WO2015008844A1 - Fgfr阻害剤耐性癌の治療薬 - Google Patents
Fgfr阻害剤耐性癌の治療薬 Download PDFInfo
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- WO2015008844A1 WO2015008844A1 PCT/JP2014/069105 JP2014069105W WO2015008844A1 WO 2015008844 A1 WO2015008844 A1 WO 2015008844A1 JP 2014069105 W JP2014069105 W JP 2014069105W WO 2015008844 A1 WO2015008844 A1 WO 2015008844A1
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Definitions
- Fibroblast growth factor is involved in the regulation of various physiological processes such as cell proliferation, cell migration and differentiation.
- the physiological activity of FGF is mediated by a specific cell surface receptor, fibroblast growth factor receptor (FGFR).
- FGFR belongs to the receptor-type protein tyrosine kinase family, and is composed of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain.
- Four types of FGFR have been identified so far (FGFR1). , FGFR2, FGFR3 and FGFR4).
- FGFR forms a dimer by the binding of FGF and is activated by phosphorylation. Receptor activation induces the recruitment and activation of specific downstream signaling molecules and expresses physiological functions.
- Non-Patent Documents 1, 2, or 3 Abnormal activation of the FGF / FGFR signal in human cancer is attributed to autocrine or paracrine mechanisms due to FGFR overexpression and / or gene amplification, gene mutation, chromosomal translocation, or overproduction of the ligand FGF. ing.
- signal abnormality is considered to be one of the causes of treatment resistance of existing chemotherapy anticancer agents or other receptor tyrosine kinase inhibitors in human cancer (Non-patent Document 4).
- it is known to be associated with various diseases caused by abnormal angiogenic processes such as solid tumors, rheumatoid arthritis, psoriasis, retinopathy, age-related macular degeneration, etc. Patent Document 5).
- the therapy targeting FGF / FGFR signaling has a direct anti-tumor effect on tumor cells highly dependent on FGF / FGFR signaling, as well as tumors induced by FGF / FGFR signaling. Since it can exhibit an inhibitory action on angiogenesis, it can be expected to be a target therapy that can be expected to have a sufficient antitumor effect. Furthermore, it is an effective therapeutic means as a therapeutic enhancer for existing chemotherapy anticancer agents or other receptor tyrosine kinase inhibitors, or for cancer types that have become resistant to treatment or refractory cancer types. Is expected to be able to provide
- Patent Document 1 widely discloses fused bicyclic compounds having mTOR inhibitory activity, but all compounds with specific disclosure are imidazopyrazine compounds, and there is no description of FGFR inhibitory activity.
- Patent Document 2 discloses a compound having a characteristic substituent at the 3-position of the pyrazolopyrimidine ring as a BTK inhibitor, but does not describe FGFR inhibitory activity.
- Patent Document 3 discloses a compound having a characteristic substituent at the 5-position of the pyrrolopyrimidine ring as an HSP90 inhibitor, but does not describe FGFR inhibitory activity.
- the tumor may acquire resistance to the inhibitor due to the FGFR mutation, which may cause a worsening of the prognosis of the tumor patient.
- the problem to be solved by the present invention is to provide an anticancer agent for treating a tumor resistant to another antitumor agent that inhibits FGFR and a method for treating such a tumor.
- the present inventors have found that the 3,5-disubstituted benzenealkynyl compounds or salts thereof have an antitumor effect, and such tumors It was found to be very effective as a treatment method.
- the present invention is based on such novel findings.
- Item 1 An antitumor agent for administration to a tumor patient having resistance to an FGFR inhibitor, the antitumor agent comprising a 3,5-disubstituted benzenealkynyl compound represented by the following general formula (I) or a salt thereof:
- R 1 is the same or different and represents a C 1 -C 6 alkyl group
- X 1 and X 2 are each independently N or CH
- Y represents the general formula (A)
- the divalent moiety represented by the formula (I) represents a nitrogen-containing C 3 -C 10 heterocycloalkylene group), the general formula (B)
- a divalent moiety represented by general formula (C) represents a C 3 -C 10 cycloalkylene group
- the divalent moiety represented by C 6 -C 12 represents an arylene group);
- R 2 represents a hydrogen atom, a C 2 -C 6 alkynyl group, —C ( ⁇ O) ORx, —C ( ⁇ O) N (Rx) (Ry), a hydroxy C 1 -C 6 alkyl group, di (C 1 -C 6 alkyl) an amino C 1 -C 6 alkyl group, or may have R3 C 2 -C 9 heteroaryl group;
- R 3 is a C 1 -C 6 alkyl group, or a di (C 1 -C 6 alkyl) amino C 1 -C 6 alkyl group;
- Z is —C (R4) ⁇ C (R 5 ) (R 6 ), or —C ⁇ C—R 7 ;
- R 4 , R 5 and R 6 are the same or different and are a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group optionally having
- a monovalent moiety represented by the formula (1) represents a nitrogen-containing C 3 -C 10 heterocycloalkyl group
- R 7 is a hydrogen atom, a C 1 -C 6 alkyl group, or a hydroxy C 1 -C 6 alkyl group
- R 8 is an -ORx, or -N (Rx) (Ry)
- R 9 is a C 1 -C 6 alkyl group, a halogen atom, or —ORx
- Rx and Ry are the same or different and are a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 10 cycloalkyl group, a di (C 1 -C 6 alkyl) amino C 1 -C 6 alkyl group, A C 1 -C 6 alkoxy C 1 -C 6 alkyl group
- l is an integer from 0 to 3
- m is an integer from 1 to 3
- n is an integer of 0-2.
- Item 2 A method for treating a tumor patient having resistance to an FGFR inhibitor, which is represented by the above general formula (I) [wherein R 1 , X 1 , X 2 , Y and Z are as described above] 3, 5 -A method of treatment by administering an antitumor agent comprising a disubstituted benzenealkynyl compound or a salt thereof.
- an antitumor agent comprising a disubstituted benzenealkynyl compound or a salt thereof.
- Item 3 3,5-two represented by the above general formula (I) for the treatment of tumor patients resistant to FGFR inhibitors, wherein R 1 , X 1 , X 2 , Y and Z are as described above Substituted benzenealkynyl compounds or salts thereof.
- Item 5 In the general formula (I), (1) when X 2 is N, X 1 is N or CH, and (2) when X 2 is CH, X 1 is CH, Item 2.
- Item 6. The antitumor agent, method, compound or salt thereof or use according to any one of Items 1 to 5, wherein l is 0 or 1 in the general formula (I).
- Item 7 The antitumor agent, method, compound or salt thereof according to any one of Items 1 to 6, wherein the group represented by formula (I) is a phenylene group.
- the antitumor agent, method, compound or salt thereof according to any one of Items 1 to 7.
- Item 9 The antitumor agent, method, compound or salt thereof or use according to any one of Items 1 to 8, wherein R 1 in formula (I) is a methyl group or an ethyl group.
- Item 10 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 9, wherein the group represented by formula (I) is a phenylene group.
- Item 11 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 8, wherein the 3,5-disubstituted benzenealkynyl compound is selected from the following compound group.
- the 3,5-disubstituted benzenealkynyl compound or a salt thereof is (S) -1- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4] Item 12.
- the tumor patients are Pontinib, Regorafenib, Intedanib, Dovitinib lactate, Lenvatinib mesylate, Cediranb, Oratinib, Brivibalaninate, AZD4547, NVPbG87S Item 13.
- Item 14 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 13, wherein the tumor patient has a mutation in at least one of N550, V565, E566, and K660 of FGFR2.
- Item 15 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 13, wherein the tumor patient has a mutation in N550 of FGFR2.
- Item 16 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 13, wherein the tumor patient has a mutation in V565 of FGFR2.
- Item 17 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 13, wherein the tumor patient has a mutation in E566 of FGFR2.
- Item 18 The antitumor agent, method, compound, salt or use according to any one of Items 1 to 13, wherein the tumor patient has a mutation in K660 of FGFR2.
- the compound represented by the above general formula (I) or a salt thereof which is an active ingredient of the present invention, unexpectedly shows an antitumor effect against a tumor resistant to a conventional FGFR inhibitor. became. Therefore, the compound represented by the general formula (I) or a salt thereof is very effective against tumors resistant to conventional FGFR inhibitors among various tumors.
- GenBank accession number NP_075259 SEQ ID NO: 1.
- the present invention provides an antitumor agent for administration to a tumor patient having resistance to an FGFR inhibitor, comprising the 3,5-disubstituted benzenealkynyl compound represented by the aforementioned general formula (I) or a salt thereof. .
- a tumor having resistance to an FGFR inhibitor which is an object of prevention and / or treatment in the present invention, showed an effect on a conventionally known FGFR inhibitor, but no longer exhibits an antitumor effect by continued administration. Tumors, and tumors that have no antitumor effect from the beginning against conventionally known FGFR inhibitors.
- the tumor having resistance to the FGFR inhibitor includes, for example, a tumor having resistance to at least one of the FGFR inhibitors.
- Examples of tumor patients having resistance to the FGFR inhibitor in the present invention include patients having a mutation in at least one of FGFR2 N550, V565, E566, and K660.
- V565 corresponds to a characteristic amino acid residue called the gatekeeper of the kinase, and includes patients with mutations in this gatekeeper moiety.
- the term “FGFR2” includes a protein having the amino acid sequence represented by GenBank accession number NP — 075259 (SEQ ID NO: 1, FIG. 1), and homologs, isoforms, mutants, derivatives, and precursors thereof. Proteins cleaved from proteins are included.
- the position of FGFR2 mutation means a position corresponding to the position of the amino acid sequence represented by SEQ ID NO: 1.
- “mutation of N550” indicates that there is a mutation in asparagine at the position corresponding to the 550th amino acid of SEQ ID NO: 1 in FGFR2.
- Examples of such FGFR2 mutations include N550H, V565I, E566G, and K660M. Therefore, in a certain FGFR2, even if it is different from the mutation position of the amino acid number indicated by NP_075259 due to the presence of splicing variants, deletions, insertions, etc., the mutation corresponding to the amino acid sequence indicated by NP_075259 is also included. It is.
- the compound represented by the above general formula (I), which is an active ingredient of the antitumor agent of the present invention, is a 3,5-disubstituted compound having a condensed heteroaryl group in which an ⁇ , ⁇ unsaturated amide is substituted via a spacer site. It is a benzenealkynyl compound, which is a novel compound not described in any of the above prior art documents.
- C 1 -C 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, An isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group and the like can be mentioned, and a linear or branched alkyl group having 1 to 4 carbon atoms (preferably A C 1 -C 4 alkyl group), more preferably a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group.
- C 3 -C 10 cycloalkyl group refers to a monocyclic or polycyclic cycloalkyl group having 3 to 10 carbon atoms, preferably a monocyclic cycloalkyl group having 3 to 6 carbon atoms.
- An alkyl group (C 3 -C 6 cycloalkyl group) specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a decalyl group, etc., preferably a cyclopropyl group, a cyclobutyl group It is a group.
- the general formula (A) is a group.
- a cycloalkylene group nitrogen-containing C 3 -C 10 heterocycloalkylene group, preferably having 1 to 3 nitrogen atoms in the ring and further containing 0 to 1 oxygen atoms in the ring;
- a heterocycloalkylene group nitrogen-containing C 3 -C 5 heterocycloalkylene group, specifically, an azetidinylene group, a pyrrolidinylene group, a piperidinylene group, a piperazinylene group, a morpholinylene group, an octahydroquinolinylene group, an octahydroindylene group A azetidinylene group, a pyrrolidinylene group, a piperidinylene group
- Cycloalkylene group (C 3 -C 6 cycloalkylene group), and specific examples include a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group, a cycloheptylene group, and a decalylene group, preferably A cyclopropylene group and a (1,2- or 1,3-) cyclobutylene group.
- a nitrogen-containing C 3 -C 10 heterocycloalkyl group preferably a heterocycloalkyl having 3 to 5 carbon atoms containing 1 to 3 nitrogen atoms in the ring and further containing 0 to 1 oxygen atoms in the ring Group (nitrogen-containing C 3 -C 5 heterocycloalkyl group), specifically, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, octahydroquinolinyl group, octahydroindolyl group, etc. And preferably an azetidinyl group, a pyrrolidinyl group, a piperidinyl
- One of the nitrogen atoms on the nitrogen-containing C 3 -C 10 heterocycloalkyl group represented by formula (I) is bonded to a substituent (— (CH 2 ) m —), and the substituent (— (R 9 ) N )
- the “C 2 -C 9 heteroaryl group” means a monocyclic or bicyclic carbon containing 1 to 3 of the same or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
- a monocyclic heteroaryl group having 2 to 9 carbon atoms, preferably containing 1 to 3 of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (Monocyclic C 2 -C 5 heteroaryl group), specifically, thienyl group, furyl group, pyrrolyl group, triazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, Pyrazinyl, pyrimidinyl, pyridazinyl, isobenzofuryl, indolizinyl, isoindolyl, indolyl, indazoly
- C 2 -C 6 alkynyl group refers to a linear or branched alkynyl group having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, specifically ethynyl.
- hydroxy C 1 -C 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms having one hydroxy group, specifically, a hydroxymethyl group, Examples thereof include a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, and a hydroxyhexyl group, preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a 2-hydroxybutyl group.
- di (C 1 -C 6 alkyl) amino C 1 -C 6 alkyl group has an amino group having two linear or branched alkyl groups having 1 to 6 carbon atoms.
- 1 to 6 carbon atoms are linear or branched alkyl groups, preferably 1 to 4 carbon atoms having an amino group having 2 linear or branched alkyl groups having 1 to 4 carbon atoms
- a linear or branched alkyl group (di (C 1 -C 4 alkyl) amino C 1 -C 4 alkyl group) specifically, dimethylaminomethyl group, dimethylaminoethyl group, dimethylaminopropyl Group, dimethylaminobutyl group, dimethylamipentyl group, dimethylaminohexyl group, diethylaminomethyl group, diethylaminoethyl group, diethylaminopropyl group, diethylaminobutyl group, die Examples include luminpentyl group
- C 1 -C 6 alkoxy C 1 -C 6 alkyl group means a linear or branched alkoxy group having 1 to 6 carbon atoms or a straight chain having 1 to 6 carbon atoms or A branched alkyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms having a linear or branched alkoxy group having 1 to 4 carbon atoms (C 1 -C 4 alkoxy C 1 -C 4 alkyl group), specifically, methoxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, methoxypentyl group, methoxyhexyl group, ethoxymethyl group, ethoxyethyl group, ethoxy Propyl group, ethoxybutyl group, ethoxypentyl group, ethoxyhexyl group, propoxymethyl group, butoxymethyl group, pentyloxymethyl group
- halogen atom examples include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, and a fluorine atom is preferable.
- preferred combinations of X 1 and X 2 include (1) when X 2 is N, X 1 is N or CH, and (2) when X 2 is CH, X 1 is CH.
- l is preferably 0 or 1.
- Y represents general formula (A).
- Y is preferably a combination of Y and Z.
- Z is —C (R 4 ) ⁇ C (R 5 ) (R 6 ) or —C ⁇ C—R 7
- Y is the general formula (B) or general formula (C).
- R 1 is preferably a C 1 -C 4 alkyl group, and more preferably a methyl group or an ethyl group.
- R 2 preferably has a hydrogen atom, a C 2 -C 6 alkynyl group, —C ( ⁇ O) OR x , a hydroxy C 1 -C 4 alkyl group, or R 3.
- An optionally substituted C 2 -C 9 heteroaryl group more preferably an ethynyl group, a methoxycarbonyl group, a hydroxymethyl group, or a 1,3,4-oxadiazolyl group optionally having R 3 .
- R 3 is preferably a C 1 -C 4 alkyl group or a di (C 1 -C 4 alkyl) amino C 1 -C 4 alkyl group, more preferably a methyl group or dimethylamino. It is a methyl group.
- R 4 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and still more preferably a hydrogen atom.
- R 5 and R 6 are preferably a hydrogen atom, a C 1 -C 4 alkyl group optionally having one R 8 , or general formula (D).
- R 9 is preferably 1.
- R 9 is preferably a C 1 -C 4 alkyl group, a fluorine atom or a hydroxyl group, more preferably a methyl group, a fluorine atom or a hydroxyl group.
- n is preferably 0 or 1.
- R 7 is preferably a hydrogen atom, a C 1 -C 4 alkyl group, or a hydroxy C 1 -C 4 alkyl group, more preferably a hydrogen atom, a hydroxymethyl group, a methyl group, Or a 2-hydroxy-2-methyl-ethyl group.
- R 8 is preferably a hydroxyl group or —N (R x ) (R y ).
- R x and R y are preferably a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 10 cycloalkyl group, or a C 1 -C 4 alkoxy C 1 -C 4 alkyl group,
- a hydrogen atom, a methyl group, an ethyl group, a tert-butyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, or a 2-methoxyethyl group is preferable.
- R 1 is a C 1 -C 4 alkyl group
- X 1 and X 2 are each independently N or CH
- Y is a group of general formula (A ) Or general formula (C)
- R 2 may have a hydrogen atom, a C 2 -C 6 alkynyl group, —C ( ⁇ O) OR x , a hydroxy C 1 -C 4 alkyl group, or R 3 A good C 2 -C 9 heteroaryl group;
- R 3 is a C 1 -C 4 alkyl group or a di (C 1 -C 4 alkyl) amino C 1 -C 4 alkyl group;
- R 4 is a hydrogen atom or a halogen atom;
- R 5 and R 6 are the same or different, An atom, a C 1 -C 4 alkyl group optionally having R 8 or a general formula (D)
- R 7 is a hydrogen atom, a C 1 -C 4 alkyl group, or a hydroxy C 1 -C 4 alkyl group
- R 8 is a hydroxyl group or —N (R x ) (R be a y)
- R 9 is C 1 -C 4 alkyl group, a fluorine atom, or a hydroxyl group
- R x and R y the same or different, a hydrogen atom, C 1 -C 4 alkyl groups, C 3 -C 10 cycloalkyl group, or a C 1 -C 4 alkoxy C 1 -C 4 alkyl group
- l is 0 or 1
- m is 1, compounds wherein n is 0 or 1 is preferred.
