Novel tetrahydroisoquinoline alkaloid compounds containing macrocycles

Abstract

[Problem] To provide: a novel tetrahydroisoquinoline (THIQ) alkaloid compound having a macrocyclic structure; an intermediate of the compound; and a method for producing the compound. [Solution] Provided is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. The present invention also provides: a method for synthesizing this compound; and an intermediate compound useful in this synthesis.

Description

[Technical Field]

[0001] The present invention relates to a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, an intermediate thereof, and a method for producing the same. [Background technology]

[0002] Tetrahydroisoquinoline alkaloids, typified by saframycin A, are compounds with a complex pentacyclic skeleton in which multiple tetrahydroisoquinoline (THIQ) rings are linked together. THIQ alkaloids are known to alkylate DNA double strands and have high antitumor activity (e.g., Non-Patent Document 1). However, they also have the problem of being highly toxic to normal cells. [ka]

[0003] Ecteinascidin 743 (trade name "Yondelis") is the only natural product to be clinically used as an antitumor drug. Ecteinascidin 743 shares the same backbone (unit A) as saframycin A and also contains a third THIQ-linked macrolactone ring (unit B). Unit A is thought to multipoint recognize DNA duplexes via hydrogen bonds and alkylate them in a sequence-selective manner, while unit B exerts its antitumor activity by inhibiting the access of proteins that interact with DNA, such as transcription factors (Non-Patent Document 2). The physiological activities of lurbinectedin (PM01183), a synthetic analogue with a modified THIQ moiety in ecteinascidin 743, and Zalypsis (registered trademark), an analogue without a macrocycle, have also been studied (Non-Patent Documents 3 and 4, etc.).

[0004] Although various studies on the total synthesis of THIQ alkaloids, which exhibit such excellent antitumor activity, have been actively conducted, the extremely complex polycyclic structure requires complex starting materials and multiple synthetic steps, which poses production efficiency problems. In particular, the above-mentioned ecteinascidin 743 was semisynthesized from cyanosafracin B obtained by mass cultivation using a multi-step method requiring 24 steps, but the macrocyclic structure of the analogs obtained by this method is limited to that identical to that of the natural product ecteinascidin 743.

[0005] Meanwhile, research is being conducted around the world into the synthesis of THIQ alkaloid analogues that do not have a macrocycle, but none of these have been marketed as drugs because they are highly toxic to normal cells as well. Therefore, the construction of a macrocycle skeleton is thought to be extremely important for the expression of selective toxicity to cancer cells, but no synthetic methods that enable the diversification of the macrocycle skeleton have been reported at present. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Scott, JD; Williams, RM Chem. Rev. 2002, 102, 1669. [Non-patent document 2] Le, VH; Inai, M.; Williams, RM; Kan, T.Nat. Prod. Rep. 2015, 32, 328. [Non-patent document 3] Daniele G. Soares, Miriana S. Machado, Celine J. Rocca, et al. Mol. Cancer. Ther. 2011, 10, 1481-1489. [Non-patent document 4] Bradley J. Petek, Robin L. Jones, Molecules 2014, 19, 12328-12335. Summary of the Invention

[0007] In light of this background, there is a need for novel tetrahydroisoquinoline (THIQ) alkaloid compounds having macrocyclic structures, methods for synthesizing them, and intermediates therefor.

[0008] We have discovered a synthetic method that allows the construction of various macrocyclic structures linked to the THIQ skeleton using cyanosafracin B as a starting material. Based on these findings, we have completed the present invention.

[0009] That is, one aspect of the present invention relates to novel THIQ alkaloid compounds having a macrocyclic structure and pharmaceutical compositions containing the compounds. In another aspect, the present invention also relates to intermediate compounds suitable for obtaining the THIQ alkaloid compounds having a macrocyclic structure, and production methods using the intermediate compounds. The present invention is, for example, as follows.

[0010] [1] A compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, A represents a single bond or an optionally substituted C1-C6 alkylene group; X 1 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof; Y 1represents a single bond, an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent radical selected from the group consisting of; Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof; X 2 -L 1 -C(=CR f 2)-CR f =CR f -L 2 -, -L 1 -CR f =CR f -C(=CR f 2)-L 2 -, -L 1 -CR f =CR f -L 2 -, -L 1 -CR f =CR f -CR f =CR f -L 2 -, -L 1 -NR b -CR f 2-C≡CL 2 -, -L 1 -C≡C-CR f 2-NR b -L 2 -, -L 1 -C≡CL 2 -, -L 1 -C≡CC≡CL 2 -, [ka] is selected from the group consisting of L 1 and L 2 each independently represents a single bond or a C1-C6 alkylene group, R f are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Z 1 and Z 2 are each independently -NR c -or-CR d R e - represents R c , R d , and R e are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group, or R c and R d together and they combine to form Z 1 and Z 2 together form a 5- or 6-membered ring structure, which may be substituted with 1 to 4 substituents; R a are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group, or each R a may be taken together to form a ring structure including the oxygen atom to which they are attached; R b are each independently a hydrogen atom or an optionally substituted C-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; R 1 is a methyl group; R 2 is a hydrogen atom or an optionally substituted C1-C6 alkyl group; R 3 is a methyl group; R 4is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom. [2] The compound according to [1], represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 , Y 1 , Y 2 , R 4 , and R 5 is the same as that described in [1], X 1c represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X 1d is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; L 3 is a single bond, an optionally substituted alkylene group, an optionally substituted alkenylene group, a carbonyl group, -C(=S)-, -C(=NR b )-, -C(O)O-, -C(O)NR b -, -OC(O)-, -NR b -, an ether group, a thioether group, and combinations thereof; R b represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group.

[0011] [3] The compound according to [1] or [2], represented by the following formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), or formula (Ih), or a pharmaceutically acceptable salt thereof. [ka] [In the formula, X 1a is an oxygen atom, a sulfur atom, -NR b - or an optionally substituted methylene group, X 1b is an oxygen atom, a sulfur atom, =NR b or an optionally substituted methylene group, X 1c represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X 1d is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; X 2a represents an optionally substituted C1-C6 alkylene group, L X2a , L X2b and L X2c are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Y 1 represents an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent radical selected from the group consisting of; Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NRb )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, and an amino acid residue; L Y2a , L Y2b and L Y2c are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Z 1 and Z 2 are each independently N or CR e represents R e is a hydrogen atom or an optionally substituted C1-C6 alkyl group, R 4 is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R 8 is a hydrogen atom, an optionally substituted aryl group, an optionally substituted C-C 20 represents an alkyl group, an optionally substituted allyl group, a propargyl group, and a nitrogen-protecting group, R b are each independently a hydrogen atom or an optionally substituted C-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group. [4] In formulas (Ic) to (Ih), X 1a is an oxygen atom or -NR b - represents X 1b represents an oxygen atom, X 1c represents a hydrogen atom, an optionally substituted C1-C20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X 1d represents a methyl group, X 2a represents a C1-C3 alkylene group, L X2a , L X2b and L X2c each independently represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, or an optionally substituted aryl group; Y 1 represents an ether group; Y 2 represents a C1-C3 alkylene group; L Y2a , L Y2b and L Y2c are each independently selected from a hydrogen atom, an optionally substituted C1-C8 alkyl group, and an optionally substituted aryl group; Z 1 and Z 2 are each independently N or CR e represents R e is a hydrogen atom or an optionally substituted C1-C6 alkyl group, R 4 is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R 8 represents a hydrogen atom, an optionally substituted phenyl group, and an optionally substituted C-C 20 is selected from alkyl groups, allyl groups, propargyl groups, and nitrogen protecting groups of the formula R b are each independently a hydrogen atom or an optionally substituted C-C 20selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups;

[0023] [3] The compound or a pharmaceutically acceptable salt thereof according to [3], wherein Me represents a methyl group. [5] In formulas (Ic) to (Ih), X 1a represents an oxygen atom, X 1b represents an oxygen atom, X 1c is selected from a hydrogen atom, a methyl group, and a propargyl group; X 1d represents a methyl group, X 2a represents a C1-C3 alkylene group, L X2a , L X2b and L X2c each independently represents a hydrogen atom, Y 1 represents an ether group; Y 2 represents a C1-C3 alkylene group; L Y2a , L Y2b and L Y2c each independently represents a hydrogen atom, Z 1 and Z 2 each independently represents a nitrogen atom or CH; R 4 represents a hydrogen atom, R 5 represents CN, R 8 represents a hydrogen atom or an optionally substituted phenyl group, The compound or pharmaceutically acceptable salt thereof according to [3] or [4], wherein Me represents a methyl group.

[0012] [5a] The compound has a macrocyclic structure (Y 1 and Y 2a macrocyclic structure comprising the 1st and 5th positions of the tetrahydroisoquinoline skeleton linked by a linking group together with the 9th and 10th carbon atoms of the tetrahydroisoquinoline skeleton),

[0013] [6] A compound according to any one of [1] to [5] selected from the following group, or a pharmaceutically acceptable salt thereof: [ka] TIFF0007760183000007.tif109170 (wherein Me represents a methyl group.)

[0014] [7] A compound represented by the following formula (IIIc) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 1c represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X 1d is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; L X2a and L X2b are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Y 1 represents an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent radical selected from the group consisting of; Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b-, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, and an amino acid residue; R 4 is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R b represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group. [8] The compound according to [7], which is the following compound, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, Me represents a methyl group.]

[0015] [9] A compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, A is a single bond or an optionally substituted C1-C6 alkylene group; X 1 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NRb C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof; Y 1 represents a single bond, an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent radical selected from the group consisting of; Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof; M 1 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, -N(R b )2, optionally substituted alkylene-N(R b )2, selected from a hydroxyl group, a carbonyl group, a thiol group, and a halogen atom; M 2 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, -N(R b )2, optionally substituted alkylene-N(R b )2, selected from a hydroxyl group, a carbonyl group, a thiol group, and a halogen atom; R bare each independently selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group; R a are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group, or each R a may be taken together to form a ring structure including the oxygen atom to which they are attached; R 1 is a methyl group; R 2 is a hydrogen atom or an optionally substituted C1-C6 alkyl group; R 3 is a methyl group; R 4 is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom.

[0016]

[10] The compound according to [9], which is represented by the following formula (IIc), formula (IId), formula (IIe), or formula (IIf), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 1a is an oxygen atom, a sulfur atom, -NR b - or an optionally substituted methylene group, X 1b is an oxygen atom, a sulfur atom, =NR b or an optionally substituted methylene group, X 1c represents a hydrogen atom, an optionally substituted C1-C 20selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X 1d is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; X 2a represents an optionally substituted C1-C6 alkylene group, L X2a , L X2b and L X2c are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Y 1 represents an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent radical selected from the group consisting of; Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, and an amino acid residue; L Y2a , L Y2b and L Y2c are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Z 1 and Z 2 are each independently N or CR e represents R e is a hydrogen atom or an optionally substituted C1-C6 alkyl group, R 4is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R b represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group.

[11] In formulas (IIc) to (IIf), X 1a is an oxygen atom or -NR b - represents X 1b represents an oxygen atom, X 1c represents a hydrogen atom, an optionally substituted C1-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X 1d represents a methyl group, X 2a represents a C1-C3 alkylene group, L X2a , L X2b and L X2c each independently represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, or an optionally substituted aryl group; Y 1 represents an ether group; Y 2 represents a C1-C3 alkylene group; L Y2a , L Y2b and L Y2c are each independently selected from a hydrogen atom, an optionally substituted C1-C8 alkyl group, and an optionally substituted aryl group; R 4is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an aryl group, an allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group, R 5 represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R b are each independently a hydrogen atom or an optionally substituted C-C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups;

[10] The compound or a pharmaceutically acceptable salt thereof according to

[10] , wherein Me represents a methyl group.

[12] In formulas (IIc) to (IIf), X 1a represents an oxygen atom, X 1b represents an oxygen atom, X 1c is selected from a hydrogen atom, a methyl group, a propargyl group, and a nitrogen protecting group; X 1d represents a methyl group, X 2a represents a C1-C3 alkylene group, L X2a , L X2b and L X2c each independently represents a hydrogen atom, Y 1 represents an ether group; Y 2 represents a C1-C3 alkylene group; L Y2a , L Y2b and L Y2c each independently represents a hydrogen atom, R 4 represents a hydrogen atom or a protecting group for a phenolic hydroxyl group, R 5 represents CN, The compound or pharmaceutically acceptable salt thereof according to

[10] or

[11] , wherein Me represents a methyl group.

[0017]

[13] The compound according to [9], selected from the following group: [ka] [In the formula, Me represents a methyl group, R 4 represents a hydrogen atom or a protecting group for a phenolic hydroxyl group, R b are each independently a hydrogen atom or an optionally substituted C-C 20 and is selected from an alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group.

[0018]

[14] A pharmaceutical composition comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [14a] A pharmaceutical composition comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound does not contain a protecting group for a phenolic hydroxyl group and does not contain a nitrogen-protecting group. [14b] The compound according to any one of [1] to

[13] (wherein R 4 is a hydrogen atom, and R b is a substituent other than a nitrogen protecting group) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[15] A DNA alkylating agent comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof. [15a] A DNA alkylating agent comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, wherein the compound does not contain a protecting group for a phenolic hydroxyl group and does not contain a nitrogen protecting group. [15b] The compound according to any one of [1] to

[13] (wherein R 4 is a hydrogen atom, and Rb is a substituent other than a nitrogen protecting group) or a pharmaceutically acceptable salt thereof.

[16] An anticancer agent comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof. [16a] An anticancer agent comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, wherein the compound does not contain a protecting group for a phenolic hydroxyl group and does not contain a nitrogen protecting group. [16b] The compound according to any one of [1] to

[13] (wherein R 4 is a hydrogen atom, and R b is a substituent other than a nitrogen protecting group) or a pharmaceutically acceptable salt thereof.

[17] The anticancer agent according to

[16] , [16a] or [16b], wherein the target disease is selected from the group consisting of breast cancer, brain tumor, colon cancer, lung cancer, ovarian cancer and gastric cancer.

[18] A method for producing a DNA alkylating agent or an anticancer agent having a tetrahydroisoquinoline skeleton, using the compound according to any one of [9] to

[13] .

[19] Use of the compound according to any one of [9] to

[13] for producing a DNA alkylating agent or an anticancer agent having a tetrahydroisoquinoline skeleton.

[0019]

[20] A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, comprising any one of the following steps (A) to (C): Step (A): subjecting a compound represented by the following formula (IIc) to a ring-closing olefin metathesis reaction in the presence of a ruthenium catalyst or a tungsten catalyst to obtain a compound represented by formula (Ic); [ka] Step (B): subjecting a compound represented by the following formula (IId) to a ring-closing ene-metathesis reaction in the presence of a ruthenium catalyst or a tungsten catalyst to obtain a compound represented by formula (Id); [ka] Step (C): subjecting a compound represented by the following formula (IIe) to a ring-closing ene-metathesis reaction in the presence of a ruthenium catalyst or a tungsten catalyst to obtain a compound represented by formula (If); [ka] [where, X 1a , X 1b , X 1c , X 1d , X 2a , L X2a , L X2b , L X2c , Y 1 , Y 2 , L Y2a , L Y2b , L Y2c , R 4 , R 5 and Me are as defined in

[10] ; R 4 represents a protecting group for a phenolic hydroxyl group.] [twenty one] A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, comprising the following step (D): Step (D): Reacting the compound represented by formula (Id) with the compound represented by formula (IVa) to obtain the compound represented by formula (Ie). [ka] [where, X 1a , X 1b , X 1c , X 1d , X 2a , L X2c , Y 1 , Y 2 , L Y2a , L Y2b , LY2c , R 4 , R 5 , R 8 、 Z 1 、 Z 2 and Me are as defined in

[10] ; R 4 represents a protecting group for a phenolic hydroxyl group.] [twenty two] A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, comprising the following step (E): Step (E): A production method comprising reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst to obtain a compound represented by formula (Ig): [ka] [where, X 1c , X 1d , L X2a , L X2b , Y 1 , Y 2 , L Y2a , R 4 , R 5 , and Me are as defined in

[10] ; R 4 represents a protecting group for a phenolic hydroxyl group.] [twenty three] A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, comprising the following step (F): Step (F): A production method comprising reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst and a ligand to obtain a compound represented by formula (IIIc): [ka] [where, X 1c , X 1d , L X2a , L X2b , Y 2 , LY2a , R 4 , R 5 , and Me are as defined in

[10] ; R 4 represents a protecting group for a phenolic hydroxyl group.] [twenty four] A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, comprising the following step (G): Step (G): In the above formula (Ia), L 3 is -OC(O)- (where L 3 The carbon atom of formula (Ia) is NX 1c and obtaining a compound of formula (Ii) by elimination of CO2 from the compound (which is bonded to the nitrogen atom of formula (Ii)). [ka] [where, X 1c , X 1d , X 2 , Y 1 , Y 2 , R 4 and Me has the same meaning as described in [2]; L 3 is -OC(O)- (where L 3 The carbon atom of formula (Ia) is NX 1c (bonded to the nitrogen atom of [twenty five] A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, comprising the following step (H): Step (H): In the above formula (Ic), X 1a and X 1b is an oxygen atom (O) by elimination of CO2 to obtain a compound of formula (Ih). [ka] [where, X 1c , X 1d , X 2a , L X2c , Y 1 , Y 2 , LY2c , R 4 , R 5 , and Me are as defined in [3]; X 1a and X 1b represents an oxygen atom (O).

[0020] The present invention has at least one of the following advantages. (1) In some embodiments, novel compounds are provided that have a variety of macrocyclic structures linked to a THIQ backbone. (2) The compounds of some embodiments have excellent DNA alkylating ability and antitumor activity. (3) The compounds of some embodiments have functional groups in the molecule that can chemoselectively react with various agents, allowing for derivatization into a variety of analogues, and therefore can serve as lead compounds with further improved antitumor activity. Thus, the present invention can contribute to the development of novel antitumor drugs. (4) In some embodiments, there is provided a method for producing compounds having diverse macrocyclic structures linked to a THIQ skeleton from cyanosafracin B. According to this production method, a variety of macrocyclic structures can be efficiently synthesized in a small number of steps using cyanosafracin B as a starting material. DETAILED DESCRIPTION OF THE INVENTION

[0021] The following describes embodiments of the present invention. The scope of the present invention is not limited to these descriptions, and other than the following examples, the present invention can be implemented with appropriate modifications within the scope that does not depart from the spirit of the present invention.

[0022] 1.Definition "C X -C Y " X and Y in the formula represent the number of carbon atoms. For example, "C1-C4" represents 1 to 4 carbon atoms.

[0023] As used herein, the term "hydrocarbon group" refers to a group in which one or more hydrogen atoms have been removed from a linear, cyclic, or branched, saturated or unsaturated hydrocarbon having a specified number of carbon atoms. Specific examples include alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, alkylaryl groups, arylalkyl groups, alkylene groups, alkenylene groups, alkynylene groups, cycloalkylene groups, and combinations thereof. The term "unsaturated hydrocarbon group" refers to a hydrocarbon group having at least one unsaturated bond.

[0024] In this specification, the term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is linear, branched, cyclic, or a combination thereof. A cyclic alkyl group is also called a cycloalkyl group. The number of carbon atoms in the alkyl group is not particularly limited, but examples thereof include alkyl groups having 1 to 20 carbon atoms (C1-C 20 ), carbon number 1-15 (C1-C 15 ), carbon number 1~10 (C1-C 10 ), 1 to 8 carbon atoms (C1-C8), 1 to 6 carbon atoms (C1-C6), or 1 to 4 carbon atoms (C1-C4). For example, C1-C8 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, cyclohexyl, and the like.

[0025] In this specification, the term "alkylene group" refers to a divalent group consisting of a saturated aliphatic hydrocarbon that is linear, branched, cyclic, or a combination thereof. The number of carbon atoms in the alkylene group can be, for example, 1 to 20 carbon atoms (C1-C 20 ), carbon number 1-15 (C1-C 15 ), carbon number 1~10 (C1-C 10 ), 1 to 8 carbon atoms (C1-C8), 1 to 6 carbon atoms (C1-C6), 1 to 4 carbon atoms (C1-C4), or 1 to 3 carbon atoms (C1-C3).

[0026] In this specification, the term "alkenyl group" refers to a monovalent group consisting of an unsaturated hydrocarbon that has at least one carbon-carbon double bond at any position and is linear, branched, cyclic, or a combination thereof. The term "alkenylene group" refers to a divalent group consisting of an unsaturated hydrocarbon that has at least one carbon-carbon double bond at any position and is linear, branched, cyclic, or a combination thereof. Examples of "alkenyl" and "alkenylene" include, but are not limited to, monoenes, dienes, trienes, and tetraenes. The number of carbon atoms in an alkenyl group or alkenylene group is, for example, 2 to 20 carbon atoms (C2-C 20 ), carbon number 2~15 (C2-C 15 ), carbon number 2~10 (C2-C 10 ), 2 to 8 carbon atoms (C2-C8), 2 to 6 carbon atoms (C2-C6), 2 to 4 carbon atoms (C2-C4), or 2 to 3 carbon atoms (C2-C3). Examples of C2-C6 alkenyl include vinyl, propenyl, butenyl, pentenyl, and hexenyl groups. Examples of C2-C6 alkenylene include vinylene, propenylene, butenylene, pentenylene, and hexenylene groups.

[0027] In this specification, the term "alkynyl group" refers to a monovalent group consisting of an unsaturated hydrocarbon that has at least one carbon-carbon triple bond at any position and is linear, branched, cyclic, or a combination thereof. The term "alkynylene group" refers to a divalent group consisting of an unsaturated hydrocarbon that has at least one carbon-carbon triple bond at any position and is linear, branched, cyclic, or a combination thereof. The number of carbon atoms in the alkynyl group or alkynylene group can be, for example, 2 to 15 carbon atoms (C2-C 15 ), carbon number 2 to 10 (C2-C 10), having 2 to 6 carbon atoms (C2-C6), having 2 to 4 carbon atoms (C2-C4), or having 2 to 3 carbon atoms (C2-C3). Examples of C2-C6 alkynyl include acetyl, ethynyl, propynyl (e.g., propargyl, 1-propynyl), butynyl, pentynyl, and hexynyl. Examples of C2-C6 alkynylene include acetylene, ethynylene, propynylene, butynylene, pentynylene, and hexynylene.

[0028] In this specification, an alkyl group, an alkylene group, an alkenyl group, an alkenylene group, an alkynyl group, or an alkynylene group may have one or more optional substituents. Examples of the substituents include, but are not limited to, an alkoxy group, a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a mono- or di-substituted amino group, a substituted silyl group, an acyl group, an aryl group, a heteroaryl group, and a heterocyclic group. When an alkyl group has two or more substituents, the substituents may be the same or different. The same applies to the alkyl moiety of other substituents containing an alkyl moiety (e.g., an alkoxy group, an arylalkyl group, etc.).

[0029] In this specification, the term "acyl group" refers to a group in which a carbonyl group (-CO-) is bonded to the terminal of an alkyl group or aryl group. The acyl group may be either an aliphatic acyl group or an aromatic acyl group, or may be an aliphatic acyl group having an aromatic group as a substituent. Specific examples include an acetyl group.

