FUSIONED PYRIMIDIN COMPOUND OR THIS SALT, PROBE, BTK INHIBITOR, ANTITUMENT AGENT AND PHARMACEUTICAL

专利摘要:
fused pyrimidine compound or salt thereof the present invention relates to a new compound containing btk inhibitory action and a suppressive effect of cell proliferation. there is also provided a drug useful for the prevention and / or treatment of disease associated with btk, particularly cancer, based on the inhibitory action btk. a compound represented by formula (i) is described in which r1 to r3, w, a, y and z have the same meanings as defined in the specification, or a salt thereof.
公开号:BR112016002069B1
申请号:R112016002069-3
申请日:2014-08-11
公开日:2020-08-18
发明作者:Satoru Iguchi；Fumihito HOSOI；Takeshi Sagara
申请人:Taiho Pharmaceutical Co., Ltd；
IPC主号:

专利说明:

Technical field
[001] The present invention relates to a new fused pyrimidine compound or a salt thereof, which has Bruton's tyrosine kinase (BTK) inhibitory action and a pharmaceutical composition containing it. TECHNICAL STATUS
[002] It is known that several protein kinases exist in vivo and are involved in the regulation of a variety of functions. Bruton tyrosine kinase (BTK) is a protein kinase that is related to Tec kinases, and is a non-receptor tyrosine kinase that plays an important role related to the control of, for example, proliferation, survival, differentiation and activation of B cells downstream of the B Cell Receptor (BCR) signal (non-patent document 1). An inhibitor capable of controlling BTK activity is considered to be useful as a therapeutic agent for diseases associated with abnormal hyperactivity of the BTK signaling pathway (eg, cancer).
[003] Regarding the compound showing BTK inhibitory activity, PCI-32765 (non-patent document 2) and the compounds described in patent documents 1 and 2 are known.
[004] The compounds described in patent documents 1 and 2 are also known to exhibit high inhibitory activity for EGFR (Epidermal growth factor Receptor / Epidermal growth factor receptor 3) for example, in addition to BTK. However, since such a multi-kinase inhibitor suppresses, for example, cell proliferation by inhibiting various signaling pathways, there is concern about a variety of side effects. For example, it is known that EGFR binds to its ligand, for example, epidermal growth factor (EGF), and participates in the proliferation and survival (eg, inhibition of apoptosis) of various cells (non-patent document 3) . However, it is known that inhibitors that target EGFR cause side effects such as skin disorders and gastrointestinal dysfunction in common, and it is assumed that these side effects may be related to the inhibition of the wild type EGFR signaling pathway (non-patent document 4) .
[005] Thus, PCI-45292 is known as a compound that has an inhibitory activity against BTK with a weak inhibitory activity against EGFR (Non-patent document 5).
[006] As described above, from the point of view of reducing side effects, a highly selective BTK inhibitor is desired which has a high inhibitory activity against BTK with low inhibitory activities against other kinases such as EGFR. Citation list Patent document Patent document 1: WO 2011/090760 Patent document 2: WO 2009/158571 Non-patent document Non-patent document 1: Schaeffer and Schwartzberg, Curr. Op. Imm., 2000, 282-288 Non-patent document 2: Proc. Natl. Acad. Know. USA., 2010 Jul 20; 107 (29): 13075-80 Non-patent document 3: Nature Rev. Cancer, Vol. 6, pp. 803-811 (2006) Non-patent document 4: Nature Rev. Clin. Oncol., Vol. 6, pp. 98-109 (2012) Non-patent document 5: American College of Rheumatology Annual Meeting, Atlanta, GA, 6-11 November, 2010) Brief description of invention Technical problem
[007] An object of the present invention is to provide a new compound that strongly inhibits BTK selectively by EGFR, or a salt thereof, and a pharmaceutical composition including this compound. Solution of the problem
[008] The inventors of the present invention have carried out intensive investigations in order to solve the problems described above and consequently the inventors have found that a group of compounds represented by the following formula (I) exhibit excellent inhibitory activity against BTK and excellent kinase selectivity and are useful as medicines for the treatment of diseases involving BTK, such as cancer. Thus, the inventors have completed the present invention. That is, the object of the present invention is to provide a compound represented by the following general formula (I), or a salt thereof:

[009] where A represents - (CH2) n-X-, - (θH2) m-NH-, or - (C3-C7 cycloalkylene) -NH-; n represents an integer from 0 to 2; m represents an integer from 1 to 4; X represents C3-C10 nitrogen-containing heterocycloalkylene which may have one or more substituents; Y represents -C (R4) = C (R5) (Re) or -OC-R7; W and Z each independently represents N or CH;
[0010] Ri represents an amino group that can have one or more substituents;
[0011] R2 and R3, which can be the same or different, each represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group that can have one or more substituents, a C1-C6-alkoxy group that can have one or more substituents, C3-C7-cycloalkyl group which may have one or more substituents, a C6-C14 aromatic hydrocarbon group which may have one or more substituents, a polycyclic or monocyclic unsaturated heterocyclic group with 4 to 10 members containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents, or a cyano group; and
[0012] R4, Rs, Re and R7, which can be the same or different, each represents a hydrogen atom, or a C1-C6-alkyl group that can have one or more substituents.
[0013] Furthermore, the object of the present invention is to provide a probe compound containing a compound represented by the general formula above (I) or a salt thereof, a detectable marker or affinity mark, and a linker, in which the linker binds the compound to the lip or the mark.
[0014] Furthermore, it is the object of the present invention to provide a BTK Inhibitor containing a compound represented by the general formula above (I) or a salt thereof as an active ingredient.
[0015] It is also an object of the present invention to provide a pharmaceutical composition containing a compound represented by the above general formula (I) or a salt thereof.
[0016] Furthermore, it is the object of the present invention to provide an anti-tumor agent containing a compound represented by the general formula above (I) or a salt thereof as an active ingredient.
[0017] Furthermore, it is the object of the present invention to provide a compound represented by the above general formula (I) or a salt thereof, designed for tumor therapy.
[0018] It is also an object of the present invention to provide the use of a compound represented by the above formula (I) or a salt thereof, for the production of an anti-tumor agent.
[0019] In addition, it is the object of the present invention to provide a tumor treatment method, the method including the administration of a compound represented by the above general formula (I) or a salt thereof.
[0020] As a compound related to the present invention, PCI-32765 which is a clinical stage, is known as a BTK Inhibitor. PCI-32765 has a phenoxyphenyl group; however, this compound is significantly different from the compound of the present invention in that it does not have a benzoxazole group or an oxazolopyridine group, which represents a characteristic of the compound of the present invention. In addition, the compound of the present invention is defined as having a higher BTK selectivity compared to PCI-32765 (reference compound 1), as described later.
[0021] Furthermore, the compounds described in patent documents 1 and 2 also do not have a benzoxazole group or an oxazolopyridine group, which is a characteristic of the compound of the present invention, and their structures are significantly different.
[0022] Furthermore, the compound described in patent document WO 2007/067781 is known as a compound that has the structure referring to the compound of the present invention. However, the compound described here is a compound that inhibits aurora kinases, and there is no description of the presence or absence of the BTK inhibitory action. There is also no description of specific compounds containing a benzoxazole group or an oxazolopyridine group. ADVANTAGE EFFECTS OF THE INVENTION
[0023] According to the present invention, a new compound represented by the above formula (I) or a salt thereof, which is useful as a BTK Inhibitor, is provided.
[0024] It has been found that the compound of the present invention or a salt thereof has an excolent selective BTK inhibitory action and exhibits a proliferation-suppressing effect on cancer cell lines. Furthermore, since the compound of the present invention or a salt thereof strongly inhibits BTK selectively through EGFR, adverse side effects can be reduced, and an increase in safety can be expected.
[0025] The compound of the present invention or a salt thereof has an advantage that the compound or salt not only exhibits excellent metabolic stability compared to the conventional BTK inhibitor, but good exposure to plasma can be expected, and a Cyp inhibitory risk.
[0026] The compound of the present invention or a salt thereof is useful as a prophetic and / or therapeutic agent of cancer.
[0027] The compound of the present invention or a salt thereof can suppress bone metastases of cancer or tumors. BRIEF DESCRIPTION OF THE DRAWING
[0028] Figure 1 shows the results of detection by BTK labeling using fluorescent marker compound. DESCRIPTION OF ACHIEVEMENT
[0029] The compound represented by the formula (I) described above of the present invention is a compound with a 1H-pyrazolo [3,4-d] pyrimidine backbone or a 7H-pyrrolo [2,3-d] pyrimidine backbone, which is substituted with a benzoxazole group or an oxazolopyridine group as one or more substituents attached via an amide bond and the compound is a new compound that has never been described in any of the above state of the art quotations.
[0030] According to the present specification, examples of the "substituent (s)" include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a halogeno-alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, an alkenyl group, an alkoxy group, an alkoxy group, a halo-alkoxy group, a cycloalkoxy group, a cycloalkyl-alkoxy group, an aralkyloxy group, an alkylthio group, an cycloalkyl-alkylthio group, an amino group, a mono- or dialkylamino group, a cycloalkyl-alkylamino group, an acyl group, an acyloxy group, an oxo group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a saturated or unsaturated heterocyclic group, an aromatic hydrocarbon group, and a saturated heterocyclic oxy group. When the aforementioned substituents are present, the number of the substituents will typically be 1, 2 or 3.
[0031] Examples of the "halogen atom" according to the present specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The "alkyl group" according to the present specification can be any linear group or a branched group, and examples of these include C1-C6-alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, and a hexyl group.
[0033] The "halogeno-alkyl group" according to the present specification is a linear or branched alkyl group with 1 to 6 carbon atoms and 1 to 13 halogen atoms (Halogen-C1-C6-alkyl group), and examples of these include halogen-C1-C6-alkyl groups such as a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a fluoroethyl group, a 1,1,1-trifluoroethyl group, a monofluoro-n-propyl group, a perfluoro-n-propyl group, and a perfluoroisopropyl group, while preferred examples include halogen-C1-C4-alkyl groups.
[0034] Specific examples of the "cycloalkyl group" according to the present specification include C3-C7-cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The "cycloalkylene" according to the present specification represents a divalent cycloalkyl.
[0035] Examples of the "cycloalkyl-alkyl group" according to the present specification include C1-C4-C3-C7 cycloalkyl-substituted groups such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and cycloheptylmethyl.
[0036] Examples of the "aralkyl group" according to the present specification include C7-C13-aralkyl groups such as a benzyl group, a phenotyl group, a naphthylmethyl group, and a fluorenylmethyl group.
[0037] The "alkenyl group" according to the present specification means an unsaturated hydrocarbon group which can be any of a linear group, a branched group or a cyclic group and has at least one double bond. Examples of these include C2-C6-alkenyl groups such as a vinyl group, an allyl group, a 1-propenyl group, a 2-methyl-2-propenyl group, an isopropenyl group, a 1-, 2- or 3-butenyl group , a 2-, 3- or 4-pentenyl group, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 5-hexenyl group, a 1- cyclopentenyl group, a 1-cyclohexenyl group , and a 3-methyl-3-butenyl group.
The "alkynyl group" according to the present specification means an unsaturated hydrocarbon group which can be any linear group, a branched group or a cyclic group, and has at least one triple bond. Examples of these include C2-C6-alkynyl groups such as an ethynyl group, a 1- or 2-propynyl group, a 1-, 2- or 3-butynyl group, and a 1-methyl-2-propynyl group.
The "alkoxy group" according to the present specification can be any linear group or a branched group, and examples of these include C1-C6 alkoxy groups such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group , a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group.
[0040] The "halo-alkoxy group" according to the present specification is a linear or branched alkoxy group having 1 to 6 carbon atoms and 1 to 13 halogen atoms (halogen-C1-C6-alkoxy group), and examples these include halo-C1-C6 alkoxy groups such as a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a fluoroethoxy group, a 1,1,1-trifluoroethoxy group, a monofluoro-n-propoxy group, a perfluoro-n-propoxy group, and a perfluoro-isopropoxy group, while preferred examples include halogen-C1-C4-alkoxy groups.
[0041] Specific examples of the "cycloalkoxy group" according to the present specification include C3-C7-cycloalkoxy groups such as a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group and a cycloheptyloxy group.
[0042] Examples of the "cycloalkyl-alkoxy group" according to the present specification include C1-C4-C3-C7 cycloalkyl-substituted groups such as a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group and a group cycloheptylmethoxy.
[0043] Examples of the "aralkyloxy group" according to the present specification include C7-C13 aralkyloxy groups such as a benzyloxy group, a phenothyloxy group, a naphthylmethyloxy group and a fluorenylmethyloxy group.
The "alkylthio group" according to the present specification can be any linear group or a branched group, and examples of these include C1-C6 alkylthio groups such as a methylthio group, an ethylthio group, an n-propylthio group, a isopropylthio group, an n-butylthio group, an isobutylthio group, a tert-butylthio group, an n-pentylthio group, an isopentylthio group, and a hexylthio group.
Examples of the "cycloalkylalkylthio group" according to the present specification include C1-C4 alkylthio C3-C7 cycloalkyl-substituted groups such as a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, and a group cycloheptylmethylthio.
[0046] Examples of the "monoalkylamino group" according to the present specification include amino groups that linear or branched C1-C6-alkyl groups, such as a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, a tert-butylamino group, an n-pentylamino group, an isopentylamino group, and a hexylamino group.
[0047] Examples of the "dialkylamino group" according to the present specification include amino groups which are disubstituted with ouramified linear C1-C6-alkyl groups, such as a dimethylamino group, a diethylamino group, a di (n-propyl) amino group , a diisopropylamino group, a di (n-butyl) amino group, an isobutylamino group, a di (tert-butyl) amino group, a di (n-pentyl) amino group, a diisopentylamino group, and a dihexylamino group.
[0048] Examples of the "cycloalkyl-alkylamino group" according to the present specification include C1-C4 alkylamino C3-C7 cycloalkyl-substituted groups such as a cyclopropylmethylamino group, a cyclobutylmethylamino group, a cyclopentylmethylamino group, a cyclohexylmethylamino group and a cyclohexylmethylamino group lamino.
The "acyl group" according to the present specification means an alkylcarbonyl group or an arylcarbonyl group.
[0050] Examples of the "alkylcarbonyl group" according to the present specification include straight or branched (C1-C6 alkylcarbonyl) groups such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, n-pentyl isopentylcarbonyl and hexylcarbonyl.
[0051] Examples of the "arylcarbonyl group" according to the present specification include (C6-C14 arylcarbonyl groups such as phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylcarbonyl, tetrahydronaphylcarbonyl, cromanylcarbonyl, 2,3-dihydro-hydroxy indanylcarbonyl, and phenantrylcarbonyl.
The "acyloxy group" according to the present specification means an alkylcarbonyloxy group or an arylcarbonyloxy group.
[0053] Examples of the "alkylcarbonyloxy group" according to the present specification include straight or branched (C1-C6 alkylcarbonyloxy) groups such as methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonylcarbonyloxycarbonylcarbonylcarbonyloxycarbonylcarbonylcarbonyl , isopentylcarbonyloxy and hexylcarbonyloxy.
[0054] Examples of the "arylcarbonyloxy group" according to the present specification include (C6-C14 aryl) carbonyloxy groups such as phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylcarbonyloxy, tetrahydroxyoxycarbonyl, 4-hydrocarbonyl, 4-carbonyl dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenantrylcarbonyloxy.
[0055] The "alkoxycarbonyl group" according to the present specification can be any linear group or a branched group, and examples of these include (C1-C6 alkoxy) carbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, and a hexyloxycarbonyl group.
[0056] Examples of the "aralkyloxycarbonyl group" according to the present specification include (C7-C13 aralkyl) oxycarbonyl groups such as a benzyloxycarbonyl group, a phenothyloxycarbonyl group, a naphthylmethyloxycarbonyl group, and a fluorenylmethyloxycarbonyl group.
[0057JO "saturated heterocyclic group" according to the present specification can be a heterocyclic group saturated with heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specific examples of these include a morpholino group, a group 1 - pyrrolidinyl, a piperidine group, a piperazinyl group, a 4-methyl-1-piperazinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, and a thiazolidinyl group, and an oxazolidinyl group.
[0058] The "unsaturated heterocyclic group" according to the present specification is a monocyclic or polycyclic, totally or partially unsaturated heterocyclic group with heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specific examples of these include an imidazolyl group, a thienyl group, a furyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, pyridyl group, a pyrazyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group, a triazolopyridyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzoturyl group , a purinyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalyl group, a methylenedioxyphenyl group, an ethyl group nodioxiphenyl, and a dihydrobenzofuranyl group.
[0059] Examples of the "aromatic hydrocarbon group" according to the present specification include aromatic C6-C14 hydrocarbon groups such as a phenyl group, a toluyl group, a xylyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a fluorenyl group, and a tetrahydronaphthyl group.
[0060] The "saturated oxy heterocyclic group" according to the present specification is an oxy heterocyclic group saturated with heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specific examples of these include a morpholinyloxy group, a 1-pyrrolidinyloxy group, a piperidinoxy group, a piperazinyloxy group, a 4-methyl-1-piperazinyloxy group, a tetrahydrofuranoyloxy group, a tetrahydropyranyloxy group, a tetrahydrothiophenyloxy group and a thiazolidinoxyoxy group and a thiazolidinoxyoxy group.
[0061] However, the expression "CA-CB" in the description about one or more substituents in this description indicates that the substituent is one or more substituents whose number of carbons is A to B. For example, "C1-C6-alkyl group "indicates an alkyl group with 1 to 6 carbon atoms, and group," C6-C14 aromatic oxy hydrocarbon group "indicates an oxy group to which an aromatic hydrocarbon group with 6 to 14 carbon atoms is attached. Also, the expression "from A- members to B-members" indicates that the number of atoms that make up a ring (number of ring members) is A to B. For example, "4 to 10 membered saturated heterocyclic group" means a saturated heterocyclic group whose number of ring members is 4 to 10.
[0062] In the general formula (I), A represents - (CH2) n-X-, - (CH2) m-NH-, or - (C3-C7 cycloalkylene) -NH-.
[0063] n represents an integer from 0 to 2, but n is more preferably 0. Furthermore, m represents an integer from 1 to 4, but m is more preferably 2 or 3, and even more preferably 2. Examples of C3-C7 cycloalkylene include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, while cyclohexylene is more preferred.
[0064] X represents C3-C10 heterocycloalkylene containing nitrogen that may have one or more substituents; however, more specifically, X represents a divalent heterocycloalkyl with 3 to 10 carbon atoms, which can have one or more substituents, contains at least one nitrogen atom in the ring, and contains 0 to 2 hetero atoms of the same type or different types selected from an oxygen atom and a sulfur atom (C3-C10 heterocycloalkylene containing nitrogen). More specific examples of these include azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, morpholinylene, octahidroquinolinylene and octahidroindolileno.
[0065] Preferably, X represents a heterocycloalkylene having 3 to 5 carbon atoms, which may have one or more substituents and contains a nitrogen atom in the ring (C3-C5 heterocycloalkylene containing nitrogen), and X is more preferably azetidinylene, pyrrolidinylene, or piperidinylene, and even more preferably 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperidinylene.
[0066] With respect to the substituents on these heterocycloalkylenes, examples of these include substituents such as those described above; however, it is preferred that the heterocycloalkylenes are unsubstituted.
[0067] It is preferred that the nitrogen atom of C3-C10 heterocycloalkylene containing nitrogen group represented by X is attached to the carbonyl group of -COY in the general formula (I). In addition, it is preferred that the nitrogen atom of a nitrogen-containing C3-C5 heterocycloalkylene group represented by X is attached to the carbonyl group of -COY in the general formula (I). A is most preferably - (CH2) n-X-, In the general formula (I), Y represents -C (R4) = C (R5) (Re) or -OC-R7
[0068] In the general formula (I), W and Z each independently represents N or CH. Preferably, when Z is N, W is N, or when Z is CH, W is N or CH.
[0069] In the general formula (I), with respect to the "substituent (s)" for the "amino group which may have one or more substituents" represented by Ri, examples of these include substituents such as those described above; however, it is preferred that the amino group is unsubstituted.
[0070] The "amino group which may have one or more substituents" represented by Ri is preferably an amino group.
[0071] In the general formula (I), the "halogen atom" represented by R2 or R3 is preferably a fluorine atom, a chlorine atom, or a bromine atom.
[0072] In the general formula (I), the "C1-C6-alkyl group" for the "C1-C6-alkyl group which may have one or more substituents" represented by R2 or R3 is preferably a C1-C4-alkyl group , and the C1-C6-alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or ter-butyl group, and even more preferably a methyl group or an ethyl group.
[0073] With respect to the "substituent (s)" for the "C1-C6-alkyl group which may have one or more substituents" represented by R2 or R3, it is preferred that the C1-C6-alkyl group is unsubstituted, or has one or more substituents such as a halogen atom or a C1-C4-alkoxy group. It is more preferred that the C1-C6-alkyl group is unsubstituted, or has one or more substituents such as a fluorine atom or a methoxy group. In the case where the alkyl group has one or more substituents the number of substituents is not particularly limited; however, when the substituent is a halogen atom, the number of substituents is preferably 1 to 3, while when one or more substituents is a C1-C4 alkoxy group, the number of substituents is preferably 1.
[0074] The "C1-C6-alkyl group which may have one or more substituents" represented by R2 or R3 is preferably a C1-C6-alkyl group, a halogen-C1-C6-alkyl group, or a C1-C6 group -C1-C4 alkoxy-substituted alkyl; more preferably a C1-C4 alkyl group, a halogen-C1-4 alkyl group, or an alkoxy-substituted C1-C4-C4-alkyl group; even more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a ter-butyl group, a trifluoromethyl group, a trichloromethyl group, a methoxyethyl group, or an ethoxyethyl group; and more preferably a methyl group, a trifluoromethyl group, or a methoxyethyl group.
[0075] In the general formula (I), the "C1-C6 alkoxy group" for the "C1-C6 alkoxy group which may have one or more substituents" represented by R2 or R3 is preferably a "C1-C4 alkoxy group", and the "C1-C6 alkoxy group" is more preferably a methoxy group, an ethoxy group, an isopropoxy group, or an n-butoxy group, and even more preferably a methoxy group.
[0076] With respect to the "substituent (s)" for the "C1-C6 alkoxy group which may have one or more substituents" represented by R2 or R3, examples of these include substituents such as those described above; however, it is preferred that the C1-C6 alkoxy group is unsubstituted.
[0077] The "C1-C6 alkoxy group which may have one or more substituents" represented by R2 or R3 is preferably C1-C6-alkoxy group; more preferably a C1 to 04 alkoxy group; even more preferably a methoxy group, an ethoxy group, an isopropoxy group, or an n-butoxy group; and most preferably a methoxy group.
[0078] In the general formula (I), the "C3-C7 cycloalkyl group" for the "C3-C7 cycloalkyl group which may have one or more substituents" represented by R2 or R3 is preferably a C3-C6 cycloalkyl group, and more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
[0079] With respect to the "substituent (s)" for "C3-C7 cycloalkyl group which may have one or more substituents" represented by R2 or Ra, examples of these include substituents such as those described above; however, it is preferred that the C3-C7 cycloalkyl group is unsubstituted.
[0080] The "C3-C7 cycloalkyl group which may have one or more substituents" represented by R2 or R3 is preferably a C3-C6 cycloalkyl group, and more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a group cyclohexyl.
[0081] In the general formula (I), the "C6-C14 aromatic hydrocarbon group" for the "C6-C14 aromatic hydrocarbon group which may have one or more substituents" represented by R2 or R3 is preferably a phenyl group or a naphthyl group and most preferably a phenyl group.
[0082] With respect to the "substituent (s)" for the "C6-C14 aromatic hydrocarbon group which may have one or more substituents" represented by R2 or R3, it is preferred that the C6-C14 aromatic hydrocarbon group is unsubstituted, or present a halogen atom. It is more preferred that the C6-C14 aromatic hydrocarbon group is unsubstituted, or has a chlorine atom or a fluorine atom. When the C6-C14 aromatic hydrocarbon group has one or more substituents, the number of substituents is not particularly limited; however, the number of substituents is preferably 1 to 3.
[0083] The "C6-C14 aromatic hydrocarbon group which may have one or more substituents" represented by R2 or R3 is preferably a phenyl group or a naphthyl group, which is unsubstituted or may have one or more substituents with a halogen atom , and is most preferably a phenyl group, a chlorophenyl group, a fluorophenyl group, a dichlorophenyl group, or a trichlorophenyl group; even more preferably a phenyl group or a chlorophenyl group; and particularly preferably a phenyl group or a 4-chlorophenyl group.
[0084] In the general formula (I), the "monocyclic or polycyclic, heterocyclic group of 4 to 10 members unsaturated containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a carbon atom sulfur "to the" monocyclic or polycyclic, 4- to 10-membered unsaturated heterocyclic group containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents "represented by R2 or R3 is preferably a 4- to 6-membered monocyclic heterocyclic group containing a nitrogen atom, oxygen atom or sulfur atom; more preferably a 4- to 6-membered unsaturated monocyclic heterocyclic group containing a sulfur atom; even more preferably a thienyl group; and more preferably a 2-thienyl group.
[0085] With respect to the "substituent (s)" for the "4 to 10-membered heterocyclic, monocyclic or polycyclic group containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents "represented by R2 or R3, examples of which include substituents such as those described above; however, it is preferred that the unsaturated heterocyclic group is unsubstituted.
[0086] 0 "4 to 10 membered unsaturated heterocyclic, monocyclic or polycyclic group containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents "represented by R2 or Ra is preferably a 4- to 6-membered unsaturated monocyclic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom; more preferably a 4- to 6-membered unsaturated monocyclic heterocyclic group containing a sulfur atom; even more preferably a thienyl group; and even more preferably a 2-thienyl group.
[0087] In the general formula (I), the "C1-C6-alkyl group" for the "C1-C6-alkyl group which may have one or more substituents" represented by R4, Rs or Rs is preferably a C1-C4 group alkyl; more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a ter-butyl group; and even more preferably a methyl group.
[0088] With respect to the "substituent (s)" for the "C1-C6-alkyl group which may have one or more substituents" represented by R4, Rs or Rs, it is preferred that the C1-C6-alkyl Group is non- substituted, or has a substituted amino group with two C1-C4 alkyl groups (the C1-C4 alkyl group can also form a heterocycloalkyl group with a 4- to 8-membered ring, along with the nitrogen atom to which these alkyl groups are attached ). It is more preferred that the C1-C6-alkyl group is unsubstituted, or has a dimethylamino group, a methyl ethylamino group, a diethylamino group, a methylisopropylamino group, a 1-piperidinyl group or a 1-pyrrolidinyl group. When the "C1-C6-alkyl group which may have one or more substituents" has one or more substituents, the number of substituents is not particularly limited; however, the number of substituents is preferably 1.
[0089] The "C1-C6-alkyl group which may have one or more substituents" represented by R4, Rs or Re is preferably a C1-C4 alkyl group, or a C1-C4 alkyl group which is substituted with a substituted amino group with two C1-C4 alkyl groups (C1-C4 alkyl groups can form a heterocycloalkyl group with a 4- to 8-membered ring, along with the nitrogen atom to which these alkyl groups are attached). Further preferred examples of these include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a dimethylaminoethyl group, a diethylaminoethyl group, a 1-piperidinylmethyl group, and a 1-pyrrolidinylmethyl group.
[0090] In the general formula (I), the "C1-C6-alkyl group" for the "C1-C6-alkyl group which may have one or more substituents" represented by R7 is preferably a C1-C4 alkyl group; more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group; and even more preferably a methyl group.
[0091] With respect to the "substituent (s)" for the "C1-C6-alkyl group which may have one or more substituents" represented by R7, examples of these include substituents such as those described above; however, it is preferred that the C1-C6-alkyl group is unsubstituted.
[0092] The "C1-C6-alkyl group which may have one or more substituents" represented by R7 is preferably a C1-C4 alkyl group; more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group; and even more preferably a methyl group.
[0093] In the general formula (I), -C (R4) = C (R5) (R6) or -OC-R7 represented by Y is particularly preferably any one selected from:

