutylamino)but-2-en-1-one (compound of Example 16)
[00207] According to Example 13 (Step 3), except that cyclobutylamine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 17 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (diethylamino)but-2-en-1-one (compound of Example 17)
According to Example 13 (Step 3), except that diethylamine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 18 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (tert-butylamino)but-2-en-1-one (Compound of Example 18)
[00209] According to Example 13 (Step 3), except that tert-butylamine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 19 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (isopropyl(methyl)amino)but-2-en-1-one (compound of Example 19)
[00210] According to Example 13 (Step 3), except that isopropylmethylamine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 20 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (piperidin-1-yl)but-2-en-1-one (compound of Example 20)
According to Example 13 (Step 3), except that piperidine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 21 Synthesis of 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- morpholinobut-2-en-1-one (compound of Example 21)
[00212] According to Example 13 (Step 3), except that morpholine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 22 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl )-4-(3-fluoropyrrolidin-1-yl)but-2-en-1-one
[00213] According to Example 13 (Step 3), except that (S)-3-fluoropyrrolidine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 23 Synthesis of (R)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl )-4-(3-fluoropyrrolidin-1-yl)but-2-en-1-one
[00214] According to Example 13 (Step 3), except that (R)-3-fluoropyrrolidine was used in place of cyclopropylamine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 24 Synthesis of 1-(3-(4-amino-3-((3,5-diethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)prop-2 -en-1-one (compound of Example 24)
According to Example 9, except that 1,3-diethoxy-5-ethynylbenzene was used in place of 1-ethynyl-3,5-dimethoxybenzene, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 25 Synthesis of 1-(3-(4-amino-3-((3,5-diethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (dimethylamino)but-2-en-1-one (compound of Example 25)
[00216] According to Example 12, except that 1,3-diethoxy-5-ethynylbenzene was used in place of 1-ethynyl-3,5-dimethoxybenzene, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 26 Synthesis of 1-(3-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl) prop-2-en-1-one (compound of Example 26)
[00217] (Step 1) Synthesis of 3-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine- 1- tert-butyl carboxylate
[00218] DIAD (197 µL) was added to a suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (148 mg) obtained in Example 1 (Step 1), N-Boc-3-hydroxymethylpyrrolidine (154 mg), polymer supported triphenylphosphine (up to 3.0 mmol/g, 334 mg) in THF (5.0 mL), followed by stirring at room temperature for 3 hours. Insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (94.5 mg). Physical properties: m/z [M+H]+ 479.1
[00219] (Step 2) Synthesis of the compound of Example 26
[00220] According to Example 1 (Step 4), except that 3-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1 - tert-butyl yl)methyl)pyrrolidine-1-carboxylate obtained in Step 1 above was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3, tert-butyl 4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, the title compound was obtained as a white solid. Table 1 shows its physical properties. Example 27 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl )prop-2-en-1-one (compound of Example 27)
[00221] According to Example 26, except that (R)-1-Boc-3-hydroxypiperidine was used in place of N-Boc-3-hydroxymethylpyrrolidine, the title compound was obtained as a white solid. Table 1 shows its physical properties. Example 28 Synthesis of 1-((2S,4S)-4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2- (hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one (compound of Example 28)
[00222] (Step 1) Synthesis of (2S,4R)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate
[00223] 1-N-Boc-(2S,4R)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine (500 mg) was dissolved in DMF (4.0 mL) and imidazole (164 mg) was added to the dissolution . After cooling to 0 °C, tert-butylchlorodiphenylsilane (616 µL) was added to the mixture and stirred for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (655 mg). Physical properties: m/z [M+H]+ 456.2
[00224] (Step 2) Synthesis of (2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate
(2S,4R)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (300 mg) obtained in Step 1 above was dissolved in chloroform (3.0 mL). Triethylamine (137 µL) and methanesulfonyl chloride (56 µL) were added to the solution at 0 °C. After stirring at room temperature for 2.0 hours, chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oily compound (389 mg). Physical properties: m/z [M+H]+ 534.1
[00226] (Step 3) Synthesis of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1 -((2S,4S)-tert-butyl carboxylate
[00227] (2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (389 mg) obtained in Step 2 above, 3-iodine -1H-pyrazolo[3,4-d]pyrimidin-4-amine (188 mg) and potassium carbonate (363 mg) were suspended in DMF (4.0 mL), followed by stirring overnight at 80°C. °C. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (191 mg). Physical properties: m/z [M+H]+ 699.1
[00228] (Step 4) Synthesis of 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-(( (2S,4S)-tert-butyl tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate
[00229] PdCl2 (dppf) CH2Cl2 (13 mg) was added to a mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-(( (2S,4S)-tert-butyl tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate (113 mg) obtained in Step 3 above, 1-ethynyl-3,5-dimethoxybenzene (52 mg), copper (I) iodide ) (6 mg) and triethylamine (0.4 ml) in THF (4 ml). After purging with nitrogen, the resulting mixture was stirred at 85°C for 3 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After washing with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (100 mg). Physical properties: m/z [M+H]+ 733.3
[00230] (Step 5) Synthesis of 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-(hydroxymethyl (2S,4S)-tert-butyl)pyrrolidine-1-carboxylate
[00231] 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-((tert-butyldiphenylsilyloxy)methyl) (2S,4S)-tert-butyl pyrrolidine-1-carboxylate (25 mg), obtained in Step 4 above, was dissolved in THF (1.0 mL). Tetrabutylammonium fluoride supported on silica gel (up to 1.5 mmol/g, 34 mg) was added, followed by stirring overnight. Tetrabutylammonium fluoride supported on silica gel (up to 1.5 mmol/g, 30 mg) was further added thereto, and the mixture was further stirred for 2 days. After filtering off the reagent, the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (62 mg). Physical properties: m/z [M+H]+ 495.1
[00232] (Step 6) Synthesis of the compound of Example 28
According to Example 1 (Step 4), except that 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate, obtained in Step 5 above, was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazole tert-butyl [3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, the title compound was obtained as a white solid. Table 1 shows its physical properties. Example 29 Synthesis of 1-(3-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)azetidin-1-yl) prop-2-en-1-one (compound of Example 29)
According to Example 26, except that 1-Boc-3-hydroxymethylazetidine was used in place of N-Boc-3-hydroxymethylpyrrolidine, the title compound was obtained as a light yellow amorphous substance. Table 1 shows its physical properties. Example 30 Synthesis of N-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclobutyl)acrylamide (compound of Example 30)
[00235] According to Example 1, except that tert-butyl 3-hydroxycyclobutylcarbamate was used in place of N-Boc-3-hydroxypyrrolidine, the title compound was obtained as a light yellow amorphous substance. Table 1 shows its physical properties. Example 31 Synthesis of 1-(4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2 -en-1-one (compound of Example 31)
[00236] According to Example 1, except that tert-butyl 4-bromopiperidin-1-carboxylate was used in place of tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate, the title compound was obtained as a white solid. Table 1 shows its physical properties. Example 32 Synthesis of 1-((2S,4S)-4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2- ethynylpyrrolidin-1-yl)prop-2-en-1-one (compound of Example 32)
[00237] (Step 1) Synthesis of 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-ethynylpyrrolidine- (2S,4S)-tert-butyl 1-carboxylate
[00238] 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (14 mg) obtained in Example 1 (Step 1), 2-ethynyl-4- (2S,4R)-tert-butyl hydroxypyrrolidine-1-carboxylate (15 mg) synthesized by the method disclosed in WO2005/007083 and triphenylphosphine (23 mg) were suspended in THF (1.0 ml). DIAD (18 µL) was added to the suspension and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in a DMSO solution. The resulting solution was purified by preparative reverse phase H-PLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (5.0 mg). Physical properties: m/z [M+H]+ 489.2
[00239] (Step 2) Synthesis of the compound of Example 32
[00240] According to Example 1 (step 4), except that 4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl) (2S,4S)-tert-butyl-2-ethynylpyrrolidine-1-carboxylate obtained in Step 1 above was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- tert-butyl 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, the title compound was obtained as a white solid. Table 1 shows its physical properties. Example 33 Synthesis of 1-(4-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl) prop-2-en-1-one (compound of Example 33)
