Cationic chromenones and their oncological use

Abstract

The present invention relates to compounds containing a phosphonium salt group, as well as related salts, double salts, solvates, and pharmaceutical compositions. The present invention also relates to the use of such compounds and compositions in the treatment and prevention of medical disorders and diseases, particularly in the treatment and prevention of cancer.

Description

Technical Field

[0001] The present disclosure relates to phosphonium salt compounds, and related salts, multi-salts, solvates, and pharmaceutical compositions. The present disclosure also relates to the use of such compounds and compositions in the treatment and prevention of medical disorders and diseases, particularly in the prevention or treatment of cancer.

Background Art

[0002] There is a need to provide compounds having improved pharmacological properties and / or physiological properties and / or physicochemical properties, and / or compounds that are useful alternatives to known compounds.

Summary of the Invention

[0003] The present disclosure addresses the above need.

[0004] The present disclosure is defined by the claims.

[0005] A first aspect of the present disclosure is a compound of formula (1):

Chemical formula

[0006] For example, the compound may be a compound of formula (2):

Chemical formula

[0007] For example, the compound may be a compound of formula (2A):

Chemical formula

[0008] For example, the compound may be a compound of formula (2B):

Chemical formula

[0009] For example, the compound may be of formula (2C): [Chemical formula] It may also be a compound of

[0010] For example, the compound may be of formula (3): [Chemical formula] It may also be a compound of

[0011] For example, the compound may be of formula (3A): [Chemical formula] It may also be a compound of

[0012] For example, the compound may be of formula (3B): [Chemical formula] It may also be a compound of

[0013] For example, the compound may be of formula (3C): [Chemical formula] It may also be a compound of

[0014] The second aspect provides a pharmaceutically acceptable salt, double salt, or solvate of the compound of the first aspect.

[0015] The third aspect provides a pharmaceutical composition comprising the compound of the first aspect of the present disclosure, or a pharmaceutically acceptable salt, double salt, or solvate of the second aspect, and a pharmaceutically acceptable excipient.

[0016] The fourth aspect provides a compound of the first aspect, or a pharmaceutically acceptable salt, double salt, or solvate of the second aspect, or a pharmaceutical composition of the third aspect, which is used in medicine and / or for treating or preventing a disease, disorder or condition. In one embodiment, the disease, disorder or condition is cancer.

[0017] The fifth aspect provides the use of a compound of the first aspect, a pharmaceutically effective salt, double salt, or solvate of the second aspect, or a pharmaceutical composition according to the third aspect, in the manufacture of a medicament for treating or preventing a disease, disorder or condition. Typically, the treatment or prevention involves administration of the compound, salt, double salt, or solvate, or pharmaceutical composition, to a subject. In one embodiment, the disease, disorder or condition is cancer.

[0018] The sixth aspect of the present invention is a method for treating or preventing a disease, disorder or condition, comprising administering an effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, double salt, or solvate of the second aspect, or a pharmaceutical composition of the third aspect, thereby treating or preventing the disease, disorder or condition. Typically, the administration is to a subject in need thereof. In one embodiment, the disease, disorder or condition is cancer.

[0019] The seventh aspect of the present invention is a method for treating or preventing a disease, disorder or condition, comprising administering an effective amount of a compound according to formula (1) as defined herein, or a pharmaceutically acceptable salt, double salt, or solvate of the second aspect, or a pharmaceutical composition of the third aspect, thereby treating or preventing the disease, disorder or condition. Typically, the administration is to a subject in need thereof. In one embodiment, the disease, disorder or condition is cancer.

[0020] Definitions In the context of this specification, a "hydrocarbyl" substituent or the hydrocarbyl portion of a substituent, unless otherwise specified, contains only carbon and hydrogen atoms and does not contain any heteroatoms such as N, O, or S within its carbon skeleton. The hydrocarbyl group / portion may be saturated or unsaturated (including aromatic), may be straight-chain or branched, may be a cyclic group or may contain a cyclic group, where, unless otherwise specified, the cyclic group does not contain any heteroatoms such as N, O, or S within its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aryl groups / portions and all combinations of these groups / portions. Typically, a hydrocarbyl group is a C1-C 12 hydrocarbyl group. More typically, a hydrocarbyl group is a C1-C 10 hydrocarbyl group. A "hydrocarbylene" group is defined in the same manner as a divalent hydrocarbyl group.

[0021] An "alkyl" substituent or the alkyl portion of a substituent may be straight-chain or branched. Examples of alkyl groups / portions include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and n-pentyl groups / portions. Unless otherwise specified, the term "alkyl" does not include "cycloalkyl". Typically, an alkyl group is a C1-C 12 alkyl group. More typically, an alkyl group is a C1-C6 alkyl group. An "alkylene" group is defined in the same manner as a divalent alkyl group.

[0022] An "alkenyl" substituent or the alkenyl portion of a substituent refers to an unsaturated alkyl group or portion having one or more carbon-carbon double bonds. Examples of alkenyl groups / portions include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and 1,4-hexadienyl groups / portions. Unless otherwise specified, the term "alkenyl" does not include "cycloalkenyl". Typically, an alkenyl group is a C2-C 12It is an alkenyl group. More typically, the alkenyl group is a C2-C6 alkenyl group. The "alkenylene" group is defined in the same manner as a divalent alkenyl group.

[0023] The "alkynyl" substituent or the alkynyl portion of a substituent refers to an unsaturated alkyl group or portion having one or more carbon-carbon triple bonds. Examples of alkynyl groups / portions include ethynyl, propargyl, but-1-ynyl, and but-2-ynyl. Typically, the alkynyl group is a C2-C 12 It is an alkynyl group. More typically, the alkynyl group is a C2-C6 alkynyl group. The "alkynylene" group is defined in the same manner as a divalent alkynyl group.

[0024] The "haloalkyl" substituent or the haloalkyl portion of a substituent refers to an alkyl substituent or portion, an alkenyl substituent or portion, or an alkynyl substituent or portion that contains one or more carbon atoms and one or more halo atoms, such as Cl, Br, I, or F. Each halo atom has replaced a hydrogen of the alkyl substituent or portion, the alkenyl substituent or portion, or the alkynyl substituent or portion. Examples include -CH2F, -CHF2, -CHI2, -CHBr2, -CHCl2, -CF3, -CH2CF3, and CF2CH3.

[0025] The "alkoxy" substituent or the alkoxy portion of a substituent refers to an alkyl substituent or portion, an alkenyl substituent or portion, or an alkynyl substituent or portion that contains one or more carbon atoms and one or more oxygen atoms. Each oxygen atom has replaced a carbon atom (e.g., a terminal carbon or a bonded carbon) of the alkyl substituent or portion, the alkenyl substituent or portion, or the alkynyl substituent or portion. Examples include -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)(CH3).

[0026] An "alkylthio" substituent or an alkylthio group of a substituent refers to an alkyl substituent or moiety, an alkenyl substituent or moiety, or an alkynyl substituent or moiety containing one or more carbon atoms and one or more sulfur atoms. Each sulfur atom has replaced a carbon atom (e.g., a terminal carbon or a bonding carbon) of the alkyl substituent or moiety, the alkenyl substituent or moiety, or the alkynyl substituent or moiety. Examples include -SCH3, -SCH2CH3, -SCH2CH2CH3, and -SCH(CH3)(CH3).

[0027] An "alkylsulfinyl" substituent or an alkylsulfinyl group of a substituent refers to an alkyl substituent or moiety, an alkenyl substituent or moiety, or an alkynyl substituent or moiety containing one or more carbon atoms and one or more sulfinyl groups (-S(=O)-). Each sulfinyl group has replaced a carbon atom (e.g., a terminal carbon or a bonding carbon) of the alkyl substituent or moiety, the alkenyl substituent or moiety, or the alkynyl substituent or moiety. Examples include -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH2CH3, and -S(=O)CH(CH3)(CH3).

[0028] An "alkylsulfonyl" substituent or an alkylsulfonyl group of a substituent refers to an alkyl substituent or moiety, an alkenyl substituent or moiety, or an alkynyl substituent or moiety containing one or more carbon atoms and one or more sulfonyl groups (-SO2-). Each sulfonyl group has replaced a carbon atom (e.g., a terminal carbon or a bonding carbon) of the alkyl substituent or moiety, the alkenyl substituent or moiety, or the alkynyl substituent or moiety. Examples include -SO2(CH3), -SO2(CH2CH3), -SO2(CH2CH2CH3), and -SO2(CH(CH3)(CH3)).

[0029] The "aryl sulfonyl" substituent or the aryl sulfonyl group of a substituent refers to an aryl substituent or moiety containing one or more carbon atoms and one or more sulfonyl groups (-SO2-). Each sulfonyl group is replaced from a carbon atom (e.g., a terminal carbon or a bonded carbon) of an alkyl substituent or moiety, an alkenyl substituent or moiety, or an alkynyl substituent or moiety. Examples include -SO2(CH3), -SO2(CH2CH3), -SO2(CH2CH2CH3), and -SO2(CH(CH3)(CH3)).

[0030] The "cyclic" substituent or the cyclic moiety of a substituent refers to any hydrocarbyl ring, where the hydrocarbyl ring may be saturated or unsaturated and may contain one or more heteroatoms, such as N, O, or S, within its carbon skeleton. Examples of cyclic groups include the aliphatic cyclic groups, cycloalkyl groups, cycloalkenyl groups, heterocyclic groups, aryl groups, and heteroaryl groups described below. The cyclic group may be monocyclic, bicyclic (e.g., bridged, fused, or spiro), or polycyclic. Typically, the cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, the cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.

[0031] The "heterocyclic" substituent or the heterocyclic moiety of a substituent refers to a cyclic group or moiety containing one or more carbon atoms and one or more heteroatoms, such as N, O, or S, within the ring structure. Examples of heterocyclic groups include the heteroaryl groups and non-aromatic heterocyclic groups described below, such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups.

[0032] An "alicyclic" substituent or the alicyclic portion of a substituent refers to a hydrocarbyl cyclic group or portion that is not aromatic. The alicyclic group may be saturated or unsaturated and may contain one or more heteroatoms, such as N, O, or S, within its carbon skeleton. Examples include cyclopropyl, cyclohexyl, and morpholinyl. Unless otherwise specified, an alicyclic substituent or portion may include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0033] A "cycloalkyl" substituent or the cycloalkyl portion of a substituent refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a cycloalkyl substituent or portion may include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0034] A "cycloalkenyl" substituent or the cycloalkenyl portion of a substituent has one or more carbon-carbon double bonds and refers to a non-aromatic unsaturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohex-1,3-dien-1-yl. Unless otherwise specified, a cycloalkenyl substituent or portion may include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0035] An "aryl" substituent or the aryl portion of a substituent refers to an aromatic hydrocarbyl ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused-ring aromatic hydrocarbons, where all of the fused-ring systems are aromatic (excluding any ring systems that are part of or formed by any optional substituents). Examples of aryl groups / portions include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Unless otherwise specified, the term "aryl" does not include "heteroaryl".

[0036] The "heteroaryl" substituent or the heteroaryl portion of a substituent refers to an aromatic heterocyclic group or moiety. The term "heteroaryl" encompasses monocyclic aromatic heterocycles and polycyclic fused-ring aromatic heterocycles, where all of the fused-ring systems are aromatic (excluding any ring systems that are part of or formed by any optional substituents). Examples of heteroaryl groups / moieties include the following:

Chem.

[0037] For the purposes of this specification, when a combination of multiple moieties is referred to as one group, e.g., arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl, the last-mentioned moiety contains the atom at which the group is attached to the remainder of the molecule. An example of an arylalkyl group is benzyl.

[0038] Typically, a substituted group contains one, two, three, or four substituents, more typically one, two, or three substituents, more typically one or two substituents, and even more typically one substituent.

[0039] Unless otherwise specified, any divalent bridging substituent of an optionally substituted group or moiety (e.g., -O-, -S-, -NH-, -N(R β )-, or -R α -) must be connected only to the specified group or moiety and must not be connected to a second group or moiety, even if the second group or moiety itself may be optionally substituted.

[0040] The term "halo" encompasses fluoro, chloro, bromo, and iodo.

[0041] When referring to a carbon atom of a group that is replaced by an N atom, O atom, or S atom, the following is intended:

Chem.

[0042] In the context of this specification, unless otherwise specified, a C x ~C y group is defined as a group containing from x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms. Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group substituted with any substituent and / or containing any moiety. To avoid ambiguity, when calculating the number of carbon atoms in a C x ~C y group, replaced heteroatoms, such as N, O or S, are counted as carbon atoms. For example, a morpholinyl group is regarded as a C6 heterocyclic group rather than a C4 heterocyclic group.

[0043] 'Protecting group' refers to a grouping of atoms that, when attached to a reactive functional group (e.g., OH) within a compound, shields, reduces or prevents the reactivity of that functional group.

[0044] In the context of this specification, = represents a double bond and ≡ represents a triple bond.

[0045] The protection and deprotection of functional groups are described in 'Protective Groups in Organic Synthesis', 2 ndThe edition is described in T.W. Greene and P.G.M Wuts, Wiley-Interscience.

DETAILED DESCRIPTION OF THE INVENTION

[0046] The first aspect of the present invention is represented by formula (1):

CHEM.

CHEM.

CHEM.

[0047] In one embodiment, V is -R3 and W is

Chemical formula

[0048] In one embodiment of formula (1), V is -H, and W is [Chemical formula] or W is -H, and V is [Chemical formula] is.

[0049] In one embodiment of formula (1), R 3 is -H.

[0050] In one embodiment, the present invention provides a compound of formula (2): [Chemical formula] (wherein Z is -[P(R 5 )3]X, X is a counter anion, R 1 and R 2 are independently -H, -C 1~4 alkyl, -C(O)R4 、 -C(O)NHR 4 、 and -C(O)N(R 4 )2 selected from, or R 1 and R 2 together form a C 1~4 alkylene group, R 3 is H, halo, -CN, -NO2, -R β , -OH, -OR β , -SH, -SR β , -SOR β , -SO2H, -SO2R β , -SO2NH2, -SO2NHR β , -SO2N(R β )2, -NH2, -NHR β , -N(R β )2, -CHO, -COR β , -COOH, -COOR β , and -OCOR β selected from, each -R β is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C 14 cyclic group, and any -R β may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, -CON(CH3)2 or oxo (=O) group, each -R 4 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3~14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C 1~6 alkoxy, C 1~6 alkylthio, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, C 1~6 alkylsulfinyl, C 1~6 alkylsulfonyl, or arylsulfonyl, R 5 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C 14 aryl group, or C3-C 14 alicyclic group, and any -R 5 may be optionally substituted with one or more C1-C4 alkyl, halo, -CF3, -OH, -NH2, -CN, -C≡CH or oxo(=O) groups, n is an integer from 1 to 10). A compound of is provided.

[0051] In one embodiment, Z is -[P(R 5 )3]X, X is a counter anion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 3 is selected from -H, -Cl, -F, -CH3, and -OCH3, R 5 is phenyl, and each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, A compound of formula (2) is provided.

[0052] In one embodiment of formula (2), n is an integer from 1 to 5. In one embodiment of formula (2), n is an integer from 6 to 10.

[0053] In one embodiment of formula (2), R 3 is -H.

[0054] In one embodiment, the compound is of formula (2A):

Chemical formula

[0055] In one embodiment, Z is -[P(R 5 )3]X, X is a counteranion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 3 is selected from -H, -Cl, -F, -CH3, and -OCH3, R 5 is phenyl, and each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, Compounds of formula (2A) are provided.

[0056] In one embodiment of formula (2A), n is an integer from 1 to 5. In one embodiment of formula (2A), n is an integer from 6 to 10.

[0057] In one embodiment of formula (2A), R 3 is -H.

[0058] In one embodiment, the compound is of formula (2B):

Chemical formula

[0059] In one embodiment, Z is -[P(R 5 )3]X, X is a counteranion, R 1 and R 2 are independently selected from H and -C 1~4Selected from alkyl, R 3 is selected from -H, -Cl, -F, -CH3, and -OCH3, R 5 is phenyl, and each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, a compound of formula (2B) is provided.

[0060] In one embodiment of formula (2B), n is an integer from 1 to 5. In one embodiment of formula (2B), n is an integer from 6 to 10.

[0061] In one embodiment of formula (2B), R 3 is -H.

[0062] In one embodiment, the compound is of formula (2C):

Chemical formula

[0063] In one embodiment, Z is -[P(R 5 )3]X, X is a counteranion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 5 is phenyl, and each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, a compound of formula (2C) is provided.

[0064] In one embodiment of formula (2C), n is an integer from 1 to 5. In one embodiment of formula (2C), n is an integer from 6 to 10.

[0065] In one embodiment, the compound has the formula (3):

Chemical formula

[0066] In one embodiment, Z is -[P(R 5 )3]X, X is a counteranion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 3 is selected from -H, -Cl, -F, -CH3, and -OCH3, R 5 is phenyl, and each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, a compound of formula (3) is provided.

[0067] In one embodiment of formula (3), n is an integer from 1 to 5. In one embodiment of formula (3), n is an integer from 6 to 10.

[0068] In one embodiment of formula (3), R 3 is -H.

[0069] In one embodiment, the compound is of formula (3A):

Chemical formula

[0070] In one embodiment, Z is -[P(R 5 )3]X, X is a counter anion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 3 is selected from -H, -Cl, -F, -CH3, and -OCH3, R 5 is phenyl, each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, a compound of formula (3A) is provided.

[0071] In one embodiment of formula (3A), n is an integer from 1 to 5. In one embodiment of formula (3A), n is an integer from 6 to 10.

[0072] In one embodiment of formula (3A), R 3It is -H.

[0073] In one embodiment, the compound may be of formula (3B):

Chemical formula

[0074] In one embodiment, Z is -[P(R 5 )3]X, X is a counteranion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 3 is selected from -H, -Cl, -F, -CH3, -OCH3, R 5 is phenyl, and each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, A compound of formula (3B) is provided.

[0075] In one embodiment of formula (3B), n is an integer from 1 to 5. In one embodiment of formula (3B), n is an integer from 6 to 10.

[0076] In one embodiment of formula (3B), R 3 is -H.

[0077] In one embodiment, the compound may be of formula (3C):

Chemical formula

[0078] In one embodiment, Z is -[P(R 5 )3]X, X is a counteranion, R 1 and R 2 are independently selected from H and -C 1~4 alkyl, R 5 is phenyl, each R 5 is optionally substituted with -CF3, n is an integer from 1 to 10, and a compound of formula (3C) is provided.

[0079] In one embodiment of formula (3C), n is an integer from 1 to 5. In one embodiment of formula (3C), n is an integer from 6 to 10.

[0080] In the context of formulas (1), (2), (2A), (2B), (2C), (3), (3A), (3B), and (3C) described herein, the following embodiments are provided by the present disclosure.

[0081] In one embodiment, R 1 and R 2 are independently selected from H and -C 1~4 alkyl. For example, R 1 and R 2 can be independently selected from H, -CH3, and -CH2CH3. For example, R 1 and R 2 can be independently selected from H and -CH3.

[0082] In one embodiment, R 1 and R 2 are both -H.

[0083] In one embodiment, R 1 and R 2 are both -CH3.

[0084] In one embodiment, R 1 is -H, and R 2 is -CH3.

[0085] In one embodiment, R 1 is -CH3, and R 2 is -H.

[0086] In one embodiment, R 1 and R 2 together form a C 1~4 alkylene group.

[0087] In one embodiment, R 3 is selected from H, halo, -CN, -NO2, -R β , -OH, -OR β , -SH, -SR β , -SOR β , -SO2H, -SO2R β , -SO2NH2, -SO2NHR β , -SO2N(R β )2, -NH2, -NHR β , -N(R β )2, -CHO, -COR β , -COOH, -COOR β , and -OCOR β . In one embodiment, R 3 is selected from H, halo, -CN, -NO2, -R β , -SH, -SR β , -SOR β , -SO2H, -SO2R β , -SO2NH2, -SO2NHR β , -SO2N(R β )2, -NH2, -NHR β , -N(R β )2, -CHO, -COR β , -COOH, and -COOR β . In one embodiment, R 3 is selected from H, halo, -CN, -NO2, -R β , -OH, -OR β , -NH2, -NHR β , -N(R β) 2, -CHO, -COR β , -COOH, -COOR β , and -OCOR β is selected from. In one embodiment, R 3 is H, halo, -CN, -NO2, -R β , -NH2, -NHR β , -N(R β )2, -CHO, -COR β , -COOH, and -COOR β is selected from. In one embodiment, R 3 is H, halo, -CN, -NO2, -R β , -OH, -OR β , -NH2, -NHR β , and -N(R β )2 is selected from. In one embodiment, R 3 is H, halo, -CN, -NO2, -R β , -NH2, -NHR β , and -N(R β )2 is selected from. In one embodiment, R 3 is H, halo, -CN, -NO2, -R β , -OH, -OR β , and -NH2 is selected from. In one embodiment, R 3 is H, halo, -CN, -NO2, -R β , and -NH2 is selected from. In one embodiment, R 3 is selected from H, -Cl, -F, -CH3 and -OCH3. In one embodiment, R 3 is selected from H, halo, -CN, -NO2, and -NH2. In one embodiment, R 3 is H.

[0088] In one embodiment, each -R β is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C 14 cyclic group, and any -R βmay be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, -CON(CH3)2 or oxo (=O) groups.

[0089] In one embodiment, each -R β is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C 14 cyclic groups, and any -R β may be optionally substituted with one or more halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, -CON(CH3)2 or oxo (=O) groups.

[0090] In one embodiment, each -R β is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C 14 cyclic groups.

[0091] In one embodiment, each -R β is independently selected from -CF3 and -CHF2.

[0092] In one embodiment, each -R β is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 1,4-hexadienyl, ethynyl, propargyl, but-1-ynyl or but-2-ynyl groups.

[0093] In one embodiment, each -R β is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or n-pentyl groups.

[0094] In one embodiment, X is selected from, but not limited to only, halides (e.g., fluoride, chloride, bromide, or iodide) or other inorganic anions (e.g., nitrate ion, perchlorate ion, sulfate ion, bisulfate ion, or phosphate ion) or organic anions (e.g., propionate ion, butyrate ion, glycolate ion, lactate ion, mandelate ion, citrate ion, acetate ion, benzoate ion, salicylate ion, succinate ion, malate ion, tartrate ion, fumarate ion, maleate ion, hydroxymaleate ion, galactarate ion, gluconate ion, pantothenate ion, pamoate ion, methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, 2-hydroxyethanesulfonate ion, benzenesulfonate ion, toluene-p-sulfonate ion, naphthalene-2-sulfonate ion, camphorsulfonate ion, ornithinate ion, glutamate ion, or aspartate ion).

[0095] In one embodiment, X may be fluoride, chloride, bromide, or iodide. In one embodiment, X is bromide or chloride. In one embodiment, X is bromide. In one embodiment, X is chloride.

[0096] In one embodiment, each -R 5 is independently selected from H, or C1-C6 alkyl, or a C3-C 14 aryl group, and any -R 5 may be optionally substituted with one or more C1-C4 alkyl, halo, -OH, -NH2, -CN, -C≡CH, or oxo(=O) groups. Alternatively, any -R 5 may be optionally substituted with one or more -CF3.

[0097] In one embodiment, each -R 5 is independently a C3-C 14 aryl group, and any -R 5may be optionally substituted with one or more C1-C4 alkyl, halo, -OH, -NH2, -CN, -C≡CH or oxo(=O) groups. Alternatively, each R 5 may be optionally substituted with one or more -CF3.

[0098] In one embodiment, two of the R 5 groups are the same. In one embodiment, each R 5 group is the same.

[0099] In one embodiment, each -R 5 is a phenyl group, and each phenyl group may be optionally substituted with one or more C1-C4 alkyl, halo, -OH, -NH2, -CN, -C≡CH or oxo(=O) groups.

[0100] In one embodiment, each R 5 is a phenyl group.

[0101] In one embodiment, each R 5 is a phenyl group optionally substituted with -CF3. For example, each R 5 may be a phenyl group substituted with -CF3. For example, each R 5 may be a phenyl group substituted with -CF3 at the para position.

[0102] In one embodiment, Z is -[P(Ph)3]X, where X in the formula is a counteranion. For example, X may be bromide or chloride, or X may be bromide. In one embodiment, X is chloride.

[0103] In one embodiment, Z is -[P(p-CF3-Ph)3]X, where X in the formula is a counteranion. For example, X may be bromide or chloride, or X may be bromide. In one embodiment, X is chloride.

[0104] In one embodiment, each -R 4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3~14 Selected from cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C 1~6 alkoxy, C 1~6 alkylthio, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, C 1~6 alkylsulfinyl, C 1~6 alkylsulfonyl, or arylsulfonyl.

[0105] In one embodiment, each -R 4 is independently selected from C 1~4 alkyl.

[0106] In one embodiment, each -R 4 is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 1,4-hexadienyl, ethynyl, propargyl, but-1-ynyl or but-2-ynyl group.

[0107] In one embodiment, each -R 4 is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or n-pentyl group.

[0108] In one embodiment, each -R 4 is independently selected from H, methyl, ethyl, propyl, and butyl.

[0109] In one embodiment, n is an integer from 1 to 10, for example, an integer from 2 to 10. In one embodiment, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In one embodiment, n is an integer from 1 to 6 or an integer from 2 to 6. In one embodiment, n is an integer from 2 to 5. In one embodiment, n is 3, 4 or 5.

[0110] In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 6. In one embodiment, n is 8. In one embodiment, n is 10.

[0111] In one embodiment, the compound of formula (1) is selected from the following.

[0112] [Table 1] TIFF2025523982000029.tif206170TIFF2025523982000030.tif203170TIFF2025523982000031.tif205170TIFF2025523982000032.tif220170TIFF2025523982000033.tif111170

[0113] In one embodiment, the compound of formula (1) is selected from the following.

[0114] [Table 2] TIFF2025523982000035.tif57170

[0115] In one embodiment, the compound of formula (1) is selected from the following.

[0116] [Table 3] TIFF2025523982000037.tif189170TIFF2025523982000038.tif220170TIFF2025523982000039.tif220170TIFF2025523982000040.tif56170

[0117] The compound contains a quaternary phosphonium group, and X is a counter anion. Preferably, the counter anion X may be any pharmaceutically acceptable non-toxic counter ion. For example, X may be bromide or chloride, or X may be bromide. For example, X may be chloride.

[0118] The counter anion may optionally be monovalent, divalent or trivalent. Since the quaternary group is monovalent, when the counter anion is trivalent, the stoichiometric ratio of the quaternary group to the counter anion is typically 3:1, and when the counter anion is divalent, the stoichiometric ratio of the quaternary group to the counter anion is typically 2:1. When both the quaternary group and the counter anion are monovalent, the stoichiometric ratio of the quaternary group to the counter anion is typically 1:1.

[0119] In one embodiment, the counter anion is a monovalent anion. Suitable anions X include, but are not limited to, halides (e.g., fluoride, chloride, bromide or iodide) or other inorganic anions (e.g., nitrate ion, perchlorate ion, sulfate ion, bisulfate ion, or phosphate ion) or organic anions (e.g., propionate ion, butyrate ion, glycolate ion, lactate ion, mandelate ion, citrate ion, acetate ion, benzoate ion, salicylate ion, succinate ion, malate ion, tartrate ion, fumarate ion, maleate ion, hydroxymaleate ion, galactarate ion, gluconate ion, pantothenate ion, pamoate ion, methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, 2-hydroxyethanesulfonate ion, benzenesulfonate ion, toluene-p-sulfonate ion, naphthalene-2-sulfonate ion, camphorsulfonate ion, ornithinate ion, glutamate ion or aspartate ion). The counter anion may be fluoride, chloride, bromide or iodide. For example, X may be bromide or chloride, or X may be bromide.

[0120] The second aspect of the present invention provides a pharmaceutically acceptable salt, double salt, or solvate compound of any compound of the first aspect of the present invention.

[0121] The compounds of the present invention can also be used in their quaternary salt forms (as a single salt). Further, the compounds of the present invention may contain one or more (e.g., one or two) acid addition salts or alkali addition salts to form a double salt. The double salt includes salts of a group of compounds of the present invention different from the group of quaternary salts.

[0122] For the purposes of the present invention, the "double salt" of the compounds of the present invention includes acid addition salts. The acid addition salts include, but are not limited to, inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid) or other inorganic acids (e.g., nitric acid, perchloric acid, sulfuric acid, or phosphoric acid), or organic acids such as organic carboxylic acids (e.g., propionic acid, butyric acid, glycolic acid, lactic acid, mandelic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid, or hydroxysuccinic acid, tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, mucic acid, or galactaric acid, gluconic acid, pantothenic acid, or pamoic acid), organic sulfonic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluene-p-sulfonic acid, naphthalene-2-sulfonic acid, or camphorsulfonic acid), or amino acids (e.g., ornithinic acid, glutamic acid, or aspartic acid) and are preferably pharmaceutically acceptable non-toxic addition salts with suitable acids. The acid addition salts may be monoacid addition salts, diacid addition salts, triacid addition salts, or polyacid addition salts. Preferred salts are hydrohalic acid addition salts, sulfuric acid addition salts, phosphoric acid addition salts, or organic acid addition salts. A preferred salt is the hydrochloric acid addition salt.

[0123] The compounds of the present invention can be used in either the quaternary salt form or their double salt forms. For the purposes of the present invention, the "double salts" of the compounds of the present invention include those formed between the protonic acid functional groups (e.g., carboxylic acid groups) of the compounds of the present invention and suitable cations. Suitable cations include, but are not limited to, lithium ions, sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium ions. The salts can be single salts, double salts, triple salts, or double salts. The salts are preferably monolithium salts or dilithium salts, monosodium salts or disodium salts, monopotassium salts or dipotassium salts, monomagnesium salts or dimagnesium salts, monocalcium salts or dicalcium salts, or monoammonium salts or diammonium salts. The salts are more preferably monosodium salts or disodium salts or monopotassium salts or dipotassium salts.

[0124] Preferably, both the salts and double salts are pharmaceutically acceptable non-toxic salts. However, in addition to pharmaceutically acceptable salts and double salts, other salts are also included in the present invention because they have the potential to function as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or are useful for the identification, characterization, or purification of free acids or free bases.

[0125] The compounds, salts and / or double salts of the present invention may be anhydrous or in the form of hydrates (e.g., hemihydrates, monohydrates, dihydrates or trihydrates) or other solvates. Such solvates may be formed using common organic solvents including, but not limited to, alcoholic solvents such as methanol, ethanol or isopropanol.

[0126] The compounds, salts, double salts, and solvates of the present invention may contain at least one chiral center. Therefore, the compounds, salts, double salts, and solvates may exist in at least two isomeric forms. The present invention includes racemic mixtures of the compounds, salts, double salts, and solvates of the present invention, as well as enantiomerically enriched isomers and substantially enantiomerically pure isomers. For the purposes of the present invention, a "substantially enantiomerically pure" isomer of a compound contains less than 5% by weight, more typically less than 2% by weight, and most typically less than 0.5% by weight of other isomers of the same compound.

[0127] The compounds, salts, double salts, and solvates of the present invention include, but are not limited to, 12 C, 13 C, 1 H, 2 H(D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 any stable isotope, including, but not limited to, 11 C, 14 C, 3 H(T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 any radioactive isotope, including, but not limited to,

[0128] The compounds, salts, double salts, and solvates of the present invention may be in any polymorphic or amorphous form.

[0129] A third aspect of the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, double salt, or solvate of the second aspect of the present invention, and a pharmaceutically acceptable excipient.

[0130] Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Aulton’s Pharmaceutics - The Design and Manufacture of Medicines", M. E. Aulton and K.M. G. Taylor, Churchill Livingstone Elsevier, 4 th Ed., 2013.

[0131] Pharmaceutically acceptable excipients, including adjuvants, diluents or carriers that can be used in the pharmaceutical compositions of the present invention, are those conventionally used in the field of pharmaceutical formulations, and these include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphoric acid, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, for example, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and lanolin.

[0132] A fourth aspect of the present invention provides a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, double salt, or solvate compound of the second aspect of the present invention, or a pharmaceutical composition of the third aspect of the present invention, for use in medicine and / or for use in treating or preventing a disease, disorder or condition. In one embodiment, the disease, disorder or condition is cancer.

[0133] The fifth aspect of the present invention provides the use of the compound of the first aspect, the pharmaceutically effective salt, double salt, or solvate of the second aspect, or the pharmaceutical composition according to the third aspect, in the manufacture of a medicament for treating or preventing a disease, disorder, or condition. Typically, the treatment or prevention involves administration of the compound, salt, double salt, solvate, or pharmaceutical composition to a subject. In one embodiment, the disease, disorder, or condition is cancer.

[0134] The sixth aspect of the present invention provides a method for treating or preventing a disease, disorder, or condition, comprising administering an effective amount of the compound of the first aspect, or the pharmaceutically acceptable salt, double salt, or solvate of the second aspect, or the pharmaceutical composition of the third aspect, thereby treating or preventing the disease, disorder, or condition. Typically, the administration is to a subject in need thereof. In one embodiment, the disease, disorder, or condition is cancer.

[0135] The seventh aspect of the present invention provides a method for treating or preventing a disease, disorder, or condition, comprising administering an effective amount of the compound according to formula (1) as defined herein, or the pharmaceutically acceptable salt, double salt, or solvate of the second aspect, or the pharmaceutical composition of the third aspect, thereby treating or preventing the disease, disorder, or condition. Typically, the administration is to a subject in need thereof. In one embodiment, the disease, disorder, or condition is cancer.

[0136] In general embodiments, the disease, disorder, or condition is cancer.

[0137] In one embodiment, the cancer is brain cancer, breast cancer, colon cancer, leukemia, lung cancer, lymphoma, pancreatic cancer, sarcoma, or skin cancer (melanoma).

[0138] In one embodiment, the cancer is brain cancer.

[0139] In one embodiment, the cancer is breast cancer.

[0140] In one embodiment, the cancer is colon cancer.

[0141] In one embodiment, the cancer is leukemia.

[0142] In one embodiment, the cancer is lung cancer.

[0143] In one embodiment, the cancer is lymphoma.

[0144] In one embodiment, the cancer is pancreatic cancer.

[0145] In one embodiment, the cancer is sarcoma.

[0146] In one embodiment, the cancer is skin cancer (melanoma).

[0147] As used herein, the term "treatment" equally refers to curative treatment, as well as palliative or ameliorative treatment. This term encompasses obtaining a beneficial or desired physiological result, whether clinically established or not. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, prevention of symptoms, attenuation of the degree of a disease, stabilization of a condition (i.e., not worsening), delay or slowing of the progression / deterioration of a condition / symptom, improvement or alleviation of a condition / symptom, and remission (whether partial or complete). As used herein, the term "amelioration" and its variations, when the compounds, double salts, solvates, or pharmaceutical compositions of the present invention are administered, compared to when they are not administered, mean that the degree of the physiological state or symptoms and / or undesirable signs are reduced, and / or the time course of progression is slowed or extended. As used herein, the term "prevention", when used in connection with a disease, disorder or condition, relates to prophylactic or preventive treatment, as well as treatment that reduces the risk of occurrence of a disease, disorder or condition. The term "prevention" encompasses both avoiding the appearance of a disease, disorder or condition and delaying the onset of a disease, disorder or condition. Avoidance of any statistically significant appearance, delay in onset, or reduction in risk measured by a controlled clinical trial can be considered prevention of a disease, disorder or condition. Suitable subjects for prevention include subjects with an increased risk of a disease, disorder or condition identified by a genetic marker or a biochemical marker. Typically, the genetic marker or biochemical marker is suitable for the disease, disorder or condition under consideration, and examples thereof can include, for example, beta-amyloid 42, tau, and phosphorylated tau (phosphor-tau).

[0148] Unless otherwise specified, in any aspect of the present invention, the subject can be any human or other animal. Typically, the subject is a mammal, more typically a human or a domesticated mammal, such as a cow, pig, sheep, goat, horse, cat, dog, etc., and most typically, the subject is a human.

[0149] All the drugs used in the present invention can be administered by oral administration, parenteral administration (including intravenous administration, subcutaneous administration, intramuscular administration, intradermal administration, intratracheal administration, intraperitoneal administration, intra-articular administration, intracranial administration and epidural administration), airway administration (aerosol), rectal administration, vaginal administration or topical administration (including transdermal administration, oral administration, mucosal administration and sublingual administration).

[0150] Typically, the selected administration form is the one most suitable for the disorder or disease to be treated or prevented.

[0151] Regarding oral administration, the compounds, double salts, or solvated compounds of the present invention are generally provided in the form of tablets, capsules, hard gelatin capsules or soft gelatin capsules, caplets, troches or lozenges, as powders or granules, or as solutions, suspensions or dispersions.

[0152] Tablets for oral use may contain the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrants. Starches and gelatin can be mentioned as binders. When a lubricant is present, it may be magnesium stearate, stearic acid or talc. If desired, the tablets can be coated with substances such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The tablets may also be effervescent tablets and / or soluble tablets.

[0153] Examples of capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0154] Powders or granules for oral use may be in sachets or tubs. An aqueous solution, suspension or dispersion can be prepared by adding water to the powder, granule or tablet.

[0155] Any form suitable for oral administration may optionally contain a sweetening agent such as sugar, a flavoring agent, a coloring agent and / or a preservative.

[0156] Preparations for rectal administration may be provided, for example, as suppositories using a suitable base containing cocoa butter or salicylic acid.

[0157] Preparations suitable for vaginal administration may be provided, in addition to the active ingredient, as vaginal suppositories, tampons, creams, gels, pastes, foams or spray preparations containing a carrier known in the art to be suitable.

[0158] For parenteral use, the compounds, double salts or solvates of the invention are generally provided as a sterile and aqueous solution or suspension buffered to a suitable pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or glucose. Aqueous suspensions according to the invention may contain suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and tragacanth gum, and wetting agents such as lecithin. Preservatives suitable for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoic acid. The compounds of the invention may be provided as liposome formulations.

[0159] For percutaneous and other topical administration, the compounds, double salts or solvates of the invention are generally provided in the form of ointments, poultices, pastes, powders, dressings, creams, patches or patches.

[0160] Suitable suspensions and solutions for administration by airway (aerosol) can be used by placing them in an inhaler.

[0161] The dosage of the compounds, double salts, or solvates of the present invention will, of course, vary depending on the disorder or disease to be treated or prevented. Generally, appropriate dosages will fall within the range of 0.01 mg to 500 mg per kilogram of the recipient's body weight per day. The desired dosage can be provided at appropriate intervals, for example, once every two days, once a day, twice a day, three times a day, or four times a day. The desired dosage can be administered, for example, in unit dosage forms containing 1 mg to 50 g of the active ingredient per unit dosage form.

[0162] To avoid doubt, to the extent practicable, any embodiment of a given aspect of the present invention may exist in combination with any other embodiment of the same aspect of the present invention. Further, to the extent practicable, any preferred exemplary or any embodiment of any aspect of the present invention should be equally regarded as a preferred exemplary or any embodiment of any other aspect of the present invention.

Example

[0163] The following compounds are named using the following nomenclature.

[0164]

Table 4

[0165] Example - Synthesis of Compounds The compounds of the present invention are synthesized using the synthetic routes shown below.

[0166] Synthesis of SND470 (Compound 43)

Chemical formula

[0167] 3-(4-Iodophenyl)-7,8-dimethoxy-4H-chromen-4-one (43.1) A suspension of 2-(4-iodophenyl)-1-(2,3,4-trihydroxy-phenyl)ethan-1-one (37.3) (8.90 g, 1 equivalent, 24 mmol) in dry toluene (150 mL) and dry DMF (20 mL) was treated with DMF-DMA (11.5 g, 12.8 mL, 4 equivalents, 96 mmol) under a nitrogen atmosphere and heated to reflux. After the mixture was refluxed for 5 hours, additional DMF-DMA (2.87 g, 3.2 mL, 1 equivalent, 24 mmol) was added and the mixture was refluxed for an additional 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was diluted with 250 mL of EtOAc and washed with 250 mL of saturated NaHCO3. The aqueous layer was extracted with 3 × 250 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was treated with 100 mL of hot MeOH, refluxed briefly, and allowed to cool overnight. The resulting solid was filtered and washed with 4 × 10 mL of MeOH. The resulting solid was recrystallized from EtOAc / heptane to give 3-(4-iodophenyl)-7,8-dimethoxy-4H-chromen-4-one (43.1) (5.39 g, 12 mmol, 52% yield, 94% purity) as an off-white powder.

[0168] 2,2-Diphenyl-7-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (43.2) 2-(But-3-en-1-yloxy)tetrahydro-2H-pyran (2.21 g, 1.5 eq, 14 mmol) was added to a solution of 9-BBN (3.458 g, 28.3 mL, 0.5 molar concentration, 1.5 eq, 14 mmol) in THF under a nitrogen stream. After the mixture was stirred at room temperature for 22 h, a suspension of 3-(4-iodophenyl)-7,8-dimethoxy-4H-chromen-4-one (43.1) (3.856 g, 1 eq, 9.4 mmol) in NaOH (1.3 mL, 30% Wt, 1.4 eq, 13 mmol) and THF (70 mL) was added. The reaction mixture was then degassed by bubbling nitrogen through the solution, and then Pd(PPh3)4 (551 mg, 0.05 eq, 0.48 mmol) was added. The reaction mixture was degassed again, and the mixture was heated at 60 °C for 2.5 h. The reaction mixture was allowed to cool to room temperature, diluted with 250 mL of EtOAc, and washed with 250 mL of saturated NaHCO3. The aqueous layer was extracted with 250 mL of EtOAc, the organic layers were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified twice by normal-phase flash chromatography using EtOAc:heptane as the eluent to give 7,8-dimethoxy-3-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-4H-chromen-4-one (43.2) (3.063 g, 6.8 mmol, 72% yield, 97% purity) as an orange oil.

[0169] 3-(4-(4-Bromobutyl)phenyl)-7,8-dimethoxy-4H-chromen-4-one (43.3) Thionyl bromide (2.20 g, 820 μL, 2.4 eq, 10.6 mmol) was added to a solution of 7,8-dimethoxy-3-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-4H-chromen-4-one (43.2) (1.925 g, 1 eq, 4.39 mmol) in dry DCM (34 mL) and dry DMF (3.2 g, 3.4 mL, 10 eq, 44 mmol) at 5 °C under a nitrogen stream. After the reaction mixture was stirred for 1 minute, the solution was warmed to room temperature and stirred under nitrogen until completion of the reaction was confirmed by LC-MS (1.5 h). The reaction mixture was cooled to +5 °C, quenched with 50 mL of ice-cold water, and basified to pH = 8 - 9 with saturated NaHCO3. The mixture was extracted with 3 × 50 mL of DCM. The combined organic layers were washed with 75 mL of brine, then extracted with 25 mL of DCM. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. Purification by normal-phase flash chromatography gave 3-(4-(4-bromobutyl)phenyl)-7,8-dimethoxy-4H-chromen-4-one (43.3) (1.621 g, 3.8 mmol, 86% yield, 97% purity) as a white solid.

[0170] (4-(4-(7,8-Dimethoxy-4-oxo-4H-chromen-3-yl)phenyl)butyl)triphenylphosphonium bromide (43) Triphenyl-phosphine (809 mg, 5.0 eq, 3.1 mmol) was added to a solution of 3-(4-(4-bromobutyl)phenyl)-7,8-dimethoxy-4H-chromen-4-one (43.3) (258 mg, 1 eq, 0.62 mmol) in dry 1,4-dioxane (3 mL). The solution was refluxed for 44 h and then allowed to cool to room temperature. 20 mL of toluene was added and the mixture was sonicated for 45 min. The supernatant was decanted, another 20 mL of toluene was added and the mixture was sonicated again briefly. The beige solid was filtered and washed with 2×20 mL of toluene. The crude product was purified by normal phase flash chromatography using DCM:MeOH as eluent and by preparative reverse phase LC using 0.05% HBr in MeCN:H2O to give (4-(4-(7,8-dimethoxy-4-oxo-4H-chromen-3-yl)phenyl)butyl)triphenylphosphonium bromide (43) (224 mg, 0.32 mmol, 52% yield, 97% purity) as a beige powder.

[0171] Synthesis of SND490 (Compound 37) [Chemical Structure]

[0172] 2-(4-Iodophenyl)-1-(2,3,4-trihydroxyphenyl)ethan-1-one (37.3) Pyrogallol (5.51 g, 1 equiv, 43.7 mmol) and 2-(4-iodophenyl)acetic acid (11.42 g, 1 equiv, 43.6 mmol) were treated under a nitrogen stream with boron trifluoride etherate (99.2 g, 88.6 mL, 16 equiv, 699 mmol). Subsequently, the mixture was heated to 80 °C. After 6 hours, the reaction mixture was allowed to cool to room temperature and slowly poured into 250 mL of saturated NaHCO3. This was an exothermic process. The aqueous layer was extracted with 2 × 250 mL of EtOAc. The organic layers were combined and washed multiple times with 250 mL of saturated NaHCO3 until the basicity of the aqueous layer was maintained. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in 30 mL of hot MeOH and diluted with 200 mL of water. The resulting precipitate was filtered, washed with water, and dried under an air stream. The solid was transferred to a flask and a trace amount of water was evaporated together with toluene. Subsequently, the solid was dried under vacuum, then suspended in 25 mL of DCM and filtered. The purple solid on the filter was washed with 3 × 10 mL of DCM. The filtrate was purified by normal-phase flash chromatography using DCM:EtOAc as the eluent to obtain additional material. Overall, 2-(4-iodophenyl)-1-(2,3,4-trihydroxyphenyl)ethan-1-one (37.3) (10.45 g, 27 mmol, 61% yield, 95% purity) was obtained as an off-white powder.

[0173] 1-(4-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-2-(4-iodophenyl)ethan-1-one (37.4) 2-(4-Iodophenyl)-1-(2,3,4-trihydroxyphenyl)ethan-1-one (37.3) (2.956 g, 1 equivalent, 8.0 mmol), dichlorodiphenylmethane (2.00 g, 1.62 mL, 1.06 equivalents, 8.43 mmol) and diphenyl ether (18 mL) were heated to 175 °C for 30 minutes and then allowed to cool to room temperature. The reaction mixture was poured into 180 mL of heptane and left to precipitate for several hours. The resulting precipitate was filtered, washed with 4 × 25 mL of heptane and dried to give 1-(4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-2-(4-iodophenyl)ethan-1-one (37.4) (3.15 g, 5.8 mmol, 72% yield, 98% purity) as a brown solid.

[0174] 7-(4-Iodophenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.5) 1-(4-Hydroxy-2,2-diphenylbenzo[d]-[1,3]dioxol-5-yl)-2-(4-iodophenyl)ethan-1-one (37.4) (3.15 g, 1 equivalent, 5.9 mmol) was dissolved in a mixture of dry toluene (56 mL) and dry DMF (6 mL). Then, DMF-DMA (1.76 g, 1.96 mL, 2.5 equivalents, 15 mmol) was added to the solution and the reaction mixture was refluxed under nitrogen for 1.5 hours, after which reflux was stopped and the mixture was allowed to cool to room temperature. The reaction mixture was evaporated to dryness, suspended in 250 mL of EtOAc and washed with 250 mL of saturated NaHCO3. The aqueous layer was extracted with 3 × 250 mL of EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal-phase flash chromatography using DCM:EtOAc as the eluent to give 7-(4-iodophenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.5) (2.80 g, 5.1 mmol, 86% yield, 99% purity) as an off-white solid.

[0175] 2-(But-3-en-1-yloxy)tetrahydro-2H-pyran (37.10) p-Toluenesulfonic acid monohydrate (442 mg, 0.02 eq, 2.32 mmol) and 3,4-dihydro-2H-pyran (19 g, 21 mL, 2 eq, 0.23 mol) were added to a solution of but-3-en-1-ol (8.38 g, 10 mL, 1 eq, 116 mmol) in DCM (50 mL) at 0 °C. After 2 h at 0 °C, the reaction mixture was quenched with 50 mL of saturated NaHCO3, diluted with 50 mL of DCM, and the layers were separated. The organic layer was washed with 50 mL of water and 50 mL of brine, dried over sodium sulfate, filtered, and evaporated to dryness. Purification by normal-phase flash chromatography using heptane:EtOAc as eluent afforded 2-(but-3-en-1-yloxy)tetrahydro-2H-pyran (37.10) (13.75 g, 88 mmol, 76% yield) as a clear oil.

[0176] 2,2-Diphenyl-7-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.6) 2-(But-3-en-1-yloxy)tetrahydro-2H-pyran (37.10) (1.20 g, 1.5 eq, 7.7 mmol) was added to a solution of 9-BBN (1.89 g, 15.5 mL, 0.5 M, 1.5 eq, 7.75 mmol) in THF under a nitrogen stream. The solution was stirred at room temperature under nitrogen for 70 h, then a solution of 7-(4-iodophenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.5) (2.807 g, 1 eq, 5.16 mmol) in NaOH (0.96 g, 0.72 mL, 30% wt, 1.4 eq, 7.2 mmol) and THF (40 mL) was added. The reaction mixture was degassed and then Pd(PPh3)4 (469 mg, 0.08 eq, 0.41 mmol) was added. After the reaction mixture was degassed again, the mixture was heated at 60 °C for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with 150 mL of EtOAc, and washed with 150 mL of saturated NaHCO3. Then the aqueous layer was extracted with another 150 mL of EtOAc. The organic fractions were combined, dried over sodium sulfate, filtered, and evaporated to dryness. Purification by normal-phase flash chromatography using DCM:EtOAc as the eluent gave 2,2-diphenyl-7-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-6H-[1,3]dioxolo-[4,5-h]chromen-6-one (37.6) (1.276 g, 2.2 mmol, 43% yield, 99% purity) as a beige powder.

[0177] 7-(4-(4-Bromobutyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.7) Thionyl bromide (1.25 g, 465 μL, 2.4 eq, 6.0 mmol) was added to a solution of 2,2-diphenyl-7-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.6) (1.44 g, 1 eq, 2.51 mmol) in a mixture of dry DMF (1.8 g, 1.9 mL, 9.8 eq, 25 mmol) and DCM (20 mL) at 5 °C under a nitrogen stream. The reaction mixture was then warmed to room temperature and stirred for 2.5 h, after which additional thionyl bromide (0.10 g, 39 μL, 0.20 eq, 0.50 mmol) was added and the mixture was stirred for an additional 1 h. The reaction mixture was cooled in an ice bath, quenched with 40 mL of water, and basified to pH = 8 - 9 using NaHCO3. The mixture was then extracted with 4 × 30 mL of DCM. The combined organic layers were washed with 75 mL of brine and then extracted with 15 mL of DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by normal-phase flash chromatography using DCM:EtOAc as the eluent gave 7-(4-(4-bromobutyl)phenyl)-2,2-diphenyl-6H-[1,3]-dioxolo[4,5-h]chromen-6-one (37.7) (1.306 g, 2.3 mmol, 93% yield, 99% purity) as a beige foamy substance.

[0178] (4-(4-(6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-7-yl)phenyl)butyl)triphenylphosphonium bromide (37.8) Triphenylphosphine (579 mg, 5.0 eq, 2.2 mmol) was added under nitrogen to a solution of 7-(4-(4-bromobutyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (37.7) (245 mg, 1 eq, 0.44 mmol) in dry 1,4-dioxane (3 mL). The solution was refluxed for 38 h and then allowed to cool to room temperature. The oily residue at the bottom of the flask was diluted with 25 mL of toluene and sonicated for 30 min. The resulting solid was filtered and washed with 2 × 25 mL of toluene and 25 mL of Et2O. The crude product was purified by normal-phase flash chromatography using DCM:MeOH as the eluent to give (4-(4-(6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-7-yl)phenyl)butyl)-triphenylphosphonium bromide (37.8) (299 mg, 0.36 mmol, 80% yield, 97% purity) as an off-white solid.

[0179] (4-(4-(7,8-Dihydroxy-4-oxo-4H-chromen-3-yl)phenyl)butyl)triphenylphosphonium bromide (37) A solution of (4-(4-(6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-7-yl)phenyl)butyl)triphenylphosphonium bromide (37.8) (299 mg, 1 eq, 0.37 mmol) in MeCN (3 mL) was treated with concentrated HBr (0.95 mL, 48% Wt, 23 eq, 8.4 mmol) and stirred at room temperature for 2 h under nitrogen. The reaction mixture was concentrated and traces of water were removed by azeotroping with 2 × 5 mL of MeCN. The oily residue was suspended in 8 mL of DCM and evaporated to dryness. The resulting solid was suspended in 2 mL of MeCN, filtered, and dried in vacuo to give (4-(4-(7,8-dihydroxy-4-oxo-4H-chromen-3-yl)phenyl)butyl)triphenylphosphonium bromide (37) (159 mg, 0.24 mmol, 66% yield, 99% purity) as a white powder.

[0180] Synthesis of SND530 (Compound 38) [Chemistry]

[0181] (E)-3-(Dimethylamino)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one (38.8) To a solution of 1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)ethan-1-one (3.3) (5.00 g, 1.00 equivalent, 22.1 mmol) in DMF (40 mL) was added dropwise DMF-DMA (13.2 g, 14.7 mL, 5.00 equivalents, 111 mmol). The resulting mixture was heated to 74 °C overnight. When the completion of the reaction was confirmed by LCMS, the reaction mixture was cooled, quenched with water, and extracted with EtOAc (5 × 100 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. This gave (E)-3-(dimethylamino)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one (38.8) (6.20 g, 22 mmol, 99%) as a yellow crystalline solid.

[0182] 3-Iodo-8-methoxy-7-(methoxymethoxy)-4H-chromen-4-one (38.9) A solution of (E)-3-(dimethylamino)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one (38.8) (6.20 g, 1.00 equiv, 22 mmol) and iodine (8.11 g, 1.45 equiv, 32 mmol) in methanol (100 mL) was stirred at room temperature for 16 h. When the conversion was confirmed by LCMS, the reaction mixture was concentrated under vacuum to give a dark red residue. To remove the residual iodine, the resulting material was treated with saturated sodium bisulfite solution until the mixture became clear. The mixture was then extracted with DCM (3 × 40 mL), the extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. This gave 3-iodo-8-methoxy-7-(methoxymethoxy)-4H-chromen-4-one (38.9) (6.99 g, 19 mmol, 88%) as a yellow solid in sufficient purity.

[0183] 4,4,5,5-Tetramethyl-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-1,3,2-dioxaborolane (38.16) A mixture of 2-(4-(4-bromophenyl)butoxy)tetrahydro-2H-pyran (8.5) (2.00 g, 1.00 equiv, 6.39 mmol), bis(pinacolato)diboron (1.78 g, 1.10 equiv, 7.02 mmol), Pd(dppf)Cl₂·CH₂Cl₂ adduct (1.04 g, 0.20 equiv, 1.28 mmol), and potassium acetate (1.88 g, 3.00 equiv, 19.2 mmol) was added to degassed DMF. The resulting solution was further degassed and then warmed to 80 °C and stirred for 18 h. When the conversion was confirmed by TLC, the reaction mixture was cooled, poured into water, and then extracted with ethyl acetate (3 × 100 mL). The organic extract was washed with water and brine (each 100 mL), dried over sodium sulfate, filtered, and evaporated. The residual oil was purified by normal-phase column chromatography (silica, gradient of ethyl acetate in heptane), thereby obtaining the desired 4,4,5,5-tetramethyl-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-1,3,2-dioxaborolane (38.16) (1.86 g, 5.17 mmol, 81%) as a clear yellowish oil.

[0184] 8-Methoxy-7-(methoxymethoxy)-3-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-4H-chromen-4-one (38.15) To a 20 mL solution of 4,4,5,5-tetramethyl-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-1,3,2-dioxaborolane (38.16) (1.74 g, 2.50 equiv, 4.83 mmol) in 1,4-dioxane, nitrogen was continuously flowed, then Na2CO3 (492 mg, 2.40 equiv, 4.64 mmol) was added, and then a degassed solution of 3-iodo-8-methoxy-7-(methoxymethoxy)-4H-chromen-4-one (38.9) (700 mg, 1.00 equiv, 1.93 mmol) in dry 1,4-dioxane (3 mL) and a degassed solution of fresh palladium(II) acetate (22 mg, 0.05 equiv, 97 μmol) in dry 1,4-dioxane (1 mL) were added. The resulting mixture was degassed for an additional 10 minutes and then heated to 60 °C. The heating was continued for 18 hours. Then 10 mL of methanol was added and the resulting mixture was left stirring under an inert atmosphere while gradually cooling to room temperature. The mixture was diluted with EtOAc (200 mL) and washed with saturated NaHCO3 (100 mL). The aqueous layer was extracted with an additional volume of EtOAc (200 mL), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by normal-phase column chromatography (silica, gradient of dichloromethane in ethyl acetate), appropriate fractions were combined and concentrated, thereby obtaining 8-methoxy-7-(methoxymethoxy)-3-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-4H-chromen-4-one (38.15) (636 mg, 1.36 mmol, 70%) as a yellow oil.

[0185] 3-(4-(4-Bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (38.13) A solution of 8-methoxy-7-(methoxymethoxy)-3-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)-4H-chromen-4-one (38.15) (753 mg, 1 eq, 1.61 mmol) in dry DCM (15 mL) and DMF (1.1 g, 1.2 mL, 9.6 eq, 15 mmol) was cooled to 0 °C under a nitrogen atmosphere. Thionyl bromide (1.1 g, 0.40 mL, 3.2 eq, 5.2 mmol) was then added. After 10 minutes, the cooling bath was removed and the orange solution was stirred at room temperature. The progress of the reaction was monitored by LCMS. When complete (3 h), the reaction mixture was cooled in an ice bath, quenched with 30 mL of water, and basified to pH = 8 - 9 using NaHCO3. The aqueous layer was extracted with 3 x 25 mL of DCM. The combined organic layers were washed with 50 mL of brine and then extracted with 4 x 20 mL of DCM. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was suspended in acetonitrile (3 mL) and treated with HCl (0.7 g, 0.5 mL, 37% Wt, 5 eq, 8 mmol) to ensure sufficient MOM deprotection. Complete deprotection was confirmed by LCMS after 1 h. The reaction mixture was evaporated to dryness, 10 mL of acetonitrile was added, and the mixture was evaporated to dryness again. The crude product was purified by normal-phase column chromatography (silica, gradient of dichloromethane in ethyl acetate). The appropriate fractions were combined and concentrated, thereby obtaining 3-(4-(4-bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (38.13) (518 mg, 1.3 mmol, 79%) as an orange oil. This oil solidifies upon storage and changes to a yellow solid.

[0186] (4-(4-(7-Hydroxy-8-methoxy-4-oxo-4H-chromen-3-yl)phenyl)butyl)triphenylphosphonium bromide (38) In a sealed container, to a suspension of 3-(4-(4-bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (38.13) (250 mg, 1.00 equivalent, 620 μmol) in dry 1,4-dioxane (2 mL), triphenylphosphine (813 mg, 5.00 equivalents, 3.10 mmol) was added. The reaction mixture was heated at 115 °C for 18 h. Complete conversion was confirmed by LCMS and TLC (DCM:MeOH 9:1). Upon completion, the reaction mixture was diluted with toluene and diethyl ether, sonicated (until the lumped material became a light-colored powder), triturated, and filtered. The resulting solid was washed with toluene and diethyl ether and then dried under vacuum. The residual solvent was removed by dissolving the material in a minimum amount of methanol, sonicating, and evaporating with an excess of acetonitrile. This process was repeated 4 times until a beige-colored powder remained. After drying this powder, it was confirmed to be the desired product. Then, this powder was purified twice using normal-phase column chromatography (gradient of methanol in DCM), thereby obtaining (4-(4-(7-hydroxy-8-methoxy-4-oxo-4H-chromen-3-yl)phenyl)butyl)triphenylphosphonium bromide (38) (193 mg, 290 μmol, 47%) as a white solid. This solid dissolves well in methanol and DMSO.

[0187] Schematic Synthesis Scheme 1:

Chemical Structure

[0188] Preparation of Compound 2

Chemical Structure

[0189] A solution of Compound 1 (1.00 equiv) and p-TSOH (0.05 equiv) in dry DCM (5 mL / 1 g of Compound 1) was added with DHP (1.20 equiv) at 25 °C over 30 minutes, and the resulting mixture was stirred at 25 °C for 2 hours. TLC (SiO2, PE / EA = 10 / 1, Rf = 0.5) indicated that Compound 1 was consumed and new spots were detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 → 10 / 1). Compound 2 was obtained as a white oil.

[0190] Preparation of Compound 4

Chemical formula

[0191] Compound 2 (1.50 equiv) was added to a solution of 9-BBN (0.5 M, 51.45 mL, 1.50 equiv) in THF (10 mL / 1 g of Compound 2) under a nitrogen stream. The mixture was stirred at 25 °C for 24 hours under nitrogen, and then a suspension of Compound 3 (1.00 equiv) in K3PO4 (3 M, 2.50 equiv) and DMF (5 mL / 1 g of Compound 2) was added. Then, the reaction mixture was degassed with N2, and then Pd(dppf)Cl2 (0.10 equiv) was added. The reaction mixture was degassed again, and the mixture was heated at 60 °C for 2.5 hours. TLC (SiO2, PE / EA = 5 / 1, Rf = 0.3) indicated that Compound 3 was consumed and new spots were detected. The reaction mixture was filtered, extracted with ethyl acetate (40 ml × 3) and H2O (100 ml × 3), the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 → 87 / 13). Compound 4 was obtained as a yellow oil.

[0192] Preparation of Compound 5

Chemical formula

[0193] Thionyl bromide (5.00 equivalents) was added dropwise to a solution of compound 4 (1.00 equivalent) in dry DCM (20 mL / 1 g of compound 4) and DMF (10.00 equivalents) at 0 °C under a nitrogen stream. After the reaction mixture was stirred for 10 minutes, the solution was warmed to 25 °C and stirred under nitrogen until completion of the reaction was confirmed by LC-MS. TLC (petroleum ether:ethyl acetate = 5:1, twice) showed that the starting material was consumed and new spots were detected. The combined reaction mixture was poured onto ice and the mixture was basified to pH = 8 with saturated NaHCO3. The mixture was separated into DCM and water, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate, 100:0 → 83:17). Compound 5 was obtained as a yellow solid.

[0194] Preparation of the final compounds, for example SND540 - SND558

Chemical formula

[0195] To a solution of compound 5 (1.00 equivalent) in dry dioxane, PPh3 (5.00 equivalents) and NaI (0.1 equivalent) were added and the mixture was stirred at 105 °C under N2 for 16 hours. TLC (SiO2, DCM / MeOH = 10 / 1, Rf = 0.4) showed that compound 5 was consumed and new spots were detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 → 0 / 1 then DCM / MeOH = 10 / 1). The residue was purified by preparative HPLC (HCl). The product was obtained as a yellow solid.

[0196] Synthesis of SND477 Compound SND477 was synthesized using the standard procedure of the above general synthetic scheme 1. Compound SND477 has the following details.

[0197]

Table 5

[0198] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.48 (s, 1H), 7.92 - 7.85 (m, 4H), 7.84 - 7.74 (m, 12H), 7.48 - 7.46 (d, J = 8.0 Hz, 2H), 7.32 - 7.30 (d, J = 9.2 Hz, 1H), 7.22 - 7.20 (d, J = 8.4 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.66 - 3.48 (m, 2H), 2.57 - 2.55 (d, J = 7.2 Hz, 2H), 1.59 - 1.46 (m, 6H), 1.34 - 1.32 (d, J = 5.6 Hz, 2H). LCMS: MS(ESI) retention time: 2.277 minutes, (M+1) + = 627.2

[0199] Synthesis of SND479 Compound SND479 was synthesized using the standard procedure of the above-mentioned general synthetic scheme 1. Compound SND479 has the following details.

[0200]

Table 6

[0201] 11H NMR (400 MHz, DMSO-d6) δ = 8.48 (s, 1H), 7.92 - 7.84 (m, 4H), 7.83 - 7.73 (m, 12H), 7.49 - 7.47 (d, J = 8.0 Hz, 2H), 7.32 - 7.30 (d, J = 9.2 Hz, 1H), 7.25 - 7.23 (d, J = 8.0 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.61 - 3.50 (m, 2H), 2.60 - 2.58 (t, J = 7.4 Hz, 2H), 1.60 - 1.39 (m, 6H), 1.31 - 1.16 (m, 10H). LCMS: MS(ESI) retention time: 2.458 minutes, (M+1) + = 683.2

[0202] Synthesis of SND540 Compound SND540 was synthesized using the standard procedure of the above general synthetic scheme 1. Compound SND540 has the following details.

[0203]

Table 7

[0204] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 7.92 - 7.86 (m, 4H), 7.83 - 7.74 (m, 13H), 7.48 - 7.46 (d, J = 8.0 Hz, 2H), 7.33 - 7.31 (d, J = 9.2 Hz, 1H), 7.20 - 7.22 (d, J = 8.4 Hz, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 3.68 - 3.59 (m, 2H), 2.67 - 2.65 (J = 7.2 Hz, 2H), 1.80 - 1.78 (J = 7.2 Hz, 2H), 1.65 - 1.52 (m, 2H). LCMS: MS(ESI) retention time: 2.062 minutes, (M+1) + = 599.2

[0205] Synthesis of SND541 Compound SND541 was synthesized using the standard procedure of the above-schematic synthesis scheme 1. Compound SND541 has the following details.

[0206]

Table 8

[0207] 1 H NMR (400 MHz, DMSO-d6) δ = 8.49 (s, 1H), 7.92 - 7.84 (m, 4H), 7.83 - 7.73 (m, 12H), 7.43 - 7.30 (m, 4H), 7.20 - 7.18 (d, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.65 (br s, 2H), 2.84 - 2.82 (t, J = 7.2 Hz, 2H), 1.88 - 1.86 (br d, J = 8.0 Hz, 2H). LCMS: MS(ESI) retention time: 1.993 minutes, (M+1) + = 585.2.

[0208] Synthesis of SND544

Chemical formula

[0209] A solution of 3-(3-(10-bromodecyl)phenyl)-7,8-dimethoxy-4H-chromen-4-one (1.4 g, 2.79 mmol, 1 equiv) in dioxane (10 mL) was added with PPh3 (3.66 g, 13.96 mmol, 5 equiv) and NaI (41.85 mg, 279.19 μmol, 0.1 equiv), and the mixture was stirred at 105 °C for 16 h. A major new spot was detected by TLC (SiO2, DCM / MeOH = 10 / 1, Rf = 0.4). The desired mass was detected as the major peak by LCMS (EW30065-893-P1A). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 → 0 / 1 then DCM / MeOH = 10 / 1). The residue was purified by preparative HPLC (HCl). The product (689.14 mg, 956.75 μmol, yield 34.27%, HCl) was obtained as a yellow solid.

[0210] 1 H NMR (400 MHz, DMSO-d6) δ = 8.49 (s, 1H), 7.94 - 7.84 (m, 4H), 7.83 - 7.71 (m, 12H), 7.51 - 7.27 (m, 4H), 7.20 - 7.18 (d, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.58 - 3.46 (m, 2H), 2.60 - 2.58 (t, J = 7.6 Hz, 2H), 1.65 - 1.36 (m, 6H), 1.33 - 1.03 (m, 10H). LCMS: MS(ESI) retention time: 0.676 min, (M+1) + = 683.5.

[0211] Synthesis of SND544B Compound SND544B was synthesized using the standard procedure of the above general synthetic scheme 1. Compound SND544B has the following details.

[0212]

Table 9

[0213] 1 H NMR (400 MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.19 - 8.10 (m, 13H), 7.86 - 7.84 (d, J = 9.2 Hz, 1H), 7.40 - 7.29 (m, 4H), 7.20 - 7.18 (br d, J = 6.8 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.86 - 3.76 (m, 2H), 2.60 - 2.58 (br t, J = 7.6 Hz, 2H), 1.60 - 1.50 (m, 4H), 1.47 - 1.40 (m, 2H), 1.29 - 1.18 (m, 10H).

[0214] Synthesis of SND550

Chem.

[0215] Preparation of Compound 7

Chem.

[0216] A stirred solution of Compound 6 (6 g, 14.70 mmol, 1.00 equiv), Compound 6A (5.91 g, 44.10 mmol, 3.00 equiv) and K2CO3 (6.09 g, 44.10 mmol, 3.00 equiv) in DMSO (50 mL) was degassed with N2 at 25 °C for 0.5 h, then Pd(dppf)Cl2 (1.08 g, 1.47 mmol, 0.10 equiv) was added at 25 °C and the resulting mixture was stirred at 100 °C for 16 h. LCMS (EW30065 - 746 - P1A) indicated the consumption of Compound 6 and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 0 / 1 → 5 / 1). Compound 7 (2 g, 6.29 mmol, yield 42.81%, purity 97%) was obtained as a white solid.

[0217] 1 1H NMR (400 MHz, chloroform-d) δ = 8.16 - 8.00 (m, 2H), 7.59 - 7.52 (m, 2H), 7.52 - 7.45 (m, 2H), 7.09 - 7.07 (d, J = 9.2 Hz, 1H), 6.77 - 6.75 (dd, J = 10.8, 17.5 Hz, 1H), 5.81 - 5.79 (d, J = 17.6 Hz, 1H), 5.30 - 5.28 (d, J = 10.8 Hz, 1H), 4.02 (s, 6H). LCMS: MS (ESI) retention time: 0.662 minutes, (M+1) + = 309.0, EW30065 - 746 - P1B.

[0218] Preparation of Compound 8 [Chemical Structure]

[0219] To a solution of Compound 7 (1.5 g, 4.86 mmol, 1.00 equivalent) in DCM (15 mL) was added m-CPBA (1.57 g, 7.30 mmol, purity 80%, 1.50 equivalents) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. TLC (SiO2, PE / EA = 1 / 1, Rf = 0.5) indicated the consumption of Compound 7 and the detection of a new spot. LCMS (EW30065 - 764 - P1A) indicated the consumption of Compound 7 and the detection of the desired mass. The reaction mixture was quenched with saturated Na2SO3 (30 mL), extracted with DCM (10 mL × 3) and H2O (10 mL × 3), the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 0 / 1 → 2 / 1). Compound 8 (900 mg, 2.77 mmol, yield 57.04%) was obtained as a white solid and confirmed by 1H NMR.

[0220] 11H NMR (400 MHz, chloroform-d) δ = 8.08 - 8.02 (m, 2H), 7.57 - 7.55 (d, J = 8.0 Hz, 2H), 7.38 - 7.36 (d, J = 8.0 Hz, 2H), 7.09 - 7.07 (d, J = 9.2 Hz, 1H), 4.02 (s, 6H), 3.93 - 3.91 (t, J = 3.2 Hz, 1H), 3.19 - 3.17 (t, J = 4.8 Hz, 1H), 2.84 - 2.82 (dd, J = 2.4, 5.4 Hz, 1H). LCMS: MS(ESI) retention time: 0.612 minutes, (M+1) + = 325.0, EW30065 - 764 - P1B.

[0221] Preparation of Compound 9 [Chemical formula]

[0222] To a solution of Compound 8 (900 mg, 2.77 mmol, 1.00 equivalent) and borane; morpholine (280.15 mg, 2.77 mmol, 1.00 equivalent) in THF (9 mL) was added BF3·Et2O (393.85 mg, 2.77 mmol, 342.48 μL, 1.00 equivalent) dropwise at 25 °C, and then the mixture was stirred at 25 °C for 2 hours. LCMS indicated that Compound 8 was consumed and the desired mass was detected. TLC (SiO2, PE / EA = 1 / 1, Rf = 0.3) indicated that Compound 8 was consumed and a new spot was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, PE / EA = 1 / 1). Compound 9 (780 mg, 2.39 mmol, yield 86.13%) was obtained as a white solid and confirmed by 1H NMR.

[0223] 11H NMR (400 MHz, chloroform-d) δ = 8.06 (d, J = 9.0 Hz, 1H), 8.02 (s, 1H), 7.55 - 7.49 (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 9.0 Hz, 1H), 4.02 (d, J = 1.1 Hz, 6H), 3.94 - 3.87 (m, 2H), 2.92 (t, J = 6.5 Hz, 2H). LCMS: MS(ESI) retention time: 0.574 minutes, (M+1) + = 327.0, EW30065 - 767 - P1A.

[0224] Preparation of Compound 10

Chemical Structure

[0225] Thionyl bromide (2.38 g, 11.47 mmol, 888.87 μL, 4.80 equivalents) was added dropwise to a solution of Compound 9 (780 mg, 2.39 mmol, 1.00 equivalent) in dry DCM (9 mL) and DMF (1.75 g, 23.90 mmol, 1.84 mL, 10.0 equivalents) at 0 °C under a nitrogen stream. After stirring the reaction mixture for 1 minute, the solution was warmed to 25 °C and stirred under nitrogen until completion of the reaction was confirmed by LC - MS (1.5 hours). TLC (SiO2, PE / EA = 5 / 1, Rf = 0.4) indicated consumption of Compound 9 and detection of a new spot. LCMS (EW30065 - 779 - P1B) indicated consumption of Compound 9 and detection of the desired mass. The reaction mixture was poured into ice - water (10 ml), and aqueous NaHCO3 was added until pH = 8. It was extracted with DCM (10 ml × 3), the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 → 3 / 1). Compound 5 (700 mg, 1.69 mmol, yield 70.73%, purity 94%) was obtained as a white solid and confirmed by 1H NMR.

[0226] 1 1H NMR (400 MHz, chloroform-d) δ = 8.08 - 8.02 (m, 2H), 7.57 - 7.50 (m, 2H), 7.31 - 7.29 (d, J = 8.0 Hz, 2H), 7.09 - 7.07 (d, J = 9.2 Hz, 1H), 4.03 - 4.01 (d, J = 1.2 Hz, 6H), 3.61 - 3.5J = 7.7 Hz, 2H), 3.23 - 3.21 (t, J = 7.6 Hz, 2H). LCMS: MS(ESI) retention time: 0.670 minutes, (M+1) + = 390.9, EW30065 - 779 - P1B.

[0227] Preparation of Compound SND550 [Chemical formula]

[0228] To a solution of Compound 10 (700 mg, 1.80 mmol, 1.00 equivalent) in dioxane (7 mL) was added PPh3 (2.36 g, 8.99 mmol, 5.00 equivalents) and NaI (26.96 mg, 179.84 μmol, 0.10 equivalent), and the mixture was stirred at 105 °C under N2 for 12 hours. LCMS (EW30065 - 784 - P1A) indicated that Compound 10 had been consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (HCl). SND550 (188.77 mg, 300.69 μmol, yield 16.72%, purity 96.86%, HCl) was obtained as a yellow solid.

[0229] 11H NMR (400 MHz, DMSO-d6) δ = 8.50 (s, 1H), 7.96 - 7.85 (m, 10H), 7.84 - 7.77 (m, 6H), 7.55 - 7.53 (d, J = 8.0 Hz, 2H), 7.40 - 7.38 (d, J = 8.0 Hz, 2H), 7.33 - 7.31 (d, J = 9.2 Hz, 1H), 4.04 - 3.94 (m, 5H), 3.89 (s, 3H), 2.99 - 2.89 (m, 2H). LCMS: MS(ESI) retention time: 1.957 minutes, (M+1) + = 571.2, EW30065 - 784 - P1F1.

[0230] Synthesis of SND551 Compound SND551 was synthesized using the standard procedure of the above - outlined general synthetic scheme 1. Compound SND551 has the following details.

[0231]

Table 10

[0232] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.56 (s, 1H), 7.93 - 7.86 (m, 4H), 7.84 - 7.74 (m, 12H), 7.40 - 7.38 (d, J = 12.0 Hz, 1H), 7.37 - 7.27 (m, 3H), 3.97 (s, 3H), 3.89 (s, 3H), 3.67 - 3.65 (t, J = 14.8 Hz, 2H), 2.73 - 2.63 (m, 2H), 1.84 - 1.72 (m, 2H), 1.61 - 1.59 (br d, J = 7.6 Hz, 2H). LCMS: MS(ESI) retention time: 2.077 minutes, (M+1) + = 617.2, EW30065 - 780 - P1F.

[0233] Synthesis of SND552 Compound SND552 was synthesized using the standard procedure of the above-described schematic synthesis scheme 1. Compound SND552 has the following details.

[0234]

Table 11

[0235] 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 7.93 - 7.87 (m, 3H), 7.86 - 7.75 (m, 13H), 7.35 - 7.29 (m, 2H), 7.13 - 7.11 (d, J = 11.4 Hz, 1H), 7.08 - 7.06 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.71 - 3.61 (m, 2H), 2.70 - 2.68 (t, J = 7.2 Hz, 2H), 1.87 - 1.75 (m, 2H), 1.67 - 1.52 (m, 2H). LCMS: MS(ESI) retention time: 2.017 minutes, (M+1) + = 617.1, EW30065 - 818 - P1F.

[0236] Synthesis of SND553 Compound SND553 was synthesized using the standard procedure of the above-described schematic synthesis scheme 1. Compound SND553 has the following details.

[0237]

Table 12

[0238] 11H NMR (400 MHz, DMSO-d6) δ = 8.37 (s, 1H), 7.94 - 7.88 (m, 3H), 7.85 - 7.75 (m, 13H), 7.41 - 7.39 (d, J = 1.2 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.21 - 7.19 (J = 1.2, 7.9 Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.72 - 3.60 (m, 2H), 2.73 - 2.64 (m, 2H), 1.85 - 1.73 (m, 2H), 1.66 - 1.54 (m, 2H). LCMS: MS(ESI) retention time: 2.080 minutes, (M+1) + = 633.1.

[0239] Synthesis of SND554 Compound SND554 was synthesized using the standard procedure of the above general synthetic scheme 1. Compound SND554 has the following details.

[0240]

Table 13

[0241] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.57 (s, 1H), 7.93 - 7.86 (m, 4H), 7.84 - 7.76 (m, 12H), 7.66 - 7.64 (d, J = 1.6 Hz, 1H), 7.47 - 7.45 (J = 1.6, 7.9 Hz, 1H), 7.35 - 7.33 (t, J = 9.2 Hz, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 3.72 - 3.62 (m, 2H), 2.77 - 2.75 (t, J = 7.2 Hz, 2H), 1.84 - 1.73 (m, 2H), 1.64 - 1.62 (d, J = 7.2 Hz, 2H). LCMS: MS(ESI) retention time: 2.127 minutes, (M+1) + = 633.1.

[0242] Synthesis of SND555 Compound SND555 was synthesized using the standard procedure of the above-sketched Synthetic Scheme 1. Compound SND555 has the following details.

[0243]

Table 14

[0244] 1 H NMR (400 MHz, DMSO-d6) δ = 8.30 - 8.24 (m, 1H), 7.93 - 7.88 (m, 3H), 7.86 - 7.75 (m, 13H), 7.32 - 7.30 (d, J = 9.2 Hz, 1H), 7.08 - 7.06 (d, J = 7.2 Hz, 2H), 7.03 - 6.99 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.65 - 3.63 (dd, J = 7.6, 13.4 Hz, 2H), 2.64 - 2.62 (t, J = 7.2 Hz, 2H), 2.10 (s, 3H), 1.84 - 1.73 (m, 2H), 1.68 - 1.53 (m, 2H). LCMS: MS(ESI) retention time: 2.065 minutes, (M+1) + = 613.2.

[0245] Synthesis of SND556 Compound SND556 was synthesized using the standard procedure of the above-sketched Synthetic Scheme 1. Compound SND556 has the following details.

[0246]

Table 15

[0247] 11H NMR (400 MHz, DMSO-d6) δ = 8.44 (s, 1H), 7.93 - 7.87 (m, 3H), 7.85 - 7.75 (m, 13H), 7.35 - 7.25 (m, 3H), 7.14 - 7.12 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.66 (br s, 2H), 2.69 - 2.59 (m, 2H), 2.26 (s, 3H), 1.79 - 1.69 (m, 2H), 1.68 - 1.57 (m, 2H). LCMS: MS(ESI) retention time: 2.077 minutes, (M+1) + = 613.2

[0248] Synthesis of SND557 Compound SND557 was synthesized using the standard procedure of the above-mentioned general synthetic scheme 1. Compound SND557 has the following details.

[0249]

Table 16

[0250] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.93 - 7.88 (m, 3H), 7.84 - 7.76 (m, 13H), 7.30 - 7.28 (d, J = 9.2 Hz, 1H), 7.11 - 7.09 (d, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.79 - 6.77 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.67 (br s, 5H), 2.67 - 2.65 (t, J = 7.2 Hz, 2H), 1.89 - 1.75 (m, 2H), 1.70 - 1.54 (m, 2H). LCMS: MS(ESI) retention time: 2.027 minutes, (M+1) + = 629.2

[0251] Synthesis of SND558 Compound SND558 was synthesized using the standard procedure of the above-described general synthetic scheme 1. Compound SND558 has the following details.

[0252]

Table 17

[0253] 1 H NMR (400 MHz, DMSO-d6) δ = 8.52 (s, 1H), 7.92 - 7.86 (m, 4H), 7.83 - 7.74 (m, 12H), 7.33 - 7.31 (d, J = 9.2 Hz, 1H), 7.14 - 7.12 (d, J = 8.4 Hz, 2H), 7.09 - 7.03 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.75 (s, 3H), 3.65 - 3.63 (t, J = 14.4 Hz, 2H), 2.62 - 2.60 (t, J = 7.2 Hz, 2H), 1.81 - 1.68 (m, 2H), 1.64 - 1.51 (m, 2H). LCMS: MS(ESI) retention time: 2.072 minutes, (M+1) + = 627.9.

[0254] Example - Biological Experiments Experimental Method System Antitumor Activity Against a Panel of Cancer Cell Lines The antitumor activity of the compound was evaluated by using the CellTiter-Glow™ Luminescent Cell Viability assay (Promega No. G7572) according to the manufacturer's instructions. The compound was tested at five or six concentrations (highest concentration 10 μM) diluted 1:2 in triplicate well conditions.

[0255] Tumor cells were grown up to a maximum of 20 passages in RPMI 1640 medium or DMEM medium supplemented with 10% (v / v) fetal bovine serum and 50 μg / ml gentamicin under a humidified atmosphere with 37 °C and 5% CO2. The passages were performed once or twice a week. Cells were harvested using TrypLE or PBS buffer containing 1 mM EDTA, and the percentage of viable cells was determined using a cell counter.

[0256] Cells were harvested from logarithmic-phase cultures, counted, and plated in 96-well flat-bottom microtiter plates at a cell density (4000 - 20000 cells per well depending on the growth rate of the cell line) corresponding to the growth rate of the cell line in RPMI 1640 medium or DMEM medium supplemented with 10% (v / v) fetal bovine serum and 50 μg / ml gentamicin (140 μl / well). The cultures were incubated in a humidified atmosphere with 37 °C and 5% CO2. After 24 hours, 10 μl of the test compound or control medium was added, and the cells were left for an additional 72 hours. The compound was serially diluted in DMSO, transferred to the cell culture medium, and added to the assay plates. The DMSO concentration was kept constant at less than 0.2% v / v across the assay plates. The viability of the cells was quantified by the CellTiter-Glow™ Luminescent Cell Viability assay (Promega No. G7572). Luminescence was measured using a microplate luminometer (EnVision Perkin Elmer).

[0257] For each tumor model, sigmoid concentration-response curves were fitted to the data points (test and control, T / C values) obtained using GraphPad Prism 5.02 software. IC 50 values were reported as the absolute IC 50 values, which are the concentrations of the test compound at the intersection of the T / C = 50% of the concentration-response curve.

[0258] Apoptosis activity against a panel of tumor cell lines Apoptosis activity was evaluated using the Caspase-Glo 3 / 7 Assay kit (Promega - G8091) according to the manufacturer's instructions. Cells were grown as described above, harvested from logarithmic-phase cultures, counted, and plated in 96-well black flat-bottom microtiter plates at a cell density according to the growth rate of the cell line (3000 - 10000 cells per well according to the growth rate of the cell line). After incubation overnight, compounds were added to the cell plates at various concentrations (up to 10 mM), and the DMSO concentration was maintained at 0.1% over a 24-hour treatment period. 100 μL of Caspase-Glo 3 / 7 Reagent was added to each well of the 96-well plate containing 100 μL of culture medium, left at room temperature for 30 minutes, and then luminescence was measured with a microplate luminometer (EnVision Perkin Elmer). The induced relative Caspase 3 / 7 activity of the tested compounds was determined by the following formula: Relative Caspase 3 / 7 activity (magnification) = (RLU compound - RLU blank) / (RLU control - RLU blank).

[0259] Inhibition of signal transduction pathways Inhibition of various cell pathways known to be involved in malignancies was tested using the SelectScreen Cell-based Pathway Profiling GeneBLAzer™ cell signal transduction pathway-specific CellSensor™ cell lines (Thermo Fisher). This assay is based on β-lactamase reporter activity that can be modulated and quantitatively and selectively measured with the LiveBLAzer™-FRET B / G Loading Substrate.

[0260] In the SelectScreen Cell-Based Pathway Profiling Service, XLfit from IDBS is used. The dose-response curve is curve-fitted to model number 205 (sigmoid dose-response model). Custom logic for the data analysis tool was built by Thermo Fisher to account for the various compound characteristics that can be observed in the functional assay.

[0261] Specific conditions for the tested pathway: JAK / STAT-ISRE-bla HEK 293T - Inhibitor Screening, Activated by IFN-alpha Thaw ISRE-bla HEK 293T cells and resuspend them to a concentration of 625,000 cells per mL in assay medium (OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U / mL / 100 μg / mL Pen / Strep). Add 32 μL of the cell suspension to each well of a 384-well TC-treated assay plate. Incubate the cells in the assay medium in the plate in a humidified incubator at 37 °C / 5% CO2 for 16 to 24 hours. Add 4 μL of JAK inhibitor I (control inhibitor, starting concentration 1000 nM) or a 10× serial dilution of the compound to the appropriate wells of the plate and pre-incubate with the cells in a humidified incubator at 37 °C / 5% CO2 for 30 minutes. Add 4 μL of 10× control activator IFN-alpha at the predetermined EC80 concentration to the wells containing the control inhibitor or the compound. Incubate the plate in a humidified incubator at 37 °C / 5% CO2 for 5 hours. Add 8 μL of 1 μM substrate loading solution to each well and incubate the plate at room temperature for 2 hours. Read the plate on a fluorescence plate reader.

[0262] MAPK / MEK / B-raf-AP1-bla A375 - Inhibitor Screening, Constitutive Activation Thaw the AP1-bla A375 cells and resuspend them in assay medium (OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U / mL / 100 μg / mL Pen / Strep) to a concentration of 312,500 cells per mL. Add 4 μL of a Raf1 kinase inhibitor (control inhibitor, starting concentration 10,000 nM) or a 10× serial dilution of the compound to the appropriate wells of a TC-treated assay plate. Add 32 μL of the cell suspension (10,000 cells) to the wells. Add 4 μL of assay medium to all wells to bring the final assay volume to 40 μL. Incubate the plate in a humidified incubator at 37 °C / 5% CO2 for 16 to 24 hours. Add 8 μL of 1 μM substrate loading solution to each well and incubate the plate at room temperature for 2 hours. Read the plate on a fluorescence plate reader.

[0263] NFκB-NFκB-bla Jurkat - inhibitor screening, activated by TNF-alpha Thaw the NFκB-bla Jurkat cells and resuspend them in assay medium (DMEM, 10% dialyzed FBS, 25 mM HEPES, pH 7.3, 0.1 mM NEAA, 100 U / mL / 100 μg / mL Pen / Strep) to a concentration of 625,000 cells per mL. Add 4 μL of wissakerrin A (control inