TW201629015A - Hydronaphthoquinoline derivatives - Google Patents

Abstract

The present invention provides a compound represented by general formula (I) which has excellent retinoic acid receptor-related orphan receptor γt inhibitory activity and IL-17 production inhibitory activity, or a pharmaceutically acceptable salt thereof. (In the formula, U represents a phenyl group, pyridyl group, tetrahydrofuryl group, tetrahydropyranyl group or benzyl group which may be independently mono- to tetra-substituted by groups selected from among halogen atoms, C1-C6 alkyl groups and C1-C6 alkoxy groups, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group or the like; R1 represents a hydrogen atom, a halogen atom, a hydroxyl group or the like; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom, a halogen atom, a hydroxyl group or the like; R4 represents a hydrogen atom or the like; R5 represents a C1-C6 alkyl group which may be independently mono- to tetra-substituted by groups selected from among a hydroxyl group and C1-C6 alkoxy groups, a hydrogen atom or the like; R6 represents a C1-C6 alkyl group which may be independently mono- or di-substituted by groups selected from among C1-C6 alkylsulfonyl groups and a hydroxyl group, a hydrogen atom, a hydroxyl group or the like; R7 represents a hydrogen atom or a fluorine atom; R8 represents a hydrogen atom, a fluorine atom or the like; R9 represents a hydrogen atom; T represents a single bond, an oxygen atom or a group represented by formula -NH-; Y may be the same or different and each represents a halogen atom or a C1-C6 alkyl group; m represents an integer of 0-3; a saturated ring containing a nitrogen atom may be fused with a cyclopropane ring to form a fused ring; and n represents an integer of 1-3.)

Description

Hydronaphthalene quinoline derivative

The present invention relates to a compound or a pharmaceutically acceptable salt thereof for use as a therapeutic drug for dryness or the like, which has excellent retinoic acid receptor-related orphan receptor γt (In the present specification, there is a case where the abbreviation is RORγt).

Although most autoimmune diseases are thought to be unexplained, it has been previously known to be deeply involved in T cell abnormalities in most diseases. In particular, a large number of helper T cells (Th1 cells) that produce IFN-γ have been reported for a long time, but the abnormality of Th1 cells also has a problem that cannot fully explain the pathogenesis of the disease, but with Th1 cells. There are doubts about the conclusions. In 2006, a large number of helper T cells (Th17 cells) producing IL-17 have been reported, and the promotion of autoimmune diseases is closely related to the abnormality of Th17 cells. Since then, research related to Th17 cells has been vigorously carried out, and its relevance has become apparent in some autoimmune diseases, and the importance of Th17 cells has become noticed. The process of differentiation of Th17 cells by naive T cells and the production of IL-17 by Th17 cells play a role in the nuclear reciator of RORγt. RORγt knockout mice In the initial T cells, the differentiation into Th17 cells is inhibited, and the production of IL-17 is inhibited, and the pathogenesis of experimental autoimmune encephalomyelitis, which is a pathological pattern of multiple sclerosis, is suppressed. The result (Non-Patent Document 1). Further, in other pathological patterns, there is a report that RORγt differentiates into Th17 cells, produces IL-17, and plays an important role in the pathogenesis (Non-Patent Document 2-3). From such knowledge, it is considered that a substance that inhibits the transcriptional activity of RORγt, that is, a RORγt inhibitor, may be a therapeutic drug such as an autoimmune disease.

Since the cause of the autoimmune disease has not been known so far, the treatment method uses an immunosuppressive agent that comprehensively suppresses immunity. However, in this treatment method, the effect of the cause of the autoimmune disease itself is not expected, because it is only a symptomatic treatment method, so it is not considered to have sufficient therapeutic effect, or there is more recurrence if the remission is not achieved. Therefore, in order to achieve a sufficient therapeutic effect and to achieve remission, a treatment suitable for the cause of an autoimmune disease is necessary. Recently, it has been confirmed that IL-17 produces an abnormality of Th17 cells which is hyperthyroidism, which is the cause of some autoimmune diseases. However, at the present point, since there is no method for treating abnormalities of Th17 cells, a new treatment method for improving the abnormality of Th17 cells is necessary.

Non-patent documents 4 to 7 have been reported to have a compound having a RORγt inhibitory action. In particular, as a steroid skeleton-like compound having a RORγt inhibitory action, non-patent documents 8 to 11 describe a cholesterol derivative. Further, Non-Patent Document 12 and Patent Document 1 describe Digoxin and its derivatives. Patent Document 2 and Patent Document 3 describe a bile acid derivative. Only the equivalent of the class is described in these documents. The moiety of the D ring of the alcohol skeleton is a compound of a carbon 5 member ring. Non-patent document 13 describes ursolic acid. Ursolic acid is a 5-ring compound.

Prior technical literature Patent literature

Patent Document 1 WO2012/074547

Patent Document 2 WO2013/041519

Patent Document 3 WO2014/147016

Non-patent literature

Non-Patent Document 1 Cell, 126, 1121-1133 (2006)

Non-Patent Document 2 The Journal of Clinical Investigation, 122, 2252-2256 (2012)

Non-Patent Document 3 Arthritis and Rheumatology, 66, 579-588 (2014)

Non-Patent Document 4 Journal of Medicinal Chemistry 2014, 57, 5871-5892

Non-Patent Document 5 Drug Discovery Today 2014, 19(8), 1205-1211

Non-Patent Document 6 Annual reports in Medicinal Chemistry 2013, 48, 169-182

Non-Patent Document 7 Medicinal Chemistry Communications 2013, 4, 764-776

Non-Patent Document 8 Journal of Biological Chemistry 2004, 279, 14033-14038

Non-Patent Document 9 Journal of Biological Chemistry 2010, 285, 5013-5025

Non-Patent Document 10 Biochimica et Biophysica Acta 2010, 1801, 917-923

Non-Patent Document 11 Molecular Endocrinology 2010, 24, 923-929

Non-Patent Document 12 Journal of Biological Chemistry 2011, 286, 31409-31417

Non-Patent Document 13 Journal of Biological Chemistry 2011, 286, 22707-22710

The inventors conducted intensive studies on a compound having a RORγt inhibitory effect, and found that a hydronaphthalene compound having a specific chemical structure has selective and excellent differentiation inhibition effect of Th17 cells and inhibition of IL-17 production, for autologous It is useful for the prevention and treatment of diseases related to RORγt such as immune diseases. The present inventors have found that the hydronaphthalene compound can be used for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease ( Crohn's disease, ulcerative colitis, etc., Sjögren syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes Graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Behcet's Disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, An autoimmune disease such as Giant Cell Arteriris, contact dermatitis, optic neuritis, or the production of IL-17 is an active ingredient of a drug involved in pathological colorectal cancer. The present invention has been completed based on the above knowledge findings.

The invention is as follows:

(1) a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

Wherein U represents C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ halogenated cycloalkyl, C ₃ -C ₆ halogenated cycloalkenyl or independently 1 to 4 selected from halogen atoms, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy groups substituted phenyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl group or a benzyl group; R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or C ₂ -C _{a 7} alkylcarbonyloxy group; R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group; R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; R ² and R ³ together form oxo; R ⁴ represents a hydrogen atom or independently substituted with 1 to 2 C ₁ -C ₆ alkyl group selected from a sulfo group and a hydroxyl group of the acyl-substituted C ₁ -C ₆ Alkyl; R ⁵ represents a hydrogen atom; C ₂ -C ₇ alkylcarbonyl; independently from 1 to 4 selected from a fluorine atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkyl sulfonate acyl, carboxy, aminocarbonyl, C ₁ -C ₆ alkoxycarbonyl group, and substituted triazolyl group of C ₁ -C ₆ alkyl; or independently substituted with 3-4 selected from a fluorine atom, a hydroxyl group and a hydroxyl group Methyl group Substituted 2-tetrahydropyranyl; or R ⁴ and a group represented by the formula -OR ^{5 taken} together to represent a pendant oxy group; R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, or may be independently selected from 1 to 2 a C ₁ -C ₆ alkyl group substituted with a C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and a cyano group; R ⁷ represents a hydrogen atom or a fluorine atom; R ⁸ represents a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁹ Represents a hydrogen atom; or R ⁸ and R ^{9 taken} together to represent a pendant oxy group; T represents a single bond, an oxygen atom or a group represented by the formula -NH-; Y is the same or differently represents a halogen atom or a C ₁ -C ₆ An alkyl group; m represents an integer of 0 to 3; a saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a condensed ring; n represents an integer of 1 to 3. ].

In the present invention, suitable ones are as follows.

(2) A compound of the formula (I) as defined in (1) or a pharmaceutically acceptable salt thereof, wherein U represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, (C ₁ - C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ cycloalkenyl group, C ₃ -C ₆ halogenated cycloalkyl group, C ₃ -C _a halogenated cycloalkenyl group or a phenyl group, a pyridyl group, a tetrahydrofuranyl group or a tetrahydro group which may be independently substituted with 1 to 4 groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkoxy group. Piperidyl or benzyl; R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C ₂ -C ₇ alkylcarbonyloxy group; R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group; R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; or R ² and R ³ together with a carbon atom to be bonded represent a carbonyl group; R ⁴ represents a hydrogen atom, (C ₁ -C) ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group or C ₁ -C ₆ dihydroxyalkyl group; R ⁵ represents a hydrogen atom; C ₂ -C ₇ alkylcarbonyl group; independently can be passed through 1 to 4 atoms selected from fluoro, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl group, a carboxyl group and a carbonyl group of the amino C ₁ -C ₆ alkyl; or independently substituted 3 Or 4 selected from fluorine atoms and hydroxyl groups Hydroxy substituted methyl group of the 2-tetrahydropyranyl group; or R ⁴ and -OR together represent the formula are bonded with a carbon atom of a carbonyl group represents ^5; R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, (C _{a 1} -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group, a C ₁ -C ₆ hydroxyalkyl group or a C ₁ -C ₆ cyanoalkyl group; R ⁷ represents a hydrogen atom or a fluorine atom; R ⁸ represents a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁹ represents a hydrogen atom; or R ⁸ and R ⁹ together with a carbon atom to be bonded represent a carbonyl group; T represents a single bond, an oxygen atom or a group represented by the formula -NH-; Y is the same or different to represent a halogen atom or a C ₁ -C ₆ alkyl group; m represents an integer of 0 to 3; a saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a condensed ring; n represents An integer from 1 to 3.

(3) The compound of (1) or (2) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is the formula (Ia).

(4) A compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is the formula (Ib).

(5) A compound of (1) or (2) or a pharmaceutically acceptable salt thereof, wherein The general formula (I) is a general formula (Ic).

(6) selected from (1) to (5) or the like of a compound of a pharmaceutically acceptable salt thereof, wherein U is C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl group, ( C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ halogenated cycloalkyl group or independently 1 to 3 halogen atoms Substituted phenyl or tetrahydropyranyl.

(7) A compound selected from any one of (1) to (5) or a pharmaceutically acceptable salt thereof, wherein U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ cycloalkyl group, A C ₃ -C ₆ halogenated cycloalkyl group or a tetrahydropyranyl group which may be substituted with one halogen atom.

(8) A compound according to any one of (1) to (5) or a pharmaceutically acceptable salt thereof, wherein U is 3,3,3-trifluoropropyl, cyclohexyl or 4-fluorocyclo Hexyl, (1S)-3,3-difluorocyclopentyl, 2-tetrahydropyranyl, (R)-2-tetrahydropyranyl, 4-fluorotetrahydropyran-2-yl, 5- Fluorotetrapyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl.

(9) selected from (1) to (8) or a compound according to any of the other pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen atom.

(10) is selected from (1) to (8) or a compound according to any of the other pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

(11) A compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or a methyl group.

(12) A compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group.

(13) A compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a hydroxyl group or a methoxy group.

(14) A compound according to any one of (1) to (13), or an isotopically-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom or may be 1 to 2 Hydroxyl substituted C ₁ -C ₆ alkyl.

(15) A compound according to any one of (1) to (14), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group base.

(16) A compound of any one of (1) to (15) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group; Up to 3 C ₁ -C ₆ alkyl groups selected from the group consisting of hydroxyl, methoxy, methanesulfonyl, aminocarbonyl, tert-butoxycarbonyl and triazolyl; or independently 3 or 4 a 2-tetrahydropyranyl group substituted with a fluorine atom, a hydroxyl group, and a hydroxymethyl group.

(17) A compound according to any one of (1) to (15) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, (R) )-2,3-dihydroxypropyl or (S)-2,3-dihydroxypropyl.

(18) A compound according to any one of (1) to (15) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a methyl group or (R)-2,3-dihydroxypropyl base.

(19) A compound selected from any one of (1) to (18) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxymethyl group.

(20) selected from (1) to (18) or a compound according to any of the other pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom, a hydroxyl group, or hydroxymethyl group.

(21) A compound according to any one of (1) to (20) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a hydrogen atom.

(22) is selected from (1) to (21) or a compound according to any of the other pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom.

(23) A compound according to any one of (1) to (22) or a pharmaceutically acceptable salt thereof, wherein T is a single bond.

(24) A compound according to any one of (1) to (23) or a pharmaceutically acceptable salt thereof, wherein Y is a methyl group.

(25) A compound according to any one of (1) to (24) or a pharmaceutically acceptable salt thereof, wherein m is 0.

(26) A compound according to any one of (1) to (25) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

(27) A compound according to any one of (1) to (26) or a pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, and a saturated ring containing a nitrogen atom is condensed with a cyclopropane ring. The fused ring formed by the ring is a compound of 3-indene bicyclo[4.1.0]heptane ring or a pharmaceutically acceptable salt thereof.

Compound (28) (1) of the like, or a pharmaceutically acceptable salt thereof, wherein formula (I) of formula (I), of the U-C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl group , (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ halogenated cycloalkyl group or independently 1 to 3 a halogen-substituted phenyl group or a tetrahydropyranyl group; R ¹ is a hydrogen atom or a halogen atom; R ² is a hydrogen atom or a methyl group; R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group; ⁴ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with 1 to 2 hydroxyl groups; R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, and a (R)-2,3-dihydroxy group a propyl or (S)-2,3-dihydroxypropyl group; or a group represented by R ⁴ and the formula -OR ^{5 taken} together to represent a pendant oxy group; and R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxyl group. Methyl; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁹ is a hydrogen atom; T is a single bond; Y is a methyl group; m is an integer from 0 to 3; n is 1 Or 2.

(29) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (I), and U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ naphthenic acid group, C ₃ -C ₆ cycloalkyl, or halide may be substituted with a halogen atom tetrahydropyranyl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; R ³ is a hydrogen atom, a hydroxyl group, or a Alkyl; R ⁴ is a hydrogen atom, methyl, hydroxymethyl or 2,3-dihydroxypropyl; R ⁵ is a hydrogen atom, methyl, 2,3-dihydroxypropyl, (R)-2,3 - Dihydroxypropyl or (S)-2,3-dihydroxypropyl; R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group or a hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; a saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a 3-fluorene bicyclo[4.1.0]heptane ring. .

(30) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (I), and U is 3,3,3-trifluoropropyl, cyclohexyl, 4- Fluorocyclohexyl, (1S)-3,3-difluorocyclopentyl, 2-tetrahydropyranyl, (R)-2-tetrahydropyranyl, 4-fluorotetrahydropyran-2-yl, 5-fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ³ is a hydrogen atom, a hydroxyl group or Methoxy; R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group or a (R)-2,3-dihydroxypropyl group; and R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxyl group. Methyl; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; a saturated ring containing a nitrogen atom may also be a cyclopropane The ring is condensed to form a 3-indolyl [4.1.0] heptane ring.

(31) A compound of (1), wherein the formula (I) is a formula (I), and U is a cyclohexyl group, a 2-tetrahydropyranyl group, a (R)-2-tetrahydropyranyl group, 5- Fluorotetrapyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; R ³ is a hydrogen atom, a hydroxyl group or a methoxy group; R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl; R ⁵ is a hydrogen atom, methyl or (R) -2,3- dihydroxypropyl; R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; a saturated ring containing a nitrogen atom may also be a ring The propane ring is condensed to form a 3-indolylbicyclo[4.1.0]heptane ring.

(32) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ia) wherein U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkane , (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ cycloalkyl group, C ₃ -C ₆ halogenated cycloalkyl group or independently 1 to 3 a halogen-substituted phenyl group or a tetrahydropyranyl group; R ¹ is a hydrogen atom or a halogen atom; R ² is a hydrogen atom or a methyl group; and R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group; R ⁴ is a C ₁ -C ₆ alkyl group in which a hydrogen atom may be substituted with 1 to 2 hydroxyl groups; R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, and a (R)-2,3-dihydroxy group. a propyl or (S)-2,3-dihydroxypropyl group; or a group represented by R ⁴ and the formula -OR ^{5 taken} together to represent a pendant oxy group; and R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxyl group. Methyl; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁹ is a hydrogen atom; T is a single bond; Y is a methyl group; m is an integer from 0 to 3; n is 1 Or 2.

(33) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ia) wherein U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ ring An alkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a tetrahydropyranyl group which may be substituted with 1 halogen atom; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; and R ³ is a hydrogen atom, a hydroxyl group or Methoxy; R ⁴ is a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, (R)-2, 3-dihydroxypropyl or (S)-2,3-dihydroxypropyl; R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group or a hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom; and R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; a saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a 3-fluorene bicyclo[4.1.0]heptane ring. .

(34) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ia) wherein U is 3,3,3-trifluoropropyl, cyclohexyl, 4 -fluorocyclohexyl, (1S)-3,3-difluorocyclopentyl, 2-tetrahydropyranyl, (R)-2-tetrahydropyranyl, 4-fluorotetrahydropyran-2-yl , 5-fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; R ³ is hydrogen An atom, a hydroxyl group or a methoxy group; R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group or a (R)-2,3-dihydroxypropyl group; and R ⁶ is a hydrogen atom. , hydroxy or hydroxymethyl; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; and a saturated ring containing a nitrogen atom is also The cyclopropane ring can be condensed to form a 3-indolyl [4.1.0] heptane ring.

(35) A compound of (1), wherein the formula (I) is a formula (Ia) wherein U is cyclohexyl, 2-tetrahydropyranyl or (R)-2-tetrahydropyranyl, 5 -fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; R ³ is a hydrogen atom And a hydroxyl group or a methoxy group; R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group or a (R)-2,3-dihydroxypropyl group; and R ⁶ is a hydrogen atom; a hydroxyl group or a hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; and a saturated ring containing a nitrogen atom may also be used. The cyclopropane ring is condensed to form a 3-indole bicyclo[4.1.0]heptane ring.

(36) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ib) or a formula (Ic), wherein U is a C ₁ -C ₆ alkyl group, C _1- C ₆ halogenated alkyl, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ halogenated cycloalkyl or A phenyl group which is independently substituted with 1 to 3 halogen atoms or a tetrahydropyranyl group; R ¹ is a hydrogen atom or a halogen atom; R ² is a hydrogen atom or a methyl group; and R ³ is a hydrogen atom, a hydroxyl group or a C ₁ - C ₆ alkoxy; R ⁴ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with 1 to 2 hydroxy groups; R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, (R) -2,3-dihydroxypropyl or (S)-2,3-dihydroxypropyl; or R ⁴ and a group represented by the formula -OR ^{5 taken} together to represent a pendant oxy group; R ⁶ is a hydrogen atom or a fluorine atom , hydroxy, methyl or hydroxymethyl; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁹ is a hydrogen atom; T is a single bond; Y is a methyl group; m is 0 to An integer of 3; n is 1 or 2.

(37) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ib) or a formula (Ic), wherein U is a C ₁ -C ₆ halogenated alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a tetrahydropyranyl group which may be substituted with 1 halogen atom; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group; R ³ Is a hydrogen atom, a hydroxyl group or a methoxy group; R ⁴ is a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group (R)-2,3-dihydroxypropyl or (S)-2,3-dihydroxypropyl; R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group or a hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; a saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a 3-fluorene double ring [ 4.1.0] Heptane ring.

(38) A compound of (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ib) or a formula (Ic), wherein U is 3,3,3-trifluoropropene , cyclohexyl, 4-fluorocyclohexyl, (1S)-3,3-difluorocyclopentyl, 2-tetrahydropyranyl, (R)-2-tetrahydropyranyl, 4-fluorotetrahydro Pyran-2-yl, 5-fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl; R ¹ is a hydrogen atom; R ² is a hydrogen atom or Methyl; R ³ is a hydrogen atom, a hydroxyl group or a methoxy group; R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group or (R)-2,3-dihydroxypropyl group R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; The saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a 3-indole bicyclo[4.1.0]heptane ring.

(39) A compound of (1), wherein the formula (I) is a formula (Ib) or a formula (Ic), wherein U is 3 cyclohexyl, 2-tetrahydropyranyl, (R)-2- Tetrahydropyranyl, 5-fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl; R ¹ is a hydrogen atom; R ² is a hydrogen atom or a methyl group R ³ is a hydrogen atom, a hydroxyl group or a methoxy group; R ⁴ is a hydrogen atom or a 2,3-dihydroxypropyl group; R ⁵ is a hydrogen atom, a methyl group or a (R)-2,3-dihydroxypropyl group; R ⁶ is a hydrogen atom, a hydroxyl group, or hydroxymethyl group; R ⁷ is a hydrogen atom or a fluorine atom; R ⁸ is a hydrogen atom; R ⁹ is a hydrogen atom; T is a single bond; m is 0; n is 1 or 2; comprising nitrogen The saturated ring of atoms can also be condensed with a cyclopropane ring to form a 3-indolyl [4.1.0] heptane ring.

(40) A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-10a, 12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, cyclohexyl[(4aS,4bR ,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)- Methyl ketone, (2R)-tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone, [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a ,7-Dihydroxy-8-methoxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H -pyran-2-yl]methanone, [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,8-dihydroxy-7-methoxy-10a,12a-dimethyl Hexahydronaphtho[2,1-f]quinolin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, cyclohexyl[(4aS,4bR, 6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl]methanone, cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS)-1 0b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone, cyclohexyl[4aS , 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecaphthalene[2 , 1-f] quinoline-1(2H)-yl]methanone, Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-(2,3-dihydroxypropyl)-6a,8-dihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone, 1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3 -dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4,4-trifluoro Butan-1-one, [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a- Dimethylhexadenaphtho[2,1-f]quinolin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, [(4aS, 4bR) ,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone, (2R)-tetrahydro-2H-pyran- 2-based [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1 -b]Indol-1-yl]methanone, [(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-8-(hydroxymethyl)-10a, 12a-di Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R) -2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][( 2R)-tetrahydro-2H-pyran-2-yl]methanone, {(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxy Propyl]-7a,8-dihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydro-2H -pyran-2-yl]methanone, {(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1,11a-dihydroxy-4a, 6a-Dimethyloctadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran-2-yl]- Ketone, {(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-di Methyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone, { (2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-dimethyl-10- Octahydro-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone ,(2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a, 6a-dimethyloctadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone, [(2S,4aR,4bS,6aS,8aS,9aR,9bR) ,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl][(2R )-tetrahydro-2H-pyran-2-yl]methanone, [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,11a-dihydroxy-2-methyl Oxy-4a,6a-dimethyloctadecyl-7H-cyclopropane [c]Naphtho[2,1-f]quinolin-7-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone, (2R)-tetrahydro -2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane] 2,1-f]quinoline-1(2H)-yl]methanone, (2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-8,10a,12a-three Methylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone, (2R)-tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-7,10a,12a-trimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl Methyl ketone, [(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8 -trihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone, [(2R,5R)-5-fluorotetrahydro-2H -pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctahydrogen -7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone, [(2R,4S)-4-fluorotetrahydro-2H-pyran-2-yl][ (1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphthalene And [2,1-f]quinolin-7-yl]methanone, [(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS, 6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quina Porphyrin-7-yl]methanone, [(1S)-3,3-difluorocyclopentyl][(4aS,4bR ,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)- Methyl ketone, (cis-4-fluorocyclohexyl) [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-1,2,11a-trihydroxy-4a,6a - dimethyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone, or (2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a - dimethyloctadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone.

(41) A compound of the compound of (40) or a pharmaceutically acceptable salt thereof.

(42) A compound which is a cyclohexyl group [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecane) [2,1-f]quinoline-1(2H)-yl]methanone.

(43) a crystal of (42) in a powder X-ray diffraction pattern obtained by irradiation of a Kα line of copper (wavelength λ = 1.54 Å) at a diffraction angle of 2θ = 4.5, 6.0, 7.5, 10.6, 12.1, 15.2, 16.6, 18.2, 24.4 and 30.7 show the main peaks.

(44) A compound which is (2R)-tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7,8-trihydroxyl -10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone.

(45) a crystal of (44) in a powder X-ray diffraction pattern obtained by irradiation of a Kα line of copper (wavelength λ = 1.54 Å) at a diffraction angle of 2θ = 9.3, 12.5, 13.9, 14.3, 15.2, 15.8, 16.8, 18.9, 20.1 and 21.0 show the main peaks.

(46) A compound which is [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecane Naphtho[2,1-f]quinolin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone.

(47) A compound which is [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a, 12a -dimethyl Hexadecahydronaphtho[2,1-f]quinolin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone.

(48) A crystal of (47) in a powder X-ray diffraction pattern obtained by irradiation with a Kα line of copper (wavelength λ = 1.54 Å) at a diffraction angle of 2θ = 5.5, 10.8, 11.0, 14.2, 14.7, 15.5, 16.3, 17.4, 20.3, and 20.6 show the main peaks.

(49) A compound which is {(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1 , 11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H- Pyran-2-yl]methanone.

(50) A compound which is (2R)-tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-1, 2, 11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone.

(51) a crystal of (50) in a powder X-ray diffraction pattern obtained by irradiation of a Kα line of copper (wavelength λ = 1.54 Å) at a diffraction angle of 2θ = 9.1, 12.3, 13.6, 14.0, 14.5, 16.0, 16.9, 18.5, 19.7 and 20.7 show the main peaks.

(52) A compound which is [(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR, 11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone.

(53) a compound which is (2R)-tetrahydro-2H-pyran-2-yl [(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS)-1, 2, 11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone.

(54) A crystal of (53) in a powder X-ray diffraction pattern obtained by irradiation of a Kα line of copper (wavelength λ = 1.54 Å) at a diffraction angle of 2θ = 13.3, 13.9, 15.0, 16.2, 16.5, 19.1, 19.4, 20.0, 20.4 and 24.2 show the main peaks.

(55) A pharmaceutical composition comprising a compound according to any one of (1) to (54) or a pharmaceutically acceptable salt thereof or a crystal of the same as an active ingredient.

(56) The pharmaceutical composition according to (55), wherein the pharmaceutical composition has a γt inhibitory action of the reticulum receptor-associated orphan receptor.

(57) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for treating and/or preventing a disease which is treated and/or prevented by inhibition of retinoic acid receptor-related orphan receptor γt .

(58) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for treating and/or preventing treatment, improvement, and treatment of symptoms by inhibition of Th17 cell differentiation and/or inhibition of IL-17 production. A disease that is alleviated and/or prevented.

(59) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammation Sexual enteropathy, Hugh's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Beth's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(60) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammation Sexual bowel disease, Hugh's syndrome or chronic obstructive lung disease.

(61) The pharmaceutical composition according to (55), wherein the pharmaceutical composition is for treating and/or preventing dryness or dryness arthritis.

(62) The pharmaceutical composition according to (59) or (60), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(63) A retinoid acid receptor-associated orphan receptor γt inhibitor, which comprises a compound selected from any one of (1) to (54) or a pharmaceutically acceptable salt thereof or the like Crystallization is an active ingredient.

(64) A use of a compound according to any one of (1) to (54), or a pharmaceutically acceptable salt thereof or a crystal thereof, for use in the manufacture of a pharmaceutical composition.

(65) The use according to (64), wherein the pharmaceutical composition is for inhibiting a composition of a reticulum receptor related orphan receptor γt.

(66) The use according to (64), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel Disease, Hugh's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease , Beth's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(67) The use according to (64), wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel A component of a disease, a Hugh's syndrome, or a chronic obstructive lung disease.

(68) The use according to (64), wherein the pharmaceutical composition is for treating and/or preventing a composition of dry or dry arthritis.

(69) The use according to (66) or (67), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(70) A compound according to any one of (1) to (54) or a pharmaceutically acceptable salt thereof or a crystal thereof, which is used for treatment and/or prevention by the reticulum Use of a method of treating and/or preventing a disease caused by an acid receptor-associated orphan receptor γt inhibition.

(71) A compound according to any one of (1) to (54), or a pharmaceutically acceptable salt thereof or a crystal thereof, for use in the treatment and/or prevention of dryness and dryness Arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Hugh's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis , asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Beth's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cells Use in methods of arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(72) A compound according to any one of (1) to (54), or a pharmaceutically acceptable salt thereof or a crystal thereof, for use in the treatment and/or prevention of dryness and dryness Arthritis, ankylosing spondylitis, multiple hard Use in a method of chemotherapy, rheumatoid arthritis, inflammatory bowel disease, Hugh's syndrome or chronic obstructive pulmonary disease.

(73) A compound according to any one of (1) to (54), or a pharmaceutically acceptable salt thereof or a crystal thereof, for use in the treatment and/or prevention of dryness or dryness Use in the method of arthritis.

(74) A compound according to (71) or (72), or a pharmaceutically acceptable salt thereof or a crystal thereof, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(75) A method for inhibiting retinoic acid receptor-associated orphan receptor γt, which is a pharmacologically effective amount of a compound selected from any one of (1) to (54) or a pharmaceutically acceptable salt thereof The salt or their crystals are administered to warm-blooded animals.

(76) A method for the treatment and/or prevention of a disease, which is a pharmacologically effective amount, for example, a compound selected from any one of (1) to (42) or a pharmaceutically acceptable salt thereof or the like Crystallization is applied to warm-blooded animals.

(77) The method according to (76), wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Hugh's syndrome, Systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Besi's disease, spheroid nephritis , cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer.

(78) The method according to (76), wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid joint Inflammation, inflammatory bowel disease, Hugh's syndrome or chronic obstructive lung disease.

(79) The method according to (76), wherein the disease is xerophytic or dry arthritis.

(80) The method according to (77) or (78), wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

(81) The method according to any one of (75) to (80) wherein the warm-blooded animal is a human.

In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

In the present invention, the "C ₁ -C ₆ alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms. For example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-Dimethylbutyl, 1,1-dimethylbutyl or 1,2-dimethylbutyl. It is preferably a linear or branched alkyl group (C ₁ -C ₃ alkyl group) having _{1 to 3} carbon atoms, more preferably a methyl group or an ethyl group (C ₁ -C ₂ alkyl group), further preferably A. base.

In the present invention, the "C ₃ -C ₆ cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. It is preferably a cyclohexyl group.

In the present invention, "C ₃ -C ₆ cycloalkenyl group" comprising a carbon - carbon double bond carbon atoms of 3 to 6 carbon monocyclic group. For example: cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl. It is preferably a cyclohexenyl group, more preferably a 1-cyclohexenyl group.

In the present invention, the "C ₁ -C ₆ halogenated alkyl group" is a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example: trifluoromethyl, trichloromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropyl or 3- Fluoropropyl. It is preferably a group in which one to five "halogen atoms" and "C ₁ -C ₃ alkyl groups" which are the same or different are bonded (C ₁ -C ₃ halogenated alkyl group), more preferably 3,3, 3-trifluoropropyl or 3,3-difluoropropyl.

In the present invention, the "C ₃ -C ₆ halogenated cycloalkyl group" is a group in which one or five of the above-mentioned "halogen atoms" which are the same or different are bonded to the above-mentioned "C ₃ -C ₆ cycloalkyl group". It is preferably a group in which one or two fluorine atoms are bonded to a cyclopropyl group or a cyclohexyl group, more preferably 2,2-difluorocyclopropyl, 3,3-difluorocyclopentyl or 3-fluorocyclo Hexyl, 4-fluorocyclohexyl, or 3,3-difluorocyclohexyl.

In the present invention, "halogenated C ₃ -C ₆ cycloalkenyl group" formed by the junction of the same or different one to five aforementioned "halogen atom" and the "C ₃ -C ₆ cycloalkenyl group" button group. Preferred is 2-fluoro-1-cyclohexenyl.

In the present invention, the "C ₁ -C ₆ alkoxy group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. base. For example: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, 2-methylbutoxy Base, 3-ethylpropoxy, hexyloxy or 2,3-dimethylbutoxy. It is preferably a C 1 to 4 linear or branched alkoxy group (C ₁ -C 4 alkoxy group), more preferably a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group), furthermore Good is methoxy.

In the present invention, "(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group" is one of the above-mentioned "C ₁ -C ₆ alkoxy group" and the aforementioned "C ₁ -C ₆ alkane" The basis of the bond. For example: methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2 An ethoxyethyl group, a 2-butoxyethyl group or a 3-isopropoxypropyl group, preferably one of the aforementioned "C ₁ -C ₄ alkoxy groups" and the aforementioned "C ₁ -C ₃ alkyl group" a bonded group ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₃ alkyl) group), more preferably one of the aforementioned "C ₁ -C ₂ alkoxy groups" and the above A C ₁ -C ₂ alkyl group-bonded group ((C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkyl) group), further preferably 1-methoxyethyl.

In the present invention, the "C ₁ -C ₆ hydroxyalkyl group" is a group in which one hydroxyl group is bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl. It is preferably a group in which one hydroxyl group is bonded to "C ₁ -C ₂ alkyl group", more preferably a hydroxymethyl group or a 2-hydroxyethyl group, still more preferably a hydroxymethyl group.

In the present invention, the "C ₁ -C ₆ dihydroxyalkyl group" is a group in which two hydroxyl groups are bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example: 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl or 3,4-dihydroxybutyl. It is preferably a group in which two hydroxyl groups are bonded to a propyl group or a butyl group, more preferably a 2,3-dihydroxypropyl group.

In the present invention, the "C ₁ -C ₆ cyanoalkyl group" is a group in which one cyano group is bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl or 3-cyanopropyl. It is preferably a group in which one cyano group is bonded to "C ₁ -C ₂ alkyl group", and more preferably a cyanomethyl group.

In the present invention, the "C ₁ -C ₆ alkylsulfonyl group" is a group in which one of the above-mentioned "C ₁ -C ₆ alkyl groups" is bonded to a sulfonyl group. For example: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or hexylsulfonyl. Preferred is a linear or branched alkylsulfonyl group (C ₁ -C ₃ alkylsulfonyl) having 1 to 3 carbon atoms, more preferably a methylsulfonyl or ethylsulfonyl group (C ₁ -C) ₂ alkylsulfonyl group), more preferably more acyl methanesulfonamide.

In the present invention, "(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group" is one of the above-mentioned "C ₁ -C ₆ alkylsulfonyl" and the above "C ₁ -C ₆ alkyl group bonded to the base. For example: methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, isopropylsulfonylmethyl, methylsulfonylethyl or hexylsulfonylpropyl, preferably a group in which one of the aforementioned "C ₁ -C ₃ alkylsulfonyl groups" is bonded to the aforementioned "C ₁ -C ₃ alkyl group" ((C ₁ -C ₃ alkylsulfonyl)-(C ₁ -C ₃ alkyl group) group), more preferably 1 to the "C ₁ -C ₂ alkylsulfonyl group" and the "C ₁ -C ₂ alkyl group" formed by bonding the groups ((C ₁ -C ₂ alkylsulfonyl)-(C ₁ -C ₂ alkyl) group, further more preferably methanesulfonylmethyl.

In the present invention, the "C ₂ -C ₇ alkylcarbonyl group" is a group in which one of the above-mentioned "C ₁ -C ₆ alkyl groups" is bonded to a carbonyl group. For example: ethyl hydrazino, propyl fluorenyl, butyl sulfhydryl, isobutyl decyl, pentylene, trimethyl ethyl or amyl. Preferably, it is a group in which a "C ₁ -C ₃ alkyl group" is bonded to a carbonyl group (C ₂ -C ₄ alkylcarbonyl group), more preferably an ethyl hydrazino group or a propyl fluorenyl group (C ₂ -C ₃ alkane). More preferably, it is an ethyl carbonyl group.

In the present invention, the "C ₁ -C ₆ alkoxycarbonyl group" is a group in which one of the above-mentioned "C ₁ -C ₆ alkoxy groups" is bonded to a carbonyl group. For example: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, pentoxide Alkylcarbonyl, 2-methylbutoxycarbonyl, 3-ethylpropoxycarbonyl, hexyloxycarbonyl or 2,3-dimethylbutoxycarbonyl. It is preferably a group in which a "C ₁ -C ₄ alkoxy group" is bonded to a carbonyl group (C ₁ -C ₄ alkoxycarbonyl group), more preferably a tertiary butyloxycarbonyl group.

In the present invention, the "C ₂ -C ₇ alkylcarbonyloxy group" is a group in which one carbonyl group bonded to the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom. For example: ethoxylated, propenyloxy, butyl fluorenyloxy, isobutyl decyloxy, pentyloxy, trimethyl ethyloxy, pentyloxy or isoamyloxy, Preferably, it is a group (C ₂ -C ₄ alkylcarbonyloxy group) bonded to the above-mentioned "C ₁ -C ₃ alkyl group" bonded to a carbonyl group and an oxygen atom, more preferably an ethoxy group or a propyl group. The decyloxy group (C ₂ -C ₃ alkylcarbonyloxy group) is further more preferably an ethoxylated group.

In the present invention, the "pyridyl group" is a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, preferably a pyridyl group.

In the present invention, the "tetrahydrofuranyl group" is 2-tetrahydrofuranyl or 3-tetrahydrofuranyl, preferably 2-tetrahydrofuranyl, more preferably (R)-2-tetrahydrofuranyl.

In the present invention, "tetrahydropyranyl" is 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, preferably 2-tetrahydropyranyl, more preferably (R)-2-tetrahydropyranyl.

In the present invention, the "triazolyl group" is preferably a 1,2,4-triazolyl group, more preferably a 1H-1,2,4-triazol-1-yl group.

In the present invention, "phenyl, pyridyl, tetrahydrofuranyl, tetrahydroperiyl which may be independently substituted with 1 to 4 groups selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkoxy group. Oryl or benzyl" is phenyl, pyridyl, tetrahydrofuranyl, tetrahydropentanyl, benzyl, or independently from 1 to 4 selected from a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ - A phenyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or benzyl group substituted with a C ₆ alkoxy group. Preferred is a phenyl or tetrahydropyranyl group which may be independently substituted with 1 to 3 halogen atoms, more preferably a tetrahydropyranyl group which may be substituted with 1 fluorine atom, still more preferably 2-tetrahydroperylene. Oryl, (R)-2-tetrahydropyranyl, 5-fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl.

In the present invention, "can be independently substituted with 1-2 C ₁ -C ₆ alkyl group selected from a sulfo group and a hydroxyl group of the acyl-substituted C ₁ -C ₆ alkyl group" is a C ₁ -C ₆ alkyl group, or an independent substituted with 1-2 groups selected from C ₁ -C ₆ acyl group and a hydroxyl group of a sulfo-substituted C ₁ -C ₆ alkyl. Preferably, the above-mentioned "C ₁ -C ₆ alkyl group", "(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group", "C ₁ -C ₆ hydroxyalkyl group" Or "C ₁ -C ₆ dihydroxyalkyl", more preferably methyl, methylsulfonylmethyl, hydroxymethyl or 2,3-dihydroxypropyl.

In the present invention, "1 to 4 independently may be selected from a fluorine atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl group, a carboxyl group, an aminocarbonyl group, a C ₁ -C _{The 6} alkoxycarbonyl group and the triazolyl group-substituted C ₁ -C ₆ alkyl group are C ₁ -C ₆ alkyl groups, or independently from 1 to 4 are selected from a fluorine atom, a hydroxyl group, and a C ₁ -C ₆ group. Alkoxy, C ₁ -C ₆ alkylsulfonyl, carboxyl, aminocarbonyl, C ₁ -C ₆ alkoxycarbonyl and triazolyl-substituted C ₁ -C ₆ alkyl. It is preferably independently substituted with 1 to 3 substituents selected from hydroxy, methoxy, methanesulfonic acyl, aminocarbonyl, three-butoxycarbonyl group and the 1,2,4-triazolyl-substituted C ₁ -C ₆ alkyl, more preferably methyl or (R)-2,3-dihydroxypropyl.

In the present invention, "2-tetrahydropyranyl group independently substituted with 3 to 4 groups selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group" is preferably a 2-tetrahydroperphenyl group independently substituted with 3 hydroxy groups. A thiol group or a 2-tetrahydropyranyl group which is independently substituted with one fluorine atom, two hydroxyl groups and one hydroxymethyl group.

In the present invention, "may independently be substituted with 1 to 2 substituents selected from C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and a cyano group-substituted C ₁ -C ₆ alkyl group" is a C ₁ -C ₆ alkyl or independently with 1 to 2 substituents selected from C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and a cyano group-substituted C ₁ -C ₆ alkyl. Preferably, the above-mentioned "C ₁ -C ₆ alkyl group", "(C ₁ -C ₆ alkylsulfonyl)-(C ₁ -C ₆ alkyl) group", "C ₁ -C ₆ hydroxyalkyl group" Or "C ₁ -C ₆ cyanoalkyl", more preferably methyl or hydroxymethyl.

In the present invention, the "saturated ring containing a nitrogen atom" means a ring corresponding to a moiety of the 4-ring compound of the formula (I) corresponding to the D ring of the steroid skeleton (a ring bonded to the base UTC(=O)-) .

In the present invention, the "saturated ring containing a nitrogen atom may be condensed with a cyclopropane ring to form a condensed ring" means that the "saturated ring containing a nitrogen atom" may be condensed with a cyclopropane ring to form a ring. a fused ring of a bicyclo[4.1.0]heptane ring (in this case, n is 1).

In the present invention, preferred formula (I) is formula (Ia), formula (Ib) or formula (Ic), and more preferred formula (I) is formula (Ia).

In the present invention, preferred U is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ a -C ₆ cycloalkyl group or a phenyl group which may be independently substituted with 1 to 3 halogen atoms or a tetrahydropyranyl group, more preferably a C ₁ -C ₆ halogenated alkyl group or a C ₃ -C ₆ naphthenic group. a C ₃ -C ₆ halogenated cycloalkyl group or a tetrahydropyranyl group which may be independently substituted with 1 halogen atom, further preferably U is 3,3,3-trifluoropropyl, cyclohexyl, 4- Fluorocyclohexyl, (1S)-3,3-difluorocyclopentyl, 2-tetrahydropyranyl, (R)-2-tetrahydropyranyl, 4-fluorotetrahydropyran-2-yl, 5-fluorotetrahydropyran-2-yl or (2R,5R)-5-fluorotetrahydropyran-2-yl.

In the present invention, preferred R ¹ is a hydrogen atom or a halogen atom, and more preferably R ¹ is a hydrogen atom.

In the present invention, preferred R ² is a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

In the present invention, preferred R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group, and more preferably R ³ is a hydrogen atom, a hydroxyl group or a methoxy group.

In the present invention, preferred R ⁴ is a hydrogen atom, a methyl group, a hydroxymethyl group or a 2,3-dihydroxypropyl group.

In the present invention, preferred R ⁵ is a hydrogen atom; a C ₂ -C ₇ alkylcarbonyl group; and C ₁ -C _{6 which} may be independently substituted with 1 to 3 groups selected from a hydroxyl group, a methoxy group and an aminocarbonyl group. An alkyl group; or a 2-tetrahydropyranyl group independently substituted with 3 or 4 groups selected from a fluorine atom, a hydroxyl group and a hydroxymethyl group, more preferably R ⁵ is a hydrogen atom, a methyl group or (R)-2 , 3-dihydroxypropyl.

In the present invention, preferred R ⁶ is a hydrogen atom, a hydroxyl group or a hydroxymethyl group.

In the present invention, preferred R ⁸ is a hydrogen atom.

In the present invention, preferred R ⁹ is a hydrogen atom.

In the present invention, preferred T is a single bond.

In the present invention, preferred Y is a methyl group.

In the present invention, preferred m is 0.

In the present invention, preferred n is 1 or 2.

The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has all of the isomers (keto-enol isomer, non-image isomer, optical isomer, rotational isomerism) Things, etc.).

The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an asymmetric carbon atom in its molecule, thereby having Various isomers. In the compounds of the present invention, such isomers and mixtures of such isomers are all represented by a single formula, i.e., by the formula (I). Accordingly, the invention is also intended to include all such isomers and mixtures of such isomers in any ratio.

As the above stereoisomer, an optically active starting material compound, or a technique which can use asymmetric synthesis or asymmetric induction, can be used to synthesize a compound related to the present invention, or can be synthesized as desired. The compounds related to the present invention are obtained by isolation using a general optical resolution method or separation method.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may contain an unnatural ratio of an atomic isotope in one or more of the atoms constituting the compound. Examples of the atomic isotope include hydrazine ( ² H), hydrazine ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). In addition, the system may, for example, compounds: tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or carbon -14 ⁽¹⁴ C) and other radioactive isotopes of radioactive flag. The radiolabeled compound can be used as a therapeutic or prophylactic agent, a research reagent such as a test reagent, and a diagnostic agent such as an in vivo imaging diagnostic agent. All isotopic variations of the compounds of the invention, whether radioactive or not, are included within the scope of the invention. Compounds of the isotopic design are also included in the compounds of the invention, and mixtures of the compounds of the isotopically labeled species are also wholly included in the compounds of the invention. The compound of the present invention which is an isotope flag can be produced by a method known in the art, for example, by using a raw material of an isotope label instead of the raw material in the production method of the present invention to be described later. A preferred isotope label compound is one or more hydrazine-substituted compounds constituting a hydrogen atom of the compound of the present invention.

The term "the pharmaceutically acceptable salt thereof" means a salt which can be used as a medicine without significant toxicity. When the compound represented by the formula (I) of the present invention has a basic group, it can be reacted with an acid and, in the case of having an acidic group, by reacting with a base to form a salt.

Examples of the basic group-based salt include a hydrohalide salt such as a hydrofluoric acid salt, a hydrochloride salt, a hydrobromide salt or a hydroiodide salt, a nitrate salt, a perchlorate salt, a sulfate salt, and a phosphoric acid salt. a mineral acid salt such as a salt; a C ₁ -C ₆ alkyl sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; a benzenesulfonate or a p-toluenesulfonate; Organic acid salts of aryl sulfonates, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates, etc.; and glycine Amino acid salts such as acid salts, persalts, arginate, ornidamine, glutamate, aspartate.

On the other hand, examples of the acid group-based salt include an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt or an iron salt. a metal salt; an inorganic salt such as an ammonium salt, a tertiary butylamine salt, a diisopropylamine salt, a tertiary octylamine salt, a dibenzylamine salt, Alkaloid salt, glucosamine salt, alkyl phenylglycine salt, ethylenediamine salt, N-methyl reduced glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, bicyclic ring Hexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine An amine salt such as an organic salt such as a salt, a tetramethylammonium salt or a hydroxymethylamine amine methane salt; and a glycinate, an amide salt, a arginine salt, an alanine salt, a glutamine An acid salt such as an acid salt or an aspartic acid salt.

The compound represented by the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof is adsorbed by water or adsorbed by being placed in the atmosphere or recrystallized. In the case of a hydrate, such a hydrate is also included in the salt of the present invention.

The compound of the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof may be solvated by absorption of some other solvent, and the solvate is also A salt included in the present invention.

The compound of the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof is preferably a compound represented by the formula (I) of the present invention or a pharmaceutically acceptable compound thereof. The salt to be allowed is more preferably a compound represented by the formula (I) of the present invention.

Further aspects of the invention pertain to crystallization of the compounds or salts of the invention. The term "crystallization" as used herein refers to a solid whose internal structure constitutes atoms (or clusters thereof) in a three-dimensional space with regular repetition, and is distinguished from an amorphous solid which does not have such a regular internal structure.

Even if the crystals of the same compound are crystallized, a plurality of crystals (crystal polymorphs) having different internal structures and physicochemical properties are formed, but the crystal of the present invention may also be any of the crystal polymorphs. It may also be a mixture of two or more crystal polymorphs.

The crystal of the present invention may be a case where water is absorbed by adherence to water by adhering it to the atmosphere, or a hydrate is formed by heating to 25 to 150 ° C under normal atmospheric conditions. Further, the crystal of the present invention may also be a case where a residual solvent is attached or a solvent in the case of crystallization is contained in the solvate.

In the present specification, the crystal of the present invention is represented by data of powder X-ray diffraction, and powder X-ray diffraction is usually measured and analyzed by a technique used in the field, for example, the method according to the embodiment can be described. Come on. Further, in general, when the hydrate or the dehydrate is absorbed and desorbed by the crystal water, the lattice constant thereof changes, and the diffraction angle (2θ) in the powder X-ray diffraction changes. Further, the peak intensity also varies depending on the difference in crystal growth surface or the like (crystal hibit). Accordingly, the crystal of the present invention is represented by the data of the powder X-ray diffraction, and the diffraction angle of the peak in the powder X-ray diffraction and the X-ray diffraction pattern are uniform crystals, which are obtained by them. Hydrates and dehydrates are also included in the scope of the invention.

The compound represented by the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof has selective and excellent differentiation inhibitory effect of Th17 cells and inhibition of IL-17 production, and is usable RORγt-related diseases such as autoimmune diseases, or IL-17 production and/or prevention of cancer associated with pathological onset. For specific diseases, it is dry, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Clone's disease, ulcerative colitis, etc.), Hugh Lun's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Beth's disease , spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. For the more appropriate disease, for the sake of Sputum, dry arthritis, ankylosing spondylitis, Hugh's syndrome or chronic obstructive pulmonary disease (COPD), especially dry or dry arthritis. Further, the compound of the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof is expected to be selectively prevented in the existing treatment method and The effect of treating abnormalities of Th17 cells.

In the present invention, the term "prevention" means that the risk of developing a disease which is diagnosed as a target by a genetic background or chronic inflammation or the like is high, and the onset of the disease is suppressed or delayed. In the case of autoimmune diseases, diseases in which the risk of morbidity can be diagnosed by single nucleotide polymorphisms (SNPs), gene mutations, and the like are known. Further, in the case of colorectal cancer, it is known that the risk of colorectal cancer is remarkably improved due to the chronic persistence of colitis. The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is expected to have a synergistic effect on the differentiation and inhibition of IL-17 production by Th17 cells. It is diagnosed as a prophylactic administration of a patient with a high risk of developing such a disease, and suppresses or delays the onset of the disease.

Fig. 1 is a powder X-ray diffraction pattern of the crystal obtained in Example 12. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Fig. 2 is a powder X-ray diffraction pattern of the crystal obtained in Example 23. The vertical axis count/second (cps) unit of the graph indicates the diffraction intensity (Intensity). The horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 3 is a powder X-ray diffraction pattern of the crystal obtained in Example 71. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 4 is a powder X-ray diffraction pattern of the crystal obtained in Example 132. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 5 is a powder X-ray diffraction pattern of the crystal obtained in Example 133. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 6 is a powder X-ray diffraction pattern of the crystal obtained in Example 134. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 7 is a powder X-ray diffraction pattern of the crystal obtained in Example 160. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 8 is a powder X-ray diffraction pattern of the crystal obtained in Example 165. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 9 is a powder X-ray diffraction pattern of the crystal obtained in Example 170. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

Figure 10 is a powder X-ray diffraction pattern of the crystal obtained in Example 177. The vertical axis of the graph represents the diffraction intensity (Intensity) in units of counts per second (cps), and the horizontal axis represents the value of the diffraction angle 2θ. The numbers 1 to 10 in the figure indicate the peak numbers of the main peaks.

[Used to implement the aspect of the invention]

The compound represented by the formula (I) of the present invention can be produced according to the methods A to N described below.

The solvent used in the reaction in each of the steps A to N described below is not particularly limited as long as it does not inhibit the reaction, does not adversely affect the reaction, and dissolves the starting material to some extent.

In the reaction of each step of the following A to N methods, the reaction temperature varies depending on the solvent, the starting materials, the reagents, and the like, and the reaction time varies depending on the solvent, the starting materials, the reagents, the reaction temperature, and the like.

In the reaction of each step of the following A to N methods, after completion of the reaction, each of the objective compounds is extracted from the reaction mixture according to a general method. For example, the reaction mixture is appropriately neutralized, and further, in the presence of insoluble matter, by filtration, an organic solvent such as water and ethyl acetate is added, and the organic layer containing the objective compound is separated to water. After washing, it is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate or the like, filtered, and then obtained by distilling off a solvent. The desired compound obtained if needed If necessary, the usual methods can be appropriately combined, for example, recrystallization, reprecipitation, and chromatography (for example, the following combination is appropriately combined and dissolved by a suitable dissolution agent: using silicone, alumina, magnesium-gelatin Adsorption column chromatography of a carrier such as Florisil or SO3H-silica (manufactured by Fuji SILYSIA); Sephadex LH-20 (manufactured by Pharmacia) and Amberlite XAD-11 (manufactured by Rohm and Haas Co., Ltd.) a method of using a synthetic adsorbent such as partition column chromatography of a carrier such as Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation); a method using ion exchange chromatography; using tannin or an alkane The cis phase ‧ reverse phase column chromatography (preferably high performance liquid chromatography) of the phthalocyanine is usually combined with a method conventionally used for separation and purification of an organic compound, and can be separated and purified. The objective compound which is insoluble in the solvent solvent can be purified by washing the obtained crude product as a solvent solvent. Further, the objective compound of each step can be directly used in the next reaction without purification.

In the reactions of the following steps A to N, U, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , T, Y, m and n represents the same meaning as the foregoing. R ¹⁰ represents a C ₁ -C ₆ alkyl group. It is preferably a methyl group or an ethyl group, more preferably a methyl group. p represents an integer from 0 to 2. L represents a leaving group. It is preferably a p-toluenesulfonyloxy group, a methanesulfonyloxy group or a chlorine atom. PRO ¹ represents a protecting group for an amine group used in the field of organic synthetic chemistry. Preferred is a benzyloxycarbonyl group, a methyloxycarbonyl group or a 9-fluorenylmethyloxycarbonyl group, more preferably a benzyloxycarbonyl group. PRO ² and PRO ³ represent a protecting group for a hydroxyl group used in the field of organic synthetic chemistry. Preferred is isopropylidene, ethyl hydrazino, benzhydryl or tert-butyl dimethyl decyl, more preferably isopropylidene, ethyl decyl or tert-butyl dimethyl decyl. Further, in the case of the A method to the N method, the unprotected amine group, the hydroxyl group and/or the carboxyl group may be protected, and the protecting group may be used for protection as needed. Also, protection is not required without protection.

The method A is a method for producing the following compound: in the compound of the formula (I), R ¹ and R ² are a hydrogen atom, and R ⁴ and a group represented by the formula -OR ⁵ together represent a pendant oxy group, and m is 0. a compound represented by the formula (II); and a compound represented by the formula (I-II) wherein R ¹ , R ² and R ⁴ are a hydrogen atom and m is 0.

A-I step

This step is a step of producing a compound represented by the formula (III) by subjecting a compound represented by the formula (II) to a deuteration reaction using a well-known organic chemistry.

By the presence of a base (sodium acetate, sodium carbonate, etc.) in a solvent (ethanol, water, acetic acid, etc. or a mixed solvent thereof), preferably from 0 ° C to the boiling point of the solvent used in the reaction. The compound represented by the formula (II) is treated with hydroxylamine from 50 ° C to the boiling point of the solvent used for the reaction. The hydroxylamine hydrochloride is used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (II). The reaction time is from 5 minutes to 150 hours, preferably from 15 minutes to 100 hours.

The compound represented by the formula (II) is a known compound or a known compound is used as a starting material, and is easily produced according to a known method or the like.

A-II step

This step is a step of producing a compound represented by the general formula (IV) by subjecting a compound represented by the general formula (III) to a Beckmann rearrangement reaction using a well-known organic chemistry.

By solvent (benzene, toluene, pyridine, 1,4-two) In the alkane, tetrahydrofuran, dichloromethane or the like or a mixed solvent thereof, the boiling point of the solvent used from the reaction at -30 ° C to the reaction is preferably from 0 ° C to the boiling point of the solvent used in the reaction. The compound represented by (III) is treated with an alkylphosphonic acid anhydride, polyphosphoric acid, phosphorus oxychloride, sulfinium chloride, p-toluenesulfonyl chloride or the like. The above reactant is used in an amount of from 0.01 to 30 mol, preferably from 0.1 to 10 mol, based on 1 mol of the compound of the formula (III). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

Step A-III

This step is a step of producing a compound represented by the formula (V) by subjecting a compound represented by the formula (IV) to a reduction reaction using a well-known organic chemistry.

By using a solvent (tetrahydrofuran, 1,4-two The alkane, benzene, toluene or the like or a mixed solvent thereof, the boiling point of the solvent used from -78 ° C to the reaction, preferably from 0 ° C to the boiling point of the solvent, is represented by the formula (IV) The compound is treated with a reducing agent (lithium aluminum hydride, diborane, lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex or hydrogenated bis(2-methoxyethoxy)aluminum). The reducing agent is used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (IV). It can be carried out by adding Lewis acid (tin chloride, trifluoroborane ether complex, etc.) as needed. The reaction time is from 1 minute to 60 hours, preferably from 5 minutes to 24 hours.

A-IV step

This step is carried out by a known method of organic chemistry for a compound represented by the general formula (V), a guanidation reaction (in the case where T is a single bond), and an urethanization reaction (where T is an oxygen atom). Or a step of producing a compound represented by the formula (VI) by a urealation reaction (where T is a group represented by the formula -NH-).

In the case of a guanidine reaction, in a solvent (benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or the like), in -30 From °C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C, in N, N-dicyclohexyl carbodiimide, 1-ethyl-3- ( 3-dimethylaminopropyl)carbodiimide, O-(7-fluorenyltriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoroborate The compound represented by the formula (V) is reacted with a carboxylic acid compound in the presence of a condensing agent or the like. The condensing agent is preferably used in an amount of from 1 to 5 mols per mol of the compound 1 represented by the formula (V) to the excess molar number. Further, a base (triethylamine, diisopropylethylamine, N-methyl group) may be added as needed. The porphyrin, 4-dimethylamine pyridine, etc.) are carried out. The alkali system uses the amount of the catalyst to an excess amount. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

Further, in the case of a guanidine reaction, in a solvent (benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, dichloromethane, water, or the like, or a mixed solvent thereof), from -30 ° C to the reaction The boiling point of the solvent to be used is preferably from 0 ° C to 100 ° C in the base (triethylamine, diisopropylethylamine, N-methyl The compound represented by the formula (V) is reacted with a carboxylic acid halide compound in the presence of a porphyrin, 4-dimethylaminopyridine, potassium carbonate or sodium hydrogencarbonate. The base is used in an excess amount of moles, preferably 0.2 to 2 moles, per mole of the compound of the formula (V). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

In the case of a urethanation reaction, in a solvent (benzene, toluene, pyridine, diethyl ether, dichloromethane, tetrahydrofuran, 1,4-two) a compound represented by the formula (V) and a halogen, in a solvent, a solvent, or a mixture thereof, at a boiling point of from -30 ° C to the solvent used in the reaction, preferably from 0 ° C to 50 ° C. It is carried out by reacting a haloformic acid ester or a dialkyl dicarbonate. It can be carried out by adding a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium hydroxide, etc.) as needed. The amount of the catalyst used in the base is increased to an excessive amount with respect to the compound represented by the formula (V). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

In the case of a ureation reaction, in a solvent (benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, 1,4-two) a compound of the formula (V) and an alkyl isocyanate in the range of from -30 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 100 ° C. It is implemented by a reaction. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

A-V step

This step is a step of producing a compound represented by the formula (VII) by subjecting a compound represented by the formula (VI) to an oxidation reaction using a well-known organic chemistry.

In solvent (benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-two Alkane or the like, in a mixed solvent thereof, at from -30 ° C to 200 ° C, preferably from 0 ° C to 120 ° C, in acetone, 2-butanone, cyclohexanone, N-methyl-4- The compound represented by the formula (VI) is reacted with an alkane alumina in the presence of a ketone such as piperidone. The alkane-alumina uses a catalyst amount to an excessive molar amount, preferably 0.2 to 2 moles, relative to the compound of the formula (VI). Further, the ketones use from 1 to an excess of moles, preferably from 1 to 10 moles. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

A-VI step

This step is a step of producing a compound represented by the formula (VIII) by subjecting a compound represented by the formula (VII) to a reduction reaction using a well-known organic chemistry.

In solvent (methanol, ethanol, diethyl ether, tetrahydrofuran, 1,4-two a compound represented by the formula (VII) and a reducing agent such as sodium borohydride in alkane or the like, or a mixed solvent thereof, at a temperature of from -78 ° C to 100 ° C, preferably from -78 ° C to room temperature. The reaction is carried out. It is carried out by adding a 1,2-reduction promoting additive (such as ruthenium chloride) as needed. The reducing agent is used in an amount of the catalyst to an excess of moles, preferably 0.25 to 2 moles, relative to the compound of the formula (VII). Further, the reduction promoting additive is used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

Step A-VII

This step is a step of producing a compound represented by the formula (IX) by subjecting a compound represented by the formula (VIII) to an epoxidation reaction using a well-known organic chemistry.

In the solvent (benzene, toluene, methanol, dichloromethane, water, etc. or a mixed solvent thereof), the formula (VIII) is obtained from -78 ° C to room temperature, preferably from -10 ° C to room temperature. The compound shown is reacted with an oxidizing agent such as an organic peroxyacid, an alkyl hydroperoxide or hydrogen peroxide. It can be carried out by adding a base (sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, etc.) as needed. Further, in the case of using alkyl hydrogen peroxide, it is in the presence of a metal oxide complex such as aluminum, vanadium, molybdenum or titanium (bis(ethylideneacetone) side vanadyl, hexacarbonyl molybdenum, etc.). get on. The base is used in an amount of from 1 to an excess of moles, preferably from 1 to 10 moles, per mole of the compound of the formula (VIII). Further, the metal oxide complex uses a catalyst amount to an excessive number of moles, preferably 0.25 to 2 moles.

Step A-VIII

This step is a step of producing a compound represented by the general formula (X) by subjecting a compound represented by the general formula (IX) to an alkylation reaction or a glycosidation reaction using a well-known organic chemical method.

In the case of an alkylation reaction, by solvent (N,N-dimethylformamide, 1,4-two In the presence of an organic or inorganic base (sodium hydride, potassium carbonate, potassium butoxide, triethylamine, etc.), an additive (triethylbenzyl chloride) is added to an alkane, tetrahydrofuran or the like or a mixed solvent thereof. The compound represented by the formula (IX) is treated with a halogenated alkane compound, a p-toluenesulfonyloxyalkyl compound or the like at from 0 ° C to 300 ° C, preferably from room temperature to 150 ° C. And proceed. The halogenated alkane compound, the p-toluenesulfonyloxyalkyl compound or the like is used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (IX). The reaction time is from 1 minute to 72 hours, preferably from 5 minutes to 48 hours.

In the case of a glycosidation reaction, in a solvent (dichloromethane, diethyl ether, toluene, etc.), from -20 ° C to 100 ° C, preferably from -10 ° C to room temperature, in an activating reagent ( In the presence of a protic acid, a Lewis acid or the like, a compound represented by the formula (IX) is reacted with a sugar donor (a halogenated glycoside, an imidate glycosyl ester, a phosphoglycoside or the like). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

A-IX step

In the present step, in the case where R ³ is a hydroxyl group, a step of producing a compound represented by the formula (II) by performing a diolation reaction using a known organic chemistry method for the compound represented by the formula (VII).

In a solvent (tertiary butanol, acetone, pyridine, benzene, carbon tetrachloride, water, etc. or a mixed solvent thereof), from -78 ° C to 100 ° C, preferably from -10 ° C to 50 ° C The compound represented by the formula (VII) is reacted with an oxidizing agent such as osmium tetroxide or osmium tetroxide. Add a co-oxidant (N-methyl-N-oxidation) as needed It is carried out by N-methylmorpholine N-oxide or the like. The oxidizing agent is used in an amount of the catalyst to an excess of the molar amount, preferably 0.1 to 2 moles, per mole of the compound of the formula (VII). The reaction time is from 10 minutes to 96 hours, preferably from 30 minutes to 24 hours.

A-X step

This step is a step of producing a compound represented by the formula (I-II) by subjecting a compound represented by the formula (X) to a ring opening reaction of an epoxide using a well-known organic chemistry. A reductive epoxide ring-opening reaction by a hydrogenation reducing agent, an epoxide ring opening reaction by a heteroreactive reagent, an epoxide ring opening reaction using an organometallic reagent, or the like is carried out.

In the case where R ³ is a hydroxyl group, in a solvent (acetone, tetrahydrofuran, 1,4-two) a compound represented by the formula (X) and an acid (perchloric acid, in an alkane, water or the like or a mixed solvent thereof) at from -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C The reaction is carried out by reaction with sulfuric acid or the like. The acid is used in an excess amount of the molar amount of the compound represented by the general formula (X), preferably from 0.25 to 2 mol. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

A-XI step

This step is a step of producing a compound represented by the formula (I-II) by subjecting a compound represented by the formula (IX) to a ring opening reaction using a well-known organic chemistry. When R ⁵ is a hydrogen atom, it is carried out in the same manner as the AX step of the A method.

A-XII step

In the present step, R ³ is a hydroxyl group, and a compound represented by the formula (I-II) is produced by subjecting a compound represented by the formula (VIII) to a diolation reaction using a well-known organic chemistry. When R ⁵ is a hydrogen atom, it is carried out in the same manner as the A-IX step of the A method.

A-XIII steps

In the present step, in the case where R ⁵ is a hydrogen atom, a step of producing a compound represented by the formula (I-II) by subjecting a compound represented by the formula (II) to a reduction reaction using a well-known organic chemistry is carried out. .

In solvent (methanol, ethanol, diethyl ether, tetrahydrofuran, 1,4-two The compound of the formula (II) and the sodium borohydride, triethyl hydrazine are used in the range of from -78 ° C to 100 ° C, preferably from -78 ° C to room temperature, in alkane or the like. The reaction is carried out by reacting a reducing agent such as sodium oxyborohydride or hydrogenated tri(tertiary butyl)borohydride. The reducing agent uses a catalyst amount to an excess of moles, preferably 0.25 to 3 moles, relative to the compound of the formula (II). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The B method is a method for producing a compound represented by the formula (I-III), and the compound represented by the formula (I-III) is a compound represented by the formula (I), R ¹ , R ² , R ⁴ And a compound wherein R ⁵ is a hydrogen atom, R ³ is a hydroxyl group, and m is 0.

(Method B)

B-I step

In this step, a protecting group (benzyloxycarbonyl group, methyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc.) is introduced by a method of a known organic chemistry for a compound represented by the formula (V). The step of producing the compound of the formula (XI).

In the case where PRO ¹ is a benzyloxycarbonyl group, it is used in a solvent (benzene, toluene, pyridine, diethyl ether, dichloromethane, tetrahydrofuran, 1,4-two). a compound represented by the formula (V) and chlorine in a solvent, a solvent, or a mixture thereof, preferably from -30 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C. It is carried out by reacting benzyl formate or dibenzyl dicarbonate. It can be carried out by adding a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium hydroxide, etc.) as needed. The amount of the catalyst used in the base is increased to an excessive amount with respect to the compound represented by the formula (V). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound represented by the formula (V) used in this step can be produced according to the A-III step of the method A.

B-II step

This step is a step of producing a compound represented by the formula (XII) by subjecting a compound represented by the formula (XI) to an oxidation reaction using a well-known organic chemistry. This is carried out in the same manner as the A-V step of the A method.

B-III step

This step is a step of producing a compound represented by the formula (XIII) by subjecting a compound represented by the formula (XII) to a reduction reaction using a well-known organic chemistry. This is carried out in the same manner as the A-VI step of the A method.

B-IV step

This step is a step of producing a compound represented by the formula (XIV) by subjecting a compound represented by the formula (XIII) to an epoxidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VII step of the A method.

B-V step

This step is a step of producing a compound represented by the formula (XV) by subjecting a compound represented by the formula (XII) to a diolation reaction using a well-known organic chemistry. This is carried out in the same manner as the A-IX step of the A method.

B-VI step

This step is a step of producing a compound represented by the formula (XVI) by subjecting a compound represented by the formula (XIII) to a diolation reaction using a well-known organic chemistry. This is carried out in the same manner as the A-IX step of the A method.

B-VII step

This step is a step of producing a compound represented by the formula (XVI) by subjecting a compound represented by the formula (XIV) to a ring opening reaction using a well-known organic chemistry. This is carried out in the same manner as the A-X step of the A method.

Step B-VIII

This step is a step of producing a compound represented by the formula (XVI) by subjecting a compound represented by the formula (XV) to a reduction reaction using a well-known organic chemistry. This was carried out in the same manner as the A-XIII step of the A method.

B-IX step

This step is carried out by introducing a protecting group (isopropylidene, ethyl fluorenyl, benzhydryl group, etc.) into a compound represented by the formula (XVI) by using a well-known organic chemistry method to produce a compound of the formula (XVII). The steps of the compounds shown.

In the case where PRO ² and PRO ³ are isopropylidene, in a solvent (acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide or the like, or a mixed solvent thereof), the acid (p-toluene) In the presence of acid, pyridinium p-toluenesulfonate, hydrochloric acid, ferric chloride, aluminum chloride, etc.), from -20 ° C to the boiling point of the solvent used in the reaction, preferably from 0 ° C to 50 ° C, The compound represented by the formula (XVI) is reacted with an isopropylidene reagent (dimethoxypropane, alkoxypropene or the like) to carry out the reaction. In the case of using acetone in a solvent, it is possible to use an isopropylidation reagent. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

In the case where PRO ² and PRO ³ are an ethyl hydrazide group, in a solvent (dichloromethane, N,N-dimethylformamide, pyridine, tetrahydrofuran, 1,4-two) In the alkane or the like, a mixed solvent thereof, the boiling point of the solvent used in the reaction from -20 ° C to the reaction, preferably from 0 ° C to 100 ° C, the compound represented by the formula (XVI) and the ethyl hydrazide group. The chemical reagent (acetic anhydride, acetyl chloride, etc.) is reacted and carried out. It can be carried out by adding a base (triethylamine, diisopropylethylamine, pyridine, 4-dimethylamine pyridine, etc.) as needed. The base is used in an excess amount of moles, preferably 0.2 to 2 moles, based on the compound of the formula (XVI). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

B-X step

This step is a step of producing a compound represented by the formula (XVIII) by subjecting a compound represented by the formula (XVII) to a deprotection reaction using a well-known organic chemistry.

In the case where PRO ¹ is a benzyloxycarbonyl group, it is used in a solvent (ethanol, propanol, methanol, ethyl acetate, tetrahydrofuran, 1,4-two). In the presence of a transition metal catalyst (palladium carbon or the like), in the presence of a transition metal catalyst (palladium carbon or the like), the boiling point of the solvent used from 0 ° C to the reaction is preferably from 0 ° C to 50 ° C by The compound represented by the formula (XVII) is subjected to catalytic hydrogenation. It is generally carried out under a hydrogen atmosphere, but cyclohexane, 1,4-cyclohexadiene or the like may be used as a hydrogen donor as needed. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

B-XI step

This step is carried out by a known organic chemistry method using a compound represented by the formula (XVIII) to carry out a guanidation reaction and a urethane reversion reaction. The step of producing a compound of the formula (XIX) by a urea hydrolysis reaction. This was carried out in the same manner as the A-IV step of the A method.

B-XII step

This step is a step of producing a compound represented by the formula (I-III) by subjecting a compound represented by the formula (XIX) to a deprotection reaction using a well-known organic chemistry.

In the case where PRO ² and PRO ³ are isopropylidene, in a solvent (methanol, ethanol, tetrahydrofuran, acetic acid, water, or the like, or a mixed solvent thereof), from -20 ° C to the boiling point of the solvent used for the reaction, It is preferred to carry out the reaction of the compound represented by the formula (XIX) with an acid (p-toluenesulfonic acid, hydrochloric acid, acetic acid, etc.) from 0 ° C to 100 ° C. The acid is used in an excess amount of the molar amount of the compound represented by the formula (XIX), preferably from 0.2 to 2 moles. In the case of acetic acid, it can also be used as a solvent. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

In the case where PRO ² and PRO ³ are an ethyl hydrazide group, in a solvent (methanol, ethanol, tetrahydrofuran, water, or the like, or a mixed solvent thereof), the boiling point of the solvent used from the reaction at -20 ° C is preferably The compound represented by the formula (XIX) is reacted with a base (potassium carbonate, sodium methoxide or the like) from 0 ° C to 50 ° C to carry out the reaction. The alkali system uses a catalyst amount to an excessive molar amount, preferably 0.1 to 2 moles, relative to the compound of the formula (XIX). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The C method is a method for producing a compound represented by the formula (I-IV) wherein R ¹ , R ² and R ⁵ in the formula (I) are a hydrogen atom, R ³ is a hydroxyl group, and m is 0.

C-I step

This step is a step of producing a compound represented by the formula (XX) by subjecting a compound represented by the formula (XIV) to an oxidation reaction using a well-known organic chemistry.

In the solvent (acetone, dichloromethane, pyridine, etc. or a mixed solvent thereof), the boiling point of the solvent used from -30 ° C to the reaction is preferably from 0 ° C to the boiling point of the solvent used in the reaction. The compound represented by the formula (XIV) is reacted with an oxidizing agent (Jones reagent, chlorochromic acid pyridine, Dess-Martin reagent, chromium oxide, or the like). The oxidizing agent is used in an amount of from 1 to an excess of moles, preferably from 1 to 10 moles, per mole of the compound of the formula (XIV). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound of the formula (XIV) used in this step can be produced according to the B-IV step of the B method.

C-II step

This step is a nucleophilic addition reaction of an organometallic reagent by using a well-known organic chemistry method for a compound represented by the general formula (XX). A step of producing a compound represented by the formula (XXI) by a nucleophilic addition reaction.

In the solvent (tetrahydrofuran, diethyl ether or the like or a mixed solvent thereof), the compound represented by the formula (XX) is organically obtained at from -78 ° C to 80 ° C, preferably from -78 ° C to room temperature. The metal reagent (Grignard reagent, alkyl lithium reagent, etc.) is reacted and carried out. The organometallic reagent uses from 1 to an excess of moles, preferably from 1 to 10 moles, per mole of the compound of the formula (XX). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

C-III step

This step is a step of producing a compound represented by the formula (XXII) by subjecting a compound represented by the formula (XXI) to a ring opening reaction using a well-known organic chemistry. When R ³ is a hydroxyl group, it is carried out in the same manner as the AX step of the A method.

C-IV step

This step is a step of producing a compound represented by the formula (XXIII) by subjecting a compound represented by the formula (XXII) to a deprotection reaction using a well-known organic chemistry. The B-X step of the B method is carried out in the same manner.

C-V step

This step produces a compound of the formula (I-IV) by subjecting a compound represented by the formula (XXIII) to a guanidation reaction, a carbamate reaction or a urea formation reaction using a well-known organic chemistry. The steps of the compounds shown. This was carried out in the same manner as the A-IV step of the A method.

The D method is a method for producing a compound represented by the formula (IV) wherein R ¹ , R ⁴ and R ⁵ in the formula (I) are a hydrogen atom, R ³ is a hydroxyl group, and m is 0.

D-I step

This step is produced by introducing a protecting group (tris-butyl dimethyl dimethyl alkyl group, triethyl decyl group, benzyl group, etc.) to a compound represented by the formula (XVI) by using a well-known organic chemistry. The step of the compound of the formula (XXIV).

In the case where PRO ² is a tertiary butyl dimethyl decyl group, it is in a solvent (dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide or the like, or a mixed solvent thereof). 20 ° C to 120 ° C, preferably from 0 ° C to 100 ° C, the compound of the formula (XVI) and tertiary dimethyl dimethyl hydrazine alkylating agent (tributyl dimethyl dimethyl chlorochloride) The reaction is carried out by reacting a group, a tributyl butyl dimethyl sulfonate or the like. It can be carried out by adding a base (imidazole, pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, sodium hydride, etc.) as needed. The base is used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (XVI). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound of the formula (XVI) used in this step can be produced according to the B-VI step, the B-VII step or the B-VIII step of the B method.

D-II step

This step is a step of producing a compound represented by the formula (XXV) by subjecting a compound represented by the formula (XXIV) to an oxidation reaction using a well-known organic chemistry. This is carried out in the same manner as the C-I step of the C method.

D-III step

This step is a step of producing a compound represented by the formula (XXVI) by subjecting an organometallic reagent to a nucleophilic addition reaction using a well-known organic chemistry method for a compound represented by the formula (XXV). This was carried out in the same manner as the C-II step of the C method.

D-IV step

This step is a step of producing a compound represented by the formula (XXVII) by subjecting a compound represented by the formula (XXVI) to a deprotection reaction using a well-known organic chemistry. This is carried out in the same manner as the B-X step of the B method.

D-V step

This step is carried out by subjecting a compound represented by the general formula (XXVII) to a mercapylation reaction, a carbamate reaction or a urea formation reaction using a well-known organic chemical method to produce a compound of the formula (XXVIII). The step of the compound. This was carried out in the same manner as the A-IV step of the A method.

D-VI step

This step is a step of producing a compound represented by the formula (I-V) by subjecting a compound represented by the formula (XXVIII) to a deprotection reaction using a well-known organic chemistry.

When PRO ² is a tertiary butyl dimethyl decyl group, it is preferably used in a solvent (methanol, ethanol, acetonitrile, tetrahydrofuran, water, or the like, or a mixed solvent thereof) at from -20 ° C to 120 ° C, preferably The compound represented by the formula (XXVIII) is reacted with an acid (trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, acetic acid or the like) from 0 ° C to 100 ° C to carry out the reaction. The acid is used in an excess amount of the molar amount of the compound of the formula (XXVIII), preferably 0.2 to 2 moles. In the case of acetic acid, it can also be used as a solvent.

Or in a solvent (dichloromethane, chloroform, acetonitrile, tetrahydrofuran, water, etc. or a mixed solvent thereof), the formula (XXVIII) is from -20 ° C to 120 ° C, preferably from 0 ° C to 100 ° C. The compound shown is reacted with a dealkylation reagent (hydrofluoric acid-pyridine, hydrofluoric acid-triethylamine, hydrofluoric acid salt, hydrofluoric acid, tetra-n-butylammonium fluoride, etc.). In the case of using tetra-n-butylammonium fluoride, an acid (acetic acid or the like) may be added as needed. The dealkylation reagent may use from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (XXVIII). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The E method is a method for producing a compound represented by the formula (I-VI) wherein R ¹ , R ² , R ⁴ and R ⁵ are a hydrogen atom and m is 0, among the compounds represented by the formula (I).

(E law)

E-I step

The case where R ³ is present based Step C ₁ -C ₆ alkoxy group, with a compound of general formula (XXIV) shown in the use of known techniques of organic chemistry, alkylation reaction, is produced the formula (XXIX The steps of the compounds shown. This was carried out in the same manner as the A-VIII step of the A method.

The compound of the formula (XXIV) used in this step can be produced according to the D-I step of the D method.

E-II step

This step is a step of producing a compound represented by the formula (XXX) by subjecting a compound represented by the formula (XXIX) to a deprotection reaction using a well-known organic chemistry. This is carried out in the same manner as the B-X step of the B method.

E-III step

This step is carried out by subjecting a compound represented by the formula (XXX) to a guanidation reaction, a urethanization reaction or a urea formation reaction using a well-known organic chemistry method to produce a compound of the formula (XXXI). The step of the compound. This was carried out in the same manner as the A-IV step of the A method.

E-IV step

This step is a step of producing a compound represented by the formula (I-VI) by subjecting a compound represented by the formula (XXXI) to a deprotection reaction using a well-known organic chemistry. This is carried out in the same manner as the D-VI step of the D method.

The F method is a method for producing a compound represented by the formula (I-VII) wherein R ² and R ⁴ are a hydrogen atom, R ³ is a hydroxyl group, and m is 0, among the compounds represented by the formula (I).

F-I step

This step is a step of producing a compound represented by the formula (XXXII) by subjecting a compound represented by the formula (X) to an acid treatment. This step can also produce a compound of the formula (I-II).

In solvent (acetone, tetrahydrofuran, 1,4-two a compound represented by the formula (X) and an acid (perchloric acid, in an alkane, water or the like or a mixed solvent thereof) at from -20 ° C to 150 ° C, preferably from 0 ° C to 100 ° C The reaction is carried out by reaction with sulfuric acid or the like. The acid is used in an excess amount of the molar amount of the compound represented by the general formula (X), preferably from 0.25 to 2 mol. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound represented by the formula (X) used in this step can be produced according to the A-VIII step of the method A.

F-II step

This step is a step of producing a compound represented by the formula (XXXIII) by subjecting a compound represented by the formula (XXXII) to an epoxidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VII step of the A method.

F-III step

This step is a step of producing a compound represented by the formula (I-VII) by subjecting a compound represented by the formula (XXXII) to a diolation reaction using a well-known organic chemistry. When R ¹ is a hydroxyl group, it is carried out in the same manner as the A-IX step of the A method.

F-IV step

This step is a step of producing a compound represented by the formula (I-VII) by subjecting a compound represented by the formula (XXXIII) to a ring opening reaction using a well-known organic chemistry. This is carried out in the same manner as the A-X step of the A method.

When R ¹ is a fluorine atom, in the solvent (dichloromethane or the like), the boiling point of the solvent used in the reaction from -20 ° C to the reaction is preferably from -10 ° C to room temperature, so that the formula (XXXIII) The compound shown is reacted with hydrofluoric acid-pyridine, hydrofluoric acid-triethylamine, hydrofluoric acid salt or the like. The above reactants are used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (XXXIII). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The method for producing the following compound G of law: Among the compounds of formula (I), ^{the, R 2, R 3, R} 4 and R ⁵ is a hydrogen atom, m is 0 of the formula (I-VIII) is A compound represented by the formula (I-IX) wherein R ² , R ³ and R ⁴ are a hydrogen atom and m is 0.

G-I step

This step is a step of producing a compound represented by the formula (XXXIV) by subjecting a compound represented by the formula (VI) to an epoxidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VII step of the A method.

The compound of the formula (VI) used in this step can be produced according to the A-IV step of the method A.

G-II step

This step is a step of producing a compound represented by the formula (I-VIII) by subjecting a compound represented by the formula (XXXIV) to a ring opening reaction using a well-known organic chemistry. This is carried out in the same manner as the A-X step of the A method.

G-III step

This step is a step of producing a compound represented by the formula (XXXV) by subjecting a compound represented by the formula (VI) to an alkylation reaction or a glycosidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VIII step of the A method.

G-IV step

This step is a step of producing a compound represented by the formula (XXXVI) by subjecting a compound represented by the formula (XXXV) to an epoxidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VII step of the A method.

G-V step

This step is a step of producing a compound represented by the formula (I-IX) by subjecting a compound represented by the formula (XXXVI) to a ring opening reaction using a well-known organic chemistry. This is carried out in the same manner as the A-X step of the A method.

G-VI step

This step is a step of producing a compound represented by the general formula (I-IX) by subjecting a compound represented by the general formula (I-VIII) to an alkylation reaction or a glycosidation reaction using a well-known organic chemical method. . This was carried out in the same manner as the A-VIII step of the A method.

The H method is a method for producing a compound represented by the formula (IX) wherein R ² , R ³ and R ⁴ are a hydrogen atom and m is 0, among the compounds represented by the formula (I).

(H method)

H-I step

This step is a step of producing a compound represented by the formula (XXXVII) by subjecting a compound represented by the formula (XI) to a epoxidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VII step of the A method.

The compound of the formula (XI) used in this step can be produced according to the B-I step of the B method.

H-II step

This step is a step of producing a compound represented by the formula (XXXVIII) by subjecting a compound represented by the formula (XXXVII) to a ring opening reaction using a well-known organic chemistry. This is carried out in the same manner as the A-X step of the A method.

H-III step

This step is a step of producing a compound represented by the formula (XXXIX) by subjecting a compound represented by the formula (XXXVIII) to a deprotection reaction using a well-known organic chemistry. This is carried out in the same manner as the B-X step of the B method.

H-IV step

This step is a step of producing a compound represented by the formula (XL) by subjecting a compound represented by the formula (XXXVIII) to an alkylation reaction or a glycosidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VIII step of the A method.

H-V step

This step is carried out by subjecting a compound represented by the formula (XXXIX) to a guanidation reaction, a carbamate reaction or a urea formation reaction using a well-known organic chemistry method to produce a compound of the formula (IX). The step of the compound. When R ⁵ is a hydrogen atom, it is carried out in the same manner as the A-IV step of the A method.

H-VI step

This step is a step of producing a compound represented by the formula (XLI) by subjecting a compound represented by the formula (XL) to a deprotection reaction using a well-known organic chemistry. This is carried out in the same manner as the B-X step of the B method.

H-VII step

This step is carried out by subjecting a compound represented by the general formula (XLI) to a guanidation reaction, a urethanization reaction or a urea formation reaction using a well-known organic chemistry method to produce a compound of the formula (IX). The step of the compound. This was carried out in the same manner as the A-IV step of the A method.

The I method is a method for producing a compound represented by the formula (XL) used in the H-VI step of the H method.

I-I step

In this step, a hydroxyl group is replaced with a leaving group (p-toluenesulfonyloxy group, methanesulfonyloxy group or chlorine atom, etc.) by using a well-known organic chemistry method for the compound represented by the general formula (XI). The step of producing a compound represented by the formula (XLII).

When a sulfonyloxy group such as an arylsulfonyloxy group or an alkylsulfonyloxy group is introduced as a leaving group, it is used in a solvent (dichloromethane, chloroform, diethyl ether, tetrahydrofuran, pyridine, etc. or the like). In the mixed solvent), the compound represented by the formula (XI) and the sulfonation reagent (p-toluenesulfonyl chloride, methanesulfonic acid) are used at from -20 ° C to 120 ° C, preferably from 0 ° C to 100 ° C. It is carried out by reacting with ruthenium chloride or the like. It can be carried out by adding a base (triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,4-dioxabicyclo[2,2,2]octane, etc.) as needed. The base may be used in an amount of from 1 to an excess of moles, preferably from 1 to 5 moles, per mole of the compound of the formula (XI). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

Further, when a chlorine atom is introduced as a leaving group, it is preferably used in a solvent (dichloromethane, chloroform, toluene or the like, or a mixed solvent thereof) at from -20 ° C to 120 ° C, preferably from 0 ° C to 100 ° The compound represented by the formula (XI) is reacted with a chlorinating reagent (sulfurium chloride, phosphorus pentachloride, etc.) at °C. It may be carried out without a solvent as needed, and the reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound of the formula (XI) used in this step can be produced according to the B-I step of the B method.

I-II step

This step is a step of producing a compound represented by the formula (XLIII) by reacting an alcohol with a compound represented by the formula (XLII) using a well-known organic chemistry.

In solvent (tetrahydrofuran, 1,4-two The compound represented by the formula (XLII) is reacted with an alcohol at from 0 ° C to 150 ° C, preferably from room temperature to 120 ° C, in an alkane, toluene or the like, or a mixed solvent thereof. It can be carried out by adding an acid (p-toluenesulfonic acid, etc.) as needed. The acid is used in an excess amount of the molar amount of the compound represented by the formula (XLII), preferably from 0.1 to 5 moles. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

Step I-III

This step is a step of producing a compound represented by the formula (XL) by subjecting a compound represented by the formula (XLIII) to an epoxidation reaction using a well-known organic chemistry. This was carried out in the same manner as the A-VII step of the A method.

The J method is a method for producing a compound represented by the formula (I-XI) wherein R ² and R ³ are a hydrogen atom and m is 0, among the compounds represented by the formula (I).

J-I step

This step is a step of producing a compound represented by the formula (XLIV) by subjecting a compound represented by the formula (XXXVIII) to an oxidation reaction using a well-known organic chemistry. This is carried out in the same manner as the C-I step of the C method.

The compound of the formula (XXXVIII) used in this step can be produced according to the H-II step of the H method.

J-II step

This step is a step of producing a compound represented by the formula (XLV) by subjecting an organometallic reagent to a nucleophilic addition reaction using a well-known organic chemistry method for a compound represented by the formula (XLIV). This was carried out in the same manner as the C-II step of the C method.

J-III step

This step is a step of producing a compound represented by the formula (XLVI) by subjecting a compound represented by the formula (XLV) to a deprotection reaction using a well-known organic chemistry. This is carried out in the same manner as the B-X step of the B method.

J-IV step

In this step, the compound of the formula (I-XI) is produced by subjecting a compound represented by the formula (XLVI) to a guanidation reaction, a urethanization reaction or a urea formation reaction using a well-known organic chemistry. The steps of the compounds shown. When R ⁵ is a hydrogen atom, it is carried out in the same manner as the A-IV step of the A method.

The compound represented by the formula (XLVII), the compound of the formula (LIV), the compound of the formula (LIX) or the compound of the formula (LXI) produced by the K method to the N method are used. The above steps A to J may be carried out to produce a compound represented by the formula (I) wherein m is 1 to 3 and/or a saturated ring containing a nitrogen atom is condensed with a cyclopropane ring to form a condensed ring. Compound.

The K method is a method of producing a compound represented by the formula (XLVII) by introducing a substituent Y onto a compound represented by the formula (II).

K-I step

This step is carried out by using a well-known organic chemistry method for the compound represented by the formula (II), and once replaced with a trimethyldecyl enol ether, the alkylation reaction is carried out by using a well-known organic chemistry method or The step of producing a compound represented by the formula (XLVII) by halogenation.

In a solvent (dichloromethane, acetonitrile, N,N-dimethylformamide, or the like), at -78 ° C to 120 ° C, preferably at -20 ° C a trimethyldecyl enol ether obtained from a compound represented by the formula (II) and a halogenated alkane (methyl iodide or the like) or a halogenating agent (N-Fluorobenzenesulfonimide) to 70 ° C , N-fluoropyridinium trifluoromethanesulfonate, chloromethyl-4-fluoro-1,4-diazabicyclo[2,2,2]octane bis(tetrafluoroborate) (Chloromethyl-4-fluoro - 1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoro borate), cesium fluoride, etc.), and a reaction-promoting reagent (titanium tetrachloride, tetra-n-butylammonium fluoride, etc.) may be added as needed. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound represented by the formula (II) is a known compound or a pericardium compound as a starting material, and is easily produced according to a known method or the like.

The L method is a method of producing a compound represented by the formula (LIV) by introducing a substituent Y onto a compound represented by the formula (VII).

L-I step

This step is a step of producing a compound represented by the formula (XLIX) by subjecting a compound represented by the formula (XLVIII) to an imino etherification reaction using a well-known organic chemistry.

The compound of the formula (XLVIII) and the trifluoromethanesulfonate are used in a solvent (dichloromethane or the like) at a boiling point of from -10 ° C to the solvent used in the reaction, preferably from 0 ° C to 50 ° C. Methyl ester, trimethyl It is carried out by reaction such as tetrafluoroborate. It can be carried out by adding a base (N,N-diisopropylethylguanamine, triethylamine, etc.) as needed. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound represented by the formula (XLVIII) is a known compound or a known compound is used as a starting material, and is easily produced according to a known method or the like. For example, it is produced from a compound represented by the general formula (IV).

L-II step

This step is a step of producing a compound represented by the formula (L) by subjecting a compound represented by the formula (XLIX) to a enol etherification reaction using a well-known organic chemistry.

In solvent (tetrahydrofuran, 1,4-two Alkane, acetone, methanol, ethanol, toluene, benzene, N,N-dimethylformamide or the like, in a mixed solvent thereof, from -20 ° C to 150 ° C, preferably from 0 ° C to 120 °C, in the presence of acid (p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.), the compound of the formula (XLIX) and the alcohol, ortho-ester (orthoformic acid ethyl ester, methyl orthoformate, two It is carried out by a reaction such as methoxypropane or the like. The acid is used in an amount of from 1 to an excess of moles, preferably from 1.1 to 5 moles, per mole of the compound of the formula (XLIX). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

L-III step

This step is a step of producing a compound represented by the formula (LI) by subjecting a compound represented by the formula (L) to an alkylation reaction or a halogenation reaction using a well-known organic chemistry.

The compound of the formula (L) is obtained from a solvent (tetrahydrofuran, diethyl ether or the like or a mixed solvent thereof) at from -78 ° C to 50 ° C, preferably from -78 ° C to room temperature. Reaction with a base (n-butyllithium, secondary butyllithium, tertiary butyllithium, etc.) followed by a halogenated alkane (methyl iodide, ethyl iodide, etc.) or a halogenating reagent (N-fluorobenzenesulfonimide, It is carried out by reacting chloromethyl-4-fluoro-1,4-diazabicyclo[2,2,2]octane bis(tetrafluoroborate). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

L-IV step

This step is a step of producing a compound represented by the formula (LII) by subjecting a compound represented by the formula (LI) to a reduction reaction using a well-known organic chemistry.

In the solvent (methanol, ethanol, etc. or a mixed solvent thereof), the boiling point of the solvent used from -20 ° C to the reaction is preferably from 0 ° C to 70 ° C, and the formula (LI) is used. The compound is reacted with a reducing agent (sodium borohydride or the like) to carry out the reaction. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

L-V step

This step is carried out by subjecting a compound represented by the formula (LII) to a guanidation reaction, a carbamate reaction or a urea formation reaction using a well-known organic chemistry method to produce a compound of the formula (LIII). The step of the compound. This was carried out in the same manner as the A-IV step of the A method.

L-VI step

This step is a step of producing a compound represented by the formula (LIV) by subjecting a compound represented by the formula (LIII) to a known organic chemical method and an acid hydrolysis reaction of an enol ether.

In a solvent (tetrahydrofuran, acetone, methanol, ethanol, N,N-dimethylformamide, water, etc. or a mixed solvent thereof), at from -10 ° C to 150 ° C, preferably from 0 ° C to The compound represented by the formula (LIII) is reacted with an acid (hydrochloric acid, sulfuric acid, etc.) at 100 ° C to carry out. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The M method is a method of producing a compound represented by the formula (LIX) by introducing a substituent Y onto a compound represented by the formula (II).

M-I step

This step is produced by introducing a protecting group (tris-butyl dimethyl dimethyl alkyl group, triethyl decyl group, benzyl group, etc.) to a compound represented by the formula (LV) by using a well-known organic chemistry. The step of the compound represented by the formula (LVI). This was carried out in the same manner as the D-I step of the D method.

The compound represented by the formula (LV) is a known compound or a known compound is used as a starting material, and is easily produced according to a known method or the like.

M-II step

This step is carried out by reacting a compound represented by the general formula (LVI) with a known organic chemistry to a 1,4-addition reaction of an α,β-unsaturated ketone to produce a compound of the formula (LVII). The step of the compound.

In the solvent (tetrahydrofuran, diethyl ether, etc.), from -78 ° C to 50 ° C, preferably from -78 ° C to room temperature, in the presence of trimethylsulfonyl chloride, the formula (LVI The compound shown is reacted with an organic copper reagent (prepared by a copper salt such as an organolithium reagent or an organomagnesium reagent). The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

M-III step

This step is carried out by subjecting a compound represented by the formula (LVII) to a deprotection reaction using a well-known organic chemistry, followed by hydrolysis of a decyl enol ether to produce a formula (LVIII). The step of the compound. In the case where PRO ² of the D-VI step of the D method is a tertiary butyl dimethyl decyl group, both reactions can be carried out simultaneously.

M-IV step

This step is a step of producing a compound represented by the formula (LIX) by introducing an ethyl hydrazide into a compound represented by the formula (LVIII) using a well-known organic chemistry. This is carried out in the same manner as in the case where PRO ² and PRO ³ of the B-IX step of the B method are an ethyl group.

The N method is a method of producing a compound represented by the formula (LXI) by introducing a cyclopropane ring onto a compound represented by the formula (II).

N-I step

This step is a step of producing a compound represented by the formula (LX) by subjecting a compound represented by the formula (LV) to a cyclopropanation reaction using a well-known organic chemistry.

In a solvent (dimethyl hydrazine or the like), the compound represented by the formula (LV) and the trimethyl iodide iodide are used at a temperature from 0 ° C to 150 ° C, preferably from 20 ° C to 100 ° C. The reagent obtained by a base (sodium hydride or the like) is reacted in a system to carry out. The reaction time is from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The compound represented by the formula (LV) is a known compound or a known compound is used as a starting material, and is easily produced according to a known method or the like.

N-II step

This step is a step of producing a compound represented by the formula (LXI) by introducing a acetyl group to a compound represented by the formula (LX) by using a well-known organic chemistry. This is carried out in the same manner as in the case where PRO ² and PRO ³ of the B-IX step of the B method are an ethyl group.

The protecting group of the above-mentioned protected amine group, hydroxyl group and/or carboxyl group means a protecting group which is cleavable by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and is generally found in organic synthetic chemistry. Protective groups that can be used (eg, see TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

The "protecting group" of the above-mentioned protected hydroxyl group is not particularly limited as long as it is a protecting group for a hydroxyl group used in the field of organic synthetic chemistry, but may be, for example, a formazan group or the aforementioned "C ₂ -C ₇ a C ₂ -C ₇ halogenated alkylcarbonyl group such as an alkylcarbonyl group, a 2,2,2-trichloroethylcarbonyl group, an alkoxyalkylcarbonyl group such as a methoxyethenyl group, an acryl group or a propyl group An "alkylcarbonyl group" such as an alkynyl group, a methacryl fluorenyl group, a crotonyl group, an isocrotonyl group or an unsaturated alkylcarbonyl group such as (E)-2-methyl-2-butenyl group; An arylcarbonyl group such as a benzamidine group, an α-naphthomethyl fluorenyl group, a β-naphthomethyl fluorenyl group, a halogenated arylcarbonyl group such as a 2-bromobenzylidene group or a 4-chlorobenzylidene group, 2, 4,6-trimethyl benzoyl group, 4-toluyl acyl (4-toluoyl) like C ₁ -C ₆ alkylated arylcarbonyl group, 4- anise and the like acyl C ₁ - a C ₆ alkoxylated arylcarbonyl group, a 4-nitrobenzylidene group, a nitroated arylcarbonyl group such as a 2-nitrobenzylidene group, a 2-(methoxycarbonyl)benzylidene group class C ₂ -C ₇ alkoxycarbonyl group of the arylcarbonyl group, 4-phenyl benzoyl group such arylated arylcarbonyl group "Arylcarbonyl group"; methoxycarbonyl, ethoxycarbonyl or the like C ₂ -C ₇ alkoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, a 2-alkyl ethoxy trimethyl silicon "Alkoxycarbonyl group" such as a halogen such as a carbonyl group or a C ₂ -C ₇ alkoxycarbonyl group substituted by a tris-(C ₁ -C ₆ alkyl)decyl group; tetrahydropyran-2-yl group; 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl, and the like "tetrahydrothiopyranyl" or "tetrahydrothiopyranyl"; tetrahydrofuran-2-yl, tetrahydrothiofuranyl-2-yl or the like, tetrahydrofuranyl or tetra Hydroxylfuranyl; trimethyldecyl, triethyldecyl, isopropyldimethylmethyl, tert-butyldimethylalkyl, methyldiisopropyldecyl, methyldi- Tri-(C ₁ -C ₆ alkyl)decyl, triphenylmethyldecyl, diphenylbutyldecyl, diphenyliso are tris-butylalkyl, triisopropyldecyl (C ₁ -C ₆ alkyl)diarylalkylene or bis-(C ₁ such as propyl decyl, phenyl diisopropyl decyl -C ₆ alkyl)arylalkylalkyl such as "decylalkyl"; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl a (C ₁ -C ₆ alkoxy)methyl group such as isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl or the like (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy)methyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl An alkoxymethyl group such as a (C ₁ -C ₆ halogenated alkoxy)methyl group; a 1-ethoxyethyl group, a 1-(isopropoxy)ethyl group or the like (C ₁ - "Substituted ethyl group" such as a C ₆ alkoxy)ethyl group, a halogenated ethyl group such as 2,2,2-trichloroethyl; a benzyl group, an α-naphthylmethyl group, a β-naphthylmethyl group, a C ₁ -C ₆ alkyl group substituted with 1 to 3 aryl groups such as diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-fluorenylmethyl, 4 -methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl An aryl ring such as 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-cyanobenzyl via C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halogen, cyano substituted "aralkyl" of C ₁ -C ₆ alkyl substituted by 1 to 3 aryl groups; vinyloxycarbonyl, allyloxy "Alkenyloxycarbonyl" such as carbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxy An arylalkyloxycarbonyl group, preferably an alkyl group, having an aryl ring such as a carbonyl group or a 4-nitrobenzyloxycarbonyl group which may be substituted by 1 or 2 C ₁ -C ₆ alkoxy groups or a nitro group. Carbonyl, decyl or aralkyl.

The "protecting group" of the above-mentioned protected carboxyl group is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of organic synthetic chemistry, but may be, for example, the above-mentioned "C ₁ -C ₆ alkyl group"; C ₂ -C ₆ alkenyl such as vinyl, allyl; ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 1-butynyl, and the like C ₂ -C ₆ alkynyl; the aforementioned "C ₁ -C ₆ halogenated alkyl group"; the aforementioned "C ₁ -C ₆ hydroxyalkyl group"; an ethyl chloromethyl group (C ₂ -C ₇ alkylcarbonyl group) And a (C ₁ -C ₆ alkyl) group; the aforementioned "aralkyl group"; or the aforementioned "alkyl group", preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

The "protecting group" of the above-mentioned protected amine group is not particularly limited as long as it is a protecting group for an amine group used in the field of organic synthetic chemistry, and can be expressed, for example, in the above-mentioned "protecting group for a hydroxyl group". "Alkylcarbonyl"; "arylcarbonyl"; "alkoxycarbonyl"; "decylalkyl"; "aralkyl"; "alkenyloxycarbonyl"; or "aralkyloxycarbonyl" Or N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, arsenyl, 5-chloroazide "Substituted methylene group forming a Schiff base" such as a diphenylmethylene group or a (5-chloro-2-hydroxyphenyl)phenylmethylene group, preferably an alkylcarbonyl group or an aromatic group A carbonyl group or an alkoxycarbonyl group is more preferably an alkoxycarbonyl group.

Protection ‧ Deprotection is a necessary step based on known methods (eg “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter G.M. Wuts, 1999, It is carried out by the method described in Wiley-Interscience Publication).

The compound of the present invention or an isotope label compound thereof or a pharmaceutically acceptable salt thereof can be administered in various forms. The administration form may, for example, be oral administration using a tablet, a capsule, a granule, an emulsion, a pill, a powder, a syrup (liquid), or an injection (intravenous) , intramuscular, subcutaneous or intraperitoneal administration), drip, suppository (rectal administration), external preparation (transdermal administration), etc. are not administered orally. Each of these preparations may be a pharmaceutical preparation using an excipient, a binder, a disintegrator, a lubricant, a flavoring agent, a dissolution aid, a suspending agent, a coating agent, a solvent, a base, etc., according to a usual method. Formulation is carried out by adjuvants which are often used in the technical field.

As a carrier, as the carrier, for example, an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid or the like; water, ethanol, and c can be used; a combination of an alcohol, a simple syrup, a glucose solution, a starch solution, a gelatin solution, a carboxymethylcellulose, a shellac, a methylcellulose, a potassium phosphate, a polyvinyl pyrrolidone, etc.; Starch, sodium alginate, agar powder, laminose powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. ; disintegration inhibitors such as white sugar, stearin, cocoa butter, hydrogenated oil; absorption enhancers such as 4-grade ammonium salts, sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin , adsorbent for bentonite, colloidal citric acid, etc.; purified talc, stearate, boric acid powder, polyethyl b A lubricant such as a glycol or the like. Further, if necessary, a tablet which can be applied to a general skin, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric coated tablet, a film-coated tablet or a double-layer ingot, or a multilayer ingot can be prepared.

In the case of use as a pill, as the carrier, for example, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc, etc.; gum arabic powder, tragacanth powder, gelatin, ethanol, etc. may be used. a binding agent; a disintegrant such as laminaria, agar, or the like.

When it is used as a suppository, it can be widely used as a carrier in the field, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

As the injection, it can be used as a liquid, emulsion or suspension. Such liquids, emulsions or suspensions are sterilized and are preferably the same as blood. The solvent used for the production of such a liquid preparation, emulsion or suspension may be used as a diluent for medical use, and is not particularly limited, and examples thereof include water, ethanol, propylene glycol, and ethoxylated iso-hard. A fatty alcohol, a polyoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester or the like. Further, in this case, in order to prepare an isotonic solution, a sufficient amount of salt, glucose or glycerin, or a general dissolution aid, a buffer, an soothing agent or the like may be contained in the preparation.

When it is used as an external preparation, it can be used as a external solid solution, an external liquid preparation (liniment, lotion), a spray, an ointment, a creams, a gel, or a patch. These external preparations can be produced according to a usual method using a solvent, a base, an additive, an excipient, or the like for a general pharmaceutical.

Further, the above-mentioned preparation may contain a coloring agent, a preservative, a flavor, a flavor, a sweetener, etc., if necessary, and may further contain other pharmaceuticals.

The amount of the active ingredient compound contained in the above-mentioned preparation is not particularly limited and can be appropriately selected from a wide range, but it is usually from 0.5 to 70% by weight, preferably from 1 to 30% by weight, based on the total composition.

The amount to be used varies depending on the symptoms, age, and the like of the patient (warm-blooded animal, especially human), but it is desirable that, in the case of oral administration, the lower limit per one time is 0.001 mg/kg body weight (preferably 0.01 mg/kg body weight), the upper limit is 500 mg/kg body weight (preferably 50 mg/kg body weight), and in the case of intravenous administration, the lower limit per one time is 0.005 mg/kg body weight (preferably 0.05 mg). /kg body weight), the upper limit is 50 mg / kg body weight (preferably 5 mg / kg body weight), the symptoms are administered from 1 to several times per day.

[Examples]

The present invention will be described in more detail below by way of examples and test examples, but the scope of the invention is not limited thereto.

The elution in the column chromatography of the examples was carried out under the observation of TLC (Thin Layer Chromatography). In the TLC observation, the TLC plate in terms of system using Merck silica gel (Merck) Corporation's 60F _254, to expand the purposes of use of the solvent in column chromatography as an elution solvent in solvent used, is detected in terms of method It is colored by a UV detector or by using phosphomolybdic acid (ethanol solution). For the column, the SK-85 (230~400mesh) made by Merck, the Hi-Flash ^TM Column, the Biotage company (SNAP, SNAP Ultra), the Moritex company (Purif-pack) or the Grace company. system (GraceResolv ^TM). In addition to general column chromatography, it is also possible to use Shanshan Co., Ltd. (FR50N, Parallel Frac FR-360, W-Prep 2XY), TELEDYNE ISCO (Companion Combi Flash), and Moritex (Purif-α2). And the automated chromatography device of Biotage (SP-1).

The purification using preparative TLC (preparative TLC) was performed using a silicone gel 60F ₂₅₄ manufactured by Merck & Co., Ltd., 1.0 mm thick, and a plate of 20 x 20 cm. Moreover, the abbreviations used in the examples have the following meanings.

Mg: mg, g: g, ml: ml, MHz: megahertz.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H NMR) spectroscopy uses tetramethyl decane as a standard material, and the chemical shift value is described as a δ value (ppm). The split pattern is represented by a single peak as s, a doublet as d, a triplet as t, a quartet as q, a broad peak as br, and a multiplet as m. The solvent was measured using CDCl ₃ : heavy chloroform or CD ₃ OD: tetramethanol.

Mass analysis (hereinafter, MS) was carried out by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method.

Further, the powder X-ray diffraction system was placed on the non-reflective sample carrier by a spatula with a dose of several mg of the test substance, and the sample was flattened by the medicine wrap, and then the peak pattern was analyzed under the following analysis conditions.

<Analysis conditions>

Model: Rigaku Rint TTR-III; sample carrier: non-reflective sample carrier

Sample: appropriate amount; X-ray production conditions: 50kV, 300mA; wavelength: 1.54Å (copper Kα line)

Scanning speed: 20 ° / min; scanning range: 2 ~ 40 °; sample width: 0.02 °.

(Example 1)

(Example 1-1)

Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-10a, 12a-dimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-yl]methanone (α-alcohol)

(Example 1-2)

Cyclohexyl [(4aS,4bR,6aS,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-yl]methanone (β-alcohol)

(step 1)

Cyclohexyl [(4aS,4bR,8S,10aR,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b ,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11 12,12a-hexadehydronaphtho[2,1-f]quinolin-8-ol (10 g) was suspended in dichloromethane (100 ml) and water (100 ml), and sodium hydrogen carbonate (9.9 g) was added. To the stirring under ice cooling, cyclohexyl carbonyl chloride (5.2 ml) was slowly added, and the mixture was stirred at 0 ° C for 4 hours and stirred. The reaction solution was poured into a two-layer solution of ethyl acetate and brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m/z: 440 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.36-5.34 (1H, m), 3.54-3.50 (1H, m), 3.46-3.35 (2H, m), 3.27-3.26 (1H, m), 2.55-2.11 ( 5H, m), 1.89-0.99 (25H, m), 1.43 (3H, s), 0.97 (3H, s).

(Step 2)

Cyclohexyl [(4aS,6aS,6bR,9S,12aR,12bS)-9-hydroxy-4a,6b-dimethyltetrahydrogen-1H-oxirane[4,4a]naphtho[2,1- f] quinoline-4(4aH)-yl]methanone (cyclohexyl[(4aS,6aS,6bR,9S,12aR,12bS)-9-hydroxy-4a,6b-dimethyltetradecahydro-1H-oxireno[4,4a]naphtho [2,1-f]quinoline-4(4aH)-yl]methanone)

To a solution of the compound (2.84 g), m. m. The reaction solution was quenched by adding a 10% aqueous sodium thiosulfate solution and saturated sodium hydrogencarbonate solution. The reaction solution was poured into two layers of ethyl acetate and saturated sodium hydrogencarbonate to give acetic acid Ester extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc)

Main product

¹ H-NMR (CDCl ₃ ) δ: 3.88 (1H, m), 3.39 (1H, m), 3.32 (1H, m), 3.19 (1H, m), 2.90 (1H, d, J = 4.4 Hz), 2.33 (1H, m), 2.33 (1H, dd, J = 3.0, 11.5 Hz), 2.00-1.08 (28H, m), 1.35 (3H, s), 1.00 (3H, s).

(Step 3)

Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-10a, 12a-dimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-yl]methanone (α-alcohol) and cyclohexyl [[4aS,4bR,6aS,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone (β-alcohol)

Lithium borohydride (545 mg) and boron trifluoride diethyl ether complex (0.039 ml) were sequentially added to a solution of the compound (2.60 g) obtained in the above step 2 in tetrahydrofuran (30 ml). . The reaction solution was added with borneol and a saturated aqueous solution of ammonium chloride to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and a mixture of ethyl acetate and dichloromethane (1:1) was added to the residue to obtain a slurry. Will get it The title compound (α-alcohol) (1.11 g).

The filtrate was further concentrated under reduced pressure, and purified by EtOAc EtOAc EtOAc EtOAc EtOAc Compound (β-alcohol) (35 mg).

α-Alcohol: Example 1-1

MS (ESI) m/z: 418 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.05 (1H, m), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 1.86-1.12 (31H , m), 1.38 (3H, s), 1.10 (1H, s), 0.92 (3H, s).

β-Alcohol: Example 1-2

MS (ESI) m/z: 418 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.13 (1H, brs), 3.41 (1H, m), 3.33 (1H, m), 3.26 (1H, m), 3.04 (1H, br), 2.77 (1H, br ), 2.34 (1H, m), 2.15 (1H, dd, J = 3.4, 14.6 Hz), 1.84-1.10 (28H, m), 1.37 (3H, s), 0.92 (1H, m), 0.88 (3H, s).

(Example 2)

Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-6,6a,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-6,6a,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

The compound obtained in the second step of Example 1 (185 mg) In a solution of alkane (3.0 ml), water (0.16 ml) and 0.1 equivalent of perchloric acid/1,4-dimer are added sequentially at room temperature. The alkane solution (0.40 ml) was stirred at the same temperature for 4 hours. Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with diethyl ether, water and diethyl ether.

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.09 (1H, m), 3.58 (1H, brs), 3.46 (1H, m), 3.36 (1H, m), 3.29 (1H, m), 2.08 (1H, m) ), 2.08 (1H, dd, J = 11.3, 12.9 Hz), 1.89-1.17 (29H, m), 1.44 (3H, s), 1.14 (3H, s), 1.10 (1H, s).

(Example 3)

(4aS, 4bR, 6aR, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a, 12a-dimethylhexadenaphtho[2,1-f]quinoline-8 ( 2H)-ketone

(step 1)

(4aS, 4bR, 6aR, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a, 12a-dimethylhexadenaphtho[2,1-f]quinoline-8 ( 2H)-ketone

To a solution of the compound (α-alcohol) (400 mg) in methylene chloride (20.0 ml) obtained in Step 3 of Example 1, Dess-Martin Periodinane (609 mg) was added at room temperature. Stir at the same temperature for 2 hours. A saturated aqueous sodium hydrogencarbonate solution and a 10% aqueous sodium thiosulfate solution were added to the reaction mixture to terminate the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Methylene chloride was added to the residue obtained by concentrating the filtrate under reduced pressure to obtain a slurry, and the solid was collected by filtration. The filtrate was concentrated under reduced pressure. EtOAc m.

MS (ESI) m / z: 416 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.42 (1H, m), 3.33 (1H, m), 3.28 (1H, m), 2.65 (1H, d, J = 15.1 Hz), 2.40-2.30 (3H, m ), 2.08 (1H, dd, J = 1.5, 15.1 Hz), 1.90-1.15 (27H, m), 1.41 (3H, s), 1.11 (3H, s).

(Example 4)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based acetate

(step 1)

Cyclohexyl [(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecano[2,1-f]quinoline-1 ( 2H)-yl]methanone

To a solution of the compound (295 mg) obtained in EtOAc (EtOAc m. m. The temperature was raised to 0 ° C and further stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. Hydrogen peroxide water (30%, 0.8 ml), potassium hydroxide aqueous solution (8 M, 0.4 ml), and water (5.0 ml) were added under ice-cooling, and the mixture was stirred at the same temperature for one hour. After the reaction mixture was neutralized with hydrochloric acid, it was poured into two layers of ethyl acetate and aq. The organic layer was washed with water, a 10% aqueous sodium thiosulfate solution, and brine, and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate /hexane)

MS (ESI) m / z: 418 (M + H) +.

(Step 2)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based acetate

To a suspension of the compound (310 mg) obtained in the above step 1 in dichloromethane (10 ml), triethylamine (0.515 ml), 4-dimethylamine pyridine (9.1 mg), Acetic anhydride (0.245 ml) was stirred at the same temperature for one night. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and the mixture was poured into ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc:EtOAc)

MS (ESI) m/z: 460 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.18 (1H, m), 3.40 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 3.14 (1H, d, J = 1.5 Hz), 2.35 (1H, m), 2.04 (3H, s), 1.85 (1H, dd, J = 3.7, 15.4 Hz), 1.84-1.03 (29H, m), 1.39 (3H, s), 0.88 (3H, s) .

(Example 5)

Cyclohexyl [(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecano[2,1-f]quinoline-1 ( 2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecano[2,1-f]quinoline-1 ( 2H)-yl]methanone

A solution of the compound (115 mg) in EtOAc (EtOAc (MeOHMeOHMeOHMeOHMeOHMeOHMeOHMeOH hour. After the reaction mixture was neutralized, it was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjj

MS (ESI) m/z: 418 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.10 (1H, brs), 3.56-3.51 (1H, br), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.71-2.65 (1H, br), 2.34 (1H, m), 1.85-1.05 (30H, m), 1.39 (3H, s), 0.87 (3H, s).

(Example 6)

(2,6-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

(step 1)

(2,6-difluorophenyl)[(4aS,4bR,8S,10aR,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8 ,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

Use (4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11 , 12,12a-hexadehydronaphtho[2,1-f]quinolin-8-ol (5.00 g) and 2,6-difluorobenzhydrazide chloride (2.60 ml), The title compound (4.75 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.31-7.27 (1H, m), 6.88-6.86 (2H, m), 5.38-5.37 (1H, m), 3.55-3.54 (1H, m), 2.79-2.77 ( 1H,m),2.56-2.52(2H,m), 2.36-2.33(1H,m), 2.25-2.23(2H,m),1.99-1.96(1H,m),1.90-1.85(2H,m), 1.78-1.75 (1H, m), 1.70-1.65 (1H, m), 1.54 (3H, s), 1.52-1.39 (9H, m), 1.20-1.07 (2H, m), 1.01 (3H, s).

(Step 2)

(2,6-difluorophenyl)[(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-hydroxy-4a,6b-dimethyltetrahydrogen-1H-ethylene oxide [4,4a]naphtho[2,1-f]quinoline-4(4aH)-yl]methanone

The title compound (1.83 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.24 (1H, m), 6.86 (2H, m), 3.90 (1H, m), 3.39-3.30 (2H, m), 3.11 (1H, m), 2.91 (1H) , d, J = 4.4 Hz), 2.07-1.15 (19H, m), 1.55 (3H, s), 1.03 (3H, s).

(Step 3)

(2,6-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

Lithium borohydride (60 mg) was added to a solution of the compound (200 mg) in tetrahydrofuran (3.0 ml) obtained in the step 2, and stirred at 60 to 70 ° C for 12 hours. The reaction was stopped by adding borneol and a saturated aqueous solution of ammonium chloride to the reaction mixture. The reaction solution is poured into ethyl acetate and a saturated aqueous solution of ammonium chloride. In the second layer, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating EtOAc (EtOAc) (HHHHHHHHHHHHHHH 19mg).

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.23 (1H, m), 6.86 (2H, m), 4.06 (1H, m), 3.46 (1H, s), 3.40-3.33 (2H, m), 3.14 (1H) , m), 1.86-1.19 (19H, m), 1.54 (3H, s), 1.08 (1H, s), 0.95 (3H, s), 0.93 (1H, m).

(Example 7)

(2,6-difluorophenyl)[(4aS,4bR,6R,6aR,8S,10aR,10bS,12aS)-6,6a,8-trihydroxy-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,6-difluorophenyl)[(4aS,4bR,6R,6aR,8S,10aR,10bS,12aS)-6,6a,8-trihydroxy-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

A compound (132 mg) was obtained as a white solid.

MS (ESI) m/z: 464 (M+H) ⁺

¹ H-NMR (DMSO-d ₆ ) δ: 7.43 (1H, m), 7.13 (2H, m), 4.43 (1H, d, J = 3.9 Hz), 4.16 (1H, d, J = 5.9 Hz), 3.78 (1H, m), 3.69 (1H, s), 3.35-3.28 (2H, m), 3.18 (1H, m), 3.00 (1H, m), 1.83 (1H, m), 1.78-1.23 (14H, m), 1.43 (3H, s), 1.18-1.04 (3H, m), 0.98 (3H, s).

(Example 8)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[ 2,1-f]quinoline-6,8-diyl diacetate

(step 1)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[ 2,1-f]quinoline-6,8-diyl diacetate

The title compound (77 mg) was obtained from m.

MS (ESI) m/z: 548 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.24 (1H, m), 6.86 (2H, m), 5.13 (1H, m), 4.73 (1H, t, J = 2.9 Hz), 3.40-3.32 (2H, m ), 3.13 (1H, m), 2.26 (1H, s), 2.05 (3H, s), 2.00 (3H, s), 1.84 (1H, m), 1.80-1.18 (17H, m), 1.56 (3H, s), 1.10 (3H, s).

(Example 9)

(2,6-difluorophenyl)[(4aS,4bR,6R,6aR,8S,10aR,10bS,12aS)-6-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadecane Naphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,6-difluorophenyl)[(4aS,4bR,6R,6aR,8S,10aR,10bS,12aS)-6-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadecane Naphtho[2,1-f]quinoline-1(2H)-yl]methanone

A solution of the compound (250 mg) in methylene chloride (EtOAc) (EtOAc) The reaction was stopped by adding an aqueous sodium hydrogencarbonate solution to the reaction mixture. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by EtOAc EtOAc EtOAc. The title compound (89 mg) was obtained as white crystal.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.23 (1H, m), 6.89-6.84 (2H, m), 4.25 (1H, m), 4.04 (1H, m), 3.43-3.33 (2H, m), 3.16(1H,m),2.08(1 H,m),1.97(1H,m),1.89-1.21(17H,m),1.55(3H,s),1.13(1H,brs),1.06(3H,d , J = 5.4 Hz).

(Embodiment 10)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H) -yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11 ,12,12a-tetradeconaphtho[2,1-f]quinolin-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone (S body: Rf=higher) and [(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11 ,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone (R body: Rf=lower)

Use (4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11 , 12,12a-hexadehydronaphtho[2,1-f]quinolin-8-ol (1.85 g) and tetrahydropyran-2-carbonyl chloride (1.14 g), by The same procedure as in the first step of Example 1 was carried out, and the reaction was carried out, and separated and purified by silica gel column chromatography [ethyl acetate / hexane]. The title compound was obtained as a non-image-isomer (S) (923 mg)

Non-image isomer (S body) (Rf=higher: low polarity)

MS (ESI) m/z: 402 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.34 - 5.33 (1H, m), 3.98-3.95 (2H, m), 3.48-3.41 (4H, m), 3.28-3.25 (1H, m), 2.29-2.12 ( 3H, m), 1.92-1.48 (17H, m), 1.44 (3H, s), 1.42-1.01 (6H, m), 0.97 (3H, s).

Non-image isomer (R body) (Rf=lower: high polarity)

MS (ESI) m/z: 402 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.34 - 5.32 (1H, m), 4.04-4.02 (1H, m), 3.98-3.96 (1H, m), 3.58-3.26 (5H, m), 2.28-2.16 ( 3H, m), 1.93-1.49 (17H, m), 1.45 (3H, s), 1.29-1.10 (6H, m), 0.97 (3H, s).

(Step 2)

[(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-hydroxy-4a,6b-dimethyltetrahydrogen-1H-oxirane[4,4a]naphtho[2, 1-f]quinoline-4(4aH)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (492 mg) was obtained as white crystals.

Main product (α-epoxide)

¹ H-NMR (CDCl ₃ ) δ: 3.99 (1H, m), 3.92 (1H, dd, J = 2.4, 10.7 Hz), 3.87 (1H, m), 3.52 (1H, m), 3.40 (1H, dt , J=2.3, 11.6 Hz), 3.27 (1H, m), 3.19 (1H, m), 2.90 (1H, d, J = 4.4 Hz), 2.03 (1H, dd, J = 11.2, 12.7 Hz), 2.02 -1.07 (24H, m), 1.36 (3H, s), 1.00 (3H, s).

(Step 3)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H) -yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

To a solution of the compound (492 mg) in EtOAc (EtOAc m. After cooling the reaction mixture, the reaction was stopped by adding borneol and a saturated aqueous solution of ammonium chloride. The reaction solution was poured into two layers of dichloromethane and a saturated aqueous sodium hydrogen carbonate solution, and extracted three times with dichloromethane/methanol (10:1). After the organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI) m/z: 420 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.05 (1H, m), 4.00 (1H, m), 3.94 (1H, dd, J = 2.4, 10.7 Hz), 3.53 (1H, m), 3.40 (1H, m ), 3.33 - 3.23 (2H, m), 1.91-1.10 (27H, m), 1.40 (3H, s), 1.07 (1H, s), 0.92 (3H, s).

(Example 11)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H) -yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-hydroxy-4a,6b-dimethyltetrahydrogen-1H-oxirane[4,4a]naphtho[2, 1-f]quinoline-4(4aH)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (847 mg) was obtained as a white solid.

Main product (α-epoxide)

¹ H-NMR (CDCl ₃ ) δ: 3.94 - 3.84 (3H, m), 3.44 - 3.32 (3H, m), 3.19 (1H, m), 2.90 (1H, d, J = 4.4 Hz), 2.03 (1H) , dd, J = 11.2, 12.7 Hz), 2.01-1.09 (24H, m), 1.35 (3H, s), 1.00 (3H, s).

(Step 2)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H) -yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (198 mg) was obtained as a white solid.

MS (ESI) m / z: 420 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.05 (1H, m), 3.95-3.91 (1H, m), 3.93 (1H, dd, J = 3.9, 8.8 Hz), 3.45-3.39 (2H, m), 3.35 (1H, m), 3.25 (1H, m), 1.89-1.11 (27H, m), 1.39 (3H, s), 1.09 (1H, s), 0.92 (3H, s).

(Embodiment 12)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9,10,10a,10b, 11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

The compound obtained in the first step of Example 1 (6.1 g) was suspended in toluene (150 ml), and cyclohexanone (15 ml) and aluminum isopropoxide (1.6 g) were added and heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate, and washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

MS (ESI) m/z: 398 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.73-5.71 (1H, m), 3.61-3.60 (2H, m), 3.46-3.43 (1H, m), 3.37-3.34 (2H, m), 2.42-0.98 ( 33H, m).

(Step 2)

Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a, 12a-dimethyl-3,4,4a,4b,5,6,8,9,10,10a,10b ,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

Sodium borohydride (57 mg) was added to a solution of the compound (300 mg) obtained in the above step 1 in ethanol (10 ml), and the mixture was stirred for 4 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc m.

MS (ESI) m / z: 400 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.25 (1H, d, J = 1.5 Hz), 4.11 (1H, m), 3.40 (1H, m), 3.32 (1H, m), 3.25 (1H, m), 2.33(1H,m), 2.14(1H,m), 2.01(1H,m),1.91-1.02(26H,m), 1.40(3H,s),0.98(3H,s),0.79(1H,m) .

(Step 3)

Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-4a, 6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[ 2,1-f]quinoline-7(5H)-yl]methanone

The title compound (212 mg) was obtained as a white solid.

MS (ESI) m / z: 416 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.42 (1H, m), 3.33 (1H, m), 3.27 (1H, m), 3.13 (1H, d, J = 4.9 Hz), 2.34(1H,m), 2.20(1H,d,J=10.3Hz), 2.07(1H,m),1.94(1H,m),1.87-1.06(25H,m),1.40(3H,s),0.96 (3H, s), 0.93 (1H, m).

(Step 4)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

The title compound (151 mg) was obtained as a white solid.

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.02 (1H, m), 3.50 (1H, m), 3.42 (1H, d, J = 3.9 Hz), 3.40 (1H, m), 3.15 (1H, m) , 2.47 (1H, m), 2.11 (1H, m), 1.91-1.13 (27H, m), 1.38 (3H, s), 1.08 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 1, and the peak having a relative intensity of 10 or more in the case where the maximum peak intensity in Fig. 1 is 100 is shown in Table 1.

(Example 13)

Cyclohexyl [(4aS,4bR,6aR,7R,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(step 1)

[(4aS,4bR,8S,10aR,10bS,12aS)-8-(benzyloxy)-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10, 10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl](cyclohexyl)methanone

To a solution of the compound (1.85 g) obtained in Step 2 of Example 12 in N,N-dimethylformamide (30 ml), sodium hydride (55 wt%, 2.02 g) at room temperature at the same temperature After stirring for 30 minutes, benzyl bromide (5.50 ml) was added and stirred for 28 hours. Under ice cooling, methanol was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 7.35 - 7.21 (5H, m), 5.36 (1H, d, J = 1.5 Hz), 4.58 (1H, d, J = 11.7 Hz), 4.52 (1H, d, J) =11.7Hz), 3.91(1H,m), 3.40(1H,m), 3.31(1H,m), 3.25(1H,m), 2.33(1H,m),2.20-1.06(27H,m),1.40 (3H, s), 0.99 (3H, s), 0.79 (1H, m).

(Step 2)

[(1aR, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aS)-2-(benzyloxy)-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5] Naphtho[2,1-f]quinoline-7(5H)-yl](cyclohexyl)methanone

The title compound (725 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.35 - 7.22 (5H, m), 4.60 (1H, d, J = 11.7 Hz), 4.58 (1H, d, J = 11.7 Hz), 3.67 (1H, dd, J = 7.8, 9.8 Hz), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 3.01 (1H, s), 2.34 (1H, m), 1.98 (1H, m), 1.89 - 1.09 (26H, m), 1.41 (3H, s), 1.04 (3H, s), 1.02 (1H, m).

(Step 3)

[(4aS,4bR,7S,8S,10aR,10bS,12aS)-8-(benzyloxy)-7-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7, 8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinolin-1(2H)-yl](cyclohexyl)methanone (allyl alcohol) And [(4aS,4bR,6aR,7R,8S,10aR,10bS,12aS)-8-(benzyloxy)-6a,7-dihydroxy-10a,12a-dimethylhexadecane] 2,1-f]quinoline-1(2H)-yl](cyclohexyl)methanone (diol)

The title compound (allyl alcohol) (139 mg) was obtained as a white solid (yield: ) (297 mg).

Allyl alcohol

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.79 (1H, m), 4.68 (1H, d, J = 11.7 Hz), 4.47 (1H, d, J = 11.7 Hz), 4.17 (1H, m), 3.42 (1 H, m), 3.35 (1H, m), 3.25 (1H, m), 3.10 (1H, m), 2.77 (1H, d, J = 2.0 Hz), 2.35 ( 1H, m), 2.24 (1H, dm), 2.01 (1H, m), 1.88-1.00 (24H, m), 1.41 (3H, s), 0.96 (3H, s).

Diol body

MS (ESI) m / z: 524 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.33 - 7.24 (5H, m), 4.59 (1H, d, J = 11.7 Hz), 4.49 (1H, d, J = 11.7 Hz), 3.87 (1H, brs), 3.57 (1H, brs), 3.40 (1H, m), 3.32 (1H, m), 3.21 (1H, m), 2.44 (1H, d, J = 4.4 Hz), 2.33 (1H, m), 1.94-1.12 (29H, m), 1.38 (3H, s), 0.88 (3H, s).

(Step 4)

Cyclohexyl [(4aS,4bR,6aR,7R,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

A 10% wet palladium carbon catalyst (300 mg) was added to a solution of the compound (diol) (297 mg) in ethanol (10 ml) in tetrahydrofuran (10 ml), and the mixture was stirred for 6 hours under hydrogen atmosphere. The catalyst was filtered, and the residue obtained was purified mjjjjjjjj

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.73 (1H, m), 3.60 (1H, d, J = 2.4 Hz), 3.50 (1H, m), 3.39 (1H, m), 3.15 (1H, m) , 2.47 (1H, m), 2.04 (1H, br), 1.93-1.11 (27H, m), 1.38 (3H, s), 0.87 (3H, s).

(Example 14)

Cyclohexyl [(4aS,4bR,6R,6aR,7R,8S,10aR,10bS,12aS)-6,6a,7,8-tetrahydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

(step 1)

[(4aS,6aS,6bR,9S,10R,10aS,11aS,12aR,12bS)-9-(benzyloxy)-10-hydroxy-4a,6b-dimethyltetrahydrogen-1H-epoxy Alkenes [4,4a]naphtho[2,1-f]quinoline-4(4aH)-yl](cyclohexyl)methanone

The title compound (66 mg) was obtained as a white solid.

MS (ESI) m/z: 522 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.24 (5H, m), 4.66 (1H, d, J = 11.7 Hz), 4.57 (1H, d, J = 11.7 Hz), 3.95 (1H, dd, J = 6.6, 9.5 Hz), 3.42 (1H, d, J = 4.4 Hz), 3.41-3.29 (3H, m), 3.20 (1H, m), 2.33 (1H, m), 2.08-1.99 (2H, m) , 1.97 (1H, d, J = 6.8 Hz), 1.78-1.08 (24H, m), 1.34 (3H, s), 1.00 (3H, s).

(Step 2)

[(4aS,4bR,6R,6aR,7R,8S,10aR,10bS,12aS)-8-(benzyloxy)-6,6a,7-trihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl](cyclohexyl)methanone

The title compound (66 mg) was obtained.

MS (ESI) m/z: 540 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.24 (5H, m), 4.66 (1H, d, J = 11.7 Hz), 4.43 (1H, d, J = 11.7 Hz), 4.05 (1H, d, J) = 7.8 Hz), 3.86 (1H, brs), 3.61 (1H, m), 3.41 (1H, m), 3.32 (1H, m), 3.21 (1H, m), 3.05 (1H, d, J = 1.5 Hz) ), 2.37-2.29 (2H, m), 1.99 (1H, m), 1.81-1.13 (26H, m), 1.39 (3H, s), 1.06 (3H, s).

(Step 3)

Cyclohexyl [(4aS,4bR,6R,6aR,7R,8S,10aR,10bS,12aS)-6,6a,7,8-tetrahydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

The title compound (48 mg) was obtained.

MS (ESI) m / z: 450 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.93 (1H, m), 3.80 (1H, d, J = 9.3 Hz), 3.70 (1H, m), 3.51 (1H, m), 3.40 (1H, m) , 3.16 (1H, dd, J = 3.2, 9.0 Hz), 2.48 (1H, m), 1.92-1.12 (26H, m), 1.41 (3H, s), 1.08 (3H, s).

(Example 15)

(Example 15-1)

Cyclohexyl [(4aS,4bR,6aR,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(Example 15-2)

Cyclohexyl [(4aS,4bR,6aR,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(step 1)

(4aS,4bR,6aR,7R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a,7-dihydroxy-10a,12a-dimethylhexadecaphthalene[2,1-f] Quinoline-8(2H)-one (β-diol) and (4aS,4bR,6aS,7S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a,7-dihydroxy-10a,12a - dimethyl hexadecahydronaphtho[2,1-f]quinoline-8(2H)-one (α-diol)

In a solution of the compound (1.50 g) obtained in Step 1 of Example 12 in acetone (16 ml)-water (4 ml), 4-methyl-N-oxidation was added sequentially at room temperature. The porphyrin (796 mg) and a 4% aqueous solution of osmium tetroxide (0.80 ml) were stirred at the same temperature for 16 hours. After adding 10% aqueous sodium thiosulfate solution and saturated sodium hydrogencarbonate water to the reaction mixture, the mixture was stirred for 1 hour, and then the mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography eluting elut elut elut elut elut ) (237 mg).

Beta-diol

MS (ESI) m / z: 432 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.47 (1H, d, J = 2.9 Hz), 3.76 (1H, d, J = 2.9 Hz), 3.41 (1H, m), 3.35-3.30 (2H, m), 2.42-2.28 (3H, m), 1.96-1.15 (26H, m), 1.39 (3H, s), 1.05 (1H, m), 0.95 (3H, s).

Alpha-diol

MS (ESI) m / z: 432 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.11 (1H, d, J = 2.0 Hz), 3.75 (1H, d, J = 2.0 Hz), 3.41 (1H, m), 3.33 (1H, m), 3.27 ( 1H, m), 2.50-2.44 (2H, m), 2.34 (1H, m), 1.95-1.13 (27H, m), 1.41 (3H, s), 1.17 (3H, s).

(Step 2)

Cyclohexyl [(4aS,4bR,6aR,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone (β-alcohol) and cyclohexyl [[4aS,4bR,6aR,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a -Dimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone (α-alcohol)

To a solution of the compound (β-diol) (908 mg) obtained in the above step 1 in methylene chloride (5.0 ml), sodium hydrogen triethyl sulfonate (803 mg) was added at room temperature, and stirred at the same temperature. hour. The reaction was stopped by adding saturated sodium hydrogencarbonate water to the reaction mixture. The reaction solution was poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate, and extracted three times with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the dried solvent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

β-Alcohol: Example 15-1

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.98 (1H, m), 3.85 (1H, d, J = 3.4 Hz), 3.51 (1H, m), 3.40 (1H, m), 3.17 (1H, m) , 2.48 (1H, m), 1.99 (1H, m), 1.89-1.16 (26H, m), 1.39 (3H, s), 1.02 (1H, m), 0.90 (3H, s).

Alpha-alcohol: Example 15-2

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.68 (1H, d, J = 8.8 Hz), 3.63 (1H, m), 3.52 (1H, m), 3.41 (1H, m), 3.18 (1H, m) , 2.48 (1H, m), 1.96 (1H, 13.1, 3.4 Hz), 1.92-1.14 (26H, m), 1.39 (3H, s), 1.05 (1H, s), 0.87 (3H, s).

(Embodiment 16)

(Example 16-1)

Cyclohexyl [(4aS,4bR,6aS,7R,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone (β-alcohol)

(Example 16-2)

Cyclohexyl [(4aS,4bR,6aS,7R,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone (α-alcohol)

(step 1)

Cyclohexyl [(4aS,4bR,6aS,7R,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone (β-alcohol) and cyclohexyl [(4aS,4bR,6aS,7R,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a -Dimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone (α-alcohol)

The title compound (β-alcohol) (28 mg) was obtained as a white solid. The title compound (α-alcohol) (121 mg).

β-Alcohol: Example 16-1

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.69 (1H, m), 3.51 (1H, m), 3.40 (1H, m), 3.31 (1H, d, J = 8.8 Hz), 3.16 (1H, m) , 2.48 (1H, m), 1.90-1.11 (28H, m), 1.39 (3H, s), 0.92 (3H, s).

Alpha-alcohol: Example 16-2

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.94 (1H, m), 3.51 (1H, m), 3.46 (1H, d, J = 3.4 Hz), 3.41 (1H, m), 3.18 (1H, m) , 2.48 (1H, m), 1.92-1.10 (28H, m), 1.39 (3H, s), 0.91 (3H, s).

(Example 17)

Cyclohexyl [(4aS,4bR,6aR,7R,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 8R, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-10a,12a-dimethyl-1,2,3,4,4a,4b,5,6,8,9, 10,10a,10b,11,12,12a-hexadehydronaphtho[2,1-f]quinolin-8-yl acetate

Triethylphosphine (891 mg), acetic acid (0.194 ml), and diethyl azodicarboxylate were added sequentially at 0 ° C in a solution of the compound (452 mg) in THF (10 ml). (diethyl Azodicarboxylate (2.2 M in toluene, 1.1 ml) was stirred at the same temperature for 4 hours. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (ethyl acetate /hexane)

¹ H-NMR (CDCl ₃ ) δ: 5.39 (1H, dd, J = 1.0, 4.9 Hz), 5.08 (1H, m), 3.41 (1H, m), 3.33 (1H, m), 3.27 (1H, m) ), 2.34 (1H, m), 2.18 (1H, m), 2.08-1.10 (25H, m), 2.01 (3H, s), 1.41 (3H, s), 0.95-0.82 (2H, m), 0.93 ( 3H, s).

(Step 2)

(1aS, 2R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-7-(cyclohexylcarbonyl)-4a,6a-dimethylhexadecahydro-1aH-oxirane [4a,5]naphtho [2,1-f]quinolin-2-yl acetate

The title compound (199 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.88 (1H, dd, J = 7.6, 9.5 Hz), 3.43 (1H, m), 3.35 (1H, m), 3.28 (1H, m), 2.81 (1H, s ), 2.35 (1H, m), 2.07-0.97 (28H, m), 2.06 (3H, s), 1.40 (3H, s), 0.95 (3H, s).

(Step 3)

(4aS, 4bR, 6aR, 7R, 8R, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a,8-dihydroxy-10a,12a-dimethyloctadecyl-[2,1- f]quinoline-7-yl acetate

The title compound (34 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 5.10 (1H, d, J = 2.9 Hz), 4.10 (1H, m), 3.42 (1H, m), 3.37-3.21 (2H, m), 2.35 (1H, m) ), 2.14 (3H, s), 1.89-1.01 (30H, m), 1.38 (3H, s), 0.86 (3H, s).

(Step 4)

Cyclohexyl [(4aS,4bR,6aR,7R,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

The title compound (28 mg) was obtained as a white solid.

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.84 (1H, m), 3.59 (1H, d, J = 3.4 Hz), 3.50 (1H, m), 3.38 (1H, m), 3.14 (1H, m) , 2.48 (1H, m), 2.16 (1H, m), 1.90-1.10 (27H, m), 1.38 (3H, s), 0.82 (3H, s).

(Embodiment 18)

Cyclohexyl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a,7-dihydroxy-10a,12a-dimethyloctadecyl-[2,1- f]quinoline-8-yl acetate

A solution of the compound (165 mg) in EtOAc (m. After adding a 5% aqueous solution of sodium acetate to the reaction mixture for 10 minutes, the reaction mixture was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate was slurried in dichloromethane to give a solid. The obtained solid was dried under reduced pressure toiel

¹ H-NMR (CDCl ₃ ) δ: 4.55 (1H, m), 3.88 (1H, m), 3.41 (1H, m), 3.36 (1H, m), 3.28 (1H, m), 2.59 (1H, m) ), 2.35 (1H, m), 2.05 (1H, m), 2.02 (3H, s), 1.84 (1H, m), 1.79 (1H, d, J = 5.4 Hz), 1.78-1.36 (18H, m) , 1.39 (3H, s), 1.32 (1H, m), 1.27-1.13 (6H, m), 1.10 (3H, s), 0.84 (1H, m).

(Step 2)

Cyclohexyl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl]methanone

The title compound (23 mg) was obtained as a white solid.

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.82 (1H, m), 3.50 (1H, m), 3.42 (1H, m), 3.40 (1H, m), 3.17 (1H, m), 2.47 (1H, m), 2.06-1.96 (2H, m), 1.89-1.13 (26H, m), 1.39 (3H, s), 1.08 (3H, s).

(Embodiment 19)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1 (2H)-benzyl formate

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11, 12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b,11 a solution of 12,12a-hexadehydronaphtho[2,1-f]quinolin-8-ol (33.5 g) in dichloromethane (600 ml), N,N-diisopropylethyl Amine (24.5 ml) was added followed by benzyl chloroformate (17.5 ml) and stirred at room temperature for 8 hr. The reaction mixture was washed with aq. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (ethyl acetate/hexane) to afford the title compound (29.8 g).

MS (ESI) m / z: 424 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.32-7.28 (5H, m), 5.31-5.31 (1H, m), 5.06-5.06 (2H, m), 3.74-3.73 (1H, m), 3.50-3.47 ( 1H, m), 3.37-3.32 (1H, m), 3.03-3.02 (1H, m), 2.29-2.27 (1H, m), 2.18-2.12 (2H, m), 1.86-0.97 (16H, m), 1.34 (3H, s), 1.52 (3H, s).

(Step 2)

(4aS, 4bR, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-8-side oxygen-3,4,4a,4b,5,6,8,9,10,10a,10b,11,12 , 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (29.6 g) was obtained from m.

MS (ESI) m/z: 422 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.70 (1H, s), 5.06 (2H, s), 3.76-3.74 (1H, m), 3.35-3.29 (1H, m) , 3.10-3.07 (1H, m), 2.42-2.26 (4H, m), 2.03-1.99 (2H, m), 1.81-1.80 (1H, m), 1.71-0.91 (11H, m), 1.37 (3H, s), 1.12 (3H, s).

(Step 3)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10,10a,10b,11, 12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound (13.0 g) obtained in the above step 2 was suspended in methanol (300 ml), and ruthenium chloride 7 hydrate (11.5 g) was added. The reaction liquid was cooled to -45 ° C, sodium borohydride (1.17 g) was added, and the mixture was stirred for 4 hours while gradually raising the temperature to 0 °C. After adding water to the reaction mixture, it was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m / z: 424 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.29-5.29 (1H, m), 5.08-5.08 (2H, m), 4.14-4.12 (1H, m), 3.78-3.76 ( 1H, m), 3.34-3.31 (1H, m), 3.06-3.04 (1H, m), 2.17-2.16 (1H, m), 2.07-2.04 (1H, m), 1.95-1.17 (15H, m), 1.36 (3H, s), 1.01 (3H, s), 0.87-0.84 (2H, m).

(Step 4)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1 -f] quinoline-7(5H)-benzyl formate

The title compound (13.1 g) was obtained from the title compound (13.1 g).

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.31 (5H, m), 5.09-5.07 (2H, m), 4.12-4.06 (1H, m), 3.80-3.76 (1H, m), 3.35-3.33 ( 1H, m), 3.16-3.15 (1H, m), 3.08-3.05 (1H, m), 2.26-0.99 (25H, m).

(Step 5)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1 (2H)-benzyl formate

The title compound (24.3 g) was obtained as a white solid.

MS (ESI) m/z: 458 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.31 (5H, m), 5.09-5.07 (2H, m), 4.15-4.13 (1H, m), 3.79-3.75 (2H, m), 3.54-3.53 ( 1H, m), 3.35-3.32 (1H, m), 3.05-3.02 (1H, m), 2.30-2.30 (1H, m), 2.20-2.19 (1H, m), 1.82-1.17 (17H, m), 1.35 (3H, s), 1.11 (3H, s).

¹ H-NMR (CD ₃ OD) δ: 7.34 - 7.24 (5H, m), 5.02 (2H, s), 4.02 (1H, m), 3.76 (1H, m), 3.42 (1H, d, J = 3.4 Hz), 3.32 (1H, m), 2.94 (1H, m), 2.11 (1H, m), 1.85 (1H, m), 1.74-1.10 (16H, m), 1.32 (3H, s), 1.08 (3H) , s).

(Embodiment 20)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1 (2H)-cyclohexyl formate

(step 1)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl (dioxolo) [5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The compound obtained in the step 5 of Example 19 (24.3 g) was suspended in acetonitrile (500 ml), and acetone dimethyl acetal (16.3 ml) and p-toluenesulfonic acid monohydrate (1.01 g) were added at 0 °C. Stir at the same temperature for 3 hours. Triethylamine (8.14 ml) was added to the reaction mixture, and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue and stirred for 30 minutes, and the precipitated solid was collected by filtration. The residue obtained by concentrating the filtrate was dissolved in ethyl acetate, and washed with water and saturated brine. Dry the organic layer with anhydrous sodium sulfate After that, the filtrate was concentrated, and the obtained residue was purified to silica gel column chromatography (ethyl acetate /hexane). The title compound (22.0 g) was obtained as a white solid.

MS (ESI) m/z: 498 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.09-5.09 (2H, m), 4.32-4.30 (1H, m), 3.81-3.76 (2H, m), 3.36-3.34 ( 1H, m), 3.06-3.04 (1H, m), 2.09-2.06 (1H, m), 1.89-1.81 (2H, m), 1.75-1.13 (28H, m).

(Step 2)

(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6]naphtho [2,1-f]quinoline-13a(4H)-alcohol

The compound (22.7 g) obtained in the above step 1 was dissolved in a mixed solvent of ethanol (150 ml) and tetrahydrofuran (300 ml), and 10% wet palladium carbon (3.00 g) was added thereto under a hydrogen atmosphere at normal temperature and atmospheric pressure. Stir under 3 hours. The catalyst was filtered and the filtrate was concentrated to give the title compound (16.2 g).

MS (ESI) m / z: 364 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.29 - 4.24 (1H, m), 3.83 - 3.82 (1H, m), 2.90 - 2.88 (1H, m), 2.73 - 2.70 (1H, m), 1.99-1.98 (1H, m), 1.81-1.07 (20H, m), 1.47 (3H, s), 1.28 (3H, s), 1.15 (3H, s), 1.08 (3H, s).

(Step 3)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecano[1,3]dioxolanyl[5, 6]Naphtho[2,1-f]quinoline-8(4H)-cyclohexyl formate

Potassium carbonate (114 mg) and cyclohexyl chloroformate (58 mg) were added sequentially to a solution of the compound (100 mg) obtained in the above step 2 in dichloromethane (4.0 ml). minute. Saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were poured and evaporated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 4.63 (1H, m), 4.28 (1H, m), 4.28 (1H, d, J = 2.9 Hz), 3.74 (1H, m), 3.26 (1H, m), 2.99 (1H, m), 2.04 (1H, m), 1.85-1.76 (4H, m), 1.73-1.12 (27H, m), 1.49 (3H, s), 1.31 (3H, s), 1.29 (3H, s).

(Step 4)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1 (2H)-cyclohexyl formate

The compound (134 mg) obtained in the above-mentioned step 3 was dissolved in a mixed solution of methanol (5 ml) and tetrahydrofuran (2.5 ml), and a 4M hydrogen chloride-ethyl acetate solution (0.05 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction liquid was concentrated under reduced pressure, the obtained residue was dissolved in methanol, and the insoluble material was filtered. A portion of the filtrate was concentrated.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.56 (1H, m), 4.03 (1H, dm), 3.75 (1H, m), 3.42 (1H, d, J = 3.9 Hz), 3.28 (1H, m) , 2.95 (1H, m), 2.11 (1H, m), 1.90-1.77 (3H, m), 1.73-1.11 (24H, m), 1.32 (3H, s), 1.09 (3H, s).

(Example 21)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-N-cyclohexyl-6a,7,8-trihydroxy-10a,12a-dimethylhexadecano[2,1-f Quinoline-1(2H)-carboxamide

(step 1)

(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-N-cyclohexyl-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolane Benzo[5,6]naphtho[2,1-f]quinoline-8(4H)-carboxamide

To a solution of the compound (100 mg) obtained from m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Stir at the same temperature for 15 minutes. The reaction mixture was evaporated to drynessnessnessnessnessnessnessness

¹ H-NMR (CDCl ₃ ) δ: 4.27 (1H, m), 4.20 (1H, d, J = 7.8 Hz), 3.77 (1H, d, J = 5.4 Hz), 3.53 (1H, m), 3.23 3.15 (2H, m), 2.88 (1H, m), 2.03 (1H, m), 1.92-0.99 (28H, m), 1.49 (3H, s), 1.31 (3H, s), 1.29 (3H, s) , 1.10 (3H, s).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-N-cyclohexyl-6a,7,8-trihydroxy-10a,12a-dimethylhexadecano[2,1-f Quinoline-1(2H)-formamide

The title compound (61 mg) was obtained as a white solid.

MS (ESI) m/z: 449 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.02 (1H, m), 3.42 (1H, d, J = 3.9 Hz), 3.39 (1H, m), 3.26 (1H, m), 3.19 (1H, m) , 2.87 (1H, m), 2.11 (1H, m), 1.86-1.07 (27H, m), 1.30 (3H, s), 1.08 (3H, s).

(Example 22)

Cyclohex-1-en-1-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohex-1-en-1-yl [(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecano[1, 3] Dioxolyl-[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone

To a solution of the compound (100 mg) obtained in Step 2 of Example 20 in dichloromethane, diisopropylethylamine (0.188 ml) And cyclohex-1-ene-1-methylhydrazine chloride (80 mg) was stirred at the same temperature for 1 hour. After the addition of methanol, the title compound (112 mg) was evaporated.

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.78 (1H, m), 4.28 (1H, m), 3.77 (1H, d, J = 4.9 Hz), 3.41-3.32 (2H, m), 3.24 (1H, m ), 2.28 (1H, m), 2.08-1.95 (4H, m), 1.86-1.77 (2H, m), 1.72-1.17 (19H, m), 1.49 (3H, s), 1.40 (3H, s), 1.29 (3H, s), 1.16 (1H, s), 1.11 (3H, s).

(Step 2)

Cyclohex-1-en-1-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

The title compound (96 mg) was obtained as a white solid.

MS (ESI) m / z: 432 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.72 (1H, m), 4.03 (1H, m), 3.45-3.41 (3H, m), 3.14 (1H, m), 2.21 (1H, m), 2.12 ( 1H, m), 2.08-2.04 (2H, m), 1.97 (1H, m), 1.86 (1H, m), 1.75-1.14 (20H, m), 1.40 (3H, s), 1.09 (3H, s) .

(Example 23)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Benzyl tetrahydropyran-2-carboxylate

Tetrahydropyran-2-carboxylic acid (300 mg) was dissolved in N,N-dimethylformamide (5 ml), potassium carbonate (382 mg) and benzyl bromide (0.260 ml) were added, and stirred at 75 ° C for 3 hours. Thereafter, it was stirred at room temperature for one night. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous sodium sulfate.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.32 (5H, m), 5.20 (2H, s), 4.11-4.09 (1H, m), 4.05-4.03 (1H, m), 3.52-3.48 (1H, m), 1.98-1.94 (1H, m), 1.89-1.86 (1H, m), 1.67-1.51 (4H, m).

(Step 2)

(2S)-Benzyl tetrahydropyran-2-carboxylate and benzyl (2R)-tetrahydropyran-2-carboxylate

The compound (460 mg) obtained in the above step 1 was optically separated to give the (2S)-tetrahydropyran-2-carboxylic acid benzyl ester (isomer A) (177 mg) and ( 2R)-Benzyltetrahydropyran-2-carboxylate (isomer B) (174 mg).

Preparation type

CHIRALPAK (AS-H) 20x250mm

Eluent: hexane / isopropanol = 99:1

Flow rate: 20ml/min

Detection wavelength: 254nM

Residence time: Isomer A (2S body): 13.2 minutes, isomer B (2R body): 16.3 minutes.

analysis

CHIRALCEL (OD-H) 4.6x150um, eluent: hexane/isopropanol = 98:2

Flow rate: 1.0ml/min

Detection wavelength: 254nM and 210nM

Residence time: Isomer A (2S body): 8.98 minutes, isomer B (2R body): 8.38 minutes.

CHIRALPAK (AS-H) 4.6x150um, eluent: hexane / isopropanol = 98:2

Flow rate: 1.0ml/min

Detection wavelength: 254nM and 210nM

Residence time: Isomer A (2S body): 8.17 minutes, isomer B (2R body): 10.8 minutes.

Isomer A (2S body)

[α] _D ²⁰ -19.1 (c1.02, dichloromethane)

References; Journal of the American Chemical Society, 132, 16374 (2010)

CHIRALCEL (OD-H) 4.6x250um, eluent: hexane/isopropanol = 98:2

Flow rate: 1.0ml/min

Detection wavelength: 215nM

Retention time: R-isomer: 15.91 minutes, [α] _D ²⁰ +17.1 (c1.73, CH ₂ Cl ₂ )

S-isomer: 17.44 min.

(Step 3)

(2R)-tetrahydropyran-2-carboxylic acid

The (2R)-tetrahydropyran-2-carboxylic acid benzyl ester (105 mg) obtained in the above step 2 was dissolved in ethanol (3 ml), and 10% wet palladium carbon (10 mg) was added thereto under a hydrogen atmosphere at room temperature. Stir at atmospheric pressure for 1 hour. The catalyst was filtered, and the filtrate was concentrated to give the title compound (55.1 mg).

¹ H-NMR (CDCl ₃ ) δ: 4.13-4.11 (1H, m), 3.99-3.97 (1H, m), 3.57-3.54 (1H, m), 2.08-2.05 (1H, m), 1.95-1.93 ( 1H, m), 1.62-1.59 (4H, m).

(Step 4)

[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5 ,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The compound (5.80 g) obtained in the above step 3 was dissolved in N,N-dimethylformamide (100 ml), and O-(7-indoletriazol-1-yl) was added under ice-cooling stirring. N,N,N',N',-tetramethyluronium hexafluorophosphate (16.9 g) and N,N-diisopropylethylamine (15.2 ml) were stirred at the same temperature for 10 minutes. Then, the N,N-dimethylformamide solution (200 ml) of the compound (16.2 g) obtained in the step 2 of Example 20 was gradually added dropwise, and the mixture was stirred at 0 ° C for 6 hours. The resulting solid was collected by filtration and washed with diethyl ether. Diluted the filtrate into ethyl acetate, followed by 1N hydrochloric acid, saturated brine, and saturated Wash with sodium bicarbonate water or saturated saline. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

MS (ESI) m / z: 476 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.27-4.25 (1H, m), 4.10-4.09 (1H, m), 3.98-3.96 (1H, m), 3.83-3.82 (1H, m), 3.61-3.58 (1H, m), 3.51-3.48 (1H, m), 3.40-3.37 (1H, m), 3.27-3.18 (2H, m), 2.01-1.18 (24H, m), 1.47 (3H, s), 1.44 (3H, s), 1.27 (3H, s), 1.13 (3H, s).

(Step 5)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

Acetic acid (50 ml) and water (13 ml) were added to the compound obtained in the above step 4 (9.35 g), and stirred for 3 hours. After the reaction liquid was neutralized with an aqueous sodium hydrogencarbonate solution, water (100 ml) was further added, and the extraction operation was carried out twice with dichloromethane: methanol (10:1). The organic layer was dried over anhydrous sodium sulfate

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.10-4.09 (1H, m), 4.06-4.04 (1H, m), 3.97-3.96 (1H, m), 3.60-3.58 (1H, m), 3.50-3.48 (1H, m), 3.45-3.44 (1H, m), 3.39-3.37 (1H, m), 3.19-3.17 (1H, m), 2.16-2.13 (1H, m), 1.88-1.17 (26H, m) , 1.42 (3H, s), 1.11 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 2, and the peak with a relative intensity of 18 or more in the case where the maximum peak intensity in Fig. 2 is 100 is shown in Table 2.

(Example 24)

(2S)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5 ,6]naphtho[2,1-f]quinoline-8(4H)-yl](tetrahydro-2H-pyran-2-yl)methanone

The compound (300 mg) obtained in the step 2 of Example 20 and tetrahydropyran-2-carboxylic acid (323 mg) were obtained by the same procedure as in the step The title compound (329 mg) of (the main product R).

MS (ESI) m / z: 476 (M+H) ⁺ .

(Step 2)

(2S)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (S) (5 mg) and (R) (69 mg) of the title compound (yield:

Rf=higher (S body) low polarity

MS (ESI) m/z: 436 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.05 - 4.01 (2H, m), 3.91 (1H, dd, J = 2.0, 11.2 Hz), 3.48 (1H, m), 3.44 - 3.39 (3H, m), 3.16 (1H, m), 2.12 (1H, m), 1.91-1.13 (23H, m), 1.39 (3H, s), 1.09 (3H, s).

Rf=lower (R body) high polarity

Consistent with Example 23.

(Embodiment 25)

[(2R,6R)-6-methyltetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxyl -10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2R)-1-(benzyloxy)hept-6-en-2-ol

(2R)-2-[(benzyloxy)methyl]oxirane ((2R)-2-[(benzyloxy)methyl]oxirane) (7.00g) and copper iodide (0.49 g) in tetrahydrofuran (350 ml), 3-butene bromide (0.5 M tetrahydrofuran solution, 100 ml) was added dropwise at -78 °C. After the completion of the dropwise addition, the temperature was gradually raised to room temperature, and further stirred for 1 hour. A saturated aqueous ammonia solution was added to the reaction mixture, and ethyl acetate was evaporated. The organic layer was dried over anhydrous MgSO.sub.

¹ H-NMR (CDCl ₃ ) δ: 7.25-7.35 (5H, m), 5.73-5.81 (1H, m), 4.98 (1H, m), 4.93 (1H, m), 4.53 (2H, s), 3.77 -3.82 (1H, m), 3.48 (1H, dd, J = 9.5, 3.2 Hz), 3.30 (1H, dd, J = 9.5, 8.1 Hz), 2.30 (1H, d, J = 3.4 Hz), 2.01- 2.09 (2H, m), 1.36-1.60 (4H, m).

(Step 2)

(6R)-7-(benzyloxy)-6-hydroxyheptan-2-one

Palladium chloride (163 mg) and p-benzoquinone (0.991 g) were added to a tetrahydrofuran-water (7/1:40 ml) solution of the compound (2.02 g) obtained in the above step 1 and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed twice with 1N aqueous sodium hydroxide. After the organic layer was dried over anhydrous magnesium sulfate (MgSO4).

MS (ESI) m / z: 219 (M-OH) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.29-7.38 (5H, m), 4.55 (2H, s), 3.80 (1H, m), 3.48-3.51 (1H, m), 3.33 (1H, dd, J = 9.3, 7.8 Hz), 2.47 (2H, t, J = 7.3 Hz), 2.14 (3H, s), 1.57-1.77 (2H, m), 1.40-1.46 (2H, m).

(Step 3)

(2R,6R)-2-[(benzyloxy)methyl]-6-methyltetrahydro-2H-pyran

A solution of the compound obtained in the above step 2 (2.06 g) and triethyl decane (1.52 ml) in methylene chloride (50 ml) was added to a trifluoroborane-diethyl ether 1.20 ml), stirred at 0 ° C for 15 minutes. Saturated brine and water were added to the reaction mixture, and the mixture was extracted twice with dichloromethane. After the organic layer was dried over anhydrous magnesium sulfate (MgSO4).

MS (ESI) m/z: 221 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.26-7.36 (5H, m), 4.61 (1H, d, J = 12.2 Hz), 4.54 (1H, d, J = 12.2 Hz), 3.58 (1H, m), 3.44-3.51(2H,m), 3.39(1H,dd,J=10.3,4.4Hz),1.80-1.84(1H,m),1.46-1.60(3H,m),1.15-1.27(2H,m), 1.20 (3H, d, J = 5.9 Hz).

(Step 4)

[(2R,6R)-6-methyltetrahydro-2H-pyran-2-yl]methanol

To a solution of the compound (1.56 g) in ethanol (15 ml) obtained in the above step 3, 20% palladium hydroxide (0.2 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. Use Celite to remove the catalyst. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate/hexane) to afford the title compound (0.66 g).

MS (ESI) m / z: 131 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.45-3.60 (4H, m), 2.14 - 2.24 (1H, m), 1.82-1.87 (1H, m), 1.45-1.61 (3H, m), 1.14-1.28 ( 2H, m), 1.18 (3H, d, J = 6.3 Hz).

(Step 5)

(2R,6R)-6-methyltetrahydro-2H-pyran-2-carboxylic acid

To a solution of the compound (0.66 g) obtained in the above step 4 in acetonitrile-water (1/1, 40 ml), iodobenzene diacetate (3.6 g) and 2-puronantane-N-oxygen were added. 2-Azaadamantane- N- oxyl (0.15 g) was stirred at room temperature for 15 minutes. A 1 N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was washed twice with dichloromethane. After adding 5N hydrochloric acid to the aqueous layer to become acidic, it was extracted once with ethyl acetate and dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate.

¹ H-NMR (CDCl ₃ ) δ: 4.01 (1H, dd, J = 11.7, 2.7 Hz), 3.57-3.65 (1H, m), 2.03-2.11 (1H, m), 1.91-1.98 (1H, m) , 1.40 - 1.66 (3H, m), 1.22-1.29 (1H, m), 1.26 (3H, d, J = 6.2 Hz).

(Step 6)

[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5 ,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R,6R)-6-methyltetrahydro-2H-pyran-2-yl]methanone

The title compound (135 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m ).

MS (ESI) m/z: 490 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.30 (1H, m), 3.97 (1H, dd, J = 2.3, 10.9 Hz), 3.80 (1H, d, J = 5.5 Hz), 3.58 (1H, m), 3.47-3.40(1H,m), 3.35-3.26(1H,m),2.07(1H,m),1.90-1.18(28H,m),1,52(3H,s), 1.45(3H,s), 1.31 (3H, s), 1.12 (3H, s).

(Step 7)

[(2R,6R)-6-methyltetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxyl -10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (88 mg) was obtained from m.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.13 (1H, m), 3.97 (1H, dd, J = 11.0, 2.3 Hz), 3.60-3.52 (2H, m), 3.43 (1H, m), 3.34-3.26 (1H, m), 2.33 (1H, m), 2.20 (1H, m), 1.90 - 1.18 (25H, m), 1.44 (3H, s), 1.19 (3H, d, J = 6.3 Hz), 1.11 ( 3H, s), 1.08 (1H, s).

(Example 26)

(2-Fluorocyclohex-1-en-1-yl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2-Fluorocyclohex-1-en-1-yl)[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethyl-10- Hexahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone

The title compound (59 mg) was obtained as a pale yellow solid (yield: EtOAc, m. ).

MS (ESI) m/z: 490 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.28 (1H, m), 3.78 (1H, d, J = 5.4 Hz), 3.43-3.38 (2H, brm), 3.28 (1H, m), 2.19-2.12 (2H , m), 2.04 (1H, m), 1.87-1.77 (2H, m), 1.76-1.13 (22H, m), 1.49 (3H, s), 1.43 (3H, s), 1.29 (3H, s), 1.10 (3H, s).

(Step 2)

(2-Fluorocyclohex-1-en-1-yl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The compound (59 mg) obtained in the above step 1 was dissolved in a mixed solvent of tetrahydrofuran (2 ml) and methanol (1 ml), and 1N hydrochloric acid (0.5 ml) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane: methanol (10:1). The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.03 (1H, m), 3.48-3.43 (2H, brm), 3.42 (1H, d, J = 3.9 Hz), 3.17 (1H, m), 2.21-2.13 ( 2H, brm), 2.12 (1 H, m), 1.86 (1H, m), 1.80-1.14 (22H, m), 1.42 (3H, s), 1.09 (3H, s).

(Example 27)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

(step 1)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-methoxy-4a,6a-dimethyltetrahydroxan-1aH-oxirane [4a,5]naphtho[2 , 1-f] quinoline-7(5H)-benzyl formate

Methyl iodide (0.637 ml) was added sequentially at room temperature to a mixture of tetrahydrofuran (4 ml) and N,N-dimethylformamide (1 ml). Sodium hydride (55 wt%, 60 mg) was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was poured into ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Compound (269 mg).

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.75 (1H, m), 3.64 (1H, m), 3.42 (3H, s), 3.32 (1H, m), 3.10 (1H, d, J = 3.4 Hz), 3.03 (1H, m), 2.06 (1H, m), 1.94 (1H) , m), 1.83 (1H, m), 1.76-1.60 (2H, m), 1.54-1.43 (5H, m), 1.37-1.29 (2H, m), 1.33 (3H, s), 1.26-1.16 (3H , m), 1.14.1.07 (2H, m), 0.97 (3H, s), 0.92 (1H, m).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecaquino[2,1-f] Quinoline-1(2H)-benzyl formate

The title compound (187 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.25 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.75 (1H, m), 3.67-3.62 (2H, m), 3.37 (3H, s), 3.31 (1H, m), 3.01 (1H, m), 2.29 (1H, s), 2.19 (1H, m), 1.84-1.52 (7H, m), 1.44-1.33 (6H, m), 1.32 (3H, s), 1.28-1.13 (4H, m), 1.09 (3H, s), 1.04 (1H, s).

(Step 3)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-methoxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-6a,7 ( 2H)-diol

The title compound (134 mg) was obtained as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.68 (1H, m), 3.63 (1H, d, J = 3.4 Hz), 3.33 (3H, s), 2.87 (1H, m), 2.70 (1H, dd, J = 4.6, 12.9 Hz), 2.11 (1H, m), 1.76-1.17 (16H, m), 1.16-0.99 (2H, m), 1.10 (3H, s), 1.04 (3H, s).

(Step 4)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

The title compound (43 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.67-3.61 (2H, m), 3.41 (1H, m), 3.36 (3H, s), 3.33 (1H, m), 3.23 (1H, m), 2.34 (1H) , m), 2.29 (1H, s), 2.19 (1H, m), 1.86-1.52 (12H, m), 1.46-1.31 (7H, m), 1.39 (3H, s), 1.28-1.15 (8H, m ), 1.09 (3H, s), 1.08 (1H, s).

(Embodiment 28)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (86 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m ).

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.94 (1H, dd, J = 2.4, 10.7 Hz), 3.66-3.61 (2H, m), 3.53 (1H, m), 3.41 (1H) , m), 3.36 (3H, s), 3.32-3.22 (2H, m), 2.29 (1H, s), 2.20 (1H, m), 1.89 (1H, m), 1.85-1.31 (17H, m), 1.40 (3H, s), 1.29-1.13 (5H, m), 1.09 (3H, s), 1.04 (1H, s).

(Example 29)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,8-dihydroxy-7-methoxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[tris-butyl(dimethyl)decyl]oxy}-6a,7-dihydroxy-10a,12a- Dimethylhexadenaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

a mixture of dichloromethane (10 ml) and tetrahydrofuran (10 ml) obtained in the step 5 of Example 23, at room temperature Imidazole (176 mg) and tertiary dimethyldimethylchloromethane (195 mg) were added in an order and stirred at the same temperature for 15 hours. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 4.10 (1H, m), 4.00 (1H, m), 3.94 (1H, dd, J = 2.4, 10.7 Hz), 3.53 (1H, m), 3.41 (1H, m ), 3.37 (1H, d, J = 4.4 Hz), 3.34 - 3.22 (2H, m), 2.65 (1H, s), 2.18 (1H, m), 1.88 (1H, m), 1.84-1.13 (22H, m), 1.40 (3H, s), 1.09 (3H, s), 1.00 (1H, s), 0.86 (9H, s), 0.06 (3H, s), 0.05 (3H, s).

(Step 2)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[tris-butyl(dimethyl)decyl]oxy}-6a-hydroxy-7-methoxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (133 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

¹ H-NMR (CDCl ₃ ) δ: 4.18 (1H, m), 4.00 (1H, m), 3.93 (1H, dd, J = 2.4, 10.7 Hz), 3.53 (1H, m), 3.47 (3H, s ), 3.40 (1H, m), 3.33 - 3.21 (2H, m), 2.96 (1H, dd, J = 1.0, 3.4 Hz), 2.15 (1H, m), 1.88 (1H, m), 1.84-1.13 ( 22H, m), 1.39 (3H, s), 1.11 (1H, s), 1.02 (3H, s), 0.88 (9H, s), 0.06 (3H, s), 0.05 (3H, s).

(Step 3)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,8-dihydroxy-7-methoxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

To a solution of the compound (133 mg) obtained in the above step 2 in tetrahydrofuran (5.0 ml), acetic acid (0.27 ml) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 4.71 ml) were added at room temperature, followed by heating under reflux. hour. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.06-3.99 (2H, m), 3.96 (1H, dd, J = 2.4, 10.7 Hz), 3.56 (1H, m), 3.52 (3H, s), 3.43 (1H) , m), 3.34 - 3.24 (2H, m), 3.07 (1H, d, J = 3.4 Hz), 2.14 (1H, m), 1.99 (1H, d, J = 11.2 Hz), 1.90 (1H, m) , 1.87-1.17 (22H, m), 1.43 (3H, s), 1.12 (1H, s), 1.04 (3H, s).

(Embodiment 30)

[(4aS,4bR,6R,6aS,7S,8S,10aR,10bS,12aS)-6-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13bR)-2,2,5a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,9,10,11,11a, 11b,12,13b-tetradecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The compound obtained in the same manner as in Step 1 of Example 2 (9.76 g) was used, and the crude product obtained by the same procedure as in Step 1 of Example 2 was reacted in the same manner as in Step 1 of Example 20 to give a product. The title compound (7.44 g) and the title compound (yield) (0.506 g) were obtained as a white solid.

Olefin body

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.76 (1H, dd, J = 2.3, 4.7 Hz), 5.05 (2H, s), 4.38 (1H, d, J = 5.9 Hz ), 4.08 (1H, m), 3.73 (1H, m), 3.34 (1H, m), 3.03 (1H, m), 2.24 (1H, m), 1.81-1.05 (14H, m), 1.49 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 1.09 (3H, s), 0.99 (1H, m).

(Step 2)

(3aS, 3bR, 4aS, 5aR, 5bS, 9aS, 11aS, 11bR, 13aS)-2,2,9a,11b-tetramethyltetrahydrogen-3aH-[1,3]dioxolanyl[5 , 6] oxirane [4,4a]naphtho[2,1-f]quinoline-9(4aH)-benzyl formate

The title compound (366 mg) was obtained as a white solid.

MS (ESI) m/z: 496 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.04 (2H, s), 4.24 (1H, m), 3.73 (1H, m), 3.40 (1H, d, J = 5.4 Hz ), 3.31 (1H, m), 3.13 (1H, d, J = 3.9 Hz), 2.98 (1H, m), 2.05 (1H, m), 1.91 (1H, m), 1.77-1.25 (12H, m) , 1.53 (3H, s), 1.29 (3H, s), 1.27 (3H, s), 1.16 (3H, s), 1.16-1.09 (2H, m).

(Step 3)

(4aS, 4bR, 6R, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1- f] quinoline-1(2H)-benzyl formate

The title compound (71.0 mg) was obtained as a white solid.

¹ H-NMR (CD ₃ OD) δ: 7.34 - 7.25 (5H, m), 5.02 (2H, s), 4.49 (1H, m), 3.99 (1H, m), 3.77 (1H, m), 3.70 ( 1H, d, J = 3.4 Hz), 3.32 (1H, m), 2.96 (1H, m), 1.93-1.16 (16H, m), 1.34 (3H, s), 1.24 (3H, d, J = 3.9 Hz ).

(Step 4)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13R, 13aS, 13bS)-13-fluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxol Cyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (50.0 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 4.51 (1H, m), 4.28 (1H, m), 3.91 (1H, d, J = 4.9 Hz), 3.75 (1H, m), 3.33 (1H, m), 3.04 (1H, m), 2.01 (1H, m), 1.84-1.18 (16H, m), 1.54 (3H, s), 1.35 (3H, s), 1.33 (3H, s), 1.25 (3H, d, J = 5.4 Hz).

(Step 5)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13R, 13aS, 13bS)-13-fluoro-2,2,5a,7a-tetramethylhexadecano[1,3]dioxolanyl[ 5,6]naphtho[2,1-f]quinoline-13a(4H)-ol

The title compound (61.0 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.51 (1H, m), 4.28 (1H, m), 3.92 (1H, d, J = 5.4 Hz), 2.92 (1H, m), 2.83 (1H, m), 1.97 (1H, m), 1.82 (1H, m), 1.75-1.12 (17H, m), 1.54 (3H, s), 1.33 (3H, s), 1.27 (3H, d, J = 5.4 Hz), 1.11 (3H, s).

(Step 6)

[(3aS,5aR,5bS,7aS,11aS,11bR,13R,13aS,13bS)-13-fluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxo Pentocyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (38.0 mg) was obtained as a white solid. m m m m m m m m m m m m .

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.52 (1H, m), 4.28 (1H, m), 4.00 (1H, m), 3.94 (1H, m), 3.91 (1H, d, J = 4.9 Hz), 3.55 (1H, m), 3.45-3.25 (3H, m), 2.00 (1H, m), 1.88 (1H, m), 1.83-1.16 (21H, m), 1.54 (3H, s), 1.44 (3H, s), 1.33 (3H, s), 1.25 (3H, d, J = 5.4 Hz).

(Step 7)

[(4aS,4bR,6R,6aS,7S,8S,10aR,10bS,12aS)-6-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (28.0 mg) was obtained as a white solid.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.50 (1H, m), 4.08 (1H, m), 3.99 (1H, m), 3.94 (1H, dd, J = 3.4, 11.2 Hz), 3.70 (1H, d, J = 3.4 Hz), 3.57 (1H, m), 3.46 (1H, m), 3.36 (1H, m), 3.17 (1H, m), 1.92-1.13 (22H, m), 1.42 (3H, s ), 1.25 (3H, d, J = 3.9 Hz).

(Example 31)

(2,6-difluorophenyl)[(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 9Z, 10aR, 10bS, 12aS)-9-(hydroxymethylene)-10a,12a-dimethyl-8-sideoxy-3,4,4a,4b,5,6,8, 9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

To a solution of the compound (2.25 g) obtained in the step 2 of Example 19 in tetrahydrofuran (100 ml), lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) was added at -20 ° C under a nitrogen atmosphere. 12 ml), stir for 20 minutes. Methyl formate (1.65 ml) was then added and stirred at room temperature for 1 hour. After distilling off the tetrahydrofuran under reduced pressure, aq. The filtrate was evaporated to dryness crystals crystals crystals crystals

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 13.7 (1H, m), 7.40-7.31 (5H, m), 5.78 (1H, s), 5.09 (2H, s), 3.78 (1H, m), 3.35 (1H) , m), 3.14 - 3.11 (1H, m), 2.42 - 2.27 (4H, m), 2.07 - 2.01 (1H, m), 1.91-1.83 (1H, m), 1.77-0.98 (11H, m), 1.39 (3H, s), 1.01 (3H, s).

(Step 2)

(4aS, 4bR, 8R, 9S, 10aR, 10bS, 12aS)-8-hydroxy-9-(hydroxymethyl)-10a,12a-dimethyl-3,4,4a,4b,5,6,8, 9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound (1.40 g) obtained in the above step 1 was dissolved in methanol (100 ml), sodium borohydride (0.24 g) was added, and the mixture was stirred at room temperature for 10 minutes. After water was added to the reaction mixture, methanol was evaporated under reduced pressure and extracted twice with dichloromethane. The organic layer was dried over anhydrous MgSO.sub.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.22 (1H, s), 5.08 (2H, s), 4.10 (1H, m), 3.80-3.73 (2H, m), 3.69 (1H, m), 3.32 (1H, m), 3.05 (1H, m), 2.55 (1H, d, J = 4.9 Hz), 2.36 (1H, dd, J = 6.1, 3.7 Hz), 2.21-2.05 ( 2H,m), 1.94(1H,m),1.86-1.63(4H,m),1.56-1.15(7H,m),1.36(3H,s),1.04(3H,s),0.97(1H,m) , 0.88-81 (2H, m).

(Step 3)

(1aS, 2S, 3S, 4aR, 4bS, 6aS, 10aS, 10bR)-2-hydroxy-3-(hydroxymethyl)-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a, 5] Naphtho[2,1-f]quinoline-7(5H)-benzyl formate

The title compound (1.00 g) was obtained as a white solid.

MS (ESI) m / z: 470 (M+H) ⁺ .

(Step 4)

(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethylhexadecaphthalene[ 2,1-f]quinoline-1(2H)-benzyl formate

A solution of the compound (1.00 g) obtained in the above step 3 in tetrahydrofuran-water (5/1, 120 ml) was added to a 70% aqueous perchloric acid solution (2 ml), and stirred at room temperature overnight. The reaction solution was neutralized by adding 5 equivalents of sodium hydroxide. The title compound (0.93 g) was obtained as a white solid.

MS (ESI) m/z: 488 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.47-7.30 (5H, m), 5.08 (2H, s), 4.09 (1H, m), 3.82-3.64 (4H, m), 3.54 (1H, m), 3.34 (1H, m), 3.04 (1H, m), 2.63 (1H, m), 2.29 (1H, m), 2.21 (1H, m), 2.10-2.04 (1H, m), 1.84-1.65 (3H, m ), 1.60-1.50 (2H, m), 1.35 (3H, s), 1.43-1.10 (10H, m), 1.17 (3H, s), 1.01 (1H, s).

(Step 5)

(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS)-7,8-bis(ethinyloxy)-9-[(ethylideneoxy)methyl]-6a-hydroxyl -10a,12a.-Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound (0.46 g) obtained in the above step 4 was dissolved in pyridine (20 ml), and acetic anhydride (10 ml) and 4-dimethylamine pyridine (0.12 g) were added and stirred at room temperature for one hour. The disappearance of the starting material was confirmed, and after adding methanol at 0 ° C, pyridine was azeotropically distilled off with toluene. To the residue obtained was added 1N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

MS (ESI) m/z: 614 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.26 (5H, m), 5.33 (1H, dd, J = 12.2, 3.9 Hz), 5.10-5.07 (3H, m), 4.08 (1H, dd, J = 10.7, 5.4 Hz), 4.01 (1H, dd, J = 10.7, 3.4 Hz), 3.78 (1H, m), 3.33 (1H, m), 3.05 (1H, m), 2.28 (1H, m), 2.06 ( 3H, s), 2.05 (3H, s), 1.97 (3H, s), 1.34 (3H, s), 1.14 (3H, s), 1.88-1.14 (17H, m).

(Step 6)

(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS)-9-[(ethoxycarbonyl)methyl]-6a-hydroxy-10a,12a-dimethyloctadecylnaphthalene [2,1-f]quinoline-7,8-diyl diacetate

The title compound (0.46 g) was obtained from m.

MS (ESI) m/z: 480 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.34 (1H, dd, J = 11.7, 3.9 Hz), 5.08 (1H, d, J = 3.9 Hz), 4.07 (1H, dd, J = 11.2, 5.4 Hz), 4.01 (1H, dd, J = 11.0, 3.2 Hz), 2.93 - 2.82 (2H, m), 2.27 (1H, s), 2.09 (3H, s), 2.06 (3H, s), 1.96 (3H, s) , 1.89-1.82 (1H, m), 1.73-1.57 (6H, m), 1.52-1.32 (5H, m), 1.26-1.15 (3H, m), 1.15 (3H, s), 1.07 (3H, s) , 1.10-1.03 (2H, m).

(Step 7)

(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS)-9-[(ethylideneoxy)methyl]-1-(2,6-difluorobenzhydryl)-6a -hydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinoline-7,8-diyldiacetate

The compound (0.10 g) obtained in the above step 6 was dissolved in toluene (10 ml), and saturated aqueous sodium hydrogen carbonate (10 ml) and difluorobenzene carboxylic acid chloride (0.040 ml) were added and stirred overnight. . The organic layer was separated and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcEtOAcEtOAc

MS (ESI) m/z: 620 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.30-7.24 (1H, m), 6.89 (2H, m), 5.34 (1H, dd, J = 11.7, 3.9 Hz), 5.09 (1H, d, J = 3.9 Hz ), 4.08 (1H, dd, J = 11.0, 5.6 Hz), 4.02 (1H, dd, J = 11.0, 3.4 Hz), 3.40 (2H, m), 3.17 (1H, m), 2.30 (1H, m) , 2.11 (3H, s), 2.07 (3H, s), 1.97 (3H, s), 1.94-1.40 (12H, m), 1.56 (3H, s), 1.34-1.20 (5H, m), 1.17 (3H , s).

(Step 8)

(2,6-difluorophenyl)[(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.10 g) was obtained as a white solid.

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.30-7.24 (1H, m), 6.92-6.86 (2H, m), 4.12-4.07 (1H, m), 3.85-3.79 (2H, m), 3.70 (1H, m), 3.56-3.53 (1H, m), 3.43-3.36 (2H, m), 3.17 (1H, m), 2.72 (1H, m), 2.49 (1H, m), 2.23 (1H, m), 2.13 -2.04 (1H, m), 1.89-1.66 (5H, m), 1.58 (3H, s), 1.56-1.14 (11H, m), 1.20 (3H, s), 1.02 (1H, s).

(Example 32)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethylhexadecane Naphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS)-9-[(ethylideneoxy)methyl]-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a- Dimethyloctadecylnaphtho[2,1-f]quinoline-7,8-diyldiacetate

The title compound (0.30 g) was obtained as a white solid. m m m m m m m m m m m m m .

MS (ESI) m/z: 590 (M+H) ⁺

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 5.33 (1H, dd, J = 12.2, 3.9 Hz), 5.08 (1H, d, 3.9 Hz), 4.08 (1H, dd, J = 11.2, 5.4 Hz), 3.99 (1H, dd, 11.2, 2.9 Hz), 3.44 (1H, m), 3.49-3.26 (2H, m), 2.41-2.23 (2H, m), 2.10 (3H, s), 2.06 (3H, s) , 1.97 (3H, s), 1.41 (3H, s), 1.97-1.14 (26H, m), 1.13 (3H, s).

(Step 2)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethylhexadecane Naphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.30 g) was obtained as a white solid.

MS (ESI) m/z: 464 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.12-4.07 (2H, m), 3.81 (1H, m), 3.67 (1H, m), 3.44 (1H, m), 3.36 (1H, m), 3.27-3.20 (2H, m), 2.73 (1H, d, J = 1.5 Hz), 2.36 (1H, m), 2.22 (1H, m), 2.08 (1H, m), 1.87-1.09 (26H, m), 1.42 ( 3H, s), 1.18 (3H, s), 0.99 (1H, s).

(Example 33)

Cyclopentyl [(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 6aS, 7S, 8S, 9S, 10aR, 10bS, 12aS)-9-[(ethoxycarbonyl)methyl]-1-(cyclopentylcarbonyl)-6a-hydroxy-10a,12a - dimethyl octadecylnaphtho[2,1-f]quinoline-7,8-diyl diacetate

The title compound was obtained in the same manner as in the step 7 of Example 31, using the compound (0.16 g) of m.

(Step 2)

Cyclopentyl [(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.020 g) was obtained as a solid.

MS (ESI) m/z: 450[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.09 (1H, m), 3.93 (1H, m), 3.83-3.79 (1H, m), 3.68 (1H, m), 3.49-3.55 (2H, m), 3.36 (1H, m), 3.30-3.25 (1H, m), 2.88 (1H, m), 2.82 (1H, m), 2.69 (1H, d, J = 1.5 Hz), 2.22 (1H, m), 2.08 ( 1H, m), 1.85-1.58 (10H, m), 1.56-1.10 (13H, m), 1.42 (3H, s), 1.18 (3H, s), 0.99 (1H, s).

(Example 34)

Cyclopentyl [(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(2-hydroxyethyl)-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 10aR, 10bS, 12aS)-1-(cyclopentylcarbonyl)-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9,10,10a,10b , 11, 12, 12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

Use (4aS, 4bR, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-1,3,4,4a,4b,5,6,9,10,10a,10b,11,12,12a-ten The title was obtained by the same procedure as in Step 1 of Example 22, using tetrahydronaphtho[2,1-f]quinolin-8(2H)-one (5.0 g) and cyclopentanemethionine chloride (2.3 ml). Compound (6.7 g).

(Step 2)

[(4aS,4bR,10aR,10bS,12aS)-1-(cyclopentylcarbonyl)-10a,12a-dimethyl-8-sideoxy-1,2,3,4,4a,4b,5,6 ,8,9,10,10a,10b,11,12,12a-hexadehydronaphtho[2,1-f]quinolin-9-yl]acetic acid tert-butyl acrylate

The title compound (0.70) was obtained as a mixture of non-mironomers by the same procedure as in the step 1 of Example 31, using the compound obtained from the above step 1 (0.65 g) and butyl bromoacetate (0.32 ml). g).

MS (ESI) m / z: 442 (M-tBu) +.

(Step 3)

Cyclopentyl [(4aS,4bR,8S,9S,10aR,10bS,12aS)-8-hydroxy-9-(2-hydroxyethyl)-10a,12a-dimethyl-3,4,4a,4b, 5,6,8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

Trifluoroacetic acid (10 ml) was added to a solution of the compound (0.70 g). After confirming the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained crude carboxylic acid was dissolved in tetrahydrofuran (30 ml), and methyl chloroformate (0.20 ml) and triethylamine (0.60 ml) were added at room temperature. Stir for 15 minutes. After filtering the precipitate, methanol (0.2 ml) and sodium borohydride (0.20 g) were added to the filtrate, and the mixture was stirred at room temperature. After the reaction mixture was concentrated, water was added and ethyl acetate was evaporated. After the organic layer was dried over anhydrous magnesium sulfate (MgSO4).

MS (ESI) m / z: 430 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.22 (1H, s), 3.90-3.82 (2H, m), 3.72 (1H, m), 3.51 (1H, m), 3.36 (1H, dd, J = 12.0, 3.7 Hz), 3.32-3.28 (1H, m), 2.81 (1H, m), 2.19-2.07 (2H, m), 1.44 (3H, s), 1.95-1.38 (21H, m), 1.28-0.79 (6H , m), 1.03 (3H, s).

(Step 4)

Cyclopentyl [(1aS, 2S, 3S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-3-(2-hydroxyethyl)-4a,6a-dimethyltetrahydro-l-a -oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The title compound (0.17 g) was obtained.

MS (ESI) m / z: 446 (M+H) ⁺ .

(Step 5)

Cyclopentyl [(4aS,4bR,6aS,7S,8S,9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(2-hydroxyethyl)-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.03 g) was obtained as a white solid.

MS (ESI) m/z: 464 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.89-3.85 (1H, m), 3.78 (1H, dd, J = 10.3, 3.9 Hz), 3.67 (1H, m), 3.58 (1H, d, J = 3.9 Hz ), 3.52 (1H, m), 3.37 (1H, m), 3.29 (1H, m), 2.81 (1H, m), 2.68 (1H, br), 2.20 (1H, m), 1.42 (3H, s) , 1.15 (3H, s), 1.86-1.08 (29H, m).

(Example 35)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS)-6a,7,8,9-tetrahydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 10aR, 10bS, 12aS)-9-hydroxy-10a,12a-dimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound obtained in the second step of Example 19 (1.08 g) and (2S,8aR)-(-)-(camphorylsulfonyl)oxyzolidine (0.76 g) were used in the same manner as in Example 31, Step 1. In the same manner, the title compound is obtained.

(Step 2)

(4aS, 4bR, 10aR, 10bS, 12aS)-9-(ethinyloxy)-10a,12a-dimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9 ,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (1.23 g) was obtained as a white solid.

MS (ESI) m/z: 495 (M+H) ⁺ .

(Step 3)

(4aS, 4bR, 8R, 10aR, 10bS, 12aS)-9-(ethinyloxy)-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,6,8, 9,10,10a,10b,11,12,12a-tetradecazin[2,1-f]quinoline-1(2H)-formic acid benzyl ester (acetate) and (4aS, 4bR, 8R, 10aR, 10bS, 12aS)-8,9-dihydroxy-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (diol)

The title compound (1.23 g), which was obtained from the mixture of the mixture of the mixture of the mixture of the mixture and the diol, was obtained.

(Step 4)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-3-(ethylideneoxy)-2-hydroxy-4a,6a-dimethyltetrahydroxan-1aH-oxirane [ 4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester (acetate) And (1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2,3-dihydroxy-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho [2,1-f]quinoline-7(5H)-benzyl formate (diol)

The title compound (1.27 g), which was obtained from the mixture of the mixture of the mixture of the mixture and the diol, was obtained by the same procedure as in the second step.

(Step 5)

(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS)-7,8,9-glycol(ethenyloxy)-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-benzyl formate

Using the compound obtained in the above-mentioned step 4 (1.27 g), the crude product obtained in the same manner as in the step 4 of Example 31 was reacted in the same manner as in the step 5 of Example 31 to give the title compound ( 0.36g).

¹ H-NMR (CDCl ₃ ) δ: 7.47-7.25 (5H, m), 5.50 (1H, dd, J = 10.5, 4.1 Hz), 5.30-5.26 (1H, m), 5.17 (1H, d, J = 4.4 Hz), 5.08 (2H, s), 3.78 (1H, m), 3.35-3.30 (1H, m), 3.05 (1H, m), 2.10.12.12 (19H, m), 2.10 (3H, s), 2.02 (3H, s), 1.96 (3H, s), 1.33 (3H, s), 1.20 (3H, s), 0.88 (1H, m).

(Step 6)

(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS)-6a-hydroxy-10a, 12a-dimethyloctadecylnaphtho[2,1-f]quinoline-7,8, 9-tristriacetate

The title compound (0.10 g) was obtained from the title compound (0.10 g).

(Step 7)

(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f Quinoline-7,8,9-triyltriacetate

The title compound (123 mg) was obtained from m.

(Step 8)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS)-6a,7,8,9-tetrahydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

The title compound (20 mg) was obtained as a white solid.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 3.85-3.76 (2H, m), 3.56 (1H, d, J = 3.9 Hz), 3.58-3.50 (1H, m), 3.46-3.40 (2H, m), 3.20 - 3.15 (1H, m), 2.52-2.48 (1H, m), 2.10 (1H, m), 1.93-1.10 (25H, m), 1.41 (3H, s), 1.15 (3H, s).

(Example 36)

Cyclohexyl [(4R,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-4,10a,12a-trimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

(step 1)

(3β)-3-{[tertiary butyl(dimethyl)decyl]oxy}androst-5,15-dien-17-one

Using (3β)-3-hydroxyandrost-5,15-dien-17-one (3.8 g) and N,N-dimethylformamide (60 ml) as a solvent, by the procedure of Example 29 The title compound (2.54 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.53 - 7.49 (1H, m), 6.05 (1H, dd, J = 6.1, 3.2 Hz), 5.40-5.36 (1H, m), 3.52-3.46 (1H, m) , 2.33-2.19 (4H, m), 1.92-0.99 (21H, m), 1.08 (3H, s), 1.07 (3H, s), 0.89 (9H, s), 0.07 (6H, s).

(Step 2)

(3β,15β)-3-{[tertiary butyl(dimethyl)decyl]oxy}-15-methyl-17-[(trimethyldecyl)oxy]androsine-5,16 -diene

A solution of copper (I) iodide (2.5 g) and lithium chloride (0.56 g) in tetrahydrofuran (30 ml) was added at -78 ° C, and methyl magnesium bromide (0.96 M tetrahydrofuran solution, 14 ml) was added. Stir at 78 ° C for 30 minutes. Then, chlorotrimethyl decane (1.2 ml) was added, and the mixture was stirred at the same temperature for 30 minutes, and then a solution of the compound (1.5 g) obtained in the above step 1 in THF (15 ml) was stirred. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and after returning to room temperature, the insoluble material was filtered using Celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine. Dry with anhydrous sodium sulfate. The filtrate was concentrated to give the title compound.

(Step 3)

(3β,15β)-3-hydroxy-15-methylandrost-5-ene-17-one

P-toluenesulfonic acid monohydrate (70 mg) was added to a solution of the compound (1. The reaction solution was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was evaporated evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

¹ H-NMR (CDCl ₃ ) δ: 5.41-5.36 (1H, m), 3.56-3.48 (1H, m), 2.48-2.38 (2H, m), 2.33 - 2.13 (4H, m), 1.87-1.75 ( 4H, m), 1.71-1.61 (2H, m), 1.54-1.40 (2H, m), 1.12-1.08 (4H, m), 1.10 (3H, d, J = 7.3 Hz), 1.04 (3H, s) , 1.02 (3H, s).

(Step 4)

(3β,15β)-15-methyl-17-oxooxindole-5-en-3-yl acetate

The title compound (1.01 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 5.43-5.39 (1H, m), 4.62-4.56 (1H, m), 2.50-2.12 (5H, m), 2.01 (3H, s), 1.87-1.40 (8H, m), 1.28-0.99 (5H, m), 1.09 (3H, d, J = 7.3 Hz), 1.05 (3H, s), 1.01 (3H, s).

(Step 5)

(3β,15β,17E)-17-(hydroxyimino)-15-methylandrost-5-en-3-yl acetate

Sodium acetate (962 mg) and hydroxylamine hydrochloride (8.42 g) were added to a solution of the compound (1.01 g) in ethanol (15 ml), dichloromethane (1.5 ml) and water (1.5 ml). Heat and reflux for 1 and a half hours. The reaction solution was cooled to room temperature, and a part of solvent was evaporated. Water was added to the residue, and the mixture was extracted with dichloromethane and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate.

¹ H-NMR (CDCl ₃ ) δ: 5.43-5.39 (1H, m), 4.62-4.56 (1H, m), 2.50-2.12 (5H, m), 2.01 (3H, s), 1.87-1.40 (8H, m), 1.28-0.99 (5H, m), 1.09 (3H, d, J = 7.3 Hz), 1.05 (3H, s), 1.01 (3H, s).

(Step 6)

(4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS)-4,10a,12a-trimethyl-2-oxo-1,2,3,4,4a,4b,5,7,8,9 ,10,10a,10b,11,12,12a-hexadehydronaphtho[2,1-f]quinolin-8-yl acetate

To a solution of the compound (919 mg) in THF (14 ml), EtOAc (EtOAc m. The reaction liquid was cooled to room temperature, and the solid obtained by adding ethyl acetate was filtered to obtain a product. Next, the filtrate was concentrated under reduced pressure, and the mixture was neutralized with a 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated, and the obtained residue was purified by chromatography (ethyl acetate / dichloromethane). The title compound (521 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 5.67 (1H, s), 5.42-5.36 (1H, m), 4.63-4.54 (1H, m), 3.70 (1H, m), 2.60 (1H, dd, J = 17.8, 8.1 Hz), 2.39-1.01 (16H, m), 2.01 (3H, s), 1.28 (3H, s), 1.03 (3H, s), 1.02 (3H, d, J = 7.3 Hz).

(Step 7)

(4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS)-4,10a,12a-trimethyl-1,2,3,4,4a,4b,5,7,8,9,10,10a, 10b,11,12,12a-hexadehydronaphtho[2,1-f]quinolin-8-ol

The compound obtained in the above step 6 (521 mg) was dissolved in 1,4-two. Alkane (15 ml) was added and lithium aluminum hydride (10% tetrahydrofuran solution, 1.7 ml) was added. In the reaction mixture, sodium sulfate 10 hydrate was added under ice cooling until no more bubbles were formed. After the addition of methylene chloride, the title compound (440 mg) was obtained.

MS (ESI) m / z: 304 (M+H) ⁺ .

(Step 8)

(4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-4,10a,12a-trimethyl-3,4,4a,4b,5,7,8,9,10,10a, 10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (424 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.35-5.32 (1H, m), 5.10-5.04 (2H, m), 3.84 (1H, m), 3.55-3.46 (1H, m), 3.32-3.25 (1H, m), 2.99-2.90 (1H, m), 2.31-0.95 (17H, m), 1.44 (3H, s), 0.97 (3H, s), 0.95 (3H, d, J = 6.8 Hz).

(Step 9)

(4R, 4aS, 4bR, 10aR, 10bS, 12aS)-4,10a,12a-trimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (353 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.71 (1H, s), 5.11-5.03 (2H, m), 3.89-3.81 (1H, m), 3.31-3.25 (1H, m), 3.05-2.98 (1H, m), 2.44 - 2.27 (4H, m), 2.11-1.96 (4H, m), 1.72-0.86 (19H, m), 1.47 (3H, s), 1.15 (3H, s), 1.00 (3H, d, J = 7.3 Hz).

(Step 10)

(4R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-4,10a,12a-trimethyl-3,4,4a,4b,5,6,8,9,10,10a, 10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (354 mg) was obtained from m.

MS (ESI) m / z: 438 (M+H) ⁺ .

(Step 11)

(1aS, 2S, 4aR, 4bS, 6aS, 10R, 10aS, 10bR, 12aR)-2-hydroxy-4a,6a,10-trimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho [2,1-f]quinoline-7(5H)-benzyl formate

The title compound (316 mg) was obtained from m.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.10-5.03 (2H, m), 4.07-4.00 (1H, m), 3.87-3.80 (1H, m), 3.32-3.26 ( 1H,m), 3.13 (1H,d,J=4.4Hz), 3.00-2.94(1H,m),2.17-1.95(5H,m),1.62-0.92(22H,m),1.44(3H,s) , 1.00 (3H, s), 0.98 (3H, d, J = 7.3 Hz).

(Step 12)

(4R, 4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-4,10a,12a-trimethylhexadena[2,1-f] Quinoline-1(2H)-benzyl formate

The title compound (284 mg) was obtained from m.

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.08-5.03 (2H, m), 4.17-4.09 (1H, m), 3.85-3.79 (1H, m), 3.54-3.50 ( 1H,m),3.33-3.27(1H,m),2.96-2.90(1H,m), 2.27-2.19(2H,m),2.11-1.93(2H,m),1.80-0.92(13H,m), 1.42 (3H, s), 1.12 (3H, s), 0.97 (3H, d, J = 6.8 Hz).

(Step 13)

(3aS, 5aR, 5bS, 7aS, 11R, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,5a,7a,11-pentamethylhexadecyl[1,3]dioxolanyl And [5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (191 mg) was obtained from m.

MS (ESI) m/z: 512 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.10-5.03 (2H, m), 4.33-4.26 (1H, m), 3.84-3.78 (2H, m), 3.33-3.28 ( 1H, m), 2.98-2.91 (1H, m), 2.14-0.96 (20H, m), 1.50 (3H, s), 1.43 (3H, s), 1.29 (3H, s), 1.14 (3H, s) , 0.97 (3H, d, J = 7.3 Hz).

(Step 14)

(3aS, 5aR, 5bS, 7aS, 11R, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,5a,7a,11-pentamethylhexadecyl[1,3]dioxolanyl And [5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (141 mg) was obtained.

(Step 15)

Cyclohexyl [(3aS,5aR,5bS,7aS,11R,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a,11-pentamethylhexadecahydro[1,3]dioxo Pentocyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone

The title compound (64.4 mg) was obtained from m.

MS (ESI) m / z: 488 (M+H) ⁺ .

(Step 16)

Cyclohexyl [(4R,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-4,10a,12a-trimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

The title compound (38.0 mg) was obtained.

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.16-4.10 (1H, m), 3.54-3.50 (1H, m), 3.47-3.43 (1H, m), 3.38-3.31 (1H, m), 3.18-3.12 ( 1H, m), 2.39-2.31 (1H, m), 2.27-2.20 (2H, m), 2.10-2.05 (2H, m), 1.80-0.98 (23H, m), 1.50 (3H, s), 1.12 ( 3H, s), 0.98 (3H, d, J = 6.3 Hz).

(Example 37)

(2R)-tetrahydro-2H-pyran-2-yl [(4R,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-4,10a,12a -trimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,11R,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a,11-pentamethylhexadecahydro[1,3]dioxolane [5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (117 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m / z: 490 (M+H) ⁺ .

(Step 2)

(2R)-tetrahydro-2H-pyran-2-yl [(4R,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-4,10a,12a -trimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (62.0 mg) was obtained from m.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.16-4.09 (1H, m), 4.03-3.98 (1H, m), 3.94 (1H, dd, J = 10.7, 2.4 Hz), 3.60-3.55 (1H, m) , 3.53-3.50(1H,m), 3.45-3.38(1H,m),3.33-3.27(1H,m),3.16(1H,dd,J=9.8,3.9Hz), 2.28-2.20(2H,m) , 2.12-2.01 (2H, m), 1.92-1.86 (1H, m), 1.80-0.97 (42H, m), 1.52 (3H, s), 1.12 (3H, s), 0.98 (3H, d, J = 6.8 Hz).

(Example 38)

(2,6-difluorophenyl)[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyl-10- Octahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

(2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8, 8a,8b,8c,9-tetradecahydrocyclopropane[4,5]cyclopenta[1,2-a]phenanthrene-7(1H)-one

Add sodium hydride (60 wt%, 0.938 g) to a solution of trimethyl iodide (5.16 g) in dimethyl hydrazine (120 ml), and stir at room temperature for 30 minutes, then add the known (3β). 3-Hydroxyandrost-5,15-dien-17-one (3.36 g) was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.

MS (ESI) m / z: 301 (M+H) ⁺ .

(Step 2)

(2S, 4aR, 4bS, 6aS, 7aS, 8aS, 8bR, 8cR)-4a, 6a-dimethyl-7-side oxygen-1,2,3,4,4a,4b,5,6,6a,7 ,7a,8,8a,8b,8c,9-hexadehydrocyclopropane[4,5]cyclopenta[1,2-a]phenanthren-2-yl acetate

The title compound (1.58 g) was obtained as a solid.

MS (ESI) m / z: 343 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.46-5.41 (1H, m), 4.64-4.54 (1H, m), 2.38-0.93 (19H, m). 2.01 (3H, s), 1.03 (3H, s) , 0.95 (3H, s).

(Step 3)

(2S, 4aR, 4bS, 6aS, 7E, 7aS, 8aS, 8bR, 8cR)-7-(hydroxyimino)-4a,6a-dimethyl-1,2,3,4,4a,4b,5 ,6,6a,7,7a,8,8a,8b,8c,9-hexadehydrocyclopropane[4,5]cyclopenta[1,2-a]phenanthr-2-yl acetate

The title compound (1.49 g) was obtained from m.

MS (ESI) m/z: 358 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.44 - 5.39 (1H, m), 4.62-4.55 (1H, m), 2.42-0.90 (19H, m), 2.01 (3H, s), 1.03 (3H, s) , 0.99 (3H, s).

(Step 4)

(2S, 4aR, 4bS, 6aS, 8aS, 9aS, 9bR, 9cR)-4a, 6a-dimethyl-8-side oxygen-2,3,4,4a,4b,5,6,6a,7,8 ,8a,9,9a,9b,9c,10-hexadecahydro-1H-cyclopropane[c]naphtho[2,1-f]quinolin-2-yl acetate

The title compound (730 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 5.45 (1H, brs), 5.43-5.39 (1H, m), 4.64 - 4.55 (1H, m), 2.38-2.26 (3H, m), 1.89-0.83 (16H, m), 2.01 (3H, s), 1.19 (3H, s), 1.02 (3H, s).

(Step 5)

(2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR)-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7,8,8a,9, 9a,9b,9c,10-hexadecahydro-1H-cyclopropane[c]naphtho[2,1-f]quinolin-2-ol

The title compound (251 mg) was obtained.

MS (ESI) m / z: 302 (M + H) +.

(Step 6)

(2,6-difluorophenyl)[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR)-2-hydroxy-4a,6a-dimethyl-1,2,3,4,4a , 4b,5,6,6a,8,8a,9,9a,9b,9c,10-hexadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl] Ketone

The title compound (43 mg) was obtained as a solid. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 442 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.28-7.22 (1H, m), 6.91-6.85 (2H, m), 5.39-5.35 (1H, m), 3.62-3.47 (3H, m), 2.99-2.94 ( 1H, m), 2.36-2.28 (2H, m), 2.26-2.18 (1H, m), 1.94 (1H, d, J = 11.2 Hz), 1.85-1.79 (3H, m), 1.73-1.64 (2H, m), 1.60 (3H, s), 1.54-1.36 (2H, m), 1.09-1.03 (2H, m), 1.00-0.93 (4H, m), 1.00 (3H, s). 0.50-0.46 (1H, m).

(Step 7)

(4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR)-7-(2,6-difluorobenzhydryl)-4a,6a-dimethyl-3,4,4a,4b,5,6 ,6a,7,8,8a,9,9a,9b,9c,10,11-hexadecahydro-2H-cyclopropane[c]naphtho[2,1-f]quinolin-2-one

The title compound (46 mg) was obtained from m.

MS (ESI) m/z: 440 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.30-7.23 (1H, m), 6.92-6.85 (2H, m), 5.74 (1H, s), 3.61-3.54 (2H, m), 3.04-3.01 (1H, m), 2.48-2.31 (4H, m), 2.29-2.22 (1H, m), 2.06-1.99 (1H, m), 1.96-1.92 (1H, m), 1.91-1.82 (1H, m), 1.71 1.36 (4H, m), 1.63 (3H, s), 1.25-0.98 (5H, m), 1.18 (3H, s), 0.55-0.49 (1H, m).

(Step 8)

(2,6-difluorophenyl)[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b ,5,6,6a,8,8a,9,9a,9b,9c,10,11-hexadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl] Ketone

The title compound (46.4 mg) was obtained from m.

MS (ESI) m / z: 442 (M+H) ⁺ .

(Step 9)

(2,6-difluorophenyl)[(1S,3aR,3bS,5aS,7aS,8aR,8bR,8cR,10aR,11aS)-1-hydroxy-3a,5a-dimethylhexadehydrocyclopropane [ c] Ethylene oxide [4a,5]naphtho[2,1-f]quinolin-6(2H)-yl]methanone

The title compound (48.0 mg) was obtained as a solid.

MS (ESI) m / z: 458 (M+H) ⁺ .

(Step 10)

(2,6-difluorophenyl)[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyl-10- Octahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (22.0 mg) was obtained from m.

MS (ESI) m / z: 476 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.28-7.24 (1H, m), 6.90-6.85 (2H, m), 4.17-4.10 (1H, m), 3.60-3.50 (4H, m), 3.01-2.95 ( 1H, m), 2.30-2.24 (2H, m), 2.03-1.92 (2H, m), 1.80-0.93 (12H, m). 1.58 (3H, s), 1.14 (3H, s), 0.51-0.45 ( 1H, m).

(Example 39)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl(2,2- ² H ₂ )hexadecyanate And [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl(2,2- ² H ₂ )-1,2,3,4,4a,4b,5,7,8,9 ,10,10a,10b,11,12,12a-hexadehydronaphtho[2,1-f]quinolin-8-ol

Using (4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-2-oxo-1,2,3,4,4a,4b,5,7,8,9,10, 10a, 10b, 11, 12, 12a-hexadehydronaphtho[2,1-f]quinolin-8-yl acetate (2.88g) and lithium aluminum halide (1M tetrahydrofuran solution, 25.0ml), borrowed The title compound (2.43 g) was obtained from m.

MS (ESI) m / z: 292 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.35-5.30 (1H, m), 3.36 (1H, m), 2.25-2.07 (3H, m), 1.85 (1H, m), 1.77 (1H, m), 1.68-1.61 (2H, m), 1.57-0.91 (12H, m), 1.04 (3H, s), 0.97 (3H, s).

(Step 2)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a,12a-dimethyl(2,2- ² H ₂ )-3,4,4a,4b,5,7,8,9 ,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (2.01 g) was obtained as a white solid.

MS (ESI) m/z: 426 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.25 (5H, m), 5.31 (1H, m), 5.07 (1H, d, J = 12.7 Hz), 5.05 (1H, d, J = 12.7 Hz), 3.49 (1H, m), 3.02 (1H, m), 2.28 (1H, m), 2.22-2.08 (2H, m), 1.85-1.58 (6H, m), 1.55-1.29 (7H, m), 1.33 ( 3H, s), 1.17 (1H, m), 1.07-0.98 (2H, m), 0.94 (3H, s).

(Step 3)

(4aS, 4bR, 10aR, 10bS , 12aS) -10a, 12a- dimethyl-8-oxo-side _{^{(2,2- 2 H 2) -3,4,4a,}} 4b, 5,6,8,9, 10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (1.52 g) was obtained as a white solid.

MS (ESI) m / z: 424 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.70 (1H, brs), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.08(1H,m),2.44-2.24(4H,m),2.05-1.98(2H,m),1.83(1H,m),1.73-1.59(4H,m),1.52-1.41(2H,m), 1.39-1.16(3H,m), 1.37(3H,s), 1.13(3H,s), 1.05-0.94(2H,m).

(Step 4)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a,12a-dimethyl(2,2- ² H ₂ )-3,4,4a,4b,5,6,8,9 ,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (1.53 g) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.26 (1H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 4.13 (1H, m), 3.02 (1H, m), 2.15 (1H, m), 2.02 (1H, m), 1.96-1.88 (2H, m), 1.80 (1H, m), 1.72-1.58 (3H, m), 1.54 (1H, m), 1.47-1.11 (8H, m), 1.34 (3H, s), 0.99 (3H, s), 0.88-0.78 (2H, m).

(Step 5)

(1aS, 2S, 4aR, 4bS , 6aS, 10aS, 10bR, 12aR) -2- hydroxy -4a, 6a- dimethyl (8,8- _² H ²⁾ tetradecahydro -1aH- oxirane [4a , 5] naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (1.59 g) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 4.03 (1H, m), 3.13 (1H, d, J = 4.4 Hz), 3.04 (1H, m), 2.20 (1H, d, J = 10.3 Hz), 2.06 (1H, m), 1.95 (1H, m), 1.82 (1H, m) ), 1.73-1.60 (2H, m), 1.55-1.13 (11H, m), 1.33 (3H, s), 1.09 (1H, m), 0.96 (3H, s), 0.93 (1H, m).

(Step 6)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl(2,2- ² H ₂ )hexadecaphthalene[2 , 1-f] quinoline-1(2H)-benzyl formate

The title compound (414 mg) was obtained as a white solid.

MS (ESI) m/z: 460 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.34 - 7.24 (5H, m), 5.02 (2H, s), 4.03 (1H, m), 3.42 (1H, d, J = 3.4 Hz), 2.94 (1H, m), 2.11 (1H, m), 1.85 (1H, m), 1.72-1.11 (16H, m), 1.32 (3H, s), 1.08 (3H, s).

(Step 7)

(4aS, 4bR, 6aS, 7S , 8S, 10aR, 10bS, 12aS) -8- ( acetyl-yloxy) -6a, 7- dihydroxy -10a, 12a- dimethyl (2,2- _² H ² Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-benzyl formate

The title compound (322 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.26 (1H, ddd, J = 3.9, 5.4, 12.2 Hz), 5.06 (1H, d, J = 12.7 Hz), 5.04 (1H) , d, J = 12.7 Hz), 3.62 (1H, m), 3.01 (1H, m), 2.19 (1H, m), 2.06 (3H, m), 1.88 (1H, d, J = 2.4 Hz), 1.84 -1.59(6H,m),1.57-1.49(2H,m),1.45-1.33(5H,m),1.32(3H,s),1.25-1.12(4H,m),1.11(3H,s),1.09 (1H, s).

(Step 8)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-10a, 12a-dimethyl(2,2- ² H ₂ ) octahydronaphtho[2,1 -f]quinoline-8-yl acetate

The title compound (242 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 5.27 (1H, m), 3.63 (1H, d, J = 3.4 Hz), 2.20 - 1.76 (4H, m), 2.05 (3H, s), 1.70-1.65 (4H , m), 1.57-1.51 (2H, m), 1.47-0.99 (12H, m), 1.13 (3H, s), 1.02 (3H, s).

(Step 9)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a,7-dihydroxy-10a,12a-dimethyl(2,2- ² H ₂ ) Octaphtho[2,1-f]quinolin-8-yl acetate

The title compound (58 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m / z: 478 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.27 (1H, m), 3.62 (1H, d, J = 3.9 Hz), 3.18 (1H, m), 2.49 (1H, m), 2.16 (1H, m) , 2.04 (3H, s), 1.92-1.17 (27H, m), 1.41 (3H, s), 1.13 (3H, s).

(Step 10)

Cyclohexyl group [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS) -6a, 7,8- trihydroxy -10a, 12a- dimethyl (2,2- _² H ²⁾ sixteen decalin And [2,1-f]quinoline-1(2H)-yl]methanone

The title compound (45 mg) was obtained as a white solid.

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.03 (1H, m), 3.42 (1H, d, J = 3.9 Hz), 3.15 (1H, m), 2.46 (1H, m), 2.11 (1H, m) , 1.87 (1H, m), 1.81-1.13 (26H, m), 1.38 (3H, s), 1.09 (3H, s).

(Embodiment 40)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl (2,2- ² H ₂ )hexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2- (carbonyl group) (2,2- ² H ₂ ) octahydronaphtho[2,1-f]quinoline-8-yl acetate

The title compound (175 mg) was obtained as a white solid. ).

MS (ESI) m/z: 480 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.25 (1H, m), 4.06 (1H, m), 3.94 (1H, m), 3.59 (1H, d, J = 3.4 Hz), 3.46 (1H, m) , 3.15 (1H, m), 2.13 (1H, m), 2.01 (3H, s), 1.92-1.80 (3H, m), 1.78-1.47 (11H, m), 1.46-1.31 (3H, m), 1.40 (3H, s), 1.27-1.14 (6H, m), 1.11 (3H, s).

(Step 2)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl (2,2- ² H ₂ )hexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (142 mg) was obtained as a white solid.

MS (ESI) m / z: 438 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.06 (1H, m), 4.02 (1H, m), 3.94 (1H, dd, J = 2.4, 11.2 Hz), 3.46 (1H, m), 3.42 (1H, d, J = 3.9 Hz), 3.15 (1H, m), 2.12 (1H, m), 1.91-1.82 (2H, m), 1.79-1.28 (17H, m), 1.40 (3H, s), 1.25-1.13 (4H, m), 1.09 (3H, s).

(Example 41)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethyl(2,2- ² H ₂ ) Hydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(1aS, 2S, 4aR, 4bS , 6aS, 10aS, 10bR, 12aR) -2- methoxy -4a, 6a- dimethyl (8,8- _² H ²⁾ oxirane tetradecahydro -1aH- [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (187 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.65 (1H, m), 3.42 (3H, s), 3.10 (1H, d, J = 3.9 Hz), 3.03 (1H, m), 2.06 (1H, m), 1.94 (1H, m), 1.82 (1H, m), 1.73-1.60 (2H, m), 1.54-1.41 (5H, m), 1.38-1.29 (2H, m), 1.33 (3H, s), 1.27-1.15 (3H, m), 1.14-1.06 (2H, m), 0.97 (3H, s), 0.93 (1H, m).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-8-methoxy-10a, 12a-dimethyl(2,2- ² H ₂ )hexadecane Naphtho[2,1-f]quinoline-1(2H)-benzyl formate

The title compound (131 mg) was obtained as a white solid.

MS (ESI) m/z: 474 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.67-3.62 (2H, m ), 3.37 (3H, s), 3.01 (1H, m), 2.28 (1H, s), 2.19 (1H, m), 1.84-1.49 (7H, m), 1.44-1.34 (6H, m), 1.32 ( 3H, s), 1.29-1.12 (4H, m), 1.09 (3H, s), 1.03 (1H, s).

(Step 3)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-methoxy-10a,12a-dimethyl(2,2- ² H ₂ )hexadecahydro[2,1- f] quinoline-6a,7(2H)-diol

The title compound (99 mg) was obtained as a white solid.

_{^{1 H-NMR (CD 3 OD}} ) δ: 3.68 (1H, m), 3.62 (1H, d, J = 3.9Hz), 3.32 (3H, s), 2.10 (1H, m), 1.75-1.16 (16H, m), 1.13 - 0.97 (2H, m), 1.10 (3H, s), 1.02 (3H, s).

(Step 4)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethyl(2,2- ² H ₂ ) Hydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (92 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 452 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.93 (1H, dd, J = 2.4, 10.7 Hz), 3.66-3.61 (2H, m), 3.41 (1H, m), 3.36 (3H) , s), 3.25 (1H, m), 2.29 (1H, s), 2.20 (1H, m), 1.89 (1H, m), 1.85-1.30 (17H, m), 1.40 (3H, s), 1.28- 1.13 (5H, m), 1.09 (3H, s), 1.04 (1H, s).

(Example 42)

1-[(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]-2-methylpropan-1-one

(step 1)

(4aS, 4bS, 10aR, 10bS, 12aS)-2-methoxy-10a,12a-dimethyl-3,4,4a,4b,5,6,9,10,10a,10b,12,12a- Dodecahydronaphtho[2,1-f]quinoline-8,11-dione

(4aS, 4bS, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-3,4,4a,4b,5,6,9,10,10a,10b,12,12a-dodecanone [2,1-f]quinoline-2,8,11(1H)-trione (19.0 g) was suspended in dichloromethane (500 ml), and methyl trifluoromethanesulfonate (8.57 ml) was added to the room. Stir under temperature for one night. An aqueous potassium carbonate solution was added to the reaction mixture, the organic layer was separated, and the aqueous layer was re-extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, and the residue was evaporated to ethylamine. Amine (4.7 g).

MS (ESI) m/z: 330 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.71 (1H, s), 3.57 (3H, s), 2.77-2.75 (1H, m), 2.59-2.56 (1H, m), 2.50-1.12 (10H, m) , 1.40 (3H, s), 0.92 (3H, s).

(Step 2)

(4aS, 4bS, 10aR, 10bS, 12aS)-8-ethoxy-2-methoxy-10a,12a-dimethyl-4,4a,4b,5,9,10,10a,10b,12, 12a-decahydronaphtho[2,1-f]quinoline-11(3H)-one

The compound (52.4 g) obtained in the above step 1 was dissolved in a mixed solution of tetrahydrofuran (320 ml) and ethanol (320 ml), and ethyl orthoformate (52.4 ml) and p-toluenesulfonic acid monohydrate (33.3 g) were added. Stir at room temperature for 1 hour. A 1 N aqueous sodium hydroxide solution was added to the reaction mixture to make it alkaline, and the solvent was distilled off, and the mixture was partitioned between ethyl acetate and saturated brine. The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m/z: 358 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.15-5.14 (1H, m), 5.06-5.05 (1H, m), 3.76-3.73 (2H, m), 3.57 (3H, s), 2.63-2.55 (2H, m), 2.46-2.23 (5H, m), 2.07-2.01 (2H, m), 1.95-1.85 (3H, m), 1.50-1.43 (2H, m), 1.28 (3H, t, J = 7.1 Hz) , 1.18-1.15 (1H, m), 1.14 (3H, s), 0.90 (3H, s).

(Step 3)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-8-ethoxy-10a,12a-dimethyl-1,2,3,4,4a,4b,5,9,10,10a,10b, 11,12,12a-tetradeconaphtho[2,1-f]quinolin-11-ol

The compound (56.2 g) obtained in the above step 2 was suspended in ethanol (1000 ml), sodium borohydride (59.5 g) was added, and the mixture was stirred overnight at room temperature. A part of the reaction liquid was distilled off, water was added, and extracted with dichloromethane. The organic layer was dried (MgSO4)

MS (ESI) m / z: 332 (M+H) ⁺ .

(Step 4)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-8-ethoxy-11-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,9,10,10a,10b, 11,12,12a-dodehydronaphtho[2,1-f]quinoline-1(2H)-benzyl formate

The title compound (66.5 g) was obtained from m.

MS (ESI) m / z: 466 (M+H) ⁺ .

(Step 5)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-11-hydroxy-10a,12a-dimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9,10,10a , 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound (62.9 g) obtained in the above step 4 was dissolved in tetrahydrofuran (1000 ml), and 1N hydrochloric acid (100 ml) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was neutralized with a 1 N aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was dried and concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

MS (ESI) m / z: 438 (M + H) ⁺

_{^{1 H-NMR (CDCl 3)}} δ: 7.34-7.32 (5H, m), 5.68 (1H, s), 5.08 (2H, s), 4.34-4.33 (1H, m), 3.82-3.78 (1H, m) , 3.31-3.27 (2H, m), 2.50-2.17 (6H, m), 1.99-1.02 (17H, m).

(Step 6)

(4aS, 4bS, 10aS, 10bR, 12aS)-10b-fluoro-10a, 12a-dimethyl-8-side oxygen-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (fluoride) And (4aS, 4bS, 10aS, 12aS)-10a, 12a-dimethyl-8-side oxygen-3,4,4a,4b,5,6,8,9,10,10a,12,12a-12 Hydrogen naphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (olefinic body)

The compound (26.1 g) obtained in the above step 5 was dissolved in dichloromethane (600 ml), and 1,8-dibibicyclo[5.4.0]undec-7-ene (16.4 ml) was added. Further, (diethylamino)difluoroindole tetrafluoroborate (25.0 g) was added thereto with stirring at -78 ° C, and the mixture was allowed to stand overnight, and gradually warmed to room temperature. Saturated sodium hydrogencarbonate water was added to the mixture and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the obtained residue was evaporated to ethylamine (hexane) (10.6 g) and the title compound (olefins) (8.61 g).

Fluoride: (Rf=lower: high polarity)

MS (ESI) m/z: 440 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.31 (5H, m), 5.84-5.84 (1H, m), 5.09-5.09 (2H, m), 3.80-3.77 (1H, m), 3.40-3.38 ( 1H, m), 3.00-2.98 (1H, m), 2.44-2.35 (6H, m), 2.08-1.43 (10H, m), 1.40 (3H, s), 1.27 (3H, s), 1.25-1.16 ( 1H, m).

Olefin body: (Rf=higher: low polarity)

MS (ESI) m / z: 420 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.33 (5H, m), 5.74-5.74 (1H, m), 5.49-5.47 (1H, m), 5.09 (2H, s), 3.78-3.73 (1H, m), 3.38-3.35 (2H, m), 2.50-2.41 (4H, m), 2.27-1.93 (6H, m), 1.82-1.44 (3H, m), 1.31 (3H, s), 1.23 (3H, s), 1.10-1.07 (1H, m).

(Step 7)

(4aS, 4bS, 8S, 10aS, 10bR, 12aS)-10b-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a,4b,5,6,8,9,10,10a, 10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (5.18 g) was obtained from the compound (m.

MS (ESI) m/z: 442 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.45-5.44 (1H, m), 5.11-5.05 (2H, m), 4.21-4.19 (1H, m), 3.78-3.76 ( 1H, m), 3.40-3.34 (1H, m), 2.94-2.92 (1H, m), 2.24-2.21 (1H, m), 2.13-2.10 (1H, m), 2.04-1.16 (16H, m), 1.37 (3H, s), 1.15 (3H, s).

(Step 8)

(1aS, 2S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR)-4b-fluoro-2-hydroxy-4a, 6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho [2,1-f]quinoline-7(5H)-benzyl formate

The title compound (4.96 g) was obtained from m.

MS (ESI) m/z: 458 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.09-5.07 (2H, m), 4.02-4.01 (1H, m), 3.78-3.77 (1H, m), 3.39-3.36 ( 1H, m), 3.23 - 3.23 (1H, m), 2.96 - 2.92 (1H, m), 2.12-1.09 (24H, m).

(Step 9)

(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f] Quinoline-1(2H)-benzyl formate (triol) And (4aS, 4bS, 7R, 8S, 10aS, 10bR, 12aS)-10b-fluoro-7,8-dihydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8, 9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (diol)

The title compound (0.93 g) was obtained as a mixture of the mixture of the triol and the diol.

(Step 10)

(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS)-7,8-bis(ethinyloxy)-10b-fluoro-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-formic acid benzyl ester (grade 3 alcohol) and (4aS, 4bS, 7R, 8S, 10aS, 10bR, 12aS)-7,8-bis(ethenyloxy)-10b-fluoro-10a,12a-dimethyl-3,4,4a,4b,5 ,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (olefinic body)

The title compound (3rd alcohol) (0.67 g) was obtained as a colorless oily substance, which was obtained as a white solid. The title compound (olefins) (0.70 g).

Grade 3 alcohol

MS (ESI) m/z: 560 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.29 (5H, m), 5.48 (1H, m), 5.08-5.04 (3H, m), 3.98 (1H, d, J = 35.6 Hz), 3.77 (1H) , m), 3.39 (1H, m), 2.94 (1H, m), 2.15-2.01 (2H, m), 2.10 (3H, s), 1.97 (3H, s), 1.89-1.40 (14H, m), 1.36 (3H, s), 1.25 (3H, s), 1.12-1.25 (1H, m).

(Step 11)

(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS)-10b-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecylnaphtho[2,1-f]quinoline-7, 8-diyldiacetate

The title compound (0.51 g) was obtained from the title compound (m.p.

MS (ESI) m/z: 426 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.47 (1H, m), 5.05 (1H, m), 3.84 (1H, d, J = 34.2 Hz), 3.20 (1H, m), 3.01 (1H, m), 2.30 (1H, m), 2.10 (3H, s), 1.97 (3H, s), 1.37 (3H, s), 1.25 (3H, s), 2.13-1.16 (18H, m).

(Step 12)

(4aS, 4bS, 6aS, 7S, 8S, 10aS, 10bR, 12aS)-10b-fluoro-6a-hydroxy-10a,12a-dimethyl-1-(2-methylpropenyl) octahydronaphthalene [2,1-f]quinoline-7,8-diyl diacetate

The title compound (116 mg) was obtained from the title compound (100 mg).

MS (ESI) m/z: 496 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.48 (1H, m), 5.05 (1H, d, J = 3.9 Hz), 3.99 (1H, d, J = 35.6 Hz), 3.49-3.42 (2H, m), 3.20-3.17(1H,m), 2.71(1H,m), 2.17-2.05(2H,m),1.87-1.18(15H,m),2.10(3H,s),1.97(3H,s), 1.44( 3H, s), 1.25 (3H, s), 1.08 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 6.3 Hz).