- R 1 is a C 1 -C 4 alkyl group; in X 1 and X 2 , (1) when X 2 is N, X 1 is N or CH Yes, (2) when X 2 is CH, X 1 is CH; in Y, the general formula (A)
- R 2 is a hydrogen atom, an ethynyl group, a methoxycarbonyl group, hydroxymethyl group, or R 3 be also be 1,3,4-oxadiazolyl group optionally having;
- R 3 is C 1 -C 4 An alkyl group; l is 0 or 1)
- Z is —C (R 4 ) ⁇ C (R 5 ) (R 6 ) or —C ⁇ C—R 7
- Y is represented by the general formula (C)
- R 2 is a hydrogen atom; l is 0 or 1
- Z is —C (R 4 ) ⁇ C (R 5 ) (R 6 );
- R 4 is a hydrogen atom or a fluorine atom;
- R 5 and R 6 are the same or Differently, a hydrogen atom, a C 1 -C 4 alkyl group having R 8 or a general formula (D)
- R 7 is a hydrogen atom, a hydroxymethyl group, a methyl group, or a 2-hydroxy-2-methyl-ethyl group
- R 8 is —N (R x ) (R y ) Yes
- R 9 is a C 1 -C 4 alkyl group, a fluorine atom, or a hydroxyl group
- R x and R y are the same or different and are a hydrogen atom, a C 1 -C 4 alkyl group, or a C 3 -C. More preferred is a compound which is a 10 cycloalkyl group or a C 1 -C 4 alkoxy C 1 -C 4 alkyl group, m is 1, and n is 0 or 1.
- R 1 is a methyl group or an ethyl group; in X 1 and X 2 , (1) when X 2 is N, X 1 is N or CH; (2) when X 2 is CH, X 1 is CH; in Y, a divalent moiety
- R 2 is a hydrogen atom, an ethynyl group, a methoxycarbonyl group, a hydroxymethyl group, or a 1,3,4-oxadiazolyl group optionally having a methyl group; l is 0 or 1)
- Z is —C (R 4 ) ⁇ C (R 5 ) (R 6 ) or —C ⁇ C—R 7
- Y is represented by the general formula (C)
- R 2 is a hydrogen atom; l is 1)
- Z is —C (R 4 ) ⁇ C (R 5 ) (R 6 );
- R 4 is a hydrogen atom;
- R 5 and R 6 are the same or different.
- Hydrogen atom, methyl group having R 8 or general formula (D)
- R 7 is a hydrogen atom, a hydroxymethyl group, a methyl group, or a 2-hydroxy-2-methyl-ethyl group
- R 8 is — N (R x ) (R y )
- R 9 is a methyl group, a fluorine atom, or a hydroxyl group
- R x and R y are the same or different and are a hydrogen atom, a methyl group, an ethyl group, tert -A butyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, or a 2-methoxyethyl group
- a compound in which m is 1 and n is 0 or 1 is more preferable.
- compound (I) which is an active ingredient of the antitumor agent according to the present invention.
- Compound (I) can be produced, for example, by the following production method or the method shown in the examples. However, the production method of compound (I) is not limited to these reaction examples. Manufacturing method 1
- P 1 represents an amino-protecting group contained in Y; and R 1 , X 1 , X 2 , Y, and Z are as defined above. ]
- Step 1 This step is a step for producing a compound represented by the general formula (III) by deprotecting the amino group protection of the compound represented by the general formula (II).
- a deprotection method a generally known method, for example, Protective Groups in Organic Synthesis, T.A. W. It can be performed by the method described in Greene, John Wiley & Sons (1981) or a method analogous thereto.
- An example of a protecting group is tert-butyloxycarbonyl.
- a tert-butyloxycarbonyl group is used as the protecting group, deprotection under acidic conditions is preferred, and examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosylic acid and the like.
- the amount of the acid to be used is preferably 1 to 100 mol per 1 mol of compound (II).
- the solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
- alcohols eg, methanol
- hydrocarbons eg, benzene, toluene, xylene, etc.
- halogenated hydrocarbons For example, methylene chloride, chloroform, 1,2-dichloroethane, etc.
- nitriles eg, acetonitrile, etc.
- ethers eg, dimethoxyethane, tetrahydrofuran, etc.
- aprotic polar solvents eg, N, N-dimethylformamide, etc.
- Dimethyl sulfoxide, hexamethylphosphoramide, etc. or a mixture thereof.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 to 120 ° C., preferably 0 to 90 ° C.
- the compound represented by the general formula (III) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.
- Step 2 This step is a compound represented by the general formula (III) and a carboxylic acid represented by Z—COOH or Z—C ( ⁇ O) —L (L represents a chlorine atom or a bromine atom).
- the compound represented by the general formula (I) is produced by an amidation reaction with the acid halide represented.
- carboxylic acid represented by Z—COOH When a carboxylic acid represented by Z—COOH is used as an amidating reagent, 0.5 to 10 moles of carboxylic acid is used per 1 mole of the compound represented by the general formula (III) in the presence of a suitable condensing agent. The reaction is preferably carried out using 1 to 3 moles.
- the said carboxylic acid can be manufactured according to a commercial item or a well-known method.
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- isopropanol, tert-butyl alcohol, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide N-methylpyrrolidinone, dimethyl sulfoxide, etc., or a mixed solvent thereof is preferred.
- the reaction temperature is usually ⁇ 78 to 200 ° C., preferably 0 to 50 ° C.
- the reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.
- Examples of the condensing agent include diphenyl phosphate azide, N, N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, 4- (4,6-dimethoxy-1,3,5-triazine-2 -Yl) -4-methylmorpholinium chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxybenzotriazole, Examples include 2-chloro-1,3-dimethylimidazolinium chloride, O- (7-azabenzotriazo-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, and the like. .
- a base can be added as necessary.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium
- organic bases such as hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium
- inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- the addition amount is 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (III).
- an acid halide represented by Z—C ( ⁇ O) —L (L represents a chlorine atom or a bromine atom) is used as an amidating reagent, with respect to 1 mol of the compound represented by the general formula (III),
- the acid halide is used in an amount of 0.5 to 5 mol, preferably 0.9 to 1.1 mol.
- the said acid halide can be manufactured according to a commercial item or a well-known method.
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, or the like A mixed solvent or the like is preferable.
- the reaction temperature is usually ⁇ 78 to 200 ° C., preferably ⁇ 20 to 50 ° C.
- the reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.
- Bases include, for example, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butylate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexa
- organic bases such as methyl disilazide, potassium hexamethyl disilazide, and butyl lithium
- inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- it can be used in an amount of 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (III).
- the compound represented by the general formula (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. .
- L 1 and L 2 represent a halogen atom
- H in YH represents hydrogen directly bonded to a nitrogen atom
- Step 3 the compound represented by the general formula (V) is produced by an amidation reaction between the compound represented by the general formula (III) and the acid halide represented by the general formula (IV). It is a process.
- the halogen atom represented by L 1 or L 2 is a bromine atom or a chlorine atom.
- the compound represented by general formula (IV) can be manufactured according to a commercial item or a well-known method.
- the reaction is performed using 0.5 to 5 mol, preferably 0.9 to 1.1 mol of the compound represented by the general formula (IV) with respect to 1 mol of the compound represented by the general formula (III).
- a base can be added as necessary.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium
- organic bases such as hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium
- inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- it can be used in an amount of 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (III).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, or the like A mixed solvent or the like is preferable.
- the reaction temperature is usually ⁇ 78 to 200 ° C., preferably 0 to 50 ° C.
- the reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.
- the compound represented by the general formula (V) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.
- Step 4 the compound represented by the general formula (V) and the amine represented by the general formula (VI) or (VI ′) are subjected to an alkylation reaction to form the general formula (I ′) or ( This is a process for producing a compound represented by I ′′).
- the compound represented by the general formula (VI) or (VI ′) can be used in an amount of 1 to 20 mol, preferably 1 to 10 mol, per 1 mol of the compound represented by the general formula (V). .
- a base can be added as necessary.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium
- organic bases such as hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium
- inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- it can be used in an amount of 1 to 100 mol, preferably 1 to 20 mol, per 1 mol of the compound represented by the general formula (V).
- the reaction solvent is not particularly limited as long as it does not hinder the reaction.
- N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidine- 2-one, acetonitrile, etc. can be used singly or in combination.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
- the compound represented by the general formula (I ′) or (I ′′) thus obtained can be obtained by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be isolated and purified.
- the compound represented by the general formula (II) used for the production of the compound (I) can be produced by, for example, production method 3 or 4. Production method 3
- L 3 and L 4 represent a leaving group; and R 1 , X 1 , X 2 , Y and P 1 are as defined above. ]
- Step 5 This step is represented by the general formula (IX) by reacting the compound represented by the general formula (VII) with the compound represented by the general formula (VIII) (Sonogashira). This is a process for producing a compound.
- This step can be carried out in accordance with a generally known method (for example, Chemical Reviews, Vol. 107, p. 874, 2007), for example, in a solvent that does not adversely affect the reaction in the presence of a transition metal catalyst and a base. Can be implemented.
- the leaving group represented by L 3 is a bromine atom or an iodine atom, and the compound can be produced according to a commercially available product or a known method.
- the compound represented by the general formula (VIII) can be used in an amount of 1 to 10 mol, preferably 1 to 3 mol relative to 1 mol of the compound represented by the general formula (VII). It is.
- transition metal catalyst examples include palladium catalyst (eg, palladium acetate, tris (dibenzylideneacetone) dipalladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride).
- palladium catalyst eg, palladium acetate, tris (dibenzylideneacetone) dipalladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride.
- a ligand eg, triphenylphosphine, tri-tert-butylphosphine, etc.
- a copper reagent eg, copper iodide, copper acetate, etc.
- the amount of the transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mol, preferably 0.01 to 0.5 mol, relative to 1 mol of the compound represented by the general formula (VII). is there.
- the amount of the ligand to be used is generally 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound represented by the general formula (VII).
- the amount of the cocatalyst to be used is generally 0.0001 to 4 mol, preferably 0.01 to 2 mol, per 1 mol of the compound represented by the general formula (VII).
- a base can be added as necessary.
- the base include triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butylate, sodium tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium
- organic bases such as hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium
- inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride.
- organic bases such as triethylamine and diisopropylethylamine are preferred.
- the amount of the base to be used is generally 0.1 to 50 mol, preferably 1 to 20 mol, per 1 mol of the compound represented by the general formula (VII).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- hydrocarbons for example, benzene, toluene, xylene and the like
- nitriles for example, acetonitrile and the like
- ethers for example, dimethoxyethane
- Tetrahydrofuran 1,4-dioxane, etc.
- alcohols eg, methanol, ethanol, etc.
- aprotic polar solvents eg, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.
- water or a mixture thereof Is mentioned.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 150 ° C.
- the compound represented by the general formula (IX) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.
- Step 6 This step is a step of producing a compound represented by the general formula (II) using the compound represented by the general formula (IX) and (X) or (XI).
- L 4 includes a leaving group such as a chlorine atom, a bromine atom, an iodine atom, methanesulfonic acid ester, p-toluenesulfonic acid ester, and the like. Can be manufactured.
- the compound represented by the general formula (X) can be used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (IX).
- Examples of the base include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, sodium hydride, potassium hydride and other inorganic bases, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine. , 4- (N, N-dimethylamino) pyridine, lutidine, collidine, and the like, and the amount of the base used is 1 to 1 mol of the compound represented by the general formula (IX). 100 mol can be used, preferably 2 to 10 mol.
- N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile, etc. may be used singly or in combination. it can.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
- general formula (XI) When general formula (XI) is used as an alkylating reagent, it can be produced using Mitsunobu reaction. This step can be performed according to a generally known method (for example, Chemical Reviews, Vol. 109, p. 2551, 2009). For example, in the presence of Mitsunobu Reagents, a phosphine reagent has an adverse effect on the reaction. It can be carried out in a solvent that does not reach. This step is usually performed using 1 to 10 mol, preferably 1 to 5 mol, of the compound represented by the general formula (XI) with respect to 1 mol of the compound represented by the general formula (IX).
- Examples of the Mitsunobu reagent include diethyl azodicarboxylate and diisopropyl azodicarboxylate.
- the amount of Mitsunobu reagent used is 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (IX).
- phosphine reagent examples include triphenylphosphine and tributylphosphine.
- the phosphine reagent is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (IX).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- toluene, benzenetetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, or a mixed solvent thereof Is preferred.
- the reaction temperature is usually ⁇ 78 to 200 ° C., preferably 0 to 50 ° C.
- the reaction time is usually 5 minutes to 3 days, preferably 10 minutes to 10 hours.
- the compound represented by the general formula (II) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can utilize for manufacture of compound (I), without separating and refining.
- Step 7 This step can be performed by the same method as in the sixth step.
- Step 8 This step can be performed by the same method as in the fifth step.
- the compound represented by the general formula (XII) used for the production of the compound (I) can be produced by, for example, production method 5.
- Step 9 This step can be performed according to the method of the sixth step.
- Step 10 This step is a method for producing a compound represented by the general formula (XII) by reacting a compound represented by the general formula (XIV) with ammonia or a salt thereof.
- the amount of ammonia or a salt thereof used in this step is usually equimolar to excess molar with respect to 1 mol of the compound represented by the general formula (XIII).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- water, methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, Dimethyl sulfoxide or the like or a mixed solvent thereof is preferable.
- the reaction temperature is usually 0 to 200 ° C., preferably room temperature to 150 ° C.
- the reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- the compound represented by the general formula (XIV) thus obtained can be isolated and purified by known separation and purification means such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be used in Step 8 without separation and purification.
- the compound represented by the general formula (IX) used for the production of the compound (I) can also be produced by, for example, production method 6. Manufacturing method 6
- Step 11 a compound represented by the general formula (XV) is reacted with SEMCl (trimethylsilylethoxymethyl chloride) in the presence of a base to produce a compound represented by the general formula (XV).
- SEMCl trimethylsilylethoxymethyl chloride
- the SEMCl used in this step is usually equimolar to excess molar relative to 1 mol of the compound represented by the general formula (XIII).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, dimethylformamide, N-methylpyrrolidone, or a mixed solvent thereof is preferable. is there.
- the base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butylate, etc.
- organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butylate, etc.
- Inorganic bases can be used.
- the amount of the base used is usually equimolar to excess molar, preferably 1 to 3 molar relative to 1 molar of the compound represented by the general formula (XIII).
- the reaction temperature is usually ⁇ 78 to 50 ° C., preferably 0 ° C. to room temperature.
- the reaction time is usually 5 minutes to 7 days, preferably 10 minutes to 24 hours.
- the compound represented by the general formula (XV) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.
- Step 12 This step can be performed according to the method of the tenth step.
- the compound represented by the general formula (XVI) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without separation and purification.
- Step 13 This step can be performed according to the method of the fifth step.
- Step 14 This step is a method for producing the compound represented by the general formula (IX) by deprotecting the compound represented by the general formula (XVII) under acidic conditions.
- a deprotection method a generally known method, for example, Protective Groups in Organic Synthesis, T.A. W. It can be performed by the method described in Greene, John Wiley & Sons (1981) or a method analogous thereto.
- Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, and tosylic acid.
- the amount of the acid used is 1 to 100 mol with respect to 1 mol of the compound represented by the general formula (XVII).
- the solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction.
- alcohols for example, methanol
- hydrocarbons for example, benzene, toluene, xylene, etc.
- halogenated hydrocarbons for example, , Methylene chloride, chloroform, 1,2-dichloroethane, etc.
- nitriles eg acetonitrile, etc.
- ethers eg dimethoxyethane, tetrahydrofuran, 1,4-dioxane etc.
- aprotic polar solvents eg N , N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.
- the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
- the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
- the compound represented by the general formula (IX) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in Step 6 without separation and purification.
- amino groups, imino groups, hydroxyl groups, carboxyl groups and amide groups, functional groups having active protons such as indole, etc. are protected reagents at appropriate steps in each production method.
- the protective group can be removed after use or by introducing the protective group into the functional group according to a conventional method.
- the “protecting group for amino group or imino group” is not particularly limited as long as it has the function.
- benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, Aralkyl groups such as p-nitrobenzyl group, benzhydryl group, trityl group and cumyl group; for example, lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, trifluoroacetyl group and trichloroacetyl group;
- Benzoyl group for example, arylalkanoyl group such as phenylacetyl group and phenoxyacetyl group; for example, lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, tert-butoxycarbonyl group;
- the “hydroxyl-protecting group” is not particularly limited as long as it has the function, but for example, a lower alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group; A lower alkylsilyl group such as a butyldimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydropyranyl group; a trimethylsilylethoxymethyl group; a benzyl group, a p-methoxybenzyl Aralkyl groups such as a group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; for example, acyl groups such as formyl group, acetyl group, trifluoroacetyl group, etc.
- the “carboxyl-protecting group” is not particularly limited as long as it has the function, but for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group; Halo lower alkyl groups such as 1,2-trichloroethyl group; for example, lower alkenyl groups such as allyl group; for example, trimethylsilylethoxymethyl group; for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group, etc. And the like, and particularly preferred are methyl group, ethyl group, tert-butyl group, allyl group, benzyl group, p-methoxybenzyl group, trimethylsilylethoxymethyl group and the like.
- the “carbonyl-protecting group” is not particularly limited as long as it has the function, and examples thereof include ketals such as ethylene ketal, trimethylene ketal, dimethyl ketal, ethylene acetal, trimethylene acetal, dimethyl acetal, and acetals. Can be mentioned.
- the method for removing the protecting group varies depending on the kind of the protecting group and the stability of the target compound (I).
- Compound (I) can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, preparative reverse phase high performance liquid chromatography, column chromatography, preparative thin layer chromatography and the like.
- the compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer
- a mixture of any isomers is also included in the compound (I).
- compound (I) has an optical isomer
- the optical isomer resolved from the racemate is also encompassed in compound (I).
- Each of these isomers can be obtained as a single compound by synthetic methods and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).
- Compound (I) or a salt thereof may be in the form of a crystal, and it is included in compound (I) or a salt thereof regardless of whether the crystal form is single or polymorphic.
- the crystal can be produced by crystallization by applying a crystallization method known per se.
- Compound (I) or a salt thereof may be a solvate (for example, a hydrate) or a non-solvate, and both are encompassed in compound (I) or a salt thereof.
- a compound labeled with an isotope eg, 3 H, 14 C, 35 S, 125 I, etc. is also encompassed in compound (I) or a salt thereof.
- a prodrug of compound (I) or a salt thereof is a compound that is converted into compound (I) or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidizes, reduces, hydrolyzes, etc.
- the prodrug of compound (I) or a salt thereof is compound (I) or a compound thereof under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, pages 163 to 198. It may change into a salt.
- the salt of compound (I) means a conventional salt used in the field of organic chemistry.
- it has a carboxyl group, it has a base addition salt or an amino group or a basic heterocyclic group in the carboxyl group.
- salts of acid addition salts in the amino group or basic heterocyclic group may be mentioned.
- the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt and ethanolamine.
- organic amine salts such as salts, diethanolamine salts, triethanolamine salts, procaine salts, and N, N′-dibenzylethylenediamine salts.
- the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, acetate, formate, maleate, fumarate, tartrate, citric acid Organic salts such as salts, ascorbates and trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
- inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
- Organic salts such as salts, ascorbates and trifluoroacetates
- sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenes
- Compound (I) or a salt thereof has excellent FGER inhibitory activity and is useful as an antitumor agent. In addition, it has an excellent selectivity for FGFR, and has the advantage of fewer side effects from other kinases.
- the target cancer is not particularly limited, but for example, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, uterus
- Examples include cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, bone / soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, mesothelioma, etc.
- Hematological cancers such as cell lymphoma, chronic lymphocytic leukemia, peripheral T-cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia, acute
- a pharmaceutical carrier is blended as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Any of an agent, an injection, a suppository, an ointment, a patch and the like may be used, and an oral agent is preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
- the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, binders, disintegrants, lubricants, coloring agents in solid preparations, solvents in liquid preparations, dissolution aids, It is blended as a suspending agent, isotonic agent, buffer, soothing agent and the like.
- formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.
- the amount of compound (I) or a salt thereof to be blended in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the compound (I) or a salt thereof is to be applied, or its dosage form.
- the oral dosage is preferably 0.05 to 1000 mg, the injection is 0.01 to 500 mg, and the suppository is 1 to 1000 mg.
- the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally.
- the dose may be 0.05 to 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into 2 to 3 times a day.
- the NMR spectrum was measured using an AL400 (400 MHz; JEOL), Mercury 400 (400 MHz; Agilent Technology) spectrometer, or an Inova 400 (400 MHz; Agilent Technology) spectrometer equipped with an OM NMR probe (Protasis).
- AL400 400 MHz; JEOL
- Mercury 400 400 MHz; Agilent Technology
- Inova 400 400 MHz; Agilent Technology
- OM NMR probe Protasis
- Example 1 1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2- Synthesis of en-1-one (Example Compound 1) (Step 1) Synthesis of 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine
- Step 3 tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate
- 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine obtained in Step 1 above, tert-butyl 3 obtained in Step 2
- a suspension of 217 mg of-(methylsulfonyloxy) pyrrolidine-1-carboxylate and 221 mg of potassium carbonate in 2.0 ml of DMF was stirred at 70 ° C.
- Step 4 Synthesis of Example Compound 1 tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] obtained in Step 3 above Pyrimidin-1-yl) pyrrolidine-1-carboxylate was added to 4 mg of 4N-hydrochloric acid / 1,4-dioxane, and the mixture was stirred at room temperature for 1.5 hours.
- Example 2 (S) -1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) Synthesis of prop-2-en-1-one (Example Compound 2) (Step 1) Synthesis of (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate
- Example 3 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) but-2- Synthesis of en-1-one (Example Compound 3)
- Example 6 (S) -1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1- Yl) -2-fluoroprop-2-en-1-one (Example Compound 6)
- Example 4 the title compound was obtained as colorless amorphous by using 2-fluoroacrylic acid instead of 4- (dimethylamino) but-2-enoic acid hydrochloride.
- Table 2 shows the physical property values.
- Example 7 (S) -1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) Synthesis of -2- (pyrrolidin-1-ylmethyl) prop-2-en-1-one (Example Compound 7) According to Example 4, instead of 4- (dimethylamino) but-2-enoic acid hydrochloride The title compound was obtained as colorless amorphous by using 2- (pyrrolidin-1-ylmethyl) acetic acid (syn. Comm. 1995, 641). Table 2 shows the physical property values.
- Step 1 Synthesis of 1,3-diethoxy-5-ethynylbenzene 4.78 g of carbon tetrabromide was dissolved in 14 mL of dichloroethane, and 7.56 g of triphenylphosphine was added at 0 ° C. After stirring at 0 ° C. for 5 minutes, a solution of 1.40 g of 3,5-diethoxybenzaldehyde in 7 mL of dichloromethane was added and stirred for 20 minutes. The reaction solution was purified by silica gel chromatography (developing solvent: hexane / ethyl acetate) to obtain 1- (2,2-dibromovinyl) -3,5-diethoxybenzene.
- the obtained compound was used in the next reaction without further purification.
- the compound obtained above was dissolved in 30 mL of THF, 10.5 mL of a hexane solution of 1.63 M n-butyllithium was added at ⁇ 78 ° C., and the mixture was stirred at ⁇ 78 ° C. for 30 minutes. After adding a saturated aqueous ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, the resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
- Step 2 According to Example 1, instead of 1-ethynyl-3,5-dimethoxybenzene, the title compound was obtained by using 1,3-diethoxy-5-ethynylbenzene obtained in Step 1 above. Obtained as a colorless amorphous. Table 2 shows the physical property values.
- Example 9 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) prop-2- Synthesis of en-1-one (Example Compound 9)
- Step 1 Synthesis of tert-butyl 3- (methylsulfonyloxy) azetidine-1-carboxylate 1.73 g of N-Boc-3-hydroxyazetidine was dissolved in 20 ml of chloroform, and 2.09 ml of triethylamine at 0 ° C. 856 ⁇ l of methanesulfonyl chloride was added. After stirring at room temperature for 0.5 hour, ethyl acetate and water were added, and the organic layer was separated.
- Step 2 Synthesis of tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidine-1-carboxylate
- Step 4 Synthesis of Example Compound 9 According to Example 1 (Step 4), tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3 Instead of 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate, tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] obtained in Step 3 above was used.
- Example 10 1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4-hydroxy Synthesis of but-2-yn-1-one (Example Compound 10)
- Example 11 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4-hydroxy Synthesis of -4-methylpent-2-yn-1-one (Example Compound 11)
- Example 10 the title compound was obtained as a colorless amorphous by using 4-hydroxy-4-methylpent-2-ynoic acid instead of 4-hydroxybut-2-ynoic acid.
- Table 3 shows the physical property values.
- Example 12 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of (dimethylamino) but-2-en-1-one (Example Compound 12)
- Example 10 4- (dimethylamino) but-2-enoic acid hydrochloride was used in place of 4-hydroxybut-2-enoic acid to obtain the title compound as a colorless amorphous.
- Table 3 shows the physical property values.
- Example 13 1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of cyclopropylamino) but-2-en-1-one (Example Compound 13)
- Step 1 Synthesis of 4-bromobut-2-enoyl chloride To 329 mg of 4-bromocrotonic acid, 3.0 ml of thionyl chloride was added and stirred at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure and further subjected to toluene azeotropy to obtain 394 mg of the title compound as a crude product.
- Step 2 (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) Synthesis of -4-bromobut-2-en-1-one Intermediate 1- (azetidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H- obtained in Example 9 above 140 mg of a crude product of pyrazolo [3,4-d] pyrimidin-4-amine was suspended in 4.5 ml of THF, and 178 ⁇ l of DIPEA was added and cooled to 0 ° C.
- Step 3 Synthesis of Example Compound 13 1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d ] 12 mg of a crude product of pyrimidin-1-yl) azetidin-1-yl) -4-bromobut-2-en-1-one was dissolved in 0.5 ml of DMF, and 5 ⁇ l of cyclopropylamine and 10 ⁇ l of DIPEA were added at room temperature. Stir for 1 hour.
- Example 14 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of Isopropylamino) but-2-en-1-one (Example Compound 14)
- Example 13 the title compound was obtained as a colorless amorphous by using isopropylamine instead of cyclopropylamine.
- Table 4 shows the physical property values.
- Example 15 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of ethyl (methyl) amino) but-2-en-1-one (Example Compound 15)
- Example 13 According to Example 13 (Step 3), ethylmethylamine was used in place of cyclopropylamine to obtain the title compound as a colorless amorphous.
- Table 4 shows the physical property values.
- Example 16 1- (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of cyclobutylamino) but-2-en-1-one (Example Compound 16)
- Example 13 the title compound was obtained as a colorless amorphous by using cyclobutylamine instead of cyclopropylamine.
- Table 4 shows the physical property values.
- Example 17 3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of diethylamino) but-2-en-1-one (Example Compound 17)
- Example 13 the title compound was obtained as a colorless amorphous by using diethylamine instead of cyclopropylamine.
- Table 5 shows the physical property values.
- Example 18 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( tert-Butylamino) but-2-en-1-one (Example Compound 18)
- Example 13 (Step 3), tert-butylamine was used in place of cyclopropylamine to obtain the title compound as a colorless amorphous.
- Table 5 shows the physical property values.
- Example 19 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of isopropyl (methyl) amino) but-2-en-1-one (Example Compound 19)
- Example 13 the title compound was obtained as a colorless amorphous by using isopropylmethylamine instead of cyclopropylamine.
- Table 5 shows the physical property values.
- Example 20 3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- ( Synthesis of Piperidin-1-yl) but-2-en-1-one (Example Compound 20)
- Example 13 the title compound was obtained as a colorless amorphous substance by using piperidine instead of cyclopropylamine.
- Table 5 shows the physical property values.
- Example 21 (3- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4-morpholino Synthesis of but-2-en-1-one (Example Compound 21)
- Example 13 the title compound was obtained as a colorless amorphous by using morpholine instead of cyclopropylamine.
- Table 6 shows the physical property values.
- Example 24 (3- (4-Amino-3-((3,5-diethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) prop-2 Synthesis of -en-1-one (Example Compound 24)
- Example 25 (3- (4-Amino-3-((3,5-diethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) azetidin-1-yl) -4- Synthesis of (dimethylamino) but-2-en-1-one (Example Compound 25)
- Example 12 1,3-diethoxy-5-ethynylbenzene was used in place of 1-ethynyl-3,5-dimethoxybenzene to obtain the title compound as a colorless amorphous.
- Table 7 shows the physical property values.
- Example 26 1- (3-((4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) pyrrolidin-1-yl) prop Synthesis of -2-en-1-one (Example Compound 26)
- Step 1 tert-butyl 3-((4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) pyrrolidine-1 Synthesis of carboxylate 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine obtained in Example 1 (Step 1) 148 mg, N-Boc To a suspension of -3-hydroxymethylpyrrolidine (154 mg) and polymer-supported triphenylphosphine ( ⁇ 3.0 mmol / g) (334 mg) in THF (5.0 ml), DIAD (197 ⁇ l) was added and stirred at room temperature for 3 hours.
- DIAD 197 ⁇ l
- Step 2 Synthesis of Example Compound 26 According to Example 1 (Step 4), tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3 Instead of 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate, tert-butyl 3-((4-amino-3-((3,5-dimethoxyphenyl) ethynyl) obtained in Step 1 above was used. The title compound was obtained as a white solid by using) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) pyrrolidine-1-carboxylate. Table 7 shows the physical property values.
- Example 26 the title compound was obtained as a white solid by using (R) -1-Boc-3-hydroxypiperidine instead of N-Boc-3-hydroxymethylpyrrolidine.
- Table 7 shows the physical property values.
- Example 28 1-((2S, 4S) -4- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) -2- ( Synthesis of hydroxymethyl) pyrrolidin-1-yl) prop-2-en-1-one (Example Compound 28)
- Step 1 Synthesis of (2S, 4R) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4-hydroxypyrrolidine-1-carboxylate 1-N-Boc- (2S, 4R)- 500 mg of 4-hydroxy-2- (hydroxymethyl) -pyrrolidine was dissolved in 4.0 ml of DMF, and 164 mg of imidazole was added. After cooling to 0 ° C., 616 ⁇ l of tert-butylchlorodiphenylsilane was added and stirred for 1 hour. Ethyl acetate and saturated sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated.
- Step 2 Synthesis of (2S, 4S) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4- (methylsulfonyloxy) pyrrolidine-1-carboxylate obtained in Step 1 above ( 2S, 4R) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4-hydroxypyrrolidine-1-carboxylate was dissolved in 3.0 ml of chloroform, 137 ⁇ l of triethylamine and methanesulfonyl were dissolved at 0 ° C. 56 ⁇ l of chloride was added.
- Step 6 Synthesis of Example Compound 28 According to Example 1 (Step 4), tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate instead of 4- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H- The title compound was obtained as a white solid by using pyrazolo [3,4-d] pyrimidin-1-yl) -2- (hydroxymethyl) pyrrolidine-1-carboxylate. Table 8 shows the physical property values.
- Example 29 1- (3-((4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) azetidin-1-yl) prop Synthesis of -2-en-1-one (Example Compound 29)
- Example 26 1-Boc-3-hydroxymethylazetidine was used in place of N-Boc-3-hydroxymethylpyrrolidine to obtain the title compound as a pale yellow amorphous.
- Table 8 shows the physical property values.
- Example 30 N- (3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclobutyl) acrylamide (Example Compound 30) Composition
- Example 1 tert-butyl 3-hydroxycyclobutylcarbamate was used instead of N-Boc-3-hydroxypyrrolidine to obtain the title compound as a pale yellow amorphous.
- Table 8 shows the physical property values.
- Example 31 (4- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2- Synthesis of en-1-one (Example Compound 31)
- Example 1 the title compound was obtained as a white solid by using tert-butyl 4-bromopiperidine-1-carboxylate instead of tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate.
- Table 8 shows the physical property values.
- Example 32 1-((2S, 4S) -4- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) -2-ethynyl Synthesis of pyrrolidin-1-yl) prop-2-en-1-one (Example Compound 32)
- Step 1 (2S, 4S) -tert-butyl 4- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) Synthesis of -2-ethynylpyrrolidine-1-carboxylate 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidine-4 obtained in Example 1 (Step 1) -14 mg of amine, 15 mg of (2S, 4R) -tert-butyl 2-ethynyl-4-hydroxypyrrolidine-1-carboxylate synthesized by the method described in the pamphlet of International Publication WO2005 / 007083, and 23 mg of triphenylphosphine in 1.0 ml of THF Suspended, added 18 ⁇ l of DIAD, and stirred at room temperature for 1 hour.
- Step 2 Synthesis of Example Compound 32 According to Example 1 (Step 4), tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3 Instead of 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate, (2S, 4S) -tert-butyl 4- (4-amino-3-((3,5 Use of -dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) -2-ethynylpyrrolidine-1-carboxylate gave the title compound as a white solid. Table 9 shows the physical property values.
- Example 33 (4-((4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) piperidin-1-yl) propaprop Synthesis of -2-en-1-one (Example Compound 33)
- Example 26 1-Boc-4-hydroxymethylpiperidine was used in place of N-Boc-3-hydroxymethylpyrrolidine to obtain the title compound as a pale yellow amorphous.
- Table 9 shows the physical property values.
- Example 34 N- (3-((4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) phenyl) acrylamide (Example compound) 34)
- Example 26 the title compound was obtained as a colorless amorphous by using (3-aminophenyl) methanol instead of N-Boc-3-hydroxymethylpyrrolidine.
- Table 9 shows the physical property values.
- Example 35 3-((4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) methyl) azetidin-1-yl)- Synthesis of 4- (dimethylamino) but-2-en-1-one (Example Compound 35)
- Example 4 (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine
- the intermediate 1- (azetidin-3-ylmethyl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidine-4- obtained in Example 29
- the title compound was obtained as a pale yellow amorphous by using amine.
- Table 9 shows the physical property values.
- Example 36 1- (4- (4-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) -4- ( Synthesis of (dimethylamino) but-2-en-1-one (Example Compound 36)
- Example 4 (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine
- the intermediate 3-((3,5-dimethoxyphenyl) ethynyl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-d] pyrimidine-4- obtained in Example 31
- the title compound was obtained as a pale yellow amorphous by using amine.
- Table 9 shows the physical property values.
- Example 4 (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine
- the intermediate 3-((3,5-dimethoxyphenyl) ethynyl) -1- (piperidin-4-ylmethyl) -1H-pyrazolo [3,4-d] pyrimidine-4- obtained in Example 33
- the title compound was obtained as a pale yellow amorphous by using amine.
- Table 10 shows the physical property values.
- Step 1 Synthesis of (S) -tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate 4-chloro- To a solution of 1.00 g of 5-iodo-7H-pyrrolo [2,3-d] pyrimidine, 1.01 g of (R) -N-Boc-3-pyrrolidinol and 1.88 g of triphenylphosphine in a 40 ml tetrahydrofuran solution, DIAD1. 41 ml was added and the reaction was stirred for 1 hour. The reaction solution was concentrated and washed with ethyl acetate to obtain 1.04 g of the title compound as a white solid. Physical property value: m / z [M + H] + 448.9
- Step 2 Synthesis of (S) -tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate
- the resulting (S) -tert-butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate was added to 400 mg of tetrahydrofuran and 2.5 ml of 28% aqueous ammonia was added, and the reaction solution was stirred at 100 ° C. for 1.5 hours in a microwave reactor.
- Step 4 Synthesis of Example Compound 38 (S) -tert-butyl 3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2] obtained in Step 3 above. , 3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate was added with 2 ml of 4N-hydrochloric acid / 1,4-dioxane and stirred at room temperature for 1.5 hours.
- Step 1 Synthesis of 4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride 1.79 g of 4-bromocrotonic acid methyl ester was dissolved in 40 ml of tetrahydrofuran, and 1.67 ml of pyrrolidine was added at 0 ° C. And stirred at room temperature for 1 hour. Diethyl ether and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the obtained product, 40 ml of 3N hydrochloric acid was added and heated to reflux at 100 ° C. for 1 hour.
- Step 2 Synthesis of Example Compound 40 Intermediate (S) -5-((3,5-dimethoxyphenyl) ethynyl) obtained in Example 38 (Step 4) according to Example 4 (Step 1) -7- (Pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine and 4- (pyrrolidin-1-yl) but-2-enoic acid obtained in Step 1 above
- the title compound was obtained as a colorless amorphous by using a salt.
- Table 10 shows the physical property values.
- Step 1 (S) -1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine- Synthesis of 1-yl) -4-bromobut-2-en-1-one Intermediate (S) -5-((3,5-dimethoxyphenyl) ethynyl) -7 obtained in Example 38 (Step 4) 100 mg of a crude product of-(pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine was suspended in 3.0 ml of chloroform, 117 ⁇ l of DIPEA was added, and the mixture was cooled to 0 ° C.
- Step 2 Synthesis of Example Compound 41 (S) -1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2] obtained in Step 1 above. , 3-d] pyrimidin-7-yl) pyrrolidin-1-yl) -4-bromobut-2-en-1-one was dissolved in 0.5 ml of DMF, 4 mg of N-methylpiperazine and 10 ⁇ l of DIPEA were dissolved. The mixture was further stirred at room temperature overnight.
- Example 41 (Step 2), 4-hydroxypiperidine was used in place of N-methylpiperazine to obtain the title compound as a colorless amorphous.
- Table 11 shows the physical property values.
- Example 41 (Step 2), 4-fluoropiperidine was used in place of N-methylpiperazine to obtain the title compound as a colorless amorphous.
- Table 11 shows the physical property values.
- Example 41 the title compound was obtained as a colorless amorphous by using 3,3-difluoropyrrolidine instead of N-methylpiperazine.
- the physical property values are shown in Table 12.
- Example 41 the title compound was obtained as colorless amorphous by using 4,4-difluoropiperidine instead of N-methylpiperazine.
- the physical property values are shown in Table 12.
- Example 4 According to Example 4 (Step 1), intermediate (S) -5-((3,5-dimethoxyphenyl) ethynyl) -7- (pyrrolidin-3-yl) obtained in Example 38 (Step 4) By using -7H-pyrrolo [2,3-d] pyrimidin-4-amine and 2-butynoic acid, the title compound was obtained as a colorless amorphous. The physical property values are shown in Table 12.
- Example 4 According to Example 4 (Step 1), intermediate (S) -5-((3,5-dimethoxyphenyl) ethynyl) -7- (pyrrolidin-3-yl) obtained in Example 38 (Step 4)
- the title compound was obtained as colorless amorphous by using -7H-pyrrolo [2,3-d] pyrimidin-4-amine and 4-hydroxy-4-methylpent-2-ynoic acid.
- the physical property values are shown in Table 12.
- Example 48 1-((S) -3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) Synthesis of -4-((R) -3-fluoropyrrolidin-1-yl) but-2-en-1-one (Example Compound 48)
- Example 41 the title compound was obtained as a colorless amorphous by using (R) -3-fluoropyrrolidine instead of N-methylpiperazine.
- Table 13 shows the physical property values.
- Example 49 1-((S) -3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidin-1-yl) Synthesis of -4-((S) -3-fluoropyrrolidin-1-yl) but-2-en-1-one (Example Compound 49)
- Example 41 the title compound was obtained as a colorless amorphous by using (S) -3-fluoropyrrolidine instead of N-methylpiperazine.
- Table 13 shows the physical property values.
- Example 41 the title compound was obtained as a colorless amorphous by using piperidine instead of N-methylpiperazine.
- Table 13 shows the physical property values.
- Example 51 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) prop-2- Synthesis of en-1-one (Example Compound 51)
- Step 2 Synthesis of tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate
- the tert obtained in Step 1 above -Butyl 3- (4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate (350 mg) with 2.5 ml of tetrahydrofuran and 2.5 ml of 28% aqueous ammonia
- the reaction solution was stirred at 100 ° C. for 1.5 hours in a microwave reactor.
- Step 3 tert-butyl 3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate
- tert-butyl 3- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate obtained in step 2 above 639 mg
- 1-ethynyl -To a mixture of 374 mg of 3,5-dimethoxybenzene, 44 mg of copper (I) iodide and 2.0 ml of triethylamine in 15 ml of THF was added 122 mg of PdCl 2 (dppf) CH 2 Cl 2 , and the atmosphere was replaced with nitrogen.
- Step 4 Synthesis of Example Compound 51 According to Example 1 (Step 4), tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate instead of tert-butyl 3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) obtained in step 3 above Removal of the Boc group using 7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidine-1-carboxylate under acidic conditions resulted in 7- (azetidin-3-yl) -5-((3 , 5-) Dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine was obtained, followed by amidation to give the title compound as a white solid.
- Example 52 3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of (dimethylamino) but-2-en-1-one (Example Compound 52)
- Example 4 tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) Instead of pyrrolidine-1-carboxylate, tert-butyl 3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2] obtained in Example 51 (Step 3) was used. , 3-d] pyrimidin-7-yl) azetidine-1-carboxylate to give the title compound as a colorless amorphous. Table 14 shows the physical property values.
- Example 53 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of pyrrolidin-1-yl) but-2-en-1-one (Example Compound 53)
- Example 4 According to Example 4 (Step 1), intermediate 7- (azetidin-3-yl) -5-((3,5-) dimethoxyphenyl) ethynyl) -7H- obtained in Example 51 (Step 4)
- pyrrolo [2,3-d] pyrimidin-4-amine and 4- (pyrrolidin-1-yl) but-2-enoic acid hydrochloride obtained in Example 40 (Step 1) the title compound was obtained. Obtained as a colorless amorphous.
- Table 14 shows the physical property values.
- Example 54 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) but-2- Synthesis of in-1-one (Example Compound 54)
- Example 4 According to Example 4 (Step 1), intermediate 7- (azetidin-3-yl) -5-((3,5-) dimethoxyphenyl) ethynyl) -7H- obtained in Example 51 (Step 4)
- pyrrolo [2,3-d] pyrimidin-4-amine and 2-butanoic acid the title compound was obtained as a colorless amorphous.
- Table 14 shows the physical property values.
- Example 55 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of azetidin-1-yl) but-2-en-1-one (Example Compound 55)
- Step 1 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) Synthesis of -4-bromobut-2-en-1-one
- Step 2 Synthesis of Example Compound 55 1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] obtained in Step 1 above. ] 10 mg of a crude product of pyrimidin-7-yl) azetidin-1-yl) -4-bromobut-2-en-1-one was suspended in 0.5 ml of THF, 7 ⁇ l of azetidine was added, and the mixture was stirred at room temperature for 1 hour. .
- Example 56 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of ethyl (methyl) amino) but-2-en-1-one (Example Compound 56)
- Example 55 (Step 2), ethylmethylamine was used in place of azetidine to obtain the title compound as a colorless amorphous.
- Table 15 shows the physical property values.
- Example 57 1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of Isopropylamino) but-2-en-1-one (Example Compound 57)
- Example 55 the title compound was obtained as a colorless amorphous by using isopropylamine instead of azetidine.
- Table 15 shows the physical property values.
- Example 58 1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of isopropyl (methyl) amino) but-2-en-1-one (Example Compound 58)
- Example 55 the title compound was obtained as a colorless amorphous by using isopropylmethylamine instead of azetidine.
- Table 15 shows the physical property values.
- Example 59 1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of diethylamino) but-2-en-1-one (Example Compound 59)
- Example 55 the title compound was obtained as a colorless amorphous by using diethylamine instead of azetidine. Physical property values are shown in Table 16.
- Example 60 (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of (2-methoxyethyl) (methyl) amino) but-2-en-1-one (Example Compound 60)
- Example 55 2-methoxy-N-methylethanamine was used in place of azetidine to obtain the title compound as a colorless amorphous. Physical property values are shown in Table 16.
- Example 61 1- (3- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) azetidin-1-yl) -4- ( Synthesis of 4-hydroxypiperidin-1-yl) but-2-en-1-one (Example Compound 61)
- Example 55 4-hydroxypiperidine was used in place of azetidine to obtain the title compound as a colorless amorphous. Physical property values are shown in Table 16.
- Example 55 the title compound was obtained as a colorless amorphous by using (S) -3-hydroxypyrrolidine instead of azetidine.
- Table 17 shows the physical property values.
- Example 55 the title compound was obtained as a colorless amorphous by using (R) -3-hydroxypyrrolidine instead of azetidine.
- Table 17 shows the physical property values.
- Example 64 (4- (4-Amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidin-1-yl) prop-2- Synthesis of en-1-one (Example Compound 64)
- Example 65 (4- (4-Amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) piperidin-1-yl) -4- ( Synthesis of (dimethylamino) but-2-en-1-one (Example Compound 65)
- Example 38 the title compound was obtained as a pale yellow amorphous by using N-Boc-4-piperidinol instead of (R) -N-Boc-3-pyrrolidinol.
- Table 17 shows the physical property values.
- Example 66 (2S, 4S) -Methyl 1-acryloyl-4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine- Synthesis of 2-carboxylate (Example Compound 66) (Step 1) 4-chloro-5-iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine Composition
- Step 2 Synthesis of 5-iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine 4-chloro-obtained in Step 1 above 200 mg of 5-iodo-7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine was dissolved in 2.0 ml of THF, 2 ml of 28% aqueous ammonia was added, and the reaction solution was stirred in a microwave reactor at 105 ° C. for 1.5 hours.
- Example 1 instead of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine, 5-iodo-7-((2- The title compound was obtained as a colorless solid by using (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine.
- Step 4 Synthesis of 5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine 5-((3,5- A solution of 4.27 g of dimethoxyphenyl) ethynyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine in 20 ml of methylene chloride is cooled to 0 ° C. 10 ml of TFA was added. The reaction solution was stirred at room temperature for 5 hours, and the solvent was distilled off under reduced pressure.
- Step 5 Synthesis of (2S, 4R) -4- (methylsulfonyloxy) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester-2-methyl ester
- (2S, 4R) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester-2-methyl ester was used instead of N-Boc-3-pyrrolidinol.
- the title compound was obtained as colorless amorphous.
- Step 7 (2S, 4S) -Methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine- Synthesis of 2-carboxylate (2S, 4S) -1-tert-butyl 2-methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H- obtained in Step 6 above A solution of 24 mg of pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1,2-dicarboxylate in 2.0 ml of methylene chloride and 2.0 ml of TFA was stirred at room temperature for 30 minutes.
- Step 8 Synthesis of Example Compound 66 (2S, 4S) -Methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2] obtained in Step 7 above. , 3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate was added with 2.0 ml of methylene chloride and 16 ⁇ l of triethylamine. After cooling to 0 ° C., 100 ⁇ l of chloroform in which 5 ⁇ l of acryl chloride was dissolved was added and stirred at room temperature for 10 minutes.
- Example 67 1-((2S, 4S) -4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- ( Synthesis of (dimethylamino) methyl) pyrrolidin-1-yl) prop-2-en-1-one (Example Compound 67)
- Step 2 (2S, 4S) -tert-butyl 4- (4-amino-5-iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2-((tert-butyldiphenylsilyl Synthesis of (oxy) methyl) pyrrolidine-1-carboxylate (2S, 4S) -tert-butyl 2-((tert-butyldiphenylsilyloxy) methyl) -4- (4-chloro-5) obtained in Step 1 above -Iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1-carboxylate was added to 10 mg of THF and 5 ml of 8N ammonia methanol solution and stirred at 120 ° C.
- Step 7 (2S, 4S) -tert-butyl 4- (4- (bis (tert-butoxycarbonyl) amino) -5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3 Synthesis of -d] pyrimidin-7-yl) -2-((dimethylamino) methyl) pyrrolidine-1-carboxylate
- Step 1 3-iodo-1H-pyrazolo [3,4-d ]
- (2S, 4S) -tert-butyl 4- 4- (bis (tert-butoxycarbonyl) amino) -5-iodo-7H-pyrrolo [2] obtained in Step 6 above was used.
- Step 8 5-((3,5-dimethoxyphenyl) ethynyl) -7-((3S, 5S) -5-((dimethylamino) methyl) pyrrolidin-3-yl) -7H-pyrrolo [2,3 -D] Synthesis of Pyrimidin-4-amine According to Example 66 (Step 7), (2S, 4S) -1-tert-butyl 2-methyl 4- (4-amino-5-((3,5-dimethoxy) (2S, 4S) -tert-butyl 4 obtained in Step 7 above instead of phenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1,2-dicarboxylate -(4- (bis (tert-butoxycarbonyl) amino) -5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-D]
- Step 9 Synthesis of Example Compound 67 According to Example 66 (Step 8), (2S, 4S) -methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H- Instead of pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate, 5-((3,5-dimethoxyphenyl) ethynyl) -7-((3S , 5S) -5-((Dimethylamino) methyl) pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine gave the title compound as a colorless amorphous. Physical property values are shown in Table 18.
- Example 68 1-((2S, 4S) -4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- ( Synthesis of 1,3,4-oxadiazol-2-yl) pyrrolidin-1-yl) prop-2-en-1-one (Example Compound 68)
- Step 4 7-((3S, 5S) -5- (1,3,4-oxadiazol-2-yl) pyrrolidin-3-yl) -5-((3,5-dimethoxyphenyl) ethynyl) Synthesis of -7H-pyrrolo [2,3-d] pyrimidin-4-amine
- Step 5 Synthesis of Example Compound 68 According to Example 66 (Step 8), (2S, 4S) -methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H- Instead of pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate, 7-((3S, 5S) -5- (1,3,4-oxa) obtained in Step 4 above was used.
- Example 69 1-((2S, 4S) -4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- ( Synthesis of 5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidin-1-yl) prop-2-en-1-one (Example Compound 69)
- Step 2 5-((3,5-dimethoxyphenyl) ethynyl) -7-((3S, 5S) -5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidine- Synthesis of 3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine
- Step 3 Synthesis of Example Compound 69 According to Example 66 (Step 8), (2S, 4S) -methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H- Instead of pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate, 5-((3,5-dimethoxyphenyl) ethynyl) -7-((3S , 5S) -5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine Gave the title compound as a pale yellow amorphous. Physical property values are shown in Table 18.
- Example 70 1-((2S, 4S) -4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- ( Synthesis of 5-((dimethylamino) methyl) -1,3,4-oxadiazol-2-yl) pyrrolidin-1-yl) prop-2-en-1-one (Example Compound 70)
- Step 2 (2S, 4S) -tert-butyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) Synthesis of -2- (5-((dimethylamino) methyl) -1,3,4-oxadiazol-2-yl) pyrrolidine-1-carboxylate (2S, 4S) -tert obtained in Step 1 above -Butyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- (2- (2- (dimethyl To a solution of amino) acetyl) hydrazinecarbonyl) pyrrolidine-1-carboxylate 100 mg in acetonitrile 3 ml were added DIPEA 105 ⁇ l and tosyl
- Step 4 Synthesis of Example Compound 70 According to Example 66 (Step 8), (2S, 4S) -methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H- Instead of pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate, 5-((3,5-dimethoxyphenyl) ethynyl) -7-((3S , 5S) -5- (5-((dimethylamino) methyl) -1,3,4-oxadiazol-2-yl) pyrrolidin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine- The title compound was obtained as a pale yellow amorphous by using 4-amine. Physical property values are shown in Table 18.
- Step 2 (2S, 4S) -4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -N— Synthesis of (2- (dimethylamino) ethyl) -N-methylpyrrolidine-2-carboxamide According to Example 66 (Step 7), (2S, 4S) -1-tert-butyl 2-methyl 4- (4-amino Instead of -5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-1,2-dicarboxylate, it is obtained in Step 1 above.
- Step 3 Synthesis of Example Compound 71 According to Example 66 (Step 8), (2S, 4S) -methyl 4- (4-amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H- Instead of pyrrolo [2,3-d] pyrimidin-7-yl) pyrrolidine-2-carboxylate, (2S, 4S) -4- (4-amino-5-((3, By using 5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) -N- (2- (dimethylamino) ethyl) -N-methylpyrrolidine-2-carboxamide
- Table 19 shows the physical property values.
- Example 72 1- (4-((4-Amino-5-((3,5-dimethoxyphenyl) ethynyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl) methyl) piperidin-1-yl)- Synthesis of 4- (dimethylamino) but-2-en-1-one (Example Compound 72) According to Example 38, instead of (R) -N-Boc-3-pyrrolidinol, N-Boc-4- The title compound was obtained as a pale yellow amorphous by using hydroxymethylpiperidine. Table 19 shows the physical property values.
- Step 1 Synthesis of 4-chloro-3-iodo-1H-pyrrolo [3,2-c] pyridine 4-chloro-1H-pyrrolo synthesized by the method described in International Publication WO 2007/095223 Pamphlet 247 mg of 3,2-c] pyridine was dissolved in 7.0 ml of DMF, cooled to 0 ° C., and 382 mg of N-iodosuccinimide was added. After stirring at room temperature for 1 hour, chloroform and water were added and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
- Step 2 Synthesis of (S) -tert-butyl 3- (4-chloro-3-iodo-1H-pyrrolo [3,2-c] pyridin-1-yl) pyrrolidine-1-carboxylate 225 mg of the obtained 4-chloro-3-iodo-1H-pyrrolo [3,2-c] pyridine was dissolved in 3.0 ml of DMF, cooled to 0 ° C., and 64.5 mg of 60% sodium hydride was added. 322 mg of (R) -tert-butyl 3- (methylsulfonyloxy) pyrrolidine-1-carboxylate obtained in Example 2 (Step 1) was added to the reaction solution using 2.0 ml of DMF and stirred overnight at room temperature.
- Step 5 Synthesis of Example Compound 73 According to Example 1 (Step 4), tert-butyl 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3 Instead of 4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate, (S) -tert-butyl 3- (4-amino-3-((3,5-dimethoxy) obtained in Step 3 above was used. Phenyl) ethynyl) -1H-pyrrolo [3,2-c] pyridin-1-yl) pyrrolidine-1-carboxylate was used to give the title compound as a white solid. Table 19 shows the physical property values.
- Reference example 2 Synthesis of 3-cyclobutyl-1- (phenylethynyl) imidazo [1,5-a] pyrazin-8-amine (Reference Example Compound 2) The compound was synthesized according to the method described in International Publication WO2007 / 087395. Table 20 shows the physical property values.
- Step 2 Synthesis of (S) -tert-butyl 3- (4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1-carboxylate 3-iodo-
- Step 5 Synthesis of Reference Example Compound 4 According to Example 4, (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo [3 (S) -3-((3,5-diisopropylphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazolo obtained in Step 4 above instead of 4-d] pyrimidin-4-amine [3,4-d] pyrimidin-4-amine was used to give the title compound as a pale yellow amorphous. Table 20 shows the physical property values.