[0030] As used herein, the term "allyl group" refers to a monovalent group represented by CH2=CH-CH2-. In this specification, the term "ether group" refers to a divalent group represented by an oxygen atom (O)-. As used herein, the term "thioether group" refers to a divalent group represented by -sulfur atom (S)-. As used herein, the term "sulfonyl group" refers to a divalent group represented by -S(=O)2-. In this specification, the term "carbonate group" refers to a divalent group represented by -OC(O)O-. In this specification, the term "acetal group" refers to a divalent group represented by RC(OR)(OR)-R. As used herein, the term "carbamate group" refers to a divalent group represented by -NRC(=O)O- or -OC(=O)NR-, where R is an optional substituent and is typically a hydrogen atom, an alkyl group, or an aryl group. As used herein, the term "amide group" refers to a divalent group represented by -NRC(=O)- or -C(=O)NR-, where R is an optional substituent and is typically a hydrogen atom, an alkyl group, or an aryl group. In this specification, the term "ester group" refers to a divalent group represented by -C(=O)O- or -OC(=O)-. As used herein, the term "silyl group" refers to a monovalent group represented by R3Si-, where R is an optional substituent and is typically an alkyl or aryl group.

[0031] As used herein, "aryl" refers to a hydrocarbon group consisting of an aromatic monocyclic or fused polycyclic ring. An aryl group refers to a monovalent or divalent group derived from an aryl. Examples include a phenyl group and a naphthyl group. An "alkylaryl group" refers to an aryl group to which one or more alkyl groups are attached. An "arylalkyl group" refers to an alkyl group having an aryl ring attached thereto.

[0032] As used herein, "heteroaryl" refers to an aromatic monocyclic or condensed polycyclic ring containing one or more (e.g., 1 to 5, or 1 to 3) heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S) atoms, and carbon atoms. A heteroaryl group refers to a monovalent or divalent group derived from a heteroaryl.

[0033] The term "carbocycle" refers to a monocyclic or fused polycyclic ring containing carbon atoms as ring-constituting atoms in the ring structure.

[0034] The term "heterocycle" refers to a monocycle or condensed polycycle whose ring structure contains, in addition to carbon atoms, one or more (e.g., 1 to 5 or 1 to 3) heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S) atoms. Heterocycles include heteroaryls and non-aromatic heterocycles. The heterocycle may be a saturated or unsaturated heterocycle. The term "non-aromatic heterocycle" refers to a non-aromatic monocycle or condensed polycycle whose ring structure contains, in addition to carbon atoms, one or more (e.g., 1 to 5 or 1 to 3) heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S) atoms. The heterocycle is typically a 3- to 20-membered monocyclic or polycyclic saturated, fully unsaturated, or partially unsaturated heterocyclic group containing at least one heteroatom (preferably 1 to 5, more preferably 1 to 3) selected from oxygen (O), nitrogen (N), and sulfur (S). A "heterocyclic group" refers to a monovalent or divalent group derived from a heterocycle.

[0035] In this specification, an aryl group, a heteroaryl group, a carbocyclic ring, or a heterocyclic ring may have one or more optional substituents on the ring. Examples of such optional substituents include, but are not limited to, an oxo group (=O), an alkyl group, an alkenyl group, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, or an acyl group. When an aryl group has two or more substituents, they may be the same or different. The same applies to the aryl moiety of other substituents containing an aryl moiety (e.g., an aryloxy group, an arylalkyl group, etc.).

[0036] In this specification, the term "alkoxy group" refers to a structure in which the alkyl group is bonded to an oxygen atom, and examples thereof include saturated alkoxy groups that are linear, branched, cyclic, or a combination thereof. The number of carbon atoms in the alkoxy group is not particularly limited, but may be, for example, 1 to 6 carbon atoms (C1-C6) or 1 to 4 carbon atoms (C1-C4). As used herein, a "halogen atom" refers to a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), or an iodine atom (I).

[0037] As used herein, the term "leaving group containing an oxygen atom, sulfur atom, nitrogen atom, or phosphorus atom" refers to a substituent that easily dissociates from a compound, along with an electron pair that contributes to covalent bond formation. Examples include a nitrile group, a hydroxyl group, a carboxylate group (-O-CO-R), a methylsulfonyl group, a trifluoromethanesulfonyl group, an isocyanate group, an azide group, and a diphenylphosphoryl group.

[0038] As used herein, the term "amino acid" refers to any compound having both an amino group and a carboxy group, including natural and unnatural amino acids. Neutral, basic, or acidic amino acids may be used. In addition to amino acids that function as neurotransmitters and other transmitters, amino acids that are components of polypeptide compounds such as physiologically active peptides (including dipeptides, tripeptides, tetrapeptides, and oligopeptides) and proteins may also be used, such as α-amino acids, β-amino acids, and γ-amino acids. Optically active amino acids are preferably used as amino acids. For example, while either D- or L-amino acids may be used for α-amino acids, it may be preferable to select optically active amino acids that function in living organisms.

[0039] As used herein, the term "amino acid residue" refers to a residue that is equivalent to the partial structure remaining after removing the hydroxyl group from the carboxy group of an amino acid, and has a structure similar to that of the so-called N-terminal residue. However, this does not exclude cases where the residue is formed by linking multiple amino acid residues. In such cases, the C-terminal amino acid residue may have a partial structure obtained by removing the hydroxyl group from the carboxy group and the hydrogen atom from the amino group of an amino acid, as described above, and the intermediate and N-terminal amino acid residues can be linked in the same manner as in a normal peptide chain.

[0040] In the present specification, when a group is defined as being "optionally substituted," the type, position, and number of substituents are not particularly limited, and when two or more substituents are present, they may be the same or different. Typical numbers of substituents are, for example, 1 to 4, 1 to 3, 1 to 2, or 1. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups (=O), acyl groups, thiol groups (-SH), propargyl groups, and aryl groups. These substituents may further contain substituents. Examples of such substituents include, but are not limited to, halogenated alkyl groups.

[0041] As used herein, the term "ring structure" means a heterocyclic or carbocyclic ring when formed by the combination of two substituents, and such rings can be saturated, unsaturated, or aromatic, and thus includes cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and non-aromatic heterocycles as defined above.

[0042] As used herein, certain substituents can form ring structures with other substituents, and when such substituents are bonded together, those skilled in the art will understand that certain substitutions, such as bonds to hydrogen, are formed. Therefore, when certain substituents are described as forming a ring structure, those skilled in the art will understand that such ring structures can be formed and are easily produced by conventional chemical reactions. Both such ring structures and their formation processes are within the knowledge of those skilled in the art. Furthermore, such heterocyclic structures may have optional substituents on the ring.

[0043] 2. THIQ alkaloid compounds containing macrocyclic structures One aspect of the present invention relates to a tetrahydroisoquinoline (THIQ) alkaloid compound containing a macrocyclic structure. This compound is characterized by having a macrocyclic structure that is linked to a THIQ skeleton and forms a closed ring. More specifically, this compound has a macrocyclic structure formed by linking the 1- and 5-positions of the THIQ skeleton with the 9- and 10-position carbon atoms of the THIQ skeleton via a linking group. The macrocyclic structure can contain heteroatoms such as oxygen, nitrogen, and sulfur atoms in addition to carbon atoms as constituent atoms. In some embodiments, the macrocyclic structure contains an amino acid residue, a linear or branched unsaturated hydrocarbon group, a sulfonyl group, an ester group, an amide group, a carbamate group, a carbonate group, an ether group, an amino group, a thioether group, a carbonyl group, or a combination thereof.

[0044] In some embodiments, the macrocyclic structure is formed by linking the 1-position and the 5-position of the THIQ skeleton in one molecule with a linking group, and is typically a 10- to 20-membered ring (preferably a 12- to 18-membered ring, more preferably a 14- to 17-membered ring).

[0045] In some embodiments, the macrocyclic structure is formed by linking the 1-position and the 5-position of the THIQ skeleton of different molecules via a linking group. In some embodiments, the macrocyclic structure is formed by linking the 1-position of the THIQ skeleton of a first molecule to the 5-position of the THIQ skeleton of a second molecule via a first linking group, and by linking the 5-position of the THIQ skeleton of the first molecule to the 1-position of the THIQ skeleton of the second molecule via a second linking group, and is typically a 15- to 40-membered ring (preferably a 24- to 36-membered ring, more preferably a 28- to 30-membered ring). In this specification, the number of members of a macrocyclic structure means the total number (minimum number) of atoms constituting the ring of the ring structure formed by linking the 1st and 5th positions of the THIQ skeleton with a linking group.

[0046] One aspect of the compound of the present invention is a compound represented by the following formula (I): [ka]

[0047] In formula (I), X 2 and Y 2 are linked together and form the X 1 and Y 1 That is, the "macrocyclic structure" in formula (I) is formed by connecting the 1st and 5th positions of the THIQ skeleton to form a ring structure (macrocyclic structure) containing "AX 1 -X 2 -Y 2 -Y 1 ". Therefore, the "macrocyclic structure" in formula (I) is formed by linking the carbon atom -AX at position 1 of the THIQ skeleton. 1 -X 2 -Y 2 -Y 1 It has a cyclic structure in which the carbon atoms at the 5th position of the THIQ skeleton, the carbon atom at the 10th position of the THIQ skeleton, and the carbon atom at the 9th position of the THIQ skeleton are linked together. In formula (I), the macrocyclic structure is, for example, a 10- to 20-membered ring (preferably a 12- to 18-membered ring, more preferably a 14- to 17-membered ring). The number of members of the macrocyclic structure in formula (I) is determined by the carbon atom at position 1 of the THIQ skeleton, -AX. 1 -X 2 -Y 2 -Y 1 -The minimum total number of atoms constituting a ring consisting of the carbon atom at position 5 of the THIQ skeleton, the carbon atom at position 10 of the THIQ skeleton, and the carbon atom at position 9 of the THIQ skeleton.

[0048] In formula (I), A is a moiety that serves as the starting point of a macrocyclic structure linked to the 1-position of the THIQ skeleton, and A is a single bond or an optionally substituted C1-C6 alkylene group. Preferably, A is a single bond, a methylene group, or an ethylene group. More preferably, A is a methylene group. In this specification, when describing the substituents of A, the left side of the described substituent is bonded to the carbon atom at position 1 of the THIQ skeleton, and the right side of the described substituent is bonded to the carbon atom at position X. 1 is assumed to be bound to

[0049] In formula (I), X 1 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof. In this specification, X 1 When describing the substituents of the formula, the left side of the described substituent is bonded to A, and the right side of the described substituent is bonded to X. 2 is assumed to be bound to

[0050] X 1 is a moiety that acts as a spacer. 1 is an amide group (-NR b C(O)-, -C(O)NR b -), an ester group (-C(O)O-, -OC(O)-), or an ether group, and more preferably an amide group (-NR b C(O)-, -C(O)NR b -) or ester groups (-C(O)O-, -OC(O)-).

[0051] In some embodiments, X 1 is -NR b C(O)-, -C(O)NR b -, alkylene group, -NR b C(O)O- or -OC(O)NR b -, -C(O)O-, -OC(O)-, -NR b -, amino acid residues, and combinations thereof.

[0052] X 1The number of carbon atoms in the alkylene group and alkenylene group in X is not particularly limited and is selected in consideration of the number of members in the macrocyclic structure. 1 The alkylene group and alkenylene group in the formula (I) have 1 to 6 carbon atoms (C1-C6) or 1 to 3 carbon atoms (C1-C3).

[0053] In formula (I), Y 1 is the starting point of the macrocyclic structure linked to the 5-position of the THIQ skeleton. 1 represents a single bond, an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent group selected from the group consisting of In this specification, Y 1 When describing the substituents of the formula (I), the left side of the described substituent is bonded to the carbon atom at position 5 of the THIQ skeleton, and the right side of the described substituent is bonded to the carbon atom at position Y. 2 is assumed to be bound to

[0054] Y 1 The number of carbon atoms in the alkylene group in is not particularly limited and is selected in consideration of the number of members in the macrocyclic structure. 1 The alkylene group in the formula (I) has 1 to 6 carbon atoms (C1-C6) or 1 to 3 carbon atoms (C1-C3).

[0055] In some embodiments, Y 1 represents an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - selected from the group consisting of: In some embodiments, Y 1 is an ether group and -NR b - selected from the group consisting of: In certain embodiments, Y 1 is an ether group.

[0056] In formula (I), Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NRb C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof. In this specification, Y 2 When describing the substituents of the group, the left side of the described substituent is Y 1 The right side of the substituent is X 2 is assumed to be bound to

[0057] In some embodiments, Y 2 is an optionally substituted C1-C6 alkylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -NR b -, amino acid residues, and combinations thereof.

[0058] In some embodiments, Y 2 represents an optionally substituted C1-C6 alkylene group, —C(O)O—, —OC(O)—, —NR b C(O)-, -C(O)NR b -, and combinations thereof. In certain embodiments, Y 2 is an optionally substituted C1-C6 (preferably C1-C3, more preferably C1-C2) alkylene group. 2 is a C1-C3 (preferably C1-C2) alkylene group. 2 is a methylene group.

[0059] In some embodiments, X1 and Y 2 At least one of the following contains an amino acid residue. In the above embodiment, X 1 and Y 2 The type of amino acid residue that can be contained in is not particularly limited. In some embodiments, the amino acid residue is a residue of an amino acid selected from the group consisting of alanine, cysteine, serine, tryptophan, threonine, lysine, arginine, propargylglycine, allylglycine, ornithine, histidine, and combinations thereof. In certain embodiments, the amino acid residue is a residue of alanine or cysteine. In one embodiment, the amino acid residue is a residue of alanine.

[0060] In some embodiments, X 1 In certain embodiments, X 1 comprises an alanine or cysteine ​​residue. 1 contains an alanine residue.

[0061] In formula (1), X 2 -L 1 -C(=CR f 2)-CR f =CR f -L 2 -, -L 1 -CR f =CR f -C(=CR f 2)-L 2 -, -L 1 -CR f =CR f -L 2 -, -L 1 -CR f =CR f --CR f =CR f -L 2 -, -L 1 -NR b -CR f 2-C≡CL 2 -, -L 1 -C≡C-CR f 2-NR b -L2 -, -L 1 -C≡CL 2 -, -L 1 -C≡CC≡CL 2 -, [ka] is a divalent group selected from the group consisting of: In this specification, X 2 When describing the substituents of the formula, the left side of the described substituent is X 1 The right side of the substituent is Y 2 That is, L 1 is X 1 is bonded to L 2 is Y 2 is bonded to.

[0062] L 1 and L 2 each independently represents a single bond or a C1-C6 alkylene group. R f are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group and an aryl group which may be substituted. Z 1 and Z 2 are each independently -NR c -or-CR d R e - represents R c , R d , and R e are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group, or R c and R d together and they combine to form Z 1 and Z 2and form a 5- or 6-membered ring structure (ring Q), which may be substituted with 1 to 4 substituents. In some embodiments, the ring structure (ring Q) may be substituted with 1 to 4 (preferably 1 to 3) substituents independently selected from a methyl group, an oxo group, a phenyl group, and a propargyl group. The ring structure (ring Q) may be a carbocyclic ring or a heterocyclic ring containing 1 to 4 (preferably 1 to 3) heteroatoms as ring-constituting atoms. L 1 and L 2 When L is an alkylene group, the number of carbon atoms may be appropriately determined depending on the number of members constituting the macrocyclic structure. 1 and L 2 When is an alkylene group, it has 1 to 6 carbon atoms (C1-C3 alkylene group), or 1 to 3 carbon atoms (C1-C3 alkylene group), or 1 to 2 carbon atoms (C1-C2 alkylene group), or 1 carbon atom (methylene group).

[0063] In some embodiments, L 1 and L 2 is a single bond, a methylene group, or an ethylene group.

[0064] In some embodiments, X 2 -C(=CH2)-CH=CH-CH2-, -CH2-CH=CH-C(=CH2)-, -CH=CH-CH2-, -CH2-CH=CH-, -C≡C-CH2, -CH2-C≡C-, -NH-CH2-C≡C-, -C≡C-CH2-NH-, [ka] Z is selected from the group consisting of 1 and Z 2 are each independently -NR c -or-CR d R e - represents R c , R d , and R d are each independently a hydrogen atom or a C1-C3 alkyl (e.g., a methyl group), or R c and Rd together and they combine to form Z 1 and Z 2 and form a 5- or 6-membered ring structure (ring Q), which may be substituted with 1 to 4 (preferably 1 to 3) substituents independently selected from a methyl group, an oxo group, a phenyl group, and a propargyl group. The ring structure (ring Q) may be substituted with 1 to 3 substituents selected from an oxo group and a phenyl group.

[0065] In certain embodiments, X 2 teeth, [ka] is selected from the group consisting of:

[0066] In certain embodiments, X 2 teeth, [ka] is selected from the group consisting of: In one embodiment, Z 1 and Z 2 each independently represents N or CH, and R 8 represents a hydrogen atom, a phenyl group, or a propargyl group. In the above embodiment, R 8 is a hydrogen atom, an optionally substituted aryl group, an optionally substituted C-C 20 represents an alkyl group, an optionally substituted allyl group, a propargyl group, and a nitrogen-protecting group. In some embodiments, R 8 represents a hydrogen atom, an optionally substituted phenyl group, and an optionally substituted C-C 20 The alkyl group, allyl group, propargyl group, and nitrogen protecting group are selected from the group consisting of: In certain embodiments, R 8 represents a hydrogen atom or an optionally substituted phenyl group.

[0067] In formula (I), Rb are each independently a hydrogen atom or an optionally substituted C-C 20 It is selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups.

[0068] In some embodiments, R b are each independently selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group. In some embodiments, R b is a hydrogen atom, an optionally substituted C1-C6 alkyl group (for example, a methyl group, an ethyl group), or a propargyl group. In certain embodiments, R b is a hydrogen atom, a methyl group, or a propargyl group. In one embodiment, R b is a nitrogen protecting group.

[0069] In formula (I), R a are each independently a hydrogen atom or an optionally substituted C1-C6 alkyl group. a When R is an alkyl group, each R a may be taken together to form a ring structure including the oxygen atom to which they are attached. Preferably, each R a are taken together to form a ring structure containing the oxygen atom to which they are bonded, and the ring structure can be a 5- to 9-membered ring.

[0070] In formula (I), R 1 is a methyl group.

[0071] In formula (I), R 2 is a hydrogen atom or an optionally substituted C1-C6 alkyl group. 2 is a methyl group.

[0072] In formula (I), R 3is a methyl group.

[0073] In formula (I), R 4 is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group. In some embodiments, R 4 represents a hydrogen atom. In some embodiments, R 4 represents a protecting group for a phenolic hydroxyl group.

[0074] In formula (I), R 5 represents a leaving group containing a cyano group (CN), a hydroxyl group, or an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom. In some embodiments, R 5 represents CN or a hydroxyl group. In one embodiment, R 5 represents CN.

[0075] In some embodiments, A is a methylene group and X 1 is an amide group (-NR b C(O)-, -C(O)NR b -) or an ester group (-C(O)O-, -OC(O)-), and R b is a hydrogen atom, a methyl group, or a propargyl group, and Y 1 is an ether group.

[0076] In some embodiments, the compound of formula (I) has formula (Ia): This form of the compound may be prepared from the starting material cyanosafracin B in a few steps. [ka]

[0077] In formula (Ia), X 2 , Y 1 , Y 2, R 4 , and R 5 is as defined in the above formula (I), and the specific and preferred embodiments described above can be used. In formula (Ia), Me represents a methyl group.

[0078] In formula (Ia), X 1c represents a hydrogen atom, an optionally substituted C1-C 20 It is selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups.

[0079] In some embodiments, X 1c is selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group (e.g., a methyl group, an ethyl group), an optionally substituted aryl group (e.g., a phenyl group), an optionally substituted allyl group, a propargyl group, and a nitrogen protecting group.

[0080] In some embodiments, X 1c is a hydrogen atom, an optionally substituted C1-C6 alkyl group (for example, a methyl group, an ethyl group), or a propargyl group. In certain embodiments, X 1c is a hydrogen atom, a methyl group, or a propargyl group.

[0081] In formula (Ia), X 1d is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids. The substituent corresponding to the side chain of various natural / unnatural amino acids is not particularly limited, and may be a group corresponding to the side chain of an amino acid bonded to the α-carbon of the amino acid. For example, the substituent corresponding to the side chain of alanine is a methyl group. The substituent corresponding to the side chain of cysteine ​​is -CH2-SH.

[0082] In certain embodiments, X 1d represents a methyl group.

[0083] In formula (Ia), L3 represents a single bond, an optionally substituted alkylene group, an optionally substituted alkenylene group, a carbonyl group, -C(=S)-, -C(=NR b )-, -C(O)O-, -C(O)NR b -, -OC(O)-, -NR b -, an ether group, a thioether group, and combinations thereof.

[0084] In some embodiments, L 3 represents a single bond, an optionally substituted alkylene group, an optionally substituted alkenylene group, a carbonyl group, -C(=S)-, -C(=NR b )-, -C(O)O-, -C(O)NR b -, -OC(O)-, -NR b -, an ether group, and a thioether group. In some embodiments, L 3 is selected from the group consisting of a single bond, an optionally substituted C1-C6 (preferably C1-C3, more preferably C1-C2) alkylene group, —C(O)O—, and —OC(O)—. In some embodiments, L 3 is selected from the group consisting of a single bond, —C(O)O—, and —OC(O)—. In certain embodiments, L 3 is a single bond. In certain embodiments, L 3 is —C(O)O— or —OC(O)—. In certain embodiments, L 3 is -OC(O)- (where L 3 The carbon atom of formula (Ia) is NX 1c (bonded to the nitrogen atom of

[0085] In formula (Ia), R b is as defined in the above formula (I), and the specific and preferred embodiments described above can be used.

[0086] In some embodiments, the compound of formula (I) is represented by formula (Ic), (Id), (Ie), (If), or (Ig): In one embodiment, the compound of formula (I) is represented by formula (Ic): In one embodiment, the compound of formula (I) is represented by formula (Id): In one embodiment, the compound of formula (I) is represented by formula (Ie): In one embodiment, the compound of formula (I) is represented by formula (If): In one embodiment, the compound of formula (I) is represented by formula (Ig): In one embodiment, the compound of formula (I) is represented by formula (Ih): These forms of the compound can be prepared from the starting material cyanosafracin B in a few steps. [ka]

[0087] In this specification, [ka] represents a bond on an sp2 carbon and indicates that any conformation of stereoisomers such as cis, trans, and conformational isomers (s-cis / s-trans) may be used.

[0088] In formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig) and formula (Ih) (hereinafter also referred to as formulas (Ic) to (Ih)), R 4 , R 5 , X 1c and X 1d is as defined in the above formula (Ia), and the specific and preferred embodiments described above can be used. In the formulae (Ic) to (Ih), Me represents a methyl group.

[0089] In formula (Ic), formula (Id), and formula (Ie), X 1a is an oxygen atom, a sulfur atom, -NR b - or an optionally substituted methylene group (-CH2-). Substituents for the methylene group include, for example, substituents corresponding to the side chains of various natural / unnatural amino acids. In some embodiments, X 1a is an oxygen atom or -NR b - represents. In certain embodiments, X 1a is an oxygen atom.

[0090] In formula (Ic), formula (Id), and formula (Ie), X 1b is an oxygen atom, a sulfur atom, =NR b or an optionally substituted methylene group (=CH2). Substituents for the methylene group include, for example, optionally substituted C1-C6 alkylene groups and aryl groups. In some embodiments, X 1b is an oxygen atom.

[0091] In formula (Ic), formula (Id), formula (Ie), formula (If), and formula (Ih), X 2a represents an optionally substituted C1-C6 alkylene group. In some embodiments, X 2a is a C1-C3 alkylene group. In one embodiment, X 2a is a methylene group.

[0092] In formulas (Ic) to (Ih), Y 1 represents an ether group, a thioether group, an optionally substituted C1-C6 alkylene group, and -NR b - is a divalent group selected from the group consisting of In some embodiments, Y 1 is an ether group and -NR b - selected from the group consisting of: In certain embodiments, Y 1 is an ether group.