(Step 13)

1-[(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]-2-methylpropan-1-one

The title compound (65 mg) was obtained as a white solid.

MS (ESI) m/z: 412 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.25 (1H, m), 3.88 (1H, d, J = 35.6 Hz), 3.56 (1H, m), 3.48-3.41 (2H, m), 3, 17 ( 1H,m), 2.72(1H,m), 2.36(1H,d,J=2.4Hz),2.16-1.38(17H,m),1.44(3H,s),1.26(3H,s),1.26-1.22 (1H, m), 1.08 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 6.3 Hz).

(Example 43)

Cyclohexyl [(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,4bS,10aR,10bS,11S,12aS)-8-ethoxy-11-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,9,10,10a ,10b,11,12,12a-dodehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (8.09 g) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

(Step 2)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-1-(cyclohexylcarbonyl)-11-hydroxy-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9, 10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

The title compound (4.69 g) was obtained from m.

MS (ESI) m/z: 414 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.68 (1H, s), 4.33-4.32 (1H, m), 3.56-3.53 (1H, m), 3.46-3.45 (1H, m), 3.38-3.33 (1H, m), 2.50-0.99 (28H, m), 1.70 (3H, s), 1.41 (3H, s).

(Step 3)

(4aS, 4bS, 10aS, 10bR, 12aS)-1-(cyclohexylcarbonyl)-10b-fluoro-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9,10, 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-8(2H)-one (fluoro) and (4aS, 4bS, 10aS, 12aS)-1-(ring) Hexylcarbonyl)-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9,10,10a,12,12a-dodehydronaphtho[2,1-f]quinoline -8(2H)-ketone (olefinic body)

The title compound (fluorine) (2.16 g) and the title compound ( olefins) (1.67 g) were obtained from the title compound (4.66 g).

Fluoride: (Rf=lower: high polarity)

MS (ESI) m / z: 416 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.81-5.80 (1H, m), 3.42-3.38 (2H, m), 3.20-3.17 (1H, m), 2.42-1.20 (28H, m), 1.44 (3H, s), 1.25 (3H, s).

Olefin body: (Rf=higher: low polarity)

MS (ESI) m/z: 396 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.70-5.70 (1H, m), 5.45-5.44 (1H, m), 3.58-3.55 (1H, m), 3.50-3.45 (1H, m), 3.26-3.24 ( 1H, m), 2.54-1.03 (32H, m).

(Step 4)

Cyclohexyl [(4aS, 4bS, 8S, 10aS, 10bR, 12aS)-10b-fluoro-8-hydroxy-10a, 12a-dimethyl-3,4,4a,4b,5,6,8,9,10 ,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (402 mg) was obtained as a white solid.

MS (ESI) m/z: 418 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.41 (1H, d, J = 1.5 Hz), 4.17 (1H, m), 3.43-3.34 (2H, m), 3.13 (1H, m), 2.34 (1H, m ), 2.21 (1H, m), 2.08 (1H, m), 2.01-1.13 (26H, m), 1.41 (3H, s), 1.12 (3H, s).

(Step 5)

Cyclohexyl [(1aS, 2S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR)-4b-fluoro-2-hydroxy-4a, 6a-dimethyltetrahydrogen-1aH-oxirane [4a,5 Naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The title compound (368 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.98 (1H, m), 3.44 - 3.34 (2H, m), 3.20 (1H, d, J = 2.4 Hz), 3.14 (1H, m), 2.35 (1H, m ), 2.07 (1H, m), 1.96 (1H, m), 1.87-1.16 (26H, m), 1.41 (3H, s), 1.07 (3H, s).

(Step 6)

Cyclohexyl [(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl]methanone

The title compound (149 mg) was obtained as a white solid.

MS (ESI) m/z: 452 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.06 (1H, m), 3.52 (1H, m), 3.44 (1H, m), 3.39 (1H, d, J = 3.9 Hz), 3.04 (1H, m) , 2.49 (1H, m), 2.19-2.09 (2H, m), 2.00-1.16 (25H, m), 1.42 (3H, s), 1.26 (3H, s).

(Example 44)

(2,6-difluorophenyl)[(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethyl-10- Hexahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,6-difluorophenyl)[(4aS,4bS,10aR,10bS,11S,12aS)-8-ethoxy-11-hydroxy-10a,12a-dimethyl-3,4,4a,4b ,5,9,10,10a,10b,11,12,12a-dodehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (9.10 g) was obtained from the title compound (m.

(Step 2)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-1-(2,6-difluorobenzhydryl)-11-hydroxy-10a,12a-dimethyl-1,3,4,4a,4b ,5,6,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

The title compound (4.54 g) was obtained from m.

MS (ESI) m / z: 444 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.33-7.24 (1H, m), 6.92-6.88 (2H, m), 5.70-5.68 (1H, m), 4.41-4.39 (1H, m), 3.66-3.62 ( 1H, m), 3.40-3.37 (1H, m), 3.20-3.17 (1H, m), 2.51-1.14 (23H, m).

(Step 3)

(4aS, 4bS, 10aS, 10bR, 12aS)-1-(2,6-difluorobenzhydryl)-10b-fluoro-10a,12a-dimethyl-1,3,4,4a,4b,5 ,6,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one (fluoro) And (4aS, 4bS, 10aS, 12aS)-1-(2,6-difluorobenzhydryl)-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9, 10,10a,12,12a-dodehydronaphtho[2,1-f]quinoline-8(2H)-one (olefinic body)

The title compound (fluorobenzene) (1.60 g) and the title compound ( olefins) (1.32 g) were obtained from the compound obtained in the above-mentioned step 2 (4.54 g).

Fluoride: (Rf=lower: high polarity)

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.30-7.28 (1H, m), 6.92-6.89 (2H, m), 5.85 (1H, s), 3.44-3.42 (1H, m), 3.35-3.33 (1H, m), 3.22-3.18 (1H, m), 2.44-2.41 (5H, m), 2.16-2.13 (1H, m), 1.91-1.83 (9H, m), 1.61 (3H, s), 1.51-1.49 ( 3H, m), 1.31 (3H, s).

Olefin body: (Rf=higher: low polarity)

MS (ESI) m/z: 426 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.30-7.29 (1H, m), 6.92-6.90 (1H, m), 5.75-5.75 (1H, m), 5.57-5.55 (1H, m), 3.72-3.68 ( 1H, m), 3.42-3.39 (1H, m), 3.20-3.17 (1H, m), 2.51-2.43 (5H, m), 2.21-1.98 (5H, m), 1.79-1.65 (2H, m), 1.56 (3H, s), 1.55-1.52 (1H, m), 1.34 (3H, s), 1.34-1.29 (1H, m), 1.14-1.11 (1H, m).

(Step 4)

(2,6-difluorophenyl)[(4aS,4bS,8S,10aS,10bR,12aS)-10b-fluoro-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5 ,6,8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (431 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.24 (1H, m), 6.89-6.85 (2H, m), 5.43 (1H, m), 4.20 (1H, m), 3.39 (1H, m), 3.26 (1H) , m), 3.15 (1H, m), 2.24 (1H, m), 2.12-1.19 (17H, m), 1.57 (3H, s), 1.16 (3H, s).

(Step 5)

(2,6-difluorophenyl)[(1aS,2S,4aS,4bR,6aS,10aS,10bS,12aR)-4b-fluoro-2-hydroxy-4a,6a-dimethyltetrahydrol-1aH- Ethylene oxide [4a,5]naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The title compound (361 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.25 (1H, m), 6.90-6.85 (2H, m), 4.01 (1H, m), 3.39 (1H, m), 3.28 (1H, m), 3.22 (1H) , d, J = 2.4 Hz), 3.16 (1H, m), 2.12 - 2.05 (2H, m), 1.96 (1H, m), 1.82-1.39 (12H, m), 1.56 (3H, s), 1.34 1.19 (3H, m), 1.10 (3H, s).

(Step 6)

(2,6-difluorophenyl)[(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethyl-10- Hexahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (52 mg) was obtained as a white solid.

MS (ESI) m/z: 482 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.41 (1H, m), 7.01 (2H, m), 4.08 (1H, m), 3.47 (1H, m), 3.40 (1H, d, J = 3.9 Hz) , 3.19-3.13 (2H, m), 2.26-2.14 (2H, m), 2.06-1.51 (12H, m), 1.57 (3H, s), 1.44-1.27 (3H, m), 1.29 (3H, s) .

(Example 45)

Cyclohexyl [(4aS,4bS,6aS,7S,8S,10aR,10bS,11S,12aS)-11-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2] ,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bS, 10aS, 10bR, 11S, 12aS)-10b-bromo-1-(cyclohexylcarbonyl)-11-fluoro-10a,12a-dimethyl-1,3,4,4a,4b,5, 6,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

1,3-Dibromo-5,5-dimethylhydantoin (866 mg) was suspended in dichloromethane (30 ml), and hydrogen fluoride pyridine (1.41 ml) was added. After the reaction mixture was stirred slightly, a solution of the compound (olefin) (2.14 g) obtained in the step 3 of Example 43 in methylene chloride (50 ml) was gradually dropped and stirred for 1 hour. In a separate vessel, 1,3-dibromo-5,5-dimethylhydantoin (866 mg) was suspended in dichloromethane (20 ml), and a solution prepared by adding hydrogen fluoride pyridine (1.41 ml) was added. The mixture was added dropwise to the reaction solution for 30 minutes. Saturated sodium hydrogencarbonate water was added to the mixture and the mixture was extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the residue obtained by concentration of the filtrate was Purification by column chromatography (EtOAc / EtOAc)

MS (ESI) m/z: 494, 496 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.77-5.76 (1H, m), 5.16-5.05 (1H, m), 3.76-3.73 (1H, m), 3.48-3.45 (2H, m), 2.78-2.75 ( 1H, m), 2.57-0.87 (31H, m).

(Step 2)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-1-(cyclohexylcarbonyl)-11-fluoro-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9, 10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

The compound obtained in the above step 1 (936 mg) was dissolved in toluene (30 ml), and hydrogenated n-butyltin (0.993 ml) and 2,2'-azobisisobutyronitrile (18.7 mg) were added at 100 ° C. Stir under heating for 30 minutes. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate and washed three times with a 10% aqueous potassium fluoride solution. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

MS (ESI) m / z: 416 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.72-5.70 (1H, m), 5.09-4.97 (1H, m), 3.89-3.86 (1H, m), 3.45-3.38 (2H, m), 2.52-1.03 ( 33H, m).

(Step 3)

Cyclohexyl [(4aS,4bS,8S,10aR,10bS,11S,12aS)-11-fluoro-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9 ,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.25 g) was obtained as a white solid.

MS (ESI) m/z: 418 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.26 (1H, m), 5.02-4.92 (1H, m), 4.16-4.12 (1H, m), 3.81 (1H, m), 3.49-3.42 (1H, m) , 3.40-3.32 (1H, m), 2.35 (1H, m), 2.25 (1H, m), 2.09-0.86 (26H, m), 1.56 (3H, d, J = 2.4 Hz), 1.19 (3H, d , J = 3.9 Hz).

(Step 4)

Cyclohexyl [(1aS, 2S, 4aR, 4bS, 5S, 6aS, 10aS, 10bS, 12aR)-5-fluoro-2-hydroxy-4a, 6a-dimethyltetrahydrogen-1aH-oxirane [4a ,5]naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The title compound (0.21 g) was obtained from m.

MS (ESI) m / z: 434 (M+H) ⁺ .

(Step 5)

Cyclohexyl [(4aS,4bS,6aS,7S,8S,10aR,10bS,11S,12aS)-11-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2] ,1-f]quinoline-1(2H)-yl]methanone

The title compound (60 mg) was obtained from m.

MS (ESI) m/z: 452 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.97-4.86 (1H, m), 4.16-4.10 (1H, m), 3.77 (1H, m), 3.54 (1H, m), 3.49-3.34 (2H, m) , 2.39-2.26 (3H, m), 1.28 (3H, d, J = 3.9 Hz), 0.82 (1H, s), 1.97-1.15 (29H, m).

(Example 46)

(2,6-difluorophenyl)[(4aS,4bS,6aS,7S,8S,10aR,10bS,11S,12aS)-11-fluoro-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bS, 10aS, 10bR, 11S, 12aS)-10b-bromo-1-(2,6-difluorobenzhydryl)-11-fluoro-10a,12a-dimethyl-1,3,4 , 4a, 4b, 5, 6, 9, 10, 10a, 10b, 11, 12, 12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

The title compound (0.55 g) was obtained from m.

MS (ESI) m/z: 524, 526 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.32-7.24 (1H, m), 6.94-6.89 (2H, m), 5.78 (1H, m), 5.20 (1H, m), 3.90 (1H, m), 3.45 (1H,m), 3.26-3.20(1H,m), 2.80(1H,m), 1.74(3H,d,J=2.4),1.64(3H,d,J=4.4Hz),2.36-1.38(14H , m).

(Step 2)

(4aS, 4bS, 10aR, 10bS, 11S, 12aS)-1-(2,6-difluorobenzhydryl)-11-fluoro-10a,12a-dimethyl-1,3,4,4a,4b ,5,6,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-8(2H)-one

The title compound (0.25 g) was obtained from m.

MS (ESI) m/z: 446 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.31-7.22 (1H, m), 6.94-6.86 (2H, m), 5.72 (1H, m), 5.18-5.08 (1H, m), 3.97 (1H, m) , 3.38 (1H, m), 3.22 (1H, m), 2.54-2.37 (3H, m), 2.32 (1H, m), 2.26-2.14 (2H, m), 2.04 (1H, m), 1.97-1.63 (6H, m), 1.74 (3H, d, J = 2.0 Hz), 1.48-1.38 (1H, m), 1.36 (3H, d, J = 4.4 Hz), 1.25-1.05 (2H, m).

(Step 3)

(2,6-difluorophenyl)[(4aS,4bS,8S,10aR,10bS,11S,12aS)-11-fluoro-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b ,5,6,8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.21 g) was obtained from m.

(Step 4)

(2,6-difluorophenyl)[(1aS,2S,4aR,4bS,5S,6aS,10aS,10bS,12aR)-5-fluoro-2-hydroxy-4a,6a-dimethyltetrahydrogen- 1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The title compound (0.29 g) was obtained from m.

MS (ESI) m/z: 464 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.28 (1H, m), 6.93-6.87 (2H, m), 5.05-4.95 (1H, m), 4.10-4.05 (1H, m), 3.94 (1H, m) , 3.38 (1H, m), 3.24 - 3.18 (1H, m), 3.19 (1H, d, J = 4.4 Hz), 2.30 (1H, d, J = 10.3 Hz), 2.21 (1H, m), 2.12 ( 1H, m), 2.00-1.32 (11H, m), 1.71 (3H, d, J = 2.0 Hz), 1.17 (3H, d, J = 4.4 Hz), 1.18-0.98 (3H, m).

(Step 5)

(2,6-difluorophenyl)[(4aS,4bS,6aS,7S,8S,10aR,10bS,11S,12aS)-11-fluoro-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (10 mg) was obtained from m.

MS (ESI) m/z: 482 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.43 (1H, m), 7.06-7.01 (2H, m), 5.05-4.95 (1H, m), 4.09-4.04 (1H, m), 3.71 (1H, m ), 3.52-3.44 (2H, m), 3.12 (1H, m), 2.21 (1H, m), 2.01-1.91 (2H, m), 1.68 (3H, d, J = 2.0 Hz), 1.29 (3H, d, J = 3.4 Hz), 1.87-1.22 (16H, m).

(Example 47)

Cyclohexyl [(3R,4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-3,10a,12a-trimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(17E)-9-fluoro-17-(hydroxyimino)androst-4-en-3-one

Using 3-ethoxy-9-fluoroandrost-3,5-dien-17-one (31.0 g), the same reaction method as in Step 5 of Example 36 was used to obtain a crude reaction product. The obtained residue was dissolved in tetrahydrofuran (300 ml), and 1N hydrochloric acid (100 ml) was added, and the mixture was stirred at room temperature for one hour. Decrease tetrahydrofuran The mixture was evaporated to dryness, and the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated to give the title compound (3.

MS (ESI) m / z: 320 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.85 (1H, d, J = 2 Hz), 2.34-2.60 (8H, m), 2.02-1.92 (2H, m), 1.80-1.56 (10H, m), 1.40 ( 1H, m), 1.32 (3H, s), 0.96 (3H, s).

(Step 2)

(4aS, 4bS, 10aS, 10bR, 12aS)-10b-fluoro-10a,12a-dimethyl-1,3,4,4a,4b,5,6,9,10,10a,10b,11,12, 12a-tetradeconaphtho[2,1-f]quinoline-2,8-dione

The title compound (20.0 g) was obtained as a white solid.

MS (ESI) m / z: 320 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.86 (1H, s), 5.81 (1H, m), 2.53-2.36 (7H, m), 2.03 (1H, m), 1.93-1.46 (10H, m), 1.30 (3H, s), 1.22 (3H, s).

(Step 3)

(4aS, 4bS, 10aS, 10bR, 12aS)-10b-fluoro-2-methoxy-10a,12a-dimethyl-3,4a,4b,5,6,9,10,10a,10b,11, 12,12a-dodehydronaphtho[2,1-f]quinoline-8(4H)-one

The title compound (7.50 g) was obtained as a white solid.

MS (ESI) m / z: 334 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.85 (1H, brd, J = 2 Hz), 3.60 (3H, s), 2.49-2.35 (5H, m), 2.32-2.18 (2H, m), 2.02-1.95 ( 1H, m), 1.88-1.63 (7H, m), 1.55-1.33 (3H, m), 1.30 (3H, s), 1.02 (3H, s).

(Step 4)

(4aS, 4bS, 10aS, 10bR, 12aS)-8-ethoxy-10b-fluoro-2-methoxy-10a,12a-dimethyl-3,4,4a,4b,5,9,10, 10a,10b,11,12,12a-dodehydronaphtho[2,1-f]quinoline

The title compound (2.90 g) was obtained from m.

MS (ESI) m / z: 362 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.29 (1H, m), 5.17 (1H, m), 3.83-3.73 (2H, m), 3.61 (3H, s), 2.36-2.25 (5H, m), 2.07 -2.02(1H,m),1.96-1.66(8H,m),1.50-1.35(2H,m),1.30(3H,t,J=6.8Hz),1.07(3H,s),1.00(3H,s ).

(Step 5)

(4aS, 4bS, 10aS, 10bR, 12aS)-8-ethoxy-10b-fluoro-2-methoxy-3,10a,12a-trimethyl-3,4,4a,4b,5,9, 10,10a,10b,11,12,12a-dodehydronaphtho[2,1-f]quinoline

n-Butyllithium (2.69 M hexane solution, 0.77 ml) was added dropwise to a solution of the compound (0.58 g) in THF (50 ml). After stirring at the same temperature for 10 minutes, it was stirred at room temperature for 10 minutes. After cooling again to -78 ° C, iodomethane (0.15 ml) was added, and after stirring for 5 minutes, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m / z: 376 (M+H) ⁺ .

(Step 6)

(4aS, 4bS, 10aS, 10bR, 12aS)-8-ethoxy-10b-fluoro-3,10a,12a-trimethyl-1,2,3,4,4a,4b,5,9,10, 10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline

The title compound (0.53 g) was obtained from m. m.

(Step 7)

Cyclohexyl [(4aS,4bS,10aS,10bR,12aS)-8-ethoxy-10b-fluoro-3,10a,12a-trimethyl-3,4,4a,4b,5,9,10,10a ,10b,11,12,12a-dodehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.69 g) was obtained as a mixture of non-mironomers, using the same procedure as in Step 7 of Example 31. ).

(Step 8)

(3R,4aS,4bS,10aS,10bR,12aS)-1-(cyclohexylcarbonyl)-10b-fluoro-3,10a,12a-trimethyl-1,3,4,4a,4b,5,6, 9,10,10a,10b,11,12,12a-tetradecazin[2,1-f]quinoline-8(2H)-one and (3S,4aS,4bS,10aS,10bR,12aS)- 1-(cyclohexylcarbonyl)-10b-fluoro-3,10a,12a-trimethyl-1,3,4,4a,4b,5,6,9,10,10a,10b,11,12,12a- Tetrahydronaphtho[2,1-f]quinoline-8(2H)-one

The compound obtained in the above step 7 (0.69 g) was obtained by the same method as in the step 5 of Example 42 to obtain a white solid. Compound (3R-methyl) (0.28 g) and title compound (3S-methyl) (0.18 g).

3R-methyl (Rf=higher: low polarity)

MS (ESI) m / z: 430 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.84 (1H, m), 3.61-3.58 (1H, m), 3.25 (1H, m), 2.76 (1H, dd, J=13.7, 8.8 Hz), 2.46-2.33 (6H, m), 1.94-1.39 (18H, m), 1.30-1.19 (3H, m), 1.32 (3H, s), 1.27 (3H, s), 0.99 (3H, d, J = 6.3), 0.79 (1H, m).

3S-methyl (Rf=lower: high polarity)

MS (ESI) m / z: 430 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.83 (1H, m), 3.34 (1H, dd, J = 12.7, 3.9 Hz), 3.19 (1H, m), 3.07 (1H, t, J = 12.4 Hz), 2.46-2.33(6H,m),2.67-1.98(3H,m),1.92-1.77(6H,m),1.70-1.65(3H,m),1.51-1.41(5H,m),1.46(3H,s ), 1.32-1.18 (4H, m), 1.27 (3H, s), 0.97 (3H, d, J = 6.8 Hz).

(Step 9)

Cyclohexyl [(3R,4aS,4bS,8S,10aS,10bR,12aS)-10b-fluoro-8-hydroxy-3,10a,12a-trimethyl-3,4,4a,4b,5,6,8 ,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.28 g) was obtained as a white solid.

MS (ESI) m / z: 432 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.44 (1H, m), 4.21 (1H, m), 3.57 (1H, m), 3.19 (1H, m), 2.75 (1H, dd, J = 13.7, 8.3 Hz ), 2.41 (1H, m), 2.2 3 (1H, m), 2.11 (1H, m), 2.01 (1H, m), 1.92 (1H, m), 1.86-1.63 (12H, m), 1.58-1.39 (6H, m), 1.31-1.21 (4H, m), 1.30 (3H, s), 1.15 (3H, s), 0.97 (3H, d, J = 6.8 Hz), 0.74 (1H, m).

(Step 10)

Cyclohexyl [(1aS, 2S, 4aS, 4bR, 6aS, 9R, 10aS, 10bS, 12aR)-4b-fluoro-2-hydroxy-4a, 6a,9-trimethyltetradecahydro-1aH-ethylene oxide [4a,5]naphtho[2,1-f]quinolin-7(5H)-yl]methanone

The title compound (0.18 g) was obtained as a white solid.

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.01 (1H, m), 3.58 (1H, dd, J = 13.7, 3.9 Hz), 3.23 (1H, d, J = 2.9 Hz), 3.23-3.18 (1H, m ), 2.75 (1H, dd, J = 13.7, 8.8 Hz), 2.45-2.40 (1H, m), 2.09 (1H, m), 1.81-1.62 (13H, m), 1.60-1.39 (7, m), 1.29 (3H, s), 1.33-1.20 (5H, m), 1.09 (3H, s), 0.98 (3H, d, J = 6.3 Hz), 0.77 (1H, m).

(Step 11)

Cyclohexyl [(3R,4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-3,10a,12a-trimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

The title compound (50.0 mg) was obtained as a white solid.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 3.88 (1H, d, J = 36.1 Hz), 3.60-3.55 (2H, m), 3.19-3.16 (1H, m), 2.74 (1H) ,dd,J=13.7,9.3Hz), 2.11(1H,m),2.02-1.97(1H,m),1.88-1.62(14H,m),1.60-1.38(6H,m),1.29(3H,s ), 1.26 (3H, s), 1.30 - 1.21 (4H, m), 0.98 (3H, d, J = 6.8 Hz), 0.79 (1H, m).

(Example 48)

Cyclohexyl [(3S,4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-3,10a,12a-trimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(3S,4aS,4bS,8S,10aS,10bR,12aS)-10b-fluoro-8-hydroxy-3,10a,12a-trimethyl-3,4,4a,4b,5,6,8 ,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.19 g) was obtained from m.

MS (ESI) m / z: 422 (M+H) ⁺ .

(Step 2)

Cyclohexyl [(1aS, 2S, 4aS, 4bR, 6aS, 9S, 10aS, 10bS, 12aR)-4b-fluoro-2-hydroxy-4a,6a,9-trimethyltetradecahydro-1aH-ethylene oxide [4a,5]naphtho[2,1-f]quinolin-7(5H)-yl]methanone

The title compound (0.18 g) was obtained as a white solid.

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.01 (1H, m), 3.33 (1H, dd, J = 12.7, 3.9 Hz), 3.23 (1H, d, J = 2.4 Hz), 3.14 (1H, m), 3,06 (1H, t, J = 12.4 Hz), 2.39 (1H, m), 2.13-1.38 (15H, m), 1.43 (3H, s), 1.33-1.20 (9H, m), 1.10 (3H, s), 0.96 (3H, d, J = 6.8 Hz), 0.97-0.91 (1H, m), 0.88 (2H, m).

(Step 3)

Cyclohexyl [(3S,4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-3,10a,12a-trimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

The title compound (50 mg) was obtained as a white solid.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.25 (1H, m), 3.87 (1H, d, J = 36.1 Hz), 3.56 (1H, m), 3.16-3.10 (1H, m), 3.08 (1H, t , J = 12.4 Hz), 2.39 (1H, m), 2.35 (1H, d, J = 2.4 Hz), 2.7-1.38 (24H, m), 1.43 (3H, s), 1.32-1.18 (4H, m) , 1.25 (3H, s), 0.97 (3H, d, J = 6.8 Hz).

(Example 49)

Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS)-10b-fluoro-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a, 12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bS, 9Z, 10aS, 10bR, 12aS)-10b-fluoro-9-(hydroxymethylene)-10a,12a-dimethyl-8-sideoxy-3,4,4a,4b,5, 6,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (3.22 g) was obtained as a solid.

MS (ES1) m / z: 468 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.43-7.30 (6H, m), 5.87 (1H, m), 5.09 (2H, s), 3.79 (1H, m), 3.39 (1H, m), 3.01-2.95 (2H, m), 2.50-2.39 (2H, m), 2.08 (1H, d, J = 14.0 Hz), 2.01 (1H, m), 1.93-1.47 (9H, m), 1.39 (3H, s), 1.29-1.17 (1H, m), 1.10 (3H, s).

(Step 2)

(4aS, 4bS, 8R, 9S, 10aS, 10bR, 12aS)-10b-fluoro-8-hydroxy-9-(hydroxymethyl)-10a,12a-dimethyl-3,4,4a,4b,5, 6,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (3.25 g) was obtained as a solid.

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.43 - 7.28 (5H, m), 5.37 (1H, s), 5.08 (2H, s), 4.14 (1H, m), 3.80-3.70 (3H, m), 3.37 (1H, m), 2.93 (1H, m), 2.61 (1H, m), 2.34 (1H, m), 2.27-2.14 (2H, m), 2.01-1.93 (1H, m), 1.85-1.47 (10H , m), 1.37 (3H, s), 1.37-1.15 (3H, m), 1.18 (3H, s).

(Step 3)

(1aS, 2S, 3S, 4aS, 4bR, 6aS, 10aS, 10bS, 12aR)-4b-fluoro-2-hydroxy-3-(hydroxymethyl)-4a,6a-dimethyltetrahydrol-1aH-ring Oxyethane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (2.00 g) was obtained as a white solid.

MS (ESI) m/z: 488 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.26 (5H, m), 5.08 (2H, s), 3.87 (1H, dd, J = 9.3, 6.3 Hz), 3.78 (1H, m), 3.68-3.65 (2H, m), 3.37 (1H, m), 3.18 (1H, s), 2.94-2.89 (1H, m), 2.65-2.62 (1H, m), 2.22 (1H, m), 2.07-1.94 (3H , m), 1.85-1.05 (13H, m), 1.37 (3H, s), 1.16 (3H, s).

(Step 4)

(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS)-10b-fluoro-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (3rd alcohol) and (4aS, 4bS, 7R, 8S, 9S, 10aS, 10bR, 12aS)-10b-fluoro- 7,8-Dihydroxy-9-(hydroxymethyl)-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10, 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (olefinic body)

Using the compound obtained in the above step 3 (2.00 g), the title compound was obtained as a mixture of a mixture of an alcohol and an olefin.

(Step 5)

(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS)-7,8-bis(ethinyloxy)-9-[(ethylideneoxy)methyl]-10b-fluorine -6a-hydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (grade 3 alcohol) and (4aS, 4bS, 7R, 8S , 9S, 10aS, 10bR, 12aS)-7,8-bis(ethinyloxy)-9-[(ethoxycarbonyl)methyl]-10b-fluoro-10a,12a-dimethyl-3 ,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (olefin body)

The title compound (3rd-order alcohol) (1.04g) and the title compound (olefinic body) (1.50g) were obtained by the same procedure as in the above-

Grade 3 alcohol

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.28 (5H, m), 5.45 (1H, dd, J = 11.7, 4.4 Hz), 5.11 (1H, d, J = 4.4 Hz), 5.08 (2H, s ), 4.10-4.02 (2H, m), 3.97 (1H, d, J = 39.7 Hz), 3.78 (1H, m), 3.39 (1H, m), 2.97-2.94 (1H, m), 2.29 (1H, m), 2.09 (3H, s), 2.08 (3H, s), 1.96 (3H, s), 1.36 (3H, s), 1.28 (3H, s), 2.10-1.49 (12H, m), 1.44-1.40 (1H, m), 1.28-1.13 (2H, m).

(Step 6)

(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS)-9-[(acetamidooxy)methyl]-10b-fluoro-6a-hydroxy-10a, 12a-dimethyl-10- Octaphtho[2,1-f]quinoline-7,8-diyldiacetate

The title compound (0.82 g) was obtained as a solid (yield: m. ).

(Step 7)

(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS)-9-[(ethoxycarbonyl)methyl]-1-(cyclohexylcarbonyl)-10b-fluoro-6a-hydroxy- 10a,12a-dimethyloctadecylnaphtho[2,1-f]quinoline-7,8-diyldiacetate

The title compound (0.49 g) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

¹ H-NMR (CDCl ₃ ) δ: 5.45 (1H, dd, J = 12.0, 4.1 Hz), 5.11 (1H, d, J = 4.1 Hz), 4.02-4.10 (2H, m), 3.98 (1H, d , J=35.6 Hz), 3.48-3.39 (2H, m), 3.20-3.17 (1H, m), 2.38 (1H, m), 2.33-2.25 (1H, m), 2.10-2.02 (2H, m), 1.88-1.63(12H,m),2.09(3H,s),2.07(3H,s),1.96(3H,s),1.60-1.38(6H),1.43(3H,s),1.28(3H,s) , 1.31-1.15 (5H).

(Step 8)

Cyclohexyl [(4aS, 4bS, 6aS, 7S, 8S, 9S, 10aS, 10bR, 12aS)-10b-fluoro-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a, 12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (0.25 g) was obtained as a white solid.

MS (ESI) m/z: 482 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.90 (1H, dd, J = 11.2, 4.4 Hz), 3.80 (1H, dd, J = 10.5, 4.1 Hz), 3.59-3.54 (2H, m), 3.50- 3.46 (1H, m), 3.44 (1H, d, J = 4.4 Hz), 3.10-3.05 (1H, m), 2.52 (1H, m), 2.21-2.12 (2H, m), 2.03-1.16 (24H, m), 1.45 (3H, s), 1.32 (3H, s).

(Example 50)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,4bR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]- Oxy}-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydro[2,1- f]quinoline-1(2H)-yl]methanone

The compound obtained in the first step of Example 1 (280 mg) and (R)-(-)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonic acid The title compound (316 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 5.30 (1H, m), 4.22 (1H, m), 4.04 (1H, dd, J = 6.3, 7.8 Hz), 3.70 (1H, dd, J = 6.6, 8.1 Hz ), 3.57-3.50 (2H, m), 3.41 (1H, dd, J = 5.9, 9.8 Hz), 3.35 (1H, m), 3.23 (1H, m), 3.15 (1H, m), 2.38-2.32 ( 2H, m), 2.18-2.09 (2H, m), 1.94-1.11 (23H, m), 1.40 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 1.01-0.94 (2H, m), 0.93 (3H, s).

(Step 2)

Cyclohexyl [(4aS,4bR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-10a,12a-dimethyl-3,4,4a,4b ,5,7,8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (252 mg) was obtained as a white solid.

MS (ESI) m/z: 474 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.30 (1H, m), 3.82 (1H, m), 3.69 (1H, m), 3.61 (1H, m), 3.56 (1H, dd, J=4.1, 9.8 Hz ), 3.51 (1H, dd, J = 6.3, 9.8 Hz), 3.41 (1H, m), 3.35 (1H, m), 3.22 (1H, m), 3.16 (1H, m), 2.94 (1H, d, J=4.4 Hz), 2.64 (1H, m), 2.38-2.31 (2H, m), 2.18-2.08 (2H, m), 1.91-1.10 (23H, m), 1.40 (3H, s), 1.02-0.94 (2H, m), 0.93 (3H, s).

(Step 3)

Cyclohexyl [(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-[(2R)-2,3-dihydroxypropoxy]-4a,6b-dimethyltetrahydrogen- 1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-yl]methanone

The title compound (121 mg) was obtained as a white solid.

Main product (α-epoxide)

MS (ESI) m/z: 490 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.80 (1H, m), 3.67 (1H, m), 3.61-3.44 (4H, m), 3.40 (1H, m), 3.32 (1H, m), 3.19 (1H) , m), 2.90 (1H, d, J = 4.4 Hz), 2.80 (1H, br), 2.47 (1H, br), 2.33 (1H, m), 2.03-1.94 (3H, m), 1.85-1.05 ( 25H, m), 1.34 (3H, s), 0.99 (3H, s).

(Step 4)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (121 mg) (77 mg) Compound Compound Compound Compound

MS (ESI) m / z: 492 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.76-3.65 (2H, m), 3.54 (1H, dd, J = 4.6, 11.0 Hz), 3.53-3.47 (2H, m), 3.47 (1H, m), 3.43-3.37 (2H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 51)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydro[2,1-f]quina Porphyrin-1(2H)-yl]methanone

The compound obtained in the first step of Example 1 (200 mg) and (S)-(-)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonic acid The title compound (237 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 5.30 (1H, m), 4.21 (1H, m), 4.03 (1H, m), 3.71 (1H, m), 3.58-3.50 (2H, m), 3.41 (1H) , m), 3.35 (1H, m), 3.23 (1H, m), 3.15 (1H, m), 2.39-2.30 (2H, m), 2.21-2.08 (2H, m), 1.92-1.10 (26H, m ), 1.399 (3H, s), 1.396 (3H, s), 1.02-0.94 (2H, m), 0.93 (3H, s).

(Step 2)

Cyclohexyl [(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-4a,6b-dimethyltetrahydrogen-1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-yl]methanone

The title compound (190 mg) was obtained as a white solid.

Main product (α-epoxide)

MS (ESI) m / z: 530 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.20 (1H, m), 4.01 (1H, dd, J = 6.6, 8.3 Hz), 3.67 (1H, dd, J = 6.3, 8.3 Hz), 3.56 (1H, dd , J=5.9, 9.8 Hz), 3.51 (1H, m), 3.41-3.29 (3H, m), 3.18 (1H, m), 2.89 (1H, d, J = 4.4 Hz), 2.32 (1H, m) , 2.04-1.95 (3H, m), 1.78-1.07 (25H, m), 1.38 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 0.98 (3H, s).

(Step 3)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }}-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (84 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.20 (1H, m), 4.02 (1H, dd, J = 6.3, 7.8 Hz), 3.75-3.66 (2H, m), 3.57 (1H, dd, J = 5.6, 9.5 Hz), 3.45-3.28 (3H, m), 3.24 (1H, m), 2.34 (1H, m), 1.92-1.08 (31H, m), 1.39 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 0.90 (3H, s).

(Step 4)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (64 mg) was obtained from m.

MS (ESI) m / z: 492 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.72 (1H, m), 3.67 (1H, m), 3.54 (1H, dd, J = 4.9, 11.2 Hz), 3.52-3.37 (5H, m), 3.17 ( 1H, dd, J = 2.7, 9.0 Hz), 2.47 (1H, m), 1.90 - 10.08 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 52)

Cyclohexyl [(4aS,4bR,6R,6aR,8S,10aR,10bS,12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6,6a-dihydroxy-10a,12a- Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,4bR,6R,6aR,8S,10aR,10bS,12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6,6a-dihydroxy-10a,12a- Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (30 mg) was obtained from m.

MS (ESI) m / z: 508 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.78 (1H, m), 3.68 (1H, m), 3.55 (1H, dd, J = 4.9, 11.2 Hz) 3.50-3.37 (6H, m), 3.16 (1H) , dd, J = 3.4, 9.3 Hz), 2.48 (1H, m), 1.97 (1H, dd, J = 11.2, 12.7 Hz), 1.91-1.60 (14H, m), 1.55 (1H, m), 1.48- 1.12 (12H, m), 1.41 (3H, s), 1.07 (3H, s).

(Example 53)

Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-6-fluoro-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-4a,6b-dimethyltetrahydrogen-1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-yl]methanone

The title compound (620 mg) was obtained from m.

Main product (α-epoxide)

¹ H-NMR (CDCl ₃ ) δ: 4.20 (1H, m), 4.02 (1H, d, J = 6.6, 8.3 Hz), 3.67 (1H, dd, J = 6.3, 8.3 Hz), 3.54-3.47 (2H) , m), 3.41 (1H, dd, J = 5.9, 9.8 Hz), 3.39 (1H, m), 3.32 (1H, m), 3.19 (1H, m), 2.89 (1H, d, J = 4.4 Hz) , 2.32 (1H, m), 2.03-1.93 (3H, m), 1.77-1.07 (25H, m), 1.38 (3H, s), 1.34 (3H, s), 1.32 (3H, s), 0.98 (3H) , s).

(Step 2)

Cyclohexyl [(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-6-fluoro-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (319 mg) was obtained as a white solid.

MS (ESI) m / z: 510 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.20 (1H, m), 3.73 (1H, m), 3.68 (1H, m), 3.54 (1H, dd, J = 4.9, 11.2 Hz), 3.52 (1H, Dd, J = 4.9, 9.8 Hz), 3.50 (1H, m), 3.47 (1H, dd, J = 5.9, 11.2 Hz), 3.41 (1H, d, J = 6.3, 9.8 Hz), 3.40 (1H, m ), 3.18 (1H, dd, J = 3.4, 9.3 Hz), 2.48 (1H, m), 1.92-1.12 (28H, m), 1.40 (3H, s), 1.00 (3H, d, J = 4.9 Hz) .

(Example 54)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyl-8-[(2S,3S)-2,3,4-trihydroxybutoxy Hexahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

{(4S,5S)-5-[(methoxymethoxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl 4-methylbenzene Sulfonate

On {(4S,5S)-5-[(methoxymethoxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol (Journal of the American Chemical Society, 1999, 121, 5829-5830.) (3.01 g) in dichloromethane (100 ml), 1,4-dibicyclobicyclo[2.2.2]octane (4.91 g) and p Toluenesulfonium chloride (4.17 g) was stirred for 5 hours while warming to room temperature. The reaction was stopped by placing borneol in the reaction solution. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 7.78 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 4.59 (2H, s), 4.17 (1H, dd, J = 3.7 , 10.5 Hz), 4.09 (1H, dd, J = 4.9, 10.5 Hz), 4.02-3.96 (2H, m), 3.64-3.58 (2H, m), 3.32 (3H, s), 2.43 (3H, s) , 1.35 (3H, s), 1.31 (3H, s).

(Step 2)

Cyclohexyl [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-8-({(4S,5S)-5-[(methoxymethoxy)methyl]-2, 2-Dimethyl-1,3-dioxolan-4-yl}methoxy)-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1 (2H) Ketone

Using the compound (α-alcohol) obtained in the step 3 of Example 1 (100 mg) and the compound obtained in the above step 1 (345 mg), m. Compound (54 mg).

¹ H-NMR (CDCl ₃ ) δ: 4.64 (2H, s), 3.96 (1H, m), 3.90 (1H, m), 3.71 (1H, m), 3.69 (1H, dd, J = 3.4, 10.7 Hz ), 3.62-3.58 (2H, m), 3.55 (1H, dd, J = 4.9, 10.3 Hz), 3.41 (1H, m), 3.35 (3H, s), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 1.91-1.10 (31H, m), 1.394 (3H, s), 1.392 (3H, s), 1.38 (3H, s), 0.90 (3H, s).

(Step 3)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyl-8-[(2S,3S)-2,3,4-trihydroxybutoxy Hexahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (35 mg) was obtained as a white solid.

MS (ESI) m/z: 522 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.74 (1H, m), 3.68 (1H, m), 3.62-3.45 (6H, m), 3.40 (1H, m), 3.16 (1H, m), 2.47 ( 1H, m), 1.91-1.09 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 55)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S,3S)-2,3-dihydroxybutoxy]-6a-hydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyl-8-{[(4S,5S)-2,2,5-trimethyl -1,3-dioxolan-4-yl]methoxy}hexadecahydro[2,1-f]quinoline-1(2H)-yl]methanone

The compound (α-alcohol) (200 mg) obtained in the third step of Example 1 and [(4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl] Methyl 4-methylbenzenesulfonate (Tetrahedron, 1987, 43, 2191-2198.) (432 mg).

¹ H-NMR (CDCl ₃ ) δ: 3.84 (1H, m), 3.70 (1H, m), 3.66 (1H, m), 3.56 (1H, dd, J = 5.6, 10.0 Hz), 3.50 (1H, dd , J=4.4, 10.0 Hz), 3.41 (1H, m), 3.33 (1H, m), 3.24 (1H, m), 2.34 (1H, m), 1.88 (1H, m), 1.84-1.07 (30H, m), 1.39 (3H, s), 1.38 (3H, s), 1.35 (3H, s), 1.27 (3H, d, J = 5.9 Hz), 0.91 (3H, s).

(Step 2)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S,3S)-2,3-dihydroxybutoxy]-6a-hydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (129 mg) was obtained as a white solid.

MS (ES1) m / z: 506 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.76-3.69 (2H, m), 3.56 (1H, m), 3.50 (1H, m), 3.45-3.37 (3H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 1.13 (3H, d, J = 6.3 Hz), 0.92 (3H, s).

(Example 56)

{[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quina Tert-butyl butyl-8-yl]oxy}acetate

(step 1)

{[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quina Tert-butyl butyl-8-yl]oxy}acetate

The compound (α-alcohol) (200 mg) obtained in the step 3 of Example 1 and butyl bromoacetate (0.211 ml) and tetrahydrofuran as a solvent were obtained in the same manner as in Step 1 of Example 27 to give The title compound (85 mg) was obtained as white crystal.

MS (ESI) m / z: 532 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.98 (1H, d, J = 16.4 Hz), 3.94 (1H, d, J = 16.4 Hz), 3.74 (1H, m), 3.41 (1H, m), 3.33 ( 1H, m), 3.24 (1H, m), 2.34 (1H, m), 1.91 (1H, m), 1.83-1.09 (29H, m), 1.44 (9H, s), 1.38 (3H, s), 1.05 (1H, s), 0.91 (3H, s).

(Example 57)

{[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quina Porphyrin-8-yl]oxy}acetic acid

(step 1)

{[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quina Porphyrin-8-yl]oxy}acetic acid

A mixture of methanol (10 ml), tetrahydrofuran (5 ml) and water (2.2 ml) obtained from Heated to reflux for 1 hour. The reaction solution was poured into two layers of dichloromethane and 1N hydrochloric acid, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [methanol/dichloromethane] and crystallised from [diethyl ether/hexane] The title compound (63 mg) was obtained.

MS (ESI) m / z: 476 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.94 (1H, d, J = 16.4 Hz), 3.91 (1H, d, J = 16.4 Hz), 3.81 (1H, m), 3.50 (1H, m), 3.40 (1H, m), 3.17 (1H, m), 2.47 (1H, m), 1.91-1.09 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 58)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S,3S)-2,3-dihydroxy-4-methoxybutoxy]-6a-hydroxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(4aS,4bR,8S,10aR,10bS,12aS)-8-({(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3- Dioxol-4-yl}methoxy)-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a- Tetradehamido[2,1-f]quinoline-1(2H)-yl](cyclohexyl)methanone

The compound (835 mg) obtained in the first step of Example 1 and {(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan Cyclo-4-yl}methyl 4-methylbenzenesulfonate (Helvetica Chimica Acta, 1981, 64, 687-702.) (5.08 g), mp. g).

MS (ESI) m / z: 634 (M+H) ⁺ .

(Step 2)

[(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-({(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl- 1,3-dioxolan-4-yl}methoxy)-4a,6b-dimethyltetrahydrogen-1H-oxirane [4,4a]naphtho[2,1-f]quina Porphyrin-4(4aH)-yl](cyclohexyl)methanone

The title compound (776 mg) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.24 (5H, m), 4.59 (1H, d, J = 12.2 Hz), 4.53 (1H, d, J = 12.2 Hz), 3.99 - 3.87 (2H, m ), 3.59-3.45 (5 H, m), 3.39 (1H, m), 3.32 (1H, m), 3.19 (1H, m), 2.87 (1H, d, J = 4.4 Hz), 2.33 (1H, m ), 1.98 (1H, m), 1.95 (1H, dd, J = 11.7, 12.7 Hz), 1.91 (1H, m), 1.79-1.05 (25H, m), 1.384 (3H, s), 1.380 (3H, s), 1.34 (3H, s), 0.97 (3H, s).

(Step 3)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-({(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1, 3-dioxolan-4-yl}methoxy)-6a-hydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-1(2H)-yl]( Cyclohexyl)methanone

The title compound (686 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.33 - 7.24 (5H, m), 4.59 (1H, d, J = 12.2 Hz), 4.54 (1H, d, J = 12.2 Hz), 3.96 (1H, m), 3.91 (1H, m), 3.67 (1H, m), 3.61-3.52 (4H, m), 3.41 (1H, m), 3.33 (1H, m), 3.24 (1H, m), 2.34 (1H, m) , 1.86-1.29 (22H, m), 1.39 (6H, s), 1.38 (3H, s), 1.26-1.08 (8H, m), 1.03 (1H, s), 0.89 (3H, s).

(Step 4)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-{[(4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (534 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 3.93 - 3.84 (2H, m), 3.75 (1H, m), 3.72-3.67 (3H, m), 3.50 (1H, dd, J = 6.8, 9.3 Hz), 3.41 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.59 (1H, dd, J = 4.4, 7.8 Hz), 2.33 (1H, m), 1.90 (1H, m), 1.84- 1.12 (29H, m), 1.39 (9H, s), 1.11 (1H, s), 0.90 (3H, s).

(Step 5)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-{[(4S,5S)-5-(methoxymethyl)-2,2-dimethyl -1,3-dioxolan-4-yl]methoxy}-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (94 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

¹ H-NMR (CDCl ₃ ) δ: 3.94 (1H, m), 3.86 (1H, m), 3.71 (1H, m), 3.58 (1H, dd, J = 5.4, 10.3 Hz), 3.54 (1H, dd , J=4.9, 10.3 Hz), 3.51 (1H, dd, J=3.8, 10.3 Hz), 3.48 (1H, dd, J=6.2, 10.3 Hz), 3.41 (1H, m), 3.38 (3H, s) , 3.33 (1H, m), 3.24 (1H, m), 2.34 (1H, m), 1.88 (1H, m), 1.84-1.53 (13H, m), 1.48-1.12 (16H, m), 1.39 (3H) , s), 1.382 (3H, s), 1.379 (3H, s), 1.10 (1H, s), 0.90 (3H, s).

(Step 6)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S,3S)-2,3-dihydroxy-4-methoxybutoxy]-6a-hydroxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

P-toluenesulfonic acid monohydrate (4.0 mg) was added to a solution of the compound (94 mg) in methanol (3 ml). After stirring at the same temperature for 5 hours, it was heated to 60 ° C and stirred for 2 hours. After the addition of triethylamine to the reaction mixture, EtOAc m.

MS (ESI) m/z: 536 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.77-3.70 (2H, m), 3.65 (1H, m), 3.57 (1H, dd, J = 5.4, 9.8 Hz), 3.53-3.37 (5H, m), 3.33 (3H, s), 3.17 (1H, m), 2.47 (1H, m), 1.91-1.10 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 59)

(Example 59-1)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-(2,3-dihydroxypropyl)-6a,8-dihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone

Non-image isomer A; (Rf=higher: low polarity)

(Example 59-2)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-(2,3-dihydroxypropyl)-6a,8-dihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone

Non-image isomer B; (Rf = lower: high polarity)

(step 1)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-8-(prop-2-en-1-yl)hexadecane Naphtho[2,1-f]quinoline-1(2H)-yl]methanone

The compound obtained in the first step of Example 3 (300 mg) was suspended in tetrahydrofuran (10 ml), and allyl magnesium bromide (17 wt% ether solution, 3.0 ml) was slowly added at 0 ° C, and stirred at the same temperature 20 minute. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the reaction mixture was poured into two layers of ethyl acetate and saturated aqueous ammonium chloride, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated, and EtOAc mjjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 5.83 (1H, m), 5.15 (1H, dd, J = 2.0, 10.3 Hz), 5.10 (1H, dd, J = 1.0, 17.1 Hz), 3.97 (1H, brs ), 3.40 (1H, m), 3.32 (1H, m), 3.24 (1H, m), 2.68 (1H, brs), 2.34 (1H, m), 2.15 (2H, d, J = 7.3 Hz), 1.85 -1.04 (30H, m), 1.39 (3H, s), 0.83 (3H, s).

(Step 2)

Cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-(2,3-dihydroxypropyl)-6a,8-dihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone

The compound (58 mg) obtained in the above step 1 was reacted by the same method as in the step 1 of Example 15 and separated and purified by a silica gel column chromatography (methanol/dichloromethane) to give a white solid. The non-Spiegelmer A (26 mg) of the title compound (Rf = higher: low polarity) and the non-image isomer B (25 mg) (Rf = lower: high polarity).

Non-image isomer A; (Rf = higher: low polarity): Example 59-1

MS (ESI) m / z: 492 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.94 (1H, m), 3.51 (1H, m), 3.41 (1H, m), 3.38 (2H, d, J = 5.4 Hz), 3.18 (1H, m) , 2.48 (1H, m), 1.89-1.11 (32H, m), 1.40 (3H, s), 0.88 (3H, s).

Non-image isomer B; (Rf = lower: high polarity): Example 59-2

MS (ESI) m / z: 492 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.94 (1H, m), 3.51 (1H, m), 3.44 - 3.39 (2H, m), 3.37 (1H, dd, J = 6.1, 11.0 Hz), 3.19 ( 1H, m), 2.48 (1H, m), 1.89-1.08 (32H, m), 1.39 (3H, s), 0.88 (3H, s).

(Embodiment 60)

Cyclohexyl [(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-8-[(methylsulfonyl)methyl]hexadecyanate And [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-8-[(methylsulfonyl)methyl]hexadecyanate And [2,1-f]quinoline-1(2H)-yl]methanone

To a solution of dimethylhydrazine (103 mg) in tetrahydrofuran (2 ml), diisopropylamino lithium (1.09 M tetrahydrofuran solution, 1.00 ml) was added at -78 ° C and stirred for 30 minutes. A suspension of the compound (150 mg) obtained in the step 1 of Example 3 in tetrahydrofuran (3 ml) was slowly added to the mixture, and the mixture was warmed to 0 ° C and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was poured into two layers of dichloromethane and a saturated aqueous solution of ammonium chloride, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness crystals. The title compound (25 mg) was obtained as white crystal.

MS (ESI) m / z: 510 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.90 (1H, s), 3.41 (1H, m), 3.33 (1H, m), 3.27 (1H, m), 3.14 (1H, d, J = 14.6 Hz), 3.05 (1H, d, J = 14.6 Hz), 3.03 (3H, s), 2.92 (1H, s), 2.34 (1H, m), 1.93 (1H, dd, J = 2.4, 14.6 Hz), 1.87-1.06 (29H, m), 1.38 (3H, s), 0.87 (3H, s).

(Example 61)

(2,6-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-8-{[(4-methylphenyl)sulfonyl]oxy}-3,4,4a,4b, 5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound obtained in the first step of Example 19 (13.6 g) was dissolved in dichloromethane (270 ml), 1,4-dibibicyclo[2.2.2] octane (10.8 g) and p Toluenesulfonium chloride (9.18 g) was stirred at 0 ° C for 1.5 hours. The reaction solution was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m/z: 578 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.80-7.79 (2H, m), 7.36-7.30 (7H, m), 5.30-5.29 (1H, m), 5.08 (2H, s), 4.32-4.31 (1H, m), 3.76-3.74 (1H, m), 3.37-3.35 (1H, m), 3.05-3.03 (1H, m), 2.45 (3H, s), 2.33-2.20 (3H, m), 1.83-0.96 ( 18H, m), 0.93 (3H, s).

(Step 2)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-10a, 12a-Dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1 (2H)-benzyl formate

Toluene was added to a mixture of the compound obtained in the above step 1 (18.7 g) and (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol (20.0 ml) (20 ml), and the mixture was stirred under heating at 95 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc) eluted

MS (ESI) m/z: 538 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.31 (5H, m), 5.33-5.32 (1H, m), 5.09 (2H, s), 4.20-4.11 (2H, m), 3.77-3.73 (2H, m), 3.60-3.57 (1H, m), 3.46-3.37 (2H, m), 3.19-3.17 (1H, m), 3.06-3.04 (1H, m), 2.46-0.95 (30H, m).

(Step 3)

(4aS,6aS,6bR,9S,12aR,12bS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-4a, 6b-Dimethyltetrahydro-1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-benzyl benzoate

The title compound (8.20 g) was obtained from m.

MS (ESI) m/z: 554 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.32 (5H, m), 5.07 (2H, s), 4.24 - 4.22 (1H, m), 4.07 - 4.02 (1H, m), 3.74 - 3.70 (2H, m), 3.57-3.53 (2H, m), 3.46-3.39 (2H, m), 3.00-2.93 (2H, m), 2.04-0.90 (30H, m).

(Step 4)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}- 6a-hydroxy-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (6.01 g) was obtained.

MS (ESI) m/z: 556 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.31 (5H, m), 5.08 (2H, s), 4.24-4.23 (1H, m), 4.07-4.04 (1H, m), 3.77-3.72 (3H, m), 3.56-3.54 (1H, m), 3.47-3.44 (1H, m), 3.37-3.27 (1H, m), 3.05-3.02 (1H, m), 1.70-1.10 (30H, m), 0.93 ( 3H, s).

(Step 5)

(4aS, 4bR, 6aR, 8S, 10aR, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-6a(2H)-ol

The title compound (144 mg) was obtained from m.

MS (ESI) m / z: 422 (M+H) ⁺ .

(Step 6)

(2,6-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3 dioxolane 4-yl]methoxy}-6a-hydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound was obtained by the same procedure as in the step 1 of Example 22, using the compound ( 213 mg) of the compound obtained in the above step 5 and 2,6-difluorobenzhydrin chloride (92.0 mg).

(Step 7)

(2,6-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (223 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.31-7.22 (1H, m), 6.93-6.85 (2H, s), 3.87-3.32 (8H, m), 3.20-3.12 (1H, m), 2.58 (1H, d, J = 4.9 Hz), 2.18-2.11 (1H, m), 1.98-1.08 (23H, m), 1.12 (1H, d, J = 6.4 Hz), 0.97 (3H, s).

(Example 62)

(2,5-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,5-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan Cyclo-4-yl]methoxy}-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound of the crude product was obtained from the compound obtained from the title compound ( 213 mg).

(Step 2)

(2,5-difluorophenyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (217 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.17-6.94 (3H, s), 3.87-3.32 (8H, m), 3.17-3.10 (1H, m), 2.58 (1H, d, J = 5.4 Hz), 2.17 -2.11 (1H, m), 1.98-1.17 (23H, m), 1.11 (1H, d, J = 5.9 Hz), 0.97 (3H, s).

(Example 63)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methylpropan-1-one

(step 1)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methylpropan-1-one

The title compound (246 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

(Step 2)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methylpropan-1-one

The title compound (98.2 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.85-3.26 (9H, m), 2.75-2.66 (1H, m), 2.59 (1H, d, J = 4.9 Hz), 2.19-2.13 (1H, m), 1.96 -1.10 (24H, m), 1.09-1.03 (6H, m), 0.94 (3H, s).

(Example 64)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methoxypropan-1-one

(step 1)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }}-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methoxypropan-1-one

The title compound was obtained by the same procedure as in Step 1 of Example 22 to give the title compound.

(Step 2)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methoxypropan-1-one

The title compound (51.4 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.07-4.01 (1H, m), 3.86-3.26 (12H, m), 2.59-2.56 (1H, m), 2.18-2.11 (1H, m), 1.96-1.08 ( 27H, m), 0.95 (3H, s).

(Example 65)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4,4-trifluorobutan-1-one

(step 1)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy -6a-hydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-1(2H)-yl]-4,4,4-trifluorobutane-1- ketone

The title compound was obtained as a white solid (yield: Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound 255mg).

(Step 2)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4,4-trifluorobutan-1-one

The title compound (63.5 mg) was obtained as a white solid.

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.86-3.22 (9H, m), 2.60-2.32 (5H, m), 2.19-2.13 (1H, m), 1.97-1.08 (24H, m), 0.94 (3H, s).

(Example 66)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4-difluorobutane-1-one

(step 1)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }}-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4-difluorobutane-1-one

The title compound was obtained as a crude product from the compound obtained from the title compound ( 211 mg).

(Step 2)

1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethyl-16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4-difluorobutane-1-one

The title compound (151 mg) was obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 6.09-5.83 (1H, m), 3.86-3.21 (9H, m), 2.59 (1H, d, J = 4.9 Hz), 2.46-2.41 (2H, m), 2.20 -2.07 (3H, m), 1.96-1.13 (23H, m), 1.11 (1H, d, J = 5.9 Hz), 0.94 (3H, s).

(Example 67)

(2,2-difluorocyclopropyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,2-difluorocyclopropyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxo Pentocyclo-4-yl]methoxy}-6a-hydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The compound (377 mg) obtained in Step 5 of Example 61 and 2,2-difluorocyclopropanecarboxylic acid (101 mg) were used, and The title compound (non-Spiegelmer A: low polarity) (192 mg) and title were obtained as white solids. Compound (non-image isomer B: highly polar) (188 mg).

Non-image isomer A: low polarity

MS (ESI) m/z: 526 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.26-4.20 (1H, m), 4.07-4.03 (1H, m), 3.77-3.68 (2H, m), 3.66-3.37 (4H, m), 3.17-3.11 ( 1H, m), 2.54-2.45 (1H, m), 1.97-1.05 (32H, m), 0.93 (3H, s).

Non-image isomer B: high polarity

MS (ESI) m/z: 526 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.26-4.20 (1H, m), 4.08-4.03 (1H, m), 3.77-3.68 (2H, m), 3.63-3.38 (4H, m), 3.28-3.22 ( 1H, m), 2.49-2.40 (1H, m), 2.15-2.06 (1H, m), 1.96-1.04 (31H, m), 0.94 (3H, s).

(Step 2)

(2,2-difluorocyclopropyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (111 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

¹ H-NMR (CDCl ₃ ) δ: 3.86-3.46 (8H, m), 3.19-3.11 (1H, m), 2.58 (1H, d, J = 5.4 Hz), 2.54-2.45 (1H, m), 2.18 -2.12 (1H, m), 1.96-1.13 (26H, m), 0.94 (3H, s).

(Example 68)

(2,2-difluorocyclopropyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,2-difluorocyclopropyl)[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (133 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

¹ H-NMR (CDCl ₃ ) δ: 3.86-3.45 (8H, m), 3.29-3.21 (1H, m), 2.58 (1H, d, J = 5.4 Hz), 2.49-2.40 (1H, m), 2.19 -2.06 (2H, m), 1.96-1.13 (25H, m), 0.95 (3H, s).

(Example 69)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl](6-methylpyridin-2-yl)methanone

(step 1)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl](6-methylpyridin-2-yl)methanone

The compound (100 mg) obtained in Step 5 of Example 61 and 6-methylpyridine-2-carboxylic acid (97.6 mg) and 1-cyano-2-ethoxy-2-oxo- oxy as a condensing agent. Ethylaminooxy)dimethylamino- The title compound (128 mg) was obtained from m.p.

(Step 2)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl](6-methylpyridin-2-yl)methanone

The title compound (104 mg) was obtained from m.

MS (ESI) m / z: 501 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.59-7.55 (1H, m), 7.21-7.17 (1H, m), 7.10-7.07 (1H, m), 3.83-3.31 (9H, m), 3.14-3.08 ( 1H, m), 2.63-2.59 (1H, m), 2.52 (3H, s), 2.25-2.19 (1H, m), 1.92-0.94 (17H, m), 1.52 (3H, s), 0.94 (3H, s).

(Embodiment 70)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl](4-methylpyridin-2-yl)methanone

(step 1)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl](4-methylpyridin-2-yl)methanone

The compound (100 mg) obtained in Step 5 of Example 61 and 4-methylpyridine-2-carboxylic acid (97.6 mg) and 1-cyano-2-ethoxy-2-oxo-oxygen as a condensing agent. Ethylaminooxy)dimethylamino- The title compound (128 mg) was obtained from m.p.

(Step 2)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl](4-methylpyridin-2-yl)methanone

The title compound (114 mg) was obtained from m.

MS (ESI) m / z: 501 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.40-8.36 (1H, m), 7.30-7.28 (1H, m), 7.09-7.05 (1H, m), 3.82-3.39 (8H, m), 3.37-3.27 ( 1H, m), 3.15-3.05 (1H, m), 2.90-2.58 (1H, m), 2.35 (3H, s), 1.90-1.17 (28H, m), 1.52 (3H, s), 0.94 (3H, s).

(Example 71)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl Ketone and [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl Ketone

The compound obtained in Step 5 of Example 61 (726 mg) and tetrahydropyran-2-methylpyridinium chloride (171 mg) were reacted in the same manner as in Step 1 of Example 22 to obtain a column layer of a rubber tube. The title compound (R) (424 mg) and the title compound (S) (422 mg).

R body (Rf=higher) low polarity

MS (ESI) m/z: (M+H)+534

¹ H-NMR (CDCl ₃ ) δ: 4.24 - 4.22 (1H, m), 4.04-3.98 (3H, m), 3.73-3.26 (8H, m), 1.92-0.93 (39H, m).

S body (Rf = lower) high polarity

MS (ESI) m/z: (M+H)+534

¹ H-NMR (CDCl ₃ ) δ: 4.24 - 4.22 (1H, m), 4.07 - 4.04 (1H, m), 3.97 - 3.95 (2H, m), 3.72-3.70 (2H, m), 3.56-3.53 ( 1H, m), 3.45-3.41 (4H, m), 3.29-3.25 (1H, m), 1.92-1.14 (44H, m), 0.93 (3H, s).

(Step 2)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (154 mg) was obtained as a white solid.

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.07 (1H, dd, J = 4.1, 8.1 Hz), 3.94 (1H, dd, J = 3.4, 10.7 Hz), 3.72 (1H, m), 3.67 (1H, m), 3.58-3.38 (6H, m), 3.36 (1H, m), 3.16 (1H, m), 1.90-1.09 (26H, m), 1.40 (3H, s), 0.92 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 3, and the peak with a relative intensity of 16 or more in the case where the maximum peak intensity in Fig. 3 is 100 is shown in Table 3.

(Example 72)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (11 mg) was obtained as a white solid.

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.04 (1H, dd, J = 2.7, 9.5 Hz), 3.91 (1H, dd, J = 3.2, 11.5 Hz), 3.72 (1H, m), 3.67 (1H, m), 3.54 (1H, dd, J = 4.6, 11.0 Hz), 3.51 (1H, dd, J = 4.6, 10.0 Hz), 3.50-3.41 (3H, m), 3.47 (1H, dd, J = 5.9, 11.0 Hz), 3.40 (1H, dd, J = 6.1, 10.0 Hz), 3.17 (1H, m), 1.90 - 1.09 (26H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 73)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R,6R)-6-methyltetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R,6R)-6-methyltetrahydro-2H- Pyran-2-yl]methanone

The title compound (135 mg) was obtained from m. ).

MS (ESI) m/z: 548 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.23 (1H, m), 4.05 (1H, m), 3.97 (1H, dd, J = 11.0, 2.3 Hz), 3.68-3.75 (2H, m), 3.53-3.62 (2H, m), 3.38-3.47 (2H, m), 3.25-3.34 (2H, m), 1.09-1.94 (27H, m), 1.43 (3H, s), 1.42 (3H, s), 1.36 (3H) , s), 1.19 (3H, d, J = 6.3 Hz) 0.93 (3H, s).

(Step 2)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R,6R)-6-methyltetrahydro-2H-pyran-2-yl]methanone

The title compound (77 mg) was obtained as a white solid.

MS (ESI) m / z: 508 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.97 (1H, dd, J = 10.8, 1.8 Hz), 3.40-3.99 (9H, m), 3.25-3.35 (2H, m), 2.65 (1H, m), 2.23 (1H, m), 1.09-1.93 (26H, m), 1.43 (3H, s), 1.19 (d, J = 6.3 Hz), 0.94 (3H, s).

(Example 74)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R)-6,6-dimethyltetrahydro-2H-pyran-2-yl]methanone

(step 1)

2-methylhept-6-en-2-ol

A solution of methyllithium (1.1 M diethyl ether solution, 100 ml) was added to a solution of methyl 5-hexenoate (6.00 g) in tetrahydrofuran (200 ml) under nitrogen atmosphere at -78 °C. Slowly warm to room temperature and stir at room temperature for 1 hour. Time. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium

(Step 2)

2-methyl-5-(oxiran-2-yl)pentan-2-ol

The title compound (2.35 g) was obtained from m.

MS (ESI) m/z: 145 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 2.91-2.96 (1H, m), 2.77 (1H, dd, J = 4.9, 3.9 Hz), 2.49 (1H, dd, J = 5.1, 2.7 Hz), 1.5-1.62 (7H, m), 1.23 (6H, s).

(Step 3)

(6,6-Dimethyltetrahydro-2H-pyran-2-yl)methanol

To a solution of (2.35 g) of methylene chloride (50 ml) obtained in the above step 2, 10-camphorsulfonic acid (1.89 g) was added and stirred at room temperature for 30 minutes. One equivalent of an aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted once with dichloromethane and ethyl acetate. The combined organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~ .

¹ H-NMR (CDCl ₃ ,) δ: 3.68 (1H, m), 3.55 (1H, m), 3.44 (1H, m), 2.16 (1H, dd, J = 7.8, 4.4 Hz), 1.64-1.70 ( 3H, m), 1.34-1.50 (3H, m), 1.21 (3H, s), 1.21 (3H, s).

(Step 4)

6,6-Dimethyltetrahydro-2H-pyran-2-carboxylic acid

The title compound (0.95 g) was obtained from m.

MS (ESI) m/z: 159 (M+H) ⁺

¹ H-NMR (CDCl ₃ ,) δ: 4.17 (1H, dd, J = 12.2, 2.9 Hz), 2.07 (1H, m), 1.68-1.80 (2H, m), 1.53 (1H, m), 1.47 (2H, m), 1.31 (3H, s), 1.25 (3H, s).

(Step 5)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-6,6-dimethyltetrahydro-2H -pyran-2-yl]methanone

The title compound (100 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m / z: 562 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.19-4.25 (2H, m), 4.05 (1H, m), 3.69-3.75 (2H, m), 3.66 (1H, m), 3.38-3.62 (2H, m) , 3.24 - 3.31 (2H, m), 1.91 (1H, m), 1.09-1.84 (26H, m), 1.42 (3H, s), 1.42 (3H, s), 1.36 (3H, s), 1.22 (3H) , s), 1.20 (3H, s), 0.93 (3H, s).

(Step 6)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R)-6,6-dimethyltetrahydro-2H-pyran-2-yl]methanone

The title compound (77 mg) was obtained as a white solid.

MS (ESI) m/z: 522 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.21 (1H, dd, J = 10.7, 2.4 Hz), 3.82 (1H, m), 3.49-3.77 (5H, m), 3.57 (1H, d, J = 4.4 Hz ), 3.24 - 3.32 (2H, m), 2.59 (1H, m), 2.16 (1H, m), 1.89-1.95 (1H, m), 1.08-1.84 (26H, m), 1.42 (3H, s), 1.22 (3H, s), 1.20 (3H, s), 0.94 (3H, s).

(Example 75)

[(2R)-5,5-difluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3 -dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

2- 2-ethyl 2-oxo-5-hexenoate

A solution of 3-butene bromide (0.5 M tetrahydrofuran solution, 200 ml) was added to a solution of diethyl oxalate (14.6 g) in tetrahydrofuran (200 ml) under nitrogen atmosphere at -78 °C. Slowly warm to room temperature and stir at room temperature for 1 hour. Time. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

¹ H-NMR (CDCl ₃ ) δ: 5.82 (1H, m), 5.07 (1H, m), 5.02 (1H, m), 4.33 (2H, q, J = 7.2 Hz), 2, 95 (2H, m ), 2.40 (2H, m), 1.37 (3H, t, J = 7.2 Hz).

(Step 2)

Ethyl 2,2-difluorohex-5-enoate

To a solution of the compound (12.7 g) obtained in the above step 1 in dichloromethane (200 ml), bis(2-methoxyethylamino)sulfur trifluoride (37.63 g) was added at -78 ° C. Stir slowly and stir for one night. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and extracted twice with dichloromethane. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

¹ H-NMR (CDCl ₃ ) δ: 5.80 (1H, m), 5.08 (1H, m), 5.03 (1H, m), 4.33 (2H, q, J = 7.2 Hz), 2.12-2.28 (4H, m ), 1.36 (3H, t, J = 7.2 Hz).

(Step 3)

2,2-difluorohex-5-en-1-ol

The title compound (8 g) was obtained from the title compound (1 g).

¹ H-NMR (CDCl ₃ ) δ: 5.84 (1H, m), 5.08 (1H, m), 5.02 (1H, m), 3.72-3.78 (2H, m), 2.28 (1H, m), 1.93-2.76 (3H, m), 1.83-1.87 (2H, m).

(Step 4)

(5,5-difluorotetrahydro-2H-pyran-2-yl)methanol

The compound (8.00 g) obtained in the above Step 3 was reacted in the same manner as in Step 2 of Example 1, and after the formation of the epoxy compound was confirmed, 10-camphorsulfonic acid (2.73) was added to the reaction mixture. g), stir at room temperature for one hour. 1N aqueous sodium hydroxide solution and aqueous sodium sulfite solution were added to the reaction liquid, and it extracted with dichloromethane. The title compound (5.34 g) was obtained as a colorless oily material.

¹ H-NMR (CDCl ₃ ) δ: 3.99 (1H, m), 3.66 (1H, dd, J = 11.7, 2.9 Hz), 3.49-3.61 (3H, m), 2.23-2.31 (1H, m), 1.82 -1.99 (2H, m), 1.68-1.75 (2H, m).

(Step 5)

5,5-difluorotetrahydro-2H-pyran-2-carboxylic acid

The title compound (0.24 g) was obtained from m.

m/z 165 (MH) ⁺

¹ H-NMR (CDCl ₃ ,) δ: 4.07-4.17 (2H, m), 3.65 (1H, m), 2.22 - 2.32 (2H, m), 1.99-2.10 (2H, m).

(Step 6)

[(2R)-5,5-difluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-{[(4S)-2, 2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6a-hydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline- 1(2H)-yl]methanone

The title compound (90 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 570 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.22 (1H, m), 4.11 (1H, dd, J = 9.0, 2.7 Hz), 4.06 (1H, m), 3.94 (1H, m), 3.69-3.75 (2H , m), 3.51-3.62 (3H, m), 3.39-3.47 (1H, m), 3.34 (1H, m), 3.23 (1H, m), 2.33-2.40 (1H, m), 2.12-2.19 (1H , m), 1.03-2.00 (23H, m), 1.42 (3H, s), 1.42 (3H, s), 1.36 (3H, s), 0.93 (3H, s).

(Step 7)

[(2R)-5,5-difluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3 -dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (90 mg) was obtained as a white solid.

MS (ESI) m / z: 530 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.11 (1H, d), 3.94 (1H, m), 3.82 (1H, m), 3.49-3.77 (7H, m), 3.34 (1H, m), 3.24 (1H) , m), 2.30-2.40 (1H, m), 2.10-2.20 (1H, m), 1.07-2.00 (25H, m), 1.42 (3H, s), 0.94 (3H, s).

(Example 76)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-[(2S)-2-hydroxy-3-(methylsulfonyl)propoxy]-10a,12a-di Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(2S)-2-hydroxy-3-({(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro- 2H-pyran-2-ylcarbonyl]octadeconaphtho[2,1-f]quinolin-8-yl}oxy)propyl 4-methylbenzenesulfonate

To a solution of the compound (340 mg) in pyridine (4 ml), m.p. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc

MS (ESI) m / z: 648 (M+H) ⁺ .

(Step 2)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-[(2S)-2-hydroxy-3-(methylsulfonyl)propoxy]-10a,12a-di Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

To a solution of the compound obtained in the above step 1 (287 mg) in N,N-dimethylformamide (5 ml), sodium methanesulfinate (136 mg) and potassium iodide (222 mg) at room temperature at 120 ° C Stir under 3 hours. After cooling the reaction mixture to room temperature, saturated sodium bicarbonate water was added to ethyl acetate extraction. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcEtOAcEtOAc

MS (ESI) m/z: 556 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.38-4.31 (1H, m), 4.06-4.00 (1H, m), 3.99-3.94 (1H, m), 3.80-3.72 (1H, m), 3.60-3.39 ( 5H, m), 3.35-3.18 (3H, m), 3.11-3.03 (4H, m), 2.88-2.84 (1H, m), 1.96-1.06 (29H, m), 0.94 (3H, s).

(Example 77)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-10a, 12a-Dimethyl-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradeconaphtho[2,1-f]quinoline-1 (2H)-benzyl formate

The compound obtained in Step 1 of Example 61 (2.31 g) and (R)-(-)-2,2-dimethyl-1,3-dioxolan-4-methanol (2.48 ml) were used. The title compound (838 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.07 (2H, s), 4.26-4.19 (1H, m), 4.07-4.02 (1H, m), 3.78-3.67 (2H, m), 3.61-3.50 (2H, m), 3.47-3.29 (2H, m), 3.03-2.96 (1H, m), 2.92 (1H, d, J = 4.4 Hz), 2.07-0.93 (30H, m) .

(Step 2)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-4a,6b-dimethyltetrahydrogen-1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-benzyl acetate

The title compound (823 mg) was obtained from m.

(Step 3)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}- 6a-hydroxy-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (578 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.08 (2H, s), 4.27-4.19 (1H, m), 4.08-4.02 (1H, m), 3.81-3.68 (3H, m), 3.63-3.28 (3H, m), 3.07-3.00 (1H, m), 1.96-1.07 (30H, m), 0.93 (3H, s).

(Step 4)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-6a(2H)-alcohol

The title compound (436 mg) was obtained as a white solid.

(Step 5)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -6a-hydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl Ketone

The title compound (125 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m / z: 534 (M+H) ⁺ .

(Step 6)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (90.2 mg) was obtained as a white solid.

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.05-4.00 (1H, m), 3.99-3.94 (1H, m), 3.85-3.39 (8H, m), 3.35-3.26 (2H, m), 2.64-2.60 ( 1H, m), 2.23-2.17 (1H, m), 1.96-1.11 (30H, m), 0.94 (3H, m).