According to Example 26, except that 1-Boc-4-hydroxymethylpiperidine was used in place of N-Boc-3-hydroxymethylpyrrolidine, the title compound was obtained as a light yellow amorphous substance. Table 1 shows its physical properties. Example 34 Synthesis of N-(3-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)acrylamide (compound of Example 34)
[00242] According to Example 26, except that (3-aminophenyl)methanol was used in place of N-Boc-3-hydroxymethylpyrrolidine, the title compound was obtained as a colorless amorphous substance. Table 1 shows its physical properties. Example 35 Synthesis of 1-(3-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)azetidin-1-yl) -4-(dimethylamino)but-2-en-1-one (compound of Example 35)
[00243] According to Example 4, except that 1-(azetidin-3-ylmethyl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (i.e., an intermediate obtained in Example 29) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4 - d]pyrimidin-4-amine, the title compound was obtained as a pale yellow amorphous substance. Table 1 shows its physical properties. Example 36 Synthesis of 1-(4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4- (dimethylamino)but-2-en-1-one (compound of Example 36)
[00244] According to Example 4, except that 3-((3,5-dimethoxyphenyl)ethynyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 31) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4 - d]pyrimidin-4-amine, the title compound was obtained as a pale yellow amorphous substance. Table 1 shows its physical properties. Example 37 Synthesis of 1-(4-((4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl) -4-(dimethylamino)but-2-en-1-one (compound of Example 37)
According to Example 4, except that 3-((3,5-dimethoxyphenyl)ethynyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ie the intermediate obtained in Example 33) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4 -d]pyrimidin-4-amine, the title compound was obtained as a light yellow amorphous substance. Table 1 shows its physical properties. Example 38 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(dimethylamino)but-2-en-1-one (compound of Example 38)
[00246] (Step 1) Synthesis of (S)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate
[00247] DIAD (1.41 mL) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), (R)-N-Boc- 3-pyrrolidinal (1.01 g) and triphenylphosphine (1.88 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain the title compound as a white solid (1.04 g). Physical properties: m/z [M+H]+ 448.9
[00248] (Step 2) Synthesis of (S)-tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate
[00249] Tetrahydrofuran (2.5 ml) and 28% aqueous ammonia (2.5 ml) were added to 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7 - (S)-tert-butyl yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1 above. The reaction mixture was stirred at 100°C for 1.5 hours using a microwave reactor. Chloroform and water were added to this to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a solid colorless compound (382 mg). Physical properties: m/z [M+H]+ 430.3
[00250] (Step 3) Synthesis of 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate of (S)-tert-butyl
[00251] PdCl2 (dppf)2 CH2Cl2 (122 mg) was added to a mixture of 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1- (S)-tert-butyl carboxylate (660 mg) obtained in Step 2 above, 1-ethynyl-3,5-dimethoxybenzene (374 mg), copper (I) iodide (44 mg) and triethylamine (2. 0 ml) in THF (15 ml). After purging with nitrogen, the resulting mixture was stirred at 80°C for 3.5 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After washing with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (714 mg). Physical properties: m/z [M+H]+ 464.1
[00252] (Step 4) Synthesis of the compound of Example 38
4N Hydrochloric acid/1,4-dioxane (2 mL) was added to 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d] (S)-tert-butyl pyrimidin-7-yl)pyrrolidine-1-carboxylate (30 mg) obtained in Step 3 above, and the mixture was stirred at room temperature for 1.5 hour. After distilling off the solvent from the resulting reaction mixture under reduced pressure, azeotropic distillation of toluene was further carried out to obtain a crude product of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-( pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (30 mg). A part of the resulting crude product (10 mg), 4-(dimethylamino)but-2-enoic acid hydrochloride (5.9 mg) and HATU (14 mg) were dissolved in DMF (1.0 ml). DIPEA (50 µL) was added to this and stirred at room temperature for 5 minutes. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by pre-parative reverse phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (3.9 mg). Table 1 shows its physical properties. Example 39 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )prop-2-en-1-one (compound of Example 39)
According to Example 1 (Step 4), except that 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7- (S)-tert-butyl yl)pyrrolidine-1-carboxylate obtained in Example 38 (E-step 3) was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)- tert-butyl 1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, a crude product of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-( pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained by removing a Boc group under acidic conditions. Thereafter, amidation was carried out to obtain the title compound as a white solid. Table 1 shows its physical properties. Example 40 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(pyrrolidin-1-yl)but-2-en-1-one (compound of Example 40)
[00255] (Step 1) Synthesis of 4-(pyrrolidin-1-yl)but-2-enoic acid hydrochloride
[00256] Methyl 4-bromocrotonate (1.79 g) was dissolved in tetrahydrofuran (40 ml), pyrrolidine (1.67 ml) was added thereto at 0°C and the mixture was stirred at room temperature for 1 hour. Diethyl ether and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. 3N Hydrochloric acid (40 ml) was added to the resulting product and the mixture was heated under reflux at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then the resulting residue was washed with a solvent mixture of 2-isopropanol and ethyl acetate to obtain the title compound as a white solid (939 mg). Physical properties: m/z [M+H]+ 156.0
[00257] (Step 2) Synthesis of the compound of Example 40
[00258] According to Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine (the intermediate obtained in Example 38 (Step 4)) and 4-(pyrrolidin-1-yl)but-2-enoic acid hydrochloride obtained in step 1 above were used, the title compound it was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 41 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(4-methylpiperazin-1-yl)but-2-en-1-one (compound of Example 41)
[00259] (Step 1) Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyrrolidin-1-yl)-4-bromobut-2-en-1-one
The crude product (100 mg) of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine (i.e. the intermediate obtained in Example 38 (Step 4)) was suspended in chloroform (3.0 mL). DIPEA (117 µL) was added to the suspension and the mixture was cooled to 0 °C. A solution of 4-bromobut-2-enoyl chloride (46 mg) obtained in Example 16 (Step 1) in chloroform (0.3 ml) was added thereto dropwise, and the resulting mixture was stirred at temp. - room temperature for 15 minutes. After quenching the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (140 mg). Physical properties: m/z [M+H]+ 509.9, 511.9
[00261] (Step 2) Synthesis of the compound of Example 41
[00262] The crude product (12 mg) of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)pyrrolidin-1-yl)-4-bromobut-2-en-1-one obtained in Step 1 above was dissolved in DMF (0.5ml). N-methylpiperazine (4 mg) and DIPEA (10 µL) were added to this, followed by stirring at room temperature overnight. After concentration under reduced pressure, the resulting residue was purified by preparative reverse phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (3.0 mg ). Table 1 shows its physical properties. Example 42 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(4-hydroxypiperidin-1-yl)but-2-en-1-one (compound of Example 42)
According to Example 41 (Step 2), except that 4-hydroxypiperidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 43 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(4-fluoropiperidin-1-yl)but-2-en-1-one (compound of Example 43)
[00264] According to Example 41 (Step 2), except that 4-fluoropiperidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 44 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(3,3-difluoropyrrolidin-1-yl)but-2-en-1-one (compound of Example 44)
[00265] According to Example 41 (Step 2), except that 3,3-difluoropyrrolidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 45 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(4,4-difluoropiperidin-1-yl)but-2-en-1-one (compound of Example 45)
[00266] According to Example 41 (Step 2), except that 4,4-difluoropiperidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 46 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )but-2-in-1-one (compound of Example 46)
[00267] According to Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine (i.e. the intermediate obtained in Example 38 (Step 4)) and 2-butynoic acid were used, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 47 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-hydroxy-4-methylpent-2-yn-1-one (Compound of Example 47)