[0094] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is preferred, in which: A represents - (CH2) n-X-; n represents 0; X represents C3-C10 nitrogen-containing heterocycloalkylene; Y represents -C (R4) = C (R5) (Ro) or -OC-R7; W and Z each independently represents N or CH; R1 represents an amino group;
[0095] R2 and R3, which may be the same or different, each represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group that may have one or more substituents, a C1-C6-alkoxy group that may have one or more substituents, C3-C7-cycloalkyl group which may have one or more substituents, a C6-C14 aromatic hydrocarbon group which may have one or more substituents, a 4- to 10-membered unsaturated heterocyclic monocyclic or polycyclic group to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents, or a cyano group; and
[0096] R4, Rs, Re and R7, which can be the same or different, each represents a hydrogen atom, or a C1-C6-alkyl group that can have one or more substituents.
In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[0098] X represents C3-C10 heterocycloalkylene containing nitrogen (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (D); Y represents -C (R4) = C (R5) (R6) or -OC-R7; W and Z each independently represent N or CH; Ri represents an amino group;
[0099] R2 and Ra, which can be the same or different, each represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group that can have one or more substituents, a C1-C6-alkoxy group that can have one or more substituents, C3-C7-cycloalkyl group which may have one or more substituents, a C6-C14 aromatic hydrocarbon group which may have one or more substituents, a 4 to 10 membered unsaturated heterocyclic, polycyclic or polycyclic group containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents, or a cyano group; and
[00100] R4, RS, Re and R7, which can be the same or different, each represents a hydrogen atom or a C1-C6-alkyl group that can have one or more substituents.
[00101] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0; X represents azetidinylene, pyrrolidinylene or piperidinylene; Y represents -C (R4) = C (R5) (R6) or -OC-R7; W and Z each independently represents N or CH; R1 represents an amino group;
[00102] R2 and R3, which can be the same or different, each represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group that can have one or more substituents, a C1-C6-alkoxy group that can have one or more substituents, C3-C7-cycloalkyl group which may have one or more substituents, a C6-C14 aromatic hydrocarbon group which may have one or more substituents, a 4 to 10 membered unsaturated heterocyclic, polycyclic or polycyclic group containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents, or a cyano group; and
[00103] R4, RS, Re and Rz, which can be the same or different, each represents a hydrogen atom or a C1-C6-alkyl group that can have one or more substituents.
[00104] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[00105] X represents azetidinylene, pyrrolidinylene or piperdinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)); Y represents -C (R4) = C (Rs) (R6) or -OC-Rz; W and Z each independently represents N or CH; R1 represents an amino group;
[00106] R2 and R3, which can be the same or different, each represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group that can have one or more substituents, a C1-C6-alkoxy group that can have one or more substituents, C3-C7-cycloalkyl group which may have one or more substituents, a C6-C14 aromatic hydrocarbon group which may have one or more substituents, an unsaturated polycyclic or monocyclic heterocyclic group with 4 to 10 members containing 1 to 3 heteroatoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more substituents, or a cyano group; and
[00107] R4, RS, Re and R7, which can be the same or different, each represents a hydrogen atom or a C1-C6-alkyl group that can have one or more substituents.
[00108] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, in which: A represents - (CH2) n-X-; n represents 0; X represents azetidinylene, pyrrolidinylene or piperdinylene; Y represents -C (R4) = C (R5) (R6) or -OC-R7; W and Z each independently represents N or CH; R1 represents an amino group;
[00109] Either of R2 and R3 represents a hydrogen atom or a C1-C6-alkyl group, while the other represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group, a halogen-C1 group -C6-alkyl, a C1-C6-C1-C4 alkoxy-substituted group, C1-C6-alkoxy group, a phenyl group that can have one or more substituents with a halogen atom, a monocyclic heterocyclic group from 4 to 6 unsaturated members containing a sulfur atom, or a cyano group; and when Y represents -C (R4) = C (R5) (R6),
[00110] R4, RS and Re, which can be the same or different, each represents a hydrogen atom, a C1-C6-alkyl group, or a C1-C6-alkyl group that is substituted with an amino group substituted with two C1-C6-alkyl groups (C1-C6-alkyl groups can form a heterocycloalkyl group with a 4- to 8-membered ring, along with the nitrogen atom to which these alkyl groups are attached); when Y represents -C = C-R , R7 represents a hydrogen atom or a C1-C6-alkyl group.
[00111] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[00112] X represents azetidinylene, pyrrolidinylene or piperdinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (D); Y represents -C (R4) = C (R5) (Re) or - OC-R7; W and Z each independently represent N or CH; R1 represents an amino group;
[00113] Either of R2 and R3 represents a hydrogen atom or a C1-C6-alkyl group, while the other represents a hydrogen atom, a halogen atom, a C1-C6-alkyl group, a halogen-C1 group -C6-alkyl, a C1-C6-C1-C4 alkoxy-substituted group, C1-C6-alkoxy group, a phenyl group that may have one or more substituents with a halogen atom, a monocyclic heterocyclic group from 4 to 6 unsaturated members containing a sulfur atom, or a cyano group; and when Y represents -C (R4) = C (R5) (R6),
[00114] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a C1-C6-alkyl group, or a C1-C6-alkyl group that is replaced with an amino group substituted with two C1-C6-alkyl groups (C1-C6-alkyl groups can form a heterocycloalkyl group with a 4- to 8-membered ring, along with the nitrogen atom to which these alkyl groups are attached); when Y represents -C = C-R , R7 represents a hydrogen atom or a C1-C6-alkyl group.
[00115] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, in which: A represents - (CH2) n-X-; n represents 0; X represents 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperdinylene; Y represents -C (R4) = C (R5) (Re) or -OC-R7;
[00116] when Z represents N, W represents N, but when Z represents CH, W represents N or CH; R1 represents an amino group;
[00117] either of R2 and R3 represents a hydrogen atom or a C1-C4 alkyl group, while the other represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 halogeno group alkyl, a C1-C4-alkoxy-substituted C1-C4-alkyl group, a C1-C4 alkoxy group, a phenyl group that may have one or more substituents with a halogen atom, a 4- to 6-membered monocyclic heterocyclic group containing a sulfur atom, or a cyano group; and when Y represents -C (R4) = C (R5) (R6),
[00118] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a C1-C6-alkyl group, or a C1-C6-alkyl group that is substituted with an amino group substituted with two C1-C6-alkyl groups (C1-C6-alkyl groups can form a heterocycloalkyl group with a 4- to 8-membered ring, along with the nitrogen atom to which these alkyl groups are attached); when Y represents -C = C-R , R7 represents a hydrogen atom or a C1-C4 alkyl group.
[00119] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[00120] X represents 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperdinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)); Y represents -C (R4) = C (R5) (Re) or -OC-Rz;
[00121] when Z represents N, W represents N, but when Z represents CH, W represents N or CH; Ri represents an amino group;
[00122] either of R2 and R3 represents a hydrogen atom or a C1-C4 alkyl group, while the other represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 halogeno group alkyl, a C1-C4-alkoxy-substituted C1-C4-alkyl group, a C1-C4 alkoxy group, a phenyl group that may have one or more substituents with a halogen atom, a 4- to 6-membered monocyclic heterocyclic group containing a sulfur atom, or a cyano group; and when Y represents -C (R4) = C (R5) (R6),
[00123] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a C1-C6-alkyl group, or a C1-C6-alkyl group that is substituted with an amino group substituted with two C1-C6-alkyl groups (C1-C6-alkyl groups can form a heterocycloalkyl group with a 4- to 8-membered ring, along with the nitrogen atom to which these alkyl groups are attached); when Y represents -C = C-Rz, R7 represents a hydrogen atom or a C1-C4 alkyl group.
[00124] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, in which: A represents - (CH2) n-X-; n represents 0; X represents 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperdinylene; Y represents -C (R4) = C (R5) (Re) or -OC-R7;
[00125] when Z represents N, W represents N, but when Z represents CH, W represents N or CH; Ri represents an amino group;
[00126] any one of R2 and R3 represents a hydrogen atom or a methyl group, while the other represents a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxy group, a methoxy group, a phenyl group, a 4-chlorophenyl group, a 2-thienyl group, or a cyano group; and when Y represents -C (R4) = C (R5) (R6),
[00127] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a methyl group, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group, or a 1-pyrrolidinylmethyl group; when Y represents -C = C-R7, R7 represents a methyl group.
[00128] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[00129] X represents 1,3-azetidinylene, 1,3-pyrrolidinylene, or 1,3-piperdinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)); Y represents -C (R4) = C (R5) (Re) or -OC-R7;
[00130] when Z represents N, W represents N, but when Z represents CH, W represents N or CH; R1 represents an amino group;
[00131] either of R2 and R3 represents a hydrogen atom or a methyl group, while the other represents a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxyethyl group, a methoxy group, a phenyl group, a 4-chlorophenyl group, a 2-thienyl group, or a cyano group; and when Y represents -C (R4) = C (R5) (R6),
[00132] R4, RS and Re, which can be the same or different, each represents a hydrogen atom, a methyl group, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group, or a 1-pyrrolidinylmethyl group; when Y represents -C = C-R , R7 represents a methyl group.
[00133] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0; R1 represents an amino group;
[00134] either of R2 and R3 represents a hydrogen atom or a methyl group, while the other represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a methoxyethyl group, a phenyl group, a 2-thienyl group , or a cyan group; (1) when Z represents N, and W represents N, X represents 1,3-piperidinylene, and Y represents a vinyl group; (2) when Z represents CH, and W represents N, X represents 1,3-pyrrolidinylene or 1,3-piperidinylene, Y represents -C (R4) = C (Rs) (R6) or -C = C- (R7 ), and when Y represents -C (R4) = C (R5) (R6),
[00135] R4, RS and Re, which can be the same or different, each represents a hydrogen atom, a methyl group, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group, or a 1-pyrrolidinylmethyl group, when Y represents -C = C- (R '), R7 represents a methyl group; and (3) when Z represents CH, and W represents CH, X represents 1,3-azetidinylene or 1,3-pyrrolidinylene, Y represents -C (R4) = C (R5) (R6), and
[00136] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group, or a group 1 - pyrrolidinylmethyl.
[00137] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0; Ri represents an amino group;
[00138] either of R2 and R3 represents a hydrogen atom or a methyl group, while the other represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a methoxyethyl group, a phenyl group, a 2-thienyl group , or a cyan group; (4) when Z represents N, and W represents N,
[00139] X represents 1,3-piperidinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)), and Y represents a vinyl group; (2) when Z represents CH, and W represents N,
[00140] X represents 1,3-pyrrolidinylene or 1,3-piperidinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)), Y represents -C (R4) = C ( R5) (Re) or -OC- (R '), and when Y represents -C (R4) = C (R5) (R6),
[00141] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a methyl group, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group, or a 1-pyrrolidinylmethyl group, and when Y represents -C = C- (R '), R7 represents a methyl group; and (3) when Z represents CH, and W represents CH,
[00142] X represents 1,3-azetidinylene or 1,3-pyrrolidinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)), Y represents -C (R4) = C ( R5) (R6), and
[00143] R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group, or a group 1 - pyrrolidinylmethyl.
[00144] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, in which: A represents - (CH2) n-X-; n represents 0; X represents 1,3-piperidinylene; Y represents a vinyl group; Z represents CH; W represents N; R1 represents an amino group; and
[00145] either of R2 and R3 represents a hydrogen atom, while the other represents a hydrogen atom, a halogen atom, or a cyan group.
[00146] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[00147] X represents 1,3-piperidinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)); Y represents a vinyl group; Z represents CH; W represents N; R1 represents an amino group; and
[00148] either of R2 and R3 represents a hydrogen atom, while the other represents a hydrogen atom, a halogen atom, or a cyan group.
[00149] With respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0; X represents 1,3-piperidinylene; Y represents a vinyl group; Z represents CH; W represents N; R1 represents an amino group; and
[00150] Either of R2 and R3 represents a hydrogen atom, while the other represents a hydrogen atom or a halogen atom.
[00151] In this case, with respect to the compound of the present invention represented by the general formula (I), a compound, or a salt thereof, is more preferred, in which: A represents - (CH2) n-X-; n represents 0;
[00152] X represents 1,3-piperidinylene (in this case, the nitrogen atom is attached to the carbonyl group of -COY in the general formula (I)); Y represents a vinyl group; Z represents CH; W represents N; R1 represents an amino group; and
[00153] either of R2 and R3 represents a hydrogen atom, while the other represents a hydrogen atom or a halogen atom.
[00154] Specific examples of the compound of the present invention include those compounds produced in the examples described below; however, the compound is not designed to be limited to them. Suitable examples of the compound of the present invention include the following compounds: (1) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H- pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 1) (2) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-bromobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 2) (3) (R) -1- (1-acryloylpiperidin-3-yl) -4 -amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 3) (4) (R) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 - (1-methacryloypiperidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3- carboxamide (representative example 4) (5) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3 - yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 5) (6) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 6) (7) (R) -1- (1 -acryloylpiperidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 7) (8 ) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1 H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (representative example 8) (9) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (oxazole [4,5-b] pyridin-2 -yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 9) (10) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- ( 4-methylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 10) (11) (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1 - (1-methacryloylpiperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 11) (12) (R) -1 - (1-acryloylpiperidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 12 ) (13) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- 3-carbo xamide (representative example 13) (14) (R, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3-yl ) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 14) (15) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but- 2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 15) (16) (R , E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (ethyl (methyl) amino) but-2-enoyl) piperidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 16) (17) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (diethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 17) (18) (R) , E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (isopropylKmetiOaminoJbut ^ -enoiOpiperidin-S-iO-IH-pyrazoloβ ^ -dlpyrimidine-S - carboxamide (representative example 18) (19) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 - (1 - (4- (pyrrolidin-1-yl ) but-2-enoyl) piperidin-3-yl) -1l-1-pyrazolo [3 , 4-d] pyrimidine-3-carboxamide (representative example 19) (20) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- ( 4- (piperidin-1-yl) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 20) (21) (R, E) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 21) (22) (R) -4-amino-N- (benzo [d] oxazol-2-yl) -1- ( 1- (but-2-yoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 22) (23) (R) -1- (1-acryloylpiperidin- 3-yl) -4-amino-N- (5,6-dimethylbenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 23) (24) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- carboxamide (representative example 24) (25) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) pyrrolidin-3 -yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (example representative 25) (26) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (3-methylbut-2-enoyl) pyrrolidin-3- yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 26) (27) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 27) (28) (R) -1- (1-acryloylpyrrolidin-3-yl) -4 -amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 28) (29) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- carboxamide (representative example 29) (30) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazole [3 , 4-d] pyrimidine-3-carboxamide (representative example 30) (31) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (4-chlorophenyl) benzo [ d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 31) (32) (R, E) -4-amino-N- (5-chlorobenzo [d ] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 32) (33) (R, E) -4- amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-ethyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3 , 4-d] pyrimidine-3-carboxamide (representative example 33) (34) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- ( 4- (diθtilamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 34) (35) (R, E) -4-amino -N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4-isopropyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3, 4-d] pyrimidine-3-carboxamide (representative example 35) (36) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4 - (pyrr ° lidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 36) (37) (R, E ) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (piPeridin-1-yl) but-2-enoyl) pyrrolidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 37) ( 38) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide (representative example 38) (39) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4-d] pyrimidine-3-carboxamide (representative example 39) (40) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 40) (41) (R) -1- (1-acryloylpyrrolidin-3-yl) - 4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 41) (42) (R, E) - 4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3, 4-d] pyrimidine-3-carboxamide (representative example 42) (43) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazole - 2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 43) (44) (R, E) -4-amino-N- (5- (trifluoromethyl) benzo [d ] oxazole-2 -yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 44) (45 ) 1 - (1-Acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide ( representative example 45) (46) 7- (1-Acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine -5-carboxamide (representative example 46) (47) (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2 - enoyl) azetidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 47) (48) (R) -7- (1-acryloylpyrrolidin-3-yl) -4- amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 48) (49) (R, E) -4-amino -N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 49) (50) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (ethyl ( methyl) amino) but-2-enoyl) pyrr olidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 50) (51) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazole- 2-yl) -7- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 51) (52 ) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidin- 3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 52) (53) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2- yl) -7- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 53) (54) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (piperidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2J3-d] pyrimidine-5-carboxamide (representative example 54) (55) (R) -7- (1-acryloylpyrrolidin-3-yl) -4-amino-N- ( 5-phenylbenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 55) (56) (R, E) -4-amino-N- (5 -phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (dimethyl amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 56) (57) (R, E) -4-amino-N- ( 5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (ethyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 57) (58) (RJE) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (diethylamino) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 58) (59) (R, E) -4-amino-N- (5-phenylbenzo [ d] oxazol-2-yl) -7- (1- (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5- carboxamide (representative example 59) (60) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (representative example 60) (61) (R, E) -4-amino-N- (5- phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (piperidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine- 5-carboxamide (representative example 61) (64) (R) -1- (1-ac riloylpiperidin-3-yl) -4-amino-N- (7-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 64) (65) (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide ( Representative example 65) (66) 1 - ((1-Acrylated poly-n-3-yl) methyl) -4-amine-N- (be nzo [d] oxazol-2-yl) -1 H - pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 66) (67) 1 - ((1-Acryloylpiperidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazole- 2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 67) (68) 1 - ((1-Acryloylpiperidin-4-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 68) (69) 1 - (1-Acryloylpiperidin-4-yl) -4- amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 69) (70) 1 - ((1-Acryloylazetidin-3- il) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (example representative 70) (71) 1 - ((1 S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 71) (72) 1 - ((1 R, 4R) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazole [3,4-d] pyrimidine-3-carboxamide (representative example 72) (73) (S, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- ( 4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 73) (74) 1 - (1-Acryloylazetidin-3- il) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 74) (75) 1 - ((1 -Acryloylazetidin-3-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 75) (76) 1 - ((1-Acryloylazetidin-3-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide (representative example 76) (77) 1 - ((1-Acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazo 1-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 77) (78) 1 - ((1 S, 4S) -4-acrylamidocyclohexyl) -4-amino-N - (5-chlorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 78) (79) 1 - (1-Acryloylazetidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 79) (80) 1 - ((1 -Acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 80) (81) 1 - ((1 S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide (representative example 81) (82) 1 - (1-Acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (representative example 82) (83) 1 - (1-Acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1 H- pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 83) (84) 1 - (1 -Acryl ilpirrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (representative example 84) (85 ) 1 - (3-Acrylamidopropyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (representative example 85) (86 ) 1 - (2-Acrylamidoethyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (Representative compound 86).
The probe compound according to the present invention includes a detectable marker or affinity tag that can be combined with the compound of the present invention, and a linker. The linker binds the compound of the present invention to the marker or mark.
[00156] There are no restrictions on the detectable marker or affinity tag as long as the marker or affinity mark can detect the binding of the probe according to the present invention with BTK; however, a marker or affinity tag containing a functional group capable of attaching to the linker through, for example, alkylation or amidation is desired. Preferably, for example, BODIPY (registered trademark) FL, BODIPY (registered trademark) R6G, BODIPY (registered trademark) TMR, BODIPY (registered trademark) 581/591, and BODIPY (registered trademark) TR, are employed as luminophores, and for example, biotin is used as a linker group. Most preferably, BODIPY (registered trademark) FL and biotin are employed.
[00157] The linker is not particularly limited in that the linker is a part that links the marker or mark to the compound of the present invention. However, it is desired that the binder has an appropriate length, properties that do not significantly affect the compound of the present invention, and a functional group that can extend the marker or mark. Preferred examples of the binder include: and a preferred example is:
and a preferred example and:

[00158] Preferred examples of the probe according to the present invention include 4-amino-N- (benzo [d] oxazol-2-yl) -1 - ((R) -1 - ((E) -4- (4 - (2- (5 - ((3aS, 4S, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl) piperazin-1-yl) but-2- enoyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide, and (R, E) -7- (3 - ((2- (4- (4- (3 - (4-amino-3- (benzo [d] oxazol-2-ylcarbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) ~ 4-oxobut-2-en -1 -yl) piperazin-1-yl) ethyl) amino) -3-oxopropyl) 5,5-difluoro-1,3-dimethyl-5H-dipyrrolo [1,2-c: 2 ', 1 -f] [ 1,3,2] diazaborinin-4-ium-5-uida.
[00159] The binding state of the compound of the present invention and BTK can be detected or quantitatively analyzed by co-treating the probe according to the present invention with, for example, a sample in the blood or spleen, or by co-treating the probe with a colular extract derived from, for example, blood or spleen. For quantitative detection or analysis, for example, biochemical techniques (for example, luminescence and fluorescence) may be used.
[00160] Next, the method of producing the compound according to the present invention was clarified.
[00161] Compound (I) of the present invention can be produced, for example, by the production method described below or by the method described in the examples. However, the method of producing the compound (I) of the present invention is not designed to be limited to these reaction examples. Production method 1

[00162] where Z, R2 and R3 respectively have the same meanings as defined above.
[00163] (step 1) The present step is a process of synthesizing a benzoxazole compound represented by the general formula (III) from an aminophenol represented by the general formula (II).
[00164] Examples of the reagent used include cyano compounds such as bromocyanine, chlorocyanate, iodocian, and 1,1-carbonimidoylbis-1H-imidazole. The reaction was carried out using 0.5 to 5 moles, and preferably 0.9 to 1.5 moles, of the cyan compound with respect to 1 mole of the compound represented by the general formula (II). However, with respect to the relevant cyan compound, a commercially available compound can be used or the cyan compound can be produced according to a known method. The solvent used in the reaction can be any solvent as long as it does not adversely affect the reaction, and for example, alcohols (for example, methanol and ethanol), hydrocarbons (for example, benzene, toluene, and xylene), halogenated hydrocarbons (for example , methylene chloride, chloroform, and 1,2-dichloroethane), nitriles (for example, acetonitrile), ethers (for example, dimethoxyethane and tetrahydrofuran), polar aprotic solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoramide), water, or mixtures of these are used. The reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours. The reaction temperature is 0 ° C to 120 ° C, and preferably 0 ° C to 90 ° C.
[00165] The compound represented by the general formula (III) which is obtainable as it is isolated and purified by known means of separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography , or it can be subjected to the subsequent step without being isolated and purified. Production method 2

[00166] where L3 and l_4 each represent an output group; Pi represents a protecting group of the amino group present in A; and W, A, Y, Z, Ri, R2 and R3 respectively have the same meanings as defined above.
[00167] (Step 2) The present step is a process of producing a compound represented by the general formula (VII) using a compound represented by the general formula (IV) and a compound represented by the general formula (V) or general formula (SAW).
[00168] When the compound represented by the general formula (V) is used as an alkylating reagent, the compound represented by the general formula (VII) can be produced in the presence of a base. In the general formula (V), l_4 represents a leaving group, for example, a chlorine atom, a bromine atom, an iodine atom, a methane sulfonic acid ester or a p-toluene sulfonic acid ester and a product commercially available may be used, or the compound may be produced according to a known method. The compound represented by the general formula (V) can be used in an amount of 1 to 10 moles, and preferably 1 to 5 moles, with respect to 1 mole of the compound represented by the general formula (IV).
[00169] Examples of the base 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. With respect to the amount of use of the base, the base can be used in an amount of 1 to 100 moles, and preferably 2 to 10 moles, with respect to 1 mole of the compound represented by the general formula (IV).
[00170] For the solvent, for example, N, N-dimethylformamide, N, N-dimethylacotamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, and acetonitrile may be used alone or as mixtures. The reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours. The reaction temperature is 0 ° C at a temperature at which the solvent boils and preferably 0 ° C to 100 ° C.
[00171] When the compound of the general formula (VI) is used as an alkylating reagent, the compound represented by the general formula (VII) can be produced using the Mitsunobu reaction. Usually, the present process can be done according to the known method (for example, Chemical Reviews, Vol. 109, p. 2551, 2009), and for example, the process can be performed in the presence of a Mitsunobu Reagent and a reagent phosphine, in a solvent that does not adversely affect the reaction. The present process is usually performed using the compound represented by the general formula (VI) in an amount of 1 to 10 moles, and preferably 1 to 5 moles, with respect to 1 mole of the compound represented by the general formula (IV).
[00172] Examples of the Mitsunobu Reagent include diethyl azodicarboxylate and diisopropyl azodicarboxylate. Regarding the amount of use of the Mitsunobu Reagent, the process is carried out using the reagent in an amount of 1 to 10 moles, and preferably 1 to 5 moles, with respect to 1 mole of the compound represented by the general formula (IV).
[00173] Examples of the phosphine reagent include triphenylphosphine and tributylphosphine. With respect to the phosphine reagent, the process is performed using the reagent in an amount of 1 to 10 moles, and preferably 1 to 5 moles, with respect to 1 mole of the compound represented by the general formula (IV).
[00174] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction; however, for example, toluene, benzene tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, or mixed solvents thereof are suitable.
[00175] The reaction temperature is usually -78 ° C to 200 ° C, and preferably 0 ° C to 50 ° C. The reaction time is usually 5 minutes to 3 days, and preferably 10 minutes to 10 hours.
[00176] The compound represented by the general formula (VII) which is obtainable as such is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography , or is subjected to the subsequent process without being isolated and purified.
[00177] (Step 3) The present step is a process of producing a compound represented by the general formula (VIII) by allowing the compound represented by the general formula (VII) to react with, for example, a transition metal and optionally a base, in a carbon monoxide atmosphere in the presence of an alcohol, in a solvent that does not adversely affect the reaction.
[00178] In the general formula (VII), the leaving group represented by l_3 is a bromine atom or an iodine atom, and with respect to the relevant compound, a commercially available product may be used or the compound may be produced accordingly with a known method.
[00179] In the present case, the pressure of carbon monoxide is usually 1 atmosphere at 10 atmospheres, and preferably 1 atmosphere at 5 atmospheres. With respect to the amount of use of the alcohol compound, the compound can be used in an amount of 1 to 10 moles, and preferably 1 to 5 moles, with respect to 1 mole of the compound represented by the general formula (VII). Examples of the alcohol compound include methanol, ethanol, propanol, isopropyl alcohol, diethylaminoethanol, isobutanol, 4- (2-hydroxyethyl) morpholine, 3-morpholinopropanol, and diethylaminopropanol.
[00180] The transition metal catalyst that can be used in the present process is, for example, a palladium catalyst (e.g. palladium acotate, tris (dibenzylidene acetone) dipaladium, bis (triphenylphosphine) palladium (ll) dichloride, or 1,1'-bis (diphenylphosphino) ferrocene-palladium (ll) dichloride-dichloromethane complex, and if necessary, a binder (e.g., triphenylphosphine, xanthos, or tri-tert-butylphosphine) is added to it. The amount of use of the transition metal catalyst can vary depending on the type of catalyst; however, the amount of use is usually 0.0001 to 1 mol, and preferably 0.001 to 0.5 mol, with respect to 1 mol of the compound represented by the general formula (VII). The amount of use of the binder is usually 0.0001 to 4 moles, and preferably 0.01 to 2 moles, with respect to 1 mole of the compound represented by the general formula (VII).
[00181] In addition, a base can be added to the reaction, if necessary. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount of use of the base is usually 0.1 to 50 moles, and preferably 1 to 20 moles, with respect to 1 mole of the compound represented by the general formula (VII).
[00182] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction, and examples of these 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, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, and hexamethylphosphoramide), water, or mixtures of these. The reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours. The reaction temperature is 0 ° C at a temperature at which the solvent boils, and preferably 0 ° C to 150 ° C.
[00183] After this reaction, once a mixture of the carboxylic acid compound (VIII) and an ester form corresponding to the alcohol used is obtained, a hydrolysis reaction is conducted in order to converge the mixture to the compound represented by the general formula (VIII). Hydrolysis is carried out using a base, and examples of these include organic bases such as diethylamine, diisopropylamine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydroxide.
[00184] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction, and examples of these 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, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, and hexamethylphosphoramide), water, or mixtures of these. The reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours. The reaction temperature is 0 ° C at a temperature at which the solvent boils, and preferably 0 ° C to 150 ° C.
[00185] The compound represented by the general formula (VIII) which is obtainable as such is isolated and purified by known means of separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or is subjected to the subsequent process without being isolated and purified.
[00186] (Step 4) The present step is a process of producing a compound represented by the general formula (IX) by carrying out an amidation reaction using compounds represented by the general formula (VIII) and general formula (III).
[00187] The process is carried out using the compound of the general formula (III) in an amount of 0.5 to 10 moles, and preferably 1 to 3 moles, with respect to 1 mole of the compound represented by the general formula (VIII), in the presence of an appropriate condensing agent or an activating agent such as an amidating reagent.
[00188] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction, and for example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, or mixed solvents thereof are suitable. The reaction temperature is usually -78 ° C to 200 ° C, and preferably 0 ° C to 50 ° C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.
[00189] Examples of the condensing agent and activating agent include diphenylphosphoric acid azide, N.N'-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3, 5-triazin-2-yl) -4-methylmorpholine, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, a combination of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole, 2- chloro-1,3-dimethylimidazolinium, O- (7-azabenzotriazo-1-yl) -N, N, N ,, N'- tetramethylhexauronium, 1,1-carbonyldiimidazole hexafluorophosphate, and N-hydroxysuccinic acid amide.
[00190] In addition, with respect to the reaction described above, a base a base can be added there, if necessary. Examples of the base 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, diazabicycloundecene, diazabicyclononene, and butyllithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount of this addition is 1 to 100 moles, and preferably 1 to 10 moles, with respect to 1 mole of the compound represented by the general formula (VIII).
[00191] The compound represented by the general formula (IX) which is obtainable as such is isolated and purified by known means of separation and purification, for example, co-concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or it can be used in the production of the compound (I) of the present invention without being isolated and purified. Production method 3

[00192] where l_3 represents an output group; and W, A, Y, Z, Pi, Ri, R2 and R3 each have the same meanings as defined above.
[00193] (Step 5) The present step is a process of producing a compound represented by the general formula (IX) by allowing the compound represented by the general formula (VII) to react with, for example, a transition metal and optionally a base, in a carbon monoxide atmosphere in the presence of compound (III), in a solvent that does not adversely affect the reaction.
[00194] In the general formula (VII), the leaving group represented by L3 is a bromine atom or an iodine atom, and a commercially available product can be used or the relevant compound can be produced according to the known method.
[00195] In the present process, the pressure of carbon monoxide is 1 atmosphere at 10 atmospheres, and preferably 1 atmosphere at 5 atmospheres.
[00196] The transition metal catalyst that can be used in the present process is, for example, a palladium catalyst (e.g. palladium acotate, tris dibenzylidene acetone) dipaladium, bis (triphenylphosphine) palladium (ll), and 1,1'-bis (diphenylphosphino) ferrocene-palladium (11) dichloride-dichloromethane complex, and if necessary, a binder (for example, triphenylphosphine, xanthos, or tri-tert-butylphosphine) is added there. use of the transition metal catalyst may vary with the type of catalyst, however, the amount of use is usually 0.0001 to 1 mole, and preferably 0.001 to 0.5 moles, with respect to 1 mole of the compound represented by the general formula (IX) The amount of use of the binders is usually 0.0001 to 4 moles, and preferably 0.01 to 2 moles, with respect to 1 mole of the compound represented by the general formula (VII).
[00197] In addition, with respect to the reaction described above, the base a base can be added there, if necessary. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butyrate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount of use of the base is usually 0.1 to 50 moles, and preferably 1 to 20 moles, with respect to 1 mole of the compound represented by the general formula (VII).
[00198] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction, and examples of these include hydrocarbons (for example, benzene, toluene, and xylene), nitriles (for example, acetonitrile), ethers (for dimethoxyethane, tetrahydrofuran, and 1,4-dioxane), alcohols (eg, methanol and ethanol), polar aprotic solvents (eg, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, and hexamethylphosphoramide), water, or mixtures of these. The reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours. The reaction temperature is 0 ° C at a temperature at which the solvent boils, and preferably 0 ° C to 150 ° C.
[00199] The compound represented by the general formula (IX) which is obtainable as such is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or it can be used in the production of the compound (I) of the present invention without being isolated and purified. Production method 4

[00200] where Pi, A, X, Y, Z, Ri, R2 and R3 respectively have the same meanings as defined above.
[00201] (Step 6) The present step is a process of producing a compound represented by the general formula (X) by deprotecting the protection of the amino group of the compound represented by the general formula (IX). The deprotection method can usually be carried out by a known method, for example, the method described in Protective Groups in Organic Synthesis, T.W. Greeno, John Wiley & sons (1981), or a method equivalent to it. An example of the protecting group is tert-butyloxycarbonyl. In the case where a tert-butyloxycarbonyl group is used as a protecting group, deprotection under acidic conditions is preferred and examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid and tosflamic acid. Alternatively, deprotection using a Lewis acid is preferred and examples of these include trimethylsilyliodine and a boron trifluoro-diethyl ether complex. The amount of use of the acid is preferably 1 to 100 moles with respect to 1 mole of compound (IX).
[00202] The solvent used in the reaction can be any solvent as long as it does not negatively affect the reaction and for example, alcohols (for example, methanol), hydrocarbons (for example, benzene, toluene, and xylene), halogenated hydrocarbons (for example , methylene chloride, chloroform, and 1,2-dichloroethane), nitriles (eg, acetonitrile), ethers (eg, dimethoxyethane and tetrahydrofuran), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoramide), or mixtures of these are used. The reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours. The reaction temperature is 0 ° C to 120 ° C, and preferably 0 ° C to 90 ° C.
[00203] The compound represented by the general formula (X) which is obtainable as such is isolated and purified by known means of separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, and chromatography, or it can be subjected to the subsequent process without being isolated and purified.
[00204] (Step 7) The present step is a process for producing the compound of the present invention represented by the general formula (I), by an amidation reaction between the compound represented by the general formula (X) and a carboxylic acid represented by Y -COOH or an acid halide represented by Y- C (= O) -L (where L represents a chlorine atom or a bromine atom).
[00205] When a carboxylic acid represented by Y-COOH is used as an amidation reagent, the amidation reaction is carried out using 0.5 to 10 moles, and preferably 1 to 3 moles, of the carboxylic acid with respect to 1 mol of the compound represented by the general formula (X), in the presence of an appropriate condensing agent. However, with respect to the relevant carboxylic acid, a commercially available product may be used, or the carboxylic acid may be produced according to a known method.
[00206] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction, and for example, isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4- dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, or mixed solvents thereof. The reaction temperature is usually -78 ° C to 200 ° C, and preferably 0 ° C to 50 ° C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.
[00207] Examples of the condensing agent include diphenylphosphoric acid azide, N, N'-dicyclohexylcarbodiimide, benzotriazol-1-yloxytrisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3,5-triazin-2- chloride il) -4-methylmorpholine, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, a combination of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole, 2-chloro-1,3- chloride dimethylimidazoline, and O- (7-azabenzotriazo-1-yl) -N, N, N ', N'- tetramethylhexauronium hexafluorophosphate.
[00208] In addition, with respect to the reaction, a base can be added there, if necessary. Examples of the base 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 butyllithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount of this addition is 1 to 100 moles, and preferably 1 to 10 moles, with respect to 1 mole of the compound represented by the general formula (X).
[00209] When an acid halide represented by YC (= O) -L (where L represents a chlorine atom or a bromine atom) is used as an amidation reagent, the reaction is carried out using 0.5 to 5 moles, and preferably 0.9 to 1.1 moles, of the acid halide with respect to 1 mole of the compound represented by the general formula (X). However, with respect to the relevant acid halide, a commercially available product can be used, or the acid halide can be produced according to a known method.
[00210] The reaction solvent is not particularly limited as long as the reaction solvent does not interrupt the reaction, and for example, water, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, acotonitrile, 1,4-dioxane, dimethylformamide, dimethylacetamide , N-methylpyrrolidinone, or mixed solvents thereof are suitable. The reaction temperature is usually -78 ° C to 200 ° C, and preferably -20 ° C to 50 ° C. The reaction time is usually 5 minutes to 3 days, and preferably 5 minutes to 10 hours.
[00211] In addition, with respect to the reaction described above, a base can be added there if necessary. Examples of the base 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 butyllithium; and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. With respect to the amount of addition, the base can be used in an amount of 1 to 100 moles, and preferably 1 to 10 moles, with respect to 1 mole of the compound represented by the general formula (X).
[00212] The compound represented by the general formula (I) which is obtainable as such can be isolated and purified by means of known separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation and chromatography. Production method 5

[00213] where Pi, W, A, Y, Z, Ri, R2 and R3 respectively have the same meanings as defined above. (Step 8 and Step 9)
[00214] The present stages are processes of production of a compound represented by the general formula (XII) when submitting the compound represented by the general formula (VIII) to procedures similar to Production method 4, Steps 6 and 7.
[00215] (Step 10) The present step is a process of producing the compound represented by the general formula (I) by subjecting the compound represented by the general formula (XII) to procedures similar to Production Method 2, Step 4.
[00216] The compound represented by the general formula (I) which is obtainable as such can be isolated and purified by means of known separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation and chromatography. Production method 6

[00217] where W, A, Z, Ri, R2 and R3 respectively have the same meanings as defined above.
[00218] (Step 11) The present step is a process of producing a compound represented by the general formula (XIII) through an amidation reaction between the compound represented by the general formula (X) and a carboxylic acid represented by "Ligand- CH = CH-COOH "or an acid halide represented by" Ligand-CH = CH-CO-L "(where L represents a chlorine atom or a bromine atom). This reaction can be carried out by reference to Production Method 4, Step 7.
[00219] It is desired that the binding unit contains, in the part for connecting the Indicator Unit and the compound, a functional group that has an appropriate length and properties that do not significantly affect the profiles of the compound, and is able to extend the Indicator Unit. Examples of the Binding Unit include:

[00220] (Step 12) The present step is a synthesis reaction of a probe compound represented »by the general formula (XIV) by the extension of an Indicator Unit to the compound represented by the general formula (XIII). This reaction can be carried out by selecting, for example, alkylation or amidation depending on the types of the Binder and indicator and the reactions can be carried out by reference to Production Method 2, Step 2 and Production Method 4, Step 7, respectively.
[00221] The Indicator Unit is a site designed to facilitate the detection of the binding state with BTK using biochemical techniques (for example, luminescence and fluorescence), by co-treatment of a probe compound containing the Indicator Unit with, for example for example, a sample in the blood or spleen, or by co-treating the probe compound with a cell extract derived from, for example, the blood or spleen. It is desired that the Indicator Unit contains a functional group that can be connected to the Binding Unit, for example, by alkylation or amidation as described above. Regarding the Indicator Unit, for example, BODIPY (registered trademark) FL, BODIPY (registered trademark) R6G, BODIPY (registered trademark) TMR, BODIPY (registered trademark) 581/591, and BODIPY (employees) registered) TR as luminophores, and for example, biotin is used as a linker group. Production method 7

[00222] where L3 represents an output group; and Pi, W, A, Y, Z, Ri, R2 and respectively have the same meanings as defined above. (Steps 13 and 14)
[00223] The present steps are processes of production of a compound represented by the general formula (XV) by subjecting the compound represented by the general formula (VII) to procedures similar to Production method 4, Steps 6 and 7. (Step 15 )
[00224] The present step is a process of producing the compound of the general formula (I) by submitting a compound represented by the general formula (XVI) to procedures similar to Production Method 3, Step 5.
[00225] The compound represented by the general formula (I) that is obtainable as such can be isolated and purified by known means of separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation and chromatography.
[00226] With respect to Production Methods 1 to 7, for an amino group, an imino group, a hydroxyl group, a carboxyl group, a carbonyl group, an amide group, and a functional group with an active proton, such as indole , a protected reagent can be used in appropriate steps in the various production methods, or a protecting group can be introduced into the relevant functional group according to a conventional method, and then the protecting group can be removed.
[00227] The "protecting group for an amino group or an imino group" is not particularly limited as long as the group has its function and examples of these include, for example, aralkyl groups such as a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o-nitrobenzyl group, a p-nitrobenzyl group, a benzhydryl group, a trityl group, and a coumyl group; for example, lower alkanoyl groups such as a formyl group, an acetyl group, a propionyl group, a butyryl group, a pivaloyl group, a trifuloroacotila group, and a trichloroacetyl group; for example, a benzoyl group; for example, arylalkaneyl groups such as a phenylacetyl group and a phenoxyacetyl group; for example, lower alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, and a tert-butoxycarbonyl group; for example, aralkyloxycarbonyl groups such as a p-nitrobenzyloxycarbonyl group and a phenothyloxycarbonyl group; for example, lower alkylsilyl groups such as a trimethylsilyl group and a tert-butyldimethylsilyl group; for example, a tetrahydropyranyl group; for example, a trimethylsilyletoxymethyl group; for example, lower alkylsulfonyl groups such as a methylsulfonyl group, an ethylsulfonyl group, and a tert-butylsulfonyl group; for example, lower alkylsulfinyl groups such as a tert-butylsulfinyl group; for example, arylsulfonyl groups such as a benzenesulfonyl group and a toluenesulfonyl group; and for example, imide groups such as a phthalimide group. Particularly, a trifluoro acotyl group, an acetyl group, a tert-butoxycarbonyl group, a benzyloxy carbonyl group, a trimethylsilyletoxymethyl group, and a coumila group are preferred.
[00228] The "protecting group for a hydroxyl group" is not particularly limited as long as the protecting group has its function, and examples of these include lower alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a tert-butyl group; for example, lower alkylsilyl groups such as a trimethylsilyl group and a tert-butyldimethylsilyl group; for example, lower methyl groups such as a methoxymethyl group and a 2-methoxyethoxymethyl group; for example, a tetrahydropyranyl group; for example, a trimethylsilyletoxymethyl group; for example, aralkyl groups such as a benzyl group, a p-methoxybenzyl group, a 2,3-dimethoxybenzyl group, an o-nitrobenzyl group, a p-nitrobezyl group and a trityl group; and for example, acyl groups such as a formyl group, an acetyl group, and a trifluoroacotyl group. Particularly, for example, a methyl group, a methoxymethyl group, a tetrahydropyranyl group, a trimethylsilyletoxymethyl group, a tert-butyldimethylsilyl group, and an acothyl group are preferred.
[00229] The "protecting group for a carboxyl group" is not particularly limited as long as the protecting group has its function, and examples of these include lower alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a tert-butyl group; for example, halo-lower alkyl groups such as a 2,2,2-trichloroethyl group; for example, lower alkenyl groups such as an allyl group; for example, a trimethylsilyletoxymethyl group; and for example, aralkyl groups such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group, and a trityl group. Particularly, for example, a methyl group, an ethyl group, a tert-butyl group, an allyl group, a benzyl group, a p-methoxybenzyl group, and a trimethylsilyletoxymethyl group are preferred.
[00230] The "protecting group for a carbonyl group" is not particularly limited as long as the protecting group has its function, and examples of these include ketals and acetals such as ethylene ketal, trimethylene ketal, dimethyl ketal, ethyl acetal, trimethylene acetal, and dimethyl accetal.
[00231] The method of removing a protecting group may vary depending on the type of the relevant protecting group and stability of the target compound. However, for example, the removal of a protecting group is carried out according to methods described in the document (see protecting groups in Organic Synthesis, 3rd Ed., Written by TW Greeno, John Wiley & Sons, 1999) or methods equivalent to it, for example, through a method of carrying out solvolysis using an acid or a base, that is, for example, placing 0.01 mol in a large excess of an acid, preferably trifluoroacetic acid, formic acid or hydrochloric acid; or an equal mole in a large excess of a base, preferably potassium hydroxide or calcium hydroxide, in practice; or by chemical reaction using, for example, a metal hydride complex or by catalytic reduction using, for example, a palladium-carbon catalyst or a Raney nickel catalyst.
[00232] The compound of the present invention can be easily isolated and purified by conventional separation means. Examples of such media include solvent extraction, recrystallization, fractional reverse phase high performance liquid chromatography, column chromatography, and fractional thin layer chromatography.
[00233] In the event that the compound of the present invention has isomers such as optical isomers, stereoisomers, regioisomers and rotamers, mixtures of any isomers are all included in the compound of the present invention. For example, when the compound of the present invention has optical isomers, separate from racemates are also included in the compound of the present invention. These isomers can each be obtained as simple compounds through synthesis techniques that are known per se and separation techniques (for example, concentration, solvent extraction, column chromatography, and recrystallization).
[00234JO The compound of the present invention or a salt thereof can be crystalline and regardless of the fact that the shape of the crystal is a simple form or a polymorphic mixture, crystals are also included in the present compound or a salt thereof. A crystal can be produced by applying a crystallization method, known per se, and carrying out crystallization. The compound of the present invention or a salt thereof can be a solvate (for example, hydrate) or it can be a non-solvate both included in the compound of the present invention or a salt thereof. Isotope-labeled compounds (for example, 3H, 14C, 35S and 1251) are also included in the compound of the present invention or a salt thereof.
[00235] A prodrug of the compound of the present invention or a salt thereof refers to a compound that becomes the compound of the present invention or a salt thereof as a result of a reaction caused by an enzyme or gastric acid in the living body under physiological conditions, that is, a compound that enzymatically causes, for example, oxidation, reduction or hydrolysis and becomes the compound of the present invention or a salt thereof, or a compound that causes, for example, hydrolysis by means of gastric acid and becomes the compound of the present invention or a salt thereof. In addition, the prodrug of the compound of the present invention or a salt thereof can also be a compound that converts to the compound of the present invention or a salt thereof under the physiological conditions described in Hirokawa Shoten Annual of 1990 "lyakuhin no Kaihatsu (Development of Pharmaceutical Products) ", Vol. 7, Molecule Design, pp. 163-198.
[00236] A salt of the compound of the present invention means a salt that is conventionally used in the field of organic chemistry and examples of these include salts such as a base addition associated with a carboxyl group. In the case where the compound of the present invention has the relevant carboxyl group; and an acid addition salt associated with an amino group or a basic heterocyclic group. In the case where the compound of the present invention has the relevant amino group or basic heterocyclic group.
[00237] Examples of the base addition salts include, for example, alkali metal salts such as sodium salt and potassium salt; for example, alkaline earth metal salts such as calcium salt and magnesium salt; for example, ammonium salt; and for example, organic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt and N.N'-dibenzylethylenediamine salt.
[00238] Examples of acid addition salt include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; for example, organic acid salts such as acotate, formate, maleate, tartrate, citrate, ascorbate, and trifluoroacetate; and for example, salts of sulfonic acid such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.
[00239] The compound of the present invention or a salt thereof has excellent BTK inhibitory action, and is useful as an anti-tumor agent. In addition, the compound or its salt has excellent selectivity in relation to BTK, and has an advantage of having reduced adverse side effects that are caused by the inhibition of other kinases as well.
[00240] The compound of the present invention or a salt thereof has excellent BTK inhibitory action. "BTK" according to the present specification includes human and non-human breast BTK's, and BTK is preferably human BTK. Therefore, the term "BTK" includes isoforms.
[00241] In addition, due to its excellent BTK inhibitory action, the compound of the present invention or a salt thereof is useful as a medicine for the prevention or treatment of diseases associated with BTK. "BTK-associated diseases" include diseases that experience a decrease in the incidence and remission rate, symptom relief and / or complete recovery as a result of deletion, suppression and / or inhibition of BTK functions. Examples of such diseases include cancers and tumors, but the diseases are not restricted to these. There are no specific restrictions on object cancers and tumors and examples of these include epithelial cancers (for example, cancers of the respiratory system, cancers of the gastrointestinal system, cancers of the reproductive system, and cancers of the secretion system), sarcomas, tumors of the hematopoietic system, tumors central nervous system and tumors of the peripheral nervous system. Preferred examples are tumors of the hematopoietic system (for example, leukemia, multiple myeloma, and malignant lymphoma). In addition, there are no specific restrictions on the type of tumor-developing organs and examples of these include head and neck carcinoma, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / duet cancer biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone sarcoma / soft tissue, hematological tumor, multiple myeloma, skin cancer, brain tumor and mesothelial cancer. Preferred examples of tumors of the hematopoietic system include acute leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, lymphobiotic lymphoma, myeloproliferative neoplasms, chronic lymphocytic leukemia, small lymphocytic lymphoma, myelodomatic lymphoma, lymphoma, lymphoma , lymphoplasmacytic lymphoma, Waldenstroem macroglobulinemia, mantle cell lymphoma, large diffuse B cell lymphoma, Burkitt lymphoma, extranodal NK / T cell lymphoma, Hodgkin lymphoma and multiple myeloma. Particularly preferred examples include hematological tumors such as B-lymphoblastic lymphoma / leukemia, follicular lymphoma, mantle cell lymphoma, nodal marginal follicular zone lymphoma, diffuse large B cell lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstroem macroglobulinemia, extranodal T / NK cell lymphoma, Hodgkin's lymphoma, myelodysplastic syndromes, acute myelogenous leukemia and acute lymphocytic leukemia.
[00242] In the case of using the compound of the present invention or a salt thereof as a medicine, various dosage forms can be employed according to the purpose of prevention or treatment by incorporating pharmaceutical carriers as necessary. The dosage form can be, for example, any of an oral preparation, an injectable preparation, a suppository preparation and an intradermal patch. These dosage forms can be produced respectively using formulation methods that are conventionally used and known to the person skilled in the art.
[00243] With respect to pharmaceutical carriers, various organic and inorganic carrier materials are used that are conventionally used as formulation materials, and pharmaceutical carriers are incorporated, for example, as an excipient, a binder, a disintegrant, a lubricant and an agent coating in solid preparations; and as a solvent, a dissolution aid, a suspending agent, an isotonic agent, a pH adjusting agent, a buffering agent and an analgesic agent in liquid preparations. In addition, if necessary, formulation additives such as an antiseptic agent, an antioxidant, a colorant, a flavoring / tasting and stabilizing agent can also be used.
[00244] Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cholesterol and calcium silicate.
[00245] Examples of the binder include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, sugar powder, and hypromellose.
[00246] Examples of the disintegrant include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially gelatinized starch.
[00247] Examples of the lubricant include talc, magnesium stearate, fatty acid esters with sucrose, stearic acid and sodium stearyl fumarate.
[00248] Examples of the coating agent include ethyl cellulose, RS copolymer of aminoalkyl methacrylate, hypromellose and sucrose.
[00249] Examples of the solvent include water, propylene glycol, and saline.
[00250] Examples of the dissolution aid include polyethylene glycol, ethanol, α-cyclodextrin, Macrogol 400, and Polysorbate 80.
[00251] Examples of the suspending agent include carrageenan, crystalline cellulose, sodium carmelose and hardened polyoxyethylene castor oil.
[00252] Examples of the isotonic agent include sodium chloride, glycerin, and potassium chloride.
[00253] Examples of the pH adjusting agent and buffering agent include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid and sodium dihydrogen phosphate.
[00254] Examples of the analgesic agent include procaine hydrochloride and lidocaine.
[00255] Examples of the antiseptic agent include ethyl para-oxybenzoate, cresol, and benzalkonium chloride.
[00256] Examples of the antioxidant include sodium sulfite, ascorbic acid and natural vitamin E.
[00257] Examples of the colorant include titanium oxide, iron sesquioxide, edible blue No. 1, and copper chlorophyll.
[00258] Examples of the flavoring / tasting agent include aspartame, saccharin, sucralose, l-menthol, and mint flavor.
[00259] Examples of the stabilizer include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide and dibutylhydroxytoluene.
[00260] In the case of preparing a solid oral preparation, an excipient, optionally an excipient, a binder, a disintegrant, a lubricant, a colorant, and a flavoring / flavoring agent are added to the compound of the present invention, and then by For example, a tablet, a coated tablet, a granular preparation, a powder preparation, and a capsule preparation can be produced by conventional methods.
[00261] In the case of preparing an injectable preparation, a pH adjusting agent, a buffering agent, a stabilizer, an isotonic agent, and a local anesthetic are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous preparations. can be produced using conventional methods.
[00262] The amounts of the compound of the present invention to be incorporated into the various unit dosage forms may vary depending on the symptoms of the patient to whom this compound is to be applied or depending on the formulation; however, it is generally desired to adjust the amount to 0.05 to 1000 mg in an oral preparation, to 0.01 to 500 mg in the injectable preparation and to 1 to 1000 mg in a suppository preparation in unit dosage form.
[00263] Furthermore, the amount of administration per day of a drug with the dosage form described above can vary with, for example, the symptoms, body weight, age and sex of the patient and cannot be determined indiscriminately. However, the amount of administration can usually be used in an amount of 0.05 to 5000 mg, and preferably 0.1 to 1000 mg, per day for adults (body weight: 50 kg), and it is preferred to administer this once to the day or in portions divided approximately 2 to 3 times. Examples
[00264] In the following, the present invention will be described more specifically by way of examples, but the present invention is not intended to be restricted to them.
[00265] Regarding the various reagents used in the examples, provided that there was no specifically different indication, commercially available products were used. For column chromatography on silica gel, a SI PURIF-PACK (registered trademark) manufactured by Schott Moritex Corp., a pre-packaged Silica KP-Sil (registered trademark) manufactured by Biotage AB, or a pre -packaged Silica HP-Sil (registered trademark) manufactured by Biotage AB. For column chromatography on basic silica gel, an NH PURIF-PACK (registered trademark) manufactured by Moritex Corp., or a pre-packed KP-NH (registered trademark) column manufactured by Biotage AB was used. For fractionation thin layer chromatography, a KIESELGEL TM60F254, Art. 5744 manufactured by Merck KGaA, an NH2 silica gel 60F254 plate manufactured by Wako Pure Chemical Industries, Ltd. was used. The NMR spectrum was measured using an AL400 (400 MHz ; JEOL, Ltd.), a MERCURY400 spectrometer (400 MHz; Agilent Technologies, Inc.), or an INOVA400 (400 MHz; Agilent Technologies, Inc.) equipped with an OMNMR (Protasis Corp.) probe type spectrometer and tetramethylsilane as an internal reference if the deuterated solvent contains tetramethylsilane, while in other cases, using an NMR solvent as an internal reference. All δ values were expressed in ppm. The microwave reaction was carried out using DISCOVER S class manufactured by CEM Corp.
[00266] The LCMS spectrum was measured using an ACQUITY SQD (quadrupole type) manufactured by Águas Corp, under the conditions described below.
[00267] Column: YMC-TRIART C18 manufactured by YMC Co., Ltd., 2.0x50 mm, 1.9 pm MS detection: positive ESI UV detection: 254 nm and 210 nm Column flow rate: 0.5 mL / min Phase mobile: Water / acetonitrile (0.1% formic acid) Injection quantity: 1 pL Gradient (Table 1) Time (min) Water Acetonitrile 0955 0.195 2.1595 3.0PARE
[00268] In addition, preparative reverse phase HPLC purification was performed using a preparative system manufactured by Águas Corp, under conditions described below.
[00269] Column: A YMC-ACTUS TRIART C18 manufactured by YMC Co., Ltd., 20x50 mm, 5 gm, connected to a YMC-ACTUS TRIART C18 manufactured by YMC Co., Ltd. 20x10 mm, 5 pm, was used . UV detection: 254 nm MS detection: positive ESI Column flow rate: 25 mL / min Mobile phase: Water / acetonitrile (0.1% formic acid) Injection quantity: 0.1 to 0.5 mL The meanings of abbreviations are shown below. s: Singlet d: Doublet t: Triplet q: Quartet dd: Double doublet dt: double triplet td: Triple doublet tt: triple triplet ddd: double doublet, double ddt: double triplet, double dtd: double triple doublet tdd: double triple triplet m: Multiplet br: wide brs: wide singlet CDI: Carbonildiimidazole DMSO-de: deuterated dimethyl sulfoxide CDCta: deuterated chloroform CD3OD: deuterated methanol THF: Tetrahydrofuran DMF: N, N-dimethylformamide DMA: N, N-dimethylacetamide Methyl-2-pyrrolidinone DMSO: Dimethyl sulfoxide TFA: Trifluoroacetic acid WSC: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBt: 1-Hydroxybenzotriazole monohydrate HATU: hexafluorophosphate (Dimethyl-N-dimethyl) - [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) metanoiminio DIAD: Diisopropyl azodicarboxylate TBAF: tetrabutylammonium fluoride DIPEA: Diisopropylethylamine BOC2O: Di-tert-butyl dicarbonate DMAP: Dimethylaminopyridine
[00270] Synthetic example 1 Synthesis of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1 -i I) pi pe ridi na-1 - carboxylate

[00271] (Step 1) Synthesis of (S) -tert-butyl 3- (methylsulfonyloxy) piperidine-1-carboxylate
[00272] 20 g of (S) -N-Boc-3-pyridinol were dissolved in 100 ml of toluene, and 21 ml of triethylamine and 9.2 ml of methanesulfonyl chloride were added there at 0 ° C. The mixture was stirred for 1 hour under ice cooling, then ethyl acetate and water were added there, and an organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride and water, and then was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then 26.8 g of the title compound was obtained as a colorless solid.
[00273] (Step 2) Synthesis of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4- d] pyrimidin-1-yl) piperidine-1-carboxylate
[00274] A suspension solution of 14.6 g of 3-iodo-1H-pyrazolo [3,4- d] pyrimidin-4-amine synthesized by the method described in patent document WO 2007/126841, 25 g of (S) -tert-butyl 3- (methylsulfonyloxy) piperidine-1-carboxylate obtained in Step 1, and 69 g of potassium carbonate in 150 ml of DMA was heated to 100 ° C, and was stirred for 10 hours. The suspension solution was cooled to room temperature, and then 300 ml of water was added there. A solid thus obtained was collected by filtration and washed with water, and The solid was dried. In this way, 26.9 g of the title compound was obtained as a yellow solid. Physical property value: m / z [M + H] + 446.2
[00275] Synthetic example 2 Synthesis of (R) -4-amino-1- (1- (tθrc-butyloxycarbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid

[00276] [2 g of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in the synthetic example
[00277] 1, 3 ml of 2-diethylaminoethanol, and 158 mg of Pd (PPh3) 2Cl2 were dissolved in 20 ml of NMP. After the System was purged with carbon monoxide, the solution was then heated to 120 ° C. After the solution was stirred for 1 hour, the solution was cooled to room temperature. 10 ml of methanol was added there, and then 6 ml of 5 N aqueous sodium hydroxide solution was added there. The mixture was stirred for 10 minutes. Water was added there, and then the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 4 with hydrochloric acid and a solid thus precipitated was collected by filtration, washed with water, and then dried. Thus, 1.26 g of the title compound was obtained as a pale yellow solid. Physical property value: m / z [M + H] + 363.1
[00278] Synthetic example) 3 Synthesis of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid

[00279] (Step 1) Synthesis of (S) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate
[00280] 935 mg of (S) - (-) - N-Boc-3-pyrrolidinol were dissolved in 15 ml of chloroform, and 1.04 ml of triethylamine and 467 p, l of methanesulfonyl chloride were added there under cooling with ice. The mixture was stirred for 1.5 hours at room temperature, then ethyl acetate and water were added there, and an organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride, and water, and then was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then 1.3 g of the title compound was obtained as a colorless oily substance. Physical property value: m / z [M + H] + 266.1
[00281] (Step 2) Synthesis of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4- d] pi ri m id in -1 -yl) p irrol id i na-1-carboxylate
[00282] A suspension of 20.0 g of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine synthesized by the method described in patent document WO 2007/126841, 23 g of (S) -terc -butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate obtained in Step 1, and 32 g of potassium carbonate in 200 ml of DMA, was heated to 85 ° C, and was stirred for 3 hours. The solution was cooled to room temperature, and then a solid obtained by adding 400 ml of water there was collected by filtration, washed with water, and then dried. In this way, 23.5 g of the title compound was obtained as a pale yellow solid. Physical property value: m / z [M + H] + 431.0.
[00283] (Step 3) Synthesis of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid
[00284] 2.0 g of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in step above 2, 3.1 ml of 2-diethylaminoethanol, and 163 mg of Pd (PPh3) 2Cl2 were dissolved in 20 ml of NMP. The system was purged with carbon monoxide, and then heated to 120 ° C. After the solution was stirred for 1 hour, the solution was cooled to room temperature, and 10 ml of methanol was added there. Then, 6 ml of a 5 N aqueous solution of sodium hydroxide was added there, and the mixture was stirred for 10 minutes. Water was added there, then the aqueous layer was washed with chloroform, and the aqueous layer was adjusted to pH 4 with hydrochloric acid. A solid so precipitated was collected by filtration, washed with water, and then dried. In this way, 1.35 g of the title compound was obtained as a pale yellow solid. Physical property value: m / z [M + H] + 349.1 Synthetic example 4 Synthesis of 5-cyanobenzo [d] oxazol-2-amine

[00285] 15.1 g of 3-amino-4-hydroxybenzonitrile were dissolved in 75 ml of ethanol and 75 ml of water, and 14.7 g of bromocyanine were added in small portions to a solution under cooling with ice. The mixture was stirred for 2 hours at room temperature, and was again cooled with ice. 112 ml of a 2 N aqueous solution of NaOH was added to a solution, and the mixture was stirred for another 30 minutes. Much of the ethanol was coarsely removed using an evaporator, and the residue was collected by filtration. The filter cake was washed with water, and then 12.12 g of the title compound was obtained. Physical property value: m / z [M + H] + 161.1
[00286] Example 1 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 H-pyrazole [3, 4-d] pyrimidine-3-carboxamide (Representative compound 1)
[00287] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazole [3,4 -d] pyrimidin-1-yl) piperidine-1-carboxylate
[00288] To a suspension solution of 94 mg of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine -3- carboxylic acid obtained in synthetic example 2 in 4 ml of THF, 50 mg of GDI were added, and the mixture was stirred for 3 hours at room temperature. 66 mg of 5-chlorobenzo [d] oxazol-2-amine were added there under ice cooling, and a 1.0 M THF solution of lithium hexamethyldisilazane was added in drops there. The mixture was stirred for 30 minutes under ice cooling, 1 ml of water was added there, and the THF solvent was removed. A solid obtained by adding 4 ml of water to the residue was filtered off, and was washed with 5 ml of hexane / ethyl acetate = 1/1. In this way, 106 mg of the title compound was obtained as a white solid. Physical property value: m / z [M + H] + 513.2. (Step 2) Synthesis of Representative Compound 1
[00289J1 ml of 4 N hydrochloric acid / 1,4-dioxane was added to 5.6 mg of (R) -tert-butyl-3- (4-amio-3- (5-chlorobenzo [d] oxazol-2- ilcarbonyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in (step 1), The mixture was stirred for 1 hour, and then the solvent was removed using a evaporator. 2 ml of chloroform and 7.6 µl of triethylamine were added to the residue, the mixture was cooled with ice, and then 0.9 µl of acryloyl chloride was added there. After the mixture was stirred for 1.5 hours, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained. After removal, the solvent was purified using a column on silica gel (eluent: ethyl acetate: methanol). In this way, 2.6 mg of the title compound was obtained as a white solid.
[00290] Example 2 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-bromobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 2).
[00291] The title compound was obtained as a white solid of (R) -4-amino- 1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine- 3-carboxylic acid of synthetic example 2 and 5-bromobenzo [d] oxazol-2-amine according to the procedure described in example 1.
[00292] Example 3 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 3). (Step 1) Synthesis of 5- (thiophen-2-yl) benzo [d] oxazol-2-amine
[00293] 100 mg of 5-bromobenzo [d] oxazol-2-amine, 249 mg of potassium phosphate, and 90 mg of thiophen-2-ylboronic acid were suspended in 2.5 ml of DME and 0.5 ml of water. 38 mg of 1,1'-bis (diphenylphosphino) ferrocono-patedio (ll) dichloride-dichloromethane was added there, and the mixture was irradiated at 140 ° C for 20 minutes using a microwave reaction apparatus. The solvent was removed from a reaction solution, and the residue was purified by amine gel chromatography (eluent: chloroform / methanol), and then 93 mg of the title compound was obtained as a pale brown solid. Physical property value: m / z [M + H] + 216.8.
[00294] (Step 2) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5-thiophen-2-yl) benzo [d] oxazol-2-yl) carbamoyl) -1H -pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate.
[00295] To a 19 mg suspension solution of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine- 3-carboxylic acid obtained in the synthetic example 2 in 2 ml of THF, 10 mg of CDI was added, and the mixture was stirred for 2 hours at room temperature. 17 mg of 5- (thiophen-2-yl) benzo [d] oxazol-2-amine obtained in Step 1 was added there under ice cooling, and 105 µl of a 1.0M THF solution of lithium hexamethyldisilazane was added in drops there. The mixture was stirred for 30 minutes under ice cooling, then 1 ml of water was added there, and the THF solvent was removed. A solid obtained by adding 4 ml of water to the residue was filtered off, and was washed with 5 ml of hexane / ethyl acetate = 1/1. In this way, 13 mg of the target substance was obtained as a pale brown solid. Physical property value: m / z [M + H] + 561.3. (Step 3) Synthesis of Representative Compound 3
[00296] 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added to 9 mg of (R) -tert-butyl-3- (4-amino-3 - ((5- (thiophen-2-yl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in (step 2), The mixture was stirred for 1 hour, and then the solvent was removed using an evaporator. 2 ml of chloroform and 12 µl of triethylamine were added to the residue, the mixture was cooled with ice, and then 1.3 µl of acryloyl chloride was added there. After the mixture was stirred for 1.5 hours, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then the residue obtained. After removal by solvent, it was purified by preparative reverse phase HPLC purification (water / nitrile acetate (0.1% formic acid)). In this way, 2.1 mg of the title compound was obtained as a white solid.
[00297] Example 4 Synthesis of (R) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1-methacryloylpiperidin-3-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 4).
[00298] The title compound was obtained as a white solid according to the procedure described in example 1, using methacryloyl chloride instead of acryloyl chloride.
[00299] Example 5 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (but-2-enoyl) piperidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 5).
The title compound was obtained as a white solid according to the procedure described in example 1, using crotonic acid chloride instead of acryloyl chloride.
[00301] Example 6 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1 H-pyrazole [3, 4-d] pyrimidine-3-carboxamide (Representative compound 6).
[00302] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5-cyanobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazole [3,4 -d] pyrimidin-1-yl) piperidine-1-carboxylate.
[00303] 2.32 g of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid in synthetic example 2, dissolved in 25 ml of DMA, 2.01 g of CDI were added there, and the mixture was stirred for 1 hour at room temperature. 1.12 g of 5-cyanobenzo [d] oxazol-2-amine were added to the reaction solution, and then, 1.23 g of sodium tert-butyrate was added there. The mixture was stirred for 2 hours at room temperature, and water was added there. Then, the pH was adjusted with 2 N hydrochloric acid, and thus a solid was precipitated from there. The solid was collected by filtration and dried. In this way, 2.66 g of the title compound was obtained as a pale yellow solid. Physical property value: m / z [M + H] + 505.3. (Step 2) Synthesis of Representative Compound 6
[00304] 2.1 g of (R) -tert-butyl-3- (4-amino-3 - (((5-cyanobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in Step 1 were suspended in 10 ml of dichloromethane, and 10 ml of TFA were added there at room temperature. The mixture was stirred for 2 hours, and then the TFA was removed using an evaporator. In addition, the residue was azeotropically distilled with toluene, the residue was mixed with 20 ml of NMP and 2 ml of water, and the mixture was cooled with ice. 2.88 g of potassium carbonate and 0.4 ml of acryloyl chloride were added there, and the mixture was stirred under ice cooling. After 2 hours, water and 2 N hydrochloric acid were added there to adjust the pH, and a solid thus obtained was collected by filtration. Then, the solid was purified by chromatography on silica gel (chloroform-methanol), and then 0.7 g of the target substance was obtained as a white solid.
[00305] Example 7 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidin-3-carboxamide (Representative compound 7).
[00306] The title compound was obtained as a pale brown solid according to the procedure described in example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) - 1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid from synthetic Example 2 and 5-methoxybenzo [d] oxazol-2-amine.
[00307] Example 8 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1H- pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 8).
[00308] The title compound was obtained as a white solid according to the procedure described in example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of synthetic Example 2 and 5- (2-methoxyethyl) benzo [d] oxazol-2-amine.
[00309] Example 9 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (oxazolo [4,5-b] pyridin-2-yl) -1H-pyrazole [3 , 4-d] pyrimidine-3-carboxamide (Representative compound 9).
[00310] The title compound was obtained as a white solid according to the procedure described in example 6, of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of synthetic example 2 and oxazole [4,5-b] pyridin-2-amine.
[00311] Example 10 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (4-methylbenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 10).
[00312] The title compound was obtained as a white solid according to the procedure described in example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of synthetic example 2 and 4-methylbenzo [d] oxazol-2-amine.
[00313] Example 11 Synthesis of (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) - 1- (1-methacryloylpiperidin-3-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 11).
[00314] The title compound was obtained as a white solid according to the procedure described in example 6, using (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1 - (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide obtained in example 12 (step 2), and using methacryloyl chloride instead of acryloyl chloride.
[00315] Example 12 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 12).
[00316] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5-fluorobenzo [d] oxazol-2-yl) carbamoyl) -1 H-pyrazole [3, 4-d] pyrimidin-1-yl) piperidin-1-carboxylate.
[00317] It is a solution of 1.0 g of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic obtained in synthetic example 2 in 10 ml of DMA, 895 mg of CDI were added, and the mixture was stirred for 1 hour at room temperature. 462 mg of 5-fluorobenzo [d] oxazol-2-amine were added there, and 9 ml of a 1.0M THF solution of sodium tert-butyrate was added in drops there. The mixture was stirred for 30 minutes at room temperature, and then 10 ml of a 1 N aqueous solution of NaOH was added there, and the THF solvent was removed. After the residue was stirred for 1 hour, 2 N HCI and water-MeOH were added there to precipitate the mixture. Then, a solid thus obtained was collected by filtration, and then 1.14 g of the title compound was obtained as a light yellow solid. Physical property value: m / z [M + H] + 497.2.
[00318] (Step 2) Synthesis of (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1- (piperidin-3-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide.
[00319] 3.06 g of (R) -tert-butyl-3- (4-amino-3- (5-fluorobenzo [d] oxazol-2-ylcarbonyl) -1H-pyrazolo [3,4-d] pyrimidin -1-yl) piperidine-1-carboxylate obtained in Step 1 and 5.5 g of sodium iodide were suspended in 30 ml of acetonitrile, and 4.7 ml of trimethylsilyl chloride were added there at room temperature. The mixture was stirred for 1 hour at room temperature, a saturated aqueous solution of sodium bicarbonate was added there, and in this way a solid was precipitated. After the system was stirred for 10 minutes, the solid was collected by filtration and dried, and then 2.07 g of the title compound was obtained as a light brown solid. Physical property value: m / z [M + H] + 398.0. (Step 3) Synthesis of Representative Compound 12
[00320] 2 g of (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1- (piperidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide obtained in Step 2 and 2.1 g of potassium carbonate were dissolved in 20 ml of NMP and 2 ml of water, and the solution was stirred under ice cooling. 0.4 ml of acryloyl chloride was added there, and the mixture was stirred for 1 hour. Water was added there, and the pH was adjusted with hydrochloric acid. A precipitated solid was collected by filtration. The solid thus collected by filtration was purified by chromatography on silica gel (eluent: chloroform-methanol), and 1.79 g of the title compound were obtained as a white solid.
[00321] Example 13 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide (Representative compound 13).
[00322] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylate.
[00323] 300 mg of (R) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in synthetic example 1 were dissolved in 3 ml of NMP. 118 mg of benzo [d] oxazol-2-amine, 20 mg of xanthos, and 0.15 ml of N-methylmorpholine were added there, and a degassing operation was performed. Then, 7.6 mg of palladium acetate was added there, and in a carbon monoxide atmosphere, the mixture was heated to 110 ° C and stirred for 2 hours. After the mixture was cooled, 4.5 ml of methanol and 0.45 ml of a 5 N aqueous solution of sodium hydroxide were added there, and the mixture was stirred for 30 minutes at room temperature. Then, the pH was adjusted to 5.3 with 2N HCI, and a solid thus obtained was collected by filtration. The crude product was purified using a column on silica gel (eluent: chloroform-methanol), and then 257 mg of the title compound were obtained as a white solid. Physical property value: m / z [M + H] + 479.3. (Step 2) Synthesis of Representative Compound 13
[00324] 5 g of (R) -tert-butyl-3- (4-amino-3 - ((benzo [d] oxazol-2-yl) carbamoyl) - 1H-pyrazolo [3,4-d] pyrimidin- 1-yl) piperidine-1-carboxylate obtained in Step 1 were suspended in 50 ml of acotonitrile, and 7.85 g of sodium iodide were added there. 6.65 ml of trimethylsilyl chloride was added dropwise there while stirring at room temperature, and the mixture was stirred for 1 hour. 87.5 ml of water and 12.5 ml of a 5 N aqueous solution of sodium hydroxide were added there, and then the system was ice-cooled. 0.895 ml of acryloyl chloride were added in drops there, and the mixture was stirred for 1 hour under ice cooling. A solid obtained by adding water there was collected by filtration, washed with water, and dried. In this way, 4.13 g of the title compound was obtained as a white solid.
[00325] Example 14 Synthesis of (R, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 14).
[00326] The title compound was obtained as a white solid according to the procedure described in example 13, using crotonic acid chloride instead of acryloyl chloride.
[00327] Example 15 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 15).
[00328] 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added to 5 mg of (R) -tert-butyl-3- (4-amino-3 - ((5-chlorobenzo [d] oxazol-2 -yl) carbamoyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in Step 1 of example 1, and the mixture was stirred for 10 minutes. Then, the solvent was removed using an evaporator, and the system was azeotropically distilled with toluene. The residue was dissolved in 1 ml of DMF, and 8.5 g of diisopropylethylamine, 2.4 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride, and 5.5 mg of HATU were added there. The mixture was stirred for 1 hour at room temperature, and then the solution was found under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 3.96 mg of the title compound was obtained as a white solid.
[00329] Example 16 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (ethyl (methyl) amino) but- 2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 16).
[00330] The title compound was obtained as a white solid according to the procedure described in example 15, using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00331] Example 17 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (diethylamino) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 17)
[00332] The title compound was obtained as a white solid according to the procedure described in example 15, using (E) -4- (diethylamino) but-2-enoic acid hydrochloride instead of acid hydrochloride (E ) -4- (dimethylamino) but-2-enoic.
[00333] Example 18 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (isopropyl (methyl) amino) but- 2-enoyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 18)
[00334] The title compound was obtained as a white solid according to the procedure described in example 15, using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00335] Example 19 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (pyrrolidin-1-yl) but- 2-enoyl) piperidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 19)
[00336] The title compound was obtained as a white solid according to the procedure described in Example 15, using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00337] Example 20 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (piperidin-1-yl) but- 2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 20)
[00338] The title compound was obtained as a white solid according to the procedure described in Example 15, using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00339] Example 21 Synthesis of (R, E) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino ) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (Representative compound 21)
[00340] The title compound was obtained as a white solid according to the procedure described in example 15, using (R) -tert-butyl-3- (4-amino-3 - ((5- (thiophen-2 -yl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in example 3 (step 2).
[00341] Example 22 Synthesis of (R) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (but-2-inoyl) piperidin-3-yl) -1H- pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 22)
[00342] The title compound was obtained as a pale yellow solid according to the procedure described in example 15, using (R) -tert-butyl-3- (4-amino-3 - ((benzo [d] oxazole -2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in example 13 (step 1), and but-2-inoic acid instead of hydrochloride (E) -4- (dimethylamino) but-2-enoic acid.
[00343] Example 23 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5,6-dimethylbenzo [d] oxazol-2-yl) -1H-pyrazole [3 , 4-d] pyrimidine-3-carboxamide (Representative compound 23)
[00344] (Step 1) Synthesis of (R) -1- (1-acyloxypiperidin-3-yl) -4-amino-1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid
[00345] Á 1 g of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of the example synthetic 3, 15 ml of 4 N hydrochloric acid / 1,4-dioxane were added, and the mixture was stirred for 1 hour at room temperature. Then, the solvent was removed, and the system was azeotropically distilled by adding toluene there. 50 ml of chloroform and 3.8 ml of triethylamine were added to the residue. While the mixture was stirring, 780 µl of acryloyl chloride was slowly added there. After the completion of the reaction was confirmed, the reaction was terminated by the addition of 2-propanol. The solvent was removed, and an aqueous solution of formic acid was added to the residue. When the mixture was adjusted to pH 3, a solid was precipitated. A solid thus obtained was collected by filtration and dried, and then 840 mg of the title compound was obtained as a yellow solid. Physical property value: m / z [M + H] + 318.1 (Step 2) Synthesis of Representative Compound 23
[00346] 5 mg (R) -1- (1-acyloxypiperidin-3-yl) -4-amino-1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid obtained in the above step 1 were dissolved in 150 µl DMF. To this solution, 8.26 pi of diisopropylethylamine, 3.85 mg of 5.6-dimethylbenzo [d] oxazol-2-amine, and 9 mg of HATU were added. After the mixture was stirred overnight, 850 µl of DMSO was added there, and the mixture was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 1.2 mg of the title compound was obtained as a white solid.
[00347] Example 24 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 24)
[00348] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazole [3,4 -d] pyrimidin-1-yl) pyridine-1-carboxylate
[00349] It is a 100 mg solution of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidine n-3-yl) -1 H-pyrazolo [3,4-d ] pyrimidine-3-carboxylic obtained in synthetic example 3 in 5 ml of DMF, 56 mg of CDI was added, and the mixture was stirred for 1 hour at room temperature. 73 mg of 5-chlorobenzo [d] oxazol-2-amine was added there under ice cooling, and 17 mg of 60% sodium hydride was added there. After the mixture was stirred for 30 minutes under ice cooling, 1 ml of water was added there to end the reaction. The reaction solution was found, and it was purified by column on silica gel chromatography (eluent: chloroform-methanol). In this way, 114 mg of the title compound was obtained as a white solid. Physical property value: m / z [M + H] + 499.1 (Step 2) Synthesis of Representative Compound 2
[00350] 15 mg (R) -tert-butyl-3- (4-amino-3 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 1 was mixed with 1.5 ml of 4 N hydrochloric acid / 1,4-dioxane, The mixture was stirred for 1 hour, and then the solvent was removed using an evaporator. 2 ml of chloroform and 21 pi of triethylamine were added to the residue, the mixture was cooled with ice, and then 2.4 pi of acryloyl chloride was added there. After the mixture was stirred for 3 hours, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained after removing the solvent was purified using a column on silica gel (eluent: ethyl acetate: methanol). In this way, 6.8 mg of the title compound was obtained as a white solid.
[00351] Example 25 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (but-2-enoyl) pyrrolidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 25)
[00352] The title compound was obtained as a white solid according to the procedure described in example 24, using crotonic acid chloride instead of acryloyl chloride.
[00353] Example 26 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (3-methylbut-2-enoyl) pyrrolidin-3 -yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 26)
[00354] The title compound was obtained as a white solid according to the procedure described in example 24, using 3-methylbut-2-enoyl chloride instead of acryloyl chloride.
[00355] Example 27 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide (Representative compound 27)
[00356] The title compound was obtained as a white solid according to the procedure described in example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidIn-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of synthetic example 3 and benzo [d] oxazol-2-amine.
[00357] Example 28 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 28)
[00358] The title compound was obtained as a white solid according to the procedure described in example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1H -pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of synthetic example 3 and 5- (thiophen-2-yl) benzo [d] oxazol-2-amine.
[00359] Example 29 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methylbenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 29)
[00360] The title compound was obtained as a pale yellow according to the procedure described in example 24, of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of the synthetic example 3 and 5-methylbenzo [d] oxazol-2-amine.
[00361] Example 30 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 30)
[00362] The title compound was obtained as a pale yellow solid according to the procedure described in example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) - 1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of synthetic example 3 and 5-fluorobenzo [d] oxazol-2-amine.
[00363] Example 31 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (4-chlorophenyl) benzo [d] oxazol-2-yl) -1 H -pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 31) (Step 1) Synthesis of 5- (4-chlorophenyl) benzo [d] oxazol-2-amine
[00364] The title compound was obtained as a white solid according to the procedure described in Step 1 of Example 3, using 4-chlorophenylboronic acid instead of thiophen-2-ylboronic acid. Physical property value: m / z [M + H] + 245.1 (Step 2) Synthesis of Representative Compound 31
[00365] The title compound was obtained as a white solid according to the procedure described in example 24, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid from synthetic example 3 and 5- (4-chlorophenyl) benzo [d] oxazol-2-amine obtained in step 1 above.
[00366] Example 32 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 32)
[00367] Á 15 mg of (R) -tert-butyl-3- (4-amino-3 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1 H-pyrazolo [3,4- d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 1 of example 24, 1.5 ml of 4 N hydrochloric acid / 1,4-dioxane were added, and the mixture was stirred for 10 minutes. Then, the solvent was removed using an evaporator, and the residue was azeotroped with toluene. The residue was dissolved in 1 ml of DMF, and 13 µl of diisopropylethylamine, 3.7 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride, and 8.4 mg of HATU were added there. After the mixture was stirred for 1 hour at room temperature, the solution was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 4.2 mg of the title compound was obtained as a white solid.
[00368] Example 33 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (ethyl (methyl) amino) but- 2-enoyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 33)
[00369] The title compound was obtained as a white solid according to the procedure described in example 32, using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride.
[00370] Example 34 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 34)
[00371] The title compound was obtained as a white solid according to the procedure described in example 32, using (E) -4- (diethylamino) but-2-enoic acid hydrochloride instead of acid hydrochloride (E ) -4- (dimethylamino) but-2-enoic.
[00372] Example 35 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (isopropyl (methyl) amino) but- 2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 35)
[00373] The title compound was obtained as a white solid according to the procedure described in example 32, using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00374] Example 36 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (pyrrolidin-1-yl) but- 2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 36)
[00375] The title compound was obtained as a white solid according to the procedure described in example 32, using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00376] Example 37 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1- (1- (4- (piperidin-1-yl) but- 2-enoyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 37)
[00377] The title compound was obtained as a white solid according to the procedure described in example 32, using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00378] Example 38 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 38)
[00379] The title compound was obtained as a white solid according to the procedure described in example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid from synthetic example 3 and 5-methoxybenzo [d] oxazol-2-amine.
[00380] Example 39 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 39)
[00381] The title compound was obtained as a white solid according to the procedure described in example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid from synthetic example 3 and 5-cyanobenzo [d] oxazol-2-amine.
[00382] Example 40 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1 H -pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 40)
[00383] The compound was obtained as a pale yellow solid according to the procedure described in example 6, (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid from synthetic example 3 and 5- (2-methoxyethyl) benzo [d] oxazol-2-amine.
[00384] Example 41 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 41)
[00385] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5-phenylbenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazole [3,4 -d] pyrimidin-1-yl) pyrrolidine-1-carboxylate
[00386] 20 mg (R) -4-amino-1- (1- (tθrc-butyloxycarbonyl) pyrrolidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of the synthetic example 3 were suspended in 1 ml of THF, and 12 mg of CDI were added there at room temperature with stirring. The mixture was stirred overnight at room temperature, 24 mg of 5-phenylbenzo [d] oxazol-2-amine was added there, and then the mixture was cooled with ice. 172 µl of 1.0M lithium hexamethyldisilazane THF solution was added in drops there. After the mixture was stirred for 1 hour, the reaction was terminated by the addition of 30 pJ of acetic acid to it. After the solvent was removed, the residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 12.8 mg of the title compound was obtained as a white solid. Physical property value: m / z [M + H] + 541.1 (Step 2) Synthesis of Representative Compound 41
[00387] At 12.8 mg of (R) -tert-butyl-3- (4-amino-3 - ((5-phenylbenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazole [3,4 -d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in the above step 1, 1.5 ml of 4 N hydrochloric acid / 1,4-dioxane were added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the system was azeotropically distilled with 1 ml of toluene. 1 ml of chloroform and 16 pJ of triethylamine were added to the residue, and the mixture was stirred under ice cooling. 1.9 µl of acryloyl chloride was added to the solution, and the mixture was stirred for 1 hour. Then, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted using chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained. After removal of the solvent it was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 3.46 mg of the title compound was obtained as a white solid.
[00388] Example 42 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 42)
[00389] Á 5 mg of (R) -tert-butyl-3- (4-amino-3 - (((5-phenylbenzo [d] oxazol-2-yl) corbamoyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 1 of example 41, 1 ml of N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 30 minutes. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. The residue was dissolved in 1 ml of DMF, 7.9 pi of diisopropylethylamine, 2.2 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride, and 5.18 mg of HATU were added there . The mixture was stirred for 1 hour at room temperature, and then the solution was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 3.04 mg of the title compound was obtained as a white solid.
[00390] Example 43 Synthesis of (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazol-2-yl) -1H-pyrazole [ 3,4-d] pyrimidine-3-carboxamide (Representative compound 43)
[00391] (Step 1) Synthesis of (R) -tert-butyl-3- (4-amino-3 - ((5- (trifluoromethyl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazole [ 3,4-d] pyrimidin-1-yl) pyrol id i na-1-carboxylate
[00392] 32 mg (R) -4-amino-1- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid of the synthetic example 3 were suspended in 2 ml of THF, and 55 mg of CDI were added there at room temperature with stirring. The mixture was stirred overnight at room temperature, and 28 mg of 5- (trifluoromethyl) benzo [d] oxazol-2-amine were added there. Then, the mixture was cooled with ice, and 183 µl of a 1.0M THF solution of lithium hexamethyldisilazane was added dropwise there. After the mixture was stirred for 1 hour, a solid obtained by adding water there was collected by filtration. The solid was washed with a mixed hexane / ethyl acetate solvent, and then 35 mg of the title compound was obtained as a pale yellow solid. Physical property value: m / z [M + H] + 533.3 (Step 2) Compound synthesis of example 43
[00393) 500 pl of dichloromethane was added to 8 mg (R) -tert-butyl- 3- (4-amino-3 - ((5- (trifluoromethyl) benzo [d] oxazol-2-yl) carbamoyl) - 1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in the above step 1, and 200 µl of trifluoroacotamic acid were added there. The mixture was stirred for 30 minutes. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. 2 ml of chloroform and 11 µl of triethylamine were added to the residue, and the mixture was stirred under ice cooling. 1.2 pl of acryloyl chloride was added to a solution, and the mixture was stirred for 1 hour. Then, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained after removing the solvent was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 1.58 mg of the title compound was obtained as a white solid.
[00394] Example 44 Synthesis of (R, E) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2 -enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 44)
[00395] Á 5 mg of (R) -tert-butyl-3- (4-amino-3 - ((5- (trifluoromethyl) benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3, 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 1 of example 43, 500 µl of dichloromethane were added, and 200 µl of trifluoroacetic acid were later added there. The mixture was stirred for 30 minutes. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. The residue was dissolved in 1 ml of DMF, and 6.5 pl of diisopropylethylamine, 1.9 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride, and 4.3 mg of HATU were added there. The mixture was stirred for 1 hour at room temperature, and then the solution was found under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 2.88 mg of the title compound was obtained as a white solid.
[00396] Example 45 Synthesis of 1- (1-acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide (Representative compound 45)
[00397] (Step 1) Synthesis of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate
[00398] J240 mg of tert-butyl 3-hydroxyazetidine-1-carboxylate were dissolved in 2 ml of chloroform, and 290 µl of triethylamine and 130 µl of methanesulfonyl chloride were added there at 0 ° C. After the mixture was stirred for 1 hour under cooling with ice, chloroform and water were added there, and an organic layer was separated. The organic layer was washed with a saturated solution of sodium hydrogen carbonate and water and then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. 300 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine synthesized by the method described in patent document WO 2007/126841, 570 mg of potassium carbonate, and 3 ml of DMA were added to the residue , and the mixture was heated to 100 ° C and stirred for 11 hours. The mixture was cooled to room temperature, and was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by amine gel chromatography (hexane / ethyl acetate = 1: 1 -> 0: 1), and then 232 mg of the title compound was obtained as a pale yellow solid. Physical property value: m / z [M + H] +417.1
[00399] (Step 2) Synthesis of 4-amino-1- (1- (tert-butyloxycarbonyl) azetidin-3-yl) - 1 H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid
[00400] 262 mg of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate obtained in Step 1 were dissolved in 10 ml of methanol and 1 ml of triethylamine. After the atmosphere was changed to a carbon monoxide atmosphere, 51 mg of 1, r-bis (diphenylphosphino) ferrocene-palladium (ll) dichloride-dichloromethane was added there, and the mixture was heated at 80 ° C for 14 hours . After the mixture was cooled, the solvent was removed from a solution, 1 ml of 1,4-dioxane was added to the residue, and 500 µl of a 5 N aqueous solution of NaOH was later added there. The mixture was stirred for 3 hours at room temperature, and then the mixture was adjusted to pH 4 with 2N hydrochloric acid. The mixture was cooled with ice, and a solid precipitated by adding water there was collected by filtration and dried. In this way, 42 mg of the title compound was obtained as a pale brown solid. Physical property value: m / z [M + H] + 335.2
[00401] (Step 3) Synthesis of tert-butyl-3- (4-amino-3 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidine-1-carboxylate
[00402] 42 mg of 4-amino-1- (1- (tert-butyloxycarbonyl) azetidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid obtained in the above step 2 were dissolved in 3 ml of DMF, 24 mg of CDI was added there, and the mixture was stirred overnight at room temperature. 4 mg of CDI was later added there, and the mixture was stirred for 30 minutes. 42 mg of 5-chlorobenzo [d] oxazol-2-amine was added to a solution, the mixture was cooled with ice, and 10 mg of sodium hydride (60%) was added there. After the mixture was stirred for 1 hour, the reaction was stopped with water, and the solvent was removed. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 34 mg of the title compound was obtained as a white solid. Physical property value: m / z [M + H] + 485.2 (Step 4) Synthesis of Representative Compound 45
[00403] 10 mg tert-butyl-3- (4-amino-3 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin-1 -yl) azetidine-1-carboxylate obtained in step 3, 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. 1 ml of chloroform and 14 µl of triethylamine were added to the residue, and the mixture was stirred under ice cooling. 1.7 µl of acryloyl chloride was added to a solution, and the mixture was stirred for 1 hour. Then, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained after removing the solvent was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 0.69 mg of the title compound was obtained as a white solid.
[00404] Example 46 Synthesis of 7- (1-acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine -5-carboxamide (Representative compound 46)
[00405] (Step 1) Synthesis of tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate

[00406] 2.3 ml of DEAD was added to 80 ml of a solution of tetrahydrofuran of 2.00 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine, 1.86 g of N- Boc-3-hyddroxiazetidine and 3.75 g of triphenylphosphine, and a reaction liquid was stirred for 1 hour. The reaction liquid was concentrated and washed with ethyl acetate, and then 2.55 g of the title compound as a white solid was obtained. Physical property value: m / z [M + H] + 435.0
[00407] (Step 2) Synthesis of tert-butyl 3- (4-amino-5-iodine-7H-pyrrolo [2,3-d] pi ri m id i n-7-yl) azet id i na-1 -carboxylate

[00408] To 1.5 g of tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate obtained in step 1, 6 ml of tetrahydrofuran and 6 ml of 28% aqueous ammonia were added, and a reaction mixture was stirred for 1.5 hours at 100 ° C in a microwave reaction apparatus. Chloroform and water were added there, and an organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. In this way, 1.5 g of the title compound was obtained as a white solid. Physical property value: m / z [M + H] + 416.0
[00409] (Step 3) Synthesis of tert-butyl 3- (4-amino-5 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin- 7-yl) azetidine-1-carboxylate
[00410] 32 mg of tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate obtained in the above step 2, 20 mg of 5-chlorobenzo [d] oxazol-2-amine, and 28, ul of diazabicycloundecene were dissolved in 1 ml of DMF, and 9 mg of 1, r-bis (diphenylphosphino) ferrocene-palladium (ll) dichloride-dichloromethane there. The mixture was stirred for 1.5 hours at 80 ° C in a carbon monoxide atmosphere. The mixture was partitioned with chloroform and water, and the organic layer was dried over sodium sulfate. Then, a residue obtained after removing the solvent was purified by chromatography on silica gel (eluent: hexane / ethyl acetate = 1/1 -> ethyl acetate / methanol = 10/1), and then 20 mg of the title compound were obtained as a pale brown solid. Physical property value: m / z [M + H] + 484.2 (Step 4) Synthesis of Representative Compound 46
[00411] Á 5 mg of tert-butyl 3- (4-amino-5 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-7- il) azetidine-1-carboxylate obtained in the above step 3, 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. 1 ml of chloroform and 14 g of triethylamine were added to the residue, and the mixture was stirred under ice cooling. 1.7 µl of acryloyl chloride was added to a solution, and the mixture was stirred for 1 hour. Then, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained after removing the solvent was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 2.21 mg of the title compound was obtained as a white solid.
[00412] Example 47 Synthesis of (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2-enoyl) azetidin- 3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 47)
[00413] Á 5 mg of tert-butyl 3- (4-amino-5 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-7- il) azetidine-1-carboxylate obtained in Step 3 of example 46, 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. The residue was dissolved in 1 ml of DMF, 14.4 pi of diisopropylethylamine, 4.1 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride and 9.4 mg of HATU were added there. After the mixture was stirred for 1 hour at room temperature, the solution was found under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 4.67 mg of the title compound was obtained.
[00414] Example 48 Synthesis of (R) -7- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrole [2,3 -d] pyrimidine-5-carboxamide (Representative compound 48)
[00415] (Step 1) Synthesis of (R) -tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate
[00416] 5.00 g of 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine synthesized by the method described in patent document WO 2005/042556, 19.1 g of (S) -tert-butyl 3 - (methylsulfonyloxy) pyrrolidine-1-carboxylate, and 23.5 g of cesium carbonate were suspended in 25 ml of acetonitrile, and the mixture was heated for 3 hours at 60 ° C. After the suspension had not been cooled, water and methanol were added there, and a solid thus obtained was collected by filtration and dried. In this way, 5.65 g of the title compound was obtained as a pale brown solid.
[00417] (Step 2) (R) -tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrol idin-1-carboxylate
[00418] Á 5 g of (R) -tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in the above step 1.40 ml of 28% aqueous ammonia was added, and a reaction liquid was stirred for 1.5 hours at 100 ° C in a microwave reaction apparatus. The mixture was stirred for 1 hour under ice cooling, and a precipitated solid was collected by filtration and washed with cold methanol. In this way, 3.91 g of the title compound was obtained as a white solid.
[00419] (Step 3) Synthesis of (R) -tert-butyl 3- (4-amino-5 - ((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrole [2,3- d] pyrimidin-7-yl) pyrrolidine-1-carboxylate
[00420] 93 mg of tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in the above step 2, 110 mg of 5-chlorobenzo [d] oxazol-2-amine, and 100 p.1 of diazabicycloundecone were dissolved in 2 ml of DMF, and 35 mg of 1, T-bis (diphenylphosphino) ferrocene-palladium (ll) dichloride-dichloromethane there. The mixture was stirred for 2.5 hours at 80 ° C in a carbon monoxide atmosphere. The mixture was partitioned with chloroform and water, and the organic layer was dried over sodium sulfate. Then, a residue obtained after removing the solvent was purified by chromatography on silica gel (eluent: hexane / ethyl acetate = 1/1 -> ethyl acetate / methanol = 10/1), and then 106 mg of the title compound were obtained as a pale brown solid. Physical property value: m / z [M + H] + 498.1 (Step 4) Synthesis of Representative Compound 48
[00421] Á 20 mg of (R) -tert-butyl 3- (4-amino-5 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrole [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in the above step 3, 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. 2 ml of chloroform and 28 pJ of triethylamine were added to the residue, and the mixture was stirred under ice cooling. 3.2 µl of acryloyl chloride was added to a solution, and the mixture was stirred for 1 hour. Then, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained after removing the solvent was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 3.52 mg of the title compound was obtained as a white solid.
[00422] Example 49 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 7- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 49)
[00423] Á 13 mg of (R) -tert-butyl 3- (4-amino-5 - (((5-chlorobenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrole [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in Step 3 of example 48, 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. The residue was dissolved in 1 ml of DMF, and 14.4 µl of diisopropylethylamine, 4.1 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride and 9.6 mg of HATU were added there. The mixture was stirred for 1 hour at room temperature, and then the solution was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 6.66 mg of the title compound was obtained.
[00424] Example 50 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 7- (1 - (4- (ethyl (methyl) amino) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 50)
[00425] The title compound was obtained as a white solid according to the procedure described in example 49, using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00426] Example 51 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 7- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 51)
[00427] The title compound was obtained as a white solid according to the procedure described in example 49, using (E) -4- (diethylamino) but-2-enoic acid hydrochloride instead of acid hydrochloride (E ) -4- (dimethylamino) but-2-enoic.
[00428] Example 52 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 7- (1- (4- (isopropyl (methyl) amino) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 52)
[00429] The title compound was obtained as a white solid according to the procedure described in example 49, using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00430] Example 53 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 7- (1- (4- (pyrrolidin-1-yl) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 53)
[00431] The title compound was obtained as a white solid according to the procedure described in example 49, using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00432] Example 54 Synthesis of (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 7- (1 - (4- (piperidin-1-yl) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 54)
[00433] The title compound was obtained as a white solid according to the procedure described in Example 49, using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00434] Example 55 Synthesis of (R) -7- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7H-pyrrole [2,3 -d] pyrimidine-5-carboxamide (Representative compound 55
[00435] (Step 1) Synthesis of (R) -tert-butyl 3- (4-amino-5 - ((5-phenylbenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrole [2,3- d] pyrimidin-7-yl) pyrrolidine-1-carboxylate
[00436] The title compound was obtained as a brown solid according to the procedure described in Step 3 of example 48, using 5-phenylbenzo [d] oxazol-2-amine instead of 5-chlorobenzo [d] oxazole- 2-amine. Physical property value: m / z [M + H] + 540.3 (Step 2) Synthesis of Representative Compound 55
[00437] The title compound was obtained as a white solid according to the procedure described in Step 4 of example 48, using (R) -tert-butyl 3- (4-amino-5 - ((5-phenylbenzo [ d] oxazol-2-yl) carbamoyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in step 1 above.
[00438] Example 56 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 7- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 56)
[00439] Á 13 mg of (R) -tert-butyl 3- (4-amino-5 - (((5-phenylbenzo [d] oxazol-2-yl) carbamoyl) -7H-pyrrole [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate obtained in Step 1 of example 55, 1 ml of 4 N hydrochloric acid / 1,4-dioxane was added, and the mixture was stirred for 1 hour. Then, the solvent was removed, and the residue was azeotropically distilled with 1 ml of toluene. The residue was dissolved in 1 ml of DMF, and 14.4 pi of diisopropylethylamine, 4.1 mg of (E) -4- (dimethylamino) but-2-enoic acid hydrochloride, and 9.6 mg of HATU were added there. After the mixture was stirred for 1 hour at room temperature, the solution was concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 6.66 mg of the title compound was obtained.
[00440] Example 57 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 7- (1- (4- (ethyl (methyl) amino) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 57)
[00441] The title compound was obtained as a white solid according to the procedure described in example 56, using (E) -4- (ethyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00442] Example 58 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 7- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 58)
[00443] The title compound was obtained as a white solid according to the procedure described in example 56, using (E) -4- (diethylamino) but-2-enoic acid hydrochloride instead of acid hydrochloride (E ) -4- (dimethylamino) but-2-enoic.
[00444] Example 59 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 7- (1- (4- (isopropyl (methyl) amino) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 59)
[00445] The title compound was obtained as a white solid according to the procedure described in example 56, using (E) -4- (isopropyl (methyl) amino) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00446] Example 60 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 7- (1- (4- (pyrrolidin-1-yl) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 60)
[00447] The title compound was obtained as a white solid according to the procedure described in example 56, using (E) -4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00448] Example 61 Synthesis of (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) - 7- (1- (4- (piperidin-1-yl) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide (Representative compound 61)
[00449] The title compound was obtained as a white solid according to the procedure described in example 56, using (E) -4- (piperidin-1-yl) but-2-enoic acid hydrochloride instead of hydrochloride of (E) -4- (dimethylamino) but-2-enoic acid.
[00450] Example 62 Synthesis of (R, E) -7- (3 - ((2- (4- (4- (3- (4-amino-3- (benzo [d] oxazol-2-ylcarbamoyl) - 1 H-pyrazolo [3,4-d] pyrimidin-1-yl) pi peridin n-1 -yl) -4-oxobut-2-en-1-yl) pi pe razi n-1 -yl) ethyl) amino) -3-oxopropyl) 5,5-difluoro-1,3-dimethyl-5H-dipyrrolo [1,2-c: 2 ', rf] [1,3,2] diazaborinin-4-ium-5-uida (Representative compound P-1)
[00451] (Step 1) Synthesis of (E) -4- (4- (2 ((tert-butoxycarbonyl) amino) ethyl) piperazin-1-yl) but-2-enoic acid
[00452] 2 g of tert-butyl- (2- (piperazin) -1-yl) ethyl) carbamate were dissolved in 20 ml of DMSO, and 1.35 ml of triethylamine was added there. To this solution, (E) -methyl 4-bromobut-2-enoate was added in a total amount of 1.14 ml at room temperature. After the mixture was stirred for 1.5 hours, the solution was added to a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was dried over sodium sulfate, then the solvent was removed, and the residue was purified by chromatography on silica gel (eluent: chloroform: methanol). 10 ml of triethylamine and 10 ml of water were added to the product obtained, and the mixture was stirred overnight at 100 ° C. The solvent was removed from a reaction solution, and 2.05 g of the title compound was obtained as an orange amorphous material.
[00453] (Step 2) Synthesis of (R, E) -tert-butyl (2- (4- (4- (3- (4-amino-3- (benzo [d] oxazol-2-ylcarbamoyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) pi perid i n-1 -yl) -4-oxobut-2-en-1-yl) pi pe razi n-1 -yl) ethyl) carbamate
[00454] 200 mg (R) -tert-butyl-3- (4-amino-3 - ((benzo [d] oxazol-2-yl) carbamoyl) -1H-pyrazolo [3,4-d] pyrimidin- 1-yl) piperidine-1-carboxylate obtained in Step 1 of example 13 were dissolved in 3 ml of chloroform, and 1 ml of trifluoroacotamic acid was added there at room temperature. After 1 hour, the solvent was removed, the residue was dissolved in acetonitrile, and triethylamine was added there. Then, the solvent was removed, the residue was redissolved in chloroform / methanol, and the solvent was removed. The residue was dissolved in 5 ml of DMF, and 176 mg of (E) -4- (4- (2 ((tert-butoxycarbonyl) amino) ethyl) piperazin-1-yl) but-2-enoic acid obtained in step above 1 was added there. 104 mg of WSC was added there, and the mixture was stirred. After 2 hours, ethyl acetate was added there, and an organic layer was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over sodium sulfate, then the solvent was removed, and the residue was purified by chromatography on silica gel (eluent: chloroform: methanol). In this way, 128.4 mg of the title compound was obtained.
[00455] (Step 3) Synthesis of (R, E) -4-amino-1- (1- (4- (4- (2-aminoethyl) piperazin-1-yl) but-2-enoyl) piperidin-3 -yl) -N- (benzo [d] oxazol-2-ylcarbamoyl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide
[00456] 128 mg of (R, E) -tert-butyl (2- (4- (4- (3- (4-amino-3- (benzo [d] oxazol-2-ylcarbamoyl) -1H-pyrazole [ 3,4-d] pyrimidin-1-yl) piperidin-1-yl) -4-oxobut-2-en-1-yl) piperazin-1-yl) ethyl) carbamate obtained in the above step 2 were dissolved in 2 ml chloroform, and 1 ml of trifluoroacetic acid was added there. After 10 minutes, the reaction solution was concentrated and dissolved in acetonitrile. Triethylamine was added there, and the mixture was concentrated again. The residue was purified by amine gel chromatography (eluent: chloroform: methanol), and 98.1 mg of the title compound was obtained. (Step 4) Synthesis of Representative Compound P-1
[00457] 93 mg of (R, E) -4-amino-1- (1- (4- (4- (2-aminoethyl) piperazin-1-yl) but-2-enoyl) piperidin-3-yl) -N- (benzo [d] oxazol-2-ylcarbamoyl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide obtained in the above step 3 were dissolved in 10 ml of chloroform, and 73 mg of 7- ( 2-carboxyethyl) -5,5-difluoro-1,3-dimethyl-5H-dipyrrolo [1,2-c: 2,, T-f] [1,3,2] diazaborinin-4-ium-5-uida , 22 mg HOBt and 48 mg WSC were added there. After the mixture was stirred for 2 hours, the reaction solution was partitioned with chloroform and the saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and then found, and the residue was purified by amine gel chromatography (eluent: chloroform: methanol). 98.1 mg of the title compound was obtained.
[00458] Example 63 Synthesis of 4-amino-N- (benzo [d] oxazol-2-yl) -1 - ((R) -1 - ((E) - 4- (4- (2- (5- ((3aS, 4S, 6aR) -2-oxohexahydro-1H-thieno [3,4-d] imidazol-4-yl) pentanamido) ethyl) piperazin-1-yl) but-2-enoyl) piperidin-3-yl ) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound P-2)
[00459] It is a 3 mg solution of (R, E) -4-amino-1- (1- (4- (4- (2-aminoethyl) piperazin-1-yl) but-2-enoyl) piperidin- 3-yl) -N- (benzo [d] oxazol-2-ylcarbamoyl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide obtained in Step 3 of example 62 in 0.5 ml of DMF, 1 , 5 mg of BIOTIN-NHS (registered trademark) and 4 µl of triethylamine were added and the mixture was stirred overnight. 0.5 ml of DMSO was added to a solution, and the mixture was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 1.0 mg of the title compound was obtained as a white solid.
[00460] Example 64 Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (7-chlorobenzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide (Representative compound 64)
[00461] (Step 1) Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid
[00462] Á 10 g of (R) -4-amino-1- (1- (tert-butyloxycarbonyl) piperidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid obtained in synthetic example 2, 50 ml of 4 N hydrochloric acid / 1,4-dioxane were added. After the mixture was stirred for 1 hour, the solvent was removed using an evaporator. 140 ml of chloroform and 25 ml of triethylamine were added to the residue, and after the mixture was cooled with ice, 2.23 ml of acryloyl chloride were added there. The mixture was stirred for 1.5 hours, and then the solvent was removed using an evaporator. An aqueous solution of formic acid at pH 3.0 was added to the residue, and the mixture was stirred for 2 hours. Then, a precipitate was collected by filtration, and was dried under reduced pressure. In this way, 8.93 g of the title compound was obtained as an off-white brown solid.
[00463] (Step 2) Synthesis of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (7-chlorobenzo [d] oxazol-2-yl) -1H-pyrazole [3 , 4-d] pyrimidine-3-carboxamide
[00464] 5 mg (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-1H-pyrazolo [3,4-d] pyrimidine-3-carboxylic acid obtained in Step 1 were dissolved in 150 , µL of DMF, and then 8.2 µl of diisopropylethylamine, 4.0 mg of 7-chlorobenzo [d] oxazol-2-amine and 9.0 mg of HATU were added. The mixture was stirred for 1 hour. 850 µl of DMSO was added to the reaction solution, and the mixture was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)). In this way, 0.36 mg of the title compound was obtained as a white solid.
[00465] Example 65 Synthesis of (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide (Representative compound 65)
[00466] (Step 1) Synthesis of (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate
[00467] The title compound as an oily compound was obtained from (R) -N-Boc-3-pyrrolidinol according to the procedure described in synthetic example 3.
[00468] (Step 2) Synthesis of (S) -tert-butyl 3- (4-amino-3-iodo-1 H-pyrazolo [3,4- d] pi rim id in-1 -yl) pyrrole id i na-1-carboxylate
[00469] The title compound was obtained as a pale yellow solid from 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine- 1-carboxylate according to the procedure described in synthetic example 3 (step 2).
[00470] (Step 3) Synthesis of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop -2-en-1-one
[00471] Á 500 mg of (S) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 2 , 5 ml of chloroform and 1.7 ml of trifluoroacetic acid were added. After the mixture was stirred for 1 hour, the solvent was removed using an evaporator. 12 ml of chloroform and 810 µl of triethylamine were added to the residue, and after the mixture had been cooled with ice, 89 µl of acryloyl chloride was added there. After the mixture was stirred for 30 minutes, the reaction was terminated with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was dried over sodium sulfate, and then a residue obtained after removing the solvent was purified using a column on silica gel (eluent: ethyl acetate: methanol). In this way, 350 mg of the title compound was obtained as a white solid.
[00472] (Step 4) Synthesis of (S) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazole [3,4 -d] pyrimidine-3-carboxamide
[00473] 20 mg of (S) -1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2- en-1-one obtained in Step 3 were dissolved in 5.20 ml of DMF, and 13 mg of benzo [d] oxazol-2-amine, 3.65 mg of PdCl2 (PPh3) 2 and 23, uL of DBU were added there. The mixture was stirred for 2 hours at 120 degrees in a carbon monoxide atmosphere, and then the solvent was removed using an evaporator. DMSO was added to the residue, and the mixture was purified by preparative reverse phase HPLC purification (water / acetonitrile (0.1% formic acid)), and then 1.9 mg of the title compound was obtained as a white solid.
[00474] Example 66 Synthesis of 1 - ((1-acryloylpyrrolidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 66)
[00475] (Step 1) Synthesis of tert-butyl 3 - (((4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) methyl) pi rol idi na- 1-carboxylate
[00476] 464 mg of the title compound were obtained as a pale yellow solid from 300 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and 396 mg of tert-butyl 3- ( bromomethyl) pyrrolidine-1-carboxylate according to the procedure described in synthetic example 3 (step 2).
[00477] (Step 2) Synthesis of 1- (3 - ((4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) methyl) pyro idi n- 1 -il) prop-2-en-1-one
[00478] 274 mg of the title compound was obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 464 mg of tert-butyl 3 - (((4-amino-3-iodo-1H-pyrazole) [3,4-d] pyrimidin-1-yl) methyl) pyrrolidine-1-carboxylate obtained in Step 1.
[00479] (Step 3) Synthesis of 1 - ((1-acryloylpyrrolidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazole [3,4- d] pyrimidine-3-carboxamide
[00480] 3.2 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (3- ((4-amino-3-iodo-1H-pyrazole [ 3,4-d] pyrimidin-1-yl) methyl) pyrrolidin-1-yl) prop-2-en-1-one obtained in Step 2.