(Example 78)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-(2-hydroxy-3-methoxypropoxy)-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-[2-(benzyloxy)-3-methoxypropoxy]-4a,6b-dimethyltetrahydrogen -1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-benzyl benzoate

The compound obtained in Step 1 of Example 61 (1.73 g) and 2-(benzyloxy)-3-methoxypropan-1-ol (Journal of Medicinal Chemistry, 1987, 30, 792) (2.94 g) were used. The title compound (905 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.25 (10H, m), 5.33-5.29 (1H, m), 5.12-5.06 (2H, m), 4.73-4.67 (2H, m), 3.79-3.32 ( 10H, m), 3.19-3.01 (2H, m), 2.40-2.32 (1H, m), 2.21-2.10 (2H, m), 1.93-0.90 (21H, m).

(Step 2)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-[2-(benzyloxy)-3-methoxypropoxy]-4a,6b-dimethyltetrahydrogen -1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4a-H)-formic acid benzyl ester

The title compound (762 mg) was obtained from m.

(Step 3)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[2-(benzyloxy)-3-methoxypropoxy]-6a-hydroxy-10a,12a-dimethyl-10- Hexahydronaphtho[2,1-f]quinoline-1(2H)-benzyl formate

The title compound (533 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.24 (10H, m), 5.11-5.05 (2H, m), 4.72-4.66 (2H, m), 3.81-3.29 (11H, m), 3.07-3.00 ( 1H, m), 1.94-0.88 (27H, m).

(Step 4)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-(2-hydroxy-3-methoxypropoxy)-10a,12a-dimethylhexadecane[2,1- f] quinoline-6a(2H)-alcohol

The title compound (337 mg) was obtained from m.

MS (ESI) m / z: 396 (M+H) ⁺ .

(Step 5)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-(2-hydroxy-3-methoxypropoxy)-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The compound (337 mg) obtained in the above step 4 and the compound (111 mg) obtained in the step 3 of Example 23, The title compound (73 mg) was obtained.

MS (ESI) m / z: 508 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.07-3.87 (3H, m), 3.77-3.68 (1H, m), 3.59-3.23 (11H, m), 2.48-2.44 (1H, m), 1.95-0.90 ( 33H, m).

(Example 79)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2S,3S)-2,3-dihydroxybutoxy]-6a-hydroxy-10a,12a-dimethyl 16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a,12a-dimethyl-8-{[(4S,5S)-2,2,5-trimethyl-1,3-dioxolane 4-yl]methoxy}-3,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydro[2,1-f] Quinoline-1(2H)-benzyl formate

The compound (1.00 g) obtained in the first step of Example 19 and [(4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl]methyl 4- Methylbenzenesulfonate (Tetrahedron, 1987, 43, 2191-2198.) (2.14 g) was obtained from the title compound (929 mg).

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.30 (1H, m), 5.07 (1H, d, J = 12.7 Hz), 5.05 (1H, d, J = 12.7 Hz), 3.76-3.70 (2H, m), 3.67 (1H, m), 3.60 (1H, m), 3.49 (1H, m), 3.35 (1H, m), 3.16 (1H, m), 3.02 (1H, m), 2.37 (1H, m), 2.20-2.07 (2H, m), 1.90-1.12 (13H, m), 1.39 (3H, s), 1.37 (3H, s), 1.33 (3H, s), 1.28 (3H, d, J = 5.9 Hz), 1.03-0.95 (2H, m), 0.93 (3H, s).

(Step 2)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-4a,6b-dimethyl-9-{[(4S,5S)-2,2,5-trimethyl-1,3- Dioxol-4-yl]methoxy}tetrahydro-1H-oxirane [4,4a]naphtho[2,1-f]quinoline-4(4aH)-benzyl benzoate

The title compound (669 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.25 (5H, m), 5.04 (2H, s), 3.83 (1H, m), 3.72 (1H, m), 3.65 (1H, m), 3.55 (1H) , m), 3.51 (1H, m), 3.48 (1H, dd, J = 4.1, 10.3 Hz), 3.30 (1H, m), 2.97 (1H, m), 2.89 (1H, d, J = 4.4 Hz) , 2.01-1.04 (18H, m), 1.38 (3H, s), 1.35 (3H, s), 1.272 (3H, s), 1.266 (3H, d, J = 5.9 Hz), 0.98 (3H, s).

(Step 3)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-10a, 12a-dimethyl-8-{[(4S,5S)-2,2,5-trimethyl-1, 3-Diethoxypentan-4-yl]methoxy}hexadehydronaphtho[2,1-f]quinoline-1(2H)-benzyl carboxylate

The title compound (226 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.25 (5H, m), 5.06 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.84 (1H, m), 3.74 (1H, m), 3.72 (1H, m), 3.66 (1H, m), 3.56 (1H, dd, J = 5.9, 10.3 Hz), 3.50 (1H, dd, J = 4.4, 10.3 Hz), 3.30 (1H, m), 3.01 (1H, m), 1.89 (1H, m), 1.79 (1H, m), 1.73-1.08 (19H, m), 1.39 (3H, s), 1.36 (3H, s), 1.31 (3H, s), 1.27 (3H, d, J = 5.9), 0.90 (3H, s).

(Step 4)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-8-{[(4S,5S)-2,2,5-trimethyl-1,3-dioxo Pentocyclo-4-yl]methoxy}hexadehydronaphtho[2,1-f]quinoline-6a(2H)-ol

The title compound (137 mg) was obtained from m.

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 3.86 (1H, m), 3.74 (1H, m), 3.61 (1H, m), 3.53 (2H, d, J = 4.9 Hz), 2.86 (1H, m) , 2.69 (1H, dd, J=4.9, 13.2 Hz), 1.87 (1H, m), 1.71-1.67 (3H, m), 1.65-1.00 (17H, m), 1.33 (3H, s), 1.31 (3H) , s), 1.24 (3H, d, J = 6.3 Hz), 1.04 (3H, s), 0.93 (3H, s).

(Step 5)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyl-8-{[(4S,5S)-2,2,5-trimethyl-1 ,3-dioxolan-4-yl]methoxy}hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran -2-yl]methanone

The title compound (66 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 548 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.94 (1H, dd, J = 2.4, 10.7 Hz), 3.84 (1H, m), 3.70 (1H, m), 3.66 (1H, m) ), 3.56 (1H, dd, J = 5.9, 10.3 Hz), 3.53 (1H, m), 3.50 (1H, dd, J = 4.4, 10.3 Hz), 3.41 (1H, m), 3.32-3.22 (2H, m), 1.93-1.84 (2H, m), 1.83-1.08 (24H, m), 1.40 (3H, s), 1.39 (3H, s), 1.36 (3H, s), 1.27 (3H, d, J = 5.9 Hz), 1.10 (1H, s), 0.91 (3H, s).

(Step 6)

[(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2S,3S)-2,3-dihydroxybutoxy]-6a-hydroxy-10a,12a-dimethyl 16 Hydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (53 mg) was obtained.

MS (ESI) m / z: 508 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, dd, J = 2.7, 11.0 Hz), 3.79-3.72 (2H, m), 3.61-3.56 (2H, m), 3.52-3.43(3H,m), 3.38(1H,m), 3.19(1H,m),1.94-1.83(3H,m),1.83-1.13(23H,m),1.43(3H,s),1.16( 3H, d, J = 6.3 Hz), 0.95 (3H, s).

(Embodiment 80)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a- Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The compound obtained in Step 3 of Example 12 (100 mg) and [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonic acid The title compound (55.0 mg) was obtained as a colorless oily material.

MS (ESI) m / z: 530 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.29-4.24 (1H, m), 4.06-4.02 (1H, m), 3.82-3.77 (2H, m), 3.68-3.65 (1H, m), 3.54-3.50 ( 1H, m), 3.45-3.39 (1H, m), 3.37-3.30 (1H, m), 3.29-3.23 (1H, m), 3.08 (1H, d, J = 2.9 Hz), 2.39-2.31 (1H, m), 2.15 (1H, d, J = 1.0 Hz), 2.07-0.84 (27H, m), 1.40 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.96 (3H, s ).

(Step 2)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-6a,7-dihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (21.0 mg) was obtained as a solid.

MS (ESI) m/z: 548 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.28-4.23 (1H, m), 4.06-4.02 (1H, m), 3.80-3.75 (1H, m), 3.67-3.63 (2H, m), 3.58-3.48 ( 2H,m),3.43-3.38(1H,m), 3.37-3.30(1H,m), 3.26-3.22(1H,m),2.66(1H,s),2.37-2.30(1H,m),2.25- 2.16 (1H, m), 1.83-1.05 (26H, m), 1.40 (3H, s), 1.38 (3H, s), 1.33 (3H, s), 1.09 (3H, s).

(Step 3)

Cyclohexyl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a- Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (8.0 mg) was obtained from m.

MS (ESI) m / z: 508 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.82-3.76 (1H, m), 3.76-3.71 (1H, m), 3.63 (1H, d, J = 3.4 Hz), 3.56-3.46 (6H, m), 3.44-3.39(2H,m),3.33-3.22(3H,m),3.17-3.12(3H,m),2.51-2.44(1H,m),2.16-2.09(2H,m),1.88-1.06(23H , m), 1.39 (3H, s), 1.09 (3H, s).

(Example 81)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a- Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-yl]methanone

The compound obtained in Step 3 of Example 12 (200 mg) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonic acid The title compound (126 mg) was obtained from m.

MS (ESI) m / z: 530 (M + H) ⁺

1H-NMR (CDCl ₃ ) δ: 4.29-4.24 (1H, m), 4.07-4.03 (1H, m), 3.84-3.79 (1H, m), 3.79-3.75 (1H, m), 3.63-3.55 (2H , m), 3.45-3.39 (1H, m), 3.37-3.23 (2H, m), 3.08 (1H, d, J = 2.9 Hz), 2.39-2.31 (1H, m), 2.09-2.01 (1H, m ), 1.96-1.90 (1H, m), 1.86-0.87 (26H, m), 1.40 (6H, s), 1.34 (3H, s), 0.96 (3H, s).

(Step 2)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-6a,7-dihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound was obtained in the same manner as in the step 4 of Example 31, using the compound (126 mg) of

(Step 3)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2S)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a- Dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (118 mg) was obtained from m.

¹ H-NMR (CD ₃ OD) δ: 3.81-3.77 (1H, m), 3.73-3.69 (1H, m), 3.62 (1H, d, J = 3.4 Hz), 3.59-3.46 (4H, m), 3.44-3.37(1H,m),3.33-3.24(3H,m),3.18-3.13(1H,m),2.51-2.44(1H,m),2.16-2.09(3H,m),1.87-1.09(23H , m), 1.39 (3H, s), 1.09 (3H, s).

(Example 82)

1-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a- Dimethyl hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methylpropan-1-one

(step 1)

(2S,4aR,4bS,6aS,10aS,10bR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-4a, 6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The compound obtained in Step 4 of Example 19 (5.00 g) and [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate The title compound (1.59 g) was obtained as crystals from m.

MS (ESI) m/z: 554 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.09-5.03 (2H, m), 4.31-4.23 (1H, m), 4.04 (1H, dd, J = 8.3, 6.3 Hz) , 3.81-3.78(2H,m), 3.77-3.72(1H,m), 3.67(1H,dd,J=9.8,4.9Hz), 3.52(1H,dd,J=10.0,6.1Hz),3.34-3.29 (1H, m), 3.09 (1H, d, J = 2.9 Hz), 3.03 (1H, m), 2.07-0.87 (18H, m), 1.39 (3H, s), 1.33 (6H, s), 0.96 ( 3H, s).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-6a,7-dihydroxy-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-benzyl carboxylate

The title compound (754 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.09-5.03 (2H, m), 4.28-4.24 (1H, m), 4.04 (1H, dd, J = 8.3, 6.8 Hz) , 3.80-3.73 (2H, m), 3.67-3.64 (2H, m), 3.58-3.48 (2H, m), 3.35-3.27 (1H, m), 3.04-2.98 (1H, m), 2.69 (1H, s), 2.26-2.17 (1H, m), 1.85-1.03 (18H, m), 1.41 (3H, s), 1.33 (3H, s), 1.32 (3H, s), 1.10 (3H, s).

(Step 3)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-6a,7(2H)-diol

The title compound (400 mg) was obtained from m.

(Step 4)

1-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-6a,7-dihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methylpropan-1- ketone

The title compound was obtained in the same manner as in the step 7 of Example 31 using the compound (100 mg) obtained from

(Step 5)

1-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a- Dimethyl hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]-2-methylpropan-1-one

The title compound (12.0 mg) was obtained as a solid.

MS (ESI) m/z: 468 (M+H) ⁺

1H-NMR (CDCl ₃ ) δ: 3.89-3.84 (1H, m), 3.82-3.78 (1H, m), 3.73-3.69 (1H, m), 3.66 (1H, d, J = 3.4 Hz), 3.64 3.54(4H,m), 3.47-3.42(2H,m), 3.39-3.32(1H,m), 3.28-3.24(1H,m),2.71-2.65(1H,m),2.58-2.46(1H,m ), 2.25-2.16(1H,m), 1.98-1.94(1H,m), 1.96-0.96(13H,m), 1.40(3H,s),1.10(3H,s),1.04(6H,dd,J = 7.8, 6.8 Hz).

(Example 83)

(2,6-difluorophenyl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7 -dihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2,6-difluorophenyl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-{[(4S)-2,2-dimethyl-1,3-di Oxypentan-4-yl]methoxy}-6a,7-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-1(2H)-yl]- ketone

The title compound (67.0 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 578 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.27-7.19 (1H, m), 6.89-6.83 (2H, m), 4.29-4.24 (1H, m), 4.04 (1H, dd, J = 8.5, 6.6 Hz) , 3.82-3.76 (1H, m), 3.67-3.64 (2H, m), 3.58-3.49 (2H, m), 3.42-3.33 (2H, m), 3.17-3.11 (1H, m), 2.27-2.18 ( 1H, m), 1.89-1.06 (17H, m), 1.41 (6H, s), 1.34 (3H, s), 1.12 (3H, s).

(Step 2)

(2,6-difluorophenyl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7 -dihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (45.0 mg) was obtained as a solid.

MS (ESI) m/z: 538 (M+H) ⁺

1H-NMR (CDCl ₃ ) δ: 7.27-7.23 (1H, m), 6.90-6.84 (2H, m), 3.90-3.85 (1H, m), 3.85-3.79 (1H, m), 3.74-3.69 (1H , m), 3.67 (1H, d, J = 3.9 Hz), 3.64 - 3.54 (3H, m), 3.48-3.46 (1H, m), 3.42-3.33 (2H, m), 3.17-3.11 (1H, m ), 2.62-2.50 (1H, m), 2.27-1.08 (21H, m), 1.54 (3H, s), 1.12 (3H, s).

(Example 84)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy -6a,7-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyridyl Methyl-2-yl]ketone

The title compound (200 mg) was obtained from m.

MS (ESI) m / z: 550 (M + H) ⁺

1H-NMR (CDCl ₃ ) δ: 4.30-4.22 (1H, m), 4.05-3.99 (2H, m), 3.95-3.92 (1H, m), 3.80-3.75 (1H, m), 3.67-3.23 (8H , m), 2.68-2.66 (1H, m), 2.25-2.15 (1H, m), 1.89-1.01 (23H, m), 1.40 (6H, s), 1.33 (3H, s), 1.09 (3H, s ).

(Step 2)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (164 mg) was obtained from m.

MS (ESI) m / z: 510 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.03-3.98 (1H, m), 3.95-3.92 (1H, m), 3.89-3.85 (1H, m), 3.82-3.78 (1H, m), 3.74-3.69 ( 1H, m), 3.66-3.52 (5H, m), 3.46-3.36 (1H, m), 3.33-3.23 (2H, m), 2.21-2.19 (1H, m), 1.89-1.07 (23H, m), 1.40 (3H, s), 1.09 (3H, s).

(Example 85)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7-dihydroxy-8-(2-hydroxyethoxy)-10a, 12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2S,4aR,4bS,6aS,10aS,10bR)-2-(2-tert-butoxy-2-oxoethoxyethoxy)-4a,6a-dimethyltetrahydroxan-1aH-epoxy Alkenes [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (86.0 mg) was obtained from m. ).

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.09-5.03 (2H, m), 4.07 (2H, s), 3.94-3.90 (1H, m), 3.78-3.71 (1H, m), 3.34 - 3.29 (1H, m), 3.13 (1H, d, J = 2.9 Hz), 3.05-2.99 (1H, m), 2.06-0.84 (18H, m). 1.45 (9H, s), 1.33 (3H, s), 0.96 (3H, s).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-(2-tertiary butoxy-2-oxoethoxyethoxy)-6a,7-dihydroxy-10a,12a-di Methyl hexadecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (71.0 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.25 (5H, m), 5.05 (2H, s), 4.17 (1H, d, J = 16.6 Hz), 3.90 (1H, d, J = 16.6 Hz). 3.78-3.72 (2H, m), 3.54 (1H, d, J = 2.9 Hz), 3.39 (1H, brs), 3.35-3.27 (1H, m), 3.04-2.98 (1H, m), 2.27-2.19 ( 1H, m), 1.83-1.07 (16H, m), 1.44 (9H, s), 1.32 (3H, s), 1.11 (3H, s).

(Step 3)

{[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinoline-8 -yl]oxy}acetic acid tert-butyl acrylate

The title compound (54.3 mg) was obtained from m.

(Step 4)

{[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a,7-dihydroxy-10a,12a-dimethyloctadeconaphtho[2, 3-f]quinoline-8-yl]oxy}acetic acid tert-butyl butyl ester

The title compound (29.0 mg) was obtained as a solid, m.

¹ H-NMR (CDCl ₃ ) δ: 4.17 (1H, d, J = 17.1 Hz), 3.90 (1H, d, J = 17, 1 Hz), 3.79-3.73 (1H, m), 3.55 (1H, d, J=2.9 Hz), 3.42-3.30 (3H, m), 3.26-3.22 (1H, m), 2.38-2.31 (1H, m), 2.27-2.19 (1H, m), 2.15 (1H, s), 1.80 - 1.09 (26H, m), 1.45 (9H, s), 1.39 (3H, s), 1.11 (3H, s).

(Step 5)

Cyclohexyl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7-dihydroxy-8-(2-hydroxyethoxy)-10a, 12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone

A solution of the compound (29.0 mg) in tetrahydrofuran (1 ml) obtained in the above step 4 was cooled to 0 ° C, and lithium borohydride (3.46 mg) was added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction liquid, it was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAcjHHHHHH

¹ H-NMR (CDCl ₃ ) δ: 3.83-3.78 (1H, m), 3.74-3.69 (2H, m), 3.67-3.61 (3H, m), 3.44-3.38 (1H, m), 3.37-3.30 ( 1H,m), 3.27-3.22(1H,m), 2.47(1H,s), 2.37-2.31(1H,m),2.24-2.16(1H,m),1.96-1.91(1H,m),1.81- 1.07 (25H, m), 1.39 (3H, s), 1.10 (3H, s).

(Example 86)

Cyclohexyl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1- b] 吖呯-1-yl] ketone

(step 1)

(2S,4aR,4bS,6aS,7E,10aS,10bR)-7-(hydroxyimino)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a , 7, 8, 9, 10, 10a, 10b, 11-hexadecahydrogen -2-yl acetate

Using (2S, 4aR, 4bS, 6aS, 10aS, 10bR)-4a, 6a-dimethyl-7-sideoxy-1,2,3,4,4a,4b,5,6,6a,7,8, 9,10,10a,10b,11-hexadecahydrogen The title compound (7.85 g) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 5.38-5.32 (1H, m), 4.62-4.53 (1H, m), 3.29-3.22 (1H, m), 2.35-2.23 (2H, m), 2.17-2.08 ( 1H, m), 2.02-0.95 (17H, m), 2.00 (3H, s), 1.05 (3H, s), 0.99 (3H, s).

(Step 2)

(5aS, 5bR, 9S, 11aR, 11bS, 13aS)-11a, 13a-dimethyl-2-oxo-2,3,4,5,5a,5b,6,8,9,10,11,11a ,11b,12,13,13a-hexadecahydro-1H-phenanthro[2,1-b]indole-9-yl acetate

The title compound (5.30 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 5.47 (1H, s), 5.37-5.32 (1H, m), 4.62-4.53 (1H, m), 2.56-2.46 (2H, m), 2.36-2.21 (3H, m), 2.09-2.03 (1H, m), 2.01 (3H, s), 1.91-1.82 (3H, m), 1.67-1.45 (6H, m), 2.01 (3H, s), 1.36-1.02 (6H, m), 1.26 (3H, s), 0.95 (3H, s).

(Step 3)

(5aS, 5bR, 9S, 11aR, 11bS, 13aS)-11a, 13a-dimethyl-2,3,4,5,5a,5b,6,8,9,10,11,11a,11b,12, 13,13a-hexadecahydro-1H-phenanthro[2,1-b]indole-9-ol

The title compound (4.40 g) was obtained from m.

(Step 4)

(5aS, 5bR, 9S, 11aR, 11bS, 13aS)-9-hydroxy-11a,13a-dimethyl-2,3,4,5,5a,5b,6,8,9,10,11,11a, 11b,12,13,13a-hexadecahydro-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (6.35 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.24 (5H, m), 5.35-5.31 (1H, m), 5.07 (2H, s), 3.92 (1H, brs), 3.54-3.44 (1H, m) , 3.20-3.12(1H,m), 2.37(1H,s),2.32-2.25(2H,m),2.22-2.14(1H,m),1.86-1.78(2H,m),1.71-0.89(15H, m).1.54 (3H, s), 0.94 (3H, s).

(Step 5)

(5aS, 5bR, 11aR, 11bS, 13aS)-11a, 13a-dimethyl-9-side oxygen-2,3,4,5,5a,5b,6,7,9,10,11,11a,11b ,12,13,13a-hexadehydro-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (1.97 g) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.71 (1H, s), 5.07 (2H, s), 3.92 (1H, brs), 3.65-3.55 (1H, m), 3.18 -3.12 (1H, m), 2.43-2.28 (5H, m), 2.21-2.14 (1H, m), 2.04-1.98 (2H, m), 1.89-1.83 (2H, m), 1.72-0.96 (13H, m), 1.12 (3H, s).

(Step 6)

(5aS, 5bR, 9S, 11aR, 11bS, 13aS)-9-hydroxy-11a,13a-dimethyl-2,3,4,5,5a,5b,6,7,9,10,11,11a, 11b,12,13,13a-hexadecahydro-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (1.47 g) was obtained from m.

(Step 7)

(1aS, 2S, 4aR, 4bS, 6aS, 11aS, 11bR, 13aR)-2-hydroxy-4a,6a-dimethylhexadecahydroepoxide [8,8a]phenanthrene [2,1-b]吖呯-7(1aH)-benzyl formate

The title compound (1.42 g) as an oily material was obtained from the title compound (1.

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.07 (2H, s), 4.03 (1H, s), 3.93 (1H, s), 3.22-3.14 (1H, m), 3.13 (1H, d, J = 3.9 Hz), 2.40 - 1.99 (5H, m), 1.71 - 1.00 (19H, m), 0.96 (3H, s).

(Step 8)

(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl [7,8]phenanthroline [2,1-b]indole-8-formic acid benzyl ester

A solution of the compound (1.47 g) obtained in the above step 7 in acetone (100 ml) was then evaporated. After adding saturated sodium hydrogencarbonate water to the reaction liquid, acetone was distilled off under reduced pressure. The residue was extracted with dichloromethane and washed with brine. After the organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated. The residue was purified by EtOAc EtOAcEtOAcEtOAc

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.24 (5H, m), 5.06 (2H, s), 4.32-4.24 (1H, m), 3.98-3.84 (1H, m), 3.77 (1H, d, J = 5.4 Hz), 3.24 - 3.18 (1H, m), 2.39 (1H, s), 2.11-2.03 (1H, m), 1.89 - 1.81 (2H, m), 1.72 - 0.97 (17H, m), 1.49 (6H, s), 1.29 (3H, s), 1.09 (3H, s).

(Step 9)

(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-2,2,5a,7a-tetramethyloctadecyl-14aH-[1,3]dioxolanyl[7,8 Phenanthroline [2,1-b]吖呯-14a-ol

The title compound (714 mg) was obtained from m.

(Step 10)

Cyclohexyl [(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxol Cyclo-[7,8]phenanthro[2,1-b]indole-8-yl]methanone

The title compound (51.7 mg) was obtained from m.

(Step 11)

Cyclohexyl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1- b] 吖呯-1-yl] ketone

The title compound (21 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 4.16-4.08 (1H, m), 3.54-3.32 (3H, m), 2.62-2.55 (1H, m), 2.26-1.03 (31H, m), 1.47 (3H, s), 1.08 (3H, s).

(Example 87)

(2,6-difluorophenyl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H -phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

(2,6-difluorophenyl)[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H- [1,3]dioxolanyl[7,8]phenanthro[2,1-b]indole-8-yl]methanone

The title compound (259 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

(Step 2)

(2,6-difluorophenyl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H -phenanthro[2,1-b]indol-1-yl]methanone

The title compound (169 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 7.28-7.19 (2H, m), 6.90-6.84 (1H, m), 4.17-4.09 (1H, m), 3.54-3.44 (2H, m), 3.33-3.25 ( 1H, m), 2.80 (1H, m), 2.27-1.01 (20H, m), 1.71 (3H, s), 1.11 (3H, s).

(Example 88)

Cyclopentyl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1 -b]吖呯-1-yl]methanone

(step 1)

Cyclopentyl [(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxo Pentocyclo[7,8]phenanthro[2,1-b]indole-8-yl]methanone

The title compound (120 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

(Step 2)

Cyclopentyl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1 -b]吖呯-1-yl]methanone

The title compound (62 mg) was obtained from m.

MS (ESI) m/z: 434 (M+H) ⁺

1H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 3.59-3.49 (3H, m), 3.42-3.33 (1H, m), 2.73-2.66 (1H, m), 2.63-2.55 (1H , m), 2.25-2.15 (2H, m), 1.90 - 1.02 (25H, m), 1.50 (3H, s), 1.08 (3H, s).

(Example 89)

Cyclobutyl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1 -b]吖呯-1-yl]methanone

(step 1)

Cyclobutyl [(3aS, 5aR, 5bS, 7aS, 12aS, 12bR, 14aS, 14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxo Pentocyclo[7,8]phenanthro[2,1-b]indole-8-yl]methanone

The title compound (48.7 mg) was obtained from m.

(Step 2)

Cyclobutyl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2,1 -b]吖呯-1-yl]methanone

The title compound (18.0 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 3.53-3.49 (1H, m), 3.35-3.28 (2H, m), 3.16-3.09 (1H, m), 2.63-2.57 ( 1H,m),2.43-2.35(1H,m), 2.28(1H,d,J=2.4Hz),2.22-2.08(3H,m),2.03-1.92(1H,m),1.90-1.82(2H, m), 1.81-1.73 (2H, m), 1.69-0.95 (16H, m), 1.53 (3H, s), 1.08 (3H, s).

(Embodiment 90)

2-methyl-1-[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene [2,1-b]indol-1-ylpropan-1-one

(step 1)

1-[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxol Cyclo-[7,8]phenanthro[2,1-b]indole-8-yl]-2-methylpropan-1-one

The title compound (47.4 mg) was obtained from m.

(Step 2)

2-methyl-1-[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene [2,1-b]indol-1-ylpropan-1-one

The title compound (21.0 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 4.16-4.09 (1H, m), 3.54-3.35 (3H, m), 2.66-2.56 (3H, m), 2.30-2.26 (1H, m), 2.22-2.16 ( 1H, m), 1.89-0.84 (27H, m), 1.49 (3H, s), 1.08 (3H, s), 1.06 (6H, dd, J = 11.7, 6.8 Hz).

(Example 91)

Tetrahydro-2H-pyran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenantho[2,1-b]吖呯-8-yl](tetrahydro-2H-pyran-2-yl)methanone

The title compound (52 mg) was obtained as a mixture of non-mironomers, using the same procedure as in Step 4 of Example 23, using the compound (40 mg) ).

(Step 2)

Tetrahydro-2H-pyran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (12 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 4.17-4.08 (1H, m), 4.04-3.98 (1H, m), 3.89-3.82 (1H, m), 3.79-3.67 (1H, m), 3.54-3.49 ( 1H, m), 3.45-3.31 (2H, m), 2.67-2.60 (1H, m), 2.31-2.27 (1H, m), 2.21-2.15 (1H, m), 1.93-1.85 (3H, m), 1.78-0.83 (21H, m), 1.48 (3H, s), 1.08 (3H, s).

(Example 92)

(2R)-tetrahydro-2H-pyran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyl Octadecahydro-1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenantho[2,1-b]indole-8-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.030) was obtained from the title compound (0.030). g).

¹ H-NMR (CDCl ₃ ) δ: 4.33-4.26 (1H, m), 3.98-3.91 (2H, m), 3.77 (1H, d, J = 5.4 Hz), 3.46-3.31 (3H, m), 2.66 -2.61 (1H, m), 2.09-2.02 (1H, m), 1.93-1.79 (4H, m), 1.73-1.06 (21H, m), 1.53 (3H, s), 1.49 (3H, s), 1.29 (3H, s), 1.09 (3H, s).

(Step 2)

(2R)-tetrahydro-2H-pyran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyl Octadecahydro-1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (20.0 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 4.14 - 4.09 (1H, m), 3.97-3.91 (2H, m), 3.51-3.30 (5H, m), 2.65-2.60 (1H, m), 2.25 (1H, s), 2.23 - 2.14 (1H, m), 1.93-1.78 (3H, m), 1.74 - 0.83 (20H, m), 1.52 (3H, s), 1.08 (3H, s).

(Example 93)

(2R)-tetrahydrofuran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H- Phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenantho[2,1-b]吖呯-8-yl][(2R)-tetrahydrofuran-2-yl]methanone

The compound (200 mg) obtained from the step 9 of Example 86 and (R)-(+)-tetrahydrofuran-2-carbonyl chloride (79.2 mg) were obtained in the same manner as in Step 7 of Example 31 to give a solid. The title compound (169 mg).

¹ H-NMR (CDCl ₃ ) δ: 4.52-4.44 (1H, m), 4.30-4.26 (1H, m), 4.02 (1H, m), 3.89 (1H, m), 3.77 (1H, d, J = 4.9 Hz), 3.48-3.32 (2 H, m), 2.62-2.57 (1H, m), 2.13-1.09 (24H, m). 1.55 (3H, s), 1.49 (3H, s), 1.29 (3H, s), 1.09 (3H, s).

(Step 2)

(2R)-tetrahydrofuran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H- Phenanthro[2,1-b]indol-1-yl]methanone

The title compound (143 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 4.47 (1H, dd, J = 7.8, 5.4 Hz), 4.15 - 4.09 (1H, m), 4.02 (1H, m), 3.89 (1H, dm), 3.53-3.49 (1H, m), 3.48-3.31 (2H, m), 2.30-1.11 (24H, m), 1.54 (3H, s), 1.08 (3H, s), 1.01 (1H, m).

(Example 94)

Pyridin-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2 , 1-b]吖呯-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenantho[2,1-b]dec-8-yl](pyridin-2-yl)methanone

The compound obtained in Step 9 of Example 86 (100 mg) and pyridonic acid (97.8 g) and 1- cyano-2-ethoxy-2-oxoethoxyethyleneoxy group as a condensing agent Methylamino group - The title compound (128 mg) was obtained from m.p.

(Step 2)

Pyridin-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene[2 , 1-b]吖呯-1-yl]methanone

The title compound (0.042 g) was obtained as a solid.

MS (ESI) m/z: 443 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.54 - 8.51 (1H, m), 7.73 - 7.68 (1H, m), 7.44 - 7.41 (1H, m), 7.26-7.23 (1H, m), 4.18-4. 1H,m),3.57-3.44(2H,m),3.43-3.34(1H,m),3.22-3.14(1H,m),2.88-2.81(1H,m),2.31-2.17(2H,m), 1.92-1.84 (2H, m), 1.77-0.99 (15H, m), 1.67 (3H, s), 1.11 (3H, s).

(Example 95)

(6-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen- 1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenanthro[2,1-b]ind-8-yl](6-methylpyridin-2-yl)methanone

The compound obtained in Step 9 of Example 86 (100 mg) and 6-methylpyridine-2-carboxylic acid (97.6 mg) and 1- cyano-2-ethoxy-2-oxo- oxy as a condensing agent Ethylaminooxy)dimethylamino- The title compound (132 mg) was obtained from m.p.

(Step 2)

(6-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen- 1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (49.0 mg) was obtained as a solid.

MS (ESI) m/z: 457 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.59-7.55 (1H, m), 7.22-7.20 (1H, m), 7.10-7.07 (1H, m), 4.17-4.10 (1H, m), 3.54-3.50 ( 1H, m), 3.39-3.31 (1H, m), 3.22-3.14 (1H, m), 2.88-2.82 (1H, m), 2.50 (3H, s), 2.28 (1H, d, J = 2.9 Hz) , 2.25-2.19 (1H, m), 1.97-1.85 (2H, m), 1.77-1.03 (17H, m), 1.66 (3H, s), 1.11 (3H, s).

(Example 96)

(5-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen- 1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenanthro[2,1-b]ind-8-yl](5-methylpyridin-2-yl)methanone

The compound obtained from the step 9 of Example 86 (100 mg) and 5-methylpyridine-2-carboxylic acid (54.5 mg) and 1-cyano-2-ethoxy-2-oxo- oxy Ethylaminooxy)dimethylamino- The title compound (132 mg) was obtained from m.p.

(Step 2)

(5-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen- 1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (32.0 mg) was obtained as a solid.

MS (ESI) m/z: 457 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.36-8.33 (1H, m), 7.52-7.48 (1H, m), 7.35-7.32 (1H, m), 4.16-4.09 (1H, m), 3.54-3.50 ( 1H, m), 3.41-3.32 (1H, m), 3.24 - 3.16 (1H, m), 2.87-2.81 (1H, m), 2.32 (3H, s), 2.27 (1H, d, J = 2.4 Hz) , 2.25-2.17 (1H, m), 1.95-1.85 (3H, m), 1.76-1.01 (15H, m), 1.50 (3H, s), 1.11 (3H, s).

(Example 97)

(4-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen- 1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenanthro[2,1-b]ind-8-yl](4-methylpyridin-2-yl)methanone

The compound obtained from the step 9 of Example 86 (100 mg) and 4-methylpyridine-2-carboxylic acid (54.5 mg) and 1- cyano-2-ethoxy-2-oxo- oxy Ethylaminooxy)dimethylamino- The title compound (132 mg) was obtained from m.p.

(Step 2)

(4-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen- 1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (59.0 mg) was obtained as a solid.

MS (ESI) m/z: 457 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.37-8.35 (1H, m), 7.25-7.22 (1H, m), 7.06-7.03 (1H, m), 4.16-4.09 (1H, m), 3.53-3.49 ( 1H, m), 3.41-3.31 (1H, m), 3.23 - 3.13 (1H, m), 2.87-2.79 (1H, m), 2.42-2.30 (1H, m), 2.33 (3H, s), 2.25- 2.16 (1H, m), 1.91-1.06 (18H, m), 1.67 (3H, s), 1.10 (3H, s).

(Example 98)

(3-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenanthro[2,1-b]ind-8-yl](3-methylpyridin-2-yl)methanone

The compound obtained from the step 9 of Example 86 (100 mg) and 3-methylpyridine-2-carboxylic acid (54.5 mg) and 1- cyano-2-ethoxy-2-oxo- oxy Ethylaminooxy)dimethylamino- The title compound (132 mg) was obtained from m.p.

(Step 2)

(3-methylpyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (46.0 mg) was obtained from m.

MS (ESI) m/z: 457 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.36-8.33 (1H, m), 7.50-7.46 (1H, m), 7.14-7.10 (1H, m), 4.17-4.09 (1H, m), 3.54-3.50 ( 1H, m), 3.41-3.35 (1H, m), 3.12-3.04 (1H, m), 2.89-2.84 (1H, m), 2.28 (3H, s), 2.28-2.19 (2H, m), 1.92 1.02 (18H, m), 1.50 (3H, s), 1.11 (3H, s).

(Example 99)

(3-methoxypyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen -1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-[1,3]dioxolanyl And [7,8]phenanthro[2,1-b]ind-8-yl](3-methoxypyridin-2-yl)methanone

The compound obtained from the step 9 of Example 86 (100 mg) and 3-methylpyridine-2-carboxylic acid (60.8 mg) and 1- cyano-2-ethoxy-2-oxo- oxy as a condensing agent were used. Ethylaminooxy)dimethylamino- The title compound (136 mg) was obtained from m.p.

(Step 2)

(3-methoxypyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctahydrogen -1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (32.0 mg) was obtained as a solid.

MS (ESI) m/z: 473 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.14 - 8.11 (1H, m), 7.20-7.16 (2H, m), 4.16-4.08 (1H, m), 3.80 (3H, s), 3.51 (1H, s) , 3.42-3.36 (1H, m), 3.18-3.09 (1H, m), 2.85-2.80 (1H, m), 2.40-2.33 (1H, m), 2.25-2.15 (1H, m), 1.94-1.82 ( 2H, m), 1.77-1.08 (16H, m), 1.73 (3H, s), 1.10 (3H, s).

(Embodiment 100)

(3-fluoropyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H -phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

(3-fluoropyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H -phenanthro[2,1-b]indol-1-yl]methanone

The compound obtained from the step 9 of Example 86 (40.0 mg) and 3-fluoropyridine-2-carboxylic acid (22.4 mg), and 1-cyano-2-ethoxy-2-oxo-oxy Ethylaminooxy)dimethylamino- The title compound (53.0 mg) was obtained from m.p.

(Step 2)

(3-fluoropyridin-2-yl)[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H -phenanthro[2,1-b]indol-1-yl]methanone

The title compound (9.8 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 8.38-8.35 (1H, m), 7.44-7.39 (1H, m), 7.29-7.25 (1H, m), 4.17-4.10 (1H, m), 3.55-3.50 ( 1H, m), 3.47-3.41 (1H, m), 3.19-3.14 (1H, m), 2.86-2.80 (1H, m), 2.30 (1H, s), 2.25-2.18 (1H, m), 1.91 0.99 (18H, m), 1.72 (3H, s), 1.11 (3H, s).

(Example 101)

Cyclohexyl {(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a-hydroxy-11a,13a-dimethyl 18 Hydrogen-1H-phenanthro[2,1-b]indol-1-yl}methanone

(step 1)

(5aS,5bR,9S,11aR,11bS,13aS)-11a,13a-dimethyl-9-{[(4-methylphenyl)sulfonyl]oxy}-2,3,4,5, 5a,5b,6,8,9,10,11,11a,11b,12,13,13a-hexadecahydro-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (5.44 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.78-7.76 (2H, m), 7.36-7.26 (7H, m), 5.33-5.27 (1H, m), 5.06 (2H, s), 4.34 - 4.27 (1H, m), 3.92 (1H, brs), 3.19-3.10 (1H, m), 2.42 (3H, s), 2.42-2.25 (4H, m), 1.80-0.85 (17H, m), 1.53 (3H, s) , 0.90 (3H, s).

(Step 2)

(5aS,5bR,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-11a, 13a-dimethyl-2,3,4,5,5a,5b,6,8,9,10,11,11a,11b,12,13,13a-hexadecahydro-1H-phenanthrene [2,1 -b]benzyl hydrazine-1-carboxylate

The compound (1.00 g) obtained in the above step 1 and (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol (4.47 g) were used with The title compound (513 mg) m.

¹ H-NMR (CDCl ₃ ) δ: 7.44 - 7.23 (5H, m), 5.34 - 5.30 (1H, m), 5.07 (1H, brs), 4.24 - 4.19 (1H, m), 4.07 - 4.01 (1H, m), 3.90 (1H, brs), 3.73-3.69 (1H, m), 3.59-3.53 (1H, m), 3.44-3.39 (1H, m), 3.20-3.10 (1H, m), 2.43-2.25 ( 2H, m), 2.20-2.11 (1H, m), 1.92-1.80 (1H, m), 1.69-0.92 (19H, m), 1.54 (3H, s), 1.40 (3H, s), 1.34 (3H, s), 0.92 (3H, s).

(Step 3)

(3S,6aR,6bS,11aS,13aS,13bR)-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-11a, 13b-Dimethylhexadecahydroepoxide [8a,9]phenanthro[2,1-b]indole-11(2H)-benzyl formate

The title compound (488 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.05 (2H, s), 4.22-4.17 (1H, m), 4.04-4.00 (1H, m), 3.90 (1H, brs) , 3.70-3.64 (1H, m), 3.58-3.48 (2H, m), 3.45-3.35 (1H, m), 3.17-3.06 (1H, m), 2.91 (1H, d, J = 4.4 Hz) ,2.44-2.24(1H,m), 2.20-2.12(1H,m),2.03-1.92(2H,m),1.69-0.84(17H,m),1.56(3H,s),1.38(3H,s) , 1.33 (3H, s), 0.97 (3H, s).

(Step 4)

(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}- 7a-hydroxy-11a, 13a-dimethyloctadecyl-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (369 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.06 (2H, s), 4.23-4.18 (1H, m), 4.03 (1H, m), 3.89 (1H, brs), 3.74 -3.67 (2H, m), 3.60-3.49 (1H, m), 3.46-3.35 (1H, m), 3.23-3.17 (1H, m), 1.93-1.85 (1H, m), 1.83-1.77 (1H, m), 1.68-0.90 (21H, m), 1.54 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.90 (3H, s).

(Step 5)

(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}- 11a,13a-dimethyloctadecyl-7aH-phenanthro[2,1-b]indole-7a-ol

The title compound was obtained by the same procedure as in the step 2 of Example 20 using the compound (369 mg).

(Step 6)

Cyclohexyl [(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy -7a-hydroxy-11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (38.0 mg) was obtained as a solid, m.

¹ H-NMR (CDCl ₃ ) δ: 4.23-4.18 (1H, m), 4.04-4.01 (1H, m), 3.73-3.63 (2H, m), 3.61-3.33 (6H, m), 2.62-2.55 ( 1H, m), 2.29-2.22 (1H, m), 1.91-0.87 (30H, m), 1.47 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.90 (3H, s) .

(Step 7)

Cyclohexyl {(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a-hydroxy-11a,13a-dimethyl 18 Hydrogen-1H-phenanthro[2,1-b]indol-1-yl}methanone

The title compound (23 mg) was obtained.

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.83-3.77 (1H, m), 3.76-3.66 (2H, m), 3.65-3.59 (2H, m), 3.56-3.54 (1H, m), 3.50-3.42 ( 2H,m),3.41-3.33(1H,m),2.63-2.56(2H,m),2.31-2.22(1H,m),2.20-2.13(1H,m),1.94-1.87(1H,m), 1.79-0.79 (28H, m), 1.47 (3H, s), 0.91 (3H, s).

(Example 102)

{(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a-hydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydrofuran-2-yl]methanone

(step 1)

[(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -7a-hydroxy-11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl][(2R)-tetrahydrofuran-2-yl]methanone

The compound (282 mg) and (R)-(+)-tetrahydrofuran-2-methylindole chloride (90.3 mg) obtained in the step of Example 101 were obtained in the same manner as in Step 31 of Example 31 to give a solid. The title compound (246 mg).

MS (ESI) m/z: 534 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.50-4.45 (1H, m), 4.23-4.18 (1H, m), 4.06-3.99 (2H, m), 3.92-3.86 (1H, m), 3.73-3.67 ( 2H, m), 3.60-3.50 (1H, m), 3.47-3.32 (3H, m), 2.61-2.56 (1H, m), 2.13-0.90 (26H, m), 1.54 (3H, s), 1.39 ( 3H, s), 1.33 (3H, s), 0.90 (3H, s).

(Step 2)

{(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a-hydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydrofuran-2-yl]methanone

The title compound (124 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 4.50-4.45 (1H, m), 4.02 (1H, m), 3.91-3.86 (1H, m), 3.82-3.77 (1H, m), 3.75-3.67 (2H, m), 3.65-3.58 (2H, m), 3.56-3.53 (1H, m), 3.50-3.46 (1H, m), 3.44-3.31 (2H, m), 2.59-2.56 (2H, m), 2.15- 0.87 (27H, m), 0.91 (3H, s).

(Example 103)

{(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a-hydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy} -7a-hydroxy-11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl][(2R)-tetrahydro-2H-pyran-2-yl Ketone

The compound obtained in Step 5 of Example 101 (43.0 mg) and (2R)-(+)-tetrahydropyran-2-methane chloride (25.7 mg) were used in the same manner as in Step 31 of Example 31. The title compound (54.1 mg) was obtained.

(Step 2)

{(5aS,5bR,7aR,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a-hydroxy-11a,13a-dimethyloctadecyl- 1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (40.0 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 3.97-3.91 (2H, m), 3.81-3.77 (1H, m), 3.75-3.66 (2H, m), 3.64-3.57 (2H, m), 3.56-3.53 ( 1H, m), 3.51-3.46 (1H, m), 3.45-3.38 (3H, m), 3.36-3.30 (1H, m), 2.66-2.61 (1H, m), 2.55 (1H, d, J = 5.4 Hz), 2.15-2.10 (1H, m), 1.93-0.85 (24H, m), 1.51 (3H, s), 0.91 (3H, s).

(Example 104)

2-{[(5aS,5bR,7aR,9S,11aR,11bS,13aS)-1-(cyclohexylcarbonyl)-7a-hydroxy-11a,13a-dimethyloctadecyl-1H-phenanthroline [2, 1-b]吖呯-9-yl]oxy}acetamide

(step 1)

Cyclohexyl [(5aS,5bR,9S,11aR,11bS,13aS)-9-hydroxy-11a,13a-dimethyl-2,3,4,5,5a,5b,6,8,9,10,11 ,11a,11b,12,13,13a-hexadecahydro-1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (13.9 g) was obtained from m.

MS (ESI) m/z: 414 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.36-5.30 (1H, m), 3.55-3.42 (2H, m), 3.38-3.29 (1H, m), 2.61-2.54 (1H, m), 2.32-2.23 ( 3H, m), 2.22-2.14 (1H, m), 1.86-0.81 (27H, m), 1.48 (3H, s), 0.94 (3H, s).

(Step 2)

(5aS,5bR,9S,11aR,11bS,13aS)-1-(cyclohexylcarbonyl)-11a,13a-dimethyl-2,3,4,5,5a,5b,6,8,9,10, 11,11a,11b,12,13,13a-hexadecahydro-1H-phenanthro[2,1-b]fluoren-9-yl 4-methylbenzenesulfonate

The title compound (15.7 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.79-7.76 (2H, m), 7.32-7.29 (2H, m), 5.33-5.26 (1H, m), 4.35-4.28 (1H, m), 3.52-3.41 ( 2H, m), 3.35-3.29 (1H, m), 3.01 (1H, s), 2.59-2.52 (2H, m), 2.42 (3H, s), 2.42-2.36 (2H, m), 2.32-2.20 ( 3H, m), 1.82-0.88 (42H, m), 1.46 (3H, s), 0.90 (3H, s).

(Step 3)

2-{[(5aS,5bR,9S,11aR,11bS,13aS)-1-(cyclohexylcarbonyl)-11a,13a-dimethyl-2,3,4,5,5a,5b,6,8, 9,10,11,11a,11b,12,13,13a-hexadecahydro-1H-phenanthro[2,1-b]fluoren-9-yl]oxy}acetamide

The title compound (86.0 mg) was obtained as a solid. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

¹ H-NMR (CDCl ₃ ) δ: 6.55 (1H, s), 5.42-5.32 (2H, m), 3.96 (2H, s), 3.51-3.17 (4H, m), 2.62-2.54 (1H, m) , 2.38-2.14 (4H, m), 1.88-0.94 (26H, m), 1.48 (3H, s), 0.94 (3H, s).

(Step 4)

2-{[(3S,6aR,6bS,11aS,13aS,13bR)-11-(cyclohexylcarbonyl)-11a,13b-dimethyloctadecyloxyethane [8a,9]phenanthrene[2, 1-b]indol-3-yl]oxy}acetamide

The title compound (78.0 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 6.49 (1H, brs), 5.44 (1H, brs), 3.98-3.90 (3H, m), 3.62-3.55 (1H, m), 3.46-3.38 (2H, m) , 3.33 - 3.27 (1H, m), 2.93 (1H, d, J = 4.4 Hz), 2.58-2.50 (1H, m), 2.30-2.21 (1H, m), 2.17-2.11 (1H, m), 2.05 -1.97 (2H, m), 1.75-0.94 (56H, m), 1.42 (3H, s), 0.99 (3H, s).

(Step 5)

2-{[(5aS,5bR,7aR,9S,11aR,11bS,13aS)-1-(cyclohexylcarbonyl)-7a-hydroxy-11a,13a-dimethyloctadecyl-1H-phenanthroline [2, 1-b]吖呯-9-yl]oxy}acetamide

The title compound (19.0 mg) was obtained as a solid.

MS (ESI) m / z: 489 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 6.53 (1H, brs), 5.39 (1H, brs), 4.00-3.89 (3H, m), 3.83-3.74 (1H, m), 3.62-3.26 (4H, m) , 2.63-2.58 (1H, m), 2.29-0.79 (31H, m), 1.47 (3H, s), 0.92 (3H, s).

(Example 105)

Cyclohexyl [(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyloctadecyl phenanthrene [2,1-b]吖 -1(2H)-yl]methanone

(step 1)

(2S,4aR,4bS,6aS,7E,10aS,10bR)-7-(hydroxyimino)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a , 7, 8, 9, 10, 10a, 10b, 11-hexadecahydrogen -2-yl acetate

Using (2S, 4aR, 4bS, 6aS, 10aS, 10bR)-4a, 6a-dimethyl-7-sideoxy-1,2,3,4,4a,4b,5,6,6a,7,8, 9,10,10a,10b,11-hexadecahydrogen The title compound (2.49 g) was obtained from m.

MS (ESI) m/z: 374 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.40-5.32 (1H, m), 4.61-4.55 (1H, m), 3.10 (1H, m), 2.35-0.80 (23H, m). 2.02 (3H, s) , 1.10 (3H, s), 1.00 (3H, s).

(Step 2)

(6aS,6bR,10S,12aR,12bS,14aS)-12a,14a-dimethyl-2-oxo-1,2,3,4,5,6,6a,6b,7,9,10,11 ,12,12a,12b,13,14,14a-octahydrophenanthrene[2,1-b]吖 -10-yl acetate

The title compound (1.56 g) was obtained from m.

MS (ESI) m/z: 374 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.41 (1H, s), 5.37-5.33 (1H, m), 4.61-4.52 (1H, m), 2.66-2.59 (1H, m), 2.51-2.46 (1H, m), 2.35-2.21 (3H, m), 2.00 (3H, s), 1.85-0.94 (18H, m), 1.17 (3H, s), 0.96 (3H, s).

(Step 3)

(6aS,6bR,10S,12aR,12bS,14aS)-12a,14a-dimethyl-1,2,3,4,5,6,6a,6b,7,9,10,11,12,12a, 12b,13,14,14a-octahydrophenanthrene[2,1-b]吖 -10- alcohol

The title compound (752 mg) was obtained.

MS (ESI) m / z: 318 (M+H) ⁺ .

(Step 4)

Cyclohexyl [[6aS,6bR,10S,12aR,12bS,14aS)-10-hydroxy-12a,14a-dimethyl-3,4,5,6,6a,6b,7,9,10,11,12 ,12a,12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-yl]methanone

The title compound (291 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 428 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.42 - 5.35 (1H, m), 3.59-3.51 (1H, m), 3.46-3.36 (1H, m), 3.27-3.16 (1H, m), 2.45-2.21 ( 5H, m), 1.96-0.90 (29H, m), 1.57 (3H, s), 0.99 (3H, s).

(Step 5)

(6aS,6bR,12aR,12bS,14aS)-1-(cyclohexylcarbonyl)-12a,14a-dimethyl-1,3,4,5,6,6a,6b,7,8,11,12, 12a, 12b, 13, 14, 14a-hexadecaphenanthroline [2,1-b]吖 -10(2H)-ketone

The title compound (163 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 5.71 (1H, s), 3.39 (1H, dd, J = 16.6, 5.9 Hz), 3.03 (1H, dd, J = 16.6, 8.3 Hz), 2.43-2.27 (6H) , m), 2.16-2.09 (1H, m), 2.06-2.00 (1H, m), 1.85-0.94 (26H, m), 1.51 (3H, s), 1.12 (3H, s).

(Step 6)

Cyclohexyl [(6aS,6bR,10S,12aR,12bS,14aS)-10-hydroxy-12a,14a-dimethyl-3,4,5,6,6a,6b,7,8,10,11,12 ,12a,12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-yl]methanone

The title compound (163 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 5.27 (2H, s), 4.15 - 4.09 (1H, m), 3.36 (1H, dd, J = 16.6, 5.9 Hz), 3.02 (1H, dd, J = 16.4, 8.1 Hz), 2.37-2.30 (1H, m), 2.25-2.13 (2H, m), 2.07-1.97 (2H, m), 1.97-1.90 (1H, m), 1.82-0.73 (27H, m), 1.48 (3H, s), 0.98 (3H, s).

(Step 7)

Cyclohexyl [(1aS, 2S, 4aR, 4bS, 6aS, 12aS, 12bR, 14aR)-2-hydroxy-4a, 6a-dimethylhexadecahydro-1aH-oxirane [8,8a]phenanthrene[ 2,1-b]吖 -7(5H)-yl]methanone

The title compound (141 mg) was obtained from the title compound (141 mg).

¹ H-NMR (CDCl ₃ ) δ: 4.08-4.02 (1H, m), 3.39 (1H, dd, J = 16.6, 6.3 Hz), 3.14 (1H, d, J = 4.4 Hz), 3.05 (1H, dd , J = 16.8, 8.5 Hz), 2.38-2.30 (1H, m), 2.28-2.21 (2H, m), 2.11-2.02 (2H, m), 1.89-0.93 (29H, m), 1.48 (3H, s ), 0.97 (3H, s).

(Step 8)

Cyclohexyl [(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyloctadecyl phenanthrene [2,1-b]吖 -1(2H)-yl]methanone

The title compound (100 mg) was obtained as the title compound.

¹ H-NMR (CDCl ₃ ) δ: 4.15 - 4.09 (1H, m), 3.51 (1H, m), 3.37 (1H, dd, J = 16.6, 5.9 Hz), 3.10 (1H, dd, J = 16.8, 8.5 Hz), 2.36-2.32 (1H, m), 2.28 (1H, d, J = 2.4 Hz), 2.24 - 2.16 (2H, m), 1.86-1.04 (30H, m), 1.47 (3H, s), 1.08 (3H, s).

(Example 106)

(2,6-difluorophenyl)[(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyloctadecyl phenanthrene [2,1-b]吖 -1(2H)-yl]methanone

(step 1)

(2,6-difluorophenyl)[(6aS,6bR,10S,12aR,12bS,14aS)-10-hydroxy-12a,14a-dimethyl-3,4,5,6,6a,6b,7 ,9,10,11,12,12a,12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-yl]methanone

The title compound (300 mg) was obtained as the title compound (300 mg, m. ).

MS (ESI) m/z: 458 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.33-7.21 (1H, m), 6.96-6.85 (2H, m), 5.37-5.31 (1H, m), 3.53-3.47 (1H, m), 3.30-3.24 ( 2H,m), 2.41-2.38 (1H,m),2.34-2.26(2H,m),2.24-2.16(1H,m), 1.90-0.84(19H,m),1.73(3H,s),0.96( 3H, s).

(Step 2)

(6aS,6bR,12aR,12bS,14aS)-1-(2,6-difluorobenzhydryl)-12a,14a-dimethyl-1,3,4,5,6,6a,6b,7 ,8,11,12,12a,12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -10(2H)-ketone

The title compound (167 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.45-7.18 (1H, m), 6.92-6.82 (2H, m), 5.72 (1H, s), 3.35-3.27 (1H, m), 3.20-3.14 (1H, m), 2.48-2.28 (5H, m), 2.19-2.13 (1H, m), 2.09-2.04 (1H, m), 1.77-1.01 (16H, m), 1.75 (3H, s), 1.15 (3H, s).

(Step 3)

(2,6-difluorophenyl)[(6aS,6bR,10S,12aR,12bS,14aS)-10-hydroxy-12a,14a-dimethyl-3,4,5,6,6a,6b,7 ,8,10,11,12,12a,12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-yl]methanone

The title compound (168 mg) was obtained from m.

(Step 4)

(2,6-difluorophenyl)[(1aS,2S,4aR,4bS,6aS,12aS,12bR,14aR)-2-hydroxy-4a,6a-dimethylhexadecahydro-1aH-ethylene oxide [8,8a]Philippine [2,1-b]吖 -7(5H)-yl]methanone

The title compound (161 mg) was obtained from the title compound (161 mg).

¹ H-NMR (CDCl ₃ ) δ: 7.28-7.21 (1H, m), 6.91-6.85 (2H, m), 4.08-4.03 (1H, m), 3.36-3.28 (1H, m), 3.24-3.17 ( 1H, m), 3.15 (1H, d, J = 4.4 Hz). 2.46-2.39 (1H, m), 2.31-2.21 (1H, m), 2.16-2.03 (2H, m), 1.76-0.84 (19H, m), 1.71 (3H, s), 1.00 (3H, s).

(Step 5)

(2,6-difluorophenyl)[(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyloctadecyl phenanthrene [2,1-b]吖 -1(2H)-yl]methanone

The title compound (127 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.27-7.22 (1H, m), 6.90-6.85 (2H, m), 4.16-4.09 (1H, m), 3.54-3.49 (1H, m), 3.34-3.20 ( 2H,m),2.43-2.37(1H,m), 2.28(1H,d,J=2.4Hz), 2.26-2.17(1H,m),1.92-1.85(1H,m),1.76-0.84(19H, m), 1.71 (3H, s), 1.11 (3H, s).

(Example 107)

(2R)-tetrahydro-2H-pyran-2-yl [(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyl Octahydrophenanthrene[2,1-b]吖 -1(2H)-yl]methanone

(step 1)

(6aS,6bR,10S,12aR,12bS,14aS)-10-hydroxy-12a,14a-dimethyl-3,4,5,6,6a,6b,7,9,10,11,12,12a, 12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-benzyl formate

The title compound (667 mg) was obtained from m.

MS (ESI) m/z: 452 (M+H) ⁺

_{^{1 H-NMR (CDCl 3)}} δ: 7.34-7.23 (5H, m), 5.34-5.30 (1H, m), 5.09-5.04 (2H, m), 3.60-3.53 (1H, m), 3.53-3.45 ( 1H,m), 3.17-3.08(1H,m),2.32-2.26(2H,m),2.22-2.14(1H,m),2.06-2.00(1H,m),1.86-0.93(19H,m), 1.52 (3H, s), 0.93 (3H, s).

(Step 2)

(6aS,6bR,12aR,12bS,14aS)-12a,14a-dimethyl-10-sideoxy-3,4,5,6,6a,6b,7,8,10,11,12,12a,12b ,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-benzyl formate

The title compound (699 mg) was obtained from m.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.71 (1H, s), 3.65-3.55 (2H, m), 3.08-3.00 (1H, m), 2.45-2.26 (4H, m), 2.21-2.14 (1H, m), 2.10-2.00 (2H, m), 1.89-0.97 (17H, m), 1.55 (3H, s), 1.12 (3H, s).

(Step 3)

(6aS,6bR,10S,12aR,12bS,14aS)-10-hydroxy-12a,14a-dimethyl-3,4,5,6,6a,6b,7,8,10,11,12,12a, 12b,13,14,14a-hexadecaphenanthene[2,1-b]吖 -1(2H)-benzyl formate

The title compound (700 mg) was obtained from m.

MS (ESI) m / z: 452 (M+H) ⁺ .

(Step 4)

(1aS, 2S, 4aR, 4bS, 6aS, 12aS, 12bR, 14aR)-2-hydroxy-4a,6a-dimethylhexadecahydro-1aH-oxirane [8,8a]phenanthrene [2,1 -b]吖 -7(5H)-benzyl formate

The title compound (755 mg) was obtained from m.

MS (ESI) m/z: 468 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.06 (2H, s), 4.04 (1H, brs), 3.65-3.58 (1H, m), 3.14 (1H, d, J = 4.4 Hz), 3.09-3.01 (1H, m), 2.20-2.00 (4H, m), 1.79-0.94 (19H, m), 1.51 (3H, s), 0.96 (3H, s).

(Step 5)

(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyloctadecyl phenanthrene [2,1-b]吖 -1(2H)-benzyl formate

The title compound (752 mg) was obtained from m.

MS (ESI) m/z: 468 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.05 (2H, s), 4.17 - 4.09 (1H, m), 3.63 - 3.56 (1H, m), 3.52-3.49 (1H, m), 3.14-3.06 (1H, m), 2.28-2.25 (1H, m), 2.23-2.16 (1H, m), 2.06-2.00 (1H, m), 1.92-1.87 (1H, m), 1.76- 1.02 (19H, m), 1.50 (3H, s), 1.08 (3H, s).

(Step 6)

(3aS, 5aR, 5bS, 7aS, 13aS, 13bR, 15aS, 15bS)-15a-hydroxy-2,2,5a,7a-tetramethyloctadecyl[1,3]dioxolanyl[7, 8]Philippine [2,1-b]吖 -8(4H)-benzyl formate

The title compound (505 mg) was obtained from m.

MS (ESI) m/z: 526 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.07 (2H, s), 4.32-4.26 (1H, m), 3.77 (1H, d, J = 5.4 Hz), 3.64-3.57 (1H, m), 3.14 - 3.07 (1H, m), 2.10 - 10.06 (23H, m), 1.49 (6H, s), 1.29 (3H, s), 1.09 (3H, s).

(Step 7)

(3aS,5aR,5bS,7aS,13aS,13bR,15aS,15bS)-2,2,5a,7a-tetramethyloctadecyl[1,3]dioxolanyl[7,8]phenanthrene [2,1-b]吖 -15a(4H)-alcohol

The title compound (376 mg) was obtained from m.

(Step 8)

[(3aS,5aR,5bS,7aS,13aS,13bR,15aS,15bS)-15a-hydroxy-2,2,5a,7a-tetramethyloctadecyl[1,3]dioxolanyl[7 ,8]Philippine [2,1-b]吖 -8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The compound (100 mg) obtained in the above step 7 and (R)-(+)-tetrahydropyran-2-carbonyl chloride (75.6 mg) were obtained in the same manner as in the step The title compound (115 mg).

MS (ESI) m/z: 504 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.32-4.26 (1H, m), 4.03-3.93 (2H, m), 3.77 (1H, d, J = 5.4 Hz), 3.46-3.40 (1H, m), 3.33 (1H, dd, J = 16.1, 5.9 Hz), 3.06 (1H, dd, J = 16.4, 9.5 Hz), 2.30-2.24 (1H, m), 2.10-2.02 (1H, m), 1.89-1.09 (27H , m), 1.49 (3H, s), 1.29 (6H, s), 1.09 (3H, s).

(Step 9)

(2R)-tetrahydro-2H-pyran-2-yl [(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy-12a,14a-dimethyl Octahydrophenanthrene[2,1-b]吖 -1(2H)-yl]methanone

The title compound (28.0 mg) was obtained from m.

MS (ESI) m/z: 464 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.15-4.09 (1H, m), 4.00-3.95 (2H, m), 3.53-3.49 (1H, m), 3.46-3.39 (1H, m), 3.33 (1H, Dd, J = 16.4, 6.6 Hz), 3.05 (1H, dd, J = 16.8, 9.0 Hz), 2.27-2.23 (2H, m), 2.22-2.17 (1H, m), 1.89-1.02 (26H, m) , 1.52 (3H, s), 1.08 (3H, s).

(Embodiment 108)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6a-hydroxy-10a,12a-dimethyloctadecyl[2, 1-f]quinoline-8-yl β-D-glucopyranoside

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-10a,12a-dimethyl-1,2,3,4,4a,4b,5 ,7,8,9,10,10a,10b,11,12,12a-hexadehydronaphtho[2,1-f]quinolin-8-yl 2,3,4,6-tetra-O-benzene Methotyl-β-D-glucopyranoside

2,3,4,6-tetra-O-benzylidene-1-O-(2,2,2-trichloroethaneimido)-D-glucopyranose (2,3,4 ,6-tetra-O-benzoyl-1-O-(2,2,2-trichloroethaneimidoyl)-D-glucopyranose) (Liebigs Annalen der Chemie, 1984, 7, 1343-1357.) (3.73 g) and in the examples To a solution of the compound (2.00 g) obtained in Step 1 in dichloromethane (30 ml), trimethyldecyltrifluoromethanesulfonate (0.1 M dichloromethane solution, 14.0 ml) was added at -10 °C. Stir at the same temperature for 1 hour. After adding triethylamine (0.5 ml) to the reaction mixture, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjj

MS (ESI) m / z: 1008 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.93 (2H, m), 7.88 (2H, m), 7.81 (2H, m), 7.54-7.21 (13H, m), 6.87 (2H) , m), 5.87 (1H, t, J = 9.8 Hz), 5.59 (1H, t, J = 9.8 Hz), 5.47 (1H, dd, J = 7.8, 9.8 Hz), 5.18 (1H, m), 4.91 (1H, d, J = 7.8 Hz), 4.57 (1H, dd, J = 3.2, 12.0 Hz), 4.50 (1H, dd, J = 6.1, 12.0 Hz), 4.13 (1H, m), 3.50 (1H, m), 3.42-3.32 (2H, m), 3.14 (1H, m), 2.19-2.03 (3H, m), 1.90 (1H, m), 1.81-1.16 (12H, m), 1.53 (3H, m) , 0.97 (1H, m), 0.89 (1H, m), 0.86 (3H, s).

(Step 2)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-4-(2,6-difluorobenzhydryl)-4a,6b-dimethylhexadecahydro-1H-ethylene oxide [4,4a]naphtho[2,1-f]quinolin-9-yl 2,3,4,6-tetra-O-benzimidyl-β-D-glucopyranoside

The title compound (210 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 8.01 (2H, m), 7.91-7.87 (4H, m), 7.79 (2H, m), 7.57 (13H, m), 6.86 (2H, m), 5.84 (1H) , t, J = 9.8 Hz), 5.58 (1H, t, J = 9.8 Hz), 5.46 (1H, dd, J = 7.8, 9.8 Hz), 4.87 (1H, d, J = 7.8 Hz), 4.56 (1H) , dd, J = 3.2, 12.0 Hz), 4.51 (1H, dd, J = 6.1, 12.0 Hz), 4.13 (1H, m), 3.82 (1H, m), 3.38-3.28 (2H, m), 3.12 ( 1H, m), 2.77 (1H, d, J = 4.4 Hz), 2.08-1.09 (18H, m), 1.47 (3H, s), 0.91 (3H, s).

(Step 3)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-4-(2,6-difluorobenzhydryl)-4a,6b-dimethylhexadecahydro-1H-ethylene oxide [4,4a]naphtho[2,1-f]quinolin-9-yl β-D-glucopyranoside

The title compound (524 mg) was obtained as a white solid.

¹ H-NMR (CD ₃ OD) δ: 7.40 (1H, m), 7.03-6.98 (2H, m), 4.29 (1H, d, J = 7.8 Hz), 3.87 (1H, m), 3.82 (1H, Dd, J = 1.7, 11.7 Hz), 3.63 (1H, dd, J = 5.4, 11.7 Hz), 3.43 (1H, m), 3.31-3.19 (4H, m), 3.12 (1H, m), 3.10 (1H ,dd,J=7.8,8.3Hz), 2.96(1H,d,J=4.4Hz), 2.11(1H,t,J=12.2Hz),2.09-1.97(2H,m),1.83(1H,m) , 1.77-1.20 (18H, m), 1.51 (3H, s), 1.07 (3H, s).

(Step 4)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6a-hydroxy-10a,12a-dimethyloctadecyl[2, 1-f]quinoline-8-yl β-D-glucopyranoside

The title compound (188 mg) was obtained as a white solid.

MS (ESI) m / z: 610 (M + H) ⁺

¹ H-NMR (DMSO-d ₆ ) δ: 7.44 (1H, m), 7.15-7.11 (2H, m), 4.88 (1H, d, J = 4.4 Hz), 4.86 (1H, m), 4.83 (1H) , d, J = 4.4 Hz), 4.42 (1H, t, J = 5.4 Hz), 4.12 (1H, d, J = 7.8 Hz), 3.96 (1H, m), 3.80 (1H, s), 3.63 (1H) , dd, J = 4.6, 11.0 Hz), 3.40 (1H, m), 3.33 (1H, m), 3.19 (1H, m), 3.14 (2H, d, J = 5.4 Hz), 3.07 (1H, m) , 3.00 (1H, m), 2.85 (1H, m), 1.79-1.02 (20H, m), 1.42 (3H, s), 0.84 (3H, s).

(Example 109)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6,6a-dihydroxy-10a,12a-dimethyloctahydrogen Naphtho[2,1-f]quinolin-8-yl-β-D-glucopyranoside

(step 1)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6a-hydroxy-6-iodo-10a,12a-dimethyl 18 Hydronaphtho[2,1-f]quinolin-8-yl 2,3,4,6-tetra-O-benzimidyl-β-D-glucopyranoside

Sodium iodide (183 mg) and magnesium iodide (339 mg) were sequentially added to a solution of the compound (208 mg) in m. The mixture was stirred for 15 hours while warming to room temperature. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous sodium thiosulfate solution and brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure tolu

(Step 2)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6,6a-dihydroxy-10a,12a-dimethyloctahydrogen Naphtho[2,1-f]quinolin-8-yl 2,3,4,6-tetra-O-benzimidyl-β-D-glucopyranoside

To a solution of the compound (250 mg) in 2-propanol (15 ml) obtained in the above step 1, triethylamine (0.281 ml), aqueous hypophosphite (50 wt%, 0.21 ml), and 2,2'- Azobisisobutyronitrile (25 mg) was stirred at 80 ° C for 1 hour. After the reaction mixture was cooled, the precipitated solid was dissolved in dichloromethane, and poured into ethyl acetate and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.94 (2H, m), 7.88 (2H, m), 7.80 (2H, m), 7.57-7.18 (13H, m), 6.86 (2H) , m), 5.86 (1H, t, J = 9.8 Hz), 5.59 (1H, t, J = 9.8 Hz), 5.47 (1H, dd, J = 7.8, 9.8 Hz), 4.89 (1H, d, J = 7.8 Hz), 4.59 (1H, dd, J = 3.4, 12.1 Hz), 4.50 (1H, m), 4.13 (1H, m), 4.04 (1H, m), 3.40-3.30 (3H, m), 3.13 (1H, m), 1.96-1.14 (19H, m), 1.52 (3H, s), 1.11 (1H, s), 1.00 (3H, s).

(Step 3)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6,6a-dihydroxy-10a,12a-dimethyloctahydrogen Naphtho[2,1-f]quinolin-8-yl-β-D-glucopyranoside

The title compound (55 mg) was obtained as a white solid.

MS (ESI) m/z: 626 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.40 (1H, m), 7.05-6.96 (2H, m), 4.35 (1H, d, J = 7.8 Hz), 4.15 (1H, m), 3.83 (1H, Dd, J = 1.5, 12.2 Hz), 3.63 (1H, dd, J = 5.4, 12.2 Hz), 3.48-3.39 (2H, m), 3.25-3.18 (2H, m), 3.17-3.10 (2H, m) , 2.03 (1H, t, J = 12.2 Hz), 1.89-1.25 (19H, m), 1.56 (3H, s), 1.12 (3H, s).

(Embodiment 110)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6-fluoro-6a-hydroxy-10a,12a-dimethyl 18 Hydronaphtho[2,1-f]quinolin-8-yl-β-D-glucopyranoside

(step 1)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6-fluoro-6a-hydroxy-10a,12a-dimethyl 18 Hydronaphtho[2,1-f]quinolin-8-yl 2,3,4,6-tetra-O-benzimidyl-β-D-glucopyranoside

Using 2,3,4,6-tetra-O-benzimidyl-1-O-(2,2,2-trichloroethaneimido)-D-glucopyranose (153 mg) The title compound (102 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.92 (2H, m), 7.88 (2H, m), 7.80 (2H, m), 7.54-7.46 (3H, m), 7.41-7.30 (7H, m), 7.28-7.21 (3H, m), 6.90-6.83 (2H, m), 5.86 (1H, t, J = 9.8 Hz), 5.59 (1H, t, J = 9.8 Hz), 5.47 ( 1H, dd, J = 7.8, 9.8 Hz), 4.90 (1H, d, J = 7.8 Hz), 4.58 (1H, dd, J = 3.2, 12.0 Hz), 4.50 (1H, dd, J = 6.1, 12.0 Hz) ), 4.16-3.99 (3H, m), 3.43-3.30 (2H, m), 3.14 (1H, m), 2.03-1.17 (19H, m), 1.52 (3H, s), 0.93 (3H, s).

(Step 2)

(4aS, 4bR, 6R, 6aR, 8S, 10aR, 10bS, 12aS)-1-(2,6-difluorobenzhydryl)-6-fluoro-6a-hydroxy-10a,12a-dimethyl 18 Hydronaphtho[2,1-f]quinolin-8-yl-β-D-glucopyranoside

The title compound (51 mg) was obtained as a white solid.

MS (ESI) m / z: 628 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.41 (1H, m), 7.01 (2H, m), 4.34 (1H, d, J = 7.3 Hz), 4.21 (1H, m), 4.15 (1H, m) , 3.84 (1H, dd, J = 2.0, 11. 7 Hz), 3.63 (1H, dd, J = 5.4, 11.7 Hz), 3.45 (1H, m), 3.32-3.14 (5H, m), 3.12 (1H, Dd, J = 7.3, 8.8 Hz), 2.00 (1H, m), 1.94-1.84 (3H, m), 1.81-1.37 (12H, m), 1.55 (3H, s), 1.32-1.21 (2H, m) , 1.05 (3H, d, J = 4.9 Hz).

(Embodiment 111)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl]18 Hydronaphtho[2,1-f]quinolin-8-yl-β-D-glucopyranoside

(step 1)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl]18 Hydronaphtho[2,1-f]quinolin-8-yl 2,3,4,6-tetra-O-benzimidyl-β-D-glucopyranoside

Using 2,3,4,6-tetra-O-benzylidene-1-O-(2,2,2-trichloroethaneimido)-D-glucopyranose (132 mg) The title compound (69 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, m), 7.93 (2H, m), 7.88 (2H, m), 7.80 (2H, m), 7.53-7.45 (3H, m), 7.41-7.30 (7H, m), 7.27-7.23 (2H, m), 5.85 (1H, t, J = 9.8 Hz), 5.58 (1H, t, J = 9.8 Hz), 5.45 (1H, dd, J = 7.8, 9.8 Hz), 4.88 (1H, d, J = 7.8 Hz), 4.57 (1H, dd, J = 3.4, 12.2 Hz), 4.49 (1H, dd, J = 6.1, 12.2 Hz), 4.12 (1H, m), 4.04-3.97 (2H, m), 3.93 (1H, dd, J=2.4, 10.7 Hz), 3.52 (1H, m), 3.40 (1H, m), 3.30-3.22 (2H, m), 1.94-1.84 ( 2H, m), 1.80-1.04 (24H, m), 1.37 (3H, s), 1.00 (1H, s), 0.79 (3H, s).

(Step 2)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl]18 Hydronaphtho[2,1-f]quinolin-8-yl-β-D-glucopyranoside

The title compound (33 mg) was obtained as a white solid.