[00268] According to Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-amine (i.e. the intermediate obtained in Example 38 (Step 4)) and 4-hydroxy-4-methylpent-2-ynoic acid were used, the title compound was obtained as a colorless, amorphous substance. . Table 1 shows its physical properties. Example 48 Synthesis of 1-((S)-3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-((R)-3-fluoropyrrolidin-1-yl)but-2-en-1-one (compound of Example 48)
[00269] According to Example 41 (Step 2), except that (R)-3-fluoropyrrolidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 49 Synthesis of 1-((S)-3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-((S)-3-fluoropyrrolidin-1-yl)but-2-en-1-one (compound of Example 49)
[00270] According to Example 41 (Step 2), except that (S)-3-fluoropyrrolidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 50 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl )-4-(piperidin-1-yl)but-2-en-1-one (Compound of Example 50)
[00271] According to Example 41 (Step 2), except that piperidine was used in place of N-methylpiperazine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 51 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)prop-2 -en-1-one (compound of Example 51)
[00272] (Step 1) Synthesis of tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
[00273] DIAD (1.41 mL) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), N-Boc-3-hydroxyazetidine ( 930 mg) and triphenylphosphine (1.85 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. After concentration, the reaction mixture was washed with ethyl acetate to obtain the title compound as a white solid (1.07 g). Physical properties: m/z [M+H]+ 435.0
[00274] (Step 2) Synthesis of tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
[00275] Tetrahydrofuran (2.5 mL) and 28% aqueous ammonia (2.5 mL) were added to 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7 - tert-butyl yl)azetidine-1-carboxylate (350 mg) obtained in Step 1 a-above. The reaction mixture was stirred at 100°C for 1.5 hours using a microwave reactor. Chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (340 mg). Physical properties: m/z [M+H]+ 416.0
[00276] (Step 3) Synthesis of 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate of tert-butyl
[00277] PdCl2(dppf)CH2Cl2 (122 mg) was added to a mixture of 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate of tert-butyl (639 mg) obtained in Step 2 above, 1-ethynyl-3,5-dimethoxybenzene (374 mg), copper iodide (44 mg) and triethylamine (2.0 ml) in THF (15 ml). After purging with nitrogen, the resulting mixture was stirred at 80°C for 3.5 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (704 mg). Physical properties: m/z [M+H]+ 450.1
[00278] (Step 4) Synthesis of the compound of Example 51
[00279] According to Example 1 (Step 4), except that 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7- tert-butyl yl)azetidine-1-carboxylate obtained in Step 3 was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d] tert-butyl pyrimidin-1-yl)pyrrolidine-1-carboxylate, a crude product of 7-(azetidin-3-i)-5-((3,5-)dimethoxyphenyl)ethynyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amine was obtained by removing a Boc group under acidic conditions. Thereafter, amidation was carried out to obtain the title compound as a white solid. Table 1 shows its physical properties. Example 52 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (dimethylamino)but-2-en-1-one (Compound of Example 52)
[00280] According to Example 4 (Step 1), except that 3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 - tert-butyl yl)azetidine-1-carboxylate obtained in Example 51 (Step 3) was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3 tert-butyl ,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 53 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (pyrrolidin-1-yl)but-2-en-1-one (Compound of Example 53)
[00281] According to Example 4 (Step 1), to 7-(azetidin-3-yl)-5-((3,5-)dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine The 4-amine obtained in Example 51 (Step 4) as an intermediate and 4-(pyrrolidin-1-yl)but-2-enoic acid hydrochloride obtained in Step 40 (Step 1) were used to obtain the compound of the title as a colorless, a-morphous substance. Table 1 shows its physical properties. Example 54 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)but-2 -in-1-one (Compound of Example 54)
[00282] According to Example 4 (Step 1), to 7-(azetidin-3-yl)-5-((3,5-)dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin 4-amine obtained as an intermediate in Example 51 (Step 4) and 2-butynoic acid were used to obtain the title compound as a colorless, amorphous substance. Table 1 shows its physical properties. Example 55 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (azetidin-1-yl)but-2-en-1-one (Compound of Example 55)
[00283] (Step 1) Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin- 1-yl)-4-bromobut-2-en-1-one
[00284] A crude product of 7-(azetidin-3-yl)-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (160 mg) obtained in Example 52 (Step 4) as an intermediate was suspended in THF (3.0 mL). DIPEA (202 µL) was added to this, and the mixture was cooled to 0 °C. A solution of 4-bromobut-2-enoyl chloride (75 mg) obtained in Example 16 (Step 1) in THF (0.5 ml) was added to the mixture dropwise and stirred at room temperature for 15 minutes. After quenching the reaction using a saturated sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. After drying the result on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (204 mg). Physical properties: m/z [M+H]+ 496.0, 498.0
[00285] (Step 2) Synthesis of the Compound of Example 55
[00286] The crude product of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1- yl)-4-bromobut-2-en-1-one (10 mg) (10 mg) obtained in Step 1 above was suspended in THF (0.5 ml). Azetidine (7 µL) was added thereto, and the resulting mixture was stirred for 1 hour at room temperature. After concentration under reduced pressure, the resulting residue was purified by reverse phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (1.6 mg) . Table 1 shows its physical properties. Example 56 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (ethyl(methyl)amino)but-2-en-1-one (Compound of Example 56)
[00287] According to Example 55 (Step 2), except that ethyl-methylamine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 57 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (isopropylamino)but-2-en-1-one (Compound of Example 57)
[00288] According to Example 55 (Step 2), except that isopropylamine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 58 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (isopropyl(methyl)amino)but-2-en-1-one (Compound of Example 58)
[00289] According to Example 55 (Step 2), except that iso-propylmethylamine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 59 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (diethylamino)but-2-en-1-one (Compound of Example 59)
[00290] According to Example 55 (Step 2), except that diethylamine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 60 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- ((2-methoxyethyl)(methyl)amino)but-2-en-1-one (Compound of Example 60)
[00291] According to Example 55 (Step 2), except that 2-methoxy-N-methylethanamine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 61 Synthesis of 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4- (4-hydroxypiperidin-1-yl)but-2-en-1-one (Compound of Example 61)
[00292] According to Example 55 (Step 2), except that 4-hydroxypiperidine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 62 Synthesis of (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl )-4-(3-hydroxypyrrolidin-1-yl)but-2-en-1-one (Compound of Example 62)
[00293] According to Example 55 (Step 2), except that (S)-3-hydroxypyrrolidine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 63 Synthesis of (R)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl )-4-(3-hydroxypyrrolidin-1-yl)but-2-en-1-one (Compound of Example 63)
[00294] According to Example 55 (Step 2), except that (R)-3-hydroxypyrrolidine was used in place of azetidine, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 64 Synthesis of 1-(4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)prop-2 -en-1-one (Compound of Example 64)
[00295] According to Example 39, except that N-Boc-4-piperidinol was used in place of (R)-N-Boc-3-pyrrolidinal, the title compound was obtained as a pale yellow, amorphous substance. Table 1 shows its physical properties. Example 65 Synthesis of 1-(4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)-4- (dimethylamino)but-2-en-1-one (Compound of Example 65)
According to Example 38, except that N-Boc-4-piperidinol was used in place of (R)-N-Boc-3-pyrrolidinal, the title compound was obtained as a pale yellow, amorphous substance. Table 1 shows its physical properties. Example 66 Synthesis of 1-acryloyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate from (2S ,4S)-methyl (Compound of Example 66)
[00297] (Step 1) Synthesis of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
[00298] 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.01 g) synthesized by the method disclosed in WO2005/042556, was dissolved in anhydrous THF (125 ml). After cooling to 0°C, 60% sodium hydride (4.02 g) was added to the result and the resulting mixture was stirred for 20 minutes. Thereafter, SEMCl (13.3 ml) was added thereto, and the mixture was stirred at room temperature overnight. After cooling to 0 °C again, water was added to the mixture and the reaction was stopped. The resulting product was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution. After drying the product over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a white solid (7.28 g). Physical properties: m/z [M+H]+ 410.0
[00299] (Step 2) Synthesis of 5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
The 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg) obtained in Step 1 above was dissolved in THF (2.0 ml). 28% aqueous ammonia (2 ml) was added thereto, and the reaction mixture was then stirred at 105 °C for 1.5 hour using a microwave reactor. The resulting product was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution. After drying the result on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (192 mg). Physical properties: m/z [M+H]+ 391.0
[00301] (Step 3) Synthesis of 5-((3,5-dimethoxyphenyl)ethynyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- the mine
[00302] According to Example 1 (Step 1), except that 5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 2 above was used in place of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, the title compound was obtained as a colorless solid. Physical properties: m/z [M+H]+ 425.4
[00303] (Step 4) Synthesis of 5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[00304] A solution of 5-((3,5-dimethoxyphenyl)ethynyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4 .27 g) obtained in Step 3 in methylene chloride (20 ml) was cooled to 0°C, and TFA 10 ml was added thereto. The reaction mixture was stirred at room temperature for 5 hours and the solvent was distilled off under reduced pressure. THF (50 mL) was added to the residue and the mixture was cooled to 0 °C. 4N aqueous sodium hydroxide (12.5 ml) was added thereto and the mixture was stirred at room temperature overnight. The result was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure and chloroform was added to the resulting residue. The mixture was subjected to filtration to obtain the title compound as a white solid (2.60 g). Physical properties: m/z [M+H]+ 295.3
[00305] (Step 5) Synthesis of (2S,4R)-4-(methylsulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester-2-methyl ester
[00306] According to Example 1 (Step 2), except that (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butylester-2-methylester was used in place of N-Boc -3-pyrrolidinal, the title compound was obtained as a colorless, amorphous substance.
[00307] (Step 6) Synthesis of 2-methyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine -1,2- (2S,4S)-1-tert-butyl dicarboxylate
[00308] According to Example 1 (Step 3), except that the 5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 4, (2S,4R)-4-(methylsulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tertbutylester-2-methyl ester obtained in Step 5, sodium hydride and NMP were individually used in place of 3-(( 3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate, potassium carbonate and DMF, the title compound it was obtained as a colorless, amorphous substance. Physical properties: m/z [M+H]+ 522.4
[00309] (Step 7) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate of (2S,4S)-methyl
A solution of 2-methyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1, 2-(2S,4S)-1-tert-butyl dicarboxylate (24 mg) obtained in Step 6 above in methylene chloride (2.0 mL) and TFA (2.0 mL) was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and the resulting residue was purified by basic silica gel column chromatography (developing solvent:chloroform/methanol). The title compound was thus obtained as a pale yellow amorphous substance (11.9 mg). Physical properties: m/z [M+H]+ 422.1
[00311] (Step 8) Synthesis of the Compound of Example 66
[00312] Methylene chloride (2.0 mL) and triethylamine (16 µL) were added to 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d (2S,4S)-methyl]pyrimidin-7-yl)pyrrolidine-2-carboxylate (12mg) obtained in Step 7 above. After cooling to 0 °C, chloroform (100 µL) in which acryloyl chloride (5 µL) was dissolved was added to the resulting mixture and stirred at room temperature for 10 minutes. After quenching the reaction using a saturated sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. After drying the product over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a colorless, amorphous substance (4.2 mg). Table 1 shows its physical properties. Example 67 Synthesis of 1-((2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- ((dimethylamino)methyl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 67)
[00313] (Step 1) Synthesis of 2-((tert-butyldiphenylsilyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1 -((2S,4S)-tert-butyl carboxylate
A solution of triphenylphosphine (443 mg) in THF (25 mL) was cooled to 0 °C and DIAD (340 µL) was added thereto dropwise. The reaction mixture was stirred at 0°C for 1 hour. 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (363 mg) and (2S,4R)-tert 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate -butyl (651.6 mg) obtained in Example 28 (Step 1) was added thereto and stirred at room temperature overnight. Ethyl acetate and water were added to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow amorphous substance (400 mg). m/z[M+H]+ 718.5
[00315] (Step 2) Synthesis of 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1 -((2S,4S)-tert-butyl carboxylate
[00316] THF (10 mL) and a solution of 8N ammonia in methanol (5 mL) were added to 2-((tert-butyldiphenylsilyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrolo[2 (2S,4S)-tert-butyl ,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1. The mixture was stirred at 120°C for 2 hours under micro-irradiation. -waves and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent:chloroform/ethanol) to obtain the title compound as a pale yellow solid (293 mg). Physical properties: m/z [M+H]+ 698.5
[00317] (Step 3) Synthesis of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((tert. - (2S,4S)-tert-butyl butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate
[00318] Boc2O (188 mg) and DMAP (7 mg) were added to a solution of 4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (2S,4S)-tert-butyl ((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate (200 mg) obtained in Step 2 in THF (5 mL), and the resulting mixture was stirred at room temperature for one day To the other. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow amorphous substance (238 mg). m/z [M+H]+ 898.5
[00319] (Step 4) Synthesis of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl) (2S,4S)-tert-butyl pyrrolidine-1-carboxylate
[00320] Tetrabutylammonium fluoride carried on silica gel (700 mg) (up to 1.5 mmol/g) was added to a solution of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H (2S,4S)-tert-butyl -pyrrolo[2,3-d]pyrimidin-7-yl)-2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate (237.5 mg) obtained in Step 3 in THF (5 mL), and the resulting mixture was stirred at room temperature overnight. The silica gel was filtered off and the solvent in the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow substance (185 mg). Physical properties: m/z [M+H]+ 660.2
[00321] (Step 5) Synthesis of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-formylpyrrolidine-1 -((2S,4S)-tert-butyl carboxylate
Dess-Martin periodinane (51 mg) was added to a solution of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7 (2S,4S)-tert-butyl yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (66 mg) obtained in Step 4 in methylene chloride (2 mL), and the resulting mixture was stirred at room temperature for 1 hour. More Dess-Martin periodinane (100 mg) was added to the mixture, which was stirred at room temperature for 1 hour. Dess-Martin periodin (70 mg) was further added thereto, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a 10% aqueous sodium thiosulfate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous substance (68 mg). Physical properties: m/z [M+H]+ 658.1
[00323] (Step 6) Synthesis of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((dimethylamino) (2S,4S)-tert-butyl )methyl)pyrrolidine-1-carboxylate
[00324] A THF solution in 1M dimethylamine (0.3 ml) and acetic acid (0.2 ml) were added to a solution of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H (2S,4S)-tert-butyl -pyrrolo[2,3-d]pyrimidin-7-yl)-2-formylpyrrolidine-1-carboxylate (68 mg) obtained in Step 5 in methylene chloride (2 mL), and the resulting mixture was cooled to 0°C. Sodium triacetoxyborohydride (127 mg) was added to the reaction mixture and stirred at 0°C for 2 hours s. The reaction mixture was neutralized using an aqueous solution of sodium hydrogencarbonate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous substance (31.9 mg). Physical properties: m/z [M+H]+ 687.2
[00325] (Step 7) Synthesis of 4-(4-(bis(tert-butoxycarbonyl)amino)-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)-2-((dimethylamino)methyl)pyrrolidine-1-carboxylate (2S,4S)-tert-butyl
[00326] According to Example 1 (Step 1), except that 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-((dimethylamino)methyl)pyrrolidine-1-carboxylate (2S,4S)-tert-butyl obtained in Step 6 was used in place of 3-iodo-1H-pyrazolo[3,4-d ]pyrimidin-4-amine, the title compound was obtained as a pale yellow amorphous substance. Physical properties: m/z [M+H]+ 721.5
[00327] (Step 8) Synthesis of 5-((3,5-dimethoxyphenyl)ethynyl)-7-((3S,5S)-5-((dimethylamino)methyl)pyrrolidin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine
[00328] According to Example 66 (Step 7), except that 4-(4-(bis(tert-butoxycarbonyl)amino)-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2 (2S,4S)-tert-butyl ,3-d]pyrimidin-7-yl)-2-((dimethylamino)methyl)pyrrolidine-1-carboxylate obtained in Step 7 was used in place of 2-methyl-4- (2S,4S)-1- (4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate tert-butyl the title compound was obtained as a pale yellow amorphous substance. Physical properties: m/z [M+H]+ 421.1
[00329] (Step 9) Synthesis of the Compound of Example 67
[00330] According to Example 66 (Step 8), except that 5-((3,5-dimethoxyphenyl)ethynyl)-7-((3S,5S)-5-((dimethylamino)methyl)pyrrolidin-3 - yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 8 was used in place of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H- (2S,4S)-methyl pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 68 Synthesis of 1-((2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (1,3,4-oxadiazol-2-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 68)