[00481] Example 67 Synthesis of 1 - ((1-acryloylpiperidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 67)
[00482] (Step 1) Synthesis of tert-butyl 3 - (((4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) methyl) pi perid i na- 1-carboxylate
[00483] 375 mg of the title compound were obtained as a pale yellow solid of 300 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and 416 mg of tert-butyl 3- (bromomethyl) pyrrolidine-1-carboxylate according to the procedure described in synthetic example 3 (step 2).
[00484] (Step 2) Synthesis of 1- (3 - ((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop- 2-en-1-one
[00485] 228 mg of the title compound were obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 375 g of tert-butyl-3 - (((4-amino-3-iodo-1H- pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidine-1-carboxylate obtained in Step 1.
[00486] (Step 3) Synthesis of 1 - ((1-acryloylpiperidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazole [3,4 -d] pyrimidine-3-carboxamide
[00487] 1.4 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (3- ((4-amino-3-iodo-1H- pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1-one obtained in Step 2.
[00488] Example 68 Synthesis of 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 68)
[00489] (Step 1) Synthesis of tert-butyl 4 - (((4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) methyl) pi perid i na- 1-carboxylate
[00490] 120 mg of the title compound was obtained as a pale yellow solid from 100 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and 130 mg of tert-butyl 4- ( bromomethyl) piperidine-1-carboxylate according to the procedure described in synthetic example 3 (step 2).
[00491] (Step 2) Synthesis of 1- (4 - ((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop- 2-en-1-one
[00492] 85 mg of the title compound were obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 120 mg of tert-butyl 4 - (((4-amino-3-iodo-1H-pyrazole) [3,4-d] pyrimidin-1-yl) methyl) piperidine-1-carboxylate obtained in Step 1.
[00493] (Step 3) Synthesis of 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide
[00494] 3.12 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (4- ((4-amino-3-iodine-1H- pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1-one obtained in Step 2.
[00495] Example 69 Synthesis of 1- (1-acryloylpiperidin-4-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 -carboxamide (Representative compound 69).
[00496] (Step 1) Synthesis of tert-butyl 4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidine-1-carboxylate
[00497] The title compound was obtained as a pale yellow solid from 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and tert-butyl 4-bromopiperidine-1-carboxylate according to the procedure described in synthetic example 3 (step 2).
[00498] (Step 2) Synthesis of 1- (4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en -1 -one
[00499] The title compound was obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, from tert-butyl 4- (4-amino-3-iodo-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylate obtained in Step 1.
[00500] (Step 3) Synthesis of 1- (1-acryloylpiperidin-4-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide
[00501] 24 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (4- (4-amino-3-iodo-1H-pyrazole) [3 , 4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one obtained in Step 3.
[00502] Example 70 Synthesis of 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 70)
[00503] (Step 1) Synthesis of tert-butyl 3 - ((methylsulfonyloxy) methyl) azetidine-1-carboxylate
[00504] The title compound was obtained as an oily compound from tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate according to the procedure described in synthetic example 3.
[00505] (Step 2) Synthesis of tert-butyl 3 - (((4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) methyl) azetidine-1-carboxylate
[00506] The title compound was obtained as a pale yellow solid according to the procedure described in synthetic example 3 (step 2) from 200 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4 -amine and tert-butyl 3- ((methylsulfonyloxy) methyl) azetidine-1-carboxylate obtained in Step 1.
[00507] (Step 3) Synthesis of 1- (3 - ((4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) methyl) azetidI n-1 - il) propyl-2-en-1-one
[00508] The title compound was obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, from tert-butyl 3 - ((4-amino-3-iodo-1 H-pyrazolo [3,4 -d] pyrimidin-1-yl) methyl) azetidine-1-carboxylate obtained in Step 2.
[00509] (Step 4) Synthesis of 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazole [3,4- d] pyrimidine-3-carboxamide
[00510] 2.44 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (3- ((4-amino-3-iodo-1H-pyrazole [ 3,4-d] pyrimidin-1-yl) methyl) azetidin-1-yl) propyl-2-en-1-one obtained in Step 3.
[00511] Example 71 Synthesis of 1 - ((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide (Representative compound 71)
[00512] (Step 1) Synthesis of (1R, 4RH - ((tert-butoxycarbonyl) amino) cyclohexylmethanesulfonate
[00513] 780 mg of the title compound were obtained as an oily compound of 500 mg of tert-butyl (1R, 4R) -4-cyclohexylcarbamate according to the procedure described in synthetic example 3.
[00514] (Step 2) Synthesis of tert-butyl ((1S, 4S) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexylchorbamate
[00515] 614 mg of the title compound were obtained as a pale yellow solid according to the procedure described in synthetic example 3 (step 2) from 630 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin -4-amine and 780 mg of (1R, 4R) - 4 - ((tert-butoxycarbonyl) amino) cyclohexylmethanesulfonate obtained in Step 1.
[00516] (Step 3) Synthesis of N - ((1S, 4S) ^ l- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide
[00517] 137 mg of the title compound were obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 200 mg of tert-butyl ((1 S, 4S) -4- (4-amino- 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) cyclohexylcarbamate obtained in Step 2.
[00518] (Step 4) Synthesis of 1 - ((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazole [3,4-d ] pyrimidine-3-carboxamide
[00519J2.08 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of N- ((1S, 4S) -4- (4-amino-3-iodine -1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide obtained in Step 3.
[00520] Example 72 Synthesis of 1 - ((1R, 4R) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide (Representative compound 72)
[00521] (Step 1) Synthesis of (1S, 4S) -4 - ((tert-butoxicorbonyl) amino) cyclohexylmethanesulfonate
[00522] 704 mg of the title compound were obtained as an oily compound from 500 mg of tert-butyl (1S, 4S) -4-cyclohexylcarbamate according to the procedure described in synthetic example 3.
[00523] (Step 2) Synthesis of tert-butyl ((1R, 4R) -4- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexylchorbamate
[00524] 375 mg of the title compound were obtained as a pale yellow solid according to the procedure described in synthetic example 3 (step 2) from 570 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin -4-amine and 704 mg (1S, 4S) - 4 - ((tert-butoxycarbonyl) amino) cyclohexylmethanesulfonate obtained in Step 1.
[00525] (Step 3) Synthesis of N - ((1R, 4R) -4- (4-amino-3-iodo-1H-pyrazolo [3,4- d] pyrimidin-1-yl) cyclohexyl) acrylamide
[00526] 90 mg of the title compound was obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 200 mg of tert-butyl ((1 R, 4R) -4- (4-amino- 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-1 - yl) cyclohexylcarbamate obtained in Step 2.
[00527] (Step 4) Synthesis of 1 - ((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazole [3,4-d ] pyrimidine-3-carboxamide
[00528] 3.43 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of N- ((1S, 4S) -4- (4-amino-3-iodine -1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide obtained in Step 3.
[00529] Example 73 Synthesis of (S, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin- 3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Representative compound 73)
[00530] (Step 1) (S) -tert-butyl 3- (4-amino-3- (benzo [d] oxazol-2-ylcarbamoyl) - 1H-pyrazolo [3,4-d] pyrimidin-1-yl ) pyrrolidine-1-carboxylate
[00531] The title compound was obtained according to the procedure described in Step 4 of example 65, of (S) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 2 of example 65.
[00532] (Step 2) Synthesis of (S, E) -amino-N- (benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin- 3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
[00533] 13.8 mg of the title compound were obtained as a white solid according to the procedure described in example 32, of 20 mg of (S) -tert-butyl 3- (4- amino-3- (benzo [d] oxazole -2-ylcarbamoyl) -1 H-pyrazolo [3,4-d] pyrimidin-1-i I) pyrrolidin-1 - carboxylate obtained in Step 1.
[00534] Example 74 Synthesis of 1- (1-acryloylazetidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 -carboxamide (Representative compound 74. (step 1) Synthesis of tert-butyl 3- (methylsulfonyloxy) azetidine-1-carboxylate
[00535] 774 mg of the title compound was obtained as a 500 mg oily compound of tert-butyl 3-hydroxyazetidine-1-carboxylate according to the procedure described in synthetic example 3.
[00536] (Step 2) Synthesis of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1 -yl) azetidine-1-carboxylate
[00537] 690 mg of the title compound were obtained as a pale yellow solid according to the procedure described in Synthetic Example 3 (step 2) of 670 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4 -amine and 774 mg of tert-butyl 3- (methylsulfonyloxy) azetidine-1-carboxylate obtained in Step 1.
[00538] (Step 3) Synthesis of 1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id in-1-yl) azetid in-1-yl) propi l-2-en-1-one
[00539] 129 mg of the title compound were obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 200 mg of tert-butyl 3- (4-amino-3-iodo-1 H-pyrazole [3,4-d] pyrimidin-1-yl) azetidine-1-carboxylate obtained in Step 2.
[00540] (Step 4) Synthesis of 1 - ((1-acryloylazetidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
[00541] The title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) propyl-2-en-1-one obtained in Step 3.
[00542] Example 75 Synthesis of 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (Representative compound 75)
[00543] (Step 1) 3.36 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1 - (3 - ((4-amino-3- iodo-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl l) azetid i n-1 -yl) propyl-2-en-1-one obtained in Step 3 of example 70 and 5.2 mg of 5-fluorobenzo [d] oxazol-2-amine.
[00544] Example 76 Synthesis of 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (Representative compound 76)
[00545] (Step 1) 3.76 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, 10 mg of 1 - (3 - ((4-amino-3- iodo-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl l) azetid i n-1 -yl) propyl-2-en-1-one obtained in Step 3 of example 70 and 5.2 mg of 5-chlorobenzo [d] oxazol-2-amine.
[00546] Example 77 Synthesis of 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (Representative compound 77)
[00547] (Step 1) 6.37 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (4 - ((4-amino-3- iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1-one obtained in Step 2 of example 68 and 4.8 mg of 5- fluorobenzo [d] oxazol-2-amine.
[00548] Example 78 Synthesis of 1 - ((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide (Representative compound 78)
[00549] (Step 1) 1.93 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of N - ((1S, 4S) -4- (4 -amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide obtained in Step 3 of example 72 and 5.2 mg of 5-chlorobenzo [d] oxazol-2-amine .
[00550] Example 79 Synthesis of 1- (1-acryloylazetidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide (Representative compound 79)
[00551] (Step 1) 2.21 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1 - (3- (4-amino-3-iodine -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) azetid in-1-yl) propyl-2-en -1 -one obtained in Step 3 of example 74 and 4.8 mg of 5- fluorobenzo [d] oxazol-2-amine.
[00552] Example 80 Synthesis of 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide (Representative compound 80)
[00553] (Step 1) 4.30 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (4 - ((4-amino-3- iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1-one obtained in Step 2 of example 68 and 5.2 mg of 5- chlorobenzo [d] oxazol-2-amine.
[00554] Example 81 Synthesis of 1 - ((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide (Representative compound 81)
[00555] (Step 1) 2.91 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of N - ((1S, 4S) -4- (4 -amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide obtained in Step 3 of example 72 and 4.8 mg of 5-fluorobenzo [d] oxazol-2-amine .
[00556] Example 82 Synthesis of 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 -carboxamide (Representative compound 82) (Step 1) Synthesis of tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate
[00557] The title compound was obtained as an oily compound of N-Boc-3-pyrrolidinol according to the procedure described in synthetic example 3.
[00558] (Step 2) Synthesis of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pi rim id In-1 -yl) pyrrole id i-na-1-carboxylate
[00559] The title compound was obtained as a pale yellow solid of 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate according to the procedure described in example 65 (step 2).
[00560] (Step 3) Synthesis of 1- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en -1 -one
[00561] The title compound was obtained as a white solid according to the procedure described in Step 3 of example 65, from tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate obtained in Step 2.
[00562] (Step 4) Synthesis of 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide
[00563] 3.9 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1- (3- (4-amino-3-iodo-1H-pyrazole) [3 , 4-d] pyrimidin-1-yl) pyrrolopyrrolidin-1-yl) prop-2-en-1-one obtained in Step 3.
[00564] Example 83 Synthesis of 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide (Representative compound 83)
[00565] (Step 1) 4.09 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1 - (3- (4-amino-3-iodine-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolopyrrol id in-1-yl) prop-2-en-1-one obtained in Step 3 of example 82 and 4.8 mg of 5-fluorobenzo [ d] oxazol-2-amine.
[00566] Example 84 Synthesis of 1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide (Representative compound 84)
[00567] (Step 1) 3.47 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of 1 - (3- (4-amino-3-iodine -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolopyrrol id i n-1 -yl) prop-2-en-1-one obtained in Step 3 of example 82 and 5.2 mg of 5-chlorobenzo [d] oxazol-2-amine.
[00568] Example 85 Synthesis of 1- (3-acrylamidopropyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide (Compound representative 85.
[00569] (step 1) Synthesis of tert-butyl (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) propyl) carboxylate
[00570] 223 mg of the title compound was obtained as a pale yellow solid of 200 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and 273 mg of tert-butyl (3-bromopropyl) carboxylate according to the procedure described in synthetic example 3 (step 2).
[00571] (Step 2) N- (3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) propyl) acrylamide
[00572] 125 mg of the title compound was obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 240 mg of tert-butyl (3- (4-amino-3-iodine-1 H- pyrazolo [3,4-d] pyrimidin-1-yl) propyl) carboxylate obtained in Step 1.
[00573] (Step 3) Synthesis of 1- (3-acrylamidopropyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
[00574] 3.2 mg of the title compound was obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of N- (3- (4-amino-3-iodo-1H-pyrazole) [3 , 4-d] pyrimidin-1-yl) propyl) acrylamide obtained in Step 3.
[00575] Example 86 Synthesis of 1- (2-acrylamidoethyl) -4-amino-N- (hβn7n [ri] nxa7ni-2-yl) -1H-pyrazolo [3.4-d] pyrimidine-3-carboxamide (Representative compound 86 )
[00576] (step 1) Synthesis of tert-butyl (2- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) carboxylate
[00577] 239 mg of the title compound were obtained as a pale yellow solid of 200 mg of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine and 257 mg of tert-butyl (2-bromoethyl) carboxylate according to the procedure described in synthetic example 3 (step 2).
[00578] (Step 2) N- (2- (4-amino-3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethyl) acrylamide
[00579] 140 mg of the title compound were obtained as a pale yellow solid according to the procedure described in Step 3 of example 65, of 239 mg of tert-butyl (2- (4-amino-3-iodo-1H-pyrazole) [3,4-d] pyrimidin-1-yl) ethyl) carboxylate obtained in Step 1.
[00580] (Step 3) Synthesis of 1- (2-acrylamidoethyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide
[00581] 1.8 mg of the title compound were obtained as a white solid according to the procedure described in Step 4 of example 65, of 10 mg of N- (2- (4-amino-3-iodo-1H-pyrazole) [3,4-d] pyrimidin-1-yl) ethyl) acrylamide obtained in Step 2.
[00582] Reference Example 1 Synthesis of (R) -1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1 -il) prop-2-en-1-one (Reference compound 1)
[00583] The title compound was obtained as a white solid by synthesizing the compound according to the procedure described in the method presented by patent document WO 2008/121742.
[00584] Next, the structural formulas and physical property value of the representative Compounds and Reference Compound 1 will be presented in Table 1 to Table 44. TABLE 1
Table 2

Table 3
Table 4
Table 5

Table 6

Table 7

Table 8

Table 9
Table 10


Table 11
Table 12

Table 13

Table 14
Table 15

Table 16

Table 17

Table 18
Table 19
Table 20

Table 21

Table 22

Table 23
Table 24

Table 25

Table 26
Table 27

Table 28

Table 29

Table 30

Table 31

Table 32
Table 33

Table 34
Table 35

Table 36

Table 37
Table 38

Table 39

Table 40
Table 41

Table 42

Table 43
Table 44
Test example 1 Measurement of BTK inhibitory action (in vitro)
[00585] Regarding the establishment of the conditions for a method of measuring the inhibitory activity of a compound against BTK kinase activity in vitro, it is described in the price list of consumable reagent suppliers for LabChip series (registered trademark) of PerkinElmer, Inc. that FL-PEPTIDE 2 corresponds to a substrate peptide for the measurement of BTK kinase activity. Therefore, FL-PEPTIDE 2 was used as a substrate. The purified recombinant human BTK protein used in the test was purchased from Cama Biosciences, Inc.
[00586] Regarding the measurement of the inhibitory activity of the compounds, first the compounds of the present invention were diluted in stages with dimethyl sulfoxide (DMSO). Next, BTK Protein, a substrate peptide (final concentration was 1 pM), magnesium chloride (final concentration was 10 mM), ATP (final concentration was 45 pM), and a DMSO Solution of the compounds of the present invention (final concentration of DMSO was 5%) were added to a buffer solution for kinase reaction (20 mM HEPES (pH 7.5), 2 mM dithiothitol, 0.01% Triton X-100), and after the solution was incubated for 40 minutes at 25 ° C, the kinase reaction was performed. The reaction was terminated by adding EDTA there to obtain a final concentration of 30 mM. Finally, a quantity of substrate that was not phosphorylated (S) and a phosphorylated peptide (P) were separated and detected by capillary microchannel electrophoresis using a LabChip EZ II reader (PerkinElmer, Inc.). The amounts of phosphorylation reaction were determined from the respective peak heights of S and P, and the concentration of compound at which the phosphorylation reaction could be suppressed by 50% was defined as an IC50 (nM) value. The results are shown in the following tables. [Table 45]


[Table 46]


[00587] From these test results it was found that the compounds of the present invention show an inhibitory activity against BTK in vitro.
[00588] Example of selectivity of 2 BTK inhibition test in comparison to EGFR kinase inhibitory activity (in vitro) 1) Mediation of BTK inhibitory action
[00589] BTK inhibitory action was measured in the same way as in Test example 1. 2) Mediation of EGFR inhibitory activity
[00590] Regarding the establishment of the conditions for a method of measuring the inhibitory activity of the compound against in vitro EGFR kinase inhibitory activity, it is described in the consumable reagent supply price list for PerkinElmer's LabChip series (registered trademark), Inc. that FL-PEPTIDE 22 corresponds to a substrate peptide for the mediation of EGFR kinase activity. Therefore, a biotinated peptide (biotin- EEPLYWSFPAKKK) was produced by reference to the amino acid sequence of the peptide. A purified recombinant human EGFR protein used in the test was purchased from Cama Biosciences, Inc.
[00591] Regarding the mediation of the inhibitory activity of the compounds, first the compounds of the present invention were diluted in stages with dimethyl sulfoxide (DMSO). Then, EGFR protein, a substrate peptide (final concentration was 250 nM), magnesium chloride (final rancentation was 10 mM), manganese chloride (final concentration was 10 mM), ATP (final concentration was 1.5 µM) , and the DMSO solution of the compound of the present invention (final concentration of DMSO was 2.5%) was added to a buffer solution for kinase reaction (20 mM HEPES (pH 7.5), 2 mM dithiothitol, 0.01% Triton X-100), and after the solution was incubated for 120 minutes at 25 ° C, the kinase reaction was performed. The reaction was terminated by adding EDTA there to obtain a final concentration of 24 mM. Then, a detection liquid containing PT-labeled anti-phosphorylated PT66 antibody (PerkinElmer, Inc.) and SURELIGHT APC-SA (PerkinElmer, Inc.) was added there, and the system was allowed to rest for 2 hours or more under room temperature. Finally, the amount of fluorescence after irradiation of excitation light with a wavelength of 337 nm was measured at two wavelengths of 620 nm and 665 nm, using a PHERAstar FS (BMG Labtech GmbH). The amount of phosphorylation reaction was determined from the ratio of the amounts of fluorescence at the two wavelengths, and the concentration of compound at which the phosphorylation reaction could be suppressed by 50% was defined as an IC50 (nM) value. 3) BTK inhibition selectivity
[00592] The IC50 value of inhibitory activity "EGFR (nM) / IC50 value of BTK inhibitory action (nM)" was calculated based on the results obtained in the sections above 1) and 2), and thus the inhibition selectivity of BTK of the test compound was identified. [Table 47]