- Step 2 Synthesis of Reference Example Compound 5 (S) -1- (3- (4-Amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidin-1-yl obtained in Step 1 above) ) Pyrrolidin-1-yl) -4- (dimethylamino) but-2-en-1-one 8.0 mg, 1-ethynyl-3-methoxybenzene 4.0 mg, copper (I) iodide 0.6 mg, triethylamine PdCl 2 (dppf) CH 2 Cl 2 1.3 mg was added to 8.6 ⁇ l of THF 1.0 ml mixture, purged with nitrogen, and stirred at 80 ° C.
- Test Example 1 Measurement of FGFR2 Kinase Activity Inhibitory Action
- caliper life science FL-Peptide 22 was used as a substrate.
- the purified recombinant human FGFR2 protein used for the test was purchased from Carna Bioscience.
- the test compound was serially diluted with dimethyl sulfoxide (DMSO) to a concentration 20 times the final concentration.
- DMSO dimethyl sulfoxide
- the phosphopeptide and the non-phosphorylated peptide were separated by the LabChip (registered trademark) 3000 system (Caliper Life Sciences, excitation wavelength 488 nm, detection wavelength 530 nm), and each amount was measured. The amount of the oxidation reaction was determined, and the concentration of the compound capable of suppressing the phosphorylation reaction by 50% was defined as the IC 50 value (nM). The results are shown in Table 21.
- Test Example 2 Cell growth inhibitory effect on human-derived gastric cancer cell line that highly expresses FGFR
- Human-derived gastric cancer cell line OCUM-2MD3 cell that overexpresses FGFR2 receptor was treated with Dulbecco's modified Eagle containing 10% fetal bovine serum (FBS) Routine passages were made in medium (DMEM) at cell densities not exceeding 80%.
- DMEM medium
- OCUM-2MD3 cells were suspended in the above DMEM medium and seeded in each well of a 96-well flat bottom plate so that the number of cells per well was 3,000. The cells were cultured for 1 day at 37 ° C. in an incubator containing 5% carbon dioxide gas.
- test compound was serially diluted with DMSO to a concentration 100 times the final concentration.
- a DMSO solution of the test compound is diluted with the culture medium used for the culture, and this is added to each well of the cell culture plate so that the final concentration of DMSO is 0.5% in a culture vessel containing 5% carbon dioxide gas.
- the cells were cultured at 37 ° C for 72 hours. Measurement of the number of cells at the time of addition of the test compound and after culturing for 72 hours was performed using Cell Counting Kit-8 (manufactured by Dojindo) based on the protocol recommended by Dojindo.
- the reagent contained in the kit was added to each plate, and a color reaction was performed for a predetermined time at 37 ° C.
- Test Example 3 Measurement of FGFR1 Kinase Activity Inhibitory Action
- a biotinylated peptide (biotin) with biotin modification added to its amino acid sequence with reference to caliper life science FL-Peptide 22 -EEPLYWSFPAKKK) was synthesized and used as a substrate.
- the purified recombinant human FGFR1 protein used in the test was purchased from Carna Bioscience.
- the test compound was serially diluted with dimethyl sulfoxide (DMSO) to a concentration 20 times the final concentration.
- DMSO dimethyl sulfoxide
- Test Example 4 Measurement of FGFR3 kinase activity inhibitory activity The inhibitory activity of FGFR3 kinase activity was measured according to the method of Test Example 3. Purified recombinant human FGFR3 protein was purchased from Carna Biosciences. The final concentration of ATP was 50 ⁇ M. The results are shown in Table 23.
- Test Example 5 Measurement of FGFR4 Kinase Activity Inhibitory Activity
- the inhibitory activity for FGFR4 kinase activity was measured according to the method of Test Example 3.
- Purified recombinant human FGFR4 protein was purchased from Carna Biosciences. The final concentration of ATP was 200 ⁇ M. The results are shown in Table 23.
- HEK293 cells expressing Dovitinib resistant mutant FGFR2, N550H or E566G, K660M, which is known to have a mutation in uterine cancer were established. Furthermore, a HEK293 cell line expressing V565I in which 565th valine was mutated to isoleucine at the gatekeeper site was also established. These cell lines were incubated with Example Compound 2 and AZD4547 and BGJ-398, which are known FGFR inhibitors, to examine intracellular FGFR2 phosphorylation and cell growth inhibitory effects.
- Example Compound 2 which is a novel FGFR inhibitor, has inhibitory activity similar to that of the wild type against these resistant mutant FGFR2.
- Example Compound 2 was shown to have inhibitory activity equivalent to that of wild-type FGFR2 against Dovitinib, AZD4547, and BGJ-398 resistance mutations.
- Example Compound 2 had an inhibitory activity equivalent to that of the wild type. It has been shown. From the above results, Example Compound 2 was shown to have inhibitory activity equivalent to that of wild-type FGFR2 against tumor strains having FGFR mutations refractory to Dovitinib, AZD4547, and BGJ-398.
- Test Example 7 A gastric cancer cell line, OCUM-2MD3 cell, for which FGFR2 gene amplification has been reported, was cultured in the presence of AZD4547 for about 3 months, and a cell clone that was resistant to this drug was isolated.
- the FGFR2 gene was isolated from the resistant clone, its nucleotide sequence was decoded, and compared with wild type FGFR2. Further, the resistant cell line was incubated with Example Compound 2 to examine intracellular FGFR2 phosphorylation inhibition and cell growth inhibitory action.
- a mutation in which the 660th amino acid K was N was found.
- these strains were incubated with AZD4547 and the inhibition of intracellular FGFR2 phosphorylation was examined, attenuation was observed as compared to the wild strain, and a mutation in the FGFR2 gene was considered to be one of the causes of acquired resistance.
- Example Compound 2 was treated to these clones, FGFR2 phosphorylation and growth inhibition were inhibited to the same extent as the wild type (Tables 25 and 26).
Abstract
Description
本出願は、2013年07月18日に出願された、日本国特許出願第2013-149958号明細書(その開示全体が参照により本明細書中に援用される)に基づく優先権を主張する。
本発明は、FGFR阻害剤を有効成分とする抗腫瘍剤に関する。
項1.FGFR阻害剤に対する耐性を有する腫瘍患者に投与するための抗腫瘍剤であって、下記一般式(I)で表される3,5-二置換ベンゼンアルキニル化合物又はその塩を含む抗腫瘍剤:
X1及びX2は、各々独立してN又はCHであり;
Yは、一般式(A)
R2は、水素原子、C2-C6アルキニル基、-C(=O)ORx、-C(=O)N(Rx)(Ry)、ヒドロキシC1-C6アルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はR3を有していてもよいC2-C9ヘテロアリール基であり;
R3は、C1-C6アルキル基、又はジ(C1-C6アルキル)アミノC1-C6アルキル基であり;
Zは、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
R4、R5及びR6は、同一又は相異なって、水素原子、ハロゲン原子、R8を有していてもよいC1-C6アルキル基、又は一般式(D)
R7は、水素原子、C1-C6アルキル基、又はヒドロキシC1-C6アルキル基であり;
R8は、-ORx、又は-N(Rx)(Ry)であり;
R9は、C1-C6アルキル基、ハロゲン原子、又は-ORxであり;
Rx及びRyは、同一又は相異なって、水素原子、C1-C6アルキル基、C3-C10シクロアルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はC1-C6アルコキシC1-C6アルキル基であり;
lは、0~3の整数であり;
mは、1~3の整数であり;
nは、0~2の整数である。)。
lが0又は1であり;かつ
(1)Yが一般式(A)で表される基の場合、
で表される基の場合、
(1)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン
(2)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-イン-1-オン
(3)(S)-1-(3-(4-アミノ-3-((3,5-ジエトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン
(4)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン
(5)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-ヒドロキシブタ-2-イン-1-オン
(6)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン
(7)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(シクロプロピルアミノ)ブタ-2-エン-1-オン
(8)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(イソプロピルアミノ)ブタ-2-エン-1-オン
(9)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(エチル(メチル)アミノ)ブタ-2-エン-1-オン
(10)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(シクロブチルアミノ)ブタ-2-エン-1-オン
(11)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジエチルアミノ)ブタ-2-エン-1-オン
(12)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(tert-ブチルアミノ)ブタ-2-エン-1-オン
(13)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン-1-オン
(14)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ピペリジン-1-イル)ブタ-2-エン-1-オン
(15)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン
(16)(R)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン
(17)1-((2S,4S)-4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-(ヒドロキシメチル)ピロリジン-1-イル)プロパ-2-エン-1-オン
(18)1-((2S,4S)-4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-エチニルピロリジン-1-イル)プロパ-2-エン-1-オン
(19)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン
(20)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン
(21)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ピロリジン-1-イル)ブタ-2-エン-1-オン
(22)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(4-ヒドロキシピペリジン-1-イル)ブタ-2-エン-1-オン
(23)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)ブタ-2-イン-1-オン
(24)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-ヒドロキシ-4-メチルペント-2-イン-1-オン
(25)1-((S)-3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-((S)-3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン
(26)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ピペリジン-1-イル)ブタ-2-エン-1-オン
(27)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン
(28)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン
(29)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ピロリジン-1-イル)ブタ-2-エン-1-オン
(30)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(アゼチジン-1-イル)ブタ-2-エン-1-オン
(31)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(エチル(メチル)アミノ)ブタ-2-エン-1-オン
(32)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(イソプロピルアミノ)ブタ-2-エン-1-オン
(33)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ジエチルアミノ)ブタ-2-エン-1-オン
(34)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-((2-メトキシエチル)(メチル)アミノ)ブタ-2-エン-1-オン
(35)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(4-ヒドロキシピペリジン-1-イル)ブタ-2-エン-1-オン
(36)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(3-ヒドロキシピロリジン-1-イル)ブタ-2-エン-1-オン
(37)(R)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(3-ヒドロキシピロリジン-1-イル)ブタ-2-エン-1-オン
(38)(2S,4S)-メチル 1-アクリロイル-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレート
(39)1-((2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(1,3,4-オキサジアゾール-2-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン
(40)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピロロ[3,2-c]ピリジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン
本願明細書において、一般式(A)
で表される基の2価の部分(moiety)
一般式(A)
本願明細書において一般式(B)
で表される基の2価の部分(moiety)
一般式(B)
本願明細書において一般式(C)
で表される基の2価の部分(moiety)
一般式(C)
本願明細書において一般式(D)
で表される基の1価の部分(moiety)
一般式(D)
一般式(I)中、X1及びX2において好ましい組合せとしては、(1)X2がNの場合、X1はN又はCHであり、(2)X2がCHの場合、X1はCHである。
一般式(I)中、lとしては、好ましくは0又は1である。
一般式(I)中、Yとしては、一般式(A)
で表される基、又は一般式(C)
で表される基が好ましく、一般式(A)で表される基の2価の部分(moiety)
一般式(I)中、Y及びZにおいて好ましい組合せとしては、Yが一般式(A)
で表される基の場合、Zは-C(R4)=C(R5)(R6)又は-C≡C-R7であり、Yが一般式(B)又は一般式(C)で表される基
の場合、Zは-C(R4)=C(R5)(R6)である。
で表される基であり、より好ましくは水素原子、R8を有するメチル基、又は一般式(D)
で表される基である。
一般式(I)中、mとしては、好ましくは1である。
一般式(I)中、R9としては、C1-C4アルキル基、フッ素原子、又は水酸基が好ましく、メチル基、フッ素原子、又は水酸基がより好ましい。
一般式(I)中、nとしては、好ましくは0又は1である。
化合物(I)において、一般式(I)中、R1がC1-C4アルキル基であり;X1及びX2において、(1)X2がNの場合、X1はN又はCHであり、(2)X2がCHの場合、X1はCHであり;Yにおいて、一般式(A)
(a)Yが一般式(A)
で表される基の場合、Zは-C(R4)=C(R5)(R6)又は-C≡C-R7であり、(b)Yが一般式(C)
で表される基の場合、Zは-C(R4)=C(R5)(R6)であり;R4は、水素原子又はフッ素原子であり;R5及びR6は、同一又は相異なって、水素原子、R8を有するC1-C4アルキル基、又は一般式(D)
(a)Yが一般式(A)
で表される基の場合、Zは-C(R4)=C(R5)(R6)又は-C≡C-R7であり、(b)Yが一般式(C)
で表される基の場合、Zは-C(R4)=C(R5)(R6)であり;R4は、水素原子であり;R5及びR6は、同一又は相異なって、水素原子、R8を有するメチル基、又は
一般式(D)
(1)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物2)
(2)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-イン-1-オン(実施例化合物5)
(3)(S)-1-(3-(4-アミノ-3-((3,5-ジエトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物8)
(4)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン(実施例化合物9)
(5)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-ヒドロキシブタ-2-イン-1-オン(実施例化合物10)
(6)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物12)
(7)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(シクロプロピルアミノ)ブタ-2-エン-1-オン(実施例化合物13)
(8)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(イソプロピルアミノ)ブタ-2-エン-1-オン(実施例化合物14)
(9)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(エチル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物15)
(10)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(シクロブチルアミノ)ブタ-2-エン-1-オン(実施例化合物16)
(11)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジエチルアミノ)ブタ-2-エン-1-オン(実施例化合物17)
(12)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(tert-ブチルアミノ)ブタ-2-エン-1-オン(実施例化合物18)
(13)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物19)
(14)1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物20)
(15)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物22)
(16)(R)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物23)
(17)1-((2S,4S)-4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-(ヒドロキシメチル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物28)
(18)1-((2S,4S)-4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-エチニルピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物32)
(19)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物38)
(20)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物39)
(21)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物40)
(22)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(4-ヒドロキシピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物42)
(23)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)ブタ-2-イン-1-オン(実施例化合物46)
(24)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-ヒドロキシ-4-メチルペント-2-イン-1-オン(実施例化合物47)
(25)1-((S)-3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-((S)-3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物49)
(26)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物50)
(27)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン(実施例化合物51)