[0093] In formulas (Ic) to (Ih), Y 2 represents an optionally substituted alkylene group, an optionally substituted alkenylene group, -NR b C(O)-, -C(O)NRb -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b -, a divalent group selected from the group consisting of a sulfonyl group, an ether group, a thioether group, and an amino acid residue.

[0094] In some embodiments, Y 2 represents an optionally substituted C1-C6 alkylene group, an optionally substituted C2-C6 alkenylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR b )-, -NR b -, a sulfonyl group, an ether group, a thioether group, and an amino acid residue.

[0095] In some embodiments, Y 2 is an optionally substituted C1-C6 alkylene group, -NR b C(O)-, -C(O)NR b -, -C(O)O-, -OC(O)-, -NR b C(O)O-, -OC(O)NR b -, -NR b -, amino acid residues, and combinations thereof.

[0096] In some embodiments, Y 2 represents an optionally substituted C1-C6 alkylene group, —C(O)O—, —OC(O)—, —NR b C(O)-, -C(O)NR b -, and combinations thereof.

[0097] In certain embodiments, Y 2is an optionally substituted C1-C6 (preferably C1-C3, more preferably C1-C2) alkylene group. In certain embodiments, Y 2 is a C1-C3 (preferably C1-C2) alkylene group. In one embodiment, Y 2 is a methylene group.

[0098] In formula (Ig), L X2a and L X2b are each independently a hydrogen atom or an optionally substituted C-C 20 represents an alkyl group and an aryl group which may be substituted. In some embodiments, L X2a and L X2b each independently represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, or an optionally substituted aryl group. In one embodiment, L X2a and L X2b is a hydrogen atom.

[0099] In formula (Ic), formula (Id), formula (Ie), formula (If), and formula (Ih), L X2c represents a hydrogen atom, an optionally substituted C1-C 20 represents an alkyl group and an aryl group which may be substituted. In some embodiments, L X2c represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, or an optionally substituted aryl group. In one embodiment, L X2c is a hydrogen atom.

[0100] In formula (Id), formula (Ie), and formula (If), L Y2a represents a hydrogen atom, an optionally substituted C1-C 20 represents an alkyl group and an aryl group which may be substituted. In some embodiments, L Y2ais selected from a hydrogen atom, an optionally substituted C1-C8 alkyl group, and an optionally substituted aryl group. In one embodiment, L Y2a is a hydrogen atom.

[0101] In formula (Ic), formula (Id), formula (Ie), and formula (If), L Y2b represents a hydrogen atom, an optionally substituted C1-C 20 represents an alkyl group and an aryl group which may be substituted. In some embodiments, L Y2b is selected from a hydrogen atom, an optionally substituted C1-C8 alkyl group, and an optionally substituted aryl group. In one embodiment, L Y2b is a hydrogen atom.

[0102] In formula (Ic), formula (Id), formula (Ie), formula (If) and formula (Ih), L Y2c represents a hydrogen atom, an optionally substituted C1-C 20 represents an alkyl group and an aryl group which may be substituted. In some embodiments, L Y2c is selected from a hydrogen atom, an optionally substituted C1-C8 alkyl group, and an optionally substituted aryl group. In one embodiment, L Y2c is a hydrogen atom.

[0103] In formula (Ie), Z 1 and Z 2 are each independently N or CR e represents R e is a hydrogen atom or an optionally substituted C1-C6 alkyl group. In certain embodiments, Z 1 and Z 2 each independently represents a nitrogen atom or CH.

[0104] In formula (Ie), R 8is a hydrogen atom, an optionally substituted aryl group, an optionally substituted C-C 20 represents an alkyl group, an optionally substituted allyl group, a propargyl group, and a nitrogen-protecting group. In certain embodiments, R 8 represents a hydrogen atom or an optionally substituted phenyl group. In one embodiment, R 8 is a phenyl group.

[0105] In formulas (Ic) to (Ih), R b is as defined in the above formula (I), and the specific and preferred embodiments described above can be used.

[0106] Specific examples of the compound of the present invention represented by the above formula (I) include compounds having the following structures, but are not limited to these. The numbers shown below the compounds are the numbers of the compounds synthesized in the examples. [ka] TIFF0007760183000030.tif115170 (wherein Me represents a methyl group.)

[0107] Another aspect of the present invention relates to a compound represented by the following formula (IIIc): [ka]

[0108] In the compound of formula (IIIc), the 1- and 5-positions of the THIQ skeletons of two different molecules are linked by a linking group to form a macrocyclic structure. Therefore, the compound of formula (IIIc) can also be said to be a dimer compound of the compound of formula (I). The macrocyclic structure in formula (IIIc) is, for example, a 15- to 40-membered ring (preferably a 24- to 36-membered ring, more preferably a 28- to 30-membered ring).

[0109] In formula (IIIc), X 1c , X1d , L X2a , L X2b , Y 1 , Y 2 , R 4 , R 5 , R b is as defined in the above formula (Ig), and the specific and preferred embodiments described above can be used. Me represents a methyl group.

[0110] Specific examples of the compound of the present invention represented by the above formula (IIIc) include compounds having the following structures. However, the compound is not limited to these. The compound of the present invention represented by the above formula (IIIc) is expected to exhibit DNA alkylating activity and anticancer activity, similar to the group of compounds described in the Examples. The numbers shown below the compounds are the compound numbers synthesized in the Examples. [ka]

[0111] The compounds of the present invention represented by the above formula (I), formula (Ia), formulas (Ic) to (Ih), formula (IIIc), and formulas (II), (IIc) to (IIf) described below (hereinafter also referred to as "compounds of the present invention") may exist as salts. The salts are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include base addition salts, acid addition salts, and amino acid salts. Examples of base addition salts include metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, ammonium salt, and organic amine salts such as triethylamine salt, piperidine salt, and morpholine salt. Examples of acid addition salts include mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as methanesulfonate, paratoluenesulfonate, citrate, and oxalate. Examples of amino acid salts include glycine salts. However, the salts are not limited to these salts.

[0112] The compounds of the present invention may have one or more asymmetric carbon atoms depending on the type of substituents, and may exist as stereoisomers, such as optical isomers or diastereoisomers. The asymmetric carbon atoms may have an (R) or (S) configuration. All optical isomers or diastereoisomers, and mixtures thereof, resulting from the specific configuration of the asymmetric carbon atoms present in the molecule, are within the scope of the present invention. Stereoisomerism about double bonds (geometric isomerism) is also possible, and in some embodiments, the molecule may exist as an (E) isomer or a (Z) isomer. When a molecule contains several double bonds, stereoisomerism may exist for each double bond. In addition, in certain cases, the molecule may exist as a conformational isomer. Diastereoisomers, geometric isomers, conformational isomers, and mixtures thereof are within the scope of the present invention. Pure stereoisomers, any mixtures of stereoisomers, racemates, etc. are all within the scope of the present invention.

[0113] The compounds of the present invention may exist as hydrates or solvates, and all of these substances are included in the scope of the present invention. The type of solvent that forms the solvate is not particularly limited, but examples include solvents such as ethanol, acetone, and isopropanol.

[0114] The compounds of the present invention may exist in isotopically labeled forms. All pharmaceutically acceptable salts and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are included within the scope of the present invention.

[0115] Protected forms of the compounds of the present invention are within the scope of the present invention. Suitable protecting groups are well known to those skilled in the art. General reviews of protecting groups in organic chemistry are provided in "Protecting Groups in Organic Synthesis," 5th Edition, by P. G. M. Watts, Wiley-Interscience; and "Protecting Groups," 3rd Edition, by P. J. Kocienski, Georg Thieme-Verlag. In some embodiments, the hydroxyl group of the compound of the present invention may be protected, for example, with a phenolic hydroxyl protecting group. In some embodiments, the amino group of the compound of the present invention may be protected with a nitrogen protecting group. In the present specification, the nitrogen-protecting group is not particularly limited. Specific examples of the nitrogen-protecting group include carbamate-based protecting groups including a tert-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, an acyl-based protecting group, a sulfonyl-based protecting group such as a 2-nitrobenzenesulfonyl (Ns) group, and a benzyl-based protecting group. In the present specification, the protecting group for the phenolic hydroxyl group is not particularly limited. Specific examples of the phenolic hydroxyl group include a methoxymethyl (MOM) group, an ethoxyethyl (EE) group, a tetrahydropyranyl (THP) group, a silyl protecting group including a tert-butyldimethylsilyl (TBS) group, an acyl protecting group including an acetyl (Ac) group, an acetal protecting group, a carbonate protecting group, and a sulfonyl protecting group.

[0116] In some embodiments, the hydroxyl group of the compound represented by formula (I) and formulae (Ic) to (Ih) may be in a form protected by, for example, a protecting group for a phenolic hydroxyl group. In some embodiments, R in Formula (I) and Formulas (Ic) to (Ih) 4 is a phenolic protecting group. In certain embodiments, R in formula (I) and formulas (Ic) to (Ih) 4 is selected from a methoxymethyl (MOM) group, an ethoxyethyl (EE) group, a tetrahydropyranyl (THP) group; a silyl-based protecting group including a tert-butyldimethylsilyl (TBS) group; and an acetyl (Ac) group.

[0117] In some embodiments, the amino group of the compound represented by formula (I) and formulae (Ic) to (Ih) may be in a form protected by a nitrogen-protecting group. In some embodiments, R in Formula (I) and Formulas (Ic) to (Ih) b is a nitrogen protecting group. In certain embodiments, R in formula (I) and formulas (Ic) to (Ih) b is selected from a tert-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, and a 2-nitrobenzenesulfonyl (Ns) group. In some embodiments, X in formulas (Ic) to (Ih) 1c is a nitrogen protecting group. In certain embodiments, X in formulas (Ic) to (Ih) 1c is selected from a tert-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, and a 2-nitrobenzenesulfonyl (Ns) group.

[0118] In some embodiments, the compounds of Formula (I), (Ic)-(Ih) do not contain any protecting groups. In some embodiments, in Formula (I), R b is not a nitrogen protecting group, R 4 is not a protecting group for a phenolic hydroxyl group. In some embodiments, in Formulas (Ic) to (Ih), R b is not a nitrogen protecting group, and X 1c is not a nitrogen protecting group, R 4 is not a protecting group for a phenolic hydroxyl group.

[0119] 3. THIQ alkaloid compounds without macrocyclic structures Another aspect of the present invention relates to a compound represented by the following formula (II): The compound of formula (II) is a compound in which side chain moieties are introduced at the 1st and 5th positions of the THIQ skeleton of the starting material cyanosafracin B, and modified with substituents as necessary.

[0120] [ka] In some embodiments, these compounds are intermediate compounds suitable for use in the synthesis of macrocyclic structure-containing THIQ alkaloid compounds represented by formula (I), formula (Ia), formulas (Ic) to (Ih), and formula (IIIc). The compound represented by formula (II) has a functional group in the molecule that can chemoselectively react with various reagents, allowing it to be derivatized into a variety of analogs. In some embodiments, the compound of formula (II) has excellent DNA alkylating ability and, thereby, excellent antitumor activity.

[0121] In formula (II), A, Y 1 , Y 2 , X 1 , R a , R 1 , R 2 , R 3 , and R 5 are the same as in formula (I), and the definitions and explanations of preferred embodiments described above regarding formula (I) apply as they are.

[0122] In formula (II), M 1 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, -N(R b )2, a hydroxyl group, a carbonyl group, a thiol group, and a halogen atom.

[0123] In formula (II), M 2 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, -N(R b )2, a hydroxyl group, a carbonyl group, a thiol group, and a halogen atom.

[0124] In some embodiments, M 1 represents a hydrogen atom, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or -NHR b and M 2 represents a hydrogen atom, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or -NHRb is.

[0125] In certain embodiments, M 1 and M 2 is a combination of the following: (i)M 1 is an optionally substituted alkenyl group, and M 2 is an optionally substituted alkynyl group. (ii) M 1 is an optionally substituted alkynyl group, and M 2 is an optionally substituted alkenyl group. (iii)M 1 is an optionally substituted alkenyl group, and M 2 is an optionally substituted alkenyl group. (iv) M 1 is NHR b and M 2 is an optionally substituted alkynyl group. (v)M 1 is an optionally substituted alkynyl group, and M 2 is NHR b is.

[0126] In formula (II), R b The definitions and preferred embodiments described above regarding formula (I) apply to this compound.

[0127] In some embodiments, the compound of formula (II) is represented by formula (IIc), formula (IId), formula (IIe), or formula (IIf): In one embodiment, the compound of formula (II) is represented by formula (IIc): In one embodiment, the compound of formula (II) is represented by formula (IId): In one embodiment, the compound of formula (II) is represented by formula (IIe): Compounds of these forms can be prepared from the starting material cyanosafracin B in a few steps and can be used to prepare compounds of formula (I) or formula (IIIc) having a macrocyclic structure.

[0128] [ka]

[0129] In formula (IIc), formula (IId), formula (IIe), and formula (IIf) (also referred to as formulas (IIc) to (IIf)), X 1c , X 1d , X 2a , L X2a , L X2b , L X2c , Y 1 , Y 2 , R 4 , R 5 , L Y2a , L Y2b , L Y2c , R b , R 4 , and R 5 is as defined in the above formulas (I), (Ia), (Ic) to (Ih), and (II), and the specific and preferred embodiments described above can be used. Me represents a methyl group.

[0130] Specific examples of the compound represented by the above formula (II) include those having the following structures, but are not limited to these. [ka] In the formula, Me represents a methyl group, and R 4 represents a hydrogen atom or a protecting group for a phenolic hydroxyl group (e.g., a methoxymethyl (MOM) group, a tert-butyldimethylsilyl (TBS) group, an acetyl (Ac) group, etc.), and R b are each independently a hydrogen atom or an optionally substituted C-C 20 It represents an alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a nitrogen-protecting group (e.g., a tert-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, a 2-nitrobenzenesulfonyl (Ns) group).

[0131] In one embodiment, the compound represented by formula (II) may have the following structure: The numbers shown below the compounds are the numbers of the compounds synthesized in the examples. [ka] TIFF0007760183000037.tif125170 (wherein Me represents a methyl group, MOM represents a methoxymethyl group, Ac represents an acetyl group, Ns represents a 2-nitrobenzenesulfonyl group, and TBS represents a tert-butyldimethylsilyl group.)

[0132] In one embodiment, the compound represented by formula (II) may have the following structure: [ka]

[0133] In some embodiments, the hydroxyl group of the compound represented by formula (II) and formulae (IIc) to (IIf) may be in a form protected by, for example, a protecting group for a phenolic hydroxyl group. In some embodiments, R in Formula (II), Formulas (IIc) to (IIf) 4 is a phenolic protecting group. In certain embodiments, R in formula (II) and formulas (IIc) to (IIf) 4 is selected from a methoxymethyl (MOM) group, an ethoxyethyl (EE) group, a tetrahydropyranyl (THP) group; a silyl-based protecting group including a tert-butyldimethylsilyl (TBS) group; and an acetyl (Ac) group.

[0134] In some embodiments, the amino group of the compound represented by formula (II) and formulas (IIc) to (IIf) may be in a form protected by a nitrogen-protecting group. In some embodiments, R in Formula (II), Formulas (IIc) to (IIf) b is a nitrogen protecting group. In certain embodiments, R in formula (II) and formulas (IIc) to (IIf)b is selected from a tert-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, and a 2-nitrobenzenesulfonyl (Ns) group. In some embodiments, X in formulas (IIc) to (IIf) 1c is a nitrogen protecting group. In certain embodiments, X in formulas (IIc) to (IIf) 1c is selected from a tert-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, and a 2-nitrobenzenesulfonyl (Ns) group.

[0135] In some embodiments, the compounds of Formula (II), (IIc)-(IIf) do not contain protecting groups. In some embodiments, in Formula (II), R b is not a nitrogen protecting group, R 4 is not a protecting group for a phenolic hydroxyl group. In some embodiments, in Formulas (IIc) to (IIf), R b is not a nitrogen protecting group, and X 1c is not a nitrogen protecting group, R 4 is not a protecting group for a phenolic hydroxyl group.

[0136] 4. Pharmaceutical Composition of the Present Invention One aspect of the present invention also relates to a pharmaceutical composition comprising a compound represented by the above formula (I), formula (Ia), formulas (Ic) to (Ih), formula (IIIc), and formulas (II), (IIc) to (IIf) described below (the compound of the present invention) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The term "composition" in the context of pharmaceutical composition encompasses not only a product comprising an active ingredient and an inactive ingredient constituting the carrier, but also any product that occurs directly or indirectly as a result of the association, complexation, or aggregation of any two or more ingredients, or as a result of the dissociation of one or more ingredients, or as a result of another type of reaction or interaction of one or more ingredients.

[0137] In some embodiments, the compound of the invention included in the pharmaceutical composition does not contain a protecting group. In some embodiments, the compound of the invention included in the pharmaceutical composition does not contain a protecting group for the phenolic hydroxyl group and does not contain a nitrogen protecting group. In some embodiments, the compound of the invention included in the pharmaceutical composition has the formula R 4 is a hydrogen atom, and R b If there is R b is a substituent other than a nitrogen protecting group.

[0138] As used herein, the term "pharmaceutically acceptable carrier" may be a carrier commonly used in the art, for example, excipients such as lactose, sucrose, glucose, starch, crystalline cellulose, etc.; binders such as hydroxypropyl cellulose, methyl cellulose, gelatin, tragacanth, gum arabic, sodium alginate, etc.; disintegrants such as starch, carboxymethyl cellulose, calcium carbonate, etc.; and lubricants such as magnesium stearate, talc, stearic acid, etc.

[0139] So that suitable dosage will be obtained, the pharmaceutical composition will contain an effective amount of a compound of the invention. The term "effective amount" or "therapeutically effective amount" of a compound of the invention refers to that amount of an active compound of the invention that elicits a biological or medical response in a subject, or ameliorates symptoms, relieves a condition, slows or delays the progression of a disease, or prevents a disease, etc. As used herein, "subject" refers to an animal. Examples of subjects include, but are not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In preferred embodiments, the subject is a mammal, most preferably a human.

[0140] As shown in the Examples below, the compounds of the present invention possess excellent DNA alkylation ability and, therefore, excellent antitumor activity, a finding first discovered by the present inventors. While not necessarily limited to the mechanism of action described below, the compounds of the present invention recognize DNA duplexes at multiple sites in the THIQ ring moiety (nucleic acid alkylation site) and alkylate them in a sequence-selective manner. DNA alkylated by THIQ alkaloids undergoes significant changes in three-dimensional structure, presumably resulting in the expression of excellent antitumor activity through modulation and control of the interaction pattern between nuclear proteins (e.g., nucleic acid repair enzymes and transcription factors) and DNA, as well as protein function. The present invention allows for the flexible introduction and modification of macrocyclic moieties of various numbers while maintaining the structure of the nucleic acid alkylation site of antitumor agents, such as ecteinascidin 743 (Yondelis). This potentially allows for rational modification and control of the interaction pattern with nuclear proteins at the macrocyclic moiety located opposite the nucleic acid alkylation site.

[0141] Thus, pharmaceutical compositions of the present invention comprising a compound of the present invention as an active ingredient can be DNA alkylating agents or anticancer agents and can be used to treat cancer. In some embodiments, a method for treating cancer in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutical composition comprising the same. Some embodiments of the present invention provide compounds of the present invention or compositions comprising the same for use as pharmaceuticals (e.g., antitumor agents, anticancer agents). Here, "treatment" in the present invention refers to the maintenance or suppression of the progression or metastasis of symptoms associated with cancer or malignant tumors, and is not necessarily limited to complete cure. Furthermore, "cancer" is not particularly limited and includes any malignant tumor, including sarcoma, but is preferably used to treat solid cancers. Examples include breast cancer, brain tumor, colon cancer, lung cancer, ovarian cancer, and stomach cancer.

[0142] The pharmaceutical composition of the present invention may be in any form, such as liquid, solid, powder, or gel, and examples thereof include tablets, pills, powders, capsules (soft capsules, hard capsules), granules, lozenges, chewable tablets, oral liquids, injections (intravascular, intramuscular, subcutaneous, intradermal, etc.), and suppositories. Tablets may be coated with a conventional coating, as needed, and may be made into, for example, sugar-coated tablets or film-coated tablets, or may further be made into double-layer or multi-layer tablets. Granules and powders may also be coated with a conventional coating.

[0143] The pharmaceutical composition of the present invention may contain, as needed, additives that can be used in conventional pharmaceuticals in addition to the above-mentioned carriers, depending on the form of application. Examples of such additives include various formulation ingredients such as stabilizers, diluents, pH buffers, solubilizers, solubilizers, isotonicity agents, and wetting agents, and the amounts of these ingredients can be appropriately selected by those skilled in the art.

[0144] The compounds and pharmaceutical compositions of the present invention can be administered orally or parenterally, for example, orally in the form of powder, granules, tablets, capsules, syrup, suspension, etc. as described above, or alternatively, they can be administered parenterally in the form of an injection or drip infusion, for example, in the form of an emulsion, suspension, etc.

[0145] The compounds and pharmaceutical compositions of the present invention can be administered in appropriate dosages depending on the species, sex, age, body weight, symptoms, and other factors of the target animal. A preferred daily dose per adult is, for example, 0.02 to 200 mg / kg body weight / day, preferably 0.2 to 20 mg / kg body weight / day, in terms of the amount of active ingredient. The formulations can be administered according to any dosage regimen. The administration period of the composition for preventing or treating bone diseases can be determined arbitrarily depending on the age and symptoms. For example, the composition can be administered continuously, three times a day, twice a day, once a day, every two days, every three days, or once a week, or at any period and interval.

[0146] In further embodiments of the present invention, a kit is provided comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier, hi some embodiments, the kit is for use in treating cancer.

[0147] 5. Method for producing the compound of the present invention The compounds of the present invention can typically be obtained by starting from cyanosafracin B, introducing appropriate substituents at the 1- and 5-positions of the THIQ skeleton, and then cyclizing them to form a macrocyclic structure, as shown in the Examples below. The Examples herein specifically illustrate methods for preparing representative compounds encompassed by the compounds of the present invention represented by general formula (I), general formula (II), or general formula (III). Therefore, those skilled in the art will fully understand that any compound encompassed by general formula (I), general formula (II), or general formula (III) can be synthesized based on the disclosure herein and knowledge of synthetic chemistry known in the art, and by appropriately selecting starting materials, reagents, reaction conditions, etc., as needed. In any process for preparing the compounds of various embodiments of the present invention, it may be necessary and / or desirable to protect functional or reactive groups in any of the relevant molecules. Such protection can be achieved by using conventional protecting groups. The protecting groups can be removed at a later convenient stage using methods well known in the art. The synthetic schemes described herein are illustrative and the present invention is not limited by the chemical reactions and conditions described in these schemes and examples. The various starting materials used in the schemes and examples are either commercially available or can be prepared by one skilled in the art based on synthetic chemistry knowledge known in the art.

[0148] One aspect of the present invention relates to a method for producing a tetrahydroisoquinoline (THIQ) alkaloid compound containing a macrocyclic structure (hereinafter also referred to as a "macrocyclic THIQ compound"). In a preferred embodiment, a tetrahydroisoquinoline (THIQ) alkaloid compound containing a macrocyclic structure is produced using cyanosafracin B as a starting material via a compound represented by formula (II) above. By synthesizing using a compound represented by formula (II), it is possible to efficiently produce compounds having various types of macrocyclic structures linked to a THIQ skeleton in a small number of steps (e.g., 6 to 10 steps). In certain embodiments, the macrocycle-containing THIQ compound is a compound represented by formula (I) above. In certain embodiments, the macrocycle-containing THIQ compound is a compound represented by formula (Ia) above. In certain embodiments, the macrocycle-containing THIQ compound is a compound represented by formula (Ic), (Id), (Ie), (If), or (Ig) above. In certain embodiments, the macrocycle-containing THIQ compound is a compound represented by formula (Ih) above. In certain embodiments, the macrocycle-containing THIQ compound is a compound represented by formula (IIIc) above.

[0149] In some embodiments, the macrocycle-containing THIQ compound can be obtained by using cyanosafracin B as a starting material, 1) introducing an appropriate substituent into the side chain at position 1 of the THIQ skeleton and phenolizing the p-benzoquinone moiety at position 5 of the THIQ skeleton to introduce an appropriate substituent, thereby obtaining a compound represented by formula (II); and then 2) forming a macrocycle structure using an appropriate catalyst. Hereinafter, a method for synthesizing a compound represented by formula (I) or formula (IIIc) from cyanosafracin B via a compound represented by formula (II) will be described.

[0150] In some embodiments, the method for producing the compound represented by formula (I) or formula (IIIc) includes the steps of: (1) synthesizing the compound represented by formula (II) from cyanosafracin B; (2) reacting the compound represented by formula (II) to form a macrocyclic structure; if necessary, (3) modifying the macrocyclic structure; and if necessary, (4) deprotecting the protecting group. The compound of formula (II) is a compound at the stage where side chain moieties for forming a macrocyclic structure are introduced at the 1st and 5th positions of the THIQ skeleton. 1 " and "M 2 " can be converted into a THIQ alkaloid compound having a macrocyclic structure of formula (I) or (III) by introducing an appropriate substituent into the compound according to the desired macrocyclic structure and then forming a ring structure.

[0151] (1) Synthesizing a compound of formula (II) (i) A side chain (Y 1 -Y 2 -M 2 ) introduction A hydroxyl group can be introduced at the 5-position by phenolizing the oxo moiety of p-benzoquinone at the 5-position of the THIQ skeleton of cyanosafracin B. Phenolization of the 5-position of the THIQ skeleton can typically be carried out by irradiating it with visible light to form a phenolic hydroxyl group. Since cyanosafracin B contains an amino group and a phenolic hydroxyl group, it is preferable to carry out the photocyclization reaction while protecting these groups with an amino-protecting group or a hydroxyl-protecting group. Next, after phenolization, a side chain (-Y) at the 5-position is attached. 2 -M 2 By introducing Y 1 A compound having an ether group is obtained. Next, an alkenyl halide such as allyl bromide or an alkynyl halide such as propargyl bromide is reacted with the phenolic hydroxyl group at the 5-position of the THIQ skeleton to introduce a side chain containing an alkenyl or alkynyl group at the 5-position of the THIQ skeleton.

[0152] Y in Equation (1) 1 To obtain a structure other than an ether group, for example, phenol can be converted into a trifluoromethanesulfonate ester, halogen, boron, zinc, or tin zinc, followed by various cross-coupling reactions to introduce a side chain containing an alkyl group, an alkenyl group, an alkynyl group, an amino group, a thiol group, or the like. Alternatively, an amino group can be introduced by direct amination using a photoredox catalyst (Non-Patent Documents: Margrey, KA; Levens, A.; Nicewicz, DA Angew. Chem. Int. Ed. 2017, 56, 15644). Furthermore, for the introduction of an ester group, an amide group, an ether group, a thioether group, a carbamate group, a carbonyl group, an alkyl group, a sulfonyl group, an amino group, an amino acid residue, or the like, a halogenating reagent containing these groups (e.g., allyl chloroformate or carboxybenzyl chloride) can be used.

[0153] (ii) A side chain (-AX) at position 1 of the THIQ skeleton 1 -M 1 ) introduction The side chain (-CH2-CH-C(=O)-CH(CH3)-NH2) at the 1-position of the THIQ skeleton in cyanosafracin B can be modified and used as a side chain at the 1-position of the THIQ skeleton. For example, a side chain containing an alkenyl group or an alkynyl group can be introduced by reacting an alkenyl halide such as allyl bromide or an alkynyl halide such as propargyl bromide with the amino group located at the terminal side chain of the THIQ skeleton of cyanosafracin B. Alternatively, a side chain containing an ester group (-COO-) can be introduced by reacting the terminal amino group with cesium carbonate or the like. Furthermore, halogenating reagents containing ester groups, amide groups, ether groups, thioether groups, carbamate groups, carbonyl groups, alkyl groups, sulfonyl groups, amino groups, amino acid residues, and the like (e.g., allyl chloroformate or carboxybenzyl chloride) can be used to introduce these groups.

[0154] Alternatively, the side chain at position 1 of cyanosafracin B can be removed by Edman degradation, followed by condensation or alkylation of the resulting primary amine, allowing the length of the alkyl chain of A in formula (1) to be adjusted or a structure in which A is a single bond to be obtained. After removal, side chains with various functional groups can be introduced in the same manner as above.

[0155] (iii) Modification of the substituents on the THIQ skeleton THIQ skeleton 8th place (R a ) A hydroxyl group can be introduced at the 8-position by phenolating the oxo moiety of p-benzoquinone at the 8-position of the THIQ skeleton of cyanosafracin B. The hydroxyl group introduced at the 8-position can react with the methoxy group at the 9-position of the THIQ skeleton of cyanosafracin B to form a dioxolane ring. The phenolization and dioxolane ring formation can typically be carried out by a photocyclization reaction by irradiation with visible light.

[0156] R 2 , R 4 , R 5 Modification of R 2 , R 4 , R 5 The modifications can be removed using methods well known in the art. For example, R 4 In the case of the above, any substituted alkyl group, alkenyl group, alkynyl group, or aryl group can be introduced by reacting an electrophile with the phenolic hydroxyl group. For example, R 5 Regarding the iminium cation, the addition of a nucleophile after the addition of an acid can lead to the construction of thioether, aminal, and hemiaminal structures.

[0157] (2) Macrocyclic structure formation step The formation of the macrocyclic structure in (2) above can typically be achieved by ring-closing olefin / alkyne metathesis or enyne metathesis cyclization using a ruthenium catalyst, such as the Grubbs catalyst, or a tungsten catalyst. Alternatively, the formation of the macrocyclic structure can also be achieved by a three-component ligation reaction of an amine, an alkyne, and an aldehyde / ketone using a copper catalyst.

[0158] (2-1) Intramolecular cyclization (i) Ring-closing olefin metathesis reaction and enyne metathesis cyclization In some embodiments, there is provided a production method comprising subjecting a compound of formula (II) to a ring-closing olefin / alkyne metathesis reaction or an enyne metathesis reaction using a ruthenium catalyst, such as a Grubbs catalyst, or a tungsten catalyst to obtain a compound of formula (I). [ka] In this embodiment, A, X 1 , Y 1 , Y 2 , R a , R 1 , R 2 , R 3 , and R 5 is as defined in formula (II), and the definitions and preferred embodiments described above for formula (II) apply as they are. 4 is a protecting group for a phenolic hydroxyl group. In this embodiment, M 1 and M 2 The combination is one of the following (i) to (iii). (i)M 1 is an optionally substituted alkenyl group, and M 2 is an optionally substituted alkynyl group. (ii) M 1 is an optionally substituted alkynyl group, and M 2 is an optionally substituted alkenyl group. (iii)M 1 is an optionally substituted alkenyl group, and M2 is an optionally substituted alkenyl group. X 2 is M 1 and M 2 is the corresponding group formed by reaction of

[0159] In case (i), M 1 The double bond and M 2 A ring-closing ene metathesis reaction occurs between the triple bond of X 2 -L 1 -CR f =CR f -C(=CR f 2)-L 2 -structure is formed. 1 is X 1 M other than double bond 1 It is the origin of L 2 is Y 2 M other than triple bond 2 It is the origin of R f are substituents at the double bond and triple bond portions, respectively. Therefore, the production method is 2 Ga-L 1 -CR f =CR f -C(=CR f 2)-L 2 For example, examples of the compound of formula (II) in case (i) include Example Compounds 10 and 30 described later.

[0160] In the case of (ii), M 1 triple bond and M 2 A ring-closing ene-metathesis reaction occurs between the double bond of X 2 -L 1 -C(=CR f 2)-CR f =CR f -L 2 -structure is formed. 1 is X 1 M other than triple bond 1 It is the origin of L 2 is Y 2M other than double bond 2 It is the origin of R f are substituents at the double bond and triple bond portions, respectively. Therefore, the production method is 2 Ga-L 1 -C(=CR f 2)-CR f =CR f -L 2 -

[0161] In the case of (iii), M 1 The double bond and M 2 A ring-closing olefin metathesis reaction occurs between the double bond of X 2 -L 1 -CR f =CR f -L 2 -structure is formed. 1 is X 1 M other than double bond 1 It is the origin of L 2 is Y 2 M other than double bond 2 It is the origin of R f are substituents at the double bond and triple bond portions, respectively. Therefore, the production method is 2 Ga-L 1 -CR f =CR f -L 2 For example, an example of the compound of formula (II) in case (iii) is example compound 5 described later.

[0162] In some embodiments, there is provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method comprising any one of the following steps (A) to (C):

[0163] Step (A): A compound represented by the following formula (IIc) is subjected to a ring-closing olefin / alkyne metathesis reaction or an enyne metathesis reaction using a ruthenium catalyst or a tungsten catalyst, such as a Grubbs catalyst, to obtain a compound represented by formula (Ic). [ka]

[0164] Step (B): A compound represented by the following formula (IId) is subjected to a ring-closing olefin / alkyne metathesis reaction or an enyne metathesis reaction using a ruthenium catalyst or a tungsten catalyst, such as a Grubbs catalyst, to obtain a compound represented by formula (Id). [ka]

[0165] Step (C): A compound represented by the following formula (IIe) is subjected to a ring-closing olefin / alkyne metathesis reaction or an enyne metathesis reaction using a ruthenium catalyst, such as a Grubbs catalyst, or a tungsten catalyst to obtain a compound represented by formula (If). [ka]

[0166] In the above steps (A) to (C), X 1a , X 1b , X 1c , X 1d , X 2a , L X2a , L X2b , L X2c , Y 1 , Y 2a , L Y2a , L Y2b , L Y2c , R 4 , R 5and Me have the same meanings as those described in the above formulae (IIc) to (IIe) and formulae (Ic) to (If), and the definitions and preferred embodiments described above with respect to the above formulae (IIc) to (IIe) and formulae (Ic) to (If) apply as they are. 4 represents a protecting group for a phenolic hydroxyl group.

[0167] In the above reaction, the Grubbs catalyst can be either a ruthenium catalyst, such as the first-generation Grubbs catalyst or the second-generation Grubbs catalyst, or a tungsten catalyst that can be used for alkyne-type substrates. Furthermore, new catalysts derived from the first-generation Grubbs catalyst or the second-generation Grubbs catalyst, such as Grubbs Catalyst (registered trademark) M101: dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II), can also be used. The reaction is typically carried out in a reaction solvent such as an aromatic hydrocarbon solvent such as toluene, benzene, or xylene, or dichloroethane or dichloromethane, etc. The reaction temperature is usually 0 to 100°C, preferably 20 to 60°C, and the reaction time is usually 1 to 48 hours.

[0168] (ii) Three-component ligation reaction of amines, alkynes, and aldehydes In some embodiments, a method is provided that includes reacting a compound represented by formula (II) with an aldehyde or ketone in the presence of a copper catalyst to obtain a compound represented by formula (I). [ka] In this embodiment, A, X 1 , Y 1 , Y 2 , R a , R 1 , R 2 , R 3 , R 5 , and R f is as defined in the above formula (II) and formula (I). 4is a protecting group. In this embodiment, M 1 and M 2 The combination is, for example, any one of the following (i) to (ii). (i)M 1 is NHR b or optionally substituted alkylene-N(R b )2 and M 2 is an optionally substituted alkynyl group. (ii) M 1 is an optionally substituted alkynyl group, and M 2 is NHR b or optionally substituted alkylene-N(R b )2. X 2 is M 1 and M 2 is the corresponding group formed by reaction of

[0169] In case (i), M 1 The amino group (-NHR b ) and M 2 Alkynyl group and aldehyde (HCOR f ) undergoes a three-component ligation reaction with X 2 Ga-L 1 -NR b -CR f 2-M 2 The resulting structure is an alkynylene-derived L 1 is a single bond or M 1 Therefore, the production method is a method for producing a compound of formula (I) in which X 2 Ga-L 1 -NR b -CR f 2-C≡CL 2 For example, an example of the compound of formula (II) in case (i) is example compound 26 described later.

[0170] In the case of (ii), M 1 Alkynyl group (triple bond) of M 2 The amino group (-NHRb ) and aldehydes (HCOR f ) undergoes a three-component ligation reaction with X 2 Ga-M 1 Alkynylene derived from -CHR f -NR b -L 2 - is formed. 2 is a single bond or M 2 Therefore, the production method is a method for producing a compound of formula (I) in which X 2 Ga-L 1 -C≡C-CR f 2-NR b -L 2 -

[0171] In some embodiments, there is provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method comprising the step (E) of: Step (E): A production method comprising reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst to obtain a compound represented by formula (Ig): [ka]

[0172] In the above step (E), X 1c , X 1d , L X2a , L X2b , L X2c , Y 1 , Y 2 , L Y2a , R 4 , R 5 and Me have the same meanings as those described in the above formulae (IIf) and (Ig), and the definitions and preferred embodiments described above with respect to the above formula (IIf) apply as they are. 4 represents a protecting group for a phenolic hydroxyl group.

[0173] In the above reaction, the copper catalyst may be any that is used in a three-component linking reaction, and for example, copper (I) halide such as CuBr can be used. The reaction is typically carried out in a reaction solvent such as dimethyl dicarbonate, toluene, etc. The reaction temperature is usually 0 to 100° C., preferably 20 to 60° C., and the reaction time is usually 1 to 48 hours.

[0174] (2-2) Intermolecular cyclization The macrocyclic structure in the dimeric compound of formula (III) is formed by using two compounds represented by formula (II) and combining M at the 1-position of the THIQ skeleton of the first compound (II). 1 and M at the 5-position of the THIQ skeleton of the second compound (II). 2 and M at the 5-position of the THIQ skeleton of the first compound (II). 2 and M at the 1-position of the THIQ skeleton of the second compound (II). 1 By reacting the two compounds with each other, the two compounds are linked by two linking groups X 2 The structure is formed by connecting the two via the Such macrocyclic structures can also be formed from two compounds of formula (II) using a copper-catalyzed three-component ligation reaction of an amine, an alkyne, and an aldehyde.

[0175] In some embodiments, there is provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method comprising the step (F) of: Step (F): A production method comprising reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst and a ligand to obtain a compound represented by formula (IIIc): [ka]

[0176] In the above step (F), X 1c , X 1d , L X2a , L X2b , LX2c , Y 1 , Y 2 , L Y2a , R 4 , R 5 and Me have the same meanings as those described in the above formulae (IIf) and (IIIc), and the definitions and preferred embodiments described above with respect to the above formula (IIf) apply as they are. 4 represents a protecting group for a phenolic hydroxyl group.

[0177] The copper catalyst may be any catalyst that is used in a three-component coupling reaction, and for example, copper (I) halide such as CuBr can be used. Examples of the ligand include bulky ligands such as (R,M)-PINAP and Pybox (Pyridine-2,6-bis(oxazolines))-based ligands. The reaction is typically carried out in a reaction solvent such as dimethyl dicarbonate, toluene, etc. The reaction temperature is usually 0 to 100° C., preferably 20 to 60° C., and the reaction time is usually 1 to 48 hours.

[0178] Alternatively, two compounds of formula (II) can be subjected to a ring-closing metathesis reaction in the presence of a Grubbs catalyst to give a dimer compound, under the same reaction conditions as those for the ring-closing metathesis reaction of formula (I).

[0179] (3) Modifying the Macrocyclic Structure After the formation of the macrocyclic structure, if necessary, a functional group contained in the macrocyclic structure that can be modified can be used, or a functional group that can be modified can be introduced into the macrocyclic structure, and the functional group can be used to change the substituent or structure, thereby producing compounds having a variety of macrocyclic structures.

[0180] (3-1) [4+2] Cycloaddition Reactions with Dienophiles In some embodiments, in formula (I) above, X 2 Ga-L 1 -C(=CR f 2)-CR f=CR f -L 2 -or-L 1 -C(=CR f 2)-CR f =CR f -L 2 - a compound of the formula: Z 1 =Z 2 By adding a dienophile represented by the formula (I) by a [4+2] cycloaddition reaction, X 2 Thus, in this step, a compound having a cyclic structure represented by the following formula (I) (z1) or (z2) is obtained. 2 is a group represented by the following (z1) or (z2):

[0181] [ka] Z 1 , Z 2 , L 1 and L 2 is defined as in the above formula (1).

[0182] In one embodiment, the dienophile is a substituted maleimide or a substituted 1,2,4-triazoline-3,5-dione, which can be converted to X in formula (I) above by a [4+2] cycloaddition reaction. 2 but [ka] A compound is obtained which is

[0183] In some embodiments, there is provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method comprising the step (D) of:

[0184] Step (D): Reacting the compound represented by formula (Id) with the compound represented by formula (IVa) to obtain the compound represented by formula (Ie). [ka]

[0185] In the above step (D), X 1a , X 1b , X 1c , X 1d , X 2a , L X2c , Y 1 , Y 2 , L Y2a , L Y2b , L Y2c , R 4 , R 5 , R 8 、 Z 1 、 Z 2 and Me have the same meanings as those described in the above formulae (Id) and (Ie), and the definitions and preferred embodiments described above with respect to the above formulae (Id) and (Ie) apply as they are. 4 represents a protecting group for a phenolic hydroxyl group.

[0186] The conditions for the [4+2] cycloaddition reaction using a dienophile are not particularly limited. Typically, the reaction is carried out in a reaction solvent such as dichloromethane, dichloroethane, or tetrahydrofuran (THF). The reaction temperature is usually 0 to 100°C, preferably 20 to 60°C, and the reaction time is usually 1 to 48 hours.

[0187] (3-2) CO2 elimination from carbamate In some embodiments, a compound having a modified cyclic structure of the macrocycle can be obtained by elimination of CO from the carbamate group. For example, in the above formula (I), X 1 But, -NR b C(O)O- or -OC(O)NR b - and compounds of the formula (I) where Y 2 But, -NR b C(O)O- or -OC(O)NR b - (compound having a carbamate group) to form a compound represented by the formula (I) represented by X 1 But, -NR b -or-NR b- and compounds of the formula (I) where Y 2 But, -NR b -or-NR b - is obtained.

[0188] In some embodiments, there is provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method comprising the step (G) of: Step (G): In the above formula (Ia), L 3 is -OC(O)- (where L 3 The carbon atom of formula (Ia) is NX 1c and obtaining a compound of formula (Ii) by elimination of CO2 from the compound (which is bonded to the nitrogen atom of formula (Ii)). [ka] In the above step (G), X 1c , X 1d , X 2 , Y 1 , Y 2 , R 4 and Me are the same as those described above with respect to the definitions and preferred embodiments of formula (Ia). 3 is -OC(O)- (where L 3 The carbon atom of formula (Ia) is NX 1c (bonded to the nitrogen atom of

[0189] In some embodiments, there is provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, the method comprising the following step (H): In step (H), C(═O)O (i.e., C(═X)) constituting the macrocyclic structure is reacted with C(═O)O (i.e., C(═X)). 1b )X 1a The part corresponding to Step (H): In the above formula (Ic), X 1a and X 1b is an oxygen atom (O) by elimination of CO2 to obtain a compound of formula (Ih). [ka] In the above step (H), X 1c , X 1d , X 2a , L X2c , Y 1 , Y 2 , L Y2c , R 4 , R 5 and Me have the same meanings as those described in the above formulae (Ic) and (Ih), and the definitions and preferred embodiments described above with respect to the above formulae (Ic) and (Ih) apply as they are. 1a and X 1b represents an oxygen atom (O).

[0190] The reaction conditions for the elimination of CO from the carbamate are not particularly limited. Typically, the reaction is carried out in a reaction solvent such as toluene, dichloromethane, dichloroethane, or tetrahydrofuran (THF) in the presence of a zero-valent palladium catalyst and, if necessary, a ligand such as a phosphine. The reaction temperature is usually 0 to 100°C, preferably 20 to 60°C, and the reaction time is usually 1 to 48 hours. The zero-valent palladium catalyst is not particularly limited, but examples include tris(dibenzylideneacetone)dipalladium (Pd(dba)), tetrakis(triphenylphosphine)palladium (Pd(PPh)), palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium trifluoroacetate, bis(triphenylphosphine)palladium diacetate, bis(tri-o-tolylphosphine)palladium dichloride, [1,2-bis(diphenylphosphino)ethane]palladium dichloride, and combinations thereof. Phosphine ligands include triphenylphosphine (PPh3), tri-tert-butylphosphine, SEGPHOS®, or combinations thereof.

[0191] (4) Deprotecting the protecting group Any protecting groups introduced during the course of the reaction, such as nitrogen or phenolic hydroxyl protecting groups, may be removed at a subsequent convenient stage using methods well known in the art. For example, when a tert-butyloxycarbonyl group is used as the nitrogen-protecting group, deprotection is preferably carried out under acidic conditions, and examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, and tosylic acid. For example, when an acyl protecting group is used as the protecting group for a phenolic hydroxyl group, deprotection can be carried out under reducing conditions (e.g., in the presence of a reducing agent such as DIBAL (diisobutylaluminum hydride) or LAH (lithium aluminum hydride)) or basic conditions (e.g., in the presence of NaOH or KCO / MeOH).

[0192] In one embodiment, a compound of formula (I) without a protecting group is obtained by deprotecting the protecting group contained in the compound of formula (I). In one embodiment, the protecting group contained in the compound of formula (IIIc) is deprotected to provide a compound of formula (IIIc) that does not contain the protecting group.

[0193] As described above, the intermediate compound represented by formula (II) can be suitably used in the synthesis of the macrocyclic structure-containing THIQ alkaloid compound of formula (I). Therefore, in another aspect, the present invention encompasses a method for producing a DNA alkylating agent or anticancer agent having a tetrahydroisoquinoline skeleton using the intermediate compound represented by formula (II). Similarly, in yet another aspect, the present invention also encompasses the use of the intermediate compound represented by formula (II) for producing a DNA alkylating agent or anticancer agent having a tetrahydroisoquinoline skeleton. As described above, the compound represented by formula (II) can be suitably used for synthesizing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure. Therefore, according to one aspect of the present invention, there is also provided a method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure using the compound represented by formula (II).

[0194] (5) Other intermediate compounds In some embodiments, in the above formula (I), X 2Ga-L 1 -C(=CR f 2)-CR f =CR f -L 2 -or-L 1 -CR f =CR f -C(=CR f 2)-L 2 -. Such compounds can be prepared by the method (i) or (ii) in Scheme 1 above. Compounds of this type have a partial structure -C(=CR) in the macrocyclic structure. f 2)-CR f =CR f By utilizing this partial structure, compounds having a variety of macrocyclic structures can be produced.

[0195] Hereinafter, in formula (I), -L 1 -C(=CR f 2)-CR f =CR f -L 2 Specific examples of intermediate compounds containing a macrocyclic structure are shown below. [ka] [Example]

[0196] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. In this specification, "room temperature" generally refers to about 10° C. to about 35° C. "%" refers to percent by weight unless otherwise specified. As used herein, the term "about" can mean ±10%.

[0197] The abbreviations used in the examples are conventional abbreviations well known to those skilled in the art. Some abbreviations are listed below. rt: room temperature Me: Methyl Et: Ethyl iPr: Isopropyl Ac: Acetyl AcOH: acetic acid MeOH: Methanol Ph: Phenyl MOM: methoxymethyl TBS: tert-butyldimethylsilyl TBAF: tetra-n-butylammonium fluoride Boc: tert-butoxycarbonyl Ns: 2-nitrobenzenesulfonyl Alloc: Allyloxycarbonyl Alloc-OSu:N-(allyloxycarbonyloxy)succinimide DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: dimethylformamide THF: tetrahydrofuran hexane Acetone: Acetone toluene: toluene hv: Light irradiation HPLC: High-performance liquid chromatography Grubbs II: Second-generation Grubbs catalyst (benzylidene{1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene}dichloro(tricyclohexylphosphine)ruthenium) Grubbs I: First generation Grubbs catalyst (benzylidenebis(tricyclohexylphosphine)dichlororuthenium) Grubbs cat. M101: Dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II) PCy3: Tricyclohexylphosphine reflux Allyl: Allyl PINAP: (R)-(+)-4-[2-(diphenylphosphino)-1-naphthalenyl]-n-[-1-phenylethyl]-1-phthalazinamine dba: dibenzylidene acetone

[0198] [Reagents, equipment, etc.] All reactions were carried out under a nitrogen atmosphere unless otherwise noted. NMR spectra were obtained using a JEOL JNM-ECA 500 ( 1 H / 500MHz, 13 C / 125MHz) spectrometer, Bruker VSP 500 ( 1 H / 500MHz, 13 C / 125MHz) spectrometer, Bruker AMX500( 1 H / 500MHz, 13 C / 125 MHz) spectrometer and JEOL JNM-ECS400( 1 H / 400MHz, 13 C / 100 MHz) spectrometer was used. 1 H, 13 Chloroform, acetonitrile, and dimethyl sulfoxide were used as internal standards for C-NMR. 1 H-NMR data are reported as chemical shifts (number of hydrogen atoms, multiplicity, and coupling constants). Multiplicities are reported as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), and br (broad). ESI-mass spectra were obtained using a Bruker Daltonics microTOF-QII. [Example]

[0199] 1. Synthesis of Compound 7 of the Present Invention Using the scheme shown below, we synthesized compound 7, a macrocyclic THIQ compound of the present invention, in six steps from the readily available natural product cyanosafracin B (compound 1). First, compound 3 was sequentially treated with Alloc-OSu and MOMBr to protect the terminal amino and phenolic hydroxyl groups. Photocyclization proceeded with visible light irradiation to yield phenolic compound 4. Without isolating this, compound 5 was obtained by treating it with allyl bromide. Compound 6 was synthesized by constructing the macrocyclic ring using a ring-closing olefin metathesis reaction using a second-generation Grubbs catalyst. The MOM group was removed using trifluoroacetic acid to yield compound 7. The reaction conditions for each step are described below.

[0200] [ka]

[0201] [Synthesis of Compound 2] [ka]

[0202] To a solution of cyanosafracin B (1) (70.0 mg, 0.127 mmol) in CHCl (1.27 mL, 0.10 M), Alloc-OSu (23.6 μL, 0.153 mmol, 1.2 equiv.) and NEt (26.6 μL, 0.191 mmol, 1.5 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 50 min. The mixture was then diluted with CHCl (30 mL) and quenched with saturated aqueous NHCl (20 mL). The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl (40 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give 2 (70.9 mg, 0.112 mmol, 88% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3, δ): 0.97 (3H, d, J = 6.3 Hz), 1.77 (1H, dd, J = 16.9, 11.2 Hz), 1.86 (5H, m), 2.28 (3H, s), 2.36 (3H, s), 2.43 (1H, d, J = 18.3 Hz), 2.95 (1H, dt, J = 14.1, 3.3 Hz), 3.04 (1H, dd, J = 18.3, 3.4 Hz), 3.13 (2H, dd, J = 18.0, 7.7 Hz), 3.23 (1H, dt, J = 10.9, 2.9 Hz), 3.38 (1H, d, J = 8.0 Hz), 3.76 (3H, s), 3.80-3.86 (2H, m), 4.00 (4H, m), 4.19 (1H, d, J = 1.7 Hz), 4.43 (2H, m), 4.84 (1H, d, J = 6.9 Hz), 5.03 (1H, d, J = 7.4 Hz), 5.18-5.28 (2H, m), 5.86 (1H, m), 6.27 (1H, s), 6.52 (1H, s).

[0203] [Synthesis of compound 3]

change

[0204] To a solution of compound 2 (156 mg, 0.247 mmol) in MeCN (2.3 mL, 0.11 M), iPrNEt (DIPEA, 633 μL, 3.70 mmol, 15 equiv.), DMAP (3.0 mg, 0.0247 mmol, 0.10 equiv.), and MOMBr (193 μL, 2.47 mmol, 10 equiv.) were added under ice-cooling. The mixture was stirred at 40 °C for 4 h. The reaction was quenched with 200 mM NaHPO·NaOH buffer (pH 7.0, 15 mL), and MeCN was removed under reduced pressure. Water (10 mL) was added, followed by extraction with CHCl (30 mL × 3). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 3 (157 mg, 0.231 mmol, 94% yield) as a yellow solid. 1 H NMR (500 MHz, CDCl3, δ): 1.00 (3H, d, J = 5.7 Hz), 1.87 (3H, s), 2.25 (4H, s), 2.35 (3H, s), 2.46 (1H, d, J = 18.3 Hz), 3.01-3.23 (5H, m), 3.40 (1H, d, J = 8.8 Hz), 3.58 (3H, s), 3.71 (3H, s), 3.88 (2H, m), 4.00-4.02 (4H, m), 4.26 (1H, d, J = 2.3 Hz), 4.36-4.43 (2H, m), 4.77 (1H, br), 5.14-5.17 (3H, m), 5.19-5.30 (3H, m), 5.82 (1H, m ), 6.74 (1H, s).

[0205] [Synthesis of Compound 5] [ka]

[0206] A solution of compound 3 (156 mg, 0.230 mmol) in CHCl (10 mL, 0.10 M) was stirred at room temperature for 7.5 hours under visible light irradiation using a 12 W household light bulb. The reaction solution was concentrated under reduced pressure. The crude residue was used in the next reaction without purification. To a solution of crude compound 4 in DMF (11.5 mL, 0.020 M), Cs2CO3 (300 mg, 0.920 mmol, 4.0 equiv.) and allyl bromide (26.6 μL, 0.191 mmol, 1.5 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 1.5 h. After filtration, the mixture was diluted with CHCl2 (50 mL) and 200 mM NaH2PO4·NaOH buffer (pH 7.0, 20 mL) was added. The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl2 (30 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 5 (98.9 mg, 0.138 mmol, two-step yield 60%) as a brown solid. 1 H NMR (500 MHz, CDCl3, δ): 0.86-0.92 (4H, m), 1.85 (1H, dd, J = 16.0, 12.1 Hz), 2.11 (3H, s), 2.22 (3H, s), 2.32 (3H, s), 2.64 (1H, d, J = 17.8 Hz), 3.03 (1H, dd, J = 18.3, 8.0 Hz), 3.22-3.25 (2H, m), 3.39 (1H, d, J= 6.9 Hz), 3.49-3.60 (6H, m), 3.69-3.78 (4H, m), 4.02 (1H, s), 4.08-4.12 (2H, m), 4.19-4.23 (2H, m), 4.43 (2H, d, J = 5.2 Hz), 5.08-5.41 (10H, m), 5.79-5.86 (2H, m), 5.96 (1H, d, J = 1.7 Hz), 6.06-6.14 (1H, m), 6.71 (1H, s).

[0207] [Synthesis of Compound 6] [ka]

[0208] A solution of Grubbs second-generation catalyst (13.5 mg, 15.9 μmol, 0.20 equiv.) in CHCl (30 mL) was freeze-degassed and heated to reflux, followed by the addition of a solution of compound 5 (57.2 mg, 79.7 μmol) in CHCl (9.8 mL, final concentration 2.0 mM). The mixture was heated to reflux for 2.5 h and then concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography (hexane / AcOEt) and an HPLC system (water / MeCN) to give compound 6 (17.5 mg, 25.4 μmol, 32% yield) as a brown oil. 1 H NMR (500 MHz, DMSO-d6, δ): 1.05-1.12 (3H, m), 1.80 (1H, dd, J = 15.5, 12.0 Hz), 2.05-2.10 (3H, m), 2.21 (6H, m), 2.67 (1H, d, J = 18.3 Hz), 2.90-2.94 (1H, m), 2.98-3.10 (7H, m), 3.33- 3.42 (2H, m), 3.57 (3H, m), 3.79-3.86 (4H, m), 4.13 (1H, m), 4.34-4.41 (2H, m), 4.68 (1H, dd, J = 12.9, 5.4 Hz), 5.07 (1H, d, J= 5.7 Hz), 5.19 (1H, d, J = 5.2 Hz), 5.50-5.65 (2H, m), 5.96 (1H, s), 6.00 (1H, s), 6.68 (2H, m). 13 C NMR (125 MHz, DMSO-d6, δ): 13C NMR (126 MHz, DMSO-D6) δ 9.2, 13.6, 15.2, 17.1, 20.1, 24.2, 26.3, 49.4, 54.1, 55.7, 56.1, 56.2, 56.5, 58.1, 59.2, 62.1, 71.3, 98.3, 100.7, 111.4, 112.7, 117.6, 121.6, 123.3, 124.3, 128.1, 129.2, 129.5, 130.0, 138.0, 143.8, 145.6, 147.7, 153.9, 171.1.

[0209] [Synthesis of Compound 7] [ka]

[0210] To a solution of compound 6 (5.93 mg, 8.60 μmol) in CHCl (1.0 mL, 8.6 mM), trifluoroacetic acid (26.3 μL, 344 μmol, 40 equiv.) was added under ice-cooling. After stirring at room temperature for 12.5 h, the mixture was diluted with CHCl (10 mL) and saturated aqueous NaHCO (10 mL) was added. The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl (10 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by HPLC (water / MeCN) to give compound 7 (4.89 mg, 8.60 μmol, 88% yield) as a colorless oil. 1H NMR (500 MHz, DMSO-d6, δ): 1.02 (3H, d, J = 7.4 Hz), 2.09 (3H, s), 2.17 (3H, s), 2.22 (3H, s), 3.30 (1H, d, J = 8.6 Hz), 3.72 (3H, s), 3.86-3.89 (2H, m), 4.11 (1H, s), 4.37-4.43 (2H, m), 4.52 (1H, s), 4.83 (1H, s), 5.42-5.54 (2H, m), 5.84-5.88 (1H, m), 5.96 (2H, d, J = 17.2 Hz), 6.43 (1H, s), 6.64 (1H, s). [Example]

[0211] 2. Synthesis of Compounds 13, 14, 16, and 18 of the Present Invention Using the scheme shown below, compounds 13 and 14 were synthesized in six steps from the natural product cyanosafracin B (compound 1), and compounds 16 and 18 were synthesized in seven steps. First, compound 8 was prepared by sequentially protecting the terminal amino and phenolic hydroxyl groups with Alloc-OSu and TBSCl. Visible light irradiation then induced photocyclization to give phenolic compound 9. Without isolating this, compound 10 was obtained by treatment with propargyl bromide. Compounds 11 and 12 were synthesized by constructing a macrocycle via ring-closing enyne metathesis using the first-generation Grubbs catalyst. Compounds 13 and 14 were obtained by removal of the TBS group using TBAF. Compound 12 underwent a [4+2] cyclization reaction, followed by removal of the TBS group, to give compounds 16 and 18. The reaction conditions for each step are described below.

[0212] [ka] [ka]

[0213] [Synthesis of Compound 8] [ka]

[0214] To a solution of 2 (45.0 mg, 71.0 μmol) in CHCl (0.19 mL, 0.10 M), NEt (198 μL, 1.42 mmol, 20 equiv.), DMAP (1.74 mg, 14.2 μmol, 0.20 equiv.), and TBSCl (107 mg, 710 μmol, 10 equiv.) were added at room temperature. The mixture was stirred at room temperature for 23 h. Water (30 mL) was added, followed by extraction with CHCl (30 mL × 3). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 8 (39.8 mg, 53.2 μmol, 75% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3, δ): 0.11 (3H, s), 0.35 (3H, s), 1.11-1.02 (12H, m), 1.88 (3H, s), 2.26 (3H, s), 2.39-2.45 (4H, m), 2.99-3.21 (5H, m), 3.37 (1H, d, J = 7.8 Hz), 3.56 (3H, s), 3.73-4.04 (7H, m), 4.25 (1H, d, J = 2.7 Hz), 4.36-4.48 (2H, m), 4.79 (1H, s), 5.17-5.27 (3H, m), 5.82 (1H, m), 6.60 (1H, s); HRMS (ESI, m / z): [M+H] + calcd. for C 39 H 54 N5O8Si, 748.3736; found, 748.3765.

[0215] [Synthesis of Compound 10] [ka]

[0216] A solution of 8 (12.6 mg, 16.8 μmol) in freeze-degassed THF (3.9 mL, 0.10 M) was stirred at room temperature under blue light for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the crude residue was used in the next reaction without further purification. To a solution of crude compound 9 in DMF (0.34 mL, 0.050 M) were added Cs2CO3 (21.9 mg, 67.2 μmol, 4 equiv.) and propargyl bromide (3.80 μL, 50.4 μmol, 3.0 equiv.). The mixture was stirred at room temperature for 18 h. After concentration under reduced pressure, water (30 mL) was added and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 10 (9.14 mg, 11.6 μmol, 63% yield in two steps) as a yellow solid. 1 H NMR (400 MHz, CDCl3, δ): 0.10 (3H, s), 0.36 (3H, s), 0.91-0.99 (2H, m), 1.08 (9H, s), 1.80-1.89 (2H, m), 2.14 (3H, s), 2.23 (3H, s), 2.35 (3H, s), 2.43 (1H, t, J = 2.3 Hz), 2.52-2.59 (1H, m), 3.04 (1H, q, J = 8.7 Hz), 3.21-3.25 (2H, m), 3.33-3.45 (3H, m), 3.60 (3H, m), 4.01-4.13 (2H, m), 4.18-4.36 (2H, m), 4.41 (2H, d, J = 5.0 Hz), 4.51 (1H, d, J = 15.6 Hz), 5.13-5.31 (4H, m), 5.75-5.86 (2H, m), 5.94 (1H, s), 6.57 (1H, s); HRMS (ESI, m / z): [M+H] + calcd. for C 42 H 56N5O8Si, 786.3893; found, 786.3907.

[0217] [Synthesis of compounds 11 and 12] [ka]

[0218] To a solution of compound 10 (51.9 mg, 66.0 μmol) in CHCl (6.6 mL, 0.10 M) was added Grubbs first-generation catalyst (10.9 mg, 13.2 μmol, 0.20 equiv.). The mixture was heated under reflux for 22 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl / acetone) to give compounds 11 (E-isomer, 16.6 mg, 21.1 μmol, 32% yield) and 12 (Z-isomer, 15.1 mg, 19.2 μmol, 29% yield), respectively, as white solids. 11: 1 H NMR (400 MHz, DMSO-d6, δ): 0.08 (3H, s), 0.33 (3H, s), 1.04 (11H, m), 1.13 (3H, d, J = 7.3 Hz), 1.80-1.86 (1H, m), 2.04 (3H, s), 2.19 (3H, s), 2.26 (3H, s), 2.59 (1H, m), 3.00 (2H, m), 3.32-3.38 (2H, m), 3.45-3.63 (4H, m), 3.84 (1H, m), 4.00-4.28 (3H, m), 4.43-4.53 (2H, m), 4.63 (1H, br), 5.02 (1H, br), 5.37 (1H, s), 5.50 (1H, s), 5.96-6.09 (3H, m), 6.63 (1H, s), 6.90 (1H, br); HRMS (ESI, m / z): [M-CN] + calcd. for C 41 H 55 N4O8Si, 759.3784; found, 759.3771. 12: 1H NMR (400 MHz, DMSO-d6, δ): 0.08 (3H, s), 0.34 (3H, s), 1.03 (13H, m), 2.08 (3H, s), 2.16 (3H, s), 2.24 (3H, s), 2.56 (1H, d, J = 18.3 Hz), 2.89-3.00 (4H, m), 3.31-3.50 (7H, m), 3.88 (1H, s), 4.04-4.21 (2H, m), 4.40 (1H, s), 4.65 (1H, br), 4.83 (1H, br), 5.04 (1H, br), 5.34 (1H, m), 5.52 (1H, s), 5.71 (1H, d, J = 1.1 Hz), 5.99 (2H, m), 6.13 (1H, d, J = 11.0 Hz), 6.61 (1H, s), 7.01 (1H, br); HRMS (ESI, m / z): [M+H] + calcd. for C 42 H 56 N5O8Si, 786.3893; found, 786.3887.

[0219] [Synthesis of Compound 13] [ka]

[0220] To a solution of compound 11 (6.14 mg, 7.81 μmol) in THF (0.78 mL, 0.010 M), a mixed solution of TBAF (1 M THF solution, 23.4 μL, 23.4 μmol, 3.0 equiv.) and AcOH (1.34 μL, 23.4 μmol, 3.0 equiv.) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 13 (4.69 mg, 6.98 μmol, 89% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6, δ): 1H NMR (400 MHz, DMSO-d6, δ): 1.09 (1H, d, J= 6.9 Hz), 1.86 (1H, dd, J = 15.6, 11.9 Hz), 1.99-2.20 (5H, m), 2.55 (1H, m), 2.90-3.15 (3H, m), 3.29-3.36 (2H, m), 3.50-3.64 (4H, m), 3.83 (1H, d, J= 4.6 Hz), 4.02-4.63 (5H, m), 5.08 (1H, m), 5.45 (3H, m), 5.72 (1H, d, J= 1.4 Hz), 5.98 (2H, m), 6.17 (1H, d, J = 15.6 Hz), 6.43 (1H, s), 6.84 (1H, s), 8.44 (1H, s); 13 C NMR (100 MHz, DMSO-d6, δ): 10.1, 15.2, 24.5, 25.9, 40.8, 50.2, 54.3, 54.5, 54.9, 56.0, 56.5, 58.2, 59.7, 63.9, 71.6, 100.9, 111.0, 113.3, 117.4, 118.0, 119.3, 119.7, 121.9, 124.8, 128.3, 130.1, 132.0, 138.0, 142.1, 143.3, 143.8, 147.4, 154.2, 171.9; HRMS (ESI, m / z): [M-CN] + calcd. for C 35 H 41 N4O8, 645.2919; found, 645.2920.

[0221] [Synthesis of compound 14]

change

[0222] To a solution of compound 12 (15.5 mg, 19.7 μmol) in THF (2.0 mL, 0.010 M), TBAF (1 M THF solution, 59.2 μL, 59.2 μmol, 3.0 equivalents) was added. The mixture was stirred at room temperature for 1 hour and 20 minutes and then concentrated under reduced pressure. The crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 14 (4.24 mg, 6.31 μmol, 32% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6, δ): 0.99 (3H, d, J = 6.9 Hz), 2.05-2.08 (4H, m), 2.12-2.14 (6H, m), 2.54 (1H, s), 2.80-3.08 (4H, m), 3.25-3.55 (3H, m), 3.61 (3H, s), 3.87 (1H, s), 4.02-4.09 (2H, m), 4.23-4.39 (2H, m), 4.56 (1H, d, J = 13.3 Hz), 4.82 (1H, br), 5.09 (1H, s), 5.34-5.41 (1H, m), 5.45-5.67 (2H, m), 5.95-6.00 (2H, m), 6.20 (1H, d, J = 11.4 Hz), 6.41 (1H, s), 6.87 (1H, br), 8.35 (1H, s); 13 C NMR (100 MHz, DMSO-d6, δ): 9.4, 15.2, 24.5, 26.6, 40.9, 50.0, 54.2, 55.2, 55.8, 56.1, 58.3, 59.5, 60.0, 74.7, 100.9, 110.2, 113.6, 117.5, 118.0, 119.1, 120.3, 125.2, 128.4, 129.3, 129.8, 133.0, 137.8, 143.4, 147.4, 170.9. [M-CN] + calcd. for C 35 H 41 N4O8, 645.2919; found, 645.2935.

[0223] [Synthesis of Compound 16] [ka]

[0224] To a solution of compound 11 (23.8 mg, 30.3 μmol) in CHCl (0.61 mL, 0.050 M) was added 4-phenyl-1,2,4-triazoline-3,5-dione (S1, 15.9 mg, 90.8 μmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours and 10 minutes and then concentrated under reduced pressure. The crude product was used in the next reaction without further purification. To a solution of crude compound 15 in THF (0.34 mL, 0.050 M), a mixture of TBAF (1 M in THF, 90.9 μL, 90.9 μmol, 3.0 equiv.) and AcOH (5.2 μL, 90.9 μmol, 3.0 equiv.) was added under ice-cooling. After stirring at room temperature for 3 hours, water (10 mL) was added. Extraction was performed with CHCl (20 mL × 3). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by HPLC to give compound 16 (9.01 mg, 10.6 μmol, 35% yield for both steps) as a white solid. 1 H NMR (400 MHz, DMSO-d6, δ): 1.06 (3H, d, J = 6.9 Hz), 1.83-1.98 (4H, m), 2.11-2.25 (7H, m), 2.63 (1H, d, J = 17.4 Hz), 2.78-3.15 (3H, m), 3.25-3.48 (2H, m), 3.55 (3H, s), 3.88 (1H, s), 4.09-4.68 (8H, m), 5.09 (1H, s), 5.71 (1H, d, J = 1.6 Hz), 5.94 (1H, s), 6.03 (1H, s), 6.40 (1H, br), 6.95 (1H, br), 7.37-7.58 (6H, m); 13C NMR (100 MHz, DMSO-d6, δ): 9.4, 15.1, 24.1, 40.8, 44.1, 49.5, 52.5, 54.2, 54.5, 55.8, 58.1, 59.6, 61.8, 100.9, 112.0, 113.0, 117.8, 119.9, 123.6, 125.6, 127.7, 128.3, 128.5, 130.2, 131.2, 138.1, 143.1, 143.8, 146.6, 146.9, 151.5, 171.0; HRMS (ESI, m / z): [M+H] + calcd. for C 44 H 46 N8O 10 , 847.3410; found, 847.3448.

[0225] [Synthesis of compound 17] [ka]

[0226] To a solution of compound 11 (21.3 mg, 29.8 μmol) in CHCl (3.0 mL, 0.010 M) was added N-phenylmaleimide (S2, 51.5 mg, 37.9 μmol, 5.0 equiv.). The mixture was stirred at room temperature for 20 hours and then at 35 °C for 15 hours. After concentration under reduced pressure, the crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified using an HPLC system to give two diastereomers of 17, A (2.11 mg, 2.37 μmol, 8% yield) and B (3.19 mg, 3.59 μmol, 12%), as white solids. The stereochemistry of the three chiral carbon atoms generated in this reaction remains to be determined. A: 1H NMR (400 MHz, DMSO-d6, δ): 0.05 (3H, s), 0.46 (3H, s), 0.85-0.92 (1H, m), 1.03-1.18 (16H, m), 1.25 (3H, s), 2.06-2.23 (16H, m), 2.63-2.88 (4H, m), 3.42-3.63 (2H, m), 3.78 (4H, s), 4.14-4.25 (2H, m), 4.34-4.43 (2H, m), 5.40 (1H, s), 5.70-5.71 (2H, m), 6.02 (2H, m ), 6.58 (1H, s), 7.08-7.17 (2H, m), 7.36-7.55 (4H, m); HRMS (ESI, m / z): [M+H] + calcd. for C 52 H 63 N6O 10 Si, 959.4369; found, 959.4417. B: 1 H NMR (400 MHz, DMSO-d6, δ): 0.06 (3H, s), 0.27 (3H, s), 1.00-1.11 (10H, m), 1.15 (3H, d, J = 6.9 Hz), 2.03-2.29 (11H, m), 2.72-2.98 (4H, m), 3.26-3.38 (2H, m), 3.46 (3H, s), 3.80 (1H, s), 4.07 (1H, s), 4.20-4.32 (1H, m), 4.43 (1H, br), 4.57 (1H, br), 5.43 (1H, br), 5.64 (1H, br), 5.96 (1H, s), 6.03 (1H, s), 6.49 (1H, br), 7.09 (3H, d, J = 7.3 Hz), 7.37-7.56 (3H,m), 7.58-7.77 (1H, m); HRMS (ESI, m / z): [M+H] + calcd. for C 52 H 63 N6O 10 Si, 959.4369; found, 959.4417.

[0227] [Synthesis of compound 18] [ka]

[0228] To a solution of compound 17A (2.11 mg, 2.20 μmol) in THF (0.44 mL, 0.0050 M), TBAF (1 M THF solution, 6.6 μL, 6.6 μmol, 3.0 equiv.) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and then water (10 mL) was added. Extraction was performed with CHCl (10 mL × 3). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified using an HPLC system to give compound 18 (1.02 mg, 1.21 μmol, 55% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3, δ): 1.14 (3H, d, J = 6.9 Hz), 1.36 (1H, m), 2.06 (3H, s), 2.12-2.28(6H, m), 2.35 (1H, br), 2.62-3.10 (7H, m), 3.11-3.24 (4H, m), 3.25-3.64 (4H, m), 3.66-3.96 (8H, m), 4.16 (1H, s), 4.39 (1H, d, J = 1.8 Hz), 4.48 (1H, d, J= 11.4 Hz), 5.28 (1H, s), 5.71 (1H, d, J = 1.4 Hz), 5.97 (1H, s), 6.02 (1H, s), 6.43 (1H, s), 6.68 (1H, br), 7.13-7.19 (2H, m), 7.35-7.52 (4H, m), 8.43 (1H, br); 13C NMR (100 MHz, DMSO-d6, δ): 9.3, 15.3, 18.7, 24.1, 25.5, 27.3, 40.9, 49.6, 53.9, 54.4, 55.1, 56.3, 58.1, 60.4, 100.9, 111.4, 113.1, 119.7, 126.5, 127.8, 127.9, 128.5, 132.1, 136.8, 138.2, 144.2, 146.5, 148.6, 154.0, 171.4, 176.6, 179.0; HRMS (ESI, m / z): [M+H] + calcd. for C 46 H 49 NO 10 , 845.3505; found, 845.3553. [Example]

[0229] 3. Synthesis of Compounds 28 and 29 of the Present Invention Using the scheme shown below, compound 29 was synthesized in 10 steps from the natural product cyanosafracin B (compound 1). First, compound 20 was prepared by sequentially treating it with BocO and AcO, protecting the terminal amino group and phenolic hydroxyl group. Visible light irradiation then induced photocyclization to give phenol compound 21. Without isolating this, compound 22 was treated with propargyl bromide to give compound 22. The Boc group was removed using TFA, and the primary amine was protected with an Ns group to give compound 24. The sulfonamide was methylated using iodomethane, and the Ns group was removed using benzenethiol to give compound 26. A macrocycle was constructed using formaldehyde in the presence of a monovalent copper catalyst to give compound 27. The acetyl group was removed using potassium carbonate to give compound 29. Compound 26 was also synthesized as a dimer using a copper catalyst in the presence of a ligand to give compound 28. The reaction conditions for each step are described in detail below.

[0230] [ka]

[0231] [Synthesis of Compound 19] [ka]

[0232] To a solution of compound 1 (1.00 g, 1.82 mmol) in CHCl (18.2 mL, 0.10 M), BocO (439 μL, 1.91 mmol, 1.05 equiv.) and NEt (634 μL, 4.55 mmol, 2.5 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 2 h and then quenched with saturated aqueous NHCl (10 mL). The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl (30 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl / AcOEt) to give compound 19 (1.06 g, 1.63 mmol, 89% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3, δ): 0.90 (3H, s), 1.33 (9H, s), 1.76 (1H, m), 1.86 (3H, s), 2.09 (1H, m), 2.22-2.33 (6H, m), 2.45 (1H, d, J = 18.3 Hz), 3.03-3.22 (5H, m), 3.37 (1H, d, J= 7.3 Hz), 3.68-3.80 (4H, m), 3.85 (1H, s), 3.97 (3H, s), 4.04 (1H, d, J= 2.3 Hz), 4.17 (1H, d, J = 2.3 Hz), 4.59 (1H, br), 5.24 (1H, br), 6.25 (1H, s), 6.51 (1H, s).

[0233] [Synthesis of compound 20] [ka]

[0234] To a solution of compound 19 (1.05 g, 1.62 mmol) in CHCl (16.2 mL, 0.10 M), NEt (676 μL, 4.85 mmol, 3.0 equiv.) and AcO (229 μL, 2.42 mmol, 1.5 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 2.5 h. After cooling on ice, the mixture was diluted with CHCl (10 mL) and quenched with saturated aqueous NHCl (10 mL). The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl (20 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 20 (1.09 g, 1.57 mmol, 97% yield) as a yellow solid. 1 H NMR (500 MHz, CDCl3, δ): 0.90 (3H, d, J = 4.1 Hz), 1.32 (9H, s ), 1.75 (1H, m), 1.87 (3H, s), 2.21-2.34 (6H, m ), 2.41 (3H, s), 2.52 (1H, d, J = 18.3 Hz), 2.91 (1H, m), 3.07-3.17 (4H, m), 3.38-3.40 (1H, m), 3.63-3.78 (5H, m ), 3.84 (1H, s), 3.99 (3H, s), 4.05 (1H, J = 2.3 Hz), 4.51 (1H, br), 5.49 (1H, br), 6.88 (1H, s); HRMS (ESI, m / z): [M+Na] + calcd. for C 36 H 45 N5O9Na, 714.3109; found, 714.3118.

[0235] [Synthesis of Compound 22] [ka]

[0236] A freeze-degassed solution of compound 20 (714 mg, 1.03 mmol) in THF (20.6 mL, 0.050 M) was stirred under blue light at room temperature for 1 hour and 25 minutes. The reaction solution was concentrated under reduced pressure, and the crude residue was used in the next reaction without further purification. To a solution of crude compound 21 in MeCN (10.3 mL), Cs2CO3 (673 mg, 2.06 mmol, 2.0 equiv.) and propargyl bromide (117 μL, 1.55 mmol, 1.5 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 10 hours and 30 minutes. After filtering through Celite and washing with CHCl2, the filtrate was concentrated under reduced pressure. The crude residue was purified twice by silica gel column chromatography (CHCl2 / AcOEt) and (CHCl2 / acetone) to give compound 22 (590 mg, 809 μmol, 78% yield for two steps) as a brown oil. 1 H NMR (400 MHz, CDCl3, δ): 0.88 (3H, d, J = 7.3 Hz), 1.32 (9H, s), 1.95 (1H, dd, J = 15.3, 11.7 Hz), 2.14 (3H, s), 2.25 (7H, m), 2.44 (3H, s), 2.54 (1H, t, J= 2.4 Hz), 2.68 (1H, d, J = 17.9 Hz), 3.03 (1H, q, J = 8.7 Hz), 3.12-3.21 (2H, m), 3.37-3.51 (4H, m), 3.72 (5H, m), 4.00 (1H, br), 4.08 (1H, d, J = 2.3 Hz), 4.33 (1H, dd, J = 15.1, 2.4 Hz), 4.48 (1H, dd, J = 15.1, 2.4 Hz), 4.88 (1H, br), 5.48 (1H, br), 5.86 (1H, d, J = 1.4 Hz), 5.97 (1H, d, J = 1.4 Hz), 6.85 (1H, s); HRMS (ESI, m / z): [M+H] + calcd. for C 39 H 48N5O9, 730.3447; found, 730.3456.

[0237] [Synthesis of compound 24] [ka]

[0238] To a solution of compound 22 (755 mg, 1.06 mmol) in CHCl (10.6 mL, 0.10 M), MeS (2.36 mL, 31.8 mmol, 30 equiv.) and TFA (1.63 mL, 21.2 mmol, 20 equiv.) were added under ice-cooling, and the mixture was stirred at room temperature for 18 hours and 20 minutes. The mixture was then diluted with CHCl (20 mL) and quenched with saturated aqueous NaHCO (20 mL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl (20 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was used in the next reaction without further purification. To a solution of crude compound 23 in CHCl (9.57 mL), NEt (400 μL, 2.87 mmol, 3.0 equiv.) and 2-nitrobenzenesulfonyl chloride (276 mg, 1.25 mmol, 1.3 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 10 h. After dilution with CHCl (20 mL), the mixture was quenched with saturated aqueous NHCl (20 mL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous phase was extracted with CHCl (30 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 24 (647 mg, 0.794 mmol, 75% yield for two steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3, δ): 0.94 (3H, d, J = 6.9 Hz), 2.00 (1H, dd, J = 15.3, 11.7 Hz), 2.16-2.30 (10H, m), 2.47 (3H, s), 2.52 (1H, t, J = 2.5 Hz), 2.70 (1H, d, J= 18.3 Hz), 2.99-3.39 (6H, m), 3.46-3.55 (2H, m), 3.71-3.82 (5H, m), 3.98 (1H, br), 4.06 (1H, d, J = 2.7 Hz), 4.27 (1H, dd, J = 15.3, 2.5 Hz), 4.55 (1H, dd, J = 15.3, 2.5 Hz), 5.74-5.80 (2H, m), 5.88 (1H, d, J= 1.4 Hz), 5.99 (1H, d, J = 1.4 Hz), 6.87 (1H, s), 7.63-7.84 (5H, m); [M+H] + calcd. for C 40 H 43 N6O 11 S, 815.2705; found, 815.2732.

[0239] [Synthesis of compound 25]

change

[0240] Compound 24 (368 mg, 451 μmol) in DMF To a solution of 2,4-dimethyl-3,4-trimethyl-1,4-trimethyl-2 ... 1 H NMR (400 MHz, CDCl3, δ): 1.08 (3H, d, J = 6.9 Hz), 1.82 (1H, dd, J = 15.1, 11.9 Hz), 2.16-2.23 (9H, m), 2.47 (3H, s), 2.53 (1H, t, J = 2.5 Hz), 2.75 (1H, d, J= 17.9 Hz), 2.92-3.03 (2H, m), 3.15 (1H, dt, J = 11.8, 2.6 Hz), 3.32-3.38 (2H, m), 3.70-3.79 (6H, m), 3.96 (1H, br), 4.18-4.25 (2H, m), 4.54 (1H, dd, J= 15.3, 2.5 Hz), 5.88 (1H, d, J = 1.4 Hz), 6.00 (1H, d, J = 1.4 Hz), 6.16 (1H, q, J = 4.1 Hz), 6.81 (1H, s), 7.53 (1H, dd, J = 7.7, 1.5 Hz), 7.69-7.78 (2H, m), 7.84 (1H, dd, J = 7.7, 1.5 Hz); HRMS (ESI, m / z): [M+H] + calcd. for C 41 H 45 NO 11 S, 829.2862; found, 829.2886.

[0241] [Synthesis of compound 26] [ka]

[0242] Compound 25 (177 mg, 214 μmol) in MeCN To a solution of Cs2CO3 (2.13 mL, 0.10 M), Cs2CO3 (104 mg, 321 μmol, 1.5 equiv.) and benzenethiol (26.2 μL, 256 μmol, 1.2 equiv.) were added under ice-cooling. The mixture was stirred at 30 °C for 14 h. Benzenethiol (6.54 μL, 64.1 μmol, 0.30 equiv.) was added, and the mixture was stirred at 30 °C for an additional 9 h 30 min. After filtration, 1 M hydrochloric acid (300 μL) was added, and the mixture was concentrated under reduced pressure to remove MeCN. The mixture was washed with CHCl2 (30 mL × 3), and saturated aqueous NaHCO3 solution was added to the aqueous layer under ice-cooling until the pH reached 7–8. The mixture was extracted with CHCl3 (30 mL × 3). The organic phases were combined, dried over Na2SO4, and concentrated in vacuo to give compound 26 (125 mg, 0.194 mmol, 91% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 0.96 (3H, d, J = 6.9 Hz), 1.85 (3H, s), 1.94 (1H, dd, J = 15.3, 11.7 Hz), 2.15 (3H, s,), 2.27 (6H, m), 2.45- 2.51 (4H, m), 2.54 (1H, t, J = 2.5 Hz), 2.75 (1H, d, J = 18.3 Hz), 2.97-3.09 (2H, m), 3.20 (1H, dt, J = 11.4, 2.7 Hz), 3.39 (1H, d, J = 7.8 Hz), 3.52-3.58 (2H, m), 3.70-3.75 (4H, m), 4.00 (1H, br), 4.15 (1H, d, J= 2.3 Hz), 4.26 (1H, dd, J = 15.3, 2.5 Hz), 4.44 (1H, dd, J = 15.3, 2.5 Hz), 5.89 (1H, d, J = 1.4 Hz), 5.97 (1H, d, J = 1.4 Hz), 6.67 (1H, t, J = 6.0 Hz), 6.86 (1H, s); [M+H] + calcd. for C 35 H 42 N5O7, 644.3079; found, 644.3116.

[0243] [Synthesis of compound 27]

change

[0244] In the coexistence of activated したモレキュラーシーブス 4A (722 mg), ホルムアルデヒド (21.7 mg, 724 μmol, 10 equivalents) Dicarbonic acid dicarbonate (3.24 mL) solution, compound 26 (46.6 mg, 72.4 μmol) Dicarbonic acid dimethicone A solution of 2,4-dimethyl-3,4-trimethyl-2,4-trimethyl-1 ...1,4-trimethyl-2,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-2,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4- 1 H NMR (400 MHz, CDCl3, δ): 1.01 (3H, d, J = 6.9 Hz), 1.98 (3H, s), 2.14-2.29 (12H, m), 2.37 (4H, m), 2.91 (2H, m), 3.01 (1H, dd, J = 16.5, 2.7 Hz), 3.12-3.16 (2H, m), 3.39 (1H, m), 3.68 (1H, d, J = 2.7 Hz), 3.76 (3H, s), 4.01-4.08 (2H, m), 4.21 (1H, d, J = 2.3 Hz), 4.48 (1H, d, J = 16.0 Hz), 4.70 (1H, HRMS (ESI, m / z): [M+H] + calcd. for C 36 H 42 N5O7, 656.3079; found, 656.3114.

[0245] [Synthesis of compound 28] [ka]

[0246] (R,M)-PINAP (1.04 mg, 1.86 μmol, 0.12 equiv.) was added to a solution of copper bromide (0.22 mg, 1.55 μmol, 0.10 equiv.) in dimethyl dicarbonate (2.6 mL) in the presence of activated molecular sieves 4A (311 mg) and stirred at room temperature for 1 hour and 15 minutes. To the resulting mixture, a solution of compound 26 (10.0 mg, 15.5 μmol) in dimethyl dicarbonate (0.50 mL) and formaldehyde (4.66 mg, 155 μmol, 10 equiv.) were added. The mixture was stirred at room temperature for 38 hours. After filtration, SiliaBond® Triamine (9.79 mg) was added and the mixture was stirred for 30 minutes. After filtration and concentration under reduced pressure, the crude product was passed through a Discovery® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 28 (1.58 mg, 1.2 μmol, 7.8% yield) as a colorless oil. HRMS (ESI, m / z): [M+2H] 2+ calcd. for C 36 H 42 N5O7, 656.3079; found, 656.3078.

[0247] [Synthesis of compound 29] [ka]

[0248] To a solution of compound 27 (9.90 mg, 15.1 μmol) in MeOH (0.48 mL) and water (0.12 mL), K2CO3 (10.4 mg, 75.5 μmol, 5.0 equiv.) was added under ice-cooling and stirred at room temperature for 6 hours and 30 minutes. The mixture was diluted with CHCl2 (5.0 mL) and water (5.0 mL) and quenched with 1M hydrochloric acid (400 μL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl3 (20 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was passed through a Discovery® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC system to give compound 29 (8.12 mg, 13.2 μmol, yield 88%) as a colorless oil. 1 H NMR (400 MHz, CDCl3, δ): 1.00 (3H, d, J = 6.9 Hz), 1.96 (3H, s), 2.10-2.36 (13H, m), 2.78-2.92 (2H, m), 3.10-3.20 (3H, m), 3.36 (1H, d, J = 7.8 Hz), 3.79 (3H, s), 4.01-4.12 (3H, m), 4.19 (1H, d, J = 2.7 Hz), 4.41 (1H, d, J = 16.0 Hz), 4.66 (1H, d, J = 16.0 Hz), 5.79 (1H, s), 5.85 (1H, d, J = 1.4 Hz), 6.01 (1H, d, J = 1.4 Hz), 6.48 (1H, s), 6.65 (1H, d, J = 8.5 Hz); HRMS (ESI, m / z): [M+2H] 2+ calcd. for C 17 H 20.5 N 2.5 O3, 307.6523; found, 307.6548. [Example]

[0249] 4. Synthesis of Compounds 33 and 35 of the Present Invention Using the scheme shown below, compound 33 was synthesized in 10 steps from the natural product cyanosafracin B (compound 1), and compound 35 was synthesized in 11 steps. Compound 24 was obtained using the same procedure as in Example 3. Compound 30 was synthesized by allylation of sulfonamide using allyl bromide. Compound 31 was synthesized by constructing a macrocycle using a ring-closing enyne metathesis reaction with a first-generation Grubbs catalyst. The Ns group was removed using benzenethiol to obtain compound 32. The acetyl group was removed using potassium carbonate to obtain compound 33. Compound 34 was obtained by treating compound 32 with propargyl bromide. The acetyl group was removed using potassium carbonate to obtain compound 35. The reaction conditions for each step are described below.

[0250] [ka]

[0251] [Synthesis of Compound 30] [ka]

[0252] Compound 24 (292 mg, 358 μmol) in DMF To a solution of 3.58 mL of 0.10 M HCl (3.58 mL, 0.10 M), K2CO3 (148 mg, 1.07 mmol, 3.0 equiv.) and allyl bromide (45.1 μL, 537 μmol, 1.5 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 76 h. After dilution with CHCl2 (10 mL), the mixture was quenched with saturated aqueous NH4Cl (20 mL) and water (20 mL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl2 (30 mL × 2). The combined organic phases were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / CHCl3 / acetone) to give compound 30 (244 mg, 0.285 mmol, 80% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3, δ): 1.13 (3H, d, J = 6.9 Hz), 1.83 (2H, m), 2.15- 2.24 (10H, m), 2.45 (3H, s), 2.53 (1H, t, J = 2.3 Hz), 2.71 (1H, d, J = 17.9 Hz), 2.94- 3.04 (2H, m), 3.15 (1H, m), 3.31-3.37 (2H, m), 3.62-3.76 (7H, m), 3.79-3.86 (2H, m), 3.97 (1H, br), 4.14 (1H, d, J = 2.3 Hz), 4.22 (1H, dd, J= 15.3, 2.3 Hz), 4.51 (1H, dd, J = 15.6, 2.3 Hz), 4.98-5.08 (2H, m), 5.42-5.52 (1H, m), 5.86 (1H, d, J = 1.4 Hz), 5.97 (1H, d, J = 1.4 Hz), 6.15 (1H, m), 6.79 (1H, s), 7.52 (1H, m), 7.67-7.74 (2H, m), 7.82 (1H, m); HRMS (ESI, m / z): [M+H] + calcd. for C 43 H 47 N6O 11 S, 855.3018; found, 855.3032.

[0253] [Synthesis of compound 31]

change

[0254] A solution of Grubbs first-generation catalyst (70.3 mg, 85.5 μmol, 0.30 equiv) in CHCl (26.4 mL) was heated to reflux, and a solution of compound 30 (244 mg, 285 μmol) in CHCl (2.00 mL) was added. The mixture was heated to reflux for 23 h. The reaction solution was concentrated under reduced pressure, and then 1,2-dimethoxyethane (2.85 mL) and SiliaMetS® Thiourea (565 mg) were added and stirred for 10 h 30 min. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / CHCl / acetone) to give compound 31 (87.0 mg, 102 μmol, 36% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3, δ): 1.04 (3H, d, J = 6.9 Hz), 2.08 (6H, m), 2.15-2.25 (4H, m), 2.30-2.37 (1H, m), 2.43 (3H, s), 2.56 (1H, d, J = 17.9 Hz), 2.83 (1H, m), 3.02-3.11 (3H, m), 3.20 (1H, dt, J = 11.6, 3.0 Hz), 3.45 (1H, d, J = 9.2 Hz), 3.53-3.60 (1H, m), 3.71-3.76 (5H, m), 4.03-4.13 (3H, m), 4.44 (1H, m), 4.58 (1H, d, J = 13.3 Hz), 4.88 (1H, d, J = 13.3 Hz), 4.94-5.01 (1H, m), 5.22 (1H, s), 5.54 (1H, s), 5.85-6.00 (4H, m), 6.85 (1H, s), 7.54-7.70 (4H, m), 7.78 (1H, m); HRMS (ESI, m / z): [M+H] + calcd. for C 43 H 47 NO 11 S, 855.3018; found, 855.3040.

[0255] [Synthesis of Compound 32] [ka]

[0256] Compound 31 (31.0 mg, 36.3 μmol) in MeCN To a solution of 1,2-dimethyl-3,4-dichloro-2 ... 1 H NMR (400 MHz, CDCl3, δ): 1.10 (3H, d, J = 6.9 Hz), 1.85 (1H, dd, J = 15.6, 11.9 Hz), 2.14-2.35 (12H, m), 2.45 (3H, s), 2.63-2.74 (2H, m), 2.86 (1H, m), 3.05 (2H, m), 3.16 (1H, d, J = 11.9 Hz), 3.34-3.37 (2H, m), 3.57-3.76 (5H, m), 4.00 (2H, d, J = 13.7 Hz), 4.49 (1H, d, J = 11.9 Hz), 4.62 (1H, d, J = HRMS (ESI, m / z): [M+H] + calcd. for C 37 H 44 N5O7, 670.3235; found, 670.3262.

[0257] [Synthesis of Compound 33] [ka]

[0258] To a solution of compound 32 (22.8 mg, 34.1 μmol) in MeOH (0.54 mL) and water (0.14 mL), K2CO3 (23.6 mg, 171 μmol, 5.0 equiv.) was added under ice-cooling and stirred at room temperature for 5 hours. The mixture was diluted with CHCl2 (5.0 mL) and water (5.0 mL) and quenched with 1 M hydrochloric acid (1.0 mL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl3 (20 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was passed through a Discovery® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 33 (11.3 mg, 18.0 μmol, 53% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 1.05 (3H, d, J = 6.9 Hz), 1.98-2.05 (1H, m), 2.14 (3H, s), 2.20 (1H, t, J = 2.3 Hz), 2.26-2.32 (6H, m), 2.58 (1H, d, J = 17.9 Hz), 2.65 (1H, m), 2.74-2.83 (2H, m), 2.93-3.03 (3H, m), 3.09-3.13 (2H, m), 3.36-3.43 (2H, m), 3.73 (1H, q, J = 6.9 Hz), 3.86 (3H, s), 4.00 (1H, d, J = 2.3 Hz), 4.05 (1H, br), 4.13 (1H, d, J = 3.2 Hz), 4.49 (1H, d, J= 11.9 Hz), 4.61 (1H, d, J = 11.9 Hz), 4.93-5.05 (3H, m), 5.84-5.88 (3H, m), 5.97 (1H, d, J = 1.4 Hz), 6.42 (1H, br), 6.55 (1H, s); HRMS (ESI, m / z): [M+H] + calcd. for C 35 H 42 N5O6, 628.3130; found, 628.3155.

[0259] [Synthesis of compound 34]

change

[0260] To a solution of compound 32 (17.2 mg, 2.06 mmol) in MeCN (0.51 mL), Cs2CO3 (25.1 mg, 77.0 μmol, 3.0 equiv.) and propargyl bromide (3.87 μL, 51.4 μmol, 2.0 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 30 hours and 30 minutes. Propargyl bromide (3.87 μL, 51.4 μmol, 2.0 equiv.) was added, and the mixture was stirred for an additional 14 hours. The reaction was quenched by the addition of 1 M hydrochloric acid (0.30 mL) under ice-cooling, and the aqueous layer was extracted with CHCl2 (30 mL × 3). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / CHCl3 / acetone) to give compound 34 (13.1 mg, 25.7 μmol, 72% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3, δ): 1.04 (3H, d, J = 6.9 Hz), 2.04 (1H, m), 2.15 (3H, s), 2.19 (1H, t, J= 2.3 Hz), 2.23 (3H, s), 2.34 (3H, s), 2.45 (3H, s), 2.61-2.67 (2H, m), 2.76-2.88 (2H, m), 2.94-3.10 (5H, m), 3.38-3.45 (2H, m), 3.63 (1H, d, J = 2.7 Hz), 3.70 (1H, m), 3.79 (3H, s), 4.00-4.05 (2H, m), 4.52 (1H, d, J = 11.9 Hz), 4.64 (1H, d, J = 11.9 Hz), 4.96-5.02 (2H, m), 5.09 (1H, s), 5.86 (1H, d, J = 1.4 Hz), 5.97-6.01 (2H, m), 6.47 (1H, t, J = 5.3 Hz), 6.93 (1H, s).

[0261] [Synthesis of Compound 35] [ka]

[0262] To a solution of compound 34 (8.23 mg, 11.6 μmol) in MeOH (0.46 mL) and water (0.12 mL), K2CO3 (8.03 mg, 58.1 μmol, 5.0 equiv.) was added under ice-cooling and stirred at room temperature for 4.5 hours. The mixture was diluted with CHCl2 (5.0 mL) and water (5.0 mL) and quenched with 1M hydrochloric acid (300 μL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl3 (20 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was passed through a Discovery® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC system to give compound 35 (6.61 mg, 9.93 μmol, yield 85%) as a colorless oil. 1 H NMR (400 MHz, CDCl3, δ): 1.00 (3H, d, J = 6.9 Hz), 1.96 (3H, s), 2.10-2.36 (13H, m), 2.78-2.92 (2H, m), 3.10-3.20 (3H, m), 3.36 (1H, d, J = 7.8 Hz), 3.79 (3H, s), 4.01-4.12 (3H, m), 4.19 (1H, d, J = 2.7 Hz), 4.41 (1H, d, J = 16.0 Hz), 4.66 (1H, d, J = 16.0 Hz), 5.79 (1H, s), 5.85 (1H, d, J = 1.4 Hz), 6.01 (1H, d, J = 1.4 Hz), 6.48 (1H, s), 6.65 (1H, d, J = 8.5 Hz); HRMS (ESI, m / z): [M+2H] 2+ calcd. for C 19 H 21.5 N 2.5 O3, 333.6680; found, 333.6687.

[0263] We have successfully synthesized THIQ compounds containing 14-, 15-, 16-, or 17-membered macrocyclic structures (compounds of formula (I)) and THIQ dimeric compounds containing 28-membered macrocyclic structures (compounds of formula (IIIc)) in a short number of steps (6 to 10). These compounds retain the structure of the nucleic acid alkylation moiety of THIQ compounds (Yondelis) with different macrocyclic structures, but have a different macrocyclic structure from Yondelis. Yondelis was synthesized in 24 steps from cyanosafracin B (Manzanares, I. et al. Org. Lett. 2000, 2, 2545.), and the macrocyclic structure was also limited to a 10-membered ring. The production method of the present invention has demonstrated that diverse macrocyclic structures can be efficiently synthesized flexibly and with a significantly reduced number of steps using cyanosafracin B as a starting material. [Example]

[0264] 5. Synthesis of Compounds 36 and 37 of the Present Invention [Synthesis of Compound 36] [ka]

[0265] To a solution of compound 10 (34.4 mg, 43.8 μmol) in THF (0.80 mL), TBAF (1M THF solution, 131 μL, 131 μmol, 3.0 equivalents) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Ethyl acetate (10 mL) and saturated aqueous ammonium chloride solution (30 mL) were added. Extraction was performed with ethyl acetate (10 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified using an HPLC system to give compound 36 (15.7 mg, 23.4 μmol, 53% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3, δ): 0.91 (3H, d, J = 6.9 Hz), 1.96 (1H, m), 2.14 (3H, s), 2.26 (3H, s), 2.31 (3H, s), 2.50 (1H, t, J = 2.3 Hz), 2.58 (1H, d, J= 17.9 Hz), 3.04 (1H, dd, J = 18.1, 8.0 Hz), 3.23-3.32 (2H, m), 3.37-3.44 (3H, m), 3.58-3.64 (1H, m), 3.77 (3H, s), 4.04 (2H, m), 4.16 (1H, d, J= 1.8 Hz), 4.41 (4H, m), 5.15-5.34 (4H, m), 5.77-5.87 (2H, m), 5.96-6.01 (2H, m), 6.48 (1H, s); 13 C NMR (100 MHz, DMSO-d6, δ): 9.7, 15.9, 19.0, 25.4, 26.7, 40.7, 41.9, 50.1, 55.4, 56.6, 56.9, 59.5, 60.6, 60.9, 65.7, 75.5, 79.4, 101.5, 113.0, 117.3, 117.8, 117.9, 121.0, 121.5, 129.3, 131.0, 132.7, 139.5, 143.2, 144.7, 147.2, 148.0, 155.4, 171.8; HRMS (ESI, m / z): [M+H] + calcd. for C 35 H 42 N5O6, 628.3130; found, 628.3155.

[0266] [Synthesis of compound 37]

change

[0267] To a solution of compound 26 (35.7 mg, 55.4 μmol) in MeOH (0.89 mL) and water (0.22 mL), K2CO3 (38.3 mg, 277 μmol, 5.0 equiv.) was added and stirred at room temperature for 1 hour and 15 minutes. After filtration, the mixture was diluted with CHCl2 (5.0 mL) and water (5.0 mL) and quenched with 1 M HCl (100 μL). The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl3 (10 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was passed through a Discovery® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 37 (22.4 mg, 37.2 μmol, 67% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3, δ): 0.96 (3H, d, J = 6.9 Hz), 1.82 (3H, s), 1.93 (1H, dd, J = 15.1, 11.0 Hz), 2.13 (3H, d, J = 9.6 Hz), 2.28 (6H,m), 2.44 (1H, q, J= 7.0 Hz), 2.51 (1H, t, J = 2.5 Hz), 2.67 (1H, d, J = 18.3 Hz), 2.99 (1H, dd, J = 18.3, 8.2 Hz), 3.22-3.38 (3H, m), 3.56 (2H, m), 3.76 (3H, s), 4.02 (1H, s), 4.15 (2H, m), 4.37 (2H, m ), 5.88 (1H, d, J = 1.4 Hz), 5.96 (1H, d, J = 1.4 Hz), 6.51 (2H, m). [Example]

[0268] 6. Synthesis of Compounds 42 and 44 of the Present Invention According to the scheme shown below, compound 38 was prepared from the natural product cyanosafracin B (compound 1) in four steps similar to the synthesis of compound 5, followed by the subsequent steps 3 and 4 to synthesize compounds 42 and 44. First, compound 38, in which the phenolic hydroxyl group of compound 5 was acetylated, was synthesized. Compound 38 was then subjected to ring-closing metathesis using Grubbs catalyst M101 to construct a macrocycle, synthesizing compounds 39 and 40. Compound 41 was obtained by treating isolated compound 39 with a zerovalent palladium catalyst. Compound 42 was synthesized by removing the acetyl group from compound 41. Compound 43 was then synthesized by N-propargylation, and compound 44 was then synthesized by removing the acetyl group. The reaction conditions for each step are described below.

[0269] [ka]

[0270] [Synthesis of compound 48] [ka]

[0271] To a solution of compound 2 (1.01 g, 1.59 mmol) in CHCl (15.9 mL, 0.10 M), AcO (225 μL, 2.38 mmol, 1.5 equiv.), NEt (664 μL, 4.76 mmol, 3 equiv.), and DMAP (19.4 mg, 0.0159 mmol, 0.10 equiv.) were added under ice-cooling, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with CHCl (10 mL), and saturated aqueous NHCl (10 mL) was added under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl (20 mL × 2). The combined organic phases were washed with saturated brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give compound 48 (988 mg, 1.46 mmol, 92% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3, δ): 0.89 (3H, d, J = 6.9 Hz), 1.60-1.73 (1H, m), 1.83 (3H, s), 2.19-2.24 (6H, m), 2.40-2.51 (4H, m), 2.85 (1H, d, J = 17.4 Hz), 3.02-3.12 (3H, m), 3.36 (2H, m), 3.66-3.81 (6H, m), 3.96-4.03 (4H, m), 4.36-4.45 (2H, m), 4.82 (1H, br), 5.13-5.22 (2H, m), 5.39 (1H, br), 5.74-5.84 (1H, m), 6.83 (1H, s).

[0272] [Synthesis of compound 38] [ka]

[0273] A solution of compound 48 (446 mg, 0.644 mmol) in freeze-degassed THF (12.9 mL, 0.05 M) was stirred at room temperature under blue light for 3 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude residue was used in the next reaction without further purification. To a solution of crude compound 49 in MeCN (6.44 mL, 0.10 M) were added Cs2CO3 (525 mg, 1.61 mmol, 2.5 equiv.) and propargyl bromide (109 μL, 1.29 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 12 h. The mixture was diluted with CHCl2 (10 mL) and quenched by the addition of 1 M HCl (5.0 mL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl2 (30 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3 / AcOEt) to give compound 38 (289 mg, 0.394 mmol, 61% yield for two steps) as a brown solid. 1H NMR (400 MHz, CDCl3, δ): 0.90 (3H, d, J= 6.9 Hz), 1.88-1.95 (1H, m), 2.12 (3H, s), 2.21-2.32 (7H, m), 2.37 (3H, s), 2.68 (1H, d, J = 17.9 Hz), 3.00-3.09 (2H, m), 3.20 (1H, dt, J = 11.9, 2.7 Hz), 3.38-3.56 (4H, m), 3.70-3.75 (5H, m), 4.01 (1H, br), 4.08-4.26 (3H, m), 4.43-4.44 (2H, m), 5.15-5.28 (4H, m), 5.38-5.46 (2H, m), 5.77-5.87 (2H, m), 5.96 (1H, d, J = 1.4 Hz), 6.05-6.13 (1H, m), 6.85 (1H, s).

[0274] [Synthesis of compounds 39 and 40] [ka]

[0275] To a solution of Grubbs catalyst M101 (79.4 mg, 86.0 μmol, 0.20 equiv.) in CHCl (30 mL) was added a solution of compound 38 (308 mg, 430 μmol) in CHCl (13 mL). The mixture was heated to reflux for 11 hours. SiliaMetS® Thiourea (569 mg) was added to the reaction solution and stirred for 6 hours. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / AcOEt) and HPLC to give compound 39 (Z-isomer, 130 mg, 188 μmol, 44% yield) and compound 40 (E-isomer, 49.4 mg, 71.9 μmol, 17% yield), respectively, as brown solids. 39: [α] D 23 -85.6° (c 1.0, CHCl3).; 11H NMR (400 MHz, DMSO-d6, δ): 1.06 (3H, d, J = 7.3 Hz), 2.06 - 2.24 (9H, m), 2.42 (3H, s), 2.69 (1H, d, J = 17.9 Hz), 2.95 - 3.36 (8H, m), 3.53 - 3.83 (6H, m), 4.24 - 4.41 (3H, m), 4.70 (1H, dd, J = 12.8, 5.5 Hz), 5.50 - 5.57 (1H, m), 5.71 - 5.78 (1H, m), 5.97 - 6.01 (2H, m), 6.86 (2H, br), 8.26 (1H, d, J = 3.2 Hz).; HRMS (ESI, m / z): [M+H] + calculated for C 36 H 42 N5O9, 688.2977; found, 688.2979. 40: [α] D 23 -91.9° (c 1.0, CHCl3); 1 1H NMR (400 MHz, DMSO-d6, δ): 1.03 (3H, d, J = 7.3 Hz), 2.07 - 2.20 (9H, m), 2.42 (3H, s), 2.61 - 2.69 (1H, m), 2.94 - 3.04 (4H, m), 3.23 - 3.63 (4H, m), 3.73 - 3.85 (6H, m), 4.43 (3H, s), 5.54 (1H, d, J = 8.2 Hz), 5.88 - 6.00 (3H, m), 6.87 (2H, s).; HRMS (ESI, m / z): [M - CN] + calculated for C 35 H 41 N4O9, 661.2868; found, 661.2870.

[0276] [Synthesis of Compound 41]

Chem.

[0277] Triphenylphosphine (8.91 mg, 34.0 μmol, 2.4 equiv.) and a toluene solution (400 μL) of compound 39 (9.74 mg, 14.2 μmol) were added sequentially to a freeze-degassed toluene solution (310 μL) of Pd2(dba)3 (7.78 mg, 8.50 μmol, 0.60 equiv.). The mixture was stirred at 50 °C for 4.5 h. SiliaMetS® Thiourea (112 mg) was added to the reaction solution and stirred for 11.5 h. After filtration and concentration under reduced pressure, the residue was purified by HPLC to give compound 41 (E-isomer, 4.47 mg, 6.94 μmol, 49% yield) as a colorless solid. 41: 1 H NMR (400 MHz, CDCl3, δ): 1.09 (3H, d, J = 6.9 Hz), 1.86 (1H, dd, J = 16.0, 6.9 Hz), 2.15-2.31 (11H, m), 2.43 (3H, s), 2.82-2.97 (3H, m), 3.04 (1H, d, J= 13.7 Hz), 3.08-3.16 (1H, m), 3.24 (1H, d, J = 16.5 Hz), 3.36 (1H, d, J= 7.8 Hz), 3.61-3.64 (1H, m), 3.77 (3H, s), 3.91-3.97 (1H, m), 4.02-4.10 (3H, m), 4.63 (1H, dd, J = 11.2, 6.6 Hz), 5.12-5.17 (1H, m), 5.43-5.51 (1H, m), 5.87 (1H, d, J = 1.4 Hz), 6.00 (1H, d, J = 1.4 Hz), 6.77 (1H, d, J = 9.6 Hz), 6.89 (1H, s); HRMS (ESI, m / z): [M+H] + calculated for C 35 H 42 N5O7, 644.3079; found, 644.3078.

[0278] [Synthesis of Compound 42] [ka]

[0279] A solution of compound 41 (4.43 mg, 6.88 μmol) in MeOH (552 μL) was added to an aqueous solution (138 μL) of K2CO3 (9.51 mg, 68.8 μmol, 10 equiv.) under ice-cooling and stirred at room temperature for 11 hours. The mixture was diluted with CHCl2 (2.0 mL) and water (1.0 mL) and quenched with 1 M hydrochloric acid (150 μL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl3 (20 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 42 (3.24 mg, 5.38 μmol, 78% yield) as a colorless solid. 1 H NMR (400 MHz, CDCl3, δ): 1.09 (3H, d, J = 6.9 Hz), 1.63 (1H, dd, J = 15.8, 11.7 Hz), 1.85 (1H, dd, J = 16.0, 6.9 Hz), 2.10-2.21 (4H, m), 2.26-2.34 (7H, m), 2.78 (1H, d, J = 17.9 Hz), 2.90 (1H, dd, J = 18.1, 8.0 Hz), 3.02-3.23 (5H, m), 3.34 (1H, d, J = 8.2 Hz), 3.81-3.94 (5H, m), 4.01-4.10 (5H, m), 4.52-4.62 (1H, m), 5.07-5.11 (1H, m), 5.29-5.44 (1H, m), 5.75-5.89 (2H, m), 5.99 (1H, s), 6.52 (1H, s), 6.69 (1H, d, J = 9.2 Hz).; HRMS (ESI, m / z): [M+H] + calculated for C 33 H 40 N5O6, 602.2973; found, 602.2962.

[0280] [Synthesis of compound 43] [ka]

[0281] To a solution of compound 41 (3.90 mg, 6.06 mmol) in DMF (0.60 mL), K2CO3 (12.6 mg, 90.9 μmol, 15 equiv.) and propargyl bromide (4.56 μL, 60.6 μmol, 10 equiv.) were added under ice-cooling. The mixture was stirred at room temperature for 96 h. The reaction solution was filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to give compound 43 (3.36 mg, 4.93 μmol, 81% yield) as a colorless solid. 1 H NMR (400 MHz, CDCl3, δ): 1.12 (3H, d, J = 6.9 Hz), 1.93-2.01 (1H, m), 2.11-2.20 (4H, m), 2.25-2.35 (7H, m), 2.42-2.48 (3H, m), 2.82-3.12 (8H, m), 3.37 (1H, d, J= 7.3 Hz), 3.61 (1H, d, J = 3.2 Hz), 3.78 (3H, s), 3.95-4.08 (3H, m), 4.18 (1H, d, J = 2.3 Hz), 4.66 (1H, m), 4.95 (1H, dt, J = 10.4, 5.2 HRMS (ESI, m / z): [M+H] + calculated for C 38 H 44 N5O7, 682.3235; found, 682.3223.

[0282] [Synthesis of compound 44] [ka]

[0283] To a solution of compound 43 (3.36 mg, 4.93 μmol) in MeOH (789 μL), an aqueous solution of KCO (6.81 mg, 49.3 μmol, 10 equiv.) (197 μL) was added under ice-cooling, and the mixture was stirred at room temperature for 17.5 hours. The mixture was diluted with MeOH (1.0 mL) and water (100 μL), and then quenched with 1M hydrochloric acid (70 μL) under ice-cooling. After concentration under reduced pressure, the crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 42 (2.41 mg, 3.77 μmol, 76% yield) as a colorless solid. 1 H NMR (400 MHz, CDCl3, δ): 1.13 (3H, d, J = 6.9 Hz), 1.92 (1H, dd, J = 16.0, 5.5 Hz), 2.09-2.19 (4H, m), 2.26-2.35 (8H, m), 2.81-3.14 (8H, m), 3.33-3.48 (1H, m), 3.85-3.95 (4H, m), 4.04-4.13 (3H, m), 4.21 (1H, d, J = 2.3 Hz), 4.61 (1H, dd, J = 11.5, 5.8 Hz), 4.88 (1H, dt, J = 10.4, 5.2 Hz), 5.31-5.39 (1H, m), 5.81-5.84 (2H, m), 6.00 (1H, d, J = 1.4 Hz), 6.36 (1H, d, J = 10.5 Hz), 6.50 (1H, s).; HRMS (ESI, m / z): [M-CN] + calculated for C 35 H 41 N4O6, 613.3021; ​​found, 613.2992. [Example]

[0284] 7. Synthesis of Compound 47 of the Present Invention According to the scheme shown below, compound 45 was synthesized from the natural product cyanosafracin B (compound 1) in five steps similar to the synthesis of compound 11, and then compound 47 was synthesized in the following two steps. First, the protecting group of the phenolic hydroxyl group of compound 11 was replaced with an acetyl group, and compound 45 was subjected to a [4+2] cyclization reaction to obtain compound 46. Then, the acetyl group was removed to synthesize compound 47. The reaction conditions for each step are described in detail below.

[0285] [ka]

[0286] [Synthesis of Compound 50] [ka]

[0287] A solution of 48 (512 mg, 0.739 mmol) in freeze-degassed THF (14.8 mL, 0.05 M) was stirred at room temperature under blue light for 3.5 h. The reaction solution was concentrated under reduced pressure, and the crude residue was used in the next reaction without further purification. To a solution of crude compound 49 in MeCN (7.40 mL, 0.10 M) was added propargyl bromide (111 μL, 1.48 mmol, 2.0 equiv.) and Cs2CO3 (602 mg, 1.85 mmol, 2.5 equiv.). The mixture was stirred at room temperature for 11.5 hours. The mixture was diluted with CHCl2 (10 mL) and quenched by the addition of 1 M HCl (5.0 mL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl2 (30 mL × 2). The combined organic phases were dried over NaSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / AcOEt) to give 50 (359 mg, 0.491 mmol, 66% yield for two steps) as a brown solid. 1H NMR (400 MHz, CDCl3, δ): 0.88 (3H, d, J= 7.3 Hz), 1.90-2.00 (1H, m), 2.12 (3H, s), 2.19-2.23 (6H, m), 2.42 (3H, s), 2.53 (1H, t, J = 2.3 Hz), 2.65 (1H, d, J = 17.9 Hz), 3.00 (1H, dd, J = 18.3, 8.2 Hz), 3.09-3.18 (2H, m), 3.35-3.51 (4H, m), 3.64-3.76 (4H, m), 3.97 (1H, s), 4.07 (1H, d, J = 2.3 Hz), 4.27-4.49 (4H, m), 5.11-5.21 (3H, m), 5.45 (1H, t, J = 5.7 Hz), 5.73-5.82 (2H, m), 5.93 (1H, d, J = 0.9 Hz), 6.83 (1H, s).

[0288] [Synthesis of compound 45] [ka]

[0289] A solution of compound 50 (287 mg, 401 μmol) in CHCl (10 mL) was added to a solution of Grubbs first-generation catalyst (99.4 mg, 121 μmol, 0.30 equiv.) in CHCl (30 mL). The mixture was heated to reflux for 3.5 hours. SiliaMetS® Thiourea (798 mg) was added to the reaction solution and stirred for 2 hours. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / AcOEt) and HPLC to give compound 45 (E-isomer, 94.6 mg, 188 μmol, 33% yield) and (Z-isomer, 55.8 mg, 78.1 μmol, 19% yield), respectively, as brown solids. 1H NMR (400 MHz, DMSO-d6, δ): 1.10 (3H, d, J = 6.9 Hz), 1.72-1.79 (1H, m), 2.09-2.25 (10H, m), 2.35 (3H, s), 2.69 (1H, d, J = 18.3 Hz), 2.93-3.18 (6H, m), 3.33-3.41 (2H, m), 3.53-3.83 (7H, m), 4.30-4.58 (2H, m), 4.74 (1H, br), 5.16-5.28 (1H, m), 5.42 (1H, s), 5.51(1H, s),5.65-5.71 (1H, m), 6.00 (2H, d, J = 17.9 Hz), 6.20 (1H, br), 6.68-6.96 (2H, m).; HRMS (ESI, m / z): [M+H] + calculated for C 38 H 44 N5O9, 714.3121; found, 714.3121.

[0290] [Synthesis of Compound 46] [ka]

[0291] To a solution of compound 45 (32.3 mg, 45.3 μmol) in CHCl (0.226 mL), N-propargylmaleimide (91.7 mg, 679 μmol, 15 equiv.) was added and stirred at room temperature for 13 hours. After concentration under reduced pressure, the residue was purified using a silica gel column and HPLC system to give compound 46 (18.3 mg, 21.6 μmol, 48% yield) and its diastereomer (6.02 mg, 7.09 μmol, 16%) as white solids. The absolute configuration of the diastereomers has not been determined. 46: [α] D 24 -66.6° (c1.0, CHCl3).; 1H NMR (400 MHz, acetone-d6, δ): 1.26-1.39 (5H, m), 2.03-2.08 (7H, m), 2.23 (3H, s), 2.31-2.48 (4H, m), 2.58-2.65 (4H, m), 2.87-3.03 (9H, m), 3.25-3.50 (4H, m), 3.60-3.83 (7H, m), 3.89-4.16 (6H, m), 4.39-4.49 (3H, m), 5.03 (1H, t, J= 11.0 Hz), 5.31 (1H, s), 5.71 (1H, d, J = 9.6 Hz), 5.88-6.06 (3H, m), 6.92 (1H, s).; HRMS (ESI, m / z): [M+H] + calculated for C 45 H 49 NO 11 , 849.3454; found, 849.3474.

[0292] [Synthesis of compound 47] [ka]

[0293] To a solution of compound 46 (10.1 mg, 11.9 μmol) in MeOH (952 μL), an aqueous solution (238 μL) of KCO (16.5 mg, 119 μmol, 10 equiv.) was added under ice-cooling and stirred at room temperature for 50 min. The mixture was diluted with CHCl (2.0 mL) and water (1.0 mL) and quenched with 1 M hydrochloric acid (150 μL) under ice-cooling. The organic and aqueous phases were separated, and the aqueous layer was extracted with CHCl (20 mL × 3). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The crude product was passed through a STRATA® C18 column and eluted with MeCN. After concentration, the residue was purified by HPLC to give compound 47 (5.73 mg, 7.10 μmol, 60% yield) as a colorless solid. 1H NMR (400 MHz, acetone-d6, δ): 1.20-1.33 (6H, m), 1.42-1.50 (1H, m), 2.14 (1H, s), 2.18-2.31 (3H, m), 2.35 (3H, s), 2.41 (1H, br), 2.64 (1H, s), 2.95-3.02 (2H, m), 3.37-3.48 (3H, m), 3.64-3.71 (2H, m), 3.87-3.96 (5H, m), 4.11 (2H, s), 4.19 (1H, s), 4.37-4.48 (2H, m), 4.99 (1H, t, J = 11.9 Hz), 5.27 (1H, s), 5.67 (1H, d, J = 10.1 Hz), 5.93-5.99 (3H, m), 6.53 (1H, s), 7.80 (1H, s).; HRMS (ESI, m / z): [M-CN] + calculated. for C 43 H 47 NO 10 , 807.3348; found, 807.3355. [Example]

[0294] 8. Verification of DNA alkylation ability The DNA alkylating ability of the macrocyclic THIQ compounds of the present invention (Compounds 7, 13, 14, 29, 36, 37, and 47) was examined by electrophoresis analysis of DNA duplexes. The experiment was performed according to the procedure described in the literature (Tanifuji, R.; Tsukakoshi, K.; Ikebukuro, K.; Oikawa, H., Oguri, H. Bioorg. Med. Chem. Lett., 2019, 29, 1807.). Compounds 7, 13, 14, 29, 36, and 37 were all found to exhibit DNA alkylating ability. The DNA alkylation reaction of compound 7 is outlined below. [ka] [Example]

[0295] 9. Verification of antitumor activity The macrocyclic structure-containing THIQ compounds of the present invention were administered to various cancer cell lines, and the antitumor activity (GI50 value) was observed. Specifically, the procedure was as follows, according to the literature (Yamori, T.; Matsunaga, A.; Sato, S.; Yamazaki, K.; Komi, A.; Ishizu, K. et al. Cancer Res. 1999, 59, 4042.). Cells were plated at moderate density in 96-well plates in RPMI 1640 with 5% fetal bovine serum and allowed to adhere overnight. Cells were exposed to drugs for 48 hours. Cell proliferation was then measured using the sulforhodamine B assay described by Skehan et al. (Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J.T., Bokesch H., Kenney S., Boyd MR.J. Natl. Cancer Inst. 1990, 82, 1107-1112.) Absorbance was measured at 525 nm in control wells (C) and test wells (T). Absorbance was also measured for test wells (T0), with the time of drug addition as time zero. Using these measurements, the inhibitory effect of each drug concentration on cell growth (% growth = PG) was calculated using the following formula: (T>T0): PG = 100×[(T- T0) / (C-T0)] (T <T0): PG = 100×[(T- T0) / T] The PG values ​​calculated for each cell line were plotted against the concentration (logarithm) on a semi-logarithmic graph and summarized by cancer type. The concentrations at which the dose-response curve for each cell line intersected the horizontal lines for PG = 50%, 0%, and -50% were calculated. These concentrations were calculated as Log GI 50 , Log TGI, Log LC 50In practice, two data points of drug concentration before and after the intersection with each horizontal line were used, and the drug concentration (logarithmic value) at the intersection of the line connecting the two points and the horizontal line for each PG was calculated. For comparison, literature values ​​for ecteinascidin 743 (Pharma Mar) and lurbinectedin (Pharma Mar) (non-patent literature: Leal, JFM; Martinez-Diez, M.; Cuevas, C.; Garcia-Fernandez, LF; Galmarini, CM et al. Br. J. Pharmacol. 2010, 161, 1099-1110) and the value for cyanosafracin B are also listed.

[0296] The results obtained are shown below. [Table 1]

[0297] [Table 2]

[0298] [Table 3]

[0299] [Table 4]

[0300] [Table 5]

[0301] [Table 6]

[0302] [Table 7]

[0303] [Table 8]

[0304] [Table 9]

[0305] [Table 10]

[0306] [Table 11]

[0307] [Table 12]

[0308] [Table 13]

[0309] The GI of Cyanosafracin B is shown in Table 1-13 as a comparative example. 50 The values ​​for cyanosafracin B are also shown. The values ​​for cyanosafracin B were also evaluated using the same procedure as for the compounds of this application, based on the literature (Takahashi, N.; Li, W.; Bertino, JR et al. Clin. Cancer Res. 2001, 7, 2908-2911.). As shown in the table above, compounds 7, 13, 14, 16, 18, 29, 33, 35, 42, 44, and 47, which are macrocyclic structure-containing THIQ compounds of the present invention, were found to exhibit superior antitumor activity compared to cyanosafracin B. In particular, compounds 29 and 35 were shown to have higher antitumor activity against multiple cell lines than ecteinascidin 743 or lurbinectedin. Furthermore, compounds 36 and 37, which are THIQ alkaloid compounds without a macrocyclic structure (compounds having substituents at the 1st and 5th positions of the THIQ skeleton), also showed superior antitumor activity compared to cyanosafracin B.

[0310] These results demonstrate that the THIQ alkaloid compounds of the present invention exhibit excellent DNA alkylating ability and potent antitumor activity. Furthermore, because all of the compounds of the present invention synthesized above possess functional groups on the macrocycle that can be easily modified, further improvement of their antitumor activity is possible through structural tuning. Therefore, the compounds of the present invention are clearly useful for the development of novel antitumor drugs.

[0311] The scope of the present invention is not limited to the above description, and other than the above examples, modifications and implementations may be made as appropriate without departing from the spirit of the present invention. All documents and publications described in this specification are incorporated herein by reference in their entirety, regardless of their purpose. This specification also includes the disclosures of the claims, specification, and drawings of Japanese Patent Application No. 2021-033773 (filed March 3, 2021), which is the basis for the priority claim of this application.

Claims

1. A compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof: 【Chemistry 97】 [wherein A is a single bond or an optionally substituted C １ -C ６ an alkylene group; X １ represents an optionally substituted alkylene group, an optionally substituted alkenylene group, —NR ｂ C(O)-, -C(O)NR ｂ -, -C(O)O-, -OC(O)-, -NR ｂ C(O)O-, -OC(O)NR ｂ -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR ｂ ) -, -NR ｂ a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof; Y １ represents a single bond, an ether group, a thioether group, an optionally substituted C １ -C ６ Alkylene groups, and -NR ｂ - is a divalent radical selected from the group consisting of; Y ２ represents an optionally substituted alkylene group, an optionally substituted alkenylene group, —NR ｂ C(O)-, -C(O)NR ｂ -, -C(O)O-, -OC(O)-, -NR ｂ C(O)O-, -OC(O)NR ｂ -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR ｂ ) -, -NR ｂ a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, an amino acid residue, and combinations thereof; X ２ は、-L １ -C(=CR ｆ ２ )-CR ｆ =CR ｆ -L ２ -、-L １ -CR ｆ =CR ｆ -C(=CR ｆ ２ )-L ２ -、-L １ -CR ｆ =CR ｆ -L ２ -、-L １ -CR ｆ =CR ｆ -CR ｆ =CR ｆ -L ２ -、-L １ -NR ｂ -CR ｆ ２ -C≡C-L ２ -、-L １ -C≡C-CR ｆ ２ -NR ｂ -L ２ -、-L １ -C≡C-L ２ -, -L １ -C≡C-C≡C-L ２ -、 【Chemistry 98】 is selected from the group consisting of L １ and L ２ are each independently a single bond or C １ -C ６ represents an alkylene group, R ｆ are each independently a hydrogen atom, an optionally substituted C １ -C ２０ represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Z １ and Z ２ are each independently -NR ｃ -or-CR ｄ R ｅ represents -, and R ｃ , R ｄ , and R ｅ each independently represents a hydrogen atom or an optionally substituted C １ -C ６ is an alkyl group or R ｃ and R ｄ together and they join together Z １ and Z ２ together form a 5- or 6-membered ring structure, which ring structure is optionally substituted with 1 to 4 substituents; R ａ are each independently a hydrogen atom or an optionally substituted C １ -C ６ is an alkyl group, or each R ａ may be taken together to form a ring structure including the oxygen atom to which they are attached; R ｂ are each independently a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; R １ is a methyl group; R ２ represents a hydrogen atom or an optionally substituted C １ -C ６ is an alkyl group; R ３ is a methyl group; R ４ represents a hydrogen atom, an optionally substituted C １ -C ６ is selected from an alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R ５ represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; The optional substituents in the alkyl group, alkylene group, alkenylene group, and aryl group are C １ -C ６ selected from the group consisting of an alkoxy group, a halogen atom, an amino group, an acyl group, an aryl group, a heteroaryl group, and a 3- to 20-membered heterocyclic group; Optional substituents on the aryl group include an oxo group, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C １ -C ６ selected from the group consisting of an alkoxy group, a halogen atom, an amino group, and an acyl group; the nitrogen protecting group is selected from the group consisting of a tert-butoxycarbonyl group, an allyloxycarbonyl group, and a 2-nitrobenzenesulfonyl group; the protecting group for the phenolic hydroxyl group is selected from the group consisting of a methoxymethyl group, an ethoxyethyl group, a tetrahydropyranyl group, a tert-butyldimethylsilyl group, and an acetyl group; the leaving group is selected from the group consisting of a nitrile group, a hydroxyl group, a carboxylate group, a methylsulfonyl group, a trifluoromethanesulfonyl group, an isocyanate group, an azide group, and a diphenylphosphoryl group; The number of members in the macrocyclic structure in formula (I) is 10 to 20.]

2. 2. The compound according to claim 1, which is represented by the following formula (Ia), or a pharmaceutically acceptable salt thereof: 【Hua99】 [In the formula, X ２ , Y １ , Y ２ , R ４ , and R ５ is as defined in claim 1, X １ｃ represents a hydrogen atom, an optionally substituted C １ -C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X １ｄ is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; L ３ is a single bond, an optionally substituted alkylene group, an optionally substituted alkenylene group, a carbonyl group, —C(═S)—, —C(═NR ｂ )-, -C(O)O-, -C(O)NR ｂ -, -OC(O)-, -NR ｂ -, an ether group, a thioether group, and combinations thereof; R ｂ represents a hydrogen atom, an optionally substituted C １ -C 20 selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group; The optional substituents in the alkyl group, alkylene group, alkenylene group, allyl group, and aryl group have the same meanings as those described in claim 1.

3. The compound according to claim 1 or 2, which is represented by the following formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), or formula (Ih), or a pharmaceutically acceptable salt thereof. 【Chemistry 100】 [In the formula, X １ａ represents an oxygen atom, a sulfur atom, -NR ｂ - or an optionally substituted methylene group, X １ｂ represents an oxygen atom, a sulfur atom, and ═NR ｂ or an optionally substituted methylene group, X １ｃ represents a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X １ｄ is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; X ２ａ is an optionally substituted C １ -C ６ represents an alkylene group represented by the formula: L Ｘ２ａ , L Ｘ２ｂ and L Ｘ２ｃ are each independently a hydrogen atom, an optionally substituted C １ -C ２０ represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Y １ represents an ether group, a thioether group, an optionally substituted C １ -C ６ an alkylene group represented by the formula -NR ｂ - is a divalent radical selected from the group consisting of; Y ２ represents an optionally substituted alkylene group, an optionally substituted alkenylene group, —NR ｂ C(O)-, -C(O)NR ｂ -, -C(O)O-, -OC(O)-, -NR ｂ C(O)O-, -OC(O)NR ｂ -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR ｂ ) -, -NR ｂ a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, and an amino acid residue; L Ｙ２ａ , L Ｙ２ｂ and L Ｙ２ｃ are each independently a hydrogen atom, an optionally substituted C １ -C ２０ represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Z １ and Z ２ are each independently N or CR ｅ represents R ｅ is a hydrogen atom or an optionally substituted C １ -C ６ is an alkyl group, R ４ represents a hydrogen atom, an optionally substituted C １ -C ６ is selected from an alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R ５ represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R ８ is a hydrogen atom, an optionally substituted aryl group, an optionally substituted C １ -C ２０ represents an alkyl group, an optionally substituted allyl group, a propargyl group, and a nitrogen-protecting group, R ｂ are each independently a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group; The optional substituents in the alkyl group, alkylene group, methylene group, alkenylene group, and aryl group have the same meanings as the substituents in the alkyl group, alkylene group, alkenylene group, and aryl group described in claim 1 ; The optional substituents in the aryl group have the same meanings as the substituents in the aryl group described in claim 1.

4. In formulas (Ic) to (Ih), X １ａ represents an oxygen atom or —NR ｂ represents -, X １ｂ represents an oxygen atom, X １ｃ represents a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X １ｄ represents a methyl group, X ２ａ is C １ -C ３ represents an alkylene group, L Ｘ２ａ , L Ｘ２ｂ and L Ｘ２ｃ are each independently a hydrogen atom, an optionally substituted C １ -C 8 represents an alkyl group or an optionally substituted aryl group, Y １ represents an ether group; Y ２ is C １ -C ３ represents an alkylene group; L Ｙ２a , L Ｙ２b and L Ｙ２ｃ are each independently a hydrogen atom, an optionally substituted C １ -C 8 selected from alkyl groups, and optionally substituted aryl groups; Z １ and Z ２ are each independently N or CR ｅ represents R ｅ is a hydrogen atom or an optionally substituted C １ -C ６ is an alkyl group, R ４ represents a hydrogen atom, an optionally substituted C １ -C ６ is selected from an alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R ５ represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R ８ represents a hydrogen atom, an optionally substituted phenyl group, and an optionally substituted C １ -C ２０ is selected from alkyl groups, allyl groups, propargyl groups, and nitrogen protecting groups of the formula R ｂ are each independently a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group; The optional substituents in the alkyl group, alkylene group, alkenylene group, and aryl group have the same meanings as the substituents in the alkyl group, alkylene group, alkenylene group, and aryl group described in claim 1 ; 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the optional substituents on the aryl group and phenyl group are the same as those on the aryl group described in claim 1.

5. In formulas (Ic) to (Ih), X １ａ represents an oxygen atom, X １ｂ represents an oxygen atom, X １ｃ is selected from a hydrogen atom, a methyl group, and a propargyl group; X １ｄ represents a methyl group, X ２ａ is C １ -C ３ represents an alkylene group, L Ｘ２ａ , L Ｘ２ｂ and L Ｘ２ｃ each independently represents a hydrogen atom, Y １ represents an ether group; Y ２ is C １ -C ３ represents an alkylene group; L Ｙ２a , L Ｙ２b and L Ｙ２ｃ each independently represents a hydrogen atom, Z １ and Z ２ each independently represents a nitrogen atom or CH; R ４ represents a hydrogen atom, R ５ represents CN, R ８ represents a hydrogen atom or an optionally substituted phenyl group, Me represents a methyl group; Optional substituents on the phenyl group include an oxo group, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C １ -C ６ 5. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the group is selected from the group consisting of an alkoxy group, a halogen atom, an amino group, and an acyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 【Chemistry 101】 【change】 (In the formula, Me represents a methyl group.)

7. A compound represented by the following formula (IIIc) or a pharmaceutically acceptable salt thereof: 【Chemistry 102】 [In the formula, X １ｃ represents a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; X １ｄ is selected from a hydrogen atom, a methyl group, or a substituent corresponding to the side chain of various natural / unnatural amino acids; L Ｘ２ａ and L Ｘ２ｂ are each independently a hydrogen atom, an optionally substituted C １ -C 20 represents an alkyl group represented by the formula: and an optionally substituted aryl group represented by the formula: Y １ represents an ether group, a thioether group, an optionally substituted C １ -C ６ an alkylene group represented by the formula -NR ｂ - is a divalent radical selected from the group consisting of; Y ２ represents an optionally substituted alkylene group, an optionally substituted alkenylene group, —NR ｂ C(O)-, -C(O)NR ｂ -, -C(O)O-, -OC(O)-, -NR ｂ C(O)O-, -OC(O)NR ｂ -, -OC(O)O-, carbonyl group, -C(=S)-, -C(=NR ｂ ) -, -NR ｂ a divalent group selected from the group consisting of -, a sulfonyl group, an ether group, a thioether group, and an amino acid residue; R ４ represents a hydrogen atom, an optionally substituted C １ -C ６ is selected from an alkyl group, an optionally substituted aryl group, an optionally substituted allyl group, a propargyl group, and a protecting group for a phenolic hydroxyl group; R ５ represents CN, a hydroxyl group, or a leaving group containing an oxygen atom, a sulfur atom, a nitrogen atom, or a phosphorus atom; R ｂ represents a hydrogen atom, an optionally substituted C １ -C ２０ selected from alkyl groups, optionally substituted aryl groups, optionally substituted allyl groups, propargyl groups, and nitrogen protecting groups; Me represents a methyl group; The optional substituents in the alkyl group, alkylene group, alkenylene group, and aryl group are C １ -C ６ selected from the group consisting of an alkoxy group, a halogen atom, an amino group, an acyl group, an aryl group, a heteroaryl group, and a 3- to 20-membered heterocyclic group; Optional substituents on the aryl group include an oxo group, C １ -C ６ Alkyl group, C ２ -C ６ Alkenyl group, C １ -C ６ selected from the group consisting of an alkoxy group, a halogen atom, an amino group, and an acyl group; the nitrogen protecting group is selected from the group consisting of a tert-butoxycarbonyl group, an allyloxycarbonyl group, and a 2-nitrobenzenesulfonyl group; the protecting group for the phenolic hydroxyl group is selected from the group consisting of a methoxymethyl group, an ethoxyethyl group, a tetrahydropyranyl group, a tert-butyldimethylsilyl group, and an acetyl group; The leaving group is selected from the group consisting of a nitrile group, a hydroxyl group, a carboxylate group, a methylsulfonyl group, a trifluoromethanesulfonyl group, an isocyanate group, an azide group, and a diphenylphosphoryl group.

8. 8. The compound of claim 7, which is the following compound or a pharmaceutically acceptable salt thereof: 【Chemistry 103】 [In the formula, Me represents a methyl group.]

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A DNA alkylating agent comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. An anti-cancer agent comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

12. The anticancer agent according to claim 11, wherein the target disease is selected from the group consisting of breast cancer, brain tumor, colon cancer, lung cancer, ovarian cancer, and gastric cancer.

13. A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, wherein the tetrahydroisoquinoline alkaloid compound is a compound represented by formula (Ic), (Id) or (If) according to claim 3, and the method comprises any one of the following steps (A) to (C), and, if necessary, a step of deprotecting a protecting group: Step (A): subjecting a compound represented by the following formula (IIc) to a ring-closing olefin metathesis reaction in the presence of a ruthenium catalyst or a tungsten catalyst to obtain a compound represented by formula (Ic)'; 【Chemical 107A】 Step (B): subjecting a compound represented by the following formula (IId) to a ring-closing ene-metathesis reaction in the presence of a ruthenium catalyst or a tungsten catalyst to obtain a compound represented by formula (Id)'; 【Chemical 108A】 Step (C): subjecting a compound represented by the following formula (IIe) to a ring-closing ene-metathesis reaction in the presence of a ruthenium catalyst or a tungsten catalyst to obtain a compound represented by formula (If)'; 【Chemistry 109A】 [In formulas (IIc), (IId), (IIe), (Ic)′, (Id)′, and (If)′, X １ａ , X １ｂ , X １ｃ , X １ｄ , X ２ａ , L Ｘ２ａ , L Ｘ２ｂ , L Ｘ２ｃ , Y １ , Y ２ , L Ｙ２a , L Ｙ２b , L Ｙ２ｃ , R ５ and Me are as defined in claim 3, R ４ represents a protecting group for a phenolic hydroxyl group.

14. A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, wherein the tetrahydroisoquinoline alkaloid compound is a compound represented by formula (Ie) according to claim 3, and the method comprises the following step (D), and, if necessary, a step of deprotecting a protecting group: Step (D): Reacting the compound represented by formula (Id) with the compound represented by formula (IVa) to obtain the compound represented by formula (Ie)'. 【Chemical 110A】 [In formulas (Id), (IVa), and (Ie)′, X １ａ , X １ｂ , X １ｃ , X １ｄ , X ２ａ , L Ｘ２ｃ , Y １ , Y ２ , L Ｙ２a , L Ｙ２b , L Ｙ２ｃ , R ５ , R ８ 、 Z １ 、 Z ２ and Me are as defined in claim 3, R ４ represents a protecting group for a phenolic hydroxyl group.

15. A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, wherein the tetrahydroisoquinoline alkaloid compound is a compound represented by formula (Ig) according to claim 3, and the method comprises the following step (E), and, if necessary, a step of deprotecting a protecting group: Step (E): A production method comprising reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst to obtain a compound represented by formula (Ig)'. 【Chemical 111A】 [In formulas (IIf), (IVb), and (Ig)′, X １ｃ , X １ｄ , L Ｘ２ａ , L Ｘ２ｂ , Y １ , Y ２ , L Ｙ２a , R ５ and Me are as defined in claim 3; R ４ represents a protecting group for a phenolic hydroxyl group.

16. A method for producing a tetrahydroisoquinoline alkaloid compound containing a macrocyclic structure, wherein the tetrahydroisoquinoline alkaloid compound is a compound represented by formula (IIIc) according to claim 7, and the method comprises the following step (F), and, if necessary, a step of deprotecting a protecting group: Step (F): A production method comprising reacting a compound represented by the following formula (IIf) with a compound represented by formula (IVb) in the presence of a copper catalyst and a ligand to obtain a compound represented by formula (IIIc)'. 【Chemical 112A】 [In formulas (IIf), (IVb), and (IIIc)′, X １ｃ , X １ｄ , L Ｘ２ａ , L Ｘ２ｂ , Y ２ , L Ｙ２a , R ５ and Me are as defined in claim 7; R ４ represents a protecting group for a phenolic hydroxyl group.

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