[Table 48]

[00593] From these test results, we can clearly see that the selectivity of the compound of the present invention in relation to BTK inhibition over EGFR kinase in vitro was approximately 7.5 times or more compared to that of reference compound 1, and the compounds of the present invention exhibit excellent selectivity of inhibition of BTK. From these results, it has been found that the compounds of the present invention can reduce side effects compared to existing BTKs inhibitors.
[00594] Test example 3 for measuring proliferation inhibiting activity against cell lines expressing BTK and EGFR (in vitro), and comparing their selectivity.
[00595] TMD8 cells, which are from a large diffuse B cell lymphoma cell line expressing BTK, were suspended in RPMI1640 medium (manufactured by Life Technologies Corp.) containing 1% fetal bovine serum. A431 cells that are from a highly activated human squamous cell carcinoma cell line expressing EGFR were suspended in DMEM high glucose medium (manufactured by Life Technologies Corp.) containing 10% fetal bovine serum. Cell suspensions were inoculated into each well of 384 well flat bottom microplates and the cells were cultured for 1 day at 37 ° C in an incubator containing 5% carbon dioxide gas. The compounds of the present invention and reference compound 1 were each dissolved in DMSO, and the solutions were diluted to a concentration of 500 times the final concentration of the test compound using DMSO. The DMSO solution of the test compounds was diluted with the medium used in the suspension of each well and this was added to each well of the cell culture plates so that the final DMSO concentration would be 0.2%. The cells were then cultured for 3 days at 37 ° C in an incubator containing 5% carbon dioxide gas. Counting the number of cells before adding the compounds and after culturing for 3 days in the presence of the compounds, was performed using a CELLTITER GLO (manufactured by Promega Corp.) based on the protocol recommended by Promega Corp. The inhibition of proliferation was calculated by the following formula and the concentration of the test compound inhibiting 50% (GI50 (nM)) was determined. Proliferation inhibition ratio (%) = (C - T) / (C - C0) x 100
[00596] T: Luminescence intensity of a cavity in which the test compound was added
[00597] C: Luminescence intensity of a cavity in which the test compound was not added
[00598] C0: Luminescence intensity of a well measured before the addition of the test compound.
[00599] When a comparison is made between the proliferation inhibitory activity in relation to A431 cells which depends on EGFR proliferation signaling and the proliferation inhibitory activity in relation to TMD8 cells which depends on BTK proliferation signaling, the influence of respective kinases at a colular level can be evaluated. That is, when the proliferation inhibition ratio "A431 / collateral proliferation inhibition ratio TMD8" is calculated, it appears that when the ratio value is greater the selectivity in relation to BTK over EGFR in cells is higher. The values for "A431 spinal proliferation inhibition ratio / cell proliferation inhibition ratio" a are shown in Table 49 and Table 50. [Table 49]

[Table 50]


[00600] From these test results, we found that the selectivity of BTK inhibition of the compounds of the present invention over EGFR kinase in the cell proliferation inhibition ratio (in vitro) is approximately 8.5 times or more compared to the Compound of reference 1, and the compounds of the present invention also exhibit excellent selectivity of BTK inhibition not only at kinase levels but also at cellular levels. From these results we can see that the compounds of the present invention may have reduced side effects compared to the existing BTK Inhibitor inhibitor.
[00601] Example of test 4 antitumor effect and evaluation of the reason for change in body weight
[00602] The cell line derived from TMD8 human B-cell lymphoma was subcutaneously transplanted into SCID mice. At the moment when the volume of grafted tumors reached 100 to 200 mm3, the mice were divided into groups, with 5 animals in each group by a random classification method (day 1) so that the tumor volumes in the various groups were uniform and started an oral administration. Group 1: Reference compound 1 (100 mg / kg) was orally administered once daily, Group 2: a compound of the present invention (Representative compound 13) (50 mg / kg) was orally administered once daily, Group 3 : a compound of the present invention (Representative compound 12) (50 mg / kg) was orally administered once daily and Group 4: a compound of the present invention (Representative compound 6) (50 mg / kg) was orally administered once daily. day. To compare the antitumor effect caused by the administration of the drug, the relative tumor volume (RTV), which was the tumor proliferation ratio when the tumor volume at the time of clustering was established as one, was determined by the following formula.
[00603] RTV = (tumor volume on the day of tumor volume measurement) / (tumor volume at the time of clustering)
[00604] The mean RTV values at 17 days after administration in the control group and in the compound-administered groups (groups 1 to 4) are described in Table 51.
[00605] The change in body weight (BWC) was used as an indicator of a systematic toxicity caused by drug administration. The BWC was calculated using the following formula, and the average BWC values are shown in Table 38. (Mathematical formula 1)
[00606] BWC (%) = ([(body weight of the mouse on the day of weight measurement) - (body weight of the mouse at the time of grouping)] / (body weight of the mouse at the time of grouping)) x 100 [Table 51]


[00607] As a result, the compounds of the present invention in a group administered 50 mg / kg exhibited an antitumor effect equal to or greater than that of the group in which Reference Compound 1 was administered at a dose of 100 mg / kg. kg. In addition, toxicity as an increase in body weight was not recognized in the groups to which these compounds were administered.
[00608] Therefore, we have found that the compounds of the present invention are compounds, which exhibit an excellent anti-tumor effect at lower doses compared to reference compound 1 and are highly safe.
[00609] Test example 5 Influence on body weight of SD rat by repeated administration with the compounds of the present invention (in vivo)
[00610] The influence on the increase in body weight of SD rats by repeated administration with Reference Compound 1 and the compounds of the present invention for two weeks was compared with a vehicle-administered group. The rats were grouped as follows, with four animals in each group, by a random classification method so that the average body weights of each group were almost uniform (Day 1).
[00611] Group 1: Reference compound 1 (280 mg / kg) was orally administered once daily, Group 2: a compound of the present invention (Representative compound 12) (750 mg / kg) was orally administered once daily. , and Group 3: a compound of the present invention (Representative compound 13) (750 mg / kg) was administered orally once daily.
[00612] The change in body weight (BWC) was used as an indicator of systemic toxicity caused by drug administration. BWC was calculated using the following formula.
[00613] BWC (%) = ([(rat's body weight at 14 days after administration) - (rat's body weight at the time of grouping)] / (rat's body weight at the time of grouping)) x 100
[00614] The relative body weight change ratios in each of the compound-administered groups were calculated using the following formula when the BWC in the vehicle-administered group was set to 1, and the results are shown in Table 52.
[00615] Ratio of change in relative body weight (%) = (BWC in the compound-administered group) / (BWC in the vehicle-administered group) x 100 [Table 52]

[00616] According to the results, the extent of the increase in rat body weight was very small in Group 1, which was the Reference Compound 1-administered group compared to the vehicle-administered group. While in groups 2 and 3, which were the groups to which the compounds of the present invention were administered, the increase in body weight of the rat was severely affected. The compounds of the present invention were administered with 2.5 times or more the amount of the reference compound 1 (an amount approximately 5 times in terms of AUCo-24 (µm: hr)). In addition, in Group 1, individuals suffering from a loose intestine were recognized; however, in Groups 2 and 3, none of these individuals were recognized. Therefore, the compounds of the present invention have an excellent effect in that the level of side effects is low despite the amount of exposure being greater than that of the reference compound 1.
[00617] As described above, we have found that the compounds of the present invention are compounds with higher profiles with reduced toxicity compared to Reference Compound 1.
[00618] Test example 6 Detection by BTK labeling using fluorescent labeling compound (in vitro)
[00619] The cell line derived from human B-cell lymphoma, Ramos cells were suspended in RPMI1640 medium containing 10% bovine serum, and then the cells were inoculated into a culture dish at a concentration of 2.0x106 (cells /cavity). The cells were cultured in a CO2 incubator (Sanyo Electric Biomedical Co., Ltd.) at 37 ° C for 24 hours. Representative compound P-1 and fluorescent labeled compounds which is a derivative of Reference compound 1 (PCI-33380, Non-patent document 2) (10 mM stock) were each diluted with DMSO. Each dilution was added to the cells inoculated on the plate and the cells were cultured in a CO2 incubator for 1 hour. Then, the cells were harvested and 50 µl (a colular extract (NP-40; Invitrogen, Inc.) containing 1 x protease inhibitor (Hoffmann-La Roche AG) and 1 x phosphate cocktail (Sigma-Aldrich Co.)) were added to cell sediments. Cell pellets were left on ice for 10 minutes. The amount of protein in the collected collular extract was quantitatively analyzed by a DC protein assay (Bio-Rad Laboratories, Inc.), and 20 pg of proteins per range were applied to an SDS concentration gradient gel (4% to 20% ) (Wako Pure Chemicol Industries, Ltd.). After electrophoresis was performed, images of electrophoretic gels were taken using a Molecular Dynamics Typhoon scanner (GE Healthcare, Inc.). Then, the Western blotting technique was performed using an i-Blot (Invitrogen, Inc.), and BTK protein was detected with a LAS4000 (GE Healthcore, Inc.) using a BTK antibody (Abcam) (Fig . 1).
[00620] As shown in figure 1, we found that the probe according to the present invention is a useful tool for BTK detection in an in vitro test.

权利要求:
Claims (17)
[0001]
1. Compound CHARACTERIZED by the fact that it is represented by the following general formula (I), or a salt thereof:
[0002]
2. Compound according to claim 1, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; X represents C3-C10 nitrogen-containing heterocycloalkylene; and Ri represents an amino group.
[0003]
3. A compound according to claim 1 or 2, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; X represents azetidinylene, pyrrolidinylene or piperidinylene; and Ri represents an amino group.
[0004]
A compound according to any one of claims 1 to 3, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; X represents azetidinylene, pyrrolidinylene or piperidinylene; Y represents -C (R4) = C (Rs) (R6) or -C ^ C-Rz; RI represents an amino group; either of R2 and R3 represents a hydrogen atom or a C-Cδ alkyl group, while the other represents a hydrogen atom, a halogen atom, a C1-Cs alkyl group, a C1-C1-alkyl halogen group, a C1-C6 alkyl group substituted by C1-C4 alkoxy, a C1-C6 alkoxy group, a phenyl group that may have one or more substituents with a halogen atom, a 4-membered 6-membered monocyclic heterocyclic heterocyclic group containing one atom sulfur, or a cyan group; where Y represents -C (R4) = C (R5) (R6), R4, RS and Rs, which can be the same or different, each represents a hydrogen atom, a C-Cθ alkyl group, a C-group Cs alkyl which is substituted with an amino group substituted with two C 1 -C 6 alkyl groups (the C 1 -C 6 alkyl groups can form a 4-membered 8-membered heterocycloalkyl group together with the nitrogen atom to which these alkyl groups are attached) ; and where Y represents -CHC-RZ, R7 represents a hydrogen atom or a C1-C6-alkyl group.
[0005]
A compound according to any one of claims 1 to 4, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; X represents 1,3-azetidinylene, 1,3-pyrrolidinylene or 1,3-piperidinylene; Y represents -C (R4) = C (Rs) (R6) or -CHC-RZ; where Z represents N, W represents N, while when Z represents CH, W represents N or CH; Ri represents an amino group; either of R2 and R3 represents a hydrogen atom or a C-C4 alkyl group, while the other represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a halogen-C-C4 alkyl group, a C1-C4 alkyl group substituted by C1-C4 alkoxy, a C1-C4 alkoxy group, a phenyl group that may have one or more substituents with a halogen atom, a 4-membered 6-membered monocyclic heterocyclic heterocyclic group containing one atom sulfur, or a cyan group; where Y represents -C (R4) = C (R5) (R6), R4, RÕ and Re, which can be the same or different, each represents a hydrogen atom, a Ci-Ce-alkyl group, a Ci group -Ce-alkyl which is substituted with an amino group substituted with two C1-C-alkyl groups (the C1-C6 alkyl groups can form a 4-membered to 8-membered heterocycloalkyl group together with the nitrogen atom to which these alkyl groups are connected); and where Y represents -CHC-RZ, R7 represents a hydrogen atom or a C1-C4 alkyl group.
[0006]
A compound according to any one of claims 1 to 5, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; X represents 1,3-azetidinylene, 1,3-pyrrolidinylene or 1,3-piperidinylene; Y represents -C (R4) = C (Rs) (R6) or -C = C-R '; where Z represents N, W represents N, while when Z represents CH, W represents N or CH; Ri represents an amino group; either of R2 and R3 represents a hydrogen atom or a methyl group, while the other represents a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxyethyl group, a methoxy group, a phenyl group, a 4-chlorophenyl group, a 2-thienyl group, or a cyano group; where Y represents -C (R4) = C (R5) (R6), R4, Rs and Rθ, which can be the same or different, each represents a hydrogen atom, a methyl group, a dimethylaminomethyl group, a methylethylaminomethyl group , a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group or a 1-pyrrolidinylmethyl group; and where Y represents -CHC-RZ, R7 represents a methyl group.
[0007]
A compound according to any one of claims 1 to 6, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; Ri represents an amino group; either of R2 and R3 represents a hydrogen atom or a methyl group, while the other represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a methoxyethyl group, a phenyl group, a 2-thienyl group or a group cyan; (1) when Z represents N and W represents N, X represents 1,3-piperidinylene, and Y represents a vinyl group; (2) when Z represents CH and W represents N, X represents 1,3-pyrrolidinylene or 1,3-piperidinylene, and Y represents -C (R4) = C (R5) (Re) or -C = C- (R7 ), and when Y represents -C (R4) = C (R5) (R6), R4, Rs and Re, which can be the same or different, each represents a hydrogen atom, a methyl group, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group or a 1-pyrrolidinyl methyl group; when Y represents -CHC- (R7), R7 represents a methyl group; and (3) when Z represents CH, and W represents CH, X represents 1,3-azetidinylene or 1,3-pyrrolidinylene, and Y represents -C (R4) = C (R5) (R6), and R4, RS and Re, which can be the same or different, each represents a hydrogen atom, a dimethylaminomethyl group, a methylethylaminomethyl group, a diethylaminomethyl group, a methylisopropylaminomethyl group, a 1-piperidinylmethyl group or a 1-pyrrolidinylmethyl group.
[0008]
A compound according to any one of claims 1 to 7, or a salt thereof, CHARACTERIZED by the fact that in the general formula (I): A represents - (CH2) n-X-; n represents 0; X represents 1,3-piperidinylene; Y represents a vinyl group; Z represents CH; W represents N; Ri represents an amino group; and either of R2 and R3 represents a hydrogen atom, while the other represents a hydrogen atom, a halogen atom or a cyan group.
[0009]
9. Compound CHARACTERIZED by the fact that it is described in any of the following compounds from (1) to (86), or a salt thereof: (1) (R) -1- (1-acryloylpiperidin-3-yl) -4 -amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (2) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-bromobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (3) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1Hψirazolo [3, 4-d] pyrimidine-3-carboxamide; (4) (R) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1-methacryloylpiperidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (5) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3-yl) -1H- pyrazolo [3,4-d] pyrimidine-3-carboxamide; (6) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (7) (R) -1 - (1-acryloylpiperidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (8) (R) -1 - (1-acryloylpiperidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1H-pyrazole [3, 4-d] pyrimidine-3-carboxamide; (9) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (oxazolo [4,5-b] pyridin-2-yl) -1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide; (10) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (4-methylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (11) (R) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1- (1-methacryloylpiperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (12) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4 <i] pyrimidine -3-carboxamide; (13) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4 <i] pyrimidine-3 -carboxamide; (14) (R, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) piperidin-3-yl) - 1 Hψirazolo [3 , 4-d] pyrimidine-3-carboxamide; (15) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) piperidin-3- il) -1H-pyrazolo [3J4-d] pyrimidine-3-carboxamide; (16) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (ethyl (methyl) amino) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (17) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (diethylamino) but-2-enoyl) piperidin-3- il) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (18) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 - (1 - (4- (isopropyl (methyl) amino) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (19) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (20) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (piperidin-1-yl) but-2-enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (21) (R, E) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2 -enoyl) piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (22) (R) -4-amino-N- (benzo [d] oxazol-2-yl) -1 - (1 - (but-2-inoyl) piperidin-3-yl) -1 H-pyrazolo [3 , 4-d] pyrimidine-3-carboxamide; (23) (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-N- (5,6-dimethylbenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d ] pyrimidine-3-carboxamide; (24) (R) -1 - (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (25) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (but-2-enoyl) pyrrolidin-3-yl) -1H- pyrazolo [3,4-d] pyrimidine-3-carboxamide; (26) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (3-methylbut-2-enoyl) pyrrolidin-3-yl) - 1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (27) (R) -1 - (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (28) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (thiophen-2-yl) benzo [d] oxazol-2-yl) -1H-pyrazole [ 3,4-d] pyrimidine-3-carboxamide; (29) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methylbenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4 <i] pyrimidine -3-carboxamide; (30) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (31) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (4-chlorophenyl) benzo [d] oxazol-2-yl) -1H-pyrazole [3, 4-d] pyrimidine-3-carboxamide; (32) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3- il) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (33) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 - (1 - (4- (ethyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (34) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3- il) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (35) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 - (1 - (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (36) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (37) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1- (1- (4- (piPeridin-1-yl) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (38) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-methoxybenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (39) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-cyanobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine -3-carboxamide; (40) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (2-methoxyethyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [3J4- d] pyrimidine-3-carboxamide; (41) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1H-pi razolo [3,4-d] pi rim idin-3-carboxamide; (42) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3- il) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (43) (R) -1- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4- d] pyrimidine-3-carboxamide; (44) (R, E) -4-amino-N- (5- (trifluoromethyl) benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin -3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (45) 1- (1-acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide ; (46) 7- (1-acryloylazetidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide ; (47) (E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2-enoyl) azetidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (48) (R) -7- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine -5-carboxamide; (49) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3- il) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (50) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1 - (4- (ethyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (51) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (diethylamino) but-2-enoyl) pyrrolidin-3- il) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (52) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1 - (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (53) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidiπa-5-carboxamide; (54) (R, E) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -7- (1- (4- (P'Per'din-1-yl) but- 2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (55) (R) -7- (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine -5-carboxamide; (56) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3- il) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (57) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1 - (4- (ethyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2J3-d] pyrimidine-5-carboxamide; (58) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (diθtylamino) but-2-enoyl) pyrrolidin-3- il) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (59) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1 - (4- (isopropyl (methyl) amino) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (60) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (pyrrolidin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (61) (R, E) -4-amino-N- (5-phenylbenzo [d] oxazol-2-yl) -7- (1- (4- (piPeridin-1-yl) but-2-enoyl) pyrrolidin-3-yl) 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide; (64) (R) -1 - (1-acryloylpiperidin-3-yl) -4-amino-N- (7-chlorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (65) (S) -1 - (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (66) 1 - ((1-acryloylpyrrolidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- carboxamide; (67) 1 - ((1-acryloylpiperidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- carboxamide; (68) 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3- carboxamide; (69) 1 - (1-acryloylpiperidin-4-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (70) 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4 <i] pyrimidine-3- carboxamide; (71) 1 - ((1S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide ; (72) 1 - ((1 R, 4R) -4-acrylamidocyclohexyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3 -carboxamide; (73) (S, E) -4-amino-N- (benzo [d] oxazol-2-yl) -1- (1- (4- (dimethylamino) but-2-enoyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (74) 1 - (1-acryloylazetidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (75) 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (76) 1 - ((1-acryloylazetidin-3-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (77) 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (78) 1 - ((1 S, 4S) -4-acrylamidocyclohexyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (79) 1 - (1-acryloylazetidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3- carboxamide; (80) 1 - ((1-acryloylpiperidin-4-yl) methyl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) - 1H-pyrazolo [3,4-d] pyrimidine- 3-carboxamide; (81) 1 - ((1 S: 4S) -4-acrylamidocyclohexyl) ^ - amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidine-3 -carboxamide; (82) 1 - (1-acryloylpyrrolidin-3-yl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (83) 1 - (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-fluorobenzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3- carboxamide; (84) 1 - (1-acryloylpyrrolidin-3-yl) -4-amino-N- (5-chlorobenzo [d] oxazol-2-yl) -1 Fl-pi razolo [3,4-d] pi rim id i-na-3-carboxamide; (85) 1 - (3-acrylamidopropyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4-d] pyrimidine-3-carboxamide; (86) 1 - (2-acrylamidoethyl) -4-amino-N- (benzo [d] oxazol-2-yl) -1 H-pyrazolo [3,4- d] pyrimidine-3-carboxamide.
[0010]
10. Probe CHARACTERIZED by the fact that it comprises the compound, as defined in any one of claims 1 to 9, or a salt thereof, a detectable marker or affinity mark, and a linker, wherein the linker binds the compound to the marker or to the affinity tag.
[0011]
11. BTK inhibitor CHARACTERIZED by the fact that it comprises the compound, as defined in any one of claims 1 to 9, or a salt thereof as an active ingredient.
[0012]
12. Pharmaceutical composition CHARACTERIZED by the fact that it comprises the compound, as defined in any one of claims 1 to 9, or a salt thereof.
[0013]
13. Anti-tumor agent CHARACTERIZED by the fact that it comprises the compound, as defined in any one of claims 1 to 9, or a salt thereof as an active ingredient.
[0014]
A compound according to any one of claims 1 to 9, or a salt thereof, CHARACTERIZED by the fact that it is for use in the treatment of a tumor.
[0015]
A compound according to any one of claims 1 to 9, or a salt thereof, CHARACTERIZED by the fact that it is for use in the production of an antitumor agent.
[0016]
16. Use of the compound, as defined in any of claims 1 to 9, or a salt thereof, CHARACTERIZED by the fact that it is for the manufacture of an anti-tumor agent.
[0017]
17. Use of the compound, as defined in any one of claims 1 to 9, or a salt thereof, CHARACTERIZED by the fact that it is for the manufacture of a drug for the treatment of a tumor.

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法律状态:
2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-12-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-01-28| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-08-18| 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 11/08/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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JP2013167600|2013-08-12|

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JP2013-167600|2013-08-12|

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PCT/JP2014/071158|WO2015022926A1|2013-08-12|2014-08-11|Novel fused pyrimidine compound or salt thereof|

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