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.32 (1H, d, J = 7.8 Hz), 4.12 (1H, m), 4.07 (1H, m), 3.94 (1H, dd, J = 2.9, 10.7 Hz) , 3.81 (1H, dd, J = 2.0, 11.7 Hz), 3.62 (1H, dd, J = 5.4, 11.7 Hz), 3.56 (1H, m), 3.47 (1H, m), 3.35 (1H, m), 3.30(1H,m), 3.24 (1H, t, J=8.8Hz), 3.22-3.14(2H,m), 3.10(1H,dd,J=7.8,8.8Hz),1.90-1.09(26H,m) , 1.40 (3H, s), 0.93 (3H, s).

(Example 112)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based β-D-glucopyranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 2,3,4,6-tetra-O-benzyl-β-D-glucopyranoside (β-glycoside) and (4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (α-glycoside)

For 2,3,4,6-tetra-O-benzyl-1-O-(2,2,2-trichloroethaneimido)-D-glucopyranose (656 mg) and Example 1 The compound obtained in the step 3 (200 mg) was reacted with a mixture of dichloromethane (9 ml) and acetonitrile (1 ml) as a solvent. The title compound (β-glycoside) (183 mg) and the title compound (α-glycoside) (149 mg) were obtained as white crystals.

Β-glycoside: Rf=higher, low polarity

¹ H-NMR (CDCl ₃ ) δ: 7.33 - 7.09 (20H, m), 4.91 (1H, d, J = 11.2 Hz), 4.88 (1H, d, J = 10.7 Hz), 4.78 (1H, d, J) = 10.7 Hz), 4.75 (1H, d, J = 10.7 Hz), 4.70 (1H, d, J = 11.2 Hz), 4.57 (1H, d, J = 12.2 Hz), 4.51 (1H, d, J = 12.2) Hz), 4.50 (1H, d, J = 10.7 Hz) 4.45 (1H, d, J = 7.3 Hz), 4.06 (1H, m), 3.70 (1H, dd, J = 0.9, 11.0 Hz), 3.62 (1H) , dd, J = 4.6, 11.0 Hz), 3.59 (1H, t, J = 9.3 Hz), 3.52 (1H, t, J = 9.3 Hz), 3.45-3.37 (3H, m), 3.33 (1H, m) , 3.25 (1H, m), 2.34 (1H, m), 2.01 (1H, m), 1.84-1.07 (30H, m), 1.38 (3H, s), 0.92 (3H, s).

Α-glycoside: Rf=lower, high polarity

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.09 (20H, m), 4.97 (1H, d, J = 10.7 Hz), 4.89 (1H, d, J = 3.4 Hz), 4.80 (1H, d, J = 10.7 Hz), 4.77 (1H, d, J = 10.7 Hz), 4.72 (1H, d, J = 11.7 Hz), 4.62 (1H, d, J = 11.7 Hz), 4.55 (1H, d, J = 11.7) Hz), 4.44 (1H, d, J = 11.7 Hz), 4.43 (1H, d, J = 10.7 Hz), 3.98 (1H, m), 3.94 (1H, t, J = 9.5 Hz), 3.84 (1H, m), 3.65 (1H, dd, J = 3.9, 10.7 Hz), 3.62 (1H, dd, J = 2.2, 10.7 Hz), 3.53 (1H, t, J = 9.5 Hz), 3.51 (1H, dd, J) = 3.4, 9.5 Hz), 3.41 (1H, m), 3.32 (1H, m), 3.23 (1H, m), 2.34 (1H, m), 1.87-1.06 (30H, m), 1.38 (3H, s) , 1.00 (1H, br), 0.90 (3H, s).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based β-D-glucopyranoside

The title compound (83 mg) was obtained as a white solid.

MS (ESI) m/z: 580 (M+H) ⁺

_{^{1 H-NMR (CD 3 OD}} ) δ: 4.35 (1H, d, J = 7.8Hz), 4.15 (1H, m), 3.85 (1H, dd, J = 2.2,12.0Hz), 3.65 (1H, dd, J = 5.6, 12.0 Hz), 3.53 (1H, m), 3.43 (1H, m), 3.35-3.18 (4H, m), 3.13 (1H, dd, J = 7.8, 8.5 Hz), 2.50 (1H, m ), 1.93-1.14 (30H, m), 1.41 (3H, s), 0.96 (3H, s).

(Example 113)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based α-D-glucopyranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based α-D-glucopyranoside

The title compound (82 mg) was obtained as a white solid.

MS (ESI) m/z: 580 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.89 (1H, d, J = 3.9 Hz), 4.04 (1H, m), 3.77 (1H, m), 3.65-3.60 (2H, m), 3.58 (1H, t, J = 9.3 Hz), 3.50 (1H, m), 3.40 (1H, m), 3.31 (1H, dd, J = 3.9, 9.3 Hz), 3.22 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.94 (3H, s)

(Embodiment 114)

(Example 114-1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based α-D-xylopyranoside (xylopyranoside)

(Example 114-2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based β-D-xylopyranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 2,3,4-tri-O-benzyl-D-xylopyranoside

2,3,4-Tri-O-benzyl-1-O-(2,2,2-trichloroethaneimido)-D-xylopyranoside (Liebigs Annalen der Chemie, 1984, 7, 1343-1357.) (541 mg) Compound Compound Compound Compound Compound Compound Compound Compound

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (15H, m), 4.90 (0.6H, d, J = 10.7 Hz), 4.86 (0.4H, d, J = 10.7 Hz), 4.84 - 4.82 (1.4) H, m), 4.79 (0.6H, d, J = 3.9 Hz), 4.74 - 4.68 (2H, m), 4.61 (0.6H, d, J = 12.2 Hz), 4.59 (0.6H, d, J = 11.7) Hz), 4.58 (0.4H, d, J = 11.7 Hz), 4.38 (0.4 H, d, J = 7.8 Hz), 4.01 (0.4H, m), 3.95 (0.6H, m), 3.88-3.84 (1H , m), 3.59-3.49 (2.6H, m), 3.43-3.38 (1.6H, m), 3.36-3.29 (1.4H, m), 3.27-3.22 (1H, m), 3.15 (0.4H, dd, J = 10.3, 11.7 Hz), 2.37 - 2.31 (1H, m), 1.93-1.07 (30H, m), 1.382 (1.8H, s), 1.377 (1.2H, s), 1.04 (0.6H, s), 1.03 (0.4H, s), 0.93 (1.8H, s), 0.91 (1.2H, s).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based α-D-xylopyranoside (α-glycoside) and (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a, 12a-di Methyl octahydronaphtho[2,1-f]quinolin-8-yl β-D-xylopyranoside (β-glycoside)

The compound (251 mg) obtained in the above step 1 was reacted by the same method as in the step 4 of Example 13 and purified by silica gel column chromatography (methanol / dichloromethane) to afford white solids. The title compound (α-glycoside) (32 mg) and the title compound (β-glycoside) (33 mg).

Α-glycoside; Rf=higher, low polarity: Example 114-1

MS (ESI) m / z: 550 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.83 (1H, d, J = 3.9 Hz), 4.02 (1H, m), 3.55-3.37 (6H, m), 3.30 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.89-1.11 (30H, m), 1.39 (3H, s), 0.94 (3H, s).

Β-glycoside; Rf=lower, high polarity: Example 114-2

MS (ESI) m / z: 550 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.24 (1H, d, J = 7.3 Hz), 4.04 (1H, m), 3.79 (1H, dd, J = 5.4, 11.2 Hz), 3.50 (1H, m) , 3.46-3.37 (2H, m), 3.24 (1H, t, J = 8.8 Hz), 3.18-3.06 (3H, m), 2.47 (1H, m), 1.88-1.11 (30H, m), 1.39 (3H) , s), 0.93 (3H, s).

(Example 115)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based β-L-glucopyranoside

(step 1)

2,3,4,6-tetra-O-benzylidene-1-O-(2,2,2-trichloroethaneimido)-β-L-glucopyranose

a solution of 2,3,4,6-tetra-O-benzimidyl-L-glucopyranose (Tetrahedron: Asymmetry, 1994, 5, 2109-2122.) (2.89 g) in dichloromethane (50 ml) Trichloroacetonitrile (2.45 ml) and cesium carbonate (316 mg) were sequentially added at room temperature, and stirred at the same temperature for 4 hours. The insoluble material was filtered through Celite, and the residue was evaporated to dryness crystals crystals 3.22g).

¹ H-NMR (CDCl ₃ ) δ: 8.61 (1H, s), 8.02-8.00 (2H, m), 7.94-7.91 (4H, m), 7.86-7.83 (2H, m), 7.54 (1H, m) , 7.51-7.46 (2H, m), 7.44-7.38 (3H, m), 7.36-7.32 (4H, m), 7.29-7.26 (2H, m), 6.8 1 (1H, d, J = 3.4 Hz), 6.25(1H,t,J=10.0Hz), 5.79(1H,t,J=10.0Hz),5.59(1H,dd,J=3.4,10.0Hz),4.64-4.60(2H,m),4.46(1H , dd, J = 5.1, 12.4 Hz).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 2,3,4,6-tetra-O-benzimidyl-β-L-glucopyranoside

The title compound (188 mg) was obtained as white crystals (yield: 129 mg). .

¹ H-NMR (CDCl ₃ ) δ: 8.02-7.99 (2H, m), 7.93-7.91 (2H, m), 7.89-7.87 (2H, m), 7.81-7.79 (2H, m), 7.54-7.24 ( 12H, m), 5.85 (1H, t, J = 9.8 Hz), 5.59 (1H, t, J = 9.8 Hz), 5.44 (1H, dd, J = 7.8, 9.8 Hz), 4.90 (1H, d, J = 7.8 Hz), 4.57 (1H, dd, J = 3.4, 12.2 Hz), 4.50 (1H, dd, J = 5.9, 12.2 Hz), 4.12 (1H, m), 4.05 (1H, m), 3.40 (1H) , m), 3.33 (1H, dt, J = 2.6, 12.3 Hz), 3.21 (1H, m), 2.33 (1H, m), 1.82-1.01 (30H, m), 1.35 (3H, s), 0.83 ( 1H, s), 0.78 (3H, s).

(Step 3)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based β-L-glucopyranoside

The title compound (92 mg) was obtained as white crystals.

MS (ESI) m/z: 580 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.32 (1H, d, J = 7.8 Hz), 4.10 (1H, m), 3.83 (1H, dd, J = 1.5, 12.0 Hz), 3.60 (1H, dd, J = 5.6, 12.0 Hz), 3.50 (1H, m), 3.40 (1H, m), 3.32-3.14 (4H, m), 3.09 (1H, dd, J = 7.8, 8.8 Hz), 2.47 (1H, m ), 1.91-1.11 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 116)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-glucopyranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-α-D-glucopyranoside (α-glycoside) and (4aS, 4bR, 6aR, 8S, 10aR ,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinolin-8-yl 3,4,6-tri -O-ethinyl-2-deoxy-2-fluoro-β-D-glucopyranoside (β-glycoside)

Using 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-1-O-(2,2,2-trichloroethaneimido)-α-D-glucosin An anthracite (Angewandte Chemie International Edition, 2010, 49, 8724-8728.) (163 mg) and the compound obtained in Step 3 of Example 1 (100 mg) were reacted in the same manner as in Step 1 of Example 108. The title compound (α-glycoside) (77 mg) and the title compound (β-glycoside) (59 mg) were obtained as a white solid.

Α-glycoside: Rf=higher, low polarity

¹ H-NMR (CDCl ₃ ) δ: 5.50 (1H, m), 5.17 (1H, d, J = 3.9 Hz), 4.95 (1H, t, J = 9.5 Hz), 4.43 (1H, m), 4.22 ( 1H,m),4.11-4.03(3H,m), 3.42(1H,m),3.33(1H,m),3.25(1H,m), 2.34(1H,m),2.04(3H,s),2.02 (3H, s), 2.01 (3H, s), 1.92-1.10 (31H, m), 1.38 (3H, s), 0.94 (3H, s).

Β-glycoside: Rf=lower, high polarity

¹ H-NMR (CDCl ₃ ) δ: 5.26 (1H, m), 4.98 (1H, dd, J = 9.3, 10.3 Hz), 4.62 (1H, dd, J = 2.9, 7.8 Hz), 4.23 (1H, dd , J = 5.4, 12.2 Hz), 4.22 (1H, m), 4.09 (1H, m), 4.07 (1H, dd, J = 2.4, 12.2 Hz), 3.67 (1H, m), 3.42 (1H, m) , 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.050 (3H, s), 2.046 (3H, s), 2.00 (3H, s), 1.94-1.10 (31H, m ), 1.38 (3H, s), 0.93 (3H, s).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-glucopyranoside

The title compound (39 mg) was obtained as a white solid.

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.08 (1H, d, J = 3.9 Hz), 4.14 (1H, m), 4.06 (1H, m), (1H, m), 3.81 (1H, m), 3.66-3.60(2H,m), 3.51(1H,m), 3.40(1H,m), 3.27(1H,m),3.16(1H,m),2.47(1H,m),1.90-1.09(30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 117)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-β-D-glucopyranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-β-D-glucopyranoside

The title compound (40 mg) was obtained as a white solid.

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.57 (1H, dd, J = 2.2, 7.6 Hz), 4.13 (1H, m), 3.87 (1H, m), 3.81 (1H, dd, J = 1.5, 11.7 Hz), 3.62 (1H, dd, J=5.4, 11.7 Hz), 3.57-3.48 (2H, m), 3.53 (1H, m), 3.30-3.22 (2H, m), 3.17 (1H, m), 2.47 (1H, m), 1.90-1.10 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 118)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-galactofuranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-α-D-galactofuranoside (α-glycoside) and (4aS, 4bR, 6aR, 8S, 10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinolin-8-yl 3,4,6- Tri-O-ethinyl-2-deoxy-2-fluoro-β-D-galactofuranoside (β-glycoside)

Use of 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-1-O-(2,2,2-trichloroethaneimido)-α-D-half Piperanose (Chemistry-A European) Journal (2012, 18, 8208-8215.) (163 mg) Compound (100 mg) obtained in Step 3 of Example 1 was reacted in the same manner as in Step 1 of Example 108, using a silica gel column chromatography [ The title compound (α-glycoside) (18 mg) and the title compound (β-glycoside) (96 mg) were obtained as a white solid.

Α-glycoside: Rf=higher, low polarity

¹ H-NMR (CDCl ₃ ) δ: 5.43 (1H, m), 5.35 (1H, m), 5.21. (1H, d, J = 3.4 Hz), 4.70 (1H, m), 4.28 (1H, m), 4.09-4.01 (3H, m), 3.41 (1H, m), 3.32 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.11 (3H, s), 2.03 (3H, s) , 2.00 (3H, s), 1.91-1.11 (31H, m), 1.38 (3H, s), 0.93 (3H, s).

Β-glycoside: Rf=lower, high polarity

¹ H-NMR (CDCl ₃ ) δ: 5.37 (1H, m), 5.06 (1H, m), 4.61 (1H, dd, J = 3.9, 7.8 Hz), 4.43 (1H, m), 4.14 (1H, dd , J=6.3, 11.2 Hz), 4.11 (1H, m), 4.07 (1H, dd, J=6.8, 11.2 Hz), 3.88 (1H, m), 3.41 (1H, m), 3.33 (1H, m) , 3.25 (1H, m), 2.34 (1H, m), 2.11 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 1.97-1.10 (31H, m), 1.38 (3H, s ), 0.93 (3H, s).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-galactofuranoside

The title compound (11 mg) was obtained as a white solid.

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.10 (1H, d, J = 3.9 Hz), 4.52 (1H, m), 4.05 (1H, m), 3.94-3.86 (3H, m), 3.68 (1H, Dd, J = 5.4, 10.5 Hz), 3.65 (1H, dd, J = 4.6, 10.5 Hz), 3.50 (1H, m), 3.40 (1H, m), 3.16 (1H, m), 2.47 (1H, m) ), 1.89-1.10 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 119)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-β-D-galactofuranoside

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-β-D-galactofuranoside

The title compound (77 mg) was obtained as a white solid.

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.53 (1H, dd, J = 3.4, 7.8 Hz), 4.21 (1H, m), 4.13 (1H, m), 3.84 (1H, t, J = 2.9 Hz) , 3.70 (1H, dd, J = 6.3, 11.2 Hz), 3.68 (1H, dd, J = 5.4, 11.2 Hz), 3.65 (1H, m), 3.53-3.48 (2H, m), 3.40 (1H, m ), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.93 (3H, s).

(Example 120)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-mannopyranoside (mannopyranoside)

(step 1)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-α-D-mannopyranoside

Using 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-1-O-(2,2,2-trichloroethaneimido)-D-mannopyrose (Angewandte Chemie International Edition, 2010, 49, 8724-8728.) (380 mg) of the compound (200 mg) obtained in Step 3 of Example 1 was obtained as a white solid. The title compound (α-glycoside) (351 mg).

¹ H-NMR (CDCl ₃ ) δ: 5.27 (1H, m), 5.21 (1H, m), 5.10 (1H, dd, J = 1.5, 7.3 Hz), 4.65 (1H, m), 4.22 (1H, dd , J=5.1, 12.1 Hz), 4.14-3.99 (3H, m), 3.42 (1H, m), 3.33 (1H, m), 3.25 (1H, m), 2.34 (1H, m), 2.07 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 1.87-1.11 (31H, m), 1.38 (3H, s), 0.92 (3H, s).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-mannopyranoside

The title compound (198 mg) was obtained as a white solid.

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.04 (1H, dd, J = 1.5, 7.8 Hz), 4.48 (1H, m), 4.10 (1H, m), 3.82 (1H, dd, J = 2.0, 11.7 Hz), 3.69 (1H, m), 3.65 (1H, dd, J = 5.9, 11.7 Hz), 3.59 (1H, m), 3.54 (1H, t, J = 9.0 Hz), 3.50 (1H, m), 3.40 (1H, m), 3.16 (1H, m), 2.47 (1H, m), 1.90-1.11 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Embodiment 121)

(Example 121-1)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-β-D-glucopyranoside (β-glycoside)

(Example 121-2)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-glucopyranoside (α-glycoside)

(step 1)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-based 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-D-glucopyranoside

Using 3,4,6-tri-O-ethinyl-2-deoxy-2-fluoro-1-O-(2,2,2-trichloroethaneimido)-α-D-glucosin The saccharide (154 mg) and the compound obtained in the step 1 of Example 5 (95 mg) were obtained in the same manner as in Step 1 of Example 108 to obtain a mixture of isomers (α-glycoside: β-glycoside = 4:6) The title compound (156 mg).

MS (ESI) m/z: 708 (M+H) ⁺

_{^{1 H-NMR (CDCl 3)}} δ: 5.45 (0.4H, m), 5.28 (0.6H, m), 5.23 (0.4H, d, J = 3.9Hz), 4.98 (0.6H, dd, J = 9.3, 9.8 Hz), 4.97 (0.4H, t, J = 9.8 Hz), 4.61 (0.6H, dd, J = 2.9, 7.8 Hz), 4.49 (0.4H, m), 4.28-4.04 (3.6H, m), 3.99 (0.4H, m), 3.67 (0.6H, m), 3.65 (0.6H, brs), 3.58 (0.4H, brs), 3.42-3.37 (1H, m), 3.36-3.28 (1H, m), 3.26-3.18(1H,m), 2.38-2.31(1H,m),2.06-2.00(9H,m),1.87-1.00(30H,m),1.39(1.2H,s),1.38(1.8H,s ), 0.88 (1.2H, s), 0.86 (1.8H, s).

(Step 2)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-β-D-glucopyranoside (β-glycoside)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-1-(cyclohexylcarbonyl)-6a-hydroxy-10a,12a-dimethyloctadeconaphtho[2,1-f]quinoline- 8-yl 2-deoxy-2-fluoro-α-D-glucopyranoside (α-glycoside)

The compound (156 mg) obtained in the above step 1 was reacted by the same method as in the step 1 of Example 5, and separated and purified by silica gel column chromatography (methanol / dichloromethane) to give white solids. The title compound (β-glycoside) (45 mg) and the title compound (α-glycoside) (32 mg).

Β-glycoside; Rf=higher, low polarity: Example 121-1

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.64 (1H, dd, J = 2.4, 7.8 Hz), 4.23 (1H, m), 3.91 (1H, m), 3.82 (1H, dd, J = 1.7, 12.0) Hz), 3.63 (1H, dd, J=4.9, 12.0 Hz), 3.58 (1H, m), 3.50 (1H, m), 3.41 (1H, m), 3.33-3.25 (2H, m), 3.18 (1H) , m), 2.48 (1H, m), 1.92-1.07 (30H, m), 1.40 (3H, s), 0.92 (3H, s).

Α-glycoside; Rf=lower, high polarity: Example 121-2

MS (ESI) m/z: 582 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.17 (1H, d, J = 3.9 Hz), 4.26 (1H, m), 4.15 (1H, m), 3.81 (1H, m), 3.77 (1H, dd, J = 2.0, 12.0 Hz), 3.63 (1H, dd, J = 5.6, 12.0 Hz), 3.57 (1H, m), 3.50 (1H, m), 3.41 (1H, m), 3.30 (1H, m), 3.18 (1H, m), 2.48 (1H, m), 1.89-1.07 (30H, m), 1.39 (3H, s), 0.92 (3H, s).

(Example 122)

[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-8,10a,12a-trimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS,6aS,6bR,9S,10aR,11aS,12aR,12bS)-9-hydroxy-4a,6b-dimethyltetrahydrogen-1H-oxirane[4,4a]naphtho[2,1 -f] quinoline-4(4aH)-benzyl formate

The title compound (1.04 g) was obtained from m.

MS (ESI) m/z: 440 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.07 (2H, s), 3.91 (1H, m), 3.75 (1H, m), 3.33 (1H, m), 3.00 (1H) m), 2.93 (1H, d, J = 4.3 Hz), 2.09-1.06 (19H, m), 1.30 (3H, s), 1.02 (3H, s).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)- Benzyl formate

The title compound (396 mg) was obtained from m.

MS (ESI) m/z: 442 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.30 (5H, m), 5.08 (2H, s), 4.09 (1H, m), 3.78 (1H, m), 3.34 (1H, m), 3.05 (1H) , m), 1.87-0.95 (28H, m).

(Step 3)

(4aS, 4bR, 6aR, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-8-oxohexadecane[2,1-f]quinoline-1(2H)- Benzyl formate

4-methyl-N-oxidation in a solution of the compound (1.00 g) obtained in the above step 2 in dichloromethane (10 ml) The morpholine (398 mg) and tetrapropylammonium perruthenate (79.6 mg) were stirred at room temperature for 1 hour. The insoluble material was filtered through Celite and washed with dichloromethane. The filtrate was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m / z: 440 (M+H) ⁺ .

(Step 4)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-8,10a,12a-trimethylhexadenaphtho[2,1-f]quinoline-1 (2H )-benzyl formate

Anhydrous cesium chloride (126 mg) was suspended in tetrahydrofuran (5 ml) and stirred at room temperature for 2 hr under nitrogen. The reaction solution was cooled to 0 ° C, and methyl magnesium bromide (0.96 M tetrahydrofuran solution, 0.53 ml) was added, and the mixture was stirred at the same temperature for 1.5 hours, and then added to the compound (150 mg) in tetrahydrofuran (5 ml) obtained in the above step 3. The mixture was stirred at the same temperature for 1 hour, and then stirred while warming to room temperature while stirring overnight. Further, methylmagnesium bromide (0.96 M tetrahydrofuran solution, 5.30 ml) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was evaporated. The residue obtained by EtOAc (EtOAc:EtOAc)

MS (ESI) m/z: 456 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.30 (5H, m), 5.08 (2H, s), 3.79-3.75 (1H, m), 3.37-3.32 (1H, m), 3.06-3.02 (1H, m), 2.06-0.86 (31H, m).

(Step 5)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-8,10a,12a-trimethylhexadecaquino[2,1-f]quinoline-6a,8(2H)-diol

The title compound (63.5 mg) was obtained.

MS (ESI) m / z: 322 (M+H) ⁺ .

(Step 6)

[(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-8,10a,12a-trimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (71.3) was obtained as a white solid. m. Compound Compound Compound Compound Compound Compound Compound Compound Mg).

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.04 (1H, m), 3.97 (1H, m), 3.55 (1H, m), 3.44 (1H, m), 3.33 - 3.29 (2H, m), 2.06-0.86 (28H, m), 1.42 (3H, s), 1.23 (3H, s), 0.90 (3H, s).

(Example 123)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-8-(hydroxymethyl)-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyltetrahydrol-2H-spiro[naphtho[2,1-f]quinoline-8,2 '-Ethylene oxide]-1(4bH)-benzyl formate

Dimethyl hydrazine (3 ml) was added dropwise to trimethylsulfonium iodide (300 mg) and sodium hydride (60 wt%, 54.6 mg) under a nitrogen atmosphere, and stirred at room temperature for 30 minutes. A tetrahydrofuran solution (6 ml) of the compound (400 mg) obtained in Step 3 of Example 122 was added to the mixture, and the mixture was stirred for 1 hour. After adding water to the reaction mixture and extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.29 (5H, m), 5.08 (2H, s), 3.80-3.78 (1H, m), 3.35-3.28 (1H, m), 3.05-3.02 (1H, m), 2.77 (1H, s), 2.61-2.60 (1H, m), 2.58-2.57 (1H, m), 2.32-2.28 (1H, m), 2.15-2.08 (1H, m), 1.86-0.99 ( 18H, m), 1.36 (3H, s), 0.95 (3H, s).

(Step 2)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-8-(hydroxymethyl)-10a,12a-dimethylhexadecaquino[2,1-f] Quinoline-1(2H)-benzyl formate

The compound (39.0 mg) obtained in the above step 1 was suspended in a mixture of 2-methoxyethanol (2.5 ml)-water (0.25 ml), and sodium acetate (141 mg) was added and stirred at room temperature for one hour. The mixture was stirred at 50 ° C for 2 hours and further at 80 ° C for 16 hours. After cooling the reaction mixture to room temperature, water was added and extracted with dichloromethane:methanol (10:1). The organic layer was dried over anhydrous sodium sulfate.

(Step 3)

(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS)-8-[(acetamidooxy)methyl]-6a,8-dihydroxy-10a,12a-dimethylhexadecaphthalene[ 2,1-f]quinoline-1(2H)-benzyl formate

To a solution of the compound (39.8 mg) in pyridine (2 ml), m. After the reaction liquid was concentrated under reduced pressure, toluene was added and then concentrated to remove pyridine. The obtained residue was purified to silicagel elut elut elut elut elut

MS (ESI) m / z: 514 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.30 (5H, m), 5.08 (2H, s), 3.94-3.90 (2H, m), 3.80-3.76 (1H, m), 3.34-3.30 (1H, m), 3.07-3.03 (1H, m), 2.11 (3H, s), 1.84-1.10 (22H, m), 1.35 (3H, s), 0.87 (3H, s).

(Step 4)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinolin-8-yl] Methyl acetate

The title compound (51.6 mg) was obtained.

MS (ESI) m / z: 380 (M+H) ⁺ .

(Step 5)

{(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-yl Carbonyl] octahydronaphtho[2,1-f]quinolin-8-yl}methyl acetate

The title compound (83.5 mg) was obtained from the title compound (33.5 mg).

MS (ESI) m / z: 492 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.12-4.10 (1H, m), 3.98-3.97 (1H, m), 3.87-3.84 (2H, m), 3.60-3.57 (1H, m), 3.50-3.48 ( 1H, m), 3.42-3.39 (1H, m), 3.22-3.20 (1H, m), 2.06 (3H, s), 1.88-1.14 (28H, m), 1.44 (3H, s), 0.91 (3H, s).

(Step 6)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-8-(hydroxymethyl)-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (43.6 mg) was obtained as a white solid.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.11-4.10 (1H, m), 3.98-3.96 (1H, m), 3.61-3.57 (1H, m), 3.50-3.48 (1H, m), 3.39-3.36 ( 1H, m), 3.27-3.25 (2H, m), 3.22-3.19 (1H, m), 1, 88-1.14 (29H, m), 1.44 (3H, s), 0.90 (3H, s).

(Example 124)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-8-[(methylsulfonyl)methyl]hexadecaphthalene[ 2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS, 4bR, 6aR, 8R, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-10a, 12a-dimethyl-8-[(methylindolyl)methyl]hexadecaphthalene [2, 1-f]quinoline-1(2H)-benzyl formate

Sodium methoxide (30.3 mg) was added to a solution of the compound (65.3 mg. Further, sodium methoxide (30.3 mg) was added, and the mixture was stirred at 50 ° C for 2 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate and washed with saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the filtrate was filtered. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.29 (5H, m), 5.08 (2H, s), 4.15 (1H, brs), 3.80-3.77 (1H, m), 3.34-3.30 (2H, m) , 3.05-3.02 (1H, m), 2.59-2.58 (2H, m), 2.18 (3H, s), 1.83-1.81 (1H, m), 1.69-1.09 (19H, m), 1.35 (3H, s) , 0.86 (3H, s).

(Step 2)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-8-[(methylsulfonyl)methyl]hexadecaphthalene[2 , 1-f] quinoline-1(2H)-benzyl formate

To a solution of the compound (45.8 mg), m. m. The reaction solution was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen sulfate. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

MS (ESI) m/z: 534 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.33 (5H, m), 5.08 (2H, s), 3.80-3.77 (1H, m), 3.34-3.32 (1H, m), 3.20-3.03 (3H, m), 3.06 (3H, s), 1.98-1.15 (22H, m), 1.35 (3H, s), 0.89 (3H, s).

(Step 3)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-10a,12a-dimethyl-8-[(methylsulfonyl)methyl]hexadecaquino[2,1-f]quinoline -6a,8(2H)-diol

The title compound (47.7 mg) was obtained.

MS (ESI) m / z: 400 (M+H) ⁺ .

(Step 4)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-8-[(methylsulfonyl)methyl]hexadecaphthalene[ 2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (45.8 mg) was obtained from the title compound (3.

MS (ESI) m/z: 512 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.95 (1H, brs), 4.06-3.98 (2H, m), 3.54-3.42 (2H, m), 3.33-3.28 (2H, m), 3.18-3.09 (2H, m), 3.05 (3H, s), 3.05-3.01 (1H, m), 1.97-1.12 (26H, m), 1.43 (3H, s), 0.89 (3H, s).

(Embodiment 125)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-methoxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-8-methoxy-10a, 12a-dimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-benzyl formate

The title compound (2.99 g) was obtained from m.

MS (ESI) m/z: 456 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.22 (5H, m), 5.13-5.03 (2H, m), 3.82-3.73 (1H, m), 3.56-3.55 (1H, m), 3.41-3.28 ( 4H, m), 3.09-3.00 (1H, m), 2.00-1.08 (24H, m), 0.98-0.90 (3H, m).

(Step 2)

(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-methoxy-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-6a(2H)-ol

The title compound (1.65 g) was obtained as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.71-3.58 (1H, m), 3.41-3.25 (4H, m), 2.92-2.82 (1H, m), 2.75-2.65 (1H, m), 1.97-1.86 (1H, m), 1.77-0.99 (22H, m), 0.95 (3H, s).

(Step 3)

[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-methoxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (78 mg) was obtained as a white solid. .

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.06-3.94 (2H, m), 3.63-3.52 (2H, m), 3.47-3.40 (1H, m), 3.37-3.25 (5H, m), 1.99-1.06 ( 30H, m), 0.93 (3H, s).

(Example 126)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-methoxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

cis-5-fluorotetrahydro-2H-pyran-2-carboxylic acid benzyl ester

The title compound (3.73 g) was obtained as a brown oil.

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.27 (5H, m), 5.22 (2H, s), 4.60 (1H, m), 4.23 (1H, m), 4.07 (1H, m), 3.64 (1H) m), 2.18 (1H, m), 2.06 (1H, m), 1.94-1.72 (2H, m).

(Step 2)

(2S,5S)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid benzyl ester and (2R,5R)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid benzyl ester

The compound (5.76 g) obtained in the above step 1 was optically isolated under the following conditions to give (2S,5S)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid benzyl as a colorless oil. Ester (isomer A) (2.36 g) and (2R,5R)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid benzyl ester (isomer B) (2.31 g).

CHIRALPAK (AY-H) 20×250mm

Eluent: hexane / ethanol = 7:3

Flow rate: 20ml/min

Detection wavelength: 254nM

Residence time: Isomer A (2S, 5S) body: 9.7 min, isomer B (2R, 5R) body: 14.0 min.

(Step 3)

(2R,5R)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid

The title compound (431 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 4.64 (1H, dd, J = 2.0, 46.4 Hz), 4.28 (1H, m), 4.03 (1H, dd, J = 3.9, 10.7 Hz), 3.70 (1H, dd , J = 13.2, 38.1 Hz), 2.26 (1H, m), 2.07-1.95 (2H, m), 1.83 (1H, m).

(Step 4)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aR,8S,10aR,10bS,12aS)-6a-hydroxy-8-methoxy-10a , 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (114 mg) was obtained from m. .

¹ H-NMR (CDCl ₃ ) δ: 4.59 (1H, m), 4.13 (1H, m), 4.00 (1H, m), 3.65-3.49 (3H, m), 3.41-3.31 (4H, m), 3.27 (1H, m), 2.27-2.12 (2H, m), 1.95 (1H, m), 1.88-1.13 (24H, m), 1.10 (1H, s), 0.94 (3H, s).

(Example 127)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-10a, 12a-dimethyl-8-[2-(methylsulfonyl)ethoxy] Hexahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-(2-tertiary butoxy-2-oxoethoxyethoxy)-4a,6a-dimethyltetrahydrol-1aH - oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

Sodium hydride (60 wt%, 0.910 g) and butyl bromoacetate (13.3 ml) were added to a solution of the compound (4.00 g) obtained from hour. After the reaction mixture was ice-cooled, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.09-5.03 (2H, m), 4.07 (2H, s), 3.92 (1H, m), 3.75 (1H, m), 3.32 (1H, m), 3.13 (1H, d, J = 3.4 Hz), 3.03 (1H, m), 2.05 (1H, m), 1.93 (1H, m), 1.82 (1H, m), 1.73-1.62 ( 2H, m), 1.56-0.86 (13H, m), 1.45 (9H, s), 1.33 (3H, s), 0.97 (3H, s).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-(2-tertiary butoxy-2-oxoethoxyethoxy)-6a,7-dihydroxy-10a,12a-di Methyl hexadecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (2.09 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.08 (2H, s), 4.20 (1H, d, J = 16.6 Hz), 3.92 (1H, d, J = 16.6 Hz), 3.81-3.75 (2H, m), 3.57 (1H, brd, J = 2.9 Hz), 3.42 (1H, brs), 3.34 (1H, m), 3.03 (1H, m), 2.25 (1H, m), 1.86 - 1.15 (17H, m), 1.47 (9H, s), 1.35 (3H, s), 1.14 (3H, s), 1.12 (1H, s).

(Step 3)

{[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinoline-8 -yl]oxy}acetic acid tert-butyl acrylate

The title compound (1.6 g) was obtained from m.

MS (ESI) m / z: 438 (M+H) ⁺ .

(Step 4)

({(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran- 2-terminated carbonyl] octahydronaphtho[2,1-f]quinolin-8-yl}oxy)acetic acid tert-butyl butyl ester

The title compound (1.34) was obtained as a white solid (m.m. g).

MS (ESI) m / z: 550 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.16 (1H, m), 4.01 (1H, m), 3.95-3.87 (2H, m), 3.76 (1H, m), 3.56-3.51 (2H, m), 3.41 (1H,m), 3.34(1H,m),3.32-3.22(2H,m), 2.23(1H,m),1.91-1.13(23H,m),1.44(9H,s),1.40(3H,s ).1.11(3H,s), 1.06(1H,s).

(Step 5)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-8-(2-hydroxyethoxy)-10a,12a-dimethylhexadecaphthalene[ 2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

A solution of the compound (400 mg) in tetrahydrofuran (15 ml) obtained in the above step 4 was cooled to 0 ° C, and lithium borohydride (47.6 mg) was added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction liquid, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc m.

MS (ESI) m/z: 480 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.01 (1H, m), 3.94 (1H, m), 3.80 (1H, m), 3.75-3.71 (2H, m), 3.67-3.61 (3H, m), 3.54 (1H, m), 3.41 (1H, m), 3.33-3.23 (2H, m), 2.45 (1H, s), 2.21 (1H, m), 1.93-1.14 (24H, m), 1.41 (3H, s ) 1.10 (3H, s), 1.05 (1H, s).

(Step 6)

2-({(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyridyl喃-2-ylcarbonyl]octadecylnaphtho[2,1-f]quinolin-8-yl}oxy)ethylmethanesulfonate

To a solution of the compound (436 mg) obtained from m. m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m hour. After the reaction mixture was diluted with methylene chloride, the organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc.

¹ H-NMR (CDCl ₃ ) δ: 4.37-4.33 (2H, m), 4.00 (1H, m), 3.94 (1H, m), 3.84-3.75 (3H, m), 3.63 (1H, m), 3.54 (1H,m), 3.41(1H,m),3.33-3.22(2H,m), 2.36(1H,s),2.21(1H,m),1.90-1.13(26H,m),1.40(3H,s ), 1.09 (3H, s). 1.09 (1H, m).

(Step 7)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7-dihydroxy-10a, 12a-dimethyl-8-[2-(methylsulfonyl)ethoxy] Hexahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

Add sodium methanesulfinate (0.0549 g) and potassium iodide (0.0893 g) to a solution of the compound (100 mg) of N,N-dimethylformamide (1.8 ml) obtained in the above step 6 at 120 ° C Stir for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc m.

¹ H-NMR (CDCl ₃ ) δ: 4.03-3.98 (2H, m), 3.94 (1H, m), 3.87-3.79 (2H, m), 3.71 (1H, m), 3.54 (1H, m), 3.41 (1H, m), 3.35-3.24 (3H, m), 3.14 (1H, m), 3.02 (3H, s), 2.22 (1H, m), 1.89-1.05 (25H, m), 1.40 (3H, s ), 1.09 (3H, s).

(Embodiment 128)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyl-8-[2-(1H-1,2,4-triazole) -1-yl)ethoxy]hexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyl-8-[2-(1H-1,2,4-triazole) -1-yl)ethoxy]hexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

Sodium hydride (60 wt%, 0.0287 g) was added to a solution of 1,2,4-triazole (0.0495 g) in N,N-dimethylformamide (1.8 ml), and the mixture was stirred for 10 minutes. The compound (100 mg) obtained in Example 127 Step 6 was stirred at room temperature for 18 hr. After adding water to the reaction liquid, it was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAcqqqqqqqq

¹ H-NMR (CDCl ₃ ) δ: 8.11 (1H, s), 7.94 (1H, s), 4.38-4.28 (2H, m), 4.01 (1H, m), 3.96-3.84 (3H, m), 3.71 (1H, m), 3.57-3.50 (2H, m), 3.41 (1H, m), 3.32-3.21 (2H, m), 2.33 (1H, s), 2.18 (1H, m), 1.92-1.11 (23H , m), 1.40 (3H, s). 1.06 (3H, s), 1.04 (1H, s).

(Example 129)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (3.42 g) was obtained from m.

MS (ESI) m/z: 554 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.09-5.03 (2H, m), 4.27 (1H, m), 4.04 (1H, dd, J = 8.3, 6.3 Hz), 3.81 -3.78 (2H, m), 3.75 (1H, m), 3.67 (1H, dd, J = 9.8, 4.9 Hz), 3.52 (1H, dd, J = 10.0, 6.1 Hz), 3.32 (1H, m), 3.09 (1H, d, J = 2.9 Hz), 3.03 (1H, m), 2.07-0.87 (18H, m), 1.39 (3H, s), 1.33 (6H, s), 0.96 (3H, s).

(Step 2)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecahydro[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (1.79 g) was obtained as a white solid.

MS (ESI) m / z: 532 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.05 (2H, s), 3.86 (1H, brs), 3.82-3.69 (3H, m), 3.67-3.64 (1H, m) , 3.64-3.52 (3H, m), 3.36-3, 28 (1H, m), 3.02-2.99 (1H, m), 2.78-2.63 (1H, m), 2.22-2.15 (2H, m), 1.82- 1.07 (16H, m), 1.32 (3H, s), 1.09 (3H, s).

(Step 3)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-6a,7-dihydroxy-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-benzyl carboxylate

The title compound (2.0 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.89 (1H, m), 3.83 (1H, m), 3.80-3.71 (2H, m), 3.69 (1H, d, J = 3.4 Hz), 3.66-3.55 (3H, m), 3.34 (1H, m), 3.03 (1H, m), 2.81 (1H, brd, J = 2.9 Hz), 2.66 (1H, Brs), 2.25-2.17 (2H, m), 1.87-1.14 (21H, m), 1.34 (3H, s), 1.16 (1H, s), 1.12 (3H, s).

(Step 4)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-6a,7(2H)-diol

The title compound (1.47 g) was obtained from m.

(Step 5)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }}-6a,7-dihydroxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyridyl Methyl-2-yl]ketone

Add a solution of the compound (0.098 g) in dichloromethane (2 ml), m. Stir for 1 hour. After the reaction mixture was concentrated under reduced pressure, toluene (2 ml), EtOAc (EtOAc) The reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc m.

MS (ESI) m / z: 550 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 4.06-3.98 (2H, m), 3.94 (1H, dd, J = 10.7, 2.4 Hz), 3.78 (1H, m), 3.67-3.64 (2H,m),3.57-3.49(3H,m),3.44-3.38(1H,m),3.34-3.22(2H,m),2.68(1H,s),2.37-1.06(24H,m),1.40 (6H, s), 1.33 (3H, s), 1.09 (3H, s), 1.05 (1H, s).

(Step 6)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.115 g) was obtained as a white solid.

MS (ESI) m / z: 510 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.97 (1H, dd, J = 2.0, 10.7 Hz), 3.89 (1H, m), 3.82 (1H, m), 3.73 (1H, m ), 3.68 (1H, d, J = 3.4 Hz), 3.65-3.54 (4H, m), 3.49 (1H, d, J = 4.9 Hz), 3.43 (1H, m), 3.35-3.25 (2H, m) , 2.80 (1H, br), 2.63 (1H, brs), 2.26-2.17 (2H, m), 1.91 (1H, m), 1.86-1.17 (21H, m), 1.43 (3H, s), 1.14 (1H) , s), 1.12 (3H, s).

(Embodiment 130)

{(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a,8-dihydroxy-11a,13a-dimethyl Octadecahydro-1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(1aS, 2S, 4aR, 4bS, 6aS, 11aS, 11bR, 13aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-4a,6a-dimethylhexadecahydroepoxide [8,8a]phenanthro[2,1-b]indole-7(1aH)-benzyl formate

The compound obtained in Step 7 of Example 86 (3.09 g) and (R)-2,2-dimethyl-1,3-dioxolan-4-methanol p-toluenesulfonate (9.76 g) The title compound (3.91 g) was obtained as a colorless oil.

MS (ESI) m / z: 568 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.26 (5H, m), 5.07 (2H, s), 4.27 (1H, m), 4.04 (1H, dd, J = 8.3, 6.3 Hz), 3.91 (1H) , brs), 3.81-3.78 (2H, m), 3.67 (1H, dd, J = 9.8, 4.9 Hz), 3.52 (1H, dd, J = 9.8, 5.9 Hz), 3.17 (1H, m), 3.09 ( 1H, d, J = 2.9 Hz), 2.38-0.86 (21H, m), 1.40 (3H, s), 1.33 (6H, s), 0.96 (3H, s).

(Step 2)

(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a,8-dihydroxy-11a,13a-dimethyl octahydro-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (1.53 g) was obtained as a white solid.

MS (ESI) m/z: 546 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.06 (2H, brs), 3.96-3.84 (2H, m), 3.82 (1H, m), 3.71 (1H, m), 3.67 (1H, d, J = 3.9 Hz), 3.63 - 3.53 (3H, m), 3.20 (1H, m), 2.63 (1H, brs), 2.52 (1H, br), 2.39 (1H, br), 2.22 ( 1H, m), 2.02 (1H, m), 1.91 (1H, m), 1.70-1.08 (22H, m), 1.08 (3H, s).

(Step 3)

(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-7a,8-Dihydroxy-11a, 13a-dimethyloctadecyl-1H-phenanthroline [2,1-b]indole-1-carboxylic acid benzyl ester

The title compound (1.98 g, containing an impurity) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.06 (2H, s), 4.26 (1H, m), 4.04 (1H, dd, J = 8.3, 6.8 Hz), 3.89 (1H) , brs), 3.79 (1H, m), 3.67-3.64 (2H, m), 3.59-3.48 (2H, m), 3.20 (1H, m), 2.68 (1H, s), 2.38 (1H, brs), 2.24 (1H, m), 1.90 (1H, m), 1.72-1.05 (19H, m), 1.40 (6H, s), 1.33 (3H, s), 1.09 (3H, s).

(Step 4)

(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-11a,13a-dimethyloctadecahydro-7aH-phenanthro[2,1-b]indole-7a,8-diol

The title compound (1.26 g) was obtained from m.

(Step 5)

[(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy {-7a,8-dihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl][(2R)-tetrahydro-2H-pyridyl Methyl-2-yl]ketone

The title compound (0.124) was obtained as a white solid. m. Compound Compound Compound Compound Compound Compound Compound Compound g).

MS (ESI) m/z: 564 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 4.04 (1H, dd, J = 8.3, 6.8 Hz), 3.97-3.92 (2H, m), 3.78 (1H, m), 3.68-3.63 (2H, m), 3.58-3.49 (2H, m), 3.45-3.30 (3H, m), 2.68 (1H, m), 2.62 (1H, m), 2.23 (1H, m), 2.15 (1H, s ), 1.92-1.04 (25H, m), 1.52 (3H, s), 1.41 (3H, s), 1.33 (3H, s), 1.09 (3H, s).

(Step 6)

{(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a,8-dihydroxy-11a,13a-dimethyl Octadecahydro-1H-phenanthro[2,1-b]indol-1-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.071 g) was obtained as a white solid.

MS (ESI) m / z: 524 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.98-3.92 (2H, m), 3.88 (1H, m), 3.81 (1H, m), 3.71 (1H, dd, J = 11.2, 3.9 Hz), 3.66 (1H) , d, J = 3.4 Hz), 3.63 - 3.54 (3H, m), 3.44 - 3.39 (2H, m), 3.34 (1H, m), 2.62 (1H, m), 2.22 (1H, m), 1.93 0.84 (29H, m), 1.52 (3H, s), 1.09 (3H, s).

(Example 131)

{(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1,11a-dihydroxy-4a, 6a-Dimethyloctadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran-2-yl]- ketone

(step 1)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR)-2-hydroxy-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,8, 8a,9,9a,9b,9c,10-hexadecahydro-7H-cyclopropane[c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (2.11 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.38 (1H, m), 4.33 (1H, dd, J = 2.9, 13.7 Hz), 3.53 (1H, m), 3.39 (1H) ,d,J=13.7Hz), 2.60(1H,m), 2.38-2.30(2H,m), 2.23(1H,m),1.91-1.23(13H,m),1.44(3H,s),1.13- 0.84 (4H, m), 0.99 (3H, s), 0.45 (1H, m).

(Step 2)

(4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR)-4a, 6a-dimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,8,8a,9 , 9a, 9b, 9c, 10, 11-hexadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (1.97 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.26 (5H, m), 5.75 (1H, s), 5.10 (1H, d, J = 12.2 Hz), 5.06 (1H, d, J = 12.2 Hz), 4.32 (1H, dd, J=2, 4, 13.7 Hz), 3.39 (1H, d, J = 13.7 Hz), 2.68 (1H, m), 2.49-2.25 (5H, m), 2.02 (1H, m) , 1.88 (1H, d, J = 10.7 Hz), 1.80 (1H, m), 1.73-1.58 (2H, m), 1.47 (3H, s), 1.41-1.25 (2H, m), 1.20-1.01 (3H m), 1.17 (3H, s), 0.97 (1H, m), 0.88 (1H, m), 0.48 (1H, m).

(Step 3)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,8,8a, 9,9a,9b,9c,10,11-hexadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (1.98 g) was obtained from m.

(Step 4)

(1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS)-1-hydroxy-3a,5a-dimethylhexadehydrocyclopropane [c]oxirane [4a,5] Naphtho[2,1-f]quinoline-6(2H)-formic acid benzyl ester

The title compound (1.73 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.2 Hz), 5.06 (1H, d, J = 12.2 Hz), 4.32 (1H, dd, J = 2.9, 13.7 Hz), 4.07 (1H, m), 3.39 (1H, d, J = 13.7 Hz), 3.18 (1H, d, J = 4.4 Hz), 2.63 (1H, m), 2.29-2.11 (2H , m), 1.90 (1H, d, J = 11.2 Hz), 1.71 (1H, m), 1.58-1.48 (2H, m), 1.46-0.94 (11H, m), 1.44 (3H, s), 1.02 ( 3H, s), 0.87 (1H, m), 0.46 (1H, m).

(Step 5)

(1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl Methoxy}-3a,5a-dimethylhexadehydrocyclopropane [c]oxirane [4a,5]naphtho[2,1-f]quinoline-6(2H)-formic acid benzyl ester

The compound (1.00 g) obtained in the above step 4 and (R)-2,2-dimethyl-1,3-dioxolan-4-methanol p-toluenesulfonate (3.17 g), and Tetra-n-butylammonium iodide (0.0818 g) was obtained from the title compound (0.522 g).

MS (ESI) m / z: 566 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.09-5.01 (2H, m), 4.32-4.24 (2H, m), 4.07-4.02 (1H, m), 3.84-3.78 ( 2H, m), 3.70-3.65 (1H, m), 3.55-3.50 (1H, m), 3.36 (1H, d, J = 13.2 Hz), 3.10 (1H, d, J = 2.9 Hz), 2.61-2.56 (1H, m), 2.19-2.08 (2H, m), 1.85 (1H, d, J = 10.7 Hz), 1.67-0.88 (13H, m), 1.40 (3H, s), 1.40 (3H, s), 1.34 (3H, s), 0.98 (3H, s). 0.46-0.40 (1H, m), 0.44-0.42 (1H, m).

(Step 6)

(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1,11a-dihydroxy-4a,6a - dimethyl octadecyl-7H-cyclopropane [c] naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (502 mg) was obtained from m.

MS (ESI) m / z: 544 (M+H) ⁺ .

(Step 7)

(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl Methoxy}-1,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (0.226 g) was obtained as a white solid.

MS (ESI) m/z: 584 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.09-5.00 (2H, m), 4.32-4.23 (2H, m), 4.06-4.02 (1H, m), 3.81-3.77 ( 1H, m), 3.67 - 3.64 (2H, m), 3.58-3.48 (2H, m), 3.35 (1H, d, J = 13.2 Hz), 2.70 (1H, brs), 2.61-2, 56 (1H, m), 2.33 - 2.24 (1H, m), 1.98-1.89 (2H, m), 1.74-1.63 (3H, m), 1.44-1.02 (10H, m), 1.41 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 1.11 (3H, s), 0.98-0.93 (1H, m), 0.85-0.80 (1H, m), 0.45-0.39 (1H, m).

(Step 8)

(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl Methoxy}-4a,6a-dimethyloctadecyl-11aH-cyclopropane[c]naphtho[2,1-f]quinoline-1,11a-diol

The title compound (174 mg) was obtained from m.

MS (ESI) m / z: 450 (M+H) ⁺ .

(Step 9)

[(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4- Methoxy}-1,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl][( 2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (217 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound Compound ).

MS (ESI) m / z: 562 (M+H) ⁺ .

(Step 10)

{(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1,11a-dihydroxy-4a, 6a-dimethyl 18 Hydrogen-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.15 g) was obtained as a white solid.

MS (ESI) m/z: 522 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.05-3.98 (2H, m), 3.97-3.92 (1H, m), 3.90-3.85 (1H, m), 3.84-3.78 (1H, m), 3.74-3.67 ( 2H,m), 3.65-3.54(4H,m), 3.48-3.40(3H,m),2.84-2.79(1H,m),2.32-2.24(1H,m),2.00-1.93(1H,m), 1.93-1.86 (2H, m), 1.75-0.79 (21H, m), 1.42 (3H, s), 1.11 (3H, s), 0.47-0.41 (1H, m).

(Example 132)

{(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-dimethyl Octadecahydro-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR)-4a,6a-dimethyl-2-{[(4-methylphenyl)sulfonyl]oxy}-1,2, 3,4,4a,4b,5,6,6a,8,8a,9,9a,9b,9c,10-hexadecahydro-7H-cyclopropane[c]naphtho[2,1-f]quinoline Benzyl -7-carboxylate

The title compound (1.36 g) was obtained from m.

(Step 2)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,8,8a,9,9a,9b,9c,10-hexadecahydro-7H-cyclopropane [c]Naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (0.619 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.24 (5H, m), 5.37-5.31 (1H, m), 5.10-5.01 (2H, m), 4.33-4.27 (1H, m), 4.25-4.20 ( 1H, m), 4.06-4.02 (1H, m), 3.74-3.69 (1H, m), 3.60-3.54 (1H, m), 3.45-3.40 (1H, m), 3.39-3.34 (1H, m), 3.21-3.12(1H,m), 2.59-2.53(1H,m), 2.40-2.27(2H,m),2.22-2.13(1H,m),1.91-0.82(14H,m),1.40(3H,s ), 1.40 (3H, s), 1.34 (3H, s), 0.95 (3H, s). 0.44-0.38 (1H, m).

(Step 3)

(1aS, 3aS, 5aS, 5bR, 8S, 11aR, 11bR, 11cR)-8-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy }-3a,5b-dimethylhexadehydrocyclopropane [c]oxirane [4,4a]naphtho[2,1-f]quinoline-3(3aH)-benzyl benzoate

The title compound (0.539 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 5.08 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 4.30 (1H, dd, J =13.7, 2.4 Hz), 4.23 (1H, m), 4.05 (1H, m), 3.70 (1H, m), 3.61-3.50 (2H, m), 3.42 (1H, m), 3.35 (1H, d, J = 13.2 Hz), 2.97 (1H, d, J = 4.4 Hz), 2.56 (1H, d, J = 11.7 Hz), 2.21 (1H, m), 2.07-1.96 (2H, m), 1.86-0.81 ( 13H, m), 1.41 (3H, s), 1.37 (3H, s), 1.35 (3H, s), 1.03 (3H, s), 0.96 (1H, s), 0.43 (1H, m).

(Step 4)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]- Oxy}-11a-hydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (0.375 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.23 (5H, m), 5.06 (1H, d, J = 12.2 Hz), 5.02 (1H, d, J = 12.2 Hz), 4.28 (1H, dd, J =13.7, 2.4 Hz), 4.23-4.18 (1H, m), 4.03 (1H, t, J = 7.3 Hz), 3.74-3.67 (2H, m), 3.60-3.50 (1H, m), 3.45-3.32 ( 2H,m), 2.62-2.56(1H,m), 1.94-0.92(19H,m), 1.39(3H,s), 1.38(3H,s),1.33(3H,s),0.92(3H,s) .0.84-0.78 (1H, m), 0.43-0.38 (1H, m).

(Step 5)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]- Oxy}-4a,6a-dimethyloctadecyl-11aH-cyclopropane[c]naphtho[2,1-f]quinoline-11a-ol

The title compound (134 mg) was obtained from m.

MS (ESI) m / z: 434 (M+H) ⁺ .

(Step 6)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-11a-hydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl][(2R)-tetrahydro -2H-pyran-2-yl]methanone

The title compound (0.100) was obtained as a white solid (m.m. g).

MS (ESI) m/z: 546 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.23-4.18 (1H, m), 4.06-3.98 (3H, m), 3.94 (1H, dd, J = 10.3, 2.4 Hz), 3.73-3.67 (2H, m) , 3.60-3.50 (1H, m), 3.47-3.36 (3H, m), 2.84-2.78 (1H, m), 1.94-1.82 (4H, m), 1.76-0.92 (21H, m), 1.41 (3H, s), 1.39 (3H, s), 1.33 (3H, s), 0.92 (3H, s), 0.87-0.82 (1H, m), 0.46-0.39 (1H, m).

(Step 7)

{(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-dimethyl Octadecahydro-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.091 g) was obtained as a white solid.

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.04-3.98 (2H, m), 3.97-3.93 (1H, m), 3.83-3.77 (1H, m), 3.76-3.66 (2H, m), 3.65-3.59 ( 2H, m), 3.56-3.53 (1H, m), 3.51-3.39 (3H, m), 2.85-2.80 (1H, m), 2.57-2.53 (1H, m), 2.16-2.07 (1H, m), 1.94-1.84(5H,m), 1.78-1.05(17H,m), 1.42(3H,s),0.98-0.92(2H,m),0.88-0.83(1H,m),0.46-0.41(1H,m ), 0.93 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 4, and the peak having a relative intensity of 30 or more in the case where the maximum peak intensity in Fig. 4 is 100 is shown in Table 4.

(Example 133)

{(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-dimethyl Octadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl}[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]- ketone

(step 1)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] Methoxy}-11a-hydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl][(2R,5R)- 5-fluorotetrahydro-2H-pyran-2-yl]methanone

The title compound was obtained as a white solid, m m m m m m m m m m m m m m m m m m (198 mg).

MS (ESI) m / z: 564 (M + H) +.

(Step 2)

{(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-dimethyl Octadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl}[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]- ketone

The title compound (0.141 g) was obtained as a white solid.

MS (ESI) m / z: 524 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.57 (1H, d, J = 47.3 Hz), 4.13-4.05 (2H, m), 4.01-3.96 (1H, m), 3.83-3.77 (1H, m), 3.75 -3.67 (2H, m), 3.65-3.57 (2H, m), 3.56-3.41 (3H, m), 2.83-2.77 (1H, m), 2.63 (1H, s), 2.25-2.07 (3H, m) , 1.93-0.81 (22H, m), 1.40 (3H, s), 0.93 (3H, s). 0.46-0.40 (1H, m).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 5, and the peak having a relative intensity of 8 or more in the case where the maximum peak intensity in Fig. 5 is 100 is shown in Table 5.

(Example 134)

(2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a - dimethyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphthalene And [2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (12.5 g) was obtained as a white solid.

MS (ESI) m/z: 470 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.2 Hz), 5.05 (1H, d, J = 12.2 Hz), 4.32 (1H, dd, J =2.4,13.7 Hz), 4.15 (1H, m), 3.55 (1H, t, J = 2.9 Hz), 3.38 (1H, d, J = 13.2 Hz), 2.61 (1H, m), 2.35 (1H, d , J=2.9Hz), 2.27(1H,m),2.00-1.93(2H,m),1.82(1H,d,J=5.9Hz),1.77-1.04(12H,m),1.42(3H,s) , 1.13 (3H, s), 1.10 (1H, s), 0.98 (1H, m), 0.85 (1H, m), 0.45 (1H, m).

(Step 2)

(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS)-12a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-cyclopropane [c][1 , 3] dioxolanyl[5,6]naphtho[2,1-f]quinoline-8-carboxylic acid benzyl ester

The title compound (12.2 g) was obtained as a white solid.

MS (ESI) m / z: 510 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.2 Hz), 5.05 (1H, d, J = 12.2 Hz), 4.34 - 4.29 (2H, m ), 3.82 (1H, d, J = 5.4 Hz), 3.38 (1H, d, J = 13.2 Hz), 2.62 (1H, m), 2.14 (1H, m), 2.00-1.92 (2H, m), 1.86 (1H, m), 1.74 (1H, m), 1.66-1.20 (9H, m), 1.52 (3H, s), 1.43 (3H, s), 1.32 (3H, s), 1.19 (1H, s), 1.15 (3H, s), 1.08 (1H, m), 0.99 (1H, m), 0.86 (1H, m), 0.45 (1H, m).

(Step 3)

(3aS, 5aR, 5bS, 7aS, 9aS, 10aR, 10bR, 10cR, 12aS, 12bS)-2,2,5a,7a-tetramethyloctadecyl-12aH-cyclopropane [c][1,3] Oxolylcyclo[5,6]naphtho[2,1-f]quinoline-12a-ol

The title compound (7.62 g) was obtained from the title compound (1.

MS (ESI) m/z: 376 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.32 (1H, m), 3.82 (1H, d, J = 5.4 Hz), 3.29 (1H, dd, J = 9.0, 14.4 Hz), 3.08 (1H, dd, J) = 2.9, 14.4 Hz), 2.13 (1H, m), 1.95-1.84 (2H, m), 1.67-0.94 (16H, m), 1.53 (3H, s), 1.33 (3H, s), 1.19 (3H, s), 1.00 (3H, s), 0.61 (1H, m), 0.48 (1H, m).

(Step 4)

[(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2,2,5a,7a-tetramethyloctadecyl-8H-cyclopropane [c][ 1,3]dioxolanyl[5,6]naphtho[2,1-f]quinolin-8-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (4.98) was obtained as a white solid. g).

MS (ESI) m/z: 488 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.31 (1H, m), 4.06-4.02 (2H, m), 3.97 (1H, dd, J = 2.4, 10.3 Hz), 3.81 (1H, d, J = 5.4 Hz ), 3.50-3.43 (2H, m), 2.85 (1H, m), 2.15 (1H, m), 1.97-1.08 (20H, m), 1.52 (3H, s), 1.46 (3H, s), 1.32 ( 3H, s), 1.19 (1H, s), 1.15 (3H, s), 0.99 (1H, m), 0.89 (1H, m), 0.47 (1H, m).

(Step 5)

(2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a - dimethyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (4.08 g) was obtained as a white solid.

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.15 (1H, m), 4.06-4.01 (2H, m), 3.97 (1H, dd, J = 2.4, 10.3 Hz), 3.55 (1H, t, J = 2.9 Hz ), 3.50-3.43 (2H, m), 2.84 (1H, m), 2.32 (1H, d, J = 2.4 Hz), 2.28 (1H, m), 2.01-1.88 (3H, m), 1.79 (1H, d, J = 6.3 Hz), 1.78-1.22 (15H, m), 1.45 (3H, s), 1.19-1.08 (2H, m), 1.13 (3H, s), 1.08 (1H, s), 0.99 (1H) m), 0.88 (1H, m), 0.46 (1H, m).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 6, and the peak having a relative intensity of 9 or more in the case where the maximum peak intensity in Fig. 6 is 100 is shown in Table 6.

(Example 135)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-3,3-difluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaphthalene[2, 1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(3β,16α)-3-[(4-methoxybenzyl)oxy]-17-oxooxindole-5-ene-16-yl acetate

(3β,16α)-16-hydroxy-3-[(4-methoxybenzyl)oxy]androst-5-ene-17-one (10.7 g) was used in the same manner as in the step 5 of Example 31 The title compound (13.3 g) was obtained as white crystal.

MS (ESI) m/z: 467 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.27-7.23 (2H, m), 6.87-6.83 (2H, m), 5.42-5.38 (1H, m), 5.35-5.32 (1H, m), 4.47 (2H, s), 3.78 (3H, s), 3.28-3.20 (1H, m), 2.43-2.37 (1H, m), 2.27-2.22 (1H, m), 2.09 (3H, s). 2.09-2.00 (2H, m), 1.97-1.90 (1H, m), 1.87-1.80 (3H, m), 1.69-1.33 (7H, m), 1.06-0.95 (2H, m), 1.01 (3H, s), 0.96 (3H, s).

(Step 2)

(3β,16α,17Z)-17-(hydroxyimino)-3-[(4-methoxybenzyl)oxy]androst-5-ene-16-yl acetate

The title compound (12.1 g) was obtained from the compound (11.7 g).

(Step 3)

(3R,4aS,4bR,8S,10aR,10bS,12aS)-8-[(4-methoxybenzyl)oxy]-10a,12a-dimethyl-2-oxo-1,2,3 ,4,4a,4b,5,7,8,9,10,10a,10b,11,12,12a-hexadecaquino[2,1-f]quinolin-3-yl acetate

To a solution of the compound (12.1 g) obtained in the above step 2 in THF (100 ml), propylphosphonic acid anhydride (cyclic trimer) (50% ethyl acetate solution, 7.47 ml) was added, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and dried over ethyl acetate. After drying over anhydrous sodium sulfate, pyridine (50 ml) and acetic anhydride (25 ml) were added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was stirred at room temperature. Toluene was added to the reaction mixture, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane, and then washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, EtOAc (EtOAc m.

¹ H-NMR (CDCl ₃ ) δ: 7.25-7.22 (2H, m), 6.87-6.83 (3H, m), 5.74 (1H, s), 5.34-5.30 (2H, m), 4.46 (2H, s) , 3.77 (3H, s), 3.30-3.19 (1H, m), 2.42 - 0.84 (17H, m) 2.11 (2H, s), 1.16 (3H, s), 0.96 (3H, s).

(Step 4)

(3R,4aS,4bR,8S,10aR,10bS,12aS)-8-[(4-methoxybenzyl)oxy]-10a,12a-dimethyl-1,2,3,4,4a, 4b,5,7,8,9,10,10a,10b,11,12,12a-hexadecaquino[2,1-f]quinolin-3-ol

The title compound (1.16 g) was obtained from m.

(Step 5)

(3R,4aS,4bR,8S,10aR,10bS,12aS)-3-hydroxy-8-[(4-methoxybenzyl)oxy]-10a,12a-dimethyl-3,4,4a, 4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (0.96 g) was obtained as a white solid.

MS (ESI) m/z: 560 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (7H, m), 6.87-6.83 (2H, m), 5.32-5.28 (1H, m), 5.08-5.05 (2H, m), 4.46 (2H, s), 4.06-3.99 (1H, m), 3.87 (1H, dd, J = 13.2, 4.4 Hz), 3.77 (3H, s), 3.32-3.19 (2H, m), 2.97-2.94 (1H, m) , 2.42 - 2.36 (1H, m), 2.25-2.17 (1H, m), 2.14 - 2.06 (1H, m), 1.95-1.88 (1H, m), 1.85-1.22 (11H, m), 1.27 (3H, s), 1.04-0.96 (2H, m), 0.94 (3H, s).

(Step 6)

(4aS,4bR,8S,10aR,10bS,12aS)-8-[(4-methoxybenzyl)oxy]-10a,12a-dimethyl-3-oxo-3,4,4a,4b ,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

4-methyl-N-oxidation in a solution of the compound (1.2 g) obtained in the above step 5 in dichloromethane (20 ml) The morpholine (0.38 g) and tetrapropylammonium perruthenate (0.075 g) were stirred at room temperature for 2 hours. The reaction mixture was purified by EtOAcjjjjjjjjjj

MS (ESI) m/z: 558 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.22 (7H, m), 6.87-6.83 (2H, m), 5.32-5.28 (1H, m), 5.11-5.04 (2H, m), 4.46 (2H, s), 4.42 (1H, d, J = 17.6 Hz), 3.82 (1H, d, J = 17.6 Hz), 3.77 (3H, s), 3.26-3.20 (1H, m), 3.09-3.04 (1H, m ), 2.53 (1H, dd, J = 19.0, 3.4 Hz), 2.43-2.37 (1H, m), 2.27-2.06 (3H, m), 1.96-1.90 (1H, m), 1.89-1.75 (2H, m ), 1.72-1.65 (1H, m), 1.60-1.22 (5H, m), 1.39 (3H, s), 1.09-0.94 (2H, m), 0.96 (3H, s).

(Step 7)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-3,3-difluoro-8-[(4-methoxybenzyl)oxy]-10a,12a-dimethyl-3,4,4a , 4b,5,7,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

To a solution of the compound (0.455 g), m. After cooling the reaction mixture to 0 ° C, aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAcqqqqqqqq

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.23 (7H, m), 6.87-6.83 (2H, m), 5.34-5.28 (1H, m), 5.11-5.07 (2H, m), 4.47 (2H, s), 4.3-4.03 (1H, m), 3.78 (3H, s), 3.63-3.49 (1H, m), 3.27-3.21 (1H, m), 3.29-3.19 (1H, m), 2.99-2.92 ( 1H, m), 2.44 - 2.37 (1H, m), 2.29-1.17 (12H, m), 1.08-0.99 (2H, m), 1.35 (3H, s), 0.96 (3H, s).

(Step 8)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-3,3-difluoro-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10 , 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

1,3-Dimethoxybenzene (0.194 ml) and trifluoromethanesulfonic acid (0.0218 ml) were added to a solution of the compound (0.288 g) in dichloromethane (5 ml). Stir for 18 hours. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, EtOAc (EtOAc m.

MS (ESI) m/z: 460 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.44 - 7.14 (5H, m), 5.33-5.30 (1H, m), 5.11-5.06 (2H, m), 4.12-4.03 (1H, m), 3.60-3.48 ( 2H,m), 2.99-2.93(1H,m),2.34-2.15(3H,m),2.11-2.05(1H,m),1.85-1.20(11H,m),1.09-1.00(2H,m), 1.35 (3H, s), 0.95 (3H, s).

(Step 9)

(4aS, 4bR, 10aR, 10bS, 12aS)-3,3-difluoro-10a,12a-dimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9,10, 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (0.077 g) was obtained as a white solid.

MS (ESI) m/z: 458 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.72 (1H, s), 5.09 (2H, s), 4.12-4.05 (1H, m), 3.54 (1H, m), 3.05 - 2.98 (1H, m), 2.43 - 2.24 (5H, m), 2.05-1.99 (1H, m), 1.98-1.92 (1H, m), 1.86-1.77 (1H, m), 1.72-1.52 (3H, m), 1.46-1.22 (3H, m), 1.38 (3H, s), 1.14 (3H, s), 1.09-1.01 (2H, m).

(Step 10)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-3,3-difluoro-8-hydroxy-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10 , 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (77 mg) was obtained from m.

(Step 11)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-9,9-difluoro-2-hydroxy-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5 Naphtho[2,1-f]quinoline-7(5H)-benzyl formate

The title compound (80 mg) was obtained from m.

MS (ESI) m / z: 476 (M+H) ⁺ .

(Step 12)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-3,3-difluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f] quinoline-1(2H)-benzyl formate

The title compound (0.063 g) was obtained as a white solid.

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.08 (2H, s), 4.16-4.03 (2H, m), 3.59-3.45 (2H, m), 2.97-2.90 (1H, m), 2.33-2.15 (3H, m), 1.81-1.15 (15H, m), 1.33 (3H, s), 1.09 (3H, s), 0.93 (1H, s).

(Step 13)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-10,10-difluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxo Pentylcyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (0.083 g) was obtained as a white solid.

MS (ESI) m / z: 534 (M+H) ⁺ .

(Step 14)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-10,10-difluoro-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl [5,6]naphtho[2,1-f]quinoline-13a(4H)-alcohol

The title compound (62.3 mg) was obtained from m.

(Step 15)

[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-10,10-difluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3] Oxolylcyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.023) was obtained as a white solid (m.). g).

MS (ESI) m/z: 512 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.31-4.25 (1H, m), 4.03-3.93 (3H, m), 3.76 (1H, d, J = 5.4 Hz), 3.60-3.51 (1H, m), 3.47 -3.41(1H,m), 3.17-3.12(1H,m),2.34-2.22(1H,m),2.15(1H,s),2.11-2.02(1H,m),1.91-1.05(19H,m) , 0.88-0, 82 (1H, m), 1.49 (3H, s), 1.39 (3H, s), 1.29 (3H, s), 1.10 (3H, s).

(Step 16)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-3,3-difluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaphthalene[2, 1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.021 g) was obtained as a white solid.

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.17-4.08 (1H, m), 4.04-3.93 (3H, m), 3.61-3.48 (2H, m), 3.47-3.41 (1H, m), 3.18-3.11 ( 1H, m), 2.32-2.18 (3H, m), 1.91-1.21 (21H, m), 1.38 (3H, s). 1.09 (3H, s), 0.90 (1H, s).

(Example 136)

[(4aS,4bR,6aR,8R,9R,10aR,10bS,12aS)-9-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS, 4bR, 6aR, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-8-oxohexadecane[2,1-f]quinoline-1(2H)- Benzyl formate

The title compound (0.516 g) was obtained from m.

MS (ESI) m/z: 440 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.10-5.04 (2H, m), 3.80-3.73 (1H, m), 3.35-3.27 (1H, m), 3.08-3.02 ( 1H, m), 2.65 (1H, d, J = 15.1 Hz), 2.38-2.33 (2H, m), 2.08 (1H, d, J = 15.6 Hz), 1.92-1.11 (17H, m), 1.34 (3H) , s), 1.11 (3H, s).

(Step 2)

(4aS, 4bR, 6aR, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-8-{[tris(propan-2-yl)nonanyl]oxy}-3,4,4a , 4b,5,6,6a,7,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

To a solution of the compound (0.950 g) obtained in the above step 1 in dichloromethane (10 ml), triethylamine (0.449 ml) and triisopropyl methanesulfonate (0.697 ml) Stir under 15 hours. After the reaction mixture was diluted with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. The title compound (1.29 g) was obtained.

(Step 3)

(4aS,4bR,6aR,9S,10aR,10bs,12aS)-9-fluoro-6a-hydroxy-10a,12a-dimethyl-8-oxohexadecane[2,1-f]quinoline -1(2H)-benzyl formate (β-fluoro) and (4aS,4bR,6aR,9R,10aR,10bS,12aS)-9-fluoro-6a-hydroxy-10a,12a-dimethyl-8-oxohexadecane[2,1-f]quinoline -1(2H)-benzyl formate (α-fluoro)

To a solution of the compound (1.29 g) obtained in the above step 2, N,N-dimethylformamide (30 ml), N-fluoro-N'-(chloromethyl)trisethylamine diamine The fluoroborate (0.918 g) was stirred at room temperature for 30 minutes, then triethylamine (2.6 ml) was added and the mixture was further stirred for 30 minutes. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The title compound (β-fluoro) (0.225) was obtained as a pale yellow solid (yield). g) and the title compound (α-fluoro) (0.316 g).

Β-fluoride: (Rf=higher: low polarity)

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.06 (2H, s), 5.09-4.96 (1H, m), 3.78-3.72 (1H, m), 3.36-3.27 (1H, m), 3.10-3.04 (1H, m), 2.90-2.85 (1H, m), 2.36-2.15 (2H, m), 1.95-1.02 (16H, m), 1.33 (3H, s), 1.06 (3H, s).

Α-fluoro: (Rf=lower: high polarity)

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.22 (5H, m), 5.06 (2H, s), 5.09-4.91 (1H, m), 3.79-3.73 (1H, m), 3.35-3.27 (1H, m), 3.10-3.04 (1H, m), 2.78-2.73 (1H, m), 2.27-2.20 (3H, m), 2.10-2.02 (2H, m), 1.81-1.10 (13H, m), 1.34 ( 3H, s), 1.17 (3H, s).

(Step 4)

(4aS,4bR,6aR,8R,9R,10aR,10bS,12aS)-9-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline -1(2H)-benzyl formate

To a solution of the compound (α-fluoro) (0.316 g) obtained in the above step 3, and a solution of ruthenium chloride 7 hydrate (0.772 g) in methanol (7 ml), sodium borohydride (0.0392 g) was added at -78 °C. The mixture was stirred for 20 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was filtered over Celite. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Pyridine (2 ml) and acetic anhydride (1 ml) were added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was stirred at room temperature for 2 hr. 4-Dimethylamine pyridine (0.0929 g) was added and further stirred for 1 day. After adding toluene, the residue obtained by concentration under reduced pressure was diluted with dichloromethane, and then washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, EtOAc (EtOAc m.

MS (ESI) m/z: 460 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.08-5.05 (2H, m), 4.75 (1H, m), 4.29 (1H, m), 3.75 (1H, m), 3.30 (1H, m), 3.04 (1H, m), 2.73 (1H, m), 4.29 (1H, m), 3.75 (1H, m), 3.30 (1H, m), 3.04 (1H, m), 2.73 ( 1H, m), 1.89-1.06 (14H, m). 1.32 (3H, s), 0.88 (3H, s).

(Step 5)

(4aS,4bR,6aR,8R,9R,10aR,10bS,12aS)-9-fluoro-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-6a,8(2H) -diol

The title compound (94 mg) was obtained from m.

MS (ESI) m / z: 326 (M+H) ⁺ .

(Step 6)

[(4aS,4bR,6aR,8R,9R,10aR,10bS,12aS)-9-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (50 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m ).

MS (ESI) m / z: 438 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.75 (1H, m), 4.32-4.22 (2H, m), 4.03-3.93 (2H, m), 3.53 (1H, m), 3.42 (1H, m), 3.31 -3.25 (2H, m), 2.69 (1H, m), 1.90-1.10 (24H, m), 1.41 (3H, s), 0.88 (3H, s).

(Example 137)

[(4aS,4bR,6aR,8R,9S,10aR,10bS,12aS)-9-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS,4bR,6aR,8R,9S,10aR,10bS,12aS)-9-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline -1(2H)-benzyl formate

The title compound (0.226 g) was obtained from m. m.

MS (ESI) m / z: 460 (M+H) ⁺ .

(Step 2)

(4aS,4bR,6aR,8R,9S,10aR,10bS,12aS)-9-fluoro-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-6a,8(2H) -diol

The title compound (27.6 mg) was obtained.

MS (ESI) m / z: 326 (M+H) ⁺ .

(Step 3)

[(4aS,4bR,6aR,8R,9S,10aR,10bS,12aS)-9-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The compound obtained in the above step 2 (0.0276 g) and the compound obtained in the step 3 of Example 23 (0.0221 g), The title compound (0.007 g) was obtained as a white solid.

MS (ESI) m / z: 438 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.75 (1H, m), 4.04-3.92 (3H, m), 3.58-3.25 (6H, m), 2.09 (1H, m), 1.93-0.97 (23H, m) , 1.41 (3H, s), 1.01 (3H, d, J = 2.4 Hz).

(Example 138)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-7-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-(ethinyloxy)-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10, 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (11.2 g) was obtained from m.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.23-5.17 (2H, m), 5.09-5.03 (2H, m), 3.74 (1H, m), 3.30 (1H, m) , 3.03 (1H, m), 2.18-0.79 (21H, m), 1.34 (3H, s), 1.00 (3H, s).

(Step 2)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-(ethenyloxy)-4a,6a-dimethyltetrahydroxan-1aH-oxirane [4a,5] Naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester (β-epoxide) and (1aR, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aS)-2-(B Mercaptooxy)-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester (α -epoxide)

The title compound (β-epoxide) (2.4 g) and the title compound (α) were obtained as a white solid. - epoxide) (6.4 g).

--epoxide

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.10 (1H, m), 5.08-5.03 (2H, m), 3.76 (1H, m), 3.33 (1H, m), 3.15 (1H, d, J = 3.4 Hz), 3.05 (1H, m), 2.07 (3H, s), 2.07-0.89 (15H, m), 2.07 (3H, s), 1.34 (3H, s), 0.98 ( 3H, s).

Alpha-epoxide

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.23 (5H, m), 5.05 (2H, s), 4.93 (1H, t, J = 8.8 Hz), 3.76 (1H, m), 3.31 (1H, m ), 3.04 (1H, m), 2.87 (1H, s), 2.05 (3H, s), 2.07-1.01 (18H, m), 1.35 (3H, s), 1.05 (3H, s).

(Step 3)

(1aR, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aS)-2-hydroxy-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1 -f] quinoline-7(5H)-benzyl formate

To a solution of the compound (α-epoxide) (5.78 g) in THF (30 ml)-methanol (30 ml), After the reaction mixture was neutralized with 2N aqueous hydrochloric acid, the obtained residue was evaporated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m/z: 440 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.05 (2H, s), 3.97 (1H, m), 3.76 (1H, m), 3.31 (1H, m), 3.03 (1H) , m), 2.90 (1H, s), 2.04-1.96 (2H, m), 1.91-1.77 (3H, m), 1.69-1.02 (14H, m), 1.34 (3H, s), 1.04 (3H, s ).

(Step 4)

(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-(ethenyloxy)-7-fluoro-6a-hydroxy-10a,12a-dimethylhexadecane[2] , 1-f] quinoline-1(2H)-benzyl formate

A solution of cesium tetrafluoride (1.16 g) and tetrabutylammonium dihydrogen trifluoride (1.37 g) in tetrahydrofuran (9 ml) was stirred at room temperature for 10 minutes, and then added to the above step 3. Compound (1.00g), stirred at the same temperature for 16 hours Time. The reaction solution was diluted with dichloromethane and washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate. Pyridine (4 ml) and acetic anhydride (2 ml) were added to the obtained mixture of 4-fluorobenzene and 5-fluorobenzene, and the mixture was stirred at room temperature for 3 hr. The obtained residue was diluted with dichloromethane, and then washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate.

MS (ESI) m / z: 502 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.34 - 7.23 (5H, m), 5.26 (1H, m), 5.10-5.03 (2H, m), 4.33 (1H, m), 3.75 (1H, m), 3.31 (1H, m), 3.02 (1H, m), 2.20-1.04 (19H, m), 2.07 (3H, s), 1.32 (3H, s), 1.02 (3H, d, J = 3.4 Hz).

(Step 5)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-7-fluoro-6a-hydroxy-10a, 12a-dimethyloctadecylnaphtho[2,1-f]quinoline-8- Acetate

The title compound (119 mg) was obtained from m.

MS (ESI) m / z: 368 (M + H) +.

(Step 6)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-7-fluoro-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2 -ylcarbonyl]octadeconaphtho[2,1-f]quinolin-8-yl acetate

The title compound (0.164) was obtained as a white solid (m.m. g).

MS (ESI) m/z: 480 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.27 (1H, m), 4.34 (1H, m), 4.03-3.91 (2H, m), 3.54 (1H, m), 3.41 (1H, m), 3.34-3.22 (2H, m), 2.07 (3H, s), 2.20 - 1.14 (25H, m), 1.40 (3H, s), 1.02 (3H, d, J = 2.9 Hz).

(Step 7)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-7-fluoro-6a,8-dihydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.073) was obtained as a white solid, m. m. g).

MS (ESI) m / z: 438 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.24 (1H, m), 4.13-3.98 (2H, m), 3.95 (1H, m), 3.54 (1H, m), 3.41 (1H, m), 3.33-3.23 (2H, m), 2.15 (1H, m), 1.90-1.14 (25H, m), 1.40 (3H, s). 0.99 (3H, d, J = 2.9 Hz).

(Example 139)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2] ,1-f]quinolin-7-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(1aS, 3aS, 5aS, 5bR, 8S, 9aR, 10aS, 11aR, 11bR, 11cR)-8-hydroxy-3a,5b-dimethylhexadehydrocyclopropane [c]ethylene oxide [4,4a] Naphtho[2,1-f]quinoline-3(3aH)-benzyl formate

The title compound (4.15 g) was obtained from m.

MS (ESI) m / z: 452 (M+H) ⁺ .

(Step 2)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2, 1-f] quinolin-7-carboxylic acid benzyl ester

The title compound (2.06 g) was obtained as a white solid.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.09-5.01 (2H, m), 4.29 (1H, dd, J = 13.7, 2.4 Hz), 4.07 (1H, m), 3.36 (1H, d, J = 13.2 Hz), 2.59 (1H, m), 1.94 (1H, m), 1.89-1.80 (2H, m), 1.78-0.89 (17H, m), 1.39 (3H, s), 0.94 (3H, s), 0.82 (1H, m), 0.41 (1H, m).

(Step 3)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-4a,6a-dimethyloctadecyl-11aH-cyclopropane[c]naphtho[2,1-f]quinoline- 2,11a-diol

The title compound (141 mg) was obtained from m.

MS (ESI) m/z: 320 (M+H) ⁺ .

(Step 4)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2] ,1-f]quinolin-7-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.137) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m g).

MS (ESI) m / z: 432 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.12-3.98 (3H, m), 3.95 (1H, m), 3.48-3.39 (2H, m), 2.82 (1H, m), 1.93-1.81 (4H, m) , 1.76-1.06 (21H, m), 1.42 (3H, s), 0.94 (3H, s), 0.95 (1H, m), 0.85 (1H, m), 0.43 (1H, m).

(Embodiment 140)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2] ,1-f]quinoline-7-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2] ,1-f]quinoline-7-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone

The title compound was obtained as a white solid (yield: Compound Compound Compound Compound Compound Compound Compound Compound Compound 0.072g).

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.60 (1H, m), 4.16-4.05 (3H, m), 4.01 (1H, m), 3.60 (1H, dd, J = 12.4, 35.9 Hz), 3.46 (1H) ,d,J=13.2Hz),2.83(1H,m), 2.26-2.10(2H,m),1.95(1H,d,J=10,7Hz),1.91-0.94(20H,m),1.43(3H , s), 0.97 (3H, s), 0.90-0.86 (2H, m), 0.46 (1H, m).

(Example 141)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-11a-hydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphthalene And [2,1-f]quinolin-7-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-11a-hydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho [2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (0.693 g) was obtained as a white solid.

MS (ESI) m/z: 468 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.07 (1H, d, J = 12.2 Hz), 5.03 (1H, d, J = 12.2 Hz), 4.29 (1H, dd, J =13.4, 2.7 Hz), 3.61-3.55 (1H, m), 3.36 (1H, d, J = 12.7 Hz), 3.32 (3H, s), 2.62-2.57 (1H, m), 1.97-1.82 (3H, m), 1.75-0.86 (16H, m), 1.39 (3H, s), 0.93 (3H, s), 0.84-0.79 (1H, m), 0.44-0.38 (1H, m).

(Step 2)

(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-methoxy-4a,6a-dimethyloctadecyl-11aH-cyclopropane[c]naphtho[2,1 -f]quinoline-11a-ol

The title compound (133 mg) was obtained from m.

MS (ESI) m / z: 356 (M+H) ⁺ .

(Step 3)

[(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-11a-hydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphthalene And [2,1-f]quinolin-7-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.132) was obtained as a white solid. g).

MS (ESI) m/z: 446 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.04-3.98 (2H, m), 3.97-3.93 (1H, m), 3.61-3.54 (1H, m), 3.48-3.39 (2H, m), 3.32 (3H, s), 2.84-2.79 (1H, m), 1.96-1.83 (4H, m), 1.74-0.93 (21H, m), 1.42 (3H, s), 0.93 (3H, s). 0.87-0.82 (1H, m), 0.46-0.40 (1H, m).

(Example 142)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-11a-hydroxy-2-methyl Oxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-11a-hydroxy-2-methyl Oxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m (0.161g).

MS (ESI) m/z: 464 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.57 (1H, d, J = 46.9 Hz), 4.14 - 4.05 (2H, m), 4.00 - 3.96 (1H, m), 3.63 - 3.51 (2H, m), 3.46 -3.41(1H,m),3.32(3H,s).2.83-2.77(1H,m),2.24-2.08(2H,m),1.95-0.81(22H,m),1.40(3H,s),0.93 (3H, s), 0.46-0.40 (1H, m).

(Example 143)

[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,11a-dihydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclo Propane [c]naphtho[2,1-f]quinolin-7-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(1S, 3aR, 3bS, 5aS, 7aS, 8aR, 8bR, 8cR, 10aR, 11aS)-1-methoxy-3a,5a-dimethylhexadehydrocyclopropane [c]ethylene oxide [4a, 5] Naphtho[2,1-f]quinoline-6(2H)-formic acid benzyl ester

The title compound (0.849 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.23 (5H, m), 5.07 (1H, d, J = 12.2 Hz), 5.03 (1H, d, J = 12.2 Hz), 4.29 (1H, m), 3.65 (1H, m), 3.42 (3H, s), 3.36 (1H, d, J = 13.2 Hz), 3.12 (1H, d, J = 3.4 Hz), 2.60 (1H, m), 2.21-2.10 (2H , m), 1.86 (1H, d, J = 10.7 Hz), 1.67 (1H, m), 1.56-0.93 (12H, m), 1.41 (3H, s), 0.99 (3H, s). 0.84 (1H, m), 0.43 (1H, m).

(Step 2)

(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-1,11a-dihydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclopropane [c]Naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (0.717 g) was obtained as a white solid.

MS (ESI) m/z: 484 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35 - 7.21 (5H, m), 5.06 (1H, d, J = 12.7 Hz), 5.02 (1H, d, J = 12.7 Hz), 4.29 (1H, dd, J =13.7, 2.4 Hz), 3.68-3.62 (2H, m), 3.38-3.34 (1H, m), 3.37 (3H, s), 2.58 (1H, m), 2.32-2.23 (2H, m), 1.99- 1.90 (2H, m), 1.73-0.94 (14H, m), 1.39 (3H, s), 1.11 (3H, s), 0.83 (1H, m), 0.42 (1H, m).

(Step 3)

(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-methoxy-4a, 6a-dimethyloctadecyl-11aH-cyclopropane [c]naphtho[2] ,1-f]quinoline-1,11a-diol

The title compound (145 mg) was obtained from m.

MS (ESI) m / z: 350 (M+H) ⁺ .

(Step 4)

[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,11a-dihydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclo Propane [c]naphtho[2,1-f]quinolin-7-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.135) was obtained as a white solid, m. m. g).

MS (ESI) m/z: 462 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.04-3.98 (2H, m), 3.97-3.93 (1H, m), 3.68-3.61 (2H, m), 3.47-3.36 (2H, m), 3.37 (3H, s).2.84-2.78(1H,m),2.32-2.23(2H,m),1.99-1.85(3H,m),1.78-1.03(18H,m),1.42(3H,s),1.11(3H, s), 0.99-0.94 (1H, m), 0.88-0.83 (1H, m), 0.47-0.41 (1H, m).

(Example 144)

[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,11a-dihydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclo Propane [c]naphtho[2,1-f]quinolin-7-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,11a-dihydroxy-2-methoxy-4a,6a-dimethyloctadecyl-7H-cyclo Propane [c]naphtho[2,1-f]quinolin-7-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone

The title compound was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m (0.176g).

MS (ESI) m/z: 480 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.57 (1H, d, J = 47.3 Hz), 4.14 - 4.06 (2H, m), 4.00 - 3.96 (1H, m), 3.68-3.51 (3H, m), 3.46 -3.42(1H,m), 3.37(3H,s),2.83-2.77(1H,m),2.32-2.07(3H,m),1.99-1.88(2H,m),1.82-1.02(16H,m) , 1.41 (3H, s), 1.11 (3H, s), 0.99-0.94 (1H, m), 0.88-0.83 (1H, m), 0.47-0.42 (1H, m).

(Example 145)

(2R)-tetrahydro-2H-pyran-2-yl [(3R,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-3,6a,7,8-tetrahydroxy-10a,12a - dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(3β,16α,17Z)-17-(hydroxyimino)androst-5-ene-3,16-diyldiacetate

Using (3β,16α)-17-oxo-androst-5-ene-3,16-diyldiacetate (20.9 g), the title compound (21.7) g).

(Step 2)

(3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-2-oxo-1,2,3,4,4a,4b,5,7,8,9,10 ,10a,10b,11,12,12a-hexadecaquino[2,1-f]quinoline-3,8-diyldiacetate

The title compound (2.24 g, containing an impurity) was obtained from the compound obtained in the above-mentioned step 1 (21.7 g).

(Step 3)

(3R, 4aS, 4bR, 8S, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-1,2,3,4,4a,4b,5,7,8,9,10,10a,10b, 11,12,12a-hexadehydronaphtho[2,1-f]quinoline-3,8-diol

The title compound (2.7 g) was obtained from m.

(Step 4)

(3R,4aS,4bR,8S,10aR,10bS,12aS)-3,8-dihydroxy-10a,12a-dimethyl-3,4,4a,4b,5,7,8,9,10,10a , 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (0.581 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.26 (5H, m), 5.38-5.30 (1H, m), 5.14-5.05 (2H, m), 4.10-4.02 (1H, m), 3.92-3.86 ( 1H,m),3.58-3.44(1H,m),3.34-3.25(1H,m),3.03-2.95(1H,m),2.34-2.28(1H,m),2.25-2.10(2H,m), 1.88-1.81 (2H, m), 1.74-1.25 (11H, m), 1.30 (3H, s), 1.12-0.94 (2H, m), 0.97 (3H, s).

(Step 5)

(4aS, 4bR, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-3,8-di-side oxygen-3,4,4a,4b,5,6,8,9,10,10a,10b, 11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (0.166 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.24 (5H, m), 5.73 (1H, s), 5.12-5.03 (2H, m), 4.43 (1H, d, J = 17.6 Hz), 3.81 (1H) ,d,J=17.6Hz), 3.17-3.11(1H,m),2.63-2.58(1H,m),2.45-2.15(5H,m),2.07-1.94(2H,m),1.87-1.80(1H , m), 1.74-1.61 (3H, m), 1.56-0.97 (4H, m), 1.42 (3H, s), 1.15 (3H, s).

(Step 6)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-3,8-dihydroxy-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (0.167 g) was obtained from m.

(Step 7)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2,9-dihydroxy-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[ 2,1-f]quinoline-7(5H)-benzyl formate

The title compound (0.174 g) was obtained.

(Step 8)

(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-3,6a,7,8-tetrahydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline -1(2H)-benzyl formate

The title compound (0.180 g) was obtained from m.

(Step 9)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-10,13a-dihydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl [5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (0.098 g) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

Main product (α-alcohol)

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.27 (5H, m), 5.09-5.03 (2H, m), 4.30-4.26 (1H, m), 4.05-3.97 (1H, m), 3.90-3.84 ( 1H, m), 3.78-3.74 (1H, m), 3.30-3.23 (1H, m), 2.97-2.92 (1H, m), 2.15.10.10 (18H, m), 1.49 (3H, s), 1.29 ( 3H, s), 1.27 (3H, s), 1.10 (3H, s).

(Step 10)

(3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS)-10-(benzylideneoxy)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecane [ 1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester (α-benzoate) and (3aS,5aR,5bS ,7aS,10S,11aS,11bR,13aS,13bS)-10-(benzylideneoxy)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxo Pentocyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester (β-benzoate)

To a solution of the compound (913 mg), m. . Additional benzamidine chloride (0.413 ml) was further stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. After the organic layer was dried over anhydrous sodium sulfate (MgSO4). The obtained mixture was purified by EtOAc EtOAc EtOAc (EtOAc) Ester) (188 mg).

--benzoate

MS (ESI) m / z: 618 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 8.01 (2H, d, J = 7.8 Hz), 7.57 (1H, t, J = 7.6 Hz), 7.44 (2H, t, 7.8 Hz), 7.35-7.26 (5H, m), 5.23-5.18 (1H, m), 5.10 (1H, d, J = 12.2 Hz), 5.05 (1H, d, J = 12.2 Hz), 4.33-4.28 (1H, m), 4.08 (1H, dd , J = 13.4, 4.6 Hz), 3.79 (1H, d, J = 5.4 Hz), 3.57 (1H, dd, J = 12.9, 10.0 Hz), 2.99 (1H, d, J = 12.7 Hz), 2.11-2.04 (1H, m), 1.94-1.85 (4H, m), 1.72-1.16 (12H, m), 1.52 (3H, s), 1.38 (3H, s), 1.31 (3H, s), 1.14 (3H, s ).

--benzoate

¹ H-NMR (CDCl ₃ ) δ: 7.97-7.95 (2H, m), 7.58-7.55 (1H, m), 7.43-7.40 (2H, m), 7.27-7.22 (5H, m), 5.26-5.23 ( 1H,m), 5.12 (1H,d,J=12.7Hz),5.04(1H,d,J=12.7Hz),4.33-4.29(1H,m),4.19(1H,dd,J=14.4,3.7Hz ), 3.80 (1H, d, J = 4.9 Hz), 3.56 (1H, dd, J = 14.4, 2.7 Hz), 3.05-3.01 (1H, m), 2.47-2.41 (1H, m), 2.11-2.04 ( 1H, m), 1.89-1.85 (1H, m), 1.75-1.71 (1H, m), 1.67-1.12 (13H, m), 1.56 (3H, s), 1.52 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Step 11)

(3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS)-10,13a-dihydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolane Benzo[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (620 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.29 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 4.33-4.28 (1H, m ), 4.07-4.02 (1H, m), 3.90 (1H, dd, J = 12.7, 4.4 Hz), 3.80 (1H, d, J = 5.4 Hz), 3.29 (1H, dd, J = 12.7, 9.8 Hz) , 3.00-2.96 (1H, m), 2.11-2.04 (1H, m), 1.89-1.78 (2H, m), 1.72-1.13 (15H, m), 1.52 (3H, s), 1.31 (3H, s) , 1.29 (3H, s), 1.12 (3H, s).

(Step 12)

(3aS, 5aR, 5bS, 7aS, 10R, 11aS, 11bR, 13aS, 13bS)-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6] Naphtho[2,1-f]quinoline-10,13a(4H)-diol

The title compound (84.0 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 3.88 (1H, brs), 3.81 (1H, d, J = 4.9 Hz), 3.09 (1H, d, J = 13.7 Hz), 2.79 (1H, d, J = 13.7 Hz), 2.09-2.02 (1H, m), 1.90- 1.80 (2H, m), 1.66-1.15 (17H, m), 1.52 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.04 (3H, s).

(Step 13)

[(3aS,5aR,5bS,7aS,10R,11aS,11bR,13aS,13bS)-10,13a-dihydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxol Cyclo-[5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (66.6) was obtained as a white solid (m.m. Mg).

¹ H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 4.08-3.98 (3H, m), 3.80 (1H, d, J = 5.5 Hz), 3.55 (1H, dd, J = 12.7, 4.1 Hz), 3.48 (1H, dd, J = 11.3, 2.3 Hz), 3.43 (1H, dd, J = 12.9, 9.0 Hz), 3.22-3.18 (1H, m), 2.27-2.24 (1H, m), 2.11-2.03 (1H, m), 1.94-1.19 (22H, m), 1.52 (3H, s), 1.35 (3H, s), 1.31 (3H, s), 1.12 (3H, s).

(Step 14)

(2R)-tetrahydro-2H-pyran-2-yl [(3R,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-3,6a,7,8-tetrahydroxy-10a,12a - dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (62.7 mg) was obtained as a white solid.

MS (ESI) m/z: 452 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.11-4.04 (2H, m), 4.00-3.93 (2H, m), 3.67 (1H, dd, J = 12.2, 4.9 Hz), 3.55-3.49 (1H, m ), 3.46 (1H, d, J = 3.9 Hz), 3.20 (1H, t, J = 11.7 Hz), 3.13-3.10 (1H, m), 2.20-2.13 (1H, m), 1.91-1.89 (1H, m), 1.84-1.17 (20H, m), 1.35 (3H, s), 1.12 (3H, s).

(Example 146)

(2R)-tetrahydro-2H-pyran-2-yl [(3S,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-3,6a,7,8-tetrahydroxy-10a,12a - dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(3aS, 5aR, 5bS, 7aS, 10S, 11aS, 11bR, 13aS, 13bS)-10,13a-dihydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolane Benzo[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (185 mg) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.06 (2H, s), 4.30-4.25 (1H, m), 3.91-3.86 (1H, m), 3.77 (1H, d, J=5.4 Hz), 3.70 (1H, dd, J=13.7, 3.4 Hz), 3.48 (1H, dd, J=13.9, 6.1 Hz), 3.01-2.97 (1H, m), 2.18-2.13 (1H, m ), 2.09-2.02 (1H, m), 1.87-1.81 (1H, m), 1.72-1.66 (1H, m), 1.62-1.10 (14H, m), 1.49 (3H, s), 1.36 (3H, s ), 1.29 (3H, s), 1.10 (3H, s).

(Step 2)

(3aS, 5aR, 5bS, 7aS, 10S, 11aS, 11bR, 13aS, 13bS)-2,2,5a,7a-tetramethylhexadecano[1,3]dioxolanyl[5,6] Naphtho[2,1-f]quinoline-10,13a(4H)-diol

The title compound (281 mg) was obtained as a white solid.

MS (ESI) m/z: 380 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 3.80 (1H, d, J = 5.4 Hz), 3.63-3.57 (1H, m), 2.98 (1H, dd, J = 12.4, 4.1 Hz), 2.72 (1H, dd, J = 12.0, 11.0 Hz), 2.10-2.02 (2H, m), 1.89-1.84 (1H, m), 1.72-1.02 (17H, m), 1.52 (3H, s ), 1.32 (3H, s), 1.15 (3H, s), 1.06 (3H, s).

(Step 3)

[(3aS,5aR,5bS,7aS,10S,11aS,11bR,13aS,13bS)-10,13a-dihydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxol Cyclic [5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (184 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

¹ H-NMR (CDCl ₃ ) δ: 4.32-4.28 (1H, m), 4.10-4.07 (1H, m), 4.04 (1H, dd, J = 11.0, 3.7 Hz), 3.98 (1H, dd, J = 10.7, 2.0 Hz), 3.79 (1H, d, J = 5.4 Hz), 3.59 (1H, dd, J = 14.2, 2.9 Hz), 3.52-3.46 (2H, m), 3.31 (1H, d, J = 2.9 Hz), 3.16-3.12(1H,m), 2.19-2.13(1H,m),2.12-2.06(1H,m),1.97-1.92(1H,m),1.91-1.82(2H,m),1.72- 1.14 (18H, m), 1.58 (3H, s), 1.52 (3H, s), 1.31 (3H, s), 1.14 (3H, s).

(Step 4)

(2R)-tetrahydro-2H-pyran-2-yl [(3S,4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-3,6a,7,8-tetrahydroxy-10a,12a - dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (178 mg) was obtained.

MS (ESI) m/z: 452 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.17 (1H, d, J = 10.3 Hz), 4.07-4.03 (1H, m), 4.00 (1H, d, J = 11.7 Hz), 3.95-3.91 (1H, m), 3.59 (1H, d, J = 14.2 Hz), 3.52 (1H, t, J = 10.3 Hz), 3.45 (1H, d, J = 3.4 Hz), 3.17-3.12 (1H, m), 2.23 2.13 (2H, m), 1.89 (1H, brs), 1.76-1.12 (20H, m), 1.46 (3H, s), 1.12 (3H, s).

(Example 147)

(4aS,4bR,6aS,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl Hexadecaquino[2,1-f]quinoline-7(1H)-one

(step 1)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[tris-butyl(dimethyl)decyl]oxy}-6a,7-dihydroxy-10a,12a- Dimethylhexadenaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The compound obtained in Step 5 of Example 23 (3.00 g) was suspended in N,N-dimethylformamide (20 ml), and imidazole (1.41 g) and tributylbutyl chloride were added at room temperature. After the mixture was stirred at the same temperature for 2 hours, dichloromethane (10 ml) was added and further stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure to a slurry, the solid was collected by filtration. The obtained solid was washed with EtOAc (EtOAc) The residue was purified by EtOAc EtOAc EtOAc.

MS (ESI) m / z: 550 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.13 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 2.2, 10.5 Hz), 3.56 (1H, m), 3.43 (1H, m ), 3.40 (1H, d, J = 3.9 Hz), 3.36-3.25 (2H, m), 2.67 (1H, s), 2.21 (1H, m), 1.91 (1H, m), 1.87-1.33 (17H, m), 1.43 (3H, s), 1.30-1.16 (5H, m), 1.12 (3H, s), 1.02 (1H, s), 0.89 (9H, s), 0.084 (3H, s), 0.077 (3H) , s).

(Step 2)

(4aS, 4bR, 6aS, 8S, 10aR, 10bS, 12aS)-8-{[tris-butyl(dimethyl)decyl]oxy}-6a-hydroxy-10a,12a-dimethyl-1- [(2R)-tetrahydro-2H-pyran-2-ylcarbonyl]hexadecahydronaphtho[2,1-f]quinoline-7(1H)-one

The title compound (2.96 g) was obtained as a white solid.

MS (ESI) m/z: 548 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.11 (1H, dd, J = 8.1, 11.5 Hz), 4.11 (1H, m), 3.97 (1H, m), 3.60 (1H, m), 3.49 (1H, m), 3.39 (1H, m), 3.22 (1H, m), 2.11 (1H, m), 1.98-1.85 (3H, m), 1.83-1.46 (15H, m), 1.43 (3H, s), 1.38 (1H, m), 1.30-1.14 (4H, m), 0.91 (9H, s), 0.73 (3H, s), 0.10 (3H, s), 0.04 (3H, s).

(Step 3)

(4aS,4bR,6aS,8S,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl Hexadecaquino[2,1-f]quinoline-7(1H)-one

To a solution of the compound obtained in the above step 2 (2.87 g) in tetrahydrofuran (50 ml), acetic acid (0.90 ml) and fluorinated tetra n- Butylammonium (1 M tetrahydrofuran solution, 32 ml) was stirred at the same temperature for 1 hour, and then heated to 50 ° C and stirred for 15 hours. After the reaction mixture was concentrated, ethyl acetate and aq. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.91 (1H, dd, J = 7.8, 11.7 Hz), 4.10 (1H, m), 3.97 (1H, m), 3.60 (1H, m), 3.50 (1H, m), 3.39 (1H, m), 3.22 (1H, m), 2.19 (1H, m), 1.96 (1H, m), 1.92-1.45 (17H, m), 1.43 (3H, s), 1.38 (1H) , m), 1.30-1.15 (4H, m), 0.73 (3H, s).

(Example 148)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 8R, 10aR, 10bS, 12aS)-8-(ethinyloxy)-10a,12a-dimethyl-3,4,4a,4b,5,6,8,9,10, 10a, 10b, 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

After adding acetic acid (1.18 ml) and triphenylphosphine (3.59 g) to a solution of the compound (2.90 g) obtained in the step 3 of Example 19 in tetrahydrofuran (60 ml), azodicarboxylic acid di- A tertiary butyl ester (3.15 g) was stirred at the same temperature for 30 minutes. The reaction solution was poured into two layers of ethyl acetate and saturated aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc) elute

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.42 (1H, m), 5.11 (1H, m), 5.09 (2H, s), 3.77 (1H, m), 3.32 (1H) , m), 3.06 (1H, m), 2.20 (1H, m), 2.12-1.15 (15H, m), 2.04 (3H, s), 1.37 (3H, s), 1.01 - 0.83 (2H, m), 0.96 (3H, s).

(Step 2)

(1aS, 2R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-(ethenyloxy)-4a,6a-dimethyltetrahydrogen-1aH-oxirane [4a,5] Naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (992 mg) was obtained as a white solid.

MS (ESI) m/z: 482 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 4.91 (1H, dd, J) = 9.3, 7.3 Hz), 3.79 (1H, m), 3.36 (1H, m), 3.07 (1H, m), 2.84 (1H, s), 2.10 (3H, s), 2.06 (1H, m), 1.99 (1H, m), 1.87 (1H, m), 1.79-1.00 (15H, m), 1.37 (3H, s), 0.97 (3H, s).

(Step 3)

(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS)-8-(ethenyloxy)-6a,7-dihydroxy-10a,12a-dimethylhexadecane[2, 1-f]quinoline-1(2H)-benzyl formate

The title compound (1.00 g) was obtained as white crystals.

MS (ESI) m / z: 500 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 4.57 (1H, m), 3.90 (1H, brs), 3.76 (1H, m), 3.37 (1H, m), 3.06 (1H, m), 2.60 (1H, m), 2.12-2.03 (2H, m), 2.05 (3H, s) , 1.92-1.14 (16H, m), 1.35 (3H, s), 1.12 (3H, s), 0.86 (1H, m).

(Step 4)

(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS)-6a,7-dihydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinolin-8-yl Acetate

The title compound (211 mg) was obtained as a white solid.

MS (ESI) m/z: 366 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.46 (1H, brs), 3.81 (1H, m), 2.90 (1H, m), 2.73 (1H, m), 2.54 (1H, m), 2.05 (1H, m), 1.98 (3H, s), 1.93-1.79 (2H, m), 1.76-1.64 (3H, m), 1.62-1.51 (4H, m), 1.46 (1H, m), 1.38-1.23 (4H, m), 1.20-0.99 (2H, m), 1.16 (3H, s), 1.08 (3H, s), 0.82 (1H, m).

(Step 5)

(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS)-6a,7-dihydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2- Carbocarbonyl]octadeconaphtho[2,1-f]quinolin-8-yl acetate

The title compound (168 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m / z: 478 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.46 (1H, brs), 4.10 (1H, m), 3.97 (1H, m), 3.81 (1H, m), 3.59 (1H, m), 3.50 (1H, m), 3.40 (1H, m), 3.21 (1H, m), 2.56 (1H, m), 2.04 (1H, m), 1.99 (3H, s), 1.95-1.69 (7H, m), 1.68-1.46 (10H, m), 1.44 (3H, s), 1.29-1.17 (4H, m), 1.15 (3H, s), 0.91 (1H, m).

(Step 6)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (109 mg) was obtained as a white solid.

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, m), 3.85 (1H, d, J = 2.4 Hz), 3.59 (1H, m), 3.49 (1H, m) , 3.44 (1H, d, J = 1.0 Hz), 3.38 (1H, m), 3.20 (1H, m), 2.09-1.99 (2H, m), 1.93-1.85 (2H, m), 1.83-1.14 (20H , m), 1.43 (3H, s), 1.11 (3H, s).

(Example149-1)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7R,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(Example 149-2)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7R,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS,4bR,6aR,7R,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyl-8-oxohexadecane[2,1-f]quinoline- 1(2H)-benzyl formate (β-diol) and (4aS,4bR,6aS,7S,10aR,10bS,12aS)-6a,7-dihydroxy-10a,12a-dimethyl-8-side oxygen Hexadecaquino[2,1-f]quinoline-1(2H)-formic acid benzyl ester (α-diol)

The title compound (β-diol and α-diol) (1.58 g, β) was obtained as a mixture. :α=5:1).

MS (ESI) m / z: 456 (M+H) ⁺ .

(Step 2)

(4aS, 4bR, 6aR, 7R, 10aR, 10bS, 12aS)-7-(ethenyloxy)-6a-hydroxy-10a,12a-dimethyl-8-oxohexadecane [2, 1-f] quinoline-1(2H)-benzyl formate (β-acetate) and (4aS,4bR,6aS,7S,10aR,10bS,12aS)-7-(ethenyloxy)-6a -hydroxy-10a,12a-dimethyl-8-oxohexadecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (α-acetate)

The title compound (β-acetate) (874 mg) and the title compound (α-) were obtained as a white solid. Acetate) (236 mg).

--acetate

MS (ESI) m/z: 498 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.68 (1H, s), 5.09 (2H, s), 3.79 (1H, m), 3.36 (1H, m), 3.14 (1H) , m), 2.44 (1H, m), 2.33 (1H, m), 2.23 (3H, s), 2.04-1.96 (2H, m), 1.89-1.28 (13H, m), 1.37 (3H, s), 1.21 (1H, m), 1.02 (3H, s), 0.98 (1H, m).

--acetate

MS (ESI) m/z: 498 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.30 (1H, s), 5.08 (2H, s), 3.78 (1H, m), 3.33 (1H, m), 3.07 (1H) , m), 2.53-2.42 (2H, m), 2.21 (3H, s), 1.95 (1H, m), 1.83 (1H, m), 1.78-1.50 (10H, m), 1.44-1.33 (2H, m ), 1.37 (3H, s), 1.30-1.15 (3H, m), 1.23 (3H, s).

(Step 3)

(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS)-7-(ethenyloxy)-6a,8-dihydroxy-10a,12a-dimethylhexadecane[2, 1-f] quinoline-1(2H)-benzyl formate (8S-hydroxyl) and (4aS,4bR,6aS,7R,8R,10aR,10bS,12aS)-7-(ethenyloxy)- 6a,8-dihydroxy-10a, 12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester (8R-hydroxyl)

The compound (α-acetate) (231 mg) obtained in the above step 2 was suspended in methanol (20 ml), and sodium borohydride (10 mg) was added at 0 ° C and stirred at the same temperature for 1 hour. The reaction was stopped by adding borneol and a saturated aqueous solution of ammonium chloride to the reaction mixture. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8S-hydroxyl and 8R-hydroxyl) (211 mg).

(Step 4)

(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS)-7,8-bis(ethoxyloxy)-6a-hydroxy-10a,12a-dimethylhexadecane[2, 1-f]quinoline-1(2H)-benzyl formate (8S-acetate) And (4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS)-7,8-bis(ethylideneoxy)-6a-hydroxy-10a,12a-dimethylhexadecaphthalene[2 , 1-f] quinoline-1(2H)-benzyl formate (8R-acetate)

The title compound (8S-acetate and 8R-acetate) (191 mg, 8S: 8R) was obtained as a mixture. =1.1:1).

MS (ESI) m / z: 542 (M + H) +.

(Step 5)

(4aS,4bR,6aS,7R,8S,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinoline-7,8-diyl Diacetate (8S-acetate) and (4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS)-6a-hydroxy-10a, 12a-dimethyloctadecyl[2,1 -f] quinoline-7,8-diyl diacetate (8R-acetate)

The title compound (8S-acetate and 8R-acetate) (147 mg) was obtained as a mixture of the title compound (191 mg).

MS (ESI) m / z: 408 (M+H) ⁺ .

(Step 6)

(4aS, 4bR, 6aS, 7R, 8S, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl] Octadecahydronaphtho[2,1-f]quinoline-7,8-diyl diacetate (8S-acetate) and (4aS, 4bR, 6aS, 7R, 8R, 10aR, 10bS, 12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl] Octadenahydronaphtho[2,1-f]quinoline-7,8-diyldiacetate (8R-acetate)

The title compound (8S-acetic acid) was obtained from the title compound (yield: s. Ester and 8R-acetate) (205 mg).

MS (ESI) m/z: 520 (M+H) ⁺ .

(Step 7)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7R,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinolin-1(2H)-yl]methanone (8S-hydroxyl) and (2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7R,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinolin-1(2H)-yl]methanone (8R-hydroxyl)

The title compound (8S-hydroxyl) (68 mg) and the title compound (8R-hydroxyl) were obtained as a white solid. ) (51 mg).

8S-hydroxyl: Example 149-1

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, dd, J = 1.7, 12.0 Hz), 3.72 (1H, m), 3.59 (1H, m), 3.49 (1H, m), 3.38 (1H, m), 3.34 (1H, d, J = 9.3 Hz), 3.19 (1H, m), 1.94-1.13 (24H, m), 1.43 (3H, s), 0.95 (3H, s ).

8R-hydroxyl: Example 149-2

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 4.00-3.94 (2H, m), 3.59 (1H, m), 3.50 (1H, m), 3.49 (1H, d, J = 3.4 Hz), 3.38 (1H, m), 3.20 (1H, m), 1.96-1.37 (19H, m), 1.43 (3H, s), 1.30-1.13 (5H, m), 0.94 (3H, s).

(Embodiment 150)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H) -yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-8-(ethenyloxy)-6a-hydroxy-10a,12a-dimethylhexadenaphtho[2,1-f]quina Porphyrin-1(2H)-benzyl formate

The title compound (715 mg) was obtained from m.

MS (ESI) m/z: 484 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.18 (1H, m), 5.05 (2H, s), 3.75 (1H, m), 3.30 (1H, m), 3.14 (1H) , d, J = 1.5 Hz), 3.02 (1H, m), 2.04 (3H, s), 1.88-1.73 (4H, m), 1.70-1.43 (9H, m), 1.40-1.29 (5H, m), 1.33 (3H, s), 1.18-1.02 (2H, m), 0.88 (3H, s).

(Step 2)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyloctadecylnaphtho[2,1-f]quinolin-8-yl acetate

The title compound (348 mg) was obtained as white crystals.

MS (ESI) m / z: 350 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 5.05 (1H, m), 2.97 (1H, m), 2.82 (1H, dd, J = 4.9, 13.2 Hz), 2.01 (3H, s), 1.90 (1H, Dd, J = 3.9, 15.6 Hz), 1.87-1.24 (18H, m), 1.21-1.09 (2H, m), 1.13 (3H, s), 0.94 (3H, s).

(Step 3)

(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a-hydroxy-10a,12a-dimethyl-1-[(2R)-tetrahydro-2H-pyran-2-ylcarbonyl]18 Hydronaphtho[2,1-f]quinolin-8-yl acetate

The title compound (161 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 462 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.21 (1H, m), 4.04 (1H, m), 3.99 (1H, dd, J = 2.0, 10.7 Hz), 3.53 (1H, m), 3.44 (1H, m ), 3.34 - 3.25 (2H, m), 3.17 (1H, s), 2.07 (3H, s), 1.93-1.07 (26H, m), 1.44 (3H, s), 0.91 (3H, s).

(Step 4)

[(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1 (2H) -yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (104 mg) was obtained as a white solid.

MS (ESI) m / z: 420 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.07 (1H, dd, J = 4.1, 8.1 Hz), 4.03 (1H, m), 3.94 (1H, dd, J = 3.2, 10.5 Hz), 3.56 (1H, m), 3.47 (1H, m), 3.36 (1H, m), 3.18 (1H, m), 1.89-1.07 (26H, m), 1.41 (3H, s), 0.90 (3H, s).

(Example 151)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10,10a,12a -trimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 10aR, 10bS, 12aS)-10a, 12a-dimethyl-8-side oxygen-3,4,4a,4b,5,6,8,10a,10b,11,12,12a-ten Dihydronaphtho[2,1-f]quinoline-1(2H)-benzyl formate

The compound obtained in the second step of Example 19 (5.00 g) In a solution of alkane (60 ml), tert-Butyldimethylsilyl chloride (180 mg) and 2,3-dichloro-5,6-dicyano-p-benzoquinone were added at 0 °C. (3.50 g), the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into two layers of ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water (2 times), 10% aqueous sodium carbonate (3 times), water (3 times), and brine (2 times), and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (MeOH / methylene chloride). Compound (3.59 g).

MS (ESI) m / z: 420 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 7.04 (1H, d, J = 10.3 Hz), 6.24 (1H, dd, J = 1.7, 10.3 Hz), 6.07 (1H, s ), 5.08 (2H, s), 3.77 (1H, m), 3.33 (1H, m), 3.14 (1H, m), 2.50-2.34 (2H, m), 2.14 (1H, m), 1.90 - 1.13 ( 10H, m), 1.42 (3H, s), 1.20 (3H, s), 1.03 (1H, m).

(Step 2)

(4aS, 4bR, 10S, 10aR, 10bS, 12aS)-10,10a,12a-trimethyl-8-side oxygen-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

To a solution of the compound (2.89 g) obtained in the above step 1 in tetrahydrofuran (50 ml), copper (I) bromide (198 mg) and trimethyl aluminum (1.08 M hexane solution, 7.0 ml) were sequentially added at room temperature. And trimethylsilyl chloride (1.04 ml), and stirred at the same temperature for 1 hour. After adding water to the reaction solution, it is injected with ethyl acetate and saturated sodium bicarbonate water. The two layers of the solution were extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.70 (1H, s), 5.10 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 3.78 (1H, m), 3.36 (1H, m), 3.11 (1H, m), 2.72 (1H, dd, J = 4.6, 15.9 Hz), 2.38-2.31 (2H, m), 2.24-2.10 (2H, m), 2.01 (1H, m), 1.88 (1H, m), 1.81-1.65 (2H, m), 1.59-1.20 (7H, m), 1.40 (3H, s), 1.24 (3H, s), 0.96 (1H, m), 0.93 (3H, d, J = 7.3 Hz).

(Step 3)

(4aS, 4bR, 8S, 10S, 10aR, 10bS, 12aS)-8-hydroxy-10,10a,12a-trimethyl-3,4,4a,4b,5,6,8,9,10,10a, 10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (1.76 g) was obtained as white crystals.

MS (ES1) m / z: 438 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.26 (1H, d, J = 1.5 Hz), 5.10 (1H, d, J = 12.2 Hz), 5.06 (1H, d, J) =12.2 Hz), 4.25 (1H, m), 3.77 (1H, m), 3.34 (1H, m), 3.04 (1H, m), 2.17 (1H, m), 2.10 (1H, m), 1.93-1.80 (4H, m), 1.78-1.63 (3H, m), 1.56-1.07 (8H, m), 1.38 (3H, s), 1.10 (3H, s), 0.89 (3H, d, J = 6.8 Hz), 0.80 (1H, m).

(Step 4)

(1aS, 2S, 4S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-4,4a,6a-trimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho [2,1-f]quinoline-7(5H)-benzyl formate

The title compound (1.61 g) was obtained as white crystals.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.06 (1H, d, J = 12.7 Hz), 4.06 (1H, m), 3.76 (1H, m), 3.35 (1H, m), 3.11 (1H, d, J = 3.4 Hz), 3.01 (1H, m), 2.02 (1H, m), 1.96-0.89 (17H, m), 1.37 (3H, s), 1.08 (3H, s), 0.92 (3H, d, J = 7.3 Hz).

(Step 5)

(4aS, 4bR, 6aS, 7S, 8S, 10S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10,10a,12a-trimethylhexadena[2,1-f] Quinoline-1(2H)-benzyl formate

The title compound (1.03 g) was obtained as white crystals.

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.06 (1H, d, J = 12.7 Hz), 4.32 (1H, m), 3.78 (1H, m), 3.51 (1H, m), 3.35 (1H, m), 3.04 (1H, m), 2.42 (1H, brs), 2.18 (1H, m), 2.01 (1H, m), 1.90 -1.56 (8H, m), 1.52 (1H, m), 1.49-1.38 (3H, m), 1.36 (3H, s), 1.29-1.16 (4H, m), 1.14 (3H, s), 1.10 (3H) , d, J = 7.3 Hz), 1.08 (1H, s).

(Step 6)

(4aS, 4bR, 6aS, 7S, 8S, 10S, 10aR, 10bS, 12aS)-10,10a,12a-trimethylhexadenaphtho[2,1-f]quinoline-6a,7,8 ( 2H)-triol

The title compound (710 mg) was obtained.

MS (ESI) m/z: 338 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.25 (1H, m), 3.43 (1H, d, J = 2.9 Hz), 2.96 (1H, m), 2.80 (1H, m), 2.13-2.01 (2H, m), 1.83-1.11 (16H, m), 1.16 (3H, s), 1.14 (3H, d, J = 7.3 Hz), 1.13 (3H, s).

(Step 7)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10,10a,12a -trimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (141 mg) was obtained as white crystals (yield: 141 mg). .

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.33 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 2.4, 10.7 Hz), 3.56 (1H, m), 3.51 (1H, brs) ), 3.44 (1H, m), 3.36-3.27 (2H, m), 2.35 (1H, d, J = 2.4 Hz), 2.19 (1H, m), 2.01 (1H, m), 1.91 (1H, m) , 1.86-1.17 (21H, m), 1.45 (3H, s), 1.14 (3H, s), 1.10 (3H, d, J = 7.8 Hz), 1.03 (1H, s).

(Example 152)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,9R,10aR,10bS,12aS)-6a,7,8-trihydroxy-9,10a,12a -trimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 10aR, 10bS, 12aS)-9,10a,12a-trimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9,10,10a,10b,11 , 12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

After adding a solution of the compound (5.00 g) obtained in the step 2 of Example 19 in tetrahydrofuran (70 ml), a solution of lithium diisopropylamide (1.09 M, tetrahydrofuran solution) at -70 ° C for 5 minutes, and stirring for 30 minutes. . After adding methyl iodide (2.95 ml) at the same temperature, the mixture was heated to 0 ° C and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc)

MS (ESI) m / z: 436 (M+H) ⁺ .

(Step 2)

(4aS, 4bR, 9R, 10aR, 10bS, 12aS)-9,10a,12a-trimethyl-8-sideoxy-3,4,4a,4b,5,6,8,9,10,10a,10b , 11, 12, 12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

After adding 1,8-dioxabicyclo[5.4.0]-7-undecene (1.71 ml) at room temperature to a solution of the compound (2.49 g) obtained in the above step 1 in toluene (50 ml). Heat to reflux for 36 hours. The reaction solution was poured into two layers of ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with 0.5 N of hydrochloric acid, brine, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The residue obtained by EtOAc (EtOAc) elute

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.70 (1H, s), 5.08 (2H, s), 3.78 (1H, m), 3.34 (1H, m), 3.11 (1H) , m), 2.44 (1H, m), 2.37-2.26 (2H, m), 2.08-1.97 (2H, m), 1.85 (1H, m), 1.78-1.07 (9H, m), 1.39 (3H, s ), 1.18 (3H, s), 1.11 (3H, d, J = 6.3 Hz), 1.05 - 0.94 (2H, m).

(Step 3)

(4aS, 4bR, 8S, 9R, 10aR, 10bS, 12aS)-8-hydroxy-9,10a,12a-trimethyl-3,4,4a,4b,5,6,8,9,10,10a, 10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The title compound (1.53 g) was obtained as white crystals.

MS (ESI) m / z: 438 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.28 (5H, m), 5.23 (1H, s), 5.08 (2H, s), 3.77 (1H, m), 3.67 (1H, m), 3.32 (1H) , m), 3.05 (1H, m), 2.15 (1H, m), 2.07 (1H, m), 1.93 (1H, m), 1.83 (1H, m), 1.76-0.99 (12H, m), 1.36 ( 3H, s), 1.05 (3H, d, J = 6.3 Hz), 1.01 (3H, s), 0.90-0.79 (2H, m).

(Step 4)

(1aS, 2S, 3R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-3,4a,6a-trimethyltetradecane-1aH-oxirane [4a,5]naphtho [2,1-f]quinoline-7(5H)-benzyl formate

The title compound (418 mg) was obtained.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.78 (1H, m), 3.39 (1H, t, J = 9.5 Hz), 3.33 (1H, m ), 3.14 (1H, s), 3.05 (1H, m), 2.00-0.94 (17H, m), 1.36 (3H, s), 1.01 (3H, s), 0.95 (3H, d, J = 6.3 Hz) , 0.87 (1H, t, J = 13.4 Hz).

(Step 5)

(4aS, 4bR, 6aS, 7S, 8S, 9R, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-9,10a,12a-trimethylhexadena[2,1-f] Quinoline-1(2H)-benzyl formate

The title compound (384 mg) was obtained as a white solid.

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.78 (1H, m), 3.68 (1H, m), 3.54 (1H, brs), 3.34 (1H) , m), 3.04 (1H, m), 2.34 (1H, d, J = 2.0 Hz), 2.18 (1H, m), 1.88-1.15 (17H, m), 1.35 (3H, s), 1.13 (3H, s), 1.08 (1H, s), 1.03 (3H, d, J = 6.3 Hz).

(Step 6)

(3aS, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,4,5a,7a-pentamethylhexadecahydro[1,3]dioxolanyl And [5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (434 mg) was obtained from m.

MS (ESI) m/z: 512 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.08 (2H, s), 3.83-3.75 (3H, m), 3.34 (1H, m), 3.04 (1H, m), 2.05 (1H, m), 1.87-1.64 (5H, m), 1.60 (1H, m), 1.54-1.10 (11H, m), 1.49 (3H, s), 1.36 (3H, s), 1.32 (3H, s ), 1.13 (3H, s), 1.01 (3H, d, J = 6.3 Hz).

(Step 7)

(3aS, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-2,2,4,5a,7a-pentamethylhexahydro[1,3]dioxolanyl[5, 6]Naphtho[2,1-f]quinoline-13a(4H)-alcohol

The title compound (304 mg) was obtained from m.

MS (ESI) m/z: 378 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 3.85 (1H, d, J = 5.4 Hz), 3.77 (1H, dd, J = 9.3, 5.4 Hz), 3.20 (1H, m), 3.10 (1H, m) , 2.03-1.94 (2H, m), 1.89-1.81 (2H, m), 1.79-1.59 (6H, m), 1.48-1.22 (8H, m), 1.44 (3H, s), 1.32 (3H, s) , 1.29 (3H, s), 1.17 (3H, s), 0.98 (3H, d, J = 6.8 Hz).

(Step 8)

[(3aS, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,4,5a,7a-pentamethylhexadecahydro[1,3]dioxolane [5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (119 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 490 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.97 (1H, dd, J = 2.2, 10.5 Hz), 3.82-3.80 (2H, m), 3.56 (1H, m), 3.43 (1H) , m), 3.35-3.27 (2H, m), 2.05 (1H, m), 1.91 (1H, d, J = 10.3 Hz), 1.87-1.16 (21H, m), 1.49 (3H, s), 1.44 ( 3H, s), 1.33 (3H, s), 1.17 (1H, s), 1.13 (3H, s), 1.01 (3H, d, J = 6.3 Hz).

(Step 9)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,9R,10aR,10bS,12aS)-6a,7,8-trihydroxy-9,10a,12a -trimethylhexadehydronaphtho[2,1-f]quinoline-1(2-H)-yl]methanone

The title compound (103 mg) was obtained as a white solid.

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.96 (1H, dd, J = 2.4, 10.7 Hz), 3.67 (1H, m), 3.59-3.52 (2H, m), 3.43 (1H) , m), 3.35-3.26 (2H, m), 2.36 (1H, d, J = 2.9 Hz), 2.19 (1H, m), 1.95-1.15 (22H, m), 1.89 (1H, d, J = 6.3 Hz), 1.43 (3H, s), 1.13 (3H, s), 1.07 (1H, s), 1.03 (3H, d, J = 6.3 Hz).

(Example 153)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-8,10a,12a-three Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(1aR, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-4a, 6a-dimethyl-2-oxotetradecane-1aH-oxirane [4a,5]naphtho[2,1- f] quinoline-7(5H)-benzyl formate

The title compound (893 mg) was obtained as white white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 3.78 (1H, m), 3.34 (1H, m), 3.10 (1H, m), 2.99 (1H, s), 2.31 (1H, m), 2.20 (1H, m), 2.13 (1H, m), 2.06 (1H, m), 1.87 -1.78(2H,m),1.76-1.64(2H,m),1.62-1.09(9H,m),1.37(3H,s),1.11(3H,s),1.03(1H,d,J=6.3Hz ).

(Step 2)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-2,4a,6a-trimethyltetradecahydro-1aH-oxirane [4a,5]naphtho[2] , 1-f] quinolin-7(5H)-benzyl formate (2S body: Rf=higher) and (1aS, 2R, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-2,4a , 6a-trimethyltetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester (2R body: Rf=lower)

Methylmagnesium bromide (0.92 M tetrahydrofuran solution, 3.9 ml) was added to a solution of the compound (yield: 780 mg) in THF (15 ml), and the mixture was stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction. The reaction solution was poured into two layers of ethyl acetate and brine, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2 s. 492mg).

2S body (Rf=higher: low polarity)

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.10 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.2 Hz), 3.78 (1H, m), 3.36 (1H, m), 3.06 (1H, m), 2.82 (1H, s), 2.65 (1H, s), 2.08 (1H, m), 1.99 (1H, m), 1.85 (1H, m), 1.79 - 1.09 (14H, m), 1.36 (3H, s), 1.34 (3H, s), 0.99 (3H, s), 0.92 (1H, m).

2R body (Rf=lower: high polarity)

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 3.79 (1H, m), 3.33(1H,m), 3.05(1H,m), 2.74(1H,s),2.05(1H,m),1.96(1H,m),1.92-1,79(2H,m),1,77- 1.64 (2H, m), 1.62-1.51 (2H, m), 1.50-0.98 (11H, m), 1.36 (3H, s), 1.33 (3H, s), 0.96 (3H, s).

(Step 3)

(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-8,10a,12a-trimethylhexadenaphtho[2,1-f]quinoline -1(2H)-benzyl formate

The compound (2R body) (492 mg) obtained in the above step 2 To the solution of alkane (9.0 ml), water and sulfuric acid (3M aqueous solution, 0.362 ml) were added at room temperature, and the mixture was stirred at the same temperature for 8 hours, and then allowed to stand overnight. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, it was poured into two layers of dichloromethane and saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane: methanol (10:1). After the organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated. After the methylene chloride was added to the obtained solid, the title compound (208 mg) was obtained. The residue was purified by EtOAc EtOAcjjjjjjj

MS (ESI) m/z: 472 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.07 (1H, d, J = 12.7 Hz), 5.04 (1H, d, J = 12.7 Hz), 3.75 (1H, m), 3.54 (1H, brs), 3.30 (1H, m), 3.25 (1H, dd, J = 1.5, 4.9 Hz), 3.01 (1H, m), 2.95 (1H, brs), 2.02 (1H, m), 1.87 (1H, m), 1.80 (1H, m), 1.72 (1H, d, J = 4.9 Hz), 1.71-1.22 (13H, m), 1.32 (3H, s), 1.26 (3H, s), 1.20- 1.09 (2H, m), 1.04 (3H, s).

(Step 4)

(4aS, 4bR, 6aS, 7S, 8R, 10aR, 10bS, 12aS)-8,10a,12a-trimethylhexadenaphtho[2,1-f]quinoline-6a,7,8(2H) -triol

The title compound (229 mg) was obtained as a white solid.

MS (ESI) m/z: 338 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 3.28 (1H, brs), 2.90 (1H, m), 2.77 (1H, m), 2.06 (1H, m), 1.90 (1H, m), 1.81-0.97 (21H , m), 1.28 (3H, s), 1.09 (3H, s), 1.04 (3H, s).

(Step 5)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-8,10a,12a-three Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (104 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CD ₃ OD) δ: 4.10 (1H, m), 3.97 (1H, dd, J = 3.4, 11.2 Hz), 3.59 (1H, m), 3.49 (1H, m), 3.38 (1H, m), 3.19 (1H, m), 3.13 (1H, d, J = 1.5 Hz), 2.09 (1H, m), 1.93-1.15 (23H, m), 1.43 (3H, s), 1.20 (3H, s ), 1.07 (3H, s).

(Example 154)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-7,10a,12a-three Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-{[tris-butyl(dimethyl)decyl]oxy}-6a,7-dihydroxy-7,10a, 12a-trimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

Methylmagnesium bromide (0.92 M tetrahydrofuran solution, 4.0 ml) was added at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into two layers of diethyl ether and a saturated aqueous ammonium chloride solution to stop the reaction. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. Will filter After the liquid was concentrated under reduced pressure to a slurry, the solid was collected by filtration. The obtained solid was washed with EtOAc (EtOAc) The residue was purified by EtOAc EtOAc EtOAc.

MS (ESI) m/z: 564 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.96 (1H, dd, J = 2.4, 10.7 Hz), 3.79 (1H, dd, J = 5.6, 11.5 Hz), 3.55 (1H, m ), 3.43 (1H, m), 3.36-3.26 (2H, m), 2.32 (1H, s), 1.97-1.06 (25H, m), 1.42 (3H, s), 1.17 (6H, s), 0.90 ( 9H, s), 0.084 (3H, s), 0.075 (3H, s).

(Step 2)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-7,10a,12a-three Methylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

To a solution of the compound (499 mg) in EtOAc (EtOAc m. The reaction solution was poured into two layers of chloroform and saturated brine, and extracted with chloroform:methanol (10:1). The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography eluting eluting (302 mg).

MS (ESI) m / z: 450 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 4.00 (1H, m), 3.94 (1H, dd, J = 2.4, 10.7 Hz), 3.75 (1H, m), 3.53 (1H, m), 3.41 (1H, m ), 3.34 - 3.21 (2H, m), 1.93-1.85 (2H, m), 1.82-1.58 (12H, m), 1.52-1.35 (8H, m), 1.40 (3H, s), 1.26 (3H, s ), 1.23-1.08 (5H, m), 1.13 (3H, s).

(Example 155)

[(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(3aS, 5aS, 5bR, 7aS, 11aS, 11bS, 13aS, 13bS)-5b-fluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl And [5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The compound (2.37 g) obtained in the step 8 of Example 42 was used to obtain a hydrolyzed product by the same procedure as in Step 4 of Example 31. Using the obtained hydrolyzed product, the title compound (1.55 g) was obtained.

MS (ESI) m/z: 516 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.08 (2H, s), 4.36 (1H, m), 3.92-3.84 (2H, m), 3.77 (1H, m), 3.43 -3.38(1H,m), 2.93(1H,m),2.11-1.95(5H,m),1.91-1.21(12H,m), 1.50(3H,s),1.38(3H,s),1.32(3H , s), 1.25 (3H, s).

(Step 2)

(3aS, 5aS, 5bR, 7aS, 11aS, 11bS, 13aS, 13bS)-5b-fluoro-2,2,5a,7a-tetramethylhexadecano[1,3]dioxolanyl[5, 6]Naphtho[2,1-f]quinoline-13a(4H)-alcohol

The title compound (0.133 g) was obtained from m.

MS (ESI) m/z: 382 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.36 (1H, m), 3.93-3.84 (2H, m), 2.91 (1H, m), 2.82 (1H, dd, J = 13.2, 4.9), 2.05-1.89 ( 5H), 1.77-1.09 (14H, m), 1.51 (3H, s), 1.32 (3H, s), 1.27 (3H, s), 1.09 (3H, s).

(Step 3)

[(3aS,5aS,5bR,7aS,11aS,11bS,13aS,13bS)-5b-fluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolane [5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (0.17 g) was obtained as a white solid. ).

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.38-4.34 (1H, m), 4.04 (1H, m), 3.98 (1H, dd, J=11.0, 2.2 Hz), 3.93-3.84 (2H, m), 3.59 (1H, m), 3.45 (1H, m), 3.41-3.35 (1H, m), 3.19-3.15 (1H, m), 2.13-2.07 (1H, m), 2.05-1.20 (22H, m), 1.51 (3H, s), 1.46 (3H, s), 1.32 (3H, s), 1.25 (3H, s).

(Step 4)

[(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (88 mg) was obtained from m.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.26 (1H, m), 4.04 (1H, m), 3.98 (1H, dd, J = 10.7, 2.4 Hz), 3.88 (1H, d, J = 36.1 Hz), 3.60-3.55(2H,m), 3.44(1H,m), 3.38(1H,m), 3.18-3.13(1H,m),2.41(1H,br),2.16-1.20(23H,m),1.45( 3H, s), 1.25 (3H, s), 1.13 (1H, d, J = 5.9 Hz).

(Example 156)

[(4aS,4bR,6aS,7S,8R,9R,10aR,10bS,12aS)-9-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

(2α,3β,4β,5α,17β)-2-androstane-3,4,5,17-furan ((2α,3β,4β,5α,17β)-2-androstane-3,4,5, 17-tetrole)

Adding a solution of (2α,17β)-2-fluoro-17-hydroxyandrost-4-en-3-one (13.6g) in tetrahydrofuran (400ml) in an ice bath with tri-tertiary butoxide aluminum hydride Lithium Tri-tert-butoxyaluminum Hydride (1 M tetrahydrofuran solution, 100 ml) was stirred at room temperature for 1 hour under a nitrogen atmosphere. Water (2.7 ml), 5 equivalents of sodium hydroxide solution (2.7 ml), and water (8.1 ml) were added thereto in an ice bath, and the mixture was stirred at room temperature, and the precipitated solid was filtered over Celite. The filtrate was concentrated under reduced pressure to give an alcohol. Using the obtained alcohol, an epoxy compound (13.9 g) was obtained by the same procedure as in the step 2 of Example 1. The title compound (8.00 g) was obtained as a white solid.

¹ H-NMR (CD ₃ OD) δ: 4.69 (1H, m), 4.07 (1H, m), 3.62-3.53 (2H, m), 2.11 (1H, m), 1.97 (1H, m), 1.86- 1.75 (2H, m), 1.68-0.97 (13H, s), 1.19 (3H, s), 0.72 (3H, s).

(Step 2)

(3aR, 4R, 5aR, 5bS, 7aS, 8S, 10aS, 10bS, 12aS, 12bS)-4-fluoro-2,2,5a,7a-tetramethylhexadecahydro-12aH-cyclopenta[7,8] Phenanthro[1,2-d][1,3]dioxolan-8,12a-diol

The title compound (4.82 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.83-4.68 (1H, m), 4.32 (1H, m), 3.98 (1H, dd, J = 6.3, 2.4 Hz), 3.65 (1H, m), 2.11-2.02 (2H, m), 1.88-1.71 (3H, m), 1.65-1.01 (14H, m), 1.53 (3H, s), 1.35 (3H, s), 1.17 (3H, s), 0.75 (3H, s ).

(Step 3)

(3aR, 4R, 5aR, 5bS, 7aS, 10aS, 10bR, 12aS, 12bS)-4-fluoro-12a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro-8H-cyclopenta[7, 8]phenanthroline [1,2-d][1,3]dioxolan-8-one

The title compound (2.82 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.83-4.68 (1H, m), 4.33 (1H, m), 3.99 (1H, dd, J = 5.9, 2.4 Hz), 2.46 (1H, dd, J = 19.0, 8.8 Hz), 2.14-2.05 (2H, m), 1.98-1.93 (1H, m), 1.87-1.64 (5H, m), 1.61-1.27 (9H, m), 1.54 (3H, s), 1.36 (3H) , s), 1.19 (3H, s). 088 (3H, s).

(Step 4)

(3aR, 4R, 5aR, 5bS, 7aS, 10aS, 10bS, 12aS, 12bS)-4-fluoro-8-(hydroxyimino)-2,2,5a,7a-tetramethylhexadecahydro-12aH- Cyclopenta[7,8]phenanthro[1,2-d][1,3]dioxolan-12a-ol

The title compound (3.17 g) was obtained as a mixture of the mixture.

MS (ESI) m/z: 396 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.83-4.68 (1H, m), 4.33 (1H, m), 3.99 (1H, dd, J = 5.9, 2.4 Hz), 2.70-2.23 (2H, m), 2.14 -2.04 (1H, m), 1.93-1.24 (16H, m), 1.53 (3H, s), 1.36 (3H, s), 1.21 - 0.89 (6H, m).

(Step 5)

(3aR, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-4-fluoro-2,2,5a,7a-tetramethylhexadehydro[1,3]dioxolanyl[ 5,6]naphtho[2,1-f]quinoline-13a(4H)-ol

After adding the diisobutylaluminum hydride (1.04 M toluene solution, 11 ml) at -78 ° C under a nitrogen atmosphere in a solution of the compound (0.45 g) obtained in the above step 4 in dichloromethane (25 ml) Stir at 0 ° C for 25 minutes. After cooling again to -78 ° C, ethyl acetate (5 ml) and methanol (10 ml) and a solution of Rochelle salt (150 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted twice with dichloromethane:methanol (10:1). The organic layer was concentrated under reduced vacuo.

MS (ESI) m/z: 382 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4,82-4.67 (1H, m), 4.32 (1H, m), 4.00 (1H, dd, J = 6.3, 2.4 Hz), 2.91 (1H, m), 2.78 (1H, dd, J = 12.7, 4.9 Hz), 2.01 (1H, m), 1.86-0.95 (18H, m), 1.53 (3H, s), 1.35 (3H, s), 1.14 (3H, s), 1.05 (3H, s).

(Step 6)

[(3aR, 4R, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-4-fluoro-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxo Pentocyclo[5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (30 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.81-4.66 (1H, m), 4.32 (1H, m), 4.05-3.94 (3H, m), 3.57 (1H, m), 3.43 (1H, m), 3.35 -3.28 (2H, m), 2.03 (1H, m), 1.93-1.18 (22H, m), 1.52 (3H, s), 1.44 (3H, s), 1.35 (3H, s), 1.12 (3H, s ).

(Step 7)

[(4aS,4bR,6aS,7S,8R,9R,10aR,10bS,12aS)-9-fluoro-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane[2,1 -f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The title compound (27 mg) was obtained as a white solid.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.85-4.70 (1H, m), 4.22 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 10.7, 2.4 Hz) 3.75 (1H, m), 3.57 (1H, m), 3.43 (1H, m), 3.36-3.27 (2H, m), 2.18 (1H, m), 1.93-1.11 (24H, m), 1.43 (3H, s), 1.16 (3H, s).

(Example 157)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl (2,2,6,6,7,8,9,9- ² H ₈ ) hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(4aS, 4bR, 8S, 10aR, 10bS, 12aS)-8-hydroxy-10a, 12a-dimethyl (2,2,6,6,7,8,9,9- ² H ₈ )-3,4 , 4a, 4b, 5,6,8,9,10,10a,10b,11,12,12a-tetradecahydronaphtho[2,1-f]quinoline-1(2H)-formic acid benzyl ester

The compound obtained in Step 3 of Example 39 (1.00 g) was suspended in tetrahydromethanol (10 ml), and 1,8-dioxinbicyclo[5.4.0]-7-undecene (0.02) was added at room temperature. After ml), heat to reflux. In the middle of the reaction, tetrahydrofurfuryl alcohol (20 ml) and 1,8-dioxabicyclo[5.4.0]-7-undecene (0.684 ml) were gradually added and heated under reflux for 50 hours. The reaction liquid was cooled to 0 ° C, and anhydrous cesium chloride (640 mg) and sodium borohydride (100 mg) were added, and the mixture was stirred for 4 hours while warming to room temperature. After the reaction mixture was diluted with dichloromethane, the insoluble material was filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate /hexane)

MS (ESI) m / z: 432 (M + H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.09 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 3.05 (1H, m), 1.92 (1H, dd, J=3.4, 12.7 Hz), 1.83 (1H, m), 1.75-1.61 (3H, m), 1.57 (1H, m), 1.47 (1H, m), 1.41-1.29 (3H, m), 1.36 (3H, s), 1.26-1.15 (3H, m), 1.01 (3H, s), 0.88-0.81 (2H, m).

(Step 2)

(1aS, 2S, 4aR, 4bS, 6aS, 10aS, 10bR, 12aR)-2-hydroxy-4a, 6a-dimethyl (1a, ² , 3, ^3, _{8, 8} , 12, 12-2 H ₈ ) Tetrahydrogen-1aH-oxirane [4a,5]naphtho[2,1-f]quinoline-7(5H)-formic acid benzyl ester

The title compound (668 mg) was obtained as white crystals.

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.10 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 12.7 Hz), 3.06 (1H, m), 2.21 (1H, s), 1.96 (1H, dd, J = 3.7, 12.9 Hz), 1.84 (1H, m), 1.77-0.90 (12H, m), 1.36 (3H, s), 0.99 (3H, s) .

(Step 3)

(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl (2,2,6,6,7,8,9,9 - ² H ₈ ) hexadehydronaphtho[2,1-f]quinoline-1(2H)-benzyl formate

The title compound (532 mg) was obtained as a white solid.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.36-7.27 (5H, m), 5.04 (2H, s), 2.97 (1H, m), 1.88 (1H, m), 1.73-1.29 (11H, m), 1.34 (3H, s), 1.27-1.13 (2H, m), 1.10 (3H, s).

(Step 4)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-13a-hydroxy-2,2,5a,7a-tetramethyl (3a,4,4,9,9,13,13,13b- ² H ₈ ) Hexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-formic acid benzyl ester

The title compound (489 mg) was obtained as a white solid.

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.09 (1H, d, J = 12.2 Hz), 5.07 (1H, d, J = 12.2 Hz), 3.04 (1H, m), 1.83 (1H, m), 1.74-1.29 (10H, m), 1.51 (3H, s), 1.36 (3H, s), 1.31 (3H, s), 1.27-1.14 (3H, m), 1.19 (1H, s), 1.12 (3H, s).

(Step 5)

(3aS, 5aR, 5bS, 7aS, 11aS, 11bR, 13aS, 13bS)-2,2,5a,7a-tetramethyl (3a,4,4,9,9,13,13,13b- ² H ₈ ) Hexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-13a(4H)-ol

The title compound (319 mg) was obtained from m.

MS (ESI) m/z: 372 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 1.76-1.66 (2H, m), 1.62-1.23 (11H, m), 1.44 (3H, s), 1.25 (3H, s), 1.17-1.02 (2H, m ), 1.12 (3H, s), 1.05 (3H, s).

(Step 6)

[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethyl (3a,4,4,9,9,13,13,13b - ² H ₈ )hexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R)-tetrahydro -2H-pyran-2-yl]methanone

The title compound (370 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 484 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.03 (1H, m), 3.97 (1H, dd, J = 2.4, 10.7 Hz), 3.43 (1H, m), 3.24 (1H, m), 1.92-1.12 (21H , m), 1.49 (3H, s), 1.41 (3H, s), 1.28 (3H, s), 1.09 (3H, s).

(Step 7)

(2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl (2,2,6,6,7,8,9,9- ² H ₈ ) hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (221 mg) was obtained as a white solid.

MS (ESI) m / z: 444 (M + H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.09 (1H, m), 3.97 (1H, dd, J = 2.9, 10.7 Hz), 3.49 (1H, m), 3.18 (1H, m), 1.94-1.14 ( 20H, m), 1.42 (3H, s), 1.11 (3H, s).

(Example 158)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-(difluoromethoxy)-6a,7-dihydroxy-10a,12a-dimethylhexadecane[2] ,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-8-(difluoromethoxy)-6a,7-dihydroxy-10a,12a-dimethylhexadecane[2] ,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone

The compound (200 mg) obtained in Step 5 of Example 23 was added to a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.100 ml) in acetonitrile (5.0 ml). After that, it was stirred at 60 ° C for 2 hours. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, the mixture was poured into dichloromethane and aqueous sodium hydrogen carbonate aqueous solution and extracted with dichloromethane: methanol (10:1). After the organic layer was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/hexane) and reverse phase high performance liquid chromatography [with 0.1% formic acid. Purification of acetonitrile / EtOAc (EtOAc)

MS (ESI) m/z: 486 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 6.29 (1H, t, J = 75.2 Hz), 4.66 (1H, m), 4.03 (1H, m), 3.97 (1H, dd, J = 2.0, 10.7 Hz), 3.66 (1H, brs), 3.56 (1H, m), 3.43 (1H, m), 3.35-3.26 (2H, m), 2.24 (1H, m), 2.06 (1H, d, J = 1.5 Hz), 1.95 -1.16 (23H, m), 1.43 (3H, s), 1.13 (3H, s), 1.12 (1H, s).

(Example 159)

[(2R,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(2RS, 5SR)-5-fluorotetrahydro-2H-pyran-2-yl]methanol (trans-form) and [(2RS, 5RS)-5-fluorotetrahydro-2H-pyran-2-yl]methanol (cis isomer)

To a solution of 2-fluorohex-5-en-1-ol (1.85 g) in dichloromethane, 3-chloroperoxybenzoic acid (4.1 g) was added, and stirred at room temperature overnight, then added camphorsulfonic acid (0.73 g), further stirred for 20 minutes. After adding 1 equivalent of an aqueous sodium hydroxide solution to make a basic solution, a sodium sulfate aqueous solution was added thereto, and the mixture was stirred at room temperature for 15 minutes. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography eluting elut elut elut elut elut Formula) (0.30 g).

Trans-body

¹ H-NMR (CDCl ₃ ) δ: 4.62-4.46 (1H, m), 4.15 (1H, m), 3.62 (1H, m), 3.52 (1H, dd, J=11.5, 7.1 Hz), 3.42 (1H) , m), 3.32 (1H, m) 2.30-2.24 (1H, m), 2.01 (1H, br), 1.75-1.61 (2H, m), 1.50-1.41 (1H, m).

Cis body

¹ H-NMR (CDCl ₃ ) δ: 4.67-4.57 (1H, m), 4.21-4.14 (1H, m), 3.68-3.53 (3H, m), 3.53-3.46 (1H, m), 2.24-2.13 ( 1H, m), 2.10 (1H, br), 1.85-1.65 (2H, m), 1.49-1.38 (1H, m).

(Step 2)

(2RS, 5SR)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid

To a solution of the compound (trans isomer) (0.16 g) in acetonitrile (15 ml)-water (15 ml) obtained in step 1, diacetoxyiodobenzene (0.85 g) and ruthantane-N were added. -Oxyl (9 mg), stirred at room temperature for 1 hour. To the reaction mixture was added 5 equivalents of aqueous sodium hydroxide solution to make a basic solution, and the mixture was washed twice with dichloromethane. An aqueous sodium sulfite solution and 5 equivalents of hydrochloric acid were added to the obtained aqueous layer to acidify, and extracted with dichloromethane and ethyl acetate. The organic layer was dried over anhydrous MgSO.

¹ H-NMR (CDCl ₃ ) δ: 4.68-4.54 (1H, m), 4.21 (1H, m), 4.14-4.12-(1H, m), 3.58-3.50 (1H, m), 2.33-2.17 (2H , m), 1.86-1.76 (2H, m).

(Step 3)

[(2S,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a , 7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone (5R-fluorine Body: Rf=higher) and [(2R,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a , 7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone (5S-fluorine Body: Rf=lower)

The title compound was obtained as a white solid (yield of the title compound (yield: 5R-Fluoro) (110 mg) and the title compound (5S-fluoro) (70 mg).

5R-fluoride: Rf=higher

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.57 (1H, m), 4.30 (1H, m), 4.16 (1H, dd, J = 6.8, 3.9 Hz), 3.92 (1H, m), 3.80 (1H, d , J=5.4Hz), 3.60-3.44(2H,m), 3.39(1H,m), 3.26(1H,m), 2.24(1H,m),2.11-1.13(22H,m),1.52(3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

5S-fluoride: Rf=lower

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.60 (1H, m), 4.30 (1H, m), 4.11 (1H, m), 4.06 (1H, dd, J = 7.3, 4.4 Hz), 3.79 (1H, d , J = 5.4 Hz), 3.55 (1H, m), 3.43 (1H, m), 3.32 (1H, m), 3.25 (1H, m), 2.33 (1H, m), 2.07 (1H, m), 1.92 - 1.13 (21H, m), 1.52 (3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Step 4)

[(2R,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (55 mg) was obtained as a white solid.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.66 (1H, m), 4.3-4.05 (3H, m), 3.58-3.52 (2H, m), 3.43 (1H, m), 3.32 (1H, m), 3.24 (1H,m), 2.37-2.27(2H,m), 2.23-2.17(1H,m),1.92-1.03(21H,m),1.43(3H,s),1.12(3H,s),1.03(1H , s).

(Embodiment 160)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2RS, 5RS)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid

The title compound (0.21 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 4.64 (1H, d, J = 46.4 Hz), 4.27 (1H, m), 4.05 (1H, t, J = 7.1 Hz), 3.69 (1H, dd, J = 38.1) , 13.2 Hz), 2.25 (1H, m), 2.06-1.97 (2H, m), 1.84 (1H, m).

(Step 2)

[(2S,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a , 7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone (5S-fluorine体:Rf=higher) and [(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a- Hydroxy-2,2,5a,7a-tetramethylhexadecano[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl Methyl ketone (5R-fluoride: Rf=lower)

The title compound was obtained as a white solid (yield of the title compound (yield of the title compound (0.13g) 5S-Fluoro) (70 mg) and the title compound (5R-fluoro) (70 mg).

5S-fluoride: Rf=higher

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.58 (1H, brd, J = 47.3 Hz), 4.30 (1H, m), 4.07-3.98 (2H, m), 3.80 (1H, d, J = 5.4 Hz), 3.59 (1H, dd, J=33.2, 12.7 Hz), 3.50-3.42 (2H, m), 3.25 (1H, m), 2.24-2.02 (2H, m), 1.88-1.13 (20H, m), 1.52 ( 3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.19 (1H, s), 1.13 (3H, s).

5R-fluoride: Rf=lower

MS (ESI) m/z: 494 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.59 (1H, brd, J = 47.3 Hz), 4.30 (1H, m), 4.14 (1H, m), 4.01 (1H, brd, J = 10.7 Hz), 3.80 ( 1H,d,J=5.4Hz), 3.64-3.49(2H,m), 3.40-3.33(1H,m), 3.29-3.24(1H,m), 2.25-2.04(3H,m),1.88-1.17( 19H, m), 1.52 (3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.17 (1H, s), 1.13 (3H, s).

(Step 3)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (63 mg) was obtained as a white solid.

MS (ESI) m/z: 454 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.59 (1H, brd, J = 46.9 Hz), 4.16 - 4.11 (2H, m), 4.01 (1H, brd, J = 10.3 Hz), 3.6 - 3.50 (3H, m ), 3.36 (1H, m), 3.26 (1H, m), 2.36-2.10 (5H, m), 1.87-1.07 (20H, m), 1.43 (3H, s), 1.12 (3H, s).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 7, and the peak having a relative intensity of 24 or more in the case where the maximum peak intensity in Fig. 7 is 100 is shown in Table 7.

(Example 161)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone

(step 1)

[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy-8-methoxy-10a,12a-dimethylhexadecaphthalene[2,1-f Quinoline-1(2H)-yl][(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]methanone

The title compound was obtained as a white solid (yield: Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound 70mg).

¹ H-NMR (CDCl ₃ ) δ: 4.59 (1H, brd, J = 47.8 Hz), 4.13 (1H, m), 4.01 (1H, brd, J = 10.7 Hz), 3.69-3.51 (4H, m), 3.42-3.32(1H,m), 3.39(3H,s), 3.27-3.25(1H,m), 2.31(1H,s), 2.26-2.13(3H,m),1.90-1.57(9H,m), 1.51-1.18 (10H, m), 1.43 (3H, s), 1.12 (3H, s), 1.06 (1H, s).

(Example 162)

[(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(2RS, 4SR)-2-[(benzyloxy)methyl]-4-fluorotetrahydro-2H-pyran (cis isomer) and (2RS, 4RS)-2-[(benzyloxy) Methyl]-4-fluorotetrahydro-2H-pyran (trans-form)

To a solution of benzyloxyacetaldehyde (5g) and 3-buten-1-ol (2.84ml) in dichloromethane (165ml), EtOAc (4.53ml) Stir at room temperature for 30 minutes. After adding a potassium carbonate aqueous solution to the reaction liquid, it was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~ ).

(Step 2)

[(2RS, 4SR)-4-fluorotetrahydro-2H-pyran-2-yl]methanol (cis isomer) and [(2RS, 4RS)-4-fluorotetrahydro-2H-pyran-2-yl Methanol (trans-body)

Using the compound obtained in the above step 1 (6.02 g) and 20% of palladium hydroxide as a catalyst, the title compound was obtained as a colorless oil. (0.84 g) and the title compound (trans-form) (0.60 g).

Cis body

¹ H-NMR (CDCl ₃ ) δ: 4.79-4.63 (1H, m), 4.14 - 4.05 (1H, m), 3.65 (1H, dd, J = 11.5, 3.2 Hz), 3.60 (1H, dd, J = 11.7, 6.8 Hz), 3.48-3.39 (2H, m), 2.09-1.99 (2H, m), 1.79-1.46 (2H, m).

Trans-body

¹ H-NMR (CDCl ₃ ) δ: 5.10-4.98 (1H, m), 3.91-3.81 (3H, m), 3.69-3.62 (1H, m), 3.53-3.47 (1H, m), 2.09-2.02 ( 1H, m), 1.89-1.58 (3H, m).

(Step 3)

(2RS, 4RS)-4-fluorotetrahydro-2H-pyran-2-carboxylic acid

In the two-layer solution of the compound (trans isomer) (0.60 g) obtained in the above step 2 (dichloromethane (100 ml)-water (50 ml), diethyldioxyiodobenzene (3.2 g) and AZADOL were added. (registered trademark) (34 mg) and tetrabutylammonium bromide (0.10 g) were stirred at room temperature for 2 hours. Sodium sulfite was added to the reaction mixture, and the mixture was stirred at room temperature for one hour, and then added with 5 equivalents of aqueous sodium hydroxide solution to make a mixture. The aqueous layer was washed with dichloromethane, acidified with 5N hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

¹ H-NMR (CDCl ₃ ) δ: 5.13-5.02 (1H, brd, J = 45.8 Hz), 4.40 (1H, dd, J = 12.0, 2.7 Hz), 4.05-3.99 (1H, m), 3.97-3.90 (1H, m), 2.43 - 2.34 (1H, m), 1.95-1.76 (3H, m).

(Step 4)

[(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a , 7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone (4R-fluorine And [(2S,4S)-4-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2, 2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinolin-8(4H)-yl]methanone 4S-fluoroform)

The title compound (4R-fluoro) was obtained by the same procedure as the compound obtained in the above step (3). 34 mg) and the title compound (4S-fluoro) (74 mg).

4R-fluoro

MS (ESI) m/z: 494 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.10 (1H, brd, J = 48.3), 4.41 (1H, dd, J = 10.7, 2.4 Hz), 4.30 (1H, m), 3.90-3.87 (1H, m) , 3.84 (1H, dd, J = 11.5, 2.7 Hz), 3.80 (1H, d, J = 5.4 Hz), 3.57 (1H, m), 3.33 (1H, m), 3.29-3.25 (1H, m), 2.18-2.04 (2H, m), 1.99-1.13 (21H, m), 1.52 (3H, s), 1.44 (3H, s) 1.31 (3H, s), 1.13 (3H, s).

4S-fluoride

MS (ESI) m/z: 494 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.14 - 5.03 (1H, m), 4.42-4.38 (1H, m), 4.31-4.29 (1H, m), 3.86-3.78 (3H, m), 3.47 (1H, m), 3.37 (1H, m), 3.26 (1H, m), 2.10 - 1.17 (23H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.13 (3H) , s).

(Step 5)

[(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (70 mg) was obtained as a white solid.

MS (ESI) m/z: 454[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.10 (1H, brd, J = 48.3 Hz), 4.41 (1H, dd, J = 11.2, 2.4 Hz), 4.14 (1H, m), 3.91-3.80 (2H, m ), 3.59-3.51 (2H, m), 3.36-3.29 (1H, m), 3.28-3.22 (1H, m), 2.30 (1H, br), 2.23-2.05 (2H, m), 1.96-1.16 (21H , m), 1.43 (3H, s), 1.11 (3H, s), 1.05 (1H, s).

(Example 163)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2 , 2, 5a, 7a- Tetramethyloctadecyl-8H-cyclopropane[c][1,3]dioxolanyl[5,6]naphtho[2,1-f]quinolin-8-yl]methanone

The title compound was obtained as a white solid. m. m. Compound Compound Compound Compound Compound Compound Compound Compound (80 mg).

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.60 (1H, brd, J = 46.9 Hz), 4.31 (1H, m) 4.17 - 4.08 (2H, m), 4.01 (1H, brd, J = 10.3 Hz), 3.82 (1H, d, J = 5.4 Hz), 3.73 (1H, m), 3.60 (1H, dd, J = 36.1 Hz, 12.7 Hz), 3.47 (1H, d, J = 13.2 Hz), 2.84 (1H, m ), 2.27-2.10 (3H, m), 1.99-1.09 (14H, m), 1.52 (3H, s), 1.45 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.03- 0.86 (1H, m), 0.91 - 0.87 (1H, m), 0.51 - 0.43 (1H, m).

(Step 2)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (74 mg) was obtained.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.60 (1H, brd, J = 47.3 Hz), 4.19-4.08 (3H, m), 4.03-3.98 (1H, m), 3.66-3.54 (2H, m), 3.46 (1H, d, J = 13.2 Hz), 2.83 (1H, m), 2.36-2.10 (4H, m), 2.01-1.92 (2H, m), 1.83-1.05 (16H, m), 1.44 (3H, s ), 1.14 (3H, s), 1.03-0.96 (1H, m), 0.91 - 0.86 (1H, m), 0.51 - 0.45 (1H, m).

(Example 164)

[(2R,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

(2R,5S)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid benzyl ester

A mixture of the compound (isomer A) (2.98 g) obtained in Step 2 of Example 126 and 1,8-dioxabicyclo[5.4.0]-7-undecene (3.73 ml) in a nitrogen atmosphere The mixture was stirred at 100 ° C for 3 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate and washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate.

¹ H-NMR (CDCl ₃ ) δ: 7.43-7.28 (5H, m), 5.20 (2H, s), 4.69-4.50 (1H, m), 4.24-4.10 (2H, m), 3.57-3.48 (1H, m), 2.26-2.02 (2H, m), 1.85-1.72 (2H, m).

(Step 2)

(2R,5S)-5-fluorotetrahydro-2H-pyran-2-carboxylic acid

The title compound (620 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.71-4.52 (1H, m), 4.27-4.18 (1H, m), 4.15-4.08 (1H, m), 3.58-3.49 (1H, m), 2.34-2.16 ( 2H, m), 1.86-1.72 (2H, m).

(Step 3)

[(2R,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2 ,2,5a,7a-tetramethyloctadecyl-8H-cyclopropane[c][1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8 Ketone

The title compound (166 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.67-4.53 (1H, m), 4.31 (1H, m), 4.11 (1H, dd, J = 7.8, 3.4 Hz), 4.08-4.00 (2H, m), 3.81 (1H, d, J = 5.4 Hz), 3.56-3.44 (2H, m), 2.86-2.79 (1H, m), 2.37-2.25 (1H, m), 2.20-2.10 (1H, m), 1.99-1.09 (18H, m), 1.52 (3H, s), 1.45 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.04-0.97 (1H, m), 0.88-0.81 (1H, m ), 0.54-0.45 (1H, m).

(Step 4)

[(2R,5S)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (74 mg) was obtained.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.58 (1H, m), 4.25 (1H, d, J = 3.4 Hz), 4.19 (1H, m), 4.05 - 3.95 (2H, m), 3.94 - 3.85 ( 2H,m), 3.74 (1H, s), 3.49-3.43 (2H, m), 3, 35-3, 30 (2H, m), 2.69-2.61 (1H, m), 2.17-0.94 (16H, m ), 1.29 (3H, s), 1.01 (3H, s), 0.68-0.63 (1H, m), 0.45-0.37 (1H, m).

(Example 165)

[(2R,4S)-4-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

(2RS, 4SR)-4-fluorotetrahydro-2H-pyran-2-carboxylic acid

The title compound (0.36 g) was obtained from m.

¹ H-NMR (CDCl ₃ ) δ: 4.85-4.70 (1H, m), 4.23 (1H, m), 4.07-4.02 (1H, m), 3.55 (1H, m), 2.52 (1H, m), 2.08 (1H, m), 1.88-1.77 (2H, m).

(Step 2)

(4R)-4-benzyl-3-{[(2R,4S)-4-fluorotetrahydro-2H-pyran-2-yl]carbonyl}-1,3- Azolidin-2-one

To a solution of the compound (240 mg) in toluene (20 ml) obtained in Step 1 above, triethylamine (0.67 ml) and trimethylethyl chlorobenzene (0.24 ml), and (R)-4-benzyl- 2- The oxazolidinone (0.30 g) was heated to reflux for 2 days. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m/z: 308 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.20 (5H, m), 5.01 (1H, brd, J = 10.9 Hz), 4.92-4.66 (2H, m), 4.29-4.22 (3H, m), 3.58 (1H, m), 3.58 (1H, dd, J = 13.3, 3.1 Hz), 2.80 (1H, dd, J = 13.5, 9.6 Hz), 2.44-2.35 (1H, m), 2.14-2.06 (1H, m ), 1.96-1.71 (2H, m).

(Step 3)

(2R,4S)-4-fluorotetrahydro-2H-pyran-2-carboxylic acid

Add lithium hydroxide monohydrate (0.19 g) and 30% hydrogen peroxide water (0.85 ml) to a solution of the compound (0.69 g) in tetrahydrofuran (25 ml). Stir for 1 hour. After adding an aqueous solution of sodium sulfite to the reaction mixture, the mixture was extracted twice with ethyl acetate and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in dichloromethane and washed with 1N sodium hydroxide. The aqueous layer was made acidic with 5 N of hydrochloric acid, and then extracted with dichloromethane and ethyl acetate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 4.85-4.70 (1H, m), 4.23 (1H, m), 4.07-4.02 (1H, m), 3.55 (1H, m), 2.52 (1H, m), 2.08 (1H, m), 1.88-1.77 (2H, m).

(Step 4)

[(2R,4S)-4-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2 ,2,5a,7a-tetramethyloctadecyl-8H-cyclopropane[c][1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8 Ketone

The title compound (0.11 g) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.79-4.63 (1H, m), 4.31 (1H, m), 4.16 (1H, m), 3.98-3.91 (2H, m), 3.81 (1H, d, J = 5.4 Hz), 3.47 (1H, d, J = 12.7 Hz), 3.44 - 3.39 (1H, m), 2.82 (1H, m), 2.21-2.10 (2H, m), 2.09-2.01 (1H, m), 2.00-1.74 (6H, m), 1.67-1.57 (1H, m), 1.53-1.08 (10H, m), 1.52 (3H, s), 1.46 (3H, s), 1.32 (3H, s), 1.15 ( 3H, s) 1.04-0.98 (1H, m), 0.90-0.86 (1H, m), 0.52-0.46 (1H, m).

(Step 5)

[(2R,4S)-4-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (100 mg) was obtained as a white solid.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.79-4.63 (1H, m), 4.18-4.14 (2H, m), 3.97-3.92 (2H, m), 3.58-3.53 (1H, m), 3.47 (1H, d, J = 12.7 Hz), 3.42 (1H, m), 2.82 (1H, m), 2.36 (1H, s), 2.35-2.24 (2H, m), 2.20-2.12 (1H, m), 2.08-1.07 (17H,m), 1.45(3H,s), 1.13(3H,s),1.06(1H,s),1.04-0.97(1H,m),0.91-0.84(1H,m),0.52-0.44(1H , m).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 8, and the peak having a relative intensity of 14 or more in the case where the maximum peak intensity in Fig. 8 is 100 is shown in Table 8.

(Example 166)

[(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

[(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2 ,2,5a,7a-tetramethyloctadecyl-8H-cyclopropane[c][1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8 Ketone

The title compound (35 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m ).

MS (ESI) m/z: 506 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.10 (1H, brd, J = 48.3 Hz), 4.42 (1H, dd, J = 10.5, 2.7 Hz), 4.31 (1H, m), 4.02 (1H, m), 3.91-3.81(3H,m), 3.47(1H,d,J=12.7Hz), 2.83(1H,m),2.21-1.73(9H,m),1.66-1.10(11H,m),1.52(3H, s), 1.46 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.04-0.98 (1H, m), 0.90-0.86 (1H, m), 0.52-0.46 (1H, m) .

(Step 2)

[(2R,4R)-4-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (32 mg) was obtained as a white solid.

MS (ESI) m/z: 466 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.10 (1H, m), 4.41 (1H, dd, J = 10.5, 2.7 Hz), 4.15 (1H, m), 4.02 (1H, m), 3.92-3, 83 (2H,m), 3.55(1H,m), 3.47(1H,d,J=12.7Hz),2.81(1H,m),2.34-2.24(2H,m),2.13-1.65(9H,m), 1.60-1.04(10H,m), 1.45(3H,s), 1.13(3H,s),1.06(1H,s),1.03-0.98(1H,m),0.90-0.84(1H,m),0.51- 0.45 (1H, m).

(Example 167)

[(2R,4S)-4-methyltetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxyl -10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

2-[(2S)-4-{[tertiary butyl(diphenyl)decyl]oxy}-2-methylbutyl]-1,3-dithiazide -2-carboxylic acid ethyl ester

In the tributyl butyl [(3S)-4-iodo-3-methylbutoxy] diphenyl decane (10.4 g) and 1,3-dithiazide A solution of ethyl 2-formate (5.0 g) in dimethylformamide (30 ml)-toluene (100 ml) was added sodium hydride (63 wt%, 1.19 g) at 0 ° C and stirred at room temperature for 1 hour. Thereafter, the mixture was stirred at 80 ° C for 2 hours. Water was added to the reaction solution, and a part of the organic layer was evaporated under reduced pressure. After extracting three times with hexane-ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 7.70-7.62 (4H, m), 7.45-7.34 (6H, m), 4.25-4.17 (2H, m), 3.72-3.63 (2H, m), 3.41-3.13 ( 2H, m), 2.70-2.59 (2H, m), 2.22-1.21 (7H, m), 1.31 (3H, t, J = 7.0 Hz), 1.04 (9H, s), 0.88 (3H, d, J = 6.3 Hz).

(Step 2)

(4S)-6-{[tertiary butyl(diphenyl)decyl]oxy}-4-methyl-2-oxohexanoate

To a solution of the compound (10 g) obtained in the above step 1 in acetonitrile (20 ml), EtOAc (EtOAc) Stir at temperature for 30 minutes. After adding dichloromethane (100 ml) and hexane (100 ml) and an aqueous sodium sulfite solution to the reaction mixture, the organic layer was separated. After the aqueous layer was extracted with ethyl acetate, the organic layer was combined and washed with saturated aqueous sodium hydrogen carbonate and brine. After the organic layer was dried over anhydrous magnesium sulfate (MgSO4),

¹ H-NMR (CDCl ₃ ) δ: 7.71-7.64 (4H, m), 7.47-7.35 (6H, m), 4.30 (2H, q, J = 7.2 Hz), 3.69 (2H, t, J = 6.3 Hz ), 2.84 (1H, dd, J = 17.2, 5.5 Hz), 2.67 (1H, dd, J = 17.4, 8.0 Hz), 2.34 - 2.24 (1H, m), 1.63-1.29 (5H, m), 1.04 ( 9H, s), 0.91 (3H, d, J = 6.6 Hz).

(Step 3)

(4S)ethyl-6-hydroxy-4-methyl-2-oxohexanoate

To a solution of the compound (2.60 g) obtained in the above step 2 in THF (100 ml), acetic acid (1.4 ml) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 8 ml) were added. After stirring at room temperature overnight, the organic solvent It was distilled off under reduced pressure. The obtained residue was purified by EtOAcjjjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 4.33-4.23 (2H, m), 4.07-3.98 (1H, m), 3.82-3.76 (1H, m), 3.61-3.57 (1H, m), 2.09-1.95 ( 1H, m), 1.79-1.55 (4H, m), 1.34 (3H, t, J = 7.2 Hz), 0.96 (3H, d, J = 6.7 Hz).

(Step 4)

(2R,4S)-4-methyltetrahydro-2H-pyran-2-carboxylic acid ethyl ester

A solution of the compound obtained in the above step 3 (1.31 g) and triethyl decane (1.21 ml) in dichloromethane (50 ml) ), stirring for 30 minutes. Saturated aqueous ammonium chloride solution (50 ml) and water (50 ml) were added to the mixture, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

MS (ESI) m/z: 173 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.23 (2H, q, J = 7.2 Hz), 4.16 - 4.11 (1H, m), 3.94 (1H, dd, J = 12.0, 2.2 Hz), 3.46 (1H, m ), 2.00-1.94 (1H, m), 1.74-1.64 (1H, m), 1.59-1.52 (1H, m), 1.35-1.17 (2H, m), 1.29 (3H, t, J = 7.3 Hz), 0.98 (3H, d, J = 6.8 Hz).

(Step 5)

(2R,4S)-4-methyltetrahydro-2H-pyran-2-carboxylic acid

To a solution of the compound (0.75 g) in EtOAc (EtOAc) After a part of the organic layer was distilled off under reduced pressure, water was added and extracted with dichloromethane. Add 5 equivalents of hydrochloric acid (15 ml) to the aqueous layer and change After it became acidic, it was extracted with dichloromethane and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 4.16-4.12 (1H, m), 3.96 (1H, dd, J=11.7, 2.4 Hz), 3.55-3.50 (1H, m), 2.12-2.06 (1H, m) , 1.77-1.66 (1H, m), 1.61-1.55 (1H, m), 1.33-1.14 (2H, m), 1.00 (3H, d, J = 6.8 Hz).

(Step 6)

[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1,3]dioxolanyl[5 ,6]naphtho[2,1-f]quinoline-8(4H)-yl][(2R,4S)-4-methyltetrahydro-2H-pyran-2-yl]methanone

The title compound (21 mg) was obtained as a white solid. .

MS (ESI) m/z: 490 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.34 - 4.27 (1H, m), 4.04 (1H, dd, J = 11.2, 4.4 Hz), 3.89 (1H, d, J = 10.7 Hz), 3.80 (1H, d , J = 4.9 Hz), 3.49-3.35 (3H, m), 3.31-3.24 (1H, m), 2.06 (1H, m), 1.88-1.13 (23H, m), 1.52 (3H, s), 1.43 ( 3H, s), 1.31 (3H, s), 1.13 (3H, s), 0.97 (3H, d, J = 5.4 Hz).

(Step 7)

[(2R,4S)-4-methyltetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxyl -10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (19 mg) was obtained as a white solid.

MS (ESI) m/z: 490 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.19 - 4.11 (1H, m), 4.04 (1H, dd, J = 11.2, 4.4 Hz), 3.93 - 3.87 (1H, brm), 3.54 (1H, d, J = 3.9 Hz), 3.48-3.34 (3H, m), 3.31-3.24 (1H, m), 2.24-2.14 (1H, m), 1.88-1.11 (25H, m), 1.42 (3H, s), 1.11 (3H) , s), 0.97 (3H, d, J = 6.3 Hz).

(Example 168)

(5R)-5-hydroxy-6-sideoxy-6-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]hexanoic acid

(step 1)

(5R)-5-(benzyloxy)-6-{[tertiary butyl(dimethyl)decyl]oxy}hexanal

Tert-butyl alcohol (198 ml) in {[(2R)-2-(benzyloxy)hex-5-en-1-yl]oxy}(tert-butyl)dimethyl decane (4.24 g) ), in the solution, add Adding copper (II) chloride (0.18g), bis(benzonitrile) palladium(II) chloride (0.51g), nitromethane (13.2ml), and sodium nitrite (46mg) in an oxygen atmosphere, Stir at room temperature for 5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. After the organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

¹ H-NMR (CDCl ₃ ) δ: 9.73 (1H, t, J = 1.7 Hz), 7.35-7.26 (5H, m), 4.71 (1H, d, J = 11.7 Hz), 4.55 (1H, d, J) =11.7 Hz), 3.71 (1H, dd, J = 10.5, 5.6 Hz), 3.59 (1H, dd, J = 10.5, 5.1 Hz), 3.46 (1H, m), 2.41-2.38 (2H, m), 1.81 - 1.50 (4H, m), 0.90 (9H, s), 0.06 (6H, m).

(Step 2)

(5R)-5-(benzyloxy)-6-{[tertiary butyl(dimethyl)decyl]oxy}hexanoic acid

To a two-layer solution of the compound (2.40 g) obtained in the above step 1 in dichloromethane (70 ml)-water (70 ml), diethyldioxyiodobenzene (4.6 g) and 2-pyrantane- N-oxyl (0.22 g) and tetrabutylammonium bromide (0.23 g) were stirred at room temperature for 3 hours. After extracting with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 7.70 (1H, m), 7.36-7.27 (3H, m) 7.13-7.09 (1H, m), 4.70 (1H, d, J = 11.7 Hz), 4.56 (1H, d, J = 11.7 Hz), 3.71 (1H, dd, J = 10.3, 5.9 Hz), 3.59 (1H, dd, J = 10.5, 5.1 Hz), 3.47 (1H, m), 2.34 (2H, m), 1.82-1.52 (4H, m), 0.90 (9H, s), 0.04 (6H, s).

(Step 3)

(5R)-5-(benzyloxy)-6-hydroxycaproic acid

5 HCl (5 ml) was added to a solution of the compound (2.5 g) obtained in the above-mentioned step 2 (4 ml), and the mixture was stirred at room temperature for 1 hour. Wash with dichloromethane. After adding 5 equivalents of hydrochloric acid to the aqueous layer to make it acidic again, it was extracted with dichloromethane. After the organic layer was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.29 (5H, m), 4.62 (1H, d, J = 11.2 Hz), 4.57 (1H, d, J = 11.2 Hz), 3.75-3.71 (1H, m ), 3.58-3.51 (2H, m), 2.40-2.33 (2H, m), 1.76-1.55 (4H, m).

(Step 4)

(5R)-5-(benzyloxy)-6-hydroxycaproic acid benzyl ester

The title compound (1.45 g) was obtained from m.

MS (ESI) m/z: 329[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (10H, m), 5.12 (2H, s), 4.59 (1H, d, J = 11.7 Hz), 4.53 (1H, d, J = 11.7 Hz), 3.73-3.66 (1H, m), 3.57-3, 47 (2H, m), 2.36 (2H, t, J = 7.3 Hz), 1.90-1.50 (5H, m).

(Step 5)

(2R)-2,6-bis(benzyloxy)-6-oxohexanoic acid

The title compound (1.25 g) was obtained as a pale yellow oil.

MS (ESI) m/z: 343[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.30 (10H, m), 5.11 (2H, s), 4.70 (1H, d, J = 11.2 Hz), 4.49 (1H, d, J = 11.2 Hz), 4.00 (1H, m), 2.40-2.31 (2H, m), 1.92-1.73 (4H, m).

(Step 6)

Benzyl (5R)-5-(benzyloxy)-6-[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetra Ethyl hexahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]-6-oxooxyhexanoate

The title compound (0.33) was obtained as a white solid (m.). g).

MS (ESI) m/z: 688[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (10H, m), 5.10 (2H, s), 4.63 (1H, d, J = 11.2 Hz), 4.38 (1H, d, J = 11.2 Hz), 4.31 (1H, m), 4.06 (1H, m), 3.80 (1H, d, J = 5.4 Hz), 3.62-3.59 (1H, m), 3.38-3.30 (2H, m), 2.37 (2H, t, J = 7.3 Hz), 2.12 - 2.02 (1H, m), 1.91-1.08 (22H, m), 1.52 (3H, s), 1.45 (3H, s), 1.32 (3H, s), 1.13 (3H, s ).

(Step 7)

Benzyl (5R)-5-(benzyloxy)-6-oxo-6-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]hexanoate

The title compound (0.26 g) was obtained as a white solid.

MS(ES1)m/z: 648[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (10H, m), 5.10 (2H, s), 4.63 (1H, d, J = 11.2 Hz) 4.38 (1H, d, J = 11.2 Hz), 4.14 (1H,m), 4.05 (1H, dd, J=8.1, 5.1 Hz), 3.60 (1H, m), 3.54 (1H, m), 3.38-3.28 (2H, m), 2.41-2.32 (3H, m ), 2.24 - 2.16 (1H, m), 1.91-1.16 (22H, m), 1.44 (3H, s), 1.12 (3H, s), 1.06 (1H, s).

(Step 8)

(5R)-5-hydroxy-6-sideoxy-6-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]hexanoic acid

The title compound (0.16 g) was obtained as a white solid.

MS (ESI) m/z: 468[M+H] ⁺

¹ H-NMR (CD ₃ OD) δ: 4.37 (1H, m), 4.05 (1H, m), 3.45-3.33 (4H, m), 3.21-3.15 (1H, m), 2.37-2.25 (2H, m ), 2.15 (1H, m), 1.92-1.18 (20H, m), 1.45 (3H, s), 1.12 (3H, s).

(Example 169)

4,4,4-trifluoro-1-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]butan-1-one

(step 1)

4,4,4-trifluoro-1-[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecane [1 ,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]butan-1-one

The title compound (0.22 g) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 488 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.33-4.28 (1H, m), 3.81-3.79 (1H, d, = 4.9 Hz), 3.42-3.33 (2H, m), 3.28-3.23 (1H, m), 2.56-2.33(4H,m),2.13-2.02(1H,m),1.91-1.68(5H,m),1.67-1.09(13H,m),1.52(3H,s),1.43(3H,s), 1.31 (3H, s), 1.13 (3H, s).

(Step 2)

4,4,4-trifluoro-1-[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]butan-1-one

The title compound (0.18 g) was obtained as a white solid.

MS (ESI) m/z: 448 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.18-4.11 (1H, m), 3.55-3.51 (1H, m), 3.42-3.33 (2H, m), 3.28-3.22 (1H, m), 2.57-2.29 ( 5H,m), 2.25-2.16(1H,m),1.91-1.36(13H,m), 1.42(3H,s),1.30-1.10(5H,m),1.12(3H,s),1,04( 1H, s).

(Embodiment 170)

[(1S)-3,3-Difluorocyclopentyl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(1S)-3,3-Difluorocyclopentyl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethyl-10- Hexahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone

The title compound was obtained by the same procedure as in the step 4 of Example 23 (m. 70mg).

MS (ESI) m/z: 496[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.30 (1H, m), 3.80 (1H, d, J = 5.4 Hz), 3.46-3.35 (2H, m), 3.29-3.23 (1H, m), 3.12 (1H) , m), 2.50-2.35 (1H, m), 2.28-2.13 (2H, m), 2.11-1.13 (22H, m), 1.52 (3H, s), 1.43 (3H, s), 1.32 (3H, s ), 1.13 (3H, s).

(Step 2)

[(1S)-3,3-Difluorocyclopentyl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (64 mg) was obtained.

MS (ESI) m/z: 456 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.14 (1H, m), 3.53 (1H, m), 3.44-3.34 (2H, m), 3.28-3.22 (1H, m), 3.17-3.07 (1H, m) , 2.50-2.34 (1H, m), 2.31-1.17 (25H, m), 1.42 (3H, s), 1.12 (3H, s), 1.03 (1H, s).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 9, and the peak having a relative intensity of 17 or more in the case where the maximum peak intensity in Fig. 9 is 100 is shown in Table 9.

(Example 171)

[(1R)-3,3-difluorocyclopentyl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

[(1R)-3,3-difluorocyclopentyl][(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethyl-10- Hexahydro[1,3]dioxolanyl[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone

The compound obtained in the step 2 of Example 20 (120 mg) and (1R)-3,3-difluorocyclopentanecarboxylic acid (74 mg) were obtained as a white solid. The title compound (80 mg).

MS (ESI) m/z: 496[M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.35-4.26 (1H, m), 3.80 (1H, d, J = 5.4 Hz), 3.43-3.37 (2H, m), 3.29-3.23 (1H, m), 3.13 -3.05 (1H, m), 2.53-2.39 (1H, m), 2.28-2.15 (2H, m), 2.11-1.11 (22H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.13 (3H, s).

(Step 2)

[(1R)-3,3-difluorocyclopentyl][(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone

The title compound (74 mg) was obtained.

MS (ESI) m/z: 456 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.18-4.12 (1H, m), 3.53 (1H, d, J = 3.9 Hz), 3.43-3.36 (2H, m), 3.27-3.23 (1H, m), 3.14 -3.05 (1H, m), 2.53-2.39 (1H, m), 2.34 - 2.14 (4H, m), 2.10 - 10.04 (22H, m), 1.42 (3H, s), 1.12 (3H, s).

(Example 172)

(cis-4-fluorocyclohexyl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

(step 1)

(cis-4-fluorocyclohexyl)[(3aS,5aR,5bS,7aS,11aS,11bR,13aS,13bS)-13a-hydroxy-2,2,5a,7a-tetramethylhexadecahydro[1, 3] Dioxolyl-[5,6]naphtho[2,1-f]quinoline-8(4H)-yl]methanone

The title compound (0.10 g) was obtained from EtOAc m. Compound (70 mg).

MS (ESI) m/z: 492 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.80 (1H, brd, J = 46.5 Hz), 4.30 (1H, m), 3.80 (1H, d, J = 5.5 Hz), 3.47-3.35 (2H, m), 3.33-3.26(1H,m), 2.43(1H,m), 2.15-2.00(3H,m),1.97-1.08(24H,m),1.52(3H,s),1.43(3H,s), 1.32( 3H, s), 1.13 (3H, s).

(Step 2)

(cis-4-fluorocyclohexyl)[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecane [2,1-f]quinoline-1(2H)-yl]methanone

The title compound (63 mg) was obtained as a white solid.

MS (ESI) m/z: 452 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.80 (1H, brd, J = 4.80), 4.15 (1H, m), 3.53 (1H, br), 3.44 - 3.34 (2H, m), 3.1-3.26 (1H, m), 2.43 (1H, m), 2.30 (1H, br), 2.20 (1H, m), 2.14-2.03 (2H, m), 1.94-1.15 (24H, m), 1.42 (3H, s), 1.12 (3H, s), 1.06 (1H, s).

(Example 173)

(cis-4-fluorocyclohexyl)[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyl-10- Octahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

(cis-4-fluorocyclohexyl) [(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2,2,5a,7a-tetramethyl18 Hydrogen-8H-cyclopropane[c][1,3]dioxolanyl[5,6]naphtho[2,1-f]quinolin-8-yl]methanone

The title compound was obtained as a white solid (yield: Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound 30mg).

MS (ESI) m/z: 504 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.81 (1H, brd, J = 48.8 Hz), 4.31 (1H, m), 3.88 (1H, brd, J = 13.7 Hz), 3.82 (1H, d, J = 4.9) Hz), 3.51 (1H, d, J = 13.7 Hz), 2.83 (1H, m), 2.44 (1H, m), 2.20-2.05 (3H, m), 1.98 (6H, m), 1.66-1.09 (15H , m), 1.53 (3H, s), 1.44 (3H, s), 1.32 (3H, s), 1.15 (3H, s), 1.06-0.98 (1H, m), 0.86-0.81 (1H, m), 0.51-0.44 (1H, m).

(Step 2)

(cis-4-fluorocyclohexyl)[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyl-10- Octahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (27 mg) was obtained as a white solid.

MS (ESI) m/z: 464 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4, 81 (1H, brd, J = 48.3 Hz), 4, 15 (1H, m), 3.88 (1H, brd, J = 13.7 Hz), 3.56 (1H, d , J = 3.9 Hz), 3.51 (1H, d, J = 13.7 Hz), 2.81 (1H, m), 2.44 (1H, m), 2.28 (1H, m), 2.13 - 2.05 (3H, m), 1.98 - 1.13 (22H, m), 1.43 (3H, s), 1.13 (3H, s), 1.04-0.99 (1H, m), 0.86-0.80 (1H, m), 0.49-0.45 (1H, m).

(Example 174)

[(1S,3S)-3-fluorocyclohexyl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-di Methyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

[(1S,3R,4R)-4-bromo-3-fluorocyclohexyl]methanol and [(1S,3R,4R)-3-bromo-4-fluorocyclohexyl]methanol

To a solution of N-bromosuccinimide (10.8 g) in methylene chloride (130 ml), pyridine hydrogen chloride (5.27 ml) was added, and after stirring at room temperature for 10 min, [(1S)-cyclohex-3- A solution of the alkenyl-1-ylmethanol (3.40 g) in dichloromethane (20 mL) was stirred at room temperature for one hour. Ice water and an aqueous solution of potassium carbonate were added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (CDCl ₃ ) δ: 4.94-4.86 (0.6H, m), 4.86-4.77 (0.4H, m), 4.42 (0.4H, m), 4.37 (0.6H, m), 3.61-3.47 ( 2H, m), 2.28-1.87 (5H, m), 1.69-1.32 (3H, m).

(Step 2)

[(1S,3S)-3-fluorocyclohexyl]methanol (1,3-trans) And (cis-4-fluorocyclohexyl)methanol (1,4-cis form)

After adding tributyltinhydride (10.4 ml) and 2,2'-azobisisobutyronitrile (0.026 g) at 100 ° C in a solution of the mixture obtained in the above step 1 (3.34 g) in toluene (200 ml) Stir at the same temperature for 1 hour. The reaction solution was cooled to 0 ° C, an aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was extracted twice with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by EtOAc EtOAc (EtOAc) The title compound (1,4-cis isomer) (0.61 g).

1,3-transbody

¹ H-NMR (CDCl ₃ ) δ: 4.93 (1H, brd, J = 48.3 Hz), 3.52-3.46 (2H, m) 2.09-1.88 (3H, m), 1.84-1.76 (1H, m), 1.73 1.57 (2H), 1.50-1.16 (3H, m), 1.10-0.99 (1H, m).

1,4-cis form

¹ H-NMR (CDCl ₃ ) δ: 4.84 (1H, brd, J = 48.3 Hz), 3.49 (2H, m), 2.05 (2H, m), 1.64-1.33 (8H, m).

(Step 3)

(1S,3S)-3-fluorocyclohexanecarboxylic acid

The title compound (0.33 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.93 (1H, brd, J = 47.7 Hz), 2.78 (1H, tt, J = 11.5, 3.8 Hz), 2.22 (1H, m), 2.03-1.93 (2H, m ), 1.80-1.59 (3H, m), 1.57-1.42 (2H, m).

(Step 4)

[(1S,3S)-3-fluorocyclohexyl][(3aS,5aR,5bS,7aS,9aS,10aR,10bR,10cR,12aS,12bS)-12a-hydroxy-2,2,5a,7a-tetra Octadecahydro-8H-cyclopropane[c][1,3]dioxolanyl[5,6]naphtho[2,1-f]quinolin-8-yl]methanone

The title compound (47 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 504 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4,97 (1H, brd, J = 48.3 Hz), 4.31 (1H, m), 3.96 (1H, m), 3.82 (1H, d, J = 5.4 Hz), 3.50 (1H, brd, J = 13.2 Hz), 2.89 (1H, m), 2.80 (1H, m), 2.15 (1H, m), 2.05-1.12 (23H, m), 1.52 (3H, s), 1.43 (3H, s), 1.31 (3H, s), 1.15 (3H, s), 1.05-0.99 (1H, m), 0.83-0.79 (1H, m), 0.51-0.45 (1H, m).

(Step 5)

[(1S,3S)-3-fluorocyclohexyl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-di Methyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (43 mg) was obtained from m.

MS (ESI) m/z: 464 [M+H] ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.97 (1H, brd, J = 47.3 Hz), 4.15 (1H, m) 3.95 (1H, m), 3.55 (1H, d, J = 3.9 Hz), 3.50 (1H) ,brd,J=13.7Hz), 2.89(1H,m), 2.79(1H,m), 2.28(1H,m),2.05-1.07(25H,m),1.42(3H,s),1.13(3H, s), 1.04-0.99 (1H, m), 0.83-0.79 (1H, m), 0.50-0.43 (1H, m).

(Example 175)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy- 11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl]methanone

(step 1)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,12aS,12bR,14aS,14bS)-14a-hydroxy-2,2,5a ,7a-Tetramethyloctadecyl-8H-[1,3]dioxolanyl[7,8]phenanthro[2,1-b]indole-8-yl]methanone

The title compound was obtained as a white solid. m. m m m m m m m m m m m m m m m (269mg).

(Step 2)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy- 11a,13a-dimethyloctadecyl-1H-phenanthro[2,1-b]indol-1-yl]methanone

The title compound (0.045 g) was obtained as a white solid.

MS (ESI) m/z: 468 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.63-4.50 (1H, m), 4.16-4.09 (1H, m), 4.07-3.98 (2H, m), 3.61-3.32 (5H, m), 2.66-2.62 ( 1H, m), 2.26-2.05 (4H, m), 1.90-1.01 (22H, m), 1.51 (3H, s), 1.08 (3H, s).

(Example 176)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy- 12a,14a-dimethyl octadecyl phenanthrene [2,1-b]吖 -1(2H)-yl]methanone

(step 1)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(3aS,5aR,5bS,7aS,13aS,13bR,15aS,15bS)-15a-hydroxy-2,2,5a ,7a-Tetramethyloctadecylhydro[1,3]dioxolanyl[7,8]phenanthro[2,1-b]fluorene -8(4H)-yl]methanone

The title compound (yield of the title compound (yield: Compound Compound Compound Compound Compound Compound Compound Compound 216mg).

(Step 2)

[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(6aS,6bR,8aS,9S,10S,12aR,12bS,14aS)-8a,9,10-trihydroxy- 12a,14a-dimethyl octadecyl phenanthrene [2,1-b]吖 -1(2H)-yl]methanone

The title compound (0.118 g) was obtained.

MS (ESI) m/z: 482 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 4.63-4.51 (1H, m), 4.17-3.98 (3H, m), 3.61-3.45 (2H, m), 3.40-3.34 (1H, m), 3.09-3.01 ( 1H, m), 2.37-1.03 (30H, m), 1.50 (3H, s), 1.09 (3H, s).

(Example 177)

(2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a - dimethyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

(step 1)

(3β,17β)-3-(methoxymethoxy)androst-5,15-dien-17-ol

(3β)-3-(Methoxymethoxy)androst-5,15-dien-17-one (9.71 g) was obtained as a white solid. The title compound (9.46 g).

¹ H-NMR (CDCl ₃ ) δ: 5.89 (1H, m), 5.68 (1H, m), 5.38 (1H, m), 4.69 (2H, s), 4.33 (1H, m), 3.43 (1H, m ), 3.38 (3H, s), 2.37 (1H, m), 2.28 (1H, m), 2.20 (1H, m), 1.93-1.82 (4H, m), 1.75-1.47 (6H, m), 1.27 ( 1H, s), 1.11 - 0.98 (2H, m), 1.04 (3H, s), 0.84 (3H, s).

(Step 2)

(3β,17α)-3-(methoxymethoxy)androst-5,15-dien-17-ylbenzoate

The title compound (11.22 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 8.04-8.01 (2H, m), 7.55 (1H, m), 7.45-7.42 (2H, m), 6.25 (1H, dd, J = 1.5, 5.9 Hz), 6.03 (1H, m), 5.40 (1H, d, J = 5.4 Hz), 5.34 (1H, d, J = 2.4 Hz), 4.70 (2H, s), 3.43 (1H, m), 3.38 (3H, s) , 2.47(1H,m), 2.38(1H,m), 2.32-2.17(2H,m),1.93-1.51(9H,m),1.11-1.04(2H,m),1.07(3H,s),0.99 (3H, s).

(Step 3)

(3β,17α)-3-(methoxymethoxy)androst-5,15-dien-17-ol

The title compound (7.11 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 6.10 (1H, dd, J = 1.0, 5.9 Hz), 5.97 (1H, m), 5.38 (1H, m), 4.70 (2H, s), 4.09 (1H, dd , J=2.4, 6.3 Hz), 3.44 (1H, m), 3.38 (3H, s), 2.38 (1H, m), 2.32-2.25 (2H, m), 2.18 (1H, m), 1.93-1.85 ( 2H, m), 1.79 (1H, m), 1.74-1.50 (6H, m), 1.18 (1H, d, J = 6.3 Hz), 1.12-1.01 (2H, m), 1.06 (3H, s), 0.83 (3H, s).

(Step 4)

(2S,4aR,4bS,6aS,7R,7aR,8aR,8bR,8cR)-2-(methoxymethoxy)-4a,6a-dimethyl-1,2,3,4,4a,4b ,5,6,6a,7,7a,8,8a,8b,8c,9-hexadehydrocyclopropane[4,5]cyclopenta[1,2-a]phenanthrene-7-ol

To a solution of the compound (6.81 g) in dichloromethane (100 ml) obtained in the above step 3, diethylzinc (1.06 M hexanes, 29.0 ml) and diiodomethane (2.5 ml) were added at 0 °C. After stirring at the same temperature for 1.5 hours, it was stirred at room temperature for 2 hours. The reaction was stopped by adding ethyl acetate and a saturated aqueous solution of ammonium chloride to the reaction mixture. The reaction solution was poured into two layers of ethyl acetate and aq. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. To the residue obtained by concentrating the filtrate under reduced pressure, methylene chloride and hexanes were obtained. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 5.39 (1H, m), 4.69 (2H, s), 3.91 (1H, dd, J = 3.4, 5.4 Hz), 3.43 (1H, m), 3.38 (3H, m ), 2.37 (1H, m), 2.32-2.21 (2H, m), 1.92-1.82 (2H, m), 1.76-1.37 (8H, m), 1.23 (1H, m), 1.10-1.01 (2H, m ), 1.03 (3H, s), 0.93-0.87 (3H, m), 0.92 (3H, s), 0.82 (1H, dd, J = 11.7, 4.9 Hz).

(Step 5)

(2S, 4aR, 4bS, 6aS, 7aR, 8aR, 8bR, 8cR)-2-(methoxymethoxy)-4a,6a-dimethyl-2,3,4,4a,4b,5,6 ,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropane[4,5]cyclopenta[1,2-a]phenanthrene-7(1H)-one

The title compound (4.66 g) was obtained as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ: 5.41 (1H, m), 4.69 (2H, s), 3.43 (1H, m), 3.38 (3H, s), 2.39 (1H, m), 2.36-2.25 (2H , m), 1.93-1.43 (10H, m), 1.35 (1H, m), 1.27 (1H, m), 1.15 (3H, s), 1.09-1.02 (1H, m), 1.06 (3H, s), 0.95 (1H, m), 0.87-0.84 (2H, m).

(Step 6)

(2S,4aR,4bS,6aS,7E,7aR,8aR,8bR,8cR)-N-hydroxy-2-(methoxymethoxy)-4a,6a-dimethyl-2,3,4,4a , 4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropane[4,5]cyclopenta[1,2-a]phenanthrene-7(1H)-imine

The title compound (4.71 g) was obtained as a white solid.

MS (ESI) m/z: 360 (M+H) ⁺

_{^{1 H-NMR (CDCl 3)}} δ: 5.40 (1H, m), 4.69 (2H, s), 3.43 (1H, m), 3.38 (3H, s), 2.38 (1H, m), 2.32-2.24 (2H , m), 2.08 (1H, m), 1.90 (1H, m), 1.87-1.70 (4H, m), 1.62-1.32 (5H, m), 1.25 (1H, brs), 1.16 (3H, s), 1.09-1.03 (1H, m), 1.06 (3H, s), 0.96 (1H, m), 0.75 (1H, dd, J = 4.4, 10.7 Hz), 0.70 (1H, m).

(Step 7)

(2S,4aR,4bS,6aS,8aR,9aR,9bR,9cR)-2-(methoxymethoxy)-4a,6a-dimethyl-1,2,3,4,4a,4b,5 ,6,6a,7,8a,9,9a,9b,9c,10-hexadecahydro-8H-cyclopropane [c]naphtho[2,1-f]quinolin-8-one

The title compound (4.15 g) was obtained as a white solid.

MS (ESI) m/z: 360 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 5.55 (1H, brs), 5.41 (1H, m), 4.70 (2H, s), 3.44 (1H, m), 3.38 (3H, s), 2.42-2.34 (2H , m), 2.28 (1H, m), 1.91 (1H, m), 1.86 (1H, m), 1.77-1.50 (6H, m), 1.46-1.34 (2H, m), 1.33 (3H, s), 1.26 (1H, m), 1.12-1.03 (3H, m), 1.02 (3H, s), 0.93 (1H, dd, J = 6.3, 11.2 Hz), 0.66 (1H, m).

(Step 8)

(2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR)-2-(methoxymethoxy)-4a,6a-dimethyl-2,3,4,4a,4b,5,6 ,6a,7,8,8a,9,9a,9b,9c,10-hexadecahydro-1H-cyclopropane [c]naphtho[2,1-f]quinoline

The title compound (4.09 g) was obtained as a white solid.

¹ H-NMR (CD ₃ OD) δ: 5.42 (1H, m), 4.66 (2H, s), 3.41-3.25 (2H, m), 3.34 (3H, s), 2.91 (1H, d, J=13.7) Hz), 2.42 - 2.34 (2H, m), 2.24 (1H, m), 1.95-1.85 (2H, m), 1.72-1.62 (2H, m), 1.60-1.40 (4H, m), 1.15 - 1.00 ( 3H, m), 1.10 (3H, s), 1.03 (3H, s), 0.84-0.74 (2H, m), 0.74-0.65 (2H, m), 0.07 (1H, brs).

(Step 9)

(2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR)-2-(methoxymethoxy)-4a,6a-dimethyl-1,2,3,4,4a,4b,5 ,6,6a,8,8a,9,9a,9b,9c,10-hexadecahydro-7H-cyclopropane[c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (4.87 g) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

MS (ESI) m/z: 480 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.39 (1H, m), 5.13 (1H, d, J = 12.7 Hz), 5.10 (1H, d, J = 12.7 Hz), 4.69 (2H, s), 4.50 (1H, br), 3.43 (1H, m), 3.38 (3H, s), 2.92 (1H, br), 2.48 (1H, dd, J = 9.3, 14.6 Hz), 2.44 -2.34(2H,m), 2.27(1H,m),1.92-1.83(2H,m),1.73-1.43(4H,m), 1.47(3H,s),1.36(1H,m),1.22-0.97 (4H, m), 1.00 (3H, s), 0.84-0.77 (2H, m), 0.59 (1H, m), 0.13 (1H, m).

(Step 10)

(2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR)-2-hydroxy-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,8, 8a,9,9a,9b,9c,10-hexadecahydro-7H-cyclopropane[c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (4.53 g) was obtained as a white solid.

MS (ESI) m / z: 436 (M + H) +

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.39 (1H, m), 5.13 (1H, d, J = 12.7 Hz), 5.10 (1H, d, J = 12.7 Hz), 4.50 (1H, br), 3.53 (1H, m), 2.93 (1H, br), 2.48 (1H, dd, J = 9.5, 14.4 Hz), 2.41 (1H, m), 2.32 (1H, m), 2.24 (1H, m), 1.88-1.81 (2H, m), 1.74-1.45 (5H, m), 1.47 (3H, s), 1.36 (1H, m), 1.22-0.97 (4H, m), 1.00 (3H , s), 0.83-0.77 (2H, m), 0.59 (1H, m), 0.13 (1H, m).

(Step 11)

(4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR)-4a, 6a-dimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,8,8a,9 , 9a, 9b, 9c, 10, 11-hexadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (3.73 g) was obtained as white crystals.

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.29 (5H, m), 5.75 (1H, s), 5.15-5.08 (2H, m), 4.51 (1H, br), 3.00 (1H, br), 2.51 -2.31 (7H, m), 2.03 (1H, m), 1.77-1.53 (2H, m), 1.50 (3H, s) 1.32 (1H, m), 1.24-1.07 (3H, m), 1.18 (3H, s), 1.00 (1H, m), 0.86-0.77 (2H, m), 0.62 (1H, m), 0.12 (1H, m).

(Step 12)

(2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,8,8a, 9,9a,9b,9c,10,11-hexadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (4.42 g) was obtained as a white solid.

MS (ESI) m/z: 434 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.29 (5H, m), 5.31 (1H, d, J = 1.5 Hz), 5.14 - 5.08 (2H, m), 4.50 (1H, br), 4.15 (1H) , m), 2.94 (1H, br), 2.46 (1H, dd, J = 9.3, 14.6 Hz), 2.28-2.19 (2H, m), 2.09 (1H, m), 1.96 (1H, m), 1.71 ( 1H,m),1.67-1.53(2H,m), 1.47(3H,s),1.4 3(1H,m), 1.36(1H,d,J=6.3Hz),1.30-1.09(4H,m), 1.04 (3H, s), 0.98 (1H, m), 0.86-0.78 (2H, m), 0.75 (1H, t, J = 10.7 Hz), 0.59 (1H, m), 0.09 (1H, m).

(Step 13)

(1S, 3aR, 3bS, 5aS, 7aR, 8aS, 8bR, 8cR, 10aR, 11aS)-1-hydroxy-3a,5a-dimethylhexadehydrocyclopropane [c]oxirane [4a,5] Naphtho[2,1-f]quinoline-6(2H)-formic acid benzyl ester

The title compound (4.16 g) was obtained as white crystals.

MS (ESI) m/z: 452 (M+H) ⁺

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.14-5.08 (2H, m), 4.52 (1H, br), 4.06 (1H, m), 3.16 (1H, d, J = 4.4 Hz), 2.96 (1H, br), 2.48 (1H, dd, J = 9.3, 14.2 Hz), 2.29 (1H, m), 2.23 (1H, d, J = 9.8 Hz), 2.15 (1H, m) , 1.67-1.00 (12H, m), 1.47 (3H, brs), 1.02 (3H, s), 0.83-0.78 (2H, m), 0.61 (1H, m), 0.11 (1H, m).

(Step 14)

(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphthalene And [2,1-f]quinoline-7-carboxylic acid benzyl ester

The title compound (3.62 g) was obtained as a white solid.

MS (ESI) m/z: 470 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 7.36-7.27 (5H, m), 5.07 (2H, brs), 4.44 (1H, dd, J = 7.8, 14.6 Hz), 4.06 (1H, m), 3.46 ( 1H, d, J = 2.9 Hz), 2.54 (1H, dd, J = 9.5, 14.4 Hz), 2.20 (1H, m), 1.97 (1H, m), 1.77-1.62 (2H, m), 1.60-1.07 (11H, m), 1.45 (3H, s), 1.14 (3H, s), 0.91 (1H, t, J = 10.0 Hz), 0.80 (1H, m), 0.63 (1H, m), 0.19 (1H, m).

(Step 15)

(1S, 2S, 4aR, 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS)-4a, 6a-dimethyloctadecyl-11aH-cyclopropane [c]naphtho[2,1-f]quina Porphyrin-1,2,11a-triol

The title compound (207 mg) was obtained as a white solid.

MS (ESI) m/z: 336 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.07 (1H, m), 3.46 (1H, d, J = 3.9 Hz), 3.23 (1H, m), 2.88 (1H, d, J = 13.7 Hz), 2.18 (1H, m), 1.92 (1H, m), 1.73 (1H, m), 1.61-1.03 (11H, m), 1.14 (3H, s), 1.07 (3H, s), 0.80-0.67 (4H, m ), 0.04 (1H, s).

(Step 16)

(2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a - dimethyl octadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone

The title compound (126 mg) was obtained as a white solid. Compound Compound Compound Compound Compound Compound Compound Compound

MS (ESI) m/z: 448 (M+H) ⁺

¹ H-NMR (CD ₃ OD) δ: 4.18 - 4.11 (2H, m), 4.06 (1H, m), 4.40 (1H, m), 3.54 (1H, m), 3.46 (1H, d, J = 3.4 Hz), 3.08 (1H, m), 2.66 (1H, dd, J = 9.5, 13.9 Hz), 2.21 (1H, m), 1.96 (1H, m), 1.89 (1H, m), 1.77-1.66 (2H , m), 1.65-1.07 (15H, m), 1.52 (3H, s), 1.15 (3H, s), 0.94 (1H, t, J = 10.0 Hz), 0.82 (1H, m), 0.65 (1H, m), 0.23 (1H, m).

The powder X-ray diffraction pattern of the title compound is shown in Fig. 10, and the peak having a relative intensity of 12 or more in the case where the maximum peak intensity in Fig. 10 is 100 is shown in Table 10.

(Test Example 1)

Inhibitory effect on IL-17 production by cells into which RORγt gene was introduced

(1) Production of cells into which RORγt gene was introduced

Based on the base sequence of the mRNA encoding the full length amino acid sequence of the mouse (Mus musculus) RORgamma t protein (GenBank Accession No. AF163668: http://www.metalife.com/Genbank/5679306), obtained by PCR A cDNA encoding the mRNA of a full-length protein. The obtained cDNA was inserted into a pUNO vector (InvivoGen) which is an expression vector, and the mouse RORγt expression was constructed. body. The constructed mouse RORγt expression vector was introduced into EL4 cells (mouse T lymphoma cell line) to select a medium (addition of fetal bovine serum, blasticidin S (Blasticidin S), penicillin, chain in DMEM medium The cells into which the RORγt gene was introduced were cultured.

(2) Evaluation of IL-17 production inhibition

The IL-17 production inhibition of the test compound is carried out by introducing the aforementioned cells into the RORγt gene with phorbol 12-Myristate 13-acetate (PMA) and ionomycin. The IL-17 production at the time of stimulation was measured. That is, the cells into which the RORγt gene was introduced were prepared in the above-described selection medium, and dispensed into 75,000 cells per well in a 96-well flat bottom plate (Corning). At this time, test compounds of various concentrations were simultaneously added. The cells were cultured in an incubator at a concentration of 5% CO ₂ at 37 ° C for 1 hour, and PMA was added to each well at a final concentration of 25 ng/mL and ionomycin at a final concentration of 125 ng/mL, totaling 100 μL at 5%. The CO ₂ concentration was incubated at 37 ° C for 20 hours in an incubator. Thereafter, the culture supernatant was recovered, and the mouse in the supernatant was assayed by EnVison (Perkin-Elmer) using time-resolved fluorescence using an HTRF mouse IL-17 kit (Cisbio). IL-17 concentration. Regarding the inhibition of IL-17 production by the test compound, a graph of the semi-logothmic plot of the concentration of the test compound in the presence of the test compound on the amount of IL-17 produced is equivalent to the absence of the test compound. The test compound concentration of the IL-17 production amount of 50% of the IL-17 production amount was calculated as the IC ₅₀ value. The results of inhibition of IL-17 production are shown in Table 11.

In the present test, the compound of the present invention showed an excellent inhibitory effect on IL-17 production. According to this, it can be used as cognac, dry arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (Clone's disease, ulcerative colitis, etc.), Hugh Glenn Syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Beth's disease, silk Autoimmune disease or IL-17 produced by spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis, etc. A therapeutic and/or preventive agent for cancer.

(Test Example 2)

Inhibitory effect of IL-23-induced mouse psoriasi form dermatitis

It is known that the IL-23-induced mouse dry dermatitis pattern is dependent on IL-17 (The Journal of Immunology, 186, 1495-1502 (2011)) (The Journal of Immunology, 186, 4481-4489 (2011)) .

Male mice of 7 to 10 weeks old after 5 to 10 BALB/c mice (Charles River, Japan) were used in the experiment. From day 0 to day 3, mice were intradermally administered with mouse IL-23 once a day under anesthesia (R&D Systems, 50 μg/mL in phosphate buffered saline), 1 μg / Only, and induced dermatitis (The Journal of Experimental Medicine, 203, 2577-2587 (2006)) (Nature, 445, 648-651 (2007)). In the same control, the bovine serum white was administered intradermally. The protein (Sigma, 50 μg/mL in phosphate buffered saline) was 1 μg/mouse. The dermatitis was evaluated by using a thickness gauge to measure the thickness of the ear shell after the final administration of mouse IL-23 for 24 hours (day 4) minus the IL-23 of the 0th day before the start of the ear shell. Thickness of the ear shell is used as an indicator. The test compound was suspended in a 0.5% methylcellulose solution or a 9-10% Kollidon (registered trademark) VA64 solution. The test compound or solvent is administered orally twice a day from day 0 to day 3. The dermatitis-inhibiting effect by the test compound was calculated as the inhibition rate (%) according to the following formula. The results of the dermatitis inhibitory effect are shown in Table 12.

Inhibition rate (%) = 100 × (ear shell hypertrophy when the solvent is administered - ear shell hypertrophy when the test compound is administered) / (ear shell hypertrophy when the solvent is administered - the ear shell hypertrophy of the control group)

As described above, the compound of the present invention has a dermatitis-inhibiting effect and is effective for dryness.

Formulation Example 1: Capsule

The powder of the above prescription was mixed, passed through a sieve of 60 mesh, and the powder was placed in a 250 mg gelatin capsule to prepare a capsule.

Formulation Example 2: Lozenges

The powder of the above prescription was mixed, granulated with corn starch paste, dried, and then tableted by a tableting machine to prepare a tablet of 200 mg in one tablet. This tablet can be applied to the sugar coating as needed.

[Industrial availability]

The compound of the formula (I) of the present invention or an isotope-labeled compound thereof or a pharmaceutically acceptable salt thereof has excellent retinol receptor-related orphan receptor γt inhibition and IL-17 production inhibition And can be used as a medicine.

Claims (48)

a compound of the formula (I) or a pharmaceutically acceptable salt thereof, Wherein U represents C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₃ -C ₆ halogenated cycloalkyl, C ₃ -C ₆ halogenated cycloalkenyl or independently 1 to 4 selected from halogen atoms, C ₁ -C a phenyl group, a pyridyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group or a benzyl group substituted with a ₆ alkyl group and a C ₁ -C ₆ alkoxy group; R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or a C ₂ - C ₇ group; Alkylcarbonyloxy; R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group; R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; or R ² and R ^{3 taken} together to represent a pendant oxy group; R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkane which may be independently substituted with 1 to 2 groups selected from a C ₁ -C ₆ alkylsulfonyl group and a hydroxyl group; R ⁵ represents a hydrogen atom; C ₂ -C ₇ alkylcarbonyl; independently from 1 to 4, selected from a fluorine atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonium group group, a carboxyl group, aminocarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, and substituted triazolyl group of C ₁ -C ₆ alkyl; or, independently by 3 or 4 atoms selected from fluorine, hydroxy and hydroxy methyl Base Substituting 2-tetrahydropyranyl group; or R ⁴ and a group represented by the formula -OR ⁵ together form oxo; R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group or independently substituted with 1 to 2 substituents selected from a C ₁ -C ₆ alkylsulfonyl group, a hydroxyl group and a cyano group-substituted C ₁ -C ₆ alkyl group; R ⁷ represents a hydrogen atom or a fluorine atom; R ⁸ represents a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁹ represents a hydrogen atom; or R ⁸ and R ^{9 taken} together to represent a pendant oxy group; T represents a single bond, an oxygen atom or a group represented by the formula -NH-; and Y is the same or different, and represents a halogen atom or a C ₁ -C ₆ Alkyl; m represents an integer of 0 to 3; a saturated ring containing a nitrogen atom may also be condensed with a cyclopropane ring to form a condensed ring; n represents an integer of 1 to 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ia), The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ib), The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the formula (I) is a formula (Ic), The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein U is C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenated alkyl, (C ₁ -C ₆ alkoxy) a -(C ₁ -C ₆ alkyl) group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ halogenated cycloalkyl group or a phenyl group or a tetrahydroperyl group which may be independently substituted with 1 to 3 halogen atoms喃基. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein U is 3,3,3-trifluoropropyl, cyclohexyl, 4-fluorocyclohexyl, (1S)-3 ,3-difluorocyclopentyl, 2-tetrahydropyranyl, (R)-2-tetrahydropyranyl, 4-fluorotetrahydropyran-2-yl, 5-fluorotetrahydropyran-2 -yl or (2R,5R)-5-fluorotetrahydropyran-2-yl. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen atom. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or a methyl group. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a hydroxyl group or a C ₁ -C ₆ alkoxy group. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a hydroxyl group or a methoxy group. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with 1 to 2 hydroxy groups. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom; C ₂ -C ₇ alkylcarbonyl; independently from 1 to 3 selected from a hydroxyl group, a methoxy group, a methylsulfonyl group, an aminocarbonyl group, a tert-butoxycarbonyl group, and a triazolyl group-substituted C ₁ -C ₆ alkyl group or independently 3 or 4 selected from a fluorine atom, a hydroxyl group, and a hydroxyl group A methyl group-substituted 2-tetrahydropyranyl group. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a methyl group, a 2,3-dihydroxypropyl group, or a (R)-2,3-di Hydroxypropyl or (S)-2,3-dihydroxypropyl. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group or a hydroxymethyl group. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a hydrogen atom. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein T is a single bond. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Y is a methyl group. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein m is 0. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, and a fused ring formed by condensing a ring containing a nitrogen atom and a cyclopropane ring is condensed. It is a 3-indole bicyclo[4.1.0] heptane ring. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-10a, 12a-dimethylhexadecane Naphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, cyclohexyl[(4aS,4bR,6aS,7S) ,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone ,(2R)-tetrahydro-2H-pyran-2-yl[(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethyl Base ten Hexahydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone, [(4aS,4bR,6aS,7S,8S,10aR,10bS,12aS)-6a,7-dihydroxy- 8-Methoxy-10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2- Methyl ketone, [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 8-dihydroxy-7-methoxy-10a, 12a-dimethylhexadecane] 2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, cyclohexyl[(4aS,4bR,6aS,7S,8S, 9S,10aR,10bS,12aS)-6a,7,8-trihydroxy-9-(hydroxymethyl)-10a,12a-dimethylhexadenaphtho[2,1-f]quinoline-1 ( 2H)-yl]methanone, cyclohexyl [(4aS,4bS,6aS,7S,8S,10aS,10bR,12aS)-10b-fluoro-6a,7,8-trihydroxy-10a,12a-dimethyl-10- Hexahydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone, cyclohexyl [(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)- 2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone, cyclohexyl (4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-(2,3-dihydroxypropyl)-6a,8-dihydroxy-10a,12a-dimethylhexadecaphthalene[2 ,1-f]quinoline-1(2H)-yl]methanone, 1-[(4aS,4bR,6aR,8S,10aR,10bS,12aS)-8-[(2R)-2,3-dihydroxy Propoxy -6a-hydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl]-4,4,4-trifluorobutan-1-one , [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a,12a-dimethylhexadecane Naphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl][(2S)-tetrahydro-2H-pyran-2-yl]methanone, (2R)-tetrahydro- 2H-pyran-2-yl [(5aS,5bR,7aS,8S,9S,11aR,11bS,13aS)-7a,8,9-trihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene And [2,1-b]indol-1-yl]methanone, [(4aS,4bR,6aR,8R,10aR,10bS,12aS)-6a,8-dihydroxy-8-(hydroxymethyl)- 10a,12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, [ (4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a,7-dihydroxy-10a,12a-dimethyl Hexadecaquino[2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone, {(5aS,5bR,7aS, 8S,9S,11aR,11bS,13aS)-9-[(2R)-2,3-dihydroxypropoxy]-7a,8-dihydroxy-11a,13a-dimethyloctadecyl-1H-phenanthrene And [2,1-b]吖呯-1-yl}[(2R)-tetrahydro-2H-pyran-2-yl]methanone, {(1S,2S,4aR,4bS,6aS,8aS,9aR) , 9bR, 9cR, 11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane [c Naphtho[2,1-f]quinolin-7-yl}[(2R)-tetra Hydrogen-2H-pyran-2-yl]methanone, {(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy Base]-11a-hydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H -pyran-2-yl]methanone, {(2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aR)-2-[(2R)-2,3-dihydroxypropoxy]-11a-hydroxy-4a,6a-dimethyl Octadecahydro-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl}[(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl]- Ketone, (2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a ,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone, [(2S,4aR,4bS,6aS,8aS,9aR, 9bR,9cR,11aR)-2,11a-dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl][( 2R)-tetrahydro-2H-pyran-2-yl]methanone, [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,11a-dihydroxy-2- Methoxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl][(2R,5R)-5-fluorotetrahydro -2H-pyran-2-yl]methanone, (2R)-tetrahydro-2H-pyran-2-yl [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7 , 8-trihydroxy-10a, 12a-dimethylhexadehydronaphtho[2,1-f]quinoline-1(2H)-yl]methanone, (2R)-tetrahydro-2H-pyran- 2-based [(4aS,4bR,6aS,7S,8R,10aR,10bS,12aS)-6a,7,8-trihydroxy-8,10a,12a-trimethylhexadecane[2,1- f] quinoline-1(2H)-yl]methanone, (2R)-tetrahydrogen -2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a,7,8-trihydroxy-7,10a,12a-trimethylhexadecane And [2,1-f]quinoline-1(2H)-yl]methanone, [(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(4aS,4bR,6aS) ,7S,8S,10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecahydronaphtho[2,1-f]quinoline-1(2H)-yl] Ketone, [(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a -trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone, [(2R,4S)-4- Fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-di Methyloctadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone, [(2R,4R)-4-fluorotetrahydro-2H-pyran- 2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclo Propane [c]naphtho[2,1-f]quinolin-7-yl]methanone, [(1S)-3,3-difluorocyclopentyl][(4aS,4bR,6aS,7S,8S, 10aR,10bS,12aS)-6a,7,8-trihydroxy-10a,12a-dimethylhexadecaquino[2,1-f]quinoline-1(2H)-yl]methanone, (cis 4-fluorocyclohexyl)[(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctahydrogen -7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone, or (2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR) , 4bS, 6aS, 8aR, 9aS, 9bR, 9cR, 11aS)-1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1- f] quinoline-7-yl]methanone. a compound which is a cyclohexyl group [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7,8-trihydroxy-10a, 12a-dimethylhexadecane [2, 1-f]quinoline-1(2H)-yl]methanone. a compound which is (2R)-tetrahydro-2H-pyran-2-yl [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7,8-trihydroxy-10a, 12a-Dimethylhexadehydronaphtho[2,1-f]quinolin-1(2H)-yl]methanone. A compound which is [(4aS, 4bR, 6aS, 7S, 8S, 10aR, 10bS, 12aS)-6a, 7-dihydroxy-8-methoxy-10a, 12a-dimethylhexadecane] 2,1-f]quinoline-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone. A compound which is [(4aS, 4bR, 6aR, 8S, 10aR, 10bS, 12aS)-8-[(2R)-2,3-dihydroxypropoxy]-6a-hydroxy-10a, 12a-dimethyl Hexadecahydronaphtho[2,1-f]quinolin-1(2H)-yl][(2R)-tetrahydro-2H-pyran-2-yl]methanone. A compound which is {(1S, 2S, 4aR, 4bS, 6aS, 8aS, 9aR, 9bR, 9cR, 11aS)-2-[(2R)-2,3-dihydroxypropoxy]-1,11a- Dihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl}[(2R)-tetrahydro-2H-pyran- 2-yl]methanone. A compound which is (2R)-tetrahydro-2H-pyran-2-yl [(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)-1,2,11a-three Hydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone. A compound which is [(2R,5R)-5-fluorotetrahydro-2H-pyran-2-yl][(1S,2S,4aR,4bS,6aS,8aS,9aR,9bR,9cR,11aS)- 1,2,11a-trihydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane [c]naphtho[2,1-f]quinolin-7-yl]methanone. A compound which is (2R)-tetrahydro-2H-pyran-2-yl[(1S,2S,4aR,4bS,6aS,8aR,9aS,9bR,9cR,11aS)-1,2,11a-three Hydroxy-4a,6a-dimethyloctadecyl-7H-cyclopropane[c]naphtho[2,1-f]quinolin-7-yl]methanone. A pharmaceutical composition containing a compound selected from any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition has a spectroscopy receptor-related orphan receptor γt inhibitory effect. The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is for treating and/or preventing a disease which is treated and/or prevented by inhibition of retinoic acid receptor-associated orphan receptor γt. The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is for treating and/or preventing the treatment, improvement, alleviation and/or prevention of symptoms by inhibition of Th17 cell differentiation and/or inhibition of IL-17 production. disease. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, rest Sjögren syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata , leukoplakia, Kawasaki disease, Behcet's disease, spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, Giant Cell Arteriris, contact dermatitis , optic neuritis or colorectal cancer. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is for treating and/or preventing dryness or dryness arthritis. A retinoid acid receptor-associated orphan receptor γt inhibitor comprising a compound selected from any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient. A use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition. The use of claim 39, wherein the pharmaceutical composition is for treating and/or preventing dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Hugh Lun's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Beth's disease , spheroid nephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. The use of claim 39, wherein the pharmaceutical composition is a composition for treating and/or preventing dryness or dryness arthritis. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a related orphan receptor γt inhibition associated by retinoid receptors And/or use in a method of preventing a disease. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of dryness, dryness, arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid joints Inflammation, inflammatory bowel disease, Hugh's syndrome, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata , leukoplakia, Kawasaki disease, Behcet's disease, glomerulonephritis, cardiomyopathy, aplastic anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer the use of. A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound selected from any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof to a warm-blooded animal. The method of claim 44, wherein the disease is treated and/or prevented by inhibition of retinoic acid receptor-associated orphan receptor γt. The method of claim 44, wherein the disease is dryness, dryness arthritis, ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Hugh's syndrome, systemic lupus erythematosus, Chronic obstructive pulmonary disease (COPD), atopic dermatitis, asthma, type 1 diabetes, graft-versus-host disease (GvHD), alopecia areata, leukoplakia, Kawasaki disease, Besi's disease, spheroid nephritis, cardiomyopathy, regeneration Adverse anemia, Hashimoto's disease, scleroderma, giant cell arteritis, contact dermatitis, optic neuritis or colorectal cancer. The method of claim 44, wherein the disease is dry or dry arthritis. The method of any one of claims 44 to 47, wherein the warm-blooded animal is of the class.