(28)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物52)
(29)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物53)
(30)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(アゼチジン-1-イル)ブタ-2-エン-1-オン(実施例化合物55)
(31)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(エチル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物56)
(32)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(イソプロピルアミノ)ブタ-2-エン-1-オン(実施例化合物57)
(33)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ジエチルアミノ)ブタ-2-エン-1-オン(実施例化合物59)
(34)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-((2-メトキシエチル)(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物60)
(35)1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(4-ヒドロキシピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物61)
(36)(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(3-ヒドロキシピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物62)
(37)(R)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(3-ヒドロキシピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物63)
(38)(2S,4S)-メチル 1-アクリロイル-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレート(実施例化合物66)
(39)1-((2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(1,3,4-オキサジアゾール-2-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物68)
(40)(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピロロ[3,2-c]ピリジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物73)
製造法1
製造法2
化合物(I)の製造に用いられる一般式(II)で表される化合物は、例えば、製造法3又は4により製造することが可能である。
製造法3
製造法6
カラム:YMC社製YMC-Triart C18,2.0X50mm,1.9μm
MS検出:ESI positive
UV検出:254及び210nm
カラム流速:0.5mL/min
移動相:水/アセトニトリル(0.1%ギ酸)
インジェクション量:1μL
グラディエント(table 1)
Time(min)Water Acetonitrile
0 95 5
0.1 95 5
2.1 5 95
3.0 STOP
カラム:YMC社製YMC-Actus Triart C18,20X50mm,5μm と YMC社製YMC-Actus Triart C18,20X10mm,5μmを連結したものを使用した。
UV検出:254nm
MS検出: ESI positive
カラム流速:25mL/min
移動相:水/アセトニトリル(0.1%ぎ酸)
インジェクション量:0.1-0.5mL
s:シングレット
d:ダブレット
t:トリプレット
q:カルテット
dd:ダブル ダブレット
dt:ダブル トリプレット
td:トリプル ダブレット
tt:トリプル トリプレット
ddd:ダブル ダブル ダブレット
ddt:ダブル ダブル トリプレット
dtd:ダブル トリプル ダブレット
tdd:トリプル ダブル ダブレット
m:マルチプレット
br:ブロード
brs:ブロードシングレット
DMSO-d6:重ジメチルスルホキシド
CDCl3:重クロロホルム
CD3OD:重メタノール
THF:テトラヒドロフラン
DMF:N,N-ジメチルホルムアミド
NMP:1‐メチル‐2‐ピロリジノン
DMSO:ジメチルスルホキシド
TFA:トリフルオロ酢酸
SEMCl:2-(トリメチルシリル)エトキシメチルクロライド
PdCl2(dppf)CH2Cl2: 1,1’-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体
WSC:1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩
HOBt:1-ヒドロキシベンゾトリアゾール1水和物
HATU:O-(7-アザベンゾトリアゾ-1-イル)-N,N,N’,N’- テトラメチルウロニウム ヘキサフルオロホスフェート
HBTU:O-ベンゾトリアゾール-N,N,N’,N’- テトラメチルウロニウム ヘキサフルオロホスフェート
DIAD:ジイソプロピルアゾジカルボキシレート
TBAF:テトラブチルアンモニウムフルオライド
DIPEA:ジイソプロピルエチルアミン
Boc2O:二炭酸ジ-tert-ブチル
DMAP:ジメチルアミノピリジン
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物1)の合成
(工程1)3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの合成
室温にて1.0時間撹拌したのち、酢酸エチルと水を加え、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、表題化合物を無色油状化合物として1.2g得た。物性値:m/z[M+H]+ 266.1
上記工程1で得られた3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン62mg、工程2で得られたtert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレート217mg、炭酸カリウム221mgのDMF2.0ml懸濁溶液を70℃にて一時間撹拌した。酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を淡黄色アモルファスとして36.2mg得た。物性値:m/z[M+H]+ 465.1
上記工程3で得られたtert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート32mgに4N-塩酸/1,4-ジオキサン4mlを加え、室温にて1.5時間撹拌した。得られた反応混合物の溶媒を減圧留去後、引き続きトルエン共沸を行い、3-((3,5-ジメトキシフェニル)エチニル)-1-(ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの粗生成物を32mg得た。得られた粗生成物の一部12mgにクロロホルム2.0ml、トリエチルアミン20μlを加えた。0℃に冷却後、塩化アクリル2.3μlを溶解したクロロホルム100μlを加え、室温にて10分間撹拌した。飽和炭酸水素ナトリウム溶液で反応を停止させた後、生成物を酢酸エチルで抽出、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:酢酸エチル/メタノール)にて精製し、表題化合物を白色固体として6.5mg得た。物性値を表1に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物2)の合成
(工程1)(R)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレートの合成
として149mg得た。物性値:m/z[M+H]+ 465.1
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物3)の合成
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物4)の合成
色アモルファスとして2.3mg得た。物性値を表1に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-イン-1-オン(実施例化合物5)の合成
合物を白色固体として0.7mg得た。物性値を表2に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリ80ミジン-1-イル)ピロリジン-1-イル)-2-フルオロプロパ-2-エン-1-オン(実施例化合物6)の合成
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-2-(ピロリジン-1-イルメチル)プロパ-2-エン-1-オン(実施例化合物7)の合成実施例4に準じ、4-(ジメチルアミノ)ブタ-2-エン酸 塩酸塩の代わりに2-(ピロリジン-1-イルメチル)酢酸(syn.comm.1995,641)を用いることで表記化合物を無色アモルファスとして得た。物性値を表2に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジエトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物8)の合成
四臭化炭素4.78gをジクロロエタン14mLに溶解し、0℃にてトリフェニルホスフィン7.56gを加えた。0℃にて5分間攪拌した後、3,5-ジエトキシベンズアルデヒド1.40gのジクロロメタン7mL溶液を加え、20分間攪拌した。そのまま反応溶液をシリカゲルクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し1-(2,2-ジブロモビニル)-3,5-ジエトキシベンゼンを得た。得られた化合物はさらに精製することなく次の反応に用いた。上記で得られた化合物をTHF30mLに溶解し、-78℃にて1.63M n-ブチルリチウムのヘキサン溶液10.5mLを加え、-78℃にて30分間攪拌した。飽和塩化アンモニウム水溶液を加えた後、反応混合物を酢酸エチルで抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、溶媒を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色油状物として1.31g得た。
物性値:m/z[M+H]+ 191.0
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン(実施例化合物9)の合成
N-Boc-3-ヒドロキシアゼチジン1.73gをクロロホルム20mlに溶解し、0℃にてトリエチルアミン2.09ml、メタンスルホニルクロライド856μlを加えた。室温にて0.5時間撹拌したのち、酢酸エチルと水を加え、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、水で洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、表題化合物を無色油状化合物として2.32g得た。物性値:m/z[M+H]+ 252.0
実施例1(工程4)に準じ、tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの代わりに、上記工程3で得られたtert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-カルボキシレートを用い、酸性条件下、Boc基の除去により1-(アゼチジン-3-イル)-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの粗生成物を得た後アミド化を行い、表題化合物を白色固体として得た。物性値を表2に示す。
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-ヒドロキシブタ-2-イン-1-オン(実施例化合物10)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-ヒドロキシ-4-メチルペント-2-イン-1-オン(実施例化合物11)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物12)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(シクロプロピルアミノ)ブタ-2-エン-1-オン(実施例化合物13)の合成
4-ブロモクロトン酸 329mgに塩化チオニル 3.0mlを加え80℃にて5時間撹拌した。反応液を減圧濃縮し、さらにトルエン共沸を行い、表題化合物を粗生成物として394mg得た。
上記実施例9で得られた中間体1-(アゼチジン-3-イル)-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの粗生成物140mgをTHF4.5mlに懸濁させ、DIPEA178μlを加え0℃に冷却した。上記工程1で得られた4-ブロモブタ-2-エノイルクロライド66mgのTHF 0.5ml溶液を滴下し、室温にて15分撹拌した。飽和炭酸水素ナトリウム溶液で反応を停止させた後、生成物を酢酸エチルで抽出、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、表題化合物を粗生成物として160mg得た。物性値:m/z[M+H]+ 497.0,499.0
上記工程2で得られた1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-ブロモブタ-2-エン-1-オンの粗生成物12mgをDMF0.5mlに溶解し、シクロプロピルアミン5μl、DIPEA10μlを加え、室温にて1時間撹拌した。減圧濃縮した後、得られた残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))にて精製し、表題化合物を無色アモルファスとして3.4mg得た。物性値を表3に示す。
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(イソプロピルアミノ)ブタ-2-エン-1-オン(実施例化合物14)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(エチル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物15)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(シクロブチルアミノ)ブタ-2-エン-1-オン(実施例化合物16)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジエチルアミノ)ブタ-2-エン-1-オン(実施例化合物17)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(tert-ブチルアミノ)ブタ-2-エン-1-オン(実施例化合物18)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物19)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物20)の合成
1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-モルホリノブタ-2-エン-1-オン(実施例化合物21)の合成
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オンの合成
(R)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オンの合成
1-(3-(4-アミノ-3-((3,5-ジエトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン(実施例化合物24)の合成
1-(3-(4-アミノ-3-((3,5-ジエトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物25)の合成
1-(3-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物26)の合成
実施例1(工程1)で得られた3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン148mg、N-Boc-3-ヒドロキシメチルピロリジン154 mg、ポリマー担持トリフェニルホスフィン(~3.0mmol/g)334 mgのTHF5.0ml懸濁溶液に、DIAD197μlを加え、室温にて3時間撹拌した。不溶物をろ過し、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして94.5mg得た。物性値:m/z[M+H]+ 479.1
実施例1(工程4)に準じ、tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの代わりに、上記工程1で得られたtert-ブチル 3-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピロリジン-1-カルボキシレートを用いることにより、表題化合物を白色固体として得た。物性値を表7に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物27)の合成
1-((2S,4S)-4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-(ヒドロキシメチル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物28)の合成
1-N-Boc-(2S,4R)-4-ヒドロキシ-2-(ヒドロキシメチル)-ピロリジン500mgをDMF4.0mlに溶解し、イミダゾール164mgを加えた。0℃に冷却後、tert-ブチルクロロジフェニルシラン616μlを加え1時間撹拌した。反応液に酢酸エチルと飽和炭酸水素ナトリウム溶液を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色油状物質として655mg得た。物性値:m/z[M+H]+ 456.2
上記工程1で得られた(2S,4R)-tert-ブチル 2-((tert-ブチルジフェニルシリルオキシ)メチル)-4-ヒドロキシピロリジン-1-カルボキシレート300mgをクロロホルム3.0mlに溶解し、0℃にてトリエチルアミン137μl、メタンスルホニルクロライド56μlを加えた。室温にて2.0時間撹拌したのち、クロロホルムと水を加え、有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、表題化合物を無色油状化合物として389mg得た。物性値:m/z[M+H]+ 534.1
上記工程2で得られた(2S,4S)-tert-ブチル 2-((tert-ブチルジフェニルシリルオキシ)メチル)-4-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレート389mg、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン188mg、炭酸カリウム363mgをDMF4.0mlに懸濁し、80℃にて終夜撹拌した。酢酸エチルと水を加え、有機層を分離し無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色油状物質として191mg得た。物性値:m/z[M+H]+ 699.1
上記工程4で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-((tert-ブチルジフェニルシリルオキシ)メチル)ピロリジン-1-カルボキシレート25mgをTHF 1.0mlに溶解し、シリカゲル担持テトラブチルアンモニウムフルオライド(~1.5mmol/g)34mgを加え終夜撹拌した。シリカゲル担持テトラブチルアンモニウムフルオライド(~1.5mmol/g)30mgを追加で加え、さらに二日間撹拌した。試薬をろ過した後、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして62mg得た。物性値:m/z[M+H]+ 495.1
実施例1(工程4)に準じ、tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの代わりに、上記工程5で得られた4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシレートを用いることにより、表題化合物を白色固体として得た。物性値を表8に示す。
1-(3-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)アゼチジン-1-イル)プロパ-2-エン-1-オン(実施例化合物29)の合成
N-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)シクロブチル)アクリルアミド(実施例化合物30)の合成
1-(4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物31)の合成
1-((2S,4S)-4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-エチニルピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物32)の合成
実施例1(工程1)で得られた3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン14mg、国際公開WO2005/007083号パンフレット記載の方法で合成した(2S,4R)-tert-ブチル 2-エチニル-4-ヒドロキシピロリジン-1-カルボキシレート15mg、トリフェニルホスフィン23mgをTHF1.0mlに懸濁させ、DIAD18μlを加え、室温にて1時間撹拌した。反応液を濃縮後、DMSO溶液に溶解し、逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))にて精製し、表題化合物を無色アモルファスとして5.0mg得た。物性値:m/z[M+H]+ 489.2
実施例1(工程4)に準じ、tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの代わりに、上記工程1で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)-2-エチニルピロリジン-1-カルボキシレートを用いることにより、表題化合物を白色固体として得た。物性値を表9に示す。
1-(4-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物33)の合成
N-(3-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)フェニル)アクリルアミド(実施例化合物34)の合成
1-(3-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物35)の合成
1-(4-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物36)の合成
1-(4-((4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)メチル)ピペリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物37)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物38)の合成
上記工程1で得られた(S)-tert-ブチル 3-(4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート400mgにテトラヒドロフラン2.5ml及び28%アンモニア水2.5mlを加え、反応液をマイクロウェーブ反応装置で、100℃で1.5時間撹拌した。クロロホルムと水を加え有機層を分離し、有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、表題化合物を白色固体化合物として382mg得た。物性値:m/z[M+H]+ 430.3
上記工程2で得られた(S)-tert-ブチル 3-(4-アミノ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート660mg、1-エチニル-3,5-ジメトキシベンゼン374mg、ヨウ化銅(I)44mg、トリエチルアミン2.0mlのTHF15ml混合物に、PdCl2(dppf)2CH2Cl2122mgを加え、窒素置換した後、80℃にて3.5時間撹拌した。反応液に酢酸エチルと水を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして714mg得た。物性値:m/z[M+H]+ 464.1
上記工程3で得られた(S)-tert-ブチル 3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート30mgに4N-塩酸/1,4-ジオキサン2mlを加え、室温にて1.5時間撹拌した。得られた反応混合物の溶媒を減圧留去後、引き続きトルエン共沸を行い、(S)-5-((3,5-ジメトキシフェニル)エチニル)-7-(ピロリジン-3-イル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンの粗生成物を30mg得た。得られた粗生成物の一部10mg、4-(ジメチルアミノ)ブタ-2-エン酸 塩酸塩5.9mg、HATU14mgをDMF1.0mlに溶解し、DIPEA50μl加え、室温で5分撹拌した。反応液にクロロホルムと水を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))にて精製し、表題化合物を無色アモルファスとして3.9mg得た。物性値を表10に示す。
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物39)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物40)の合成
4-ブロモクロトン酸メチルエステル1.79gをテトラヒドロフラン40mlに溶解し、0℃にてピロリジン1.67mlを加え、室温にて1時間撹拌した。反応液にジエチルエーテルと水を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた生成物に3N塩酸40mlを加え、100℃で1時間加熱環流した。反応液を減圧濃縮、得られた残渣をイソプロパノールと酢酸エチルの混合溶媒で洗浄し、表題化合物を白色固体として939mg得た。物性値:m/z[M+H]+ 156.0
実施例4(工程1)に準じ、実施例38(工程4)で得られた中間体(S)-5-((3,5-ジメトキシフェニル)エチニル)-7-(ピロリジン-3-イル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンと上記工程1で得られた4-(ピロリジン-1-イル)ブタ-2-エン酸 塩酸塩を用いることにより、表題化合物を無色アモルファスとして得た。物性値を表10に示す。
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(4-メチルピペラジン-1-イル)ブタ-2-エン-1-オン(実施例化合物41)の合成
実施例38(工程4)で得られた中間体(S)-5-((3,5-ジメトキシフェニル)エチニル)-7-(ピロリジン-3-イル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンの粗生成物100mgをクロロホルム 3.0mlに懸濁させ、DIPEA 117μlを加え0℃に冷却した。実施例16(工程1)で得られた、4-ブロモブタ-2-エノイルクロライド46mgのクロロホルム 0.3ml溶液を滴下し、室温にて15分撹拌した。飽和炭酸水素ナトリウム溶液で反応を停止させた後、生成物を酢酸エチルで抽出、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、表題化合物を粗生成物として140mg得た。物性値:m/z[M+H]+ 509.9,511.9
上記工程1で得られた(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-ブロモブタ-2-エン-1-オンの粗生成物12mgをDMF0.5mlに溶解し、N-メチルピペラジン4mg、DIPEA10μlを加え、室温にて終夜撹拌した。減圧濃縮した後、得られた残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))にて精製し、表題化合物を無色アモルファスとして3.0mg得た。物性値を表11に示す。
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(4-ヒドロキシピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物42)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(4-フルオロピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物43)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(3,3-ジフルオロピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物44)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(4,4-ジフルオロピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物45)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)ブタ-2-イン-1-オン(実施例化合物46)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-ヒドロキシ-4-メチルペンタ-2-イン-1-オン(実施例化合物47)の合成
1-((S)-3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-((R)-3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物48)の合成
1-((S)-3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-((S)-3-フルオロピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物49)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-イル)-4-(ピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物50)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)プロパ-2-エン-1-オン(実施例化合物51)の合成
4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン1.00 g、N-Boc―3-ヒドロキシアゼチジン930mg、トリフェニルホスフィン 1.85gのテトラヒドロフラン溶液40ml溶液に、DIAD1.41mlを加え、反応液を1時間撹拌した。反応液を濃縮、酢酸エチルで洗浄し、表題化合物を白色固体として1.07g得た。物性値:m/z[M+H]+ 435.0
上記工程1で得られたtert-ブチル 3-(4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレート350mgにテトラヒドロフラン2.5ml及び28%アンモニア水2.5mlを加え、反応液をマイクロウェーブ反応装置で、100℃で1.5時間撹拌した。クロロホルムと水を加え有機層を分離し、有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、表題化合物を白色固体化合物として340mg得た。物性値:m/z[M+H]+ 416.0
上記工程2で得られたtert-ブチル 3-(4-アミノ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレート639mg、1-エチニル-3,5-ジメトキシベンゼン374mg、ヨウ化銅(I)44mg、トリエチルアミン2.0mlのTHF15ml混合物に、PdCl2(dppf)CH2Cl2122mgを加え、窒素置換した後、80℃にて3.5時間撹拌した。反応液に酢酸エチルと水を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして704mg得た。物性値:m/z[M+H]+ 450.1
実施例1(工程4)に準じ、tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの代わりに、上記工程3で得られたtert-ブチル 3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-カルボキシレートを用い、酸性条件下、Boc基の除去により7-(アゼチジン-3-イル)-5-((3,5-)ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンの粗生成物を得た後アミド化を行い、表題化合物を白色固体として得た。物性値を表13に示す。
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物52)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物53)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)ブタ-2-イン-1-オン(実施例化合物54)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(アゼチジン-1-イル)ブタ-2-エン-1-オン(実施例化合物55)の合成
上記工程1で得られた1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-ブロモブタ-2-エン-1-オンの粗生成物10mgをTHF0.5mlに懸濁し、アゼチジン7μlを加え、室温にて1時間撹拌した。減圧濃縮した後、得られた残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))にて精製し、表題化合物を無色アモルファスとして1.6mg得た。物性値を表14に示す。
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(エチル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物56)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(イソプロピルアミノ)ブタ-2-エン-1-オン(実施例化合物57)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(イソプロピル(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物58)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(ジエチルアミノ)ブタ-2-エン-1-オン(実施例化合物59)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-((2-メトキシエチル)(メチル)アミノ)ブタ-2-エン-1-オン(実施例化合物60)の合成
1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(4-ヒドロキシピペリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物61)の合成
(S)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(3-ヒドロキシピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物62)の合成
(R)-1-(3-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)アゼチジン-1-イル)-4-(3-ヒドロキシピロリジン-1-イル)ブタ-2-エン-1-オン(実施例化合物63)の合成
1-(4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピペリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物64)の合成
物性値を表17に示す。
1-(4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピペリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物65)の合成
(2S,4S)-メチル 1-アクリロイル-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレート(実施例化合物66)の合成 (工程1)4-クロロ-5-ヨード-7-((2-(トリメチルシリル)エトキシ)メチル)-7H-ピロロ[2,3-d]ピリミジンの合成
上記工程1で得られた4-クロロ-5-ヨード-7-((2-(トリメチルシリル)エトキシ)メチル)-7H-ピロロ[2,3-d]ピリミジン200mgをTHF2.0mlに溶解し、28%アンモニア水2mlを加えた後、反応液をマイクロウェーブ反応装置中、105℃にて1.5時間撹拌した。生成物を酢酸エチルで抽出、有機層を有飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、表題化合物を白色固体物質として192mg得た。物性値:m/z[M+H]+ 391.0
上記工程3で得られた5-((3,5-ジメトキシフェニル)エチニル)-7-((2-(トリメチルシリル)エトキシ)メチル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン4.27gの塩化メチレン20ml溶液を0℃に冷却し、TFA10mlを加えた。反応液を室温で5時間撹拌し、溶媒を減圧留去した。残渣にTHF50mlを加えて0℃に冷却し、4N水酸化ナトリウム素溶液12.5mlを加えて室温で終夜撹拌した。酢酸エチルで抽出、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残渣にクロロホルムを加え、濾過することにより表題化合物を白色固体として2.60g得た。物性値:m/z[M+H]+ 295.3
実施例1(工程2)に準じ、N-Boc-3-ピロリジノールの代わりに(2S,4R)-4-ヒドロキシ-ピロリジン-1,2-ジカルボン酸 1-tert-ブチルエステル-2-メチルエステルを用いることにより、表題化合物を無色アモルファスとして得た。
実施例1(工程3)に準じ、3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの代わりに上記工程4で得られた5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンを用い、tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレートの代わりに上記工程5で得られた(2S,4R)-4-(メチルスルホニルオキシ)-ピロリジン-1,2-ジカルボン酸 1-tert-ブチルエステル-2-メチルエステルを用い、炭酸カリウムの代わりに水素化ナトリウムを用い、DMFの代わりにNMPを用いることにより、表題化合物を無色アモルファスとして得た。物性値:m/z[M+H]+ 522.4
上記工程6で得られた(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレート24mgの塩化メチレン2.0ml、TFA2.0ml溶液を室温にて30分撹拌した。溶媒を減圧留去し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:クロロホルム/メタノール)にて精製し、表題化合物を淡黄色アモルファスとして11.9mg得た。物性値:m/z[M+H]+ 422.1
上記工程7で得られた(2S,4S)-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレート12mgに塩化メチレン2.0ml、トリエチルアミン16μlを加えた。0℃に冷却後、塩化アクリル5μlを溶解したクロロホルム100μlを加え、室温にて10分間撹拌した。飽和炭酸水素ナトリウム溶液で反応を停止させた後、生成物を酢酸エチルで抽出、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:酢酸エチル/メタノール)にて精製し、表題化合物を無色アモルファスとして4.2mg得た。物性値を表18に示す。
1-((2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-((ジメチルアミノ)メチル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物67)の合成
トリフェニルホスフィン443mgのTHF25ml溶液を0℃に冷却し、DIAD340μlを滴下して反応液を0℃で1時間撹拌した。4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン363mgと実施例28(工程1)で得られた(2S,4R)-tert-ブチル 2-((tert-ブチルジフェニルシリルオキシ)メチル)-4-ヒドロキシピロリジン-1-カルボキシレート651.6mgを加え、室温で終夜撹拌した。酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を淡黄色アモルファスとして400mg得た。m/z[M+H]+ 718.5
上記工程1で得られた(2S,4S)-tert-ブチル 2-((tert-ブチルジフェニルシリルオキシ)メチル)-4-(4-クロロ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1-カルボキシレート400mgにTHF10ml、8Nアンモニア メタノール溶液5mlを加え、マイクロウェーブ照射下120℃で2時間撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:クロロホルム/メタノール)にて精製し、表題化合物を淡黄色固体として293mg得た。物性値:m/z[M+H]+ 698.5
上記工程2で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-((tert-ブチルジフェニルシリルオキシ)メチル)ピロリジン-1-カルボキシレート200mgのTHF5ml溶液にBoc2O188mg、DMAP7mgを加え、室温で終夜撹拌した。反応液に酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を淡黄色アモルファスとして238mg得た。m/z[M+H]+ 898.5
上記工程3で得られた(2S,4S)-tert-ブチル 4-(4-(bis(tert-ブトキシカルボニル)アミノ)-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-((tert-ブチルジフェニルシリルオキシ)メチル)ピロリジン-1-カルボキシレート237.5mgのTHF5ml溶液にシリカゲル担持テトラブチルアンモニウムフルオライド(~1.5mmol/g)700mgを加え、室温で終夜撹拌した。シリカゲルを濾別し、濾液の溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製して表題化合物を淡黄色アモルファスとして185mg得た。物性値:m/z[M+H]+ 660.2
上記工程4で得られた(2S,4S)-tert-ブチル 4-(4-(bis(tert-ブトキシカルボニル)アミノ)-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキシレート66mgの塩化メチレン2ml溶液にデスマーチンペルヨージナン51mgを加え、室温で1時間撹拌した。さらにデスマーチンペルヨージナン100mgを加え、室温で1時間撹拌した。さらにデスマーチンペルヨージナン70mgを加え、室温で1時間撹拌した。反応液に水を加え有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液、10%チオ硫酸ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥、溶媒を減圧留去して表題化合物を淡黄色アモルファスとして68mg得た。物性値:m/z[M+H]+ 658.1
上記工程5で得られた(2S,4S)-tert-ブチル 4-(4-(bis(tert-ブトキシカルボニル)アミノ)-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-ホルミルピロリジン-1-カルボキシレート68mgの塩化メチレン2ml溶液に1Mジメチルアミン THF溶液0.3ml、酢酸0.2mlを加え、0℃に冷却した。反応液にナトリウムトリアセトキシボロヒドリド127mgを加え、0℃で2時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液で中和し、有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去して表題化合物を淡黄色アモルファスとして31.9mg得た。物性値:m/z[M+H]+ 687.2
実施例1(工程1)に準じ、3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの代わりに、上記工程6で得られた(2S,4S)-tert-ブチル 4-(4-(bis(tert-ブトキシカルボニル)アミノ)-5-ヨード-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-((ジメチルアミノ)メチル)ピロリジン-1-カルボキシレートを用いることにより、表題化合物を淡黄色アモルファスとして得た。物性値:m/z[M+H]+ 721.5
実施例66(工程7)に準じ、(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレートの代わりに上記工程7で得られた(2S,4S)-tert-ブチル 4-(4-(bis(tert-ブトキシカルボニル)アミノ)-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-((ジメチルアミノ)メチル)ピロリジン-1-カルボキシレートを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値:m/z[M+H]+ 421.1
実施例66(工程8)に準じ、(2S,4S)-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレートの代わりに、上記工程8で得られた5-((3,5-ジメトキシフェニル)エチニル)-7-((3S,5S)-5-((ジメチルアミノ)メチル)ピロリジン-3-イル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンを用いることにより表題化合物を無色アモルファスとして得た。物性値を表18に示す。
1-((2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(1,3,4-オキサジアゾール-2-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物68)の合成
実施例66(工程6)で得られた(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレート393.8mgをメタノール6mlに溶解し、0℃に冷却後、4N水酸化ナトリウム水溶液3mlを加えた。反応懸濁液を室温で3時間撹拌した。反応液に5N塩酸を加えてpHを5とし、酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、表題化合物を淡黄色固体として280mg得た。物性値m/z[M+H]+ 508.3
上記工程1で得られた(2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-1-(tert-ブトキシカルボニル)ピロリジン-2-カルボン酸106mg、TBTU100mgのDMF2ml溶液にDIPEA73μl、ヒドラジン1水和物46μlを加え、室温で10分撹拌した。反応液に酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、表題化合物を淡黄色アモルファスとして93.6mg得た。物性値:m/z[M+H]+ 522.4
上記工程2で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(ヒドラジンカルボニル)ピロリジン-1-カルボキシレート93.6mgにトルエン3ml、オルト蟻酸トリメチル79μlを加え、110℃で終夜撹拌した。反応液に酢酸400μlを加え、110℃で6時間撹拌した。反応液に酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:クロロホルム/メタノール)にて精製し、表題化合物を淡黄色アモルファスとして50mg得た。物性値:m/z[M+H]+ 532.2
実施例66(工程7)に準じ、(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレートの代わりに、上記工程3で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシレート50mgを用いることにより表題化合物を淡黄色アモルファスとして30.3mg得た。m/z[M+H]+ 432.0
実施例66(工程8)に準じ、(2S,4S)-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレートの代わりに、上記工程4で得られた7-((3S,5S)-5-(1,3,4-オキサジアゾール-2-イル)ピロリジン-3-イル)-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値を表18に示す。
1-((2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物69)の合成
実施例68(工程3)に準じ、オルト蟻酸トリメチルの代わりに、オルト酢酸トリエチ
ルを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値:m/z[M+H]+ 546.5
実施例66(工程7)に準じ、(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレートの代わりに、上記工程1で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシレートを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値:m/z[M+H]+ 466.0
実施例66(工程8)に準じ、(2S,4S)-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレートの代わりに、上記工程2で得られた5-((3,5-ジメトキシフェニル)エチニル)-7-((3S,5S)-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピロリジン-3-イル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値を表18に示す。
1-((2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(5-((ジメチルアミノ)メチル)-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物70)の合成
実施例68(工程2)に準じ、ヒドラジン1水和物の代わりに、2-(ジメチルアミノ)アセトヒドラジドを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値:m/z[M+H]+ 607.3
上記工程1で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(2-(2-(ジメチルアミノ)アセチル)ヒドラジンカルボニル)ピロリジン-1-カルボキシレート100mgのアセトニトリル3ml溶液にDIPEA105μl、トシルクロリド56mgを加え、40℃で1時間撹拌した。反応液に酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:クロロホルム/メタノール)にて精製し、表題化合物を淡黄色アモルファスとして40.5mg得た。物性値:m/z[M+H]+ 589.2
実施例66(工程7)に準じ、(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレートの代わりに、上記工程2で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-(5-((ジメチルアミノ)メチル)-1,3,4-オキサジアゾール-2-イル)ピロリジン-1-カルボキシレートを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値:m/z[M+H]+ 489.2
実施例66(工程8)に準じ、(2S,4S)-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレートの代わりに、上記工程3で得られた5-((3,5-ジメトキシフェニル)エチニル)-7-((3S,5S)-5-(5-((ジメチルアミノ)メチル)-1,3,4-オキサジアゾール-2-イル)ピロリジン-3-イル)-7H-ピロロ[2,3-d]ピリミジン-4-アミンを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値を表18に示す。
(2S,4S)-1-アクリロイル-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-N-(2-(ジメチルアミノ)エチル)-N-メチルピロリジン-2-カルボキサミド(実施例化合物71)の合成
実施例68(工程1)で得られた(2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-1-(tert-ブトキシカルボニル)ピロリジン-2-カルボン酸25.4mg、TBTU17.7mg、N,N,N’-トリメチルエタン-1,2-ジアミン13μl、DIPEA26μlのアセトニトリル3ml溶液を室温で1時間撹拌した。酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:クロロホルム/メタノール)にて精製し、表題化合物を淡黄色アモルファスとして3mg得た。物性値:m/z[M+H]+ 592.4
実施例66(工程7)に準じ、(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレートの代わりに、上記工程1で得られた(2S,4S)-tert-ブチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-2-((2-(ジメチルアミノ)エチル)(メチル)カルバモイル)ピロリジン-1-カルボキシレートを用いることにより、表題化合物を無色アモルファスとして得た。物性値:m/z[M+H]+ 492.4
実施例66(工程8)に準じ、(2S,4S)-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-2-カルボキシレートの代わりに、上記工程2で得られた(2S,4S)-4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)-N-(2-(ジメチルアミノ)エチル)-N-メチルピロリジン-2-カルボキサミドを用いることにより、表題化合物を無色アモルファスとして得た。物性値を表19に示す。
1-(4-((4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)メチル)ピペリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(実施例化合物72)の合成
実施例38に準じ、(R)-N-Boc―3-ピロリジノールの代わりに、N-Boc―4-ヒドロキシメチルピペリジンを用いることにより表題化合物を淡黄色アモルファスとして得た。物性値を表19に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピロロ[3,2-c]ピリジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オン(実施例化合物73)の合成
国際公開WO2007/095223号パンフレットに記載されている方法にて合成した4-クロロ-1H-ピロロ[3,2-c]ピリジン247mgをDMF7.0mlに溶解し0℃に冷却後、N-ヨードスクシンイミド382mgを加えた。室温で一時間撹拌した後、クロロホルムと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を茶褐色固体物質して455mg得た。物性値:m/z[M+H]+ 279.1
上記工程1で得られた4-クロロ-3-ヨード-1H-ピロロ[3,2-c]ピリジン225mgをDMF3.0mlに溶解し、0℃に冷却後60%水素化ナトリウム64.5mgを加えた。実施例2(工程1)で得られた(R)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレート322mgをDMF2.0ml用いて反応液に加え、室温にて終夜撹拌した。60%水素化ナトリウム64.5mgを追加で加えた後、85℃にて終夜撹拌した。反応液に酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を粗生成物として192mg得た。物性値:m/z[M+H]+ 448.3
上記工程2で得られた(S)-tert-ブチル 3-(4-クロロ-3-ヨード-1H-ピロロ[3,2-c]ピリジン-1-イル)ピロリジン-1-カルボキシレートの粗生成物180mg、1-エチニル-3,5-ジメトキシベンゼン97mg、ヨウ化銅(I)15mg、トリエチルアミン1.0mlのTHF4.0ml混合物に、PdCl2(dppf)CH2Cl233mgを加え、窒素置換した後、50℃にて30分撹拌した。反応液に酢酸エチルと水を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして133mg得た。物性値:m/z[M+H]+ 482.4
窒素雰囲気下、上記工程3で得られた(S)-tert-ブチル 3-(4-クロロ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピロロ[3,2-c]ピリジン-1-イル)ピロリジン-1-カルボキシレート120mg、2,2’-ビス(ジフェニルフォスヒィノ)-1,1’-ビナフタレン(BINAP)26mg、tert-ブトキシナトリウム72mg、ベンゾフェノンイミン92mg、トリス(ジベンジリデンアセトン)ジパラジウム36mgをトルエン10mlに懸濁させ、115℃にて90分間撹拌した。酢酸エチルで希釈後セライトろ過し、溶媒を減圧留去した。得られた残渣に、ヒドロキシアミン塩酸塩366mg、炭酸水素ナトリウム442mg、メタノール16ml、水4mlを加え、室温にて2時間撹拌した。溶媒を減圧留去した後、酢酸エチルと飽和食塩水を加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして35mg得た。物性値:m/z[M+H]+ 463.4
実施例1(工程4)に準じ、tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの代わりに、上記工程3で得られた(S)-tert-ブチル 3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピロロ[3,2-c]ピリジン-1-イル)ピロリジン-1-カルボキシレートを用いることにより、表題化合物を白色固体として得た。物性値を表19に示す。
(R)-1-(3-(4-アミノ-3-(4-フェノキシフェニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピペリジン-1-イル)プロパ-2-エン-1-オン(参考例化合物1)の合成
国際公開WO2008/121742号パンフレットに記載の方法に準じて合成した。物性値を表20に示す。
3-シクロブチル-1-(フェニルエチニル)イミダゾ[1,5-a]ピラジン-8-アミン(参考例化合物2)の合成
国際公開WO2007/087395号パンフレットに記載の方法に準じて合成した。物性値を表20に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパン-1-オン(参考例化合物3)の合成
実施例1に準じ、(S)-3-((3,5-ジメトキシフェニル)エチニル)-1-(ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンとプロピオニルクロリドを用いることにより、表題化合物を白色固体として得た。物性値を表20に示す。
(S)-1-(3-(4-アミノ-3-((3,5-ジイソプロピルフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(参考例化合物4)の合成
(工程1)1-エチニル-3,5-ジイソプロピルベンゼンの合成
トリメチルシリルアセチレン589mg、1-ブロモ-3,5-ジイソプロピルベンゼン480mg、ヨウ化銅(I)76mg、トリエチルアミン0.11mlのTHF4ml混合物に、PdCl2(dppf)CH2Cl2163mgを加え、窒素置換した後、80℃にて4時間撹拌した。反応液に酢酸エチルと水を加え、有機層を分離し無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣に2%水酸化カリウムのメタノール溶液を10ml加え室温にて終夜撹拌した。反応液にクロロホルムと水を加え、有機層を分離し無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン)にて精製し、表題化合物を黄色油状物質として181mg得た。
(工程2)(S)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの合成
3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン446mg、(R)-tert-ブチル 3-(メチルスルホニルオキシ)ピロリジン-1-カルボキシレート450mg、炭酸カリウム692mgのDMF5.0ml懸濁溶液を85℃にて6時間撹拌した。酢酸エチルと水を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去し、得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を淡黄色アモルファスとして354mg得た。物性値:m/z[M+H]+ 431.1
(工程3)(S)-tert-ブチル 3-(4-アミノ-3-((3,5-ジイソプロピルフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートの合成
上記工程1で得られた1-エチニル-3,5-ジイソプロピルベンゼン56mg、上記工程2で得られた(S)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート43mg、ヨウ化銅(I)3.8mg、トリエチルアミン0.2mlのTHF2.0ml混合物に、PdCl2(dppf)CH2Cl28.2mgを加え、窒素置換した後、80℃にて1.5時間撹拌した。反応液に酢酸エチルと水を加え、有機層を分離した。有機層を飽和食塩水で洗浄したのち、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(展開溶媒:ヘキサン/酢酸エチル)にて精製し、表題化合物を無色アモルファスとして42mg得た。物性値:m/z[M+H]+ 489.2
(工程4)(S)-3-((3,5-ジイソプロピルフェニル)エチニル)-1-(ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの合成
実施例66(工程7)に準じ、(2S,4S)-1-tert-ブチル 2-メチル 4-(4-アミノ-5-((3,5-ジメトキシフェニル)エチニル)-7H-ピロロ[2,3-d]ピリミジン-7-イル)ピロリジン-1,2-ジカルボキシレートの代わりに上記工程3で得られた(S)-tert-ブチル 3-(4-アミノ-3-((3,5-ジイソプロピルフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレートを用いることにより表題化合物を淡黄色アモルファスとして得た。
(工程5)参考例化合物4の合成
実施例4に準じ、(S)-3-((3,5-ジメトキシフェニル)エチニル)-1-(ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンの代わりに上記工程4で得られた(S)-3-((3,5-ジイソプロピルフェニル)エチニル)-1-(ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミンを用い表題化合物を淡黄色アモルファスとして得た。物性値を表20に示す。
(S)-1-(3-(4-アミノ-3-((3-メトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(参考例化合物5)の合成
(工程1)(S)-1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オンの合成
参考例4(工程2)で得られた(S)-tert-ブチル 3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-カルボキシレート488mgに4N-塩酸/1,4-ジオキサン4mlを加え一時間撹拌し、減圧下溶媒を留去した。得られた残渣に、4-(ジメチルアミノ)ブタ-2-エン酸 塩酸塩281mg、HATU647mgのDMF5.0ml溶液を加え、さらにDIPEA 0.78ml加え終夜撹拌した。反応液を減圧下濃縮し、得られた残渣にクロロホルム50mlとエタノール50mlを加え、不溶物をろ過により除去した。ろ液を減圧下濃縮し、得られた残渣を酢酸エチル5.0mlで洗浄後乾燥し、表題化合物の粗生成物を458mg得た。物性値:m/z[M+H]+ 442.0
(工程2)参考例化合物5の合成
上記工程1で得られた(S)-1-(3-(4-アミノ-3-ヨード-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン8.0mg、1-エチニル-3-メトキシベンゼン4.0mg、ヨウ化銅(I)0.6mg、トリエチルアミン8.6μlのTHF1.0ml混合物に、PdCl2(dppf)CH2Cl21.3mgを加え、窒素置換した後、80℃にて終夜撹拌した。反応液を酢酸エチルとメタノールで希釈、得られた希釈溶液を塩基性シリカゲルで処理した後濃縮した。得られた残渣を逆相分取HPLC精製(水/アセトニトリル(0.1%ギ酸))にて精製し、表題化合物を無色アモルファスとして1.4mg得た。物性値を表20に示す。
(S)-N-(3-((4-アミノ-1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)ピロリジン-3-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)エチニル)フェニル)アセトアミド(参考例化合物6)の合成
参考例5に準じ、1-エチニル-3-メトキシベンゼンの代わりにN-(3-エチニルフェニル)アセトアミドを用いて、表題化合物を無色アモルファスとして得た。物性値を表20に示す。
(S)-1-(3-(4-アミノ-3-(ピリジン-3-イルエチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)-4-(ジメチルアミノ)ブタ-2-エン-1-オン(参考例化合物7)の合成
参考例5に準じ、1-エチニル-3-メトキシベンゼンの代わりに3-エチニルピリジンを用いて、表題化合物を無色アモルファスとして得た。物性値を表20に示す。
FGFR2キナーゼ活性に対する阻害活性測定法の条件設定において、キャリパーライフサイエンス社のFL-Peptide 22を基質として用いた。試験に用いた精製リコンビナントヒトFGFR2蛋白質はカルナバイオサイエンス社から購入した。化合物の阻害活性測定においては、まず、被検化合物をジメチルスルホキシド(DMSO)で終濃度の20倍の濃度になるように段階希釈した。次に、反応用緩衝液(15mM Tris-HCl pH7.5,0.01% Tween-20,2mM DTT)中に精製ヒトFGFR2蛋白質、FL-Peptide 22(終濃度は1.5μM)、塩化マグネシウム(終濃度は5mM)、ATP(終濃度は75μM)と被検化合物DMSO溶液(DMSOの終濃度は5%)を加えて25℃で120分間インキュベーションしキナーゼ反応を行った。そこへキャリパーライフサイエンス社のSeparation Bufferにて希釈したEDTA(終濃度は30mM)を加えてキナーゼ反応を停止させた。最後に、LabChip(登録商標)3000システム(キャリパーライフサイエンス社、励起波長488nm、検出波長530nm)でリン酸化体ペプチドと非リン酸化体ペプチドを分離し各々の量を測定し、その量比からリン酸化反応量を求め、リン酸化反応を50%抑制することのできる化合物濃度をIC50値(nM)と定義した。結果を表21に示す。
FGFR2受容体を過剰発現するヒト由来胃癌細胞株OCUM-2MD3細胞を、10%ウシ胎児血清(FBS)を含むダルベッコ変法イーグル培地(DMEM)中で、80%を超えない細胞密度で日常的に継代した。細胞増殖抑制活性の試験を開始するため、OCUM-2MD3細胞を上記DMEM培地中に懸濁し、96ウェル平底プレートの各ウェルに1ウェルあたりの細胞数が3,000個となるように播種した後、5%炭酸ガス含有の培養器中37℃で1日間培養した。翌日、被検化合物をDMSOで終濃度の100倍の濃度になるように段階希釈した。被検化合物のDMSO溶液を培養に用いた培地で希釈し、これを細胞の培養プレートの各ウェルにDMSOの最終濃度が0.5%になるように加え、5%炭酸ガス含有の培養器中37℃で72時間培養した。被検化合物の添加時及び72時間培養後の細胞数の計測は、セルカウンティングキット-8(同仁化学社製)を用いて、同仁化学社の推奨するプロトコールに基づき実施した。キット含有の試薬を各プレートに添加し、5%炭酸ガス含有の培養器中37℃で所定の時間呈色反応を行った。反応終了後、マイクロプレートリーダーを用いて、波長450nmにおける吸光度計測を行った。以下の式より増殖阻害率を算出し、50%阻害する被検化合物の濃度(GI50(nM))を求めた。結果を表22に示す。
結果、被検化合物に代表される本発明化合物は、いずれもヒト由来胃癌細胞株OCUM-2MD3細胞に対して高い増殖抑制作用を示した。
増殖阻害率(%)=(C-T)/(C-C0)X 100
T:被検化合物を添加したウェルの吸光度
C:被検化合物を添加しなかったウェルの吸光度
C0:化合物添加前に測定したウェルの吸光度
FGFR1キナーゼ活性に対する阻害活性測定法の条件設定において、キャリパーライフサイエンス社のFL-Peptide 22を参考に、そのアミノ酸配列にビオチン修飾を付加したビオチン化ペプチド(biotin-EEPLYWSFPAKKK)を合成して基質として用いた。試験に用いた精製リコンビナントヒトFGFR1蛋白質はカルナバイオサイエンス社から購入した。化合物の阻害活性測定においては、まず、被検化合物をジメチルスルホキシド(DMSO)で終濃度の20倍の濃度になるように段階希釈した。次に、反応用緩衝液(15mM Tris-HCl pH7.5,0.01% Tween-20,2mM DTT)中に精製ヒトFGFR1蛋白質、基質ペプチド(終濃度は250nM)、塩化マグネシウム(終濃度は5mM)、ATP(終濃度は190μM)と被検化合物DMSO溶液(DMSOの終濃度は5%)を加えて25℃で120分間インキュベーションしキナーゼ反応を行った。そこへ終濃度40mMになるようEDTAを加えることで反応を停止させた後、Euラベル化抗リン酸化チロシン抗体PT66(PerkinElmer)とSureLight APC-SA(PerkinElmer)を含む検出液を添加し室温で2時間以上静置した。最後に、PHERAstar FS(BMG LABTECH)で波長337nmの励起光照射時における蛍光量を620nmと665nmの二波長で測定した。二波長の蛍光量比からリン酸化反応量を求め、リン酸化反応を50%抑制することのできる化合物濃度をIC50値(nM)と定義し以下の表に示した。結果を表23に示す。
FGFR3キナーゼ活性に対する阻害活性測定は試験例3の方法に準じて行った。精製リコンビナントヒトFGFR3蛋白質はカルナバイオサイエンス株式会社より購入した。ATPの終濃度は50μMとした。結果を表23に示す。
FGFR4キナーゼ活性に対する阻害活性測定は試験例3の方法に準じて行った。精製リコンビナントヒトFGFR4蛋白質はカルナバイオサイエンス株式会社より購入した。ATPの終濃度は200μMとした。結果を表23に示す。
Dovitinib耐性変異型FGFR2、N550HまたはE566G、子宮がんで変異があることが知られているK660Mを発現させたHEK293細胞を樹立した。さらにゲートキーパーサイトで565番目のバリンをイソロイシンに変異させたV565Iを発現させたHEK293細胞株も合わせて樹立した。これらの細胞株と実施例化合物2、更には既知のFGFR阻害剤であるAZD4547, BGJ-398をインキュベーションし、細胞内のFGFR2のリン酸化、および細胞の増殖抑制効果を調べた。
FGFR2遺伝子増幅が報告されている胃癌細胞株、OCUM-2MD3細胞をAZD4547存在下約3ヶ月間培養し、この薬剤に対して耐性となる細胞クローンを単離した。耐性クローンからFGFR2遺伝子を単離し、その塩基配列を解読し、野性型FGFR2と比較した。さらに耐性細胞株を実施例化合物2とインキュベーションし、細胞内FGFR2リン酸化阻害、および細胞増殖抑制作用を調べた。
Claims (32)
- FGFR阻害剤に対する耐性を有する腫瘍患者に投与するための抗腫瘍剤であって、下記一般式(I)で表される3,5-二置換ベンゼンアルキニル化合物又はその塩を含む抗腫瘍剤:
X1及びX2は、各々独立してN又はCHであり;
Yは、一般式(A)
R2は、水素原子、C2-C6アルキニル基、-C(=O)ORx、-C(=O)N(Rx)(Ry)、ヒドロキシC1-C6アルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はR3を有していてもよいC2-C9ヘテロアリール基であり;
R3は、C1-C6アルキル基、又はジ(C1-C6アルキル)アミノC1-C6アルキル基であり;
Zは、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
R4、R5及びR6は、同一又は相異なって、水素原子、ハロゲン原子、R8を有していてもよいC1-C6アルキル基、又は一般式(D)
R7は、水素原子、C1-C6アルキル基、又はヒドロキシC1-C6アルキル基であり;
R8は、-ORx、又は-N(Rx)(Ry)であり;
R9は、C1-C6アルキル基、ハロゲン原子、又は-ORxであり;
Rx及びRyは、同一又は相異なって、水素原子、C1-C6アルキル基、C3-C10シクロアルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はC1-C6アルコキシC1-C6アルキル基であり;
lは、0~3の整数であり;
mは、1~3の整数であり;
nは、0~2の整数である。)。 - Ponatinib、Regorafenib、Intedanib、Dovitinib lactate、Lenvatinib mesylate、Cediranib、Oratinib、Brivanib alaninate、AZD4547、NVP-BGJ398、Sulfatinib、ARQ-087、S-49076、IMCA1、PRO001、及びR3Mabの少なくとも一種に耐性を有する腫瘍患者に投与するための請求項1記載の抗腫瘍剤。
- FGFR2のN550に変異を有する腫瘍患者に投与するための、請求項1又は2記載の抗腫瘍剤。
- FGFR2のV565に変異を有する腫瘍患者に投与するための、請求項1~3のいずれか1項記載の抗腫瘍剤。
- FGFR2のE566に変異を有する腫瘍患者に投与するための、請求項1~4のいずれか1項記載の抗腫瘍剤。
- FGFR2のK660に変異を有する腫瘍患者に投与するための、請求項1~5のいずれか1項記載の抗腫瘍剤。
- 3,5-二置換ベンゼンアルキニル化合物又はその塩が、(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オンまたはその塩である、請求項1~7のいずれか1項記載の抗腫瘍剤。
- FGFR阻害剤に対する耐性を有する腫瘍患者の治療法であって、下記一般式(I)で表される3,5-二置換ベンゼンアルキニル化合物又はその塩を含む抗腫瘍剤を投与することによる治療法:
X1及びX2は、各々独立してN又はCHであり;
Yは、一般式(A)
R2は、水素原子、C2-C6アルキニル基、-C(=O)ORx、-C(=O)N(Rx)(Ry)、ヒドロキシC1-C6アルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はR3を有していてもよいC2-C9ヘテロアリール基であり;
R3は、C1-C6アルキル基、又はジ(C1-C6アルキル)アミノC1-C6アルキル基であり;
Zは、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
R4、R5及びR6は、同一又は相異なって、水素原子、ハロゲン原子、R8を有していてもよいC1-C6アルキル基、又は一般式(D)
R7は、水素原子、C1-C6アルキル基、又はヒドロキシC1-C6アルキル基であり;
R8は、-ORx、又は-N(Rx)(Ry)であり;
R9は、C1-C6アルキル基、ハロゲン原子、又は-ORxであり;
Rx及びRyは、同一又は相異なって、水素原子、C1-C6アルキル基、C3-C10シクロアルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はC1-C6アルコキシC1-C6アルキル基であり;
lは、0~3の整数であり;
mは、1~3の整数であり;
nは、0~2の整数である。)。 - 腫瘍患者がPonatinib、Regorafenib、Intedanib、Dovitinib lactate、Lenvatinib mesylate、Cediranib、Oratinib、Brivanib alaninate、AZD4547、NVP-BGJ398、Sulfatinib、ARQ-087、S-49076、IMCA1、PRO001、及びR3Mabの少なくとも一種に耐性を有する腫瘍患者である請求項9記載の方法。
- 腫瘍患者がFGFR2のN550に変異を有する腫瘍患者である請求項9又は10記載の方法。
- 腫瘍患者がFGFR2のV565に変異を有する腫瘍患者である請求項9~11のいずれか1項記載の方法。
- 前記腫瘍患者がFGFR2のE566に変異を有する腫瘍患者である請求項9~12のいずれか1項記載の方法。
- 前記腫瘍患者がFGFR2のK660に変異を有する腫瘍患者である請求項9~13のいずれか1項記載の方法。
- 3,5-二置換ベンゼンアルキニル化合物又はその塩が、(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オンまたはその塩である、請求項9~15のいずれか1項記載の方法。
- FGFR阻害剤に対する耐性を有する腫瘍患者の治療のための下記一般式(I)で表される3,5-二置換ベンゼンアルキニル化合物又はその塩:
X1及びX2は、各々独立してN又はCHであり;
Yは、一般式(A)
R2は、水素原子、C2-C6アルキニル基、-C(=O)ORx、-C(=O)N(Rx)(Ry)、ヒドロキシC1-C6アルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はR3を有していてもよいC2-C9ヘテロアリール基であり;
R3は、C1-C6アルキル基、又はジ(C1-C6アルキル)アミノC1-C6アルキル基であり;
Zは、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
R4、R5及びR6は、同一又は相異なって、水素原子、ハロゲン原子、R8を有していてもよいC1-C6アルキル基、又は一般式(D)
R7は、水素原子、C1-C6アルキル基、又はヒドロキシC1-C6アルキル基であり;
R8は、-ORx、又は-N(Rx)(Ry)であり;
R9は、C1-C6アルキル基、ハロゲン原子、又は-ORxであり;
Rx及びRyは、同一又は相異なって、水素原子、C1-C6アルキル基、C3-C10シクロアルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はC1-C6アルコキシC1-C6アルキル基であり;
lは、0~3の整数であり;
mは、1~3の整数であり;
nは、0~2の整数である。)。 - 腫瘍患者がPonatinib、Regorafenib、Intedanib、Dovitinib lactate、Lenvatinib mesylate、Cediranib、Oratinib、Brivanib alaninate、AZD4547、NVP-BGJ398、Sulfatinib、ARQ-087、S-49076、IMCA1、PRO001、及びR3Mabの少なくとも一種に耐性を有する腫瘍患者である請求項17記載の化合物又はその塩。
- 腫瘍患者がFGFR2のN550に変異を有する腫瘍患者である請求項17又は18記載の化合物又はその塩。
- 腫瘍患者がFGFR2のV565に変異を有する腫瘍患者である請求項17~19のいずれか1項記載の化合物又はその塩。
- 腫瘍患者がFGFR2のE566に変異を有する腫瘍患者である請求項17~20のいずれか1項記載の化合物又はその塩。
- 腫瘍患者がFGFR2のK660に変異を有する腫瘍患者である請求項17~21のいずれか1項記載の化合物又はその塩。
- 3,5-二置換ベンゼンアルキニル化合物又はその塩が、(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オンまたはその塩である、請求項17~23のいずれか1項記載の化合物又はその塩。
- FGFR阻害剤に対する耐性を有する腫瘍患者に投与するための抗腫瘍剤を製造するための下記一般式(I)で表される3,5-二置換ベンゼンアルキニル化合物又はその塩の使用:
X1及びX2は、各々独立してN又はCHであり;
Yは、一般式(A)
R2は、水素原子、C2-C6アルキニル基、-C(=O)ORx、-C(=O)N(Rx)(Ry)、ヒドロキシC1-C6アルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はR3を有していてもよいC2-C9ヘテロアリール基であり;
R3は、C1-C6アルキル基、又はジ(C1-C6アルキル)アミノC1-C6アルキル基であり;
Zは、-C(R4)=C(R5)(R6)、又は-C≡C-R7であり;
R4、R5及びR6は、同一又は相異なって、水素原子、ハロゲン原子、R8を有していてもよいC1-C6アルキル基、又は一般式(D)
R7は、水素原子、C1-C6アルキル基、又はヒドロキシC1-C6アルキル基であり;
R8は、-ORx、又は-N(Rx)(Ry)であり;
R9は、C1-C6アルキル基、ハロゲン原子、又は-ORxであり;
Rx及びRyは、同一又は相異なって、水素原子、C1-C6アルキル基、C3-C10シクロアルキル基、ジ(C1-C6アルキル)アミノC1-C6アルキル基、又はC1-C6アルコキシC1-C6アルキル基であり;
lは、0~3の整数であり;
mは、1~3の整数であり;
nは、0~2の整数である。)。 - 腫瘍患者がPonatinib、Regorafenib、Intedanib、Dovitinib lactate、Lenvatinib mesylate、Cediranib、Oratinib、Brivanib alaninate、AZD4547、NVP-BGJ398、Sulfatinib、ARQ-087、S-49076、IMCA1、PRO001、及びR3Mabの少なくとも一種に耐性を有する腫瘍患者である請求項25記載の使用。
- 腫瘍患者がFGFR2のN550に変異を有する腫瘍患者である請求項25又は26記載の使用。
- 腫瘍患者がFGFR2のV565に変異を有する腫瘍患者である請求項25~27のいずれか1項記載の使用。
- 腫瘍患者がFGFR2のE566に変異を有する腫瘍患者である請求項25~28のいずれか1項記載の使用。
- 腫瘍患者がFGFR2のK660に変異を有する腫瘍患者である請求項25~29のいずれか1項記載の使用。
- 3,5-二置換ベンゼンアルキニル化合物又はその塩が、(S)-1-(3-(4-アミノ-3-((3,5-ジメトキシフェニル)エチニル)-1H-ピラゾロ[3,4-d]ピリミジン-1-イル)ピロリジン-1-イル)プロパ-2-エン-1-オンまたはその塩である、請求項25~32のいずれか1項記載の使用。
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WO2016159327A1 (ja) * | 2015-03-31 | 2016-10-06 | 大鵬薬品工業株式会社 | 3,5-二置換ベンゼンアルキニル化合物の結晶 |
WO2018028438A1 (zh) | 2016-08-09 | 2018-02-15 | 南京天印健华医药科技有限公司 | 作为fgfr抑制剂的杂环化合物 |
WO2018049781A1 (zh) | 2016-09-19 | 2018-03-22 | 北京天诚医药科技有限公司 | 炔代杂环化合物、其制备方法及其在医药学上的应用 |
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WO2020164603A1 (zh) | 2019-02-15 | 2020-08-20 | 石药集团中奇制药技术(石家庄)有限公司 | 固体形式的fgfr抑制剂化合物及其制备方法 |
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WO2020175704A1 (ja) * | 2019-02-28 | 2020-09-03 | 大鵬薬品工業株式会社 | 3,5-二置換ベンゼンアルキニル化合物と免疫チェックポイント阻害薬とを用いた癌治療法 |
WO2020175697A1 (ja) * | 2019-02-28 | 2020-09-03 | 大鵬薬品工業株式会社 | 3,5-二置換ベンゼンアルキニル化合物とペムブロリズマブとを用いた癌治療法 |
CN115023231A (zh) * | 2020-01-31 | 2022-09-06 | 国立大学法人京都大学 | 软骨营养不良的治疗 |
WO2021153703A1 (ja) * | 2020-01-31 | 2021-08-05 | 国立大学法人京都大学 | 軟骨形成異常症の治療 |
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EP3023101A1 (en) | 2016-05-25 |
US10124003B2 (en) | 2018-11-13 |
EP3023101B1 (en) | 2020-08-19 |
TW201536293A (zh) | 2015-10-01 |
ES2819398T3 (es) | 2021-04-15 |
JPWO2015008844A1 (ja) | 2017-03-02 |
JP6084292B2 (ja) | 2017-02-22 |
US20190015417A1 (en) | 2019-01-17 |
US10835536B2 (en) | 2020-11-17 |
US20160136168A1 (en) | 2016-05-19 |
EP3023101A4 (en) | 2017-01-04 |
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