[00331] (Step 1) Synthesis of (2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-acid yl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
2-methyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2- (2S,4S)-1-tert-butyl dicarboxylate (393.8 mg) obtained in Example 66 (Step 6) was dissolved in methanol (6 ml). After cooling to 0 °C, 4N aqueous sodium hydroxide (3 mL) was added thereto. The reaction suspension was stirred at room temperature for 3 hours. 5N hydrochloric acid was added to the reaction mixture to a pH of 5, and ethyl acetate and water were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (280 mg). Physical properties: m/z [M+H]+ 508.3
[00333] (Step 2) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydrazine (2S,4S)-tert-butyl carbonyl)pyrrolidine-1-carboxylate
[00334] DIPEA (73 μL) and hydrazine monohydrate (46 μL) were added to a solution of (2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl) acid -7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (106 mg) obtained in Step 1 a-above and TBTU (100 mg) in DMF ( 2 ml), and the resulting mixture was stirred at room temperature for 10 minutes. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous substance (93.6 mg). Physical properties: m/z [M+H]+ 522.4
[00335] (Step 3) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1 (2S,4S)-tert-butyl,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate
Toluene (3 mL) and trimethyl orthoformate (79 µL) were added to 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d (2S,4S)-tert-butyl ]pyrimidin-7-yl)-2-(hydrazinocarbonyl)pyrrolidine-1-carboxylate (93.6 mg) obtained in Step 2, and the resulting mixture was stirred at 110°C of overnight. Acetic acid (400 µL) was added to the reaction mixture and stirred at 110 °C for 6 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a pale yellow amorphous substance (50 mg). Physical properties: m/z [M+H]+ 532.2
[00337] (Step 4) Synthesis of 7-((3S,5S)-5-(1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-5-((3,5-dimethoxyphenyl) ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[00338] According to Example 66 (Step 7), except that 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl) (2S,4S)-tert-butyl-2-(1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate (50 mg), obtained in Step 3, was used in place of 2- methyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate (2S,4S )-1-tert-butyl, the title compound was obtained as a pale yellow amorphous substance (30.3 mg). m/z [M+H]+ 432.0
[00339] (Step 5) Synthesis of the Compound of Example 68
[00340] According to Example 66 (Step 8), except that 7-((3S,5S)-5-(1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-5- ((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 4 was used in place of 4-(4-amino-5-((3,5-) (2S,4S)-methyl dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate, the title compound was obtained as a pale yellow amorphous substance. Table 1 shows its physical properties. Example 69 Synthesis of 1-((2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (5-methyl-1,3,4-oxadiazol-2-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 69)
[00341] (Step 1) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(5 -methyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate (2S,4S)-tert-butyl
According to Example 68 (Step 3), except that triethyl orthoacetate was used in place of trimethyl orthoformate, the title compound was obtained as a pale yellow amorphous substance. Physical properties: m/z [M+H]+ 546.5
[00343] (Step 2) Synthesis of 5-((3,5-dimethoxyphenyl)ethynyl)-7-((3S,5S)-5-(5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[00344] According to Example 66 (Step 7), except that 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 (2S,4S)-tert-butyl -yl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate obtained in Step 1 was used in place of 2-methyl -4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate (2S,4S) -1-tert-butyl, the title compound was obtained as a pale yellow amorphous substance. Physical properties: m/z [M+H]+ 466.0
[00345] (Step 3) Synthesis of the Compound of Example 69
[00346] According to Example 66 (Step 8), except that 5-((3,5-dimethoxyphenyl)ethynyl)-7-((3S,5S)-5-(5-methyl-1,3, 4-oxadiazol-2-yl)pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 2 was used in place of 4-(4-amino-5-(( 3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate (2S,4S)-methyl, the title compound was obtained as a yellow amorphous substance - clear. Table 1 shows its physical properties. Example 70 Synthesis of 1-((2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (5-((dimethylamino)methyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound of Example 70)
[00347] (Step 1) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2 (2S,4S)-tert-butyl -(2-(dimethylamino)acetyl)hydrazinocarbonyl)pyrrolidine-1-carboxylate
According to Example 68 (Step 2), except that 2-(dimethylamino)acetohydrazide was used in place of hydrazine monohydrate, the title compound was obtained as a light yellow amorphous substance. Physical properties: m/z [M+H]+ 607.3
[00349] (Step 2) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(5 (2S,4S)-tert-butyl -((dimethylamino)methyl)-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate
[00350] DIPEA (105 µL) and tosyl chloride (56 mg) were added to a solution of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3- (2S,4S)-tert-butyl d]pyrimidin-7-yl)-2-(2-(2-(dimethylamino)acetyl)hydrazine carbonyl)pyrrolidine-1-carboxylate (100 mg) obtained in Step 1 in acetonitrile (3 mL), and the mixture was stirred at 40 °C for 1 hour. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a pale yellow amorphous substance (40.5 mg). Physical properties: m/z [M+H]+ 589.2
[00351] Synthesis of (Step 3) 5-((3,5-dimethoxyphenyl)ethynyl)-7-((3S,5S)-5-(5-((dimethylamino)methyl)-1,3,4-oxadiazole -2-yl)pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[00352] According to Example 66 (Step 7), except that 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 (2S,4S)-tert-butyl -yl)-2-(5-((dimethylamino)methyl)-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate obtained in step (2) was used in place of 2-methyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2- (2S,4S)-1-tert-butyl dicarboxylate, the title compound was obtained as a pale yellow amorphous substance. Physical properties: m/z [M+H]+ 489.2
[00353] (Step 4) Synthesis of the Compound of Example 70
[00354] According to Example 66 (Step 8), except that 5-((3,5-dimethoxyphenyl)ethynyl)-7-((3S,5S)-5-(5-((dimethylamino)methyl) -1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 3 was used in place of 4-(4-amino (2S,4S)-methia -5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate, the title compound was obtained as a pale yellow amorphous substance. Table 1 shows its physical properties. Example 71 Synthesis of (2S,4S)-1-acryloyl-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N -(2-(dimethylamino)ethyl)-N-methylpyrrolidine-2-carboxamide (Compound of Example 71)
[00355] (Step 1) Synthesis of 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(( (2S,4S)-tert-butyl 2-(dimethylamino)ethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate
A solution of (2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- acid 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (25.4 mg) obtained in Example 68 (Step 1), TBTU (17.7 mg), N,N,N'-trimethylethane-1,2-diamine ( 13 µL) and DIPEA (26 µL) in acetonitrile (3 mL) was stirred at room temperature for 1 hour. Ethyl acetate and water were added to separate the organic layer. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a pale yellow amorphous substance (3 mg). Physical properties: m/z [M+H]+ 592.4.
[00357] (Step 2) Synthesis of (2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl )-N-(2-(dimethylamino)ethyl)-N-methylpyrrolidine-2-carboxamide
[00358] According to Example 66 (Step 7), except that 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7 (2S,4S)-tert-butyl -yl)-2-((2-(dimethylamino)ethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate obtained in Step 1 above was used in place of 2-methyl-4 (2S,4S)-1 -(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate -tert-butyl, the title compound was obtained as a colorless amorphous substance. Physical properties: m/z [M+H]+ 492.4
[00359] (Step 3) Synthesis of the Compound of Example 71
[00360] According to Example 66 (Step 8), except that (2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3 - d]pyrimidin-7-yl)-N-(2-(dimethylamino)ethyl)-N-methylpyrrolidine-2-carboxamide obtained in Step 2 was used in place of 4-(4-amino-5-((3, (2S,4S)-methyl 5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate, the title compound was obtained as a colorless, amorphous substance. Table 1 shows its physical properties. Example 72 Synthesis of 1-(4-((4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl) -4-(dimethylamino)but-2-en-1-one (Compound of Example 72)
[00361] According to Example 38, except that N-Boc-4-hydroxymethylpiperidine was used in place of (R)-N-Boc-3-pyrrolidinal, the title compound was obtained as a pale yellow, amorphous substance. . Table 1 shows its physical properties. Example 73 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidin-1-yl )prop-2-en-1-one (Compound of Example 73)
[00362] (Step 1) Synthesis of 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine
4-chloro-1H-pyrrolo[3,2-c]pyridine (247 mg) synthesized by the method disclosed in WO2007/095223 was dissolved in DMF (7.0 mL). After cooling to 0°C, N-iodosuccinimide (382 mg) was added thereto. The resulting mixture was stirred at room temperature for 1 hour and then chloroform and water were added thereto to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a dark brown solid (455 mg). Physical properties: m/z [M+H]+ 279.1
[00364] (Step 2) Synthesis of (S)-tert-butyl 3-(4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1-carboxylate
The 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (225 mg) obtained in Step 1 was dissolved in DMF (3.0 mL). After cooling to 0 °C 60% sodium hydride (64.5 mg) was added to this. The (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (322 mg) obtained in Example 2 (Step 1) was added to the reaction mixture using DMF (2.0 mL), and the mixture was shaken overnight. 60% Sodium hydride (64.5 mg) was further added, and the mixture was stirred at 85°C overnight. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a crude product (192 mg). Physical properties: m/z [M+H]+ 448.3.
[00366] (Step 3) Synthesis of 3-(4-chloro-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1-carboxylate of (S)-tert-butyl
[00367] PdCl2(dppf)CH2Cl2 (33 mg) was added to a mixture of the crude product of 3-(4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine- (S)-tert-butyl 1-carboxylate (180 mg) obtained in Step 2, 1-ethynyl 3,5-dimethoxybenzene (97 mg), copper (I) iodide (15 mg) and triethylamine (1, 0 ml) in THF (4.0 ml). After purging with nitrogen, the resulting mixture was stirred at 50°C for 30 minutes. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (133 mg). Physical properties: m/z [M+H]+ 482.4.
[00368] (Step 4) Synthesis of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1-carboxylate of (S)-tert-butyl
[00369] Under a nitrogen atmosphere, 3-(4-chloro-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1- (S)-tert-butyl carboxylate (120 mg) obtained in Step 3, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) (26 mg), sodium tert-butoxide (72 mg) ), benzophenoneimine (92 mg) and tris(dibenzylideneacetone)dipalladium (36 mg) were suspended in toluene (10 ml) and the result was stirred at 115 °C for 90 minutes. After dilution with ethyl acetate, filtration on celite was carried out. The solvent was distilled off under reduced pressure. Hydroxyamine hydrochloride (366 mg), sodium bicarbonate (442 mg), methanol (16 ml) and water (4 ml) were added to the resulting residue, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. After that, ethyl acetate and a saturated sodium chloride solution were added to separate the organic layer. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (35 mg). Physical properties: m/z [M+H]+ 463.4
[00370] (Step 5) Synthesis of the Compound of Example 73
[00371] According to Example 1 (Step 4), except that 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1 (S)-tert-butyl -yl)pyrrolidine-1-carboxylate obtained in Step (3) was used in place of 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazole tert-butyl [3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, the title compound was obtained as a white solid. Table 1 shows its physical properties. Reference Example 1 Synthesis of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2- en-1-one (Compound of Reference Example 1)
[00372] The compound was synthesized according to the method disclosed in WO2008/121742. Table 2 shows its physical properties. Reference Example 2 Synthesis of 3-cyclobutyl-1-(phenylethynyl)imidazo[1,5-a]pyrazin-8-amine (Compound of Reference Example 2)
[00373] The compound was synthesized according to the method disclosed in WO2007/087395. Table 2 shows its physical properties. Reference Example 3 Synthesis of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl )propan-1-one (Compound of Reference Example 3)
[00374] According to Example 1, (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 amine and propionyl chloride were used to obtain the title compound as a white solid. Table 2 shows its physical properties. Reference Example 4 Synthesis of (S)-1-(3-(4-amino-3-((3,5-diisopropylphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1 -yl)-4-(dimethylamino)but-2-en-1-one (Compound of Reference Example 4)
[00375] (Step 1) Synthesis of 1-ethynyl-3,5-diisopropylbenzene
[00376] PdCl2 (dppf) CH2Cl2 (163 mg) was added to a mixture of trimethylsilylacetylene (589 mg), 1-bromo-3,5-diisopropylbenzene (480 mg), copper(I) iodide (76 mg) and triethylamine (0.11 ml) in THF (4 ml). After purging with nitrogen, the resulting mixture was stirred at 80°C for 4 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After drying the result on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. A 2% methanolic potassium hydroxide solution (10 ml) was added to the resulting residue, and the result was stirred at room temperature overnight. Chloroform and water were added to the reaction mixture to separate the organic layer. After drying the product over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane) to obtain the title compound as a yellow oily substance (181 mg).
[00377] (Step 2) Synthesis of (S)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (446 mg), (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (450 mg), potassium carbonate (692 mg) in DMF (5.0 ml) was stirred at 85°C for 6 hours. Ethyl acetate and water were added thereto to separate the organic layer. The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a pale yellow amorphous substance (354 mg). Physical properties: m/z [M+H]+ 431.1
[00379] (Step 3) Synthesis of 3-(4-amino-3-((3,5-diisopropylphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate of (S)-tert-butyl
[00380] PdCl2(dppf)CH2Cl2 (8.2 mg) was added to a mixture of 1-ethynyl-3,5-diisopropylbenzene (56 mg) obtained in Step 1, 3-(4-amino-3-iodine (S)-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (43 mg) obtained in Step 2, copper (I) iodide (3.8 mg ) and triethylamine (0.2 ml) in THF (2.0 ml). After purging with nitrogen, the resulting mixture was stirred at 80 °C for 1.5 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was washed with a saturated sodium chloride solution. After drying the product over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance (42 mg). Physical properties: m/z [M+H]+ 489.2
[00381] (Step 4) Synthesis of (S)-3-((3,5-diisopropylphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine
[00382] According to Example 66 (Step 7), except that 3-(4-amino-3-((3,5-diisopropylphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1 - (S)-tert-butyl yl)pyrrolidine-1-carboxylate obtained in Step (3) was used in place of 2-methyl-4-(4-amino-5-((3,5-dimethoxyphenyl)) (2S,4S)-1-tert-butyl ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate, the title compound was obtained as a yellow amorphous substance -clear.
[00383] (Step 5) Synthesis of the Compound of Reference Example 4
[00384] According to Example 4, except that (S)-3-((3,5-diisopropylphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d ]pyrimidin-4-amine obtained in Step (4) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amine, the title compound was obtained as a pale yellow amorphous substance. Table 2 shows its physical properties. Reference Example 5 Synthesis of (S)-1-(3-(4-amino-3-((3-methoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)- 4-(dimethylamino)but-2-en-1-one (Compound of Reference Example 5)
[00385] (Step 1) Synthesis of (S)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)- 4-(dimethylamino)but-2-en-1-one
4N Hydrochloric acid/1,4-dioxane (4 mL) was added to 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1 - (S)-tert-butyl carboxylate (488 mg) obtained in Reference Example 4 (Step 2), and the resulting mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure. A solution of 4-(dimethylamino)but-2-enoic acid hydrochloride (281 mg) and HATU (647 mg) in DMF (5.0 ml) was added to the resulting residue. Furthermore, DIPEA (0.78 ml) was added thereto, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and chloroform (50 ml) and ethanol (50 ml) were added to the resulting residue. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was washed with ethyl acetate (5.0 ml) and dried to obtain the crude product of the title compound (458 mg). Physical properties: m/z [M+H]+ 442.0
[00387] (Step 2) Synthesis of the Compound of Reference Example 5
[00388] PdCl2(dppf)CH2Cl2 (1.3 mg) was added to a mixture of (S)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-). 1-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one (8.0 mg) obtained in Step 1, 1-ethynyl-3-methoxybenzene (4.0 mg), copper(I) iodide (0.6 mg) and triethylamine (8.6 µL) in THF (1.0 mL). After purging with nitrogen, the resulting mixture was stirred at 80°C overnight. The reaction mixture was diluted with ethyl acetate and methanol. The resulting dilute solution was treated with basic silica gel and then concentrated. The resulting residue was purified by reverse phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (1.4 mg). Table 2 shows its physical properties. Reference Example 6 Synthesis of (S)-N-(3-((4-amino-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1H-pyrazolo[3,4-d ]pyrimidin-3-yl)ethynyl)phenyl)acetamide (Compound of Reference Example 6)
[00389] According to Reference Example 5, except that N-(3-ethynylphenyl)acetamide was used in place of 1-ethynyl-3-methoxybenzene, the title compound was obtained as a colorless, amorphous substance. Table 2 shows its physical properties. Reference Example 7 Synthesis of (S)-1-(3-(4-amino-3-(pyridin-3-ylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4 -(dimethylamino)but-2-en-1-one (Compound of Reference Example 7)
According to Reference Example 5, 5.3-ethynylpyridine was used in place of 1-ethynyl-3-methoxybenzene, the title compound was obtained as a colorless, amorphous substance. Table 2 shows its physical properties.


















Table 2
Test Example 1 Measurement of the Inhibitory Effect on FGFR2 Kinase Activity
[00391] When setting conditions for measuring the inhibitory effect of compounds on FGFR2 kinase activity, the peptide FL 22 (Caliper Life Sciences, Inc.) was used as substrate. The purified recombinant human FGFR2 protein used in the test was purchased from Carna Biosciences, Inc. In measuring the inhibitory effect of the compounds, first, a test compound was gradually diluted with dimethylsulfoxide (DMSO) to a concentration that was 20 times greater than the final concentration. Then purified human FGFR2 protein, FL 22 peptide (final concentration: 1.5 μM), magnesium chloride (final concentration: 5 mM), ATP (final concentration: 75 μM) and the DMSO solution of the test compound (final concentration of DMSO: 5%) were added to the reaction buffer (15 mM Tris-HCl pH 7.5, 0.01% Tween-20, 2 mM DTT), and the mixture was incubated at 25°C for 120 minutes to perform a kinase reaction. EDTA (final concentration: 30 mM) diluted with a separation buffer (Caliper Life Sciences, Inc.) was added thereto to terminate the kinase reaction. Finally, using a LabChip 3000 (trademark) system (Caliper Life Sciences, Inc.; excitation wavelength: 488 nm, detection wavelength: 530 nm), phosphorylated peptides and non-phosphorylated peptides were separated, and the amount of each peptide was measured. The phosphorylation level was determined from the quantitative ratio. The concentration of compound at which phosphorylation was inhibited by 50% was defined as the IC50 value (nM). Table 3 shows the results.
[00392] The results demonstrated that all the compounds of the present invention, represented by the test compounds, which had a dialkoxybenzeneethynyl group and a partial α,β-unsaturated amide structure exhibited a high FGFR2 inhibitory effect. On the other hand, the compounds of Reference Examples, which did not have a dialkoxybenzeneethynyl group or an α,β unsaturated amide partial structure, showed a markedly lesser FGFR2 inhibitory effect. Table 3
Test Example 2 Cell Growth Inhibitory Effect on Human-Derived Gastric Cancer Cell Line with High FGFR Expression
Human-derived OCUM-2MD3 gastric cancer cells, which overexpressed FGFR2, were subcultured daily in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) at a maximum cell density of 80 %. In order to initiate a test of the cell growth inhibitory effect of the compounds, OCUM-2MD3 cells were suspended in the above DMEM medium and seeded in a 96-well flat-bottom plate so that each well contained 3000 cells. Then, cells were cultured in an incubator containing 5% carbon dioxide gas at 37°C for one day. The next day, the test compound was gradually diluted with DMSO to a concentration 100 times greater than the final concentration. The DMSO solution of the test compound was diluted with the medium used for cultivation, and the diluted solution was added to each well of the cell culture plate so that the final DMSO concentration became 0.5%. Then, cells were cultured in an incubator containing 5% carbon dioxide gas at 37°C for 72 hours. Cell number was measured at the time of addition of test compound and 72 hours after cultivation, using a cell counting kit (produced by Dojindo Laboratories), according to a protocol recommended by Dojindo Laboratories. Kit reagent was added to each plate, and a color reaction was performed in an incubator containing 5% carbon dioxide gas at 37°C for a predetermined time. After completion of the reaction, absorbance at a wavelength of 450 nm was measured by a microplate reader. The cell growth inhibition rate was calculated by the formula below and the concentration of test compound at which cell growth was inhibited by 50% (GI50 (nM)) was determined. Table 4 shows the results.
The results demonstrated that all compounds of the present invention, represented by the test compounds, showed a high growth inhibitory effect on the human gastric cancer cell line OCUM-2MD3. Growth inhibition rate (%) = (CT)/(C-C0) X 100 T: absorbance of well to which test compound was added C: absorbance of well to which test compound was not added C0: absorbance of well measured before the addition of the compound Table 4
Test Example 3 Measurement of the Inhibitory Effect on FGFR1 Kinase Activity
[00395] By defining the configuration conditions for measuring the inhibitory effect of compounds on FGFR1 kinase activity, a biotinylated peptide (biotin-EEPLYWSFPAKKK) was synthesized for use as a substrate, using the amino acid sequence of the peptide FL 22 ( Caliper Life Sciences, Inc.) with biotin. The purified recombinant human FGFR1 protein used in the test was purchased from Carna Biosciences, Inc. In measuring the inhibitory effect of the compounds, first, a test compound was gradually diluted with dimethylsulfoxide (DMSO) to a concentration 20 times greater than than the final concentration. Then, the purified human FGFR1 protein, the substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 5 mM), ATP (final concentration: 190 μM) and the DMSO solution of test compound (final concentration of DMSO: 5%) were added to a reaction buffer (15 mM Tris-HCl, pH 7.5, 0.01% Tween-20, 2 mM DTT), and the mixture was incubated at 25°C for 120 minutes to perform a kinase reaction. EDTA was added to this to a final concentration of 40 mM to thereby terminate the reaction. Then, a detection solution containing EU PT66 labeled antiphosphorylated tyrosine antibodies (PerkinElmer) and SureLight APC-SA (PerkinElmer) was added, and the resulting mixture was allowed to stand at room temperature for 2 hours or more. Finally, the fluorescence intensity when excitation light with a wavelength of 337 nm was irradiated was measured by PHERAstar FS (BMG LABTECH) at two wavelengths, 620 nm and 665 nm. The amount of phosphorylation was determined from the fluorescence intensity ratio of the two wavelengths. The concentration of compound at which phosphorylation was inhibited by 50% was defined as the IC50 value (nM). Table 5 below shows the results. Test Example 4 Measurement of the Inhibitory Effect on FGFR3 Kinase Activity
[00396] The inhibitory effect of the compounds on FG-FR3 kinase activity was measured according to the method of Test Example 3. Purified recombinant human FGFR3 protein was purchased from Carna Biosciences, Inc. The final concentration of ATP was 50 µM Table 5 shows the results. Test Example 5 Measurement of the Inhibitory Effect on FGFR4 Kinase Activity
[00397] The inhibitory effect of the compounds on FG-FR4 kinase activity was measured according to the method of Test Example 3. Purified recombinant human FGFR4 protein was purchased from Carna Biosciences, Inc. The final concentration of ATP was 200 µM Table 5 shows the results.
[00398] The results of Test Examples 3 to 5 demonstrated that all compounds of the present invention, represented by the test compound, showed a high inhibitory effect on FGFR1, FGFR3 and FGFR4 and served as pan-FGFR3C inhibitors. Table 5

权利要求:
Claims (13)
[0001]
1. Compound, characterized by the fact that it is represented by Formula (I)
[0002]
2. Compound or salt thereof, according to claim 1, characterized in that in Formula (I), (1) when X2 is N, X1 is N or CH, and (2) when X2 is CH, X1 is CH.
[0003]
3. Compound or salt thereof, according to claim 1, characterized in that in Formula (I), l is 0 or 1.
[0004]
4. Compound or salt thereof, according to claim 1, characterized in that in Formula (I), (1) when Y is a group represented by Formula (A), the group represented by
[0005]
5. Compound or salt thereof, according to claim 1, characterized in that, in Formula (I), (1) when Y is a group represented by Formula (A), Z is -C(R4 )=C(R5)(R6) or C=C-R7, and (2) when Y is a group represented by Formula (B) or (C), Z is C(R4)=C(R5)(R6) .
[0006]
6. Compound or salt thereof, according to claim 1, characterized in that in Formula (I), R1 is methyl or ethyl.
[0007]
7. Compound or salt thereof, according to claim 1, characterized in that, in Formula (I), R2 is C2C6 alkynyl, -C(=O)ORx, C1-C4 hydroxyalkyl or C2-heteroaryl C9, optionally with R3.
[0008]
8. Compound or salt thereof, according to claim 1, characterized in that the compound is selected from the following group of compounds: (1) (S)-1-(3-(4-amino-3) -((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one, (2) (S) -1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2- in-1-one, (3) (S)-1-(3-(4-amino-3-((3,5-diethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one, (4) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3, 4-d]pyrimidin-1-yl)azetidin-1-yl)prop-2-en-1-one, (5) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl) )-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-hydroxybut-2-yn-1-one, (6) 1-(3-(4-amino- 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one , (7) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)- 4-(cyclopropylamino)but-2-en-1 - one, (8) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl )-4-(isopropylamino)but-2-en-1-one, (9) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4 -d]pyrimidin-1-yl)azetidin-1-yl)-4-(ethyl(methyl)amino)but-2-en-1-one, (10) 1-(3-(4-amino-3- ((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(cyclobutylamino)but-2-en-1-one, ( 11) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4- (diethylamino)but-2-en-1-one, (12) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin -1-yl)azetidin-1-yl)-4-(tert-butylamino)but-2-en-1-one, (13) 1-(3-(4-amino-3-((3,5-) dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one, (14) 1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(piperidine -1-yl)but-2-en-1-one, (15) (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-en-1-one, (16) (R)-1 -(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidin-1-yl)-4-(3- fluoropyrrolidin-1-yl)but-2-en-1-one, (17) 1-((2S,4S)-4-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-2-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one, (18) 1-(2S,4S)-4-( 4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-ethynylpyrrolidin-1-yl)prop-2-en-1- one, (19) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin- 1-yl)-4-(dimethylamino)but-2-en-1-one, (20) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one (21) (S)-1-(3-(4-amino-5-) ((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en-1 -one, (22) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin -1-il) -4-(4-hydroxypiperidin-1-yl)but-2-en-1-one, (23) (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl) )-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)but-2-yn-1-one (24) (S)-1-(3-(4-amino- 5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-hydroxy-4-methylpent-2-yn-1- one, (25) 1-((S)-3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin- 1-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-en-1-one, (26) (S)-1-(3-(4-amino-5-( (3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(piperidin-1-yl)but-2-en-1- one, (27) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl) prop-2-en-1-one, (28) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one, (29) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en-1-one, (30) 1-(3- (4-amino-5-((3,5-dimethoxyphenyl) l)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(azetidin-1-yl)but-2-en-1-one, (31) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(ethyl) (methyl)amino)but-2-en-1-one, (32) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)azetidin-1-yl)-4-(isopropylamino)but-2-en-1-one, (33) 1-(3-(4-amino-5-((3,5-) dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(diethylamino)but-2-en-1-one, (34) 1-(3 -(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-((2-methoxyethyl) (methyl)amino)but-2-en-1-one, (35) 1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)azetidin-1-yl)-4-(4-hydroxypiperidin-1-yl)but-2-en-1-one, (36) (S)-1-(3-(4- amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-yl)-4-(3-hydroxypyrrolidin-1-yl)but -2-en-1-one, (37) (R)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine -7-i l)azetidin-1-yl)-4-(3-hydroxypyrrolidin-1-yl)but-2-en-1-one, (38) (2S,4S)-methyl1-acryloyl-4-(4-amino- 5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-2-carboxylate, (39) 1-((2S,4S)-4-( 4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(1,3,4-oxadiazol-2-yl)pyrrolidin -1-yl)prop-2-en-1-one and (40) (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3 ,2-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one.
[0009]
9. FGFR inhibitor, characterized in that it comprises the compound or a salt thereof, as defined in any one of claims 1 to 8, as an active ingredient.
[0010]
10. Pharmaceutical composition, characterized in that it comprises the compound or a salt thereof, as defined in any one of claims 1 to 8, and a pharmacologically acceptable carrier.
[0011]
11. Anti-tumor agent, characterized in that it comprises the compound or a salt thereof, as defined in any one of claims 1 to 8, as an active ingredient.
[0012]
12. Compound or salt thereof, according to any one of claims 1 to 8, characterized in that it is for use in the treatment of a tumor.
[0013]
13. Use of the compound or a salt thereof, as defined in any one of claims 1 to 8, characterized in that it is in the manufacture of an antitumor agent.

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EP2657233A4|2013-12-04|

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CN103958512B|2016-01-20|

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SG2014009286A|2014-04-28|

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EP2657233A1|2013-10-30|

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HK1198164A1|2015-03-13|

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PT2657233E|2014-10-24|

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BR112014017749A2|2017-06-20|

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DK2657233T3|2014-09-22|

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JPWO2013108809A1|2015-05-11|

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TWI508964B|2015-11-21|

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KR101623286B1|2016-05-20|

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MX2014008605A|2014-08-27|

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MX351513B|2017-10-17|

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EP2657233B1|2014-08-27|

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CN103958512A|2014-07-30|

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AU2013210403B2|2016-01-14|

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JP5355825B1|2013-11-27|

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TW201335156A|2013-09-01|

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CA2854093A1|2013-07-25|

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MY171055A|2019-09-23|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2021-06-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-08-03| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/01/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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JP2012-009467|2012-01-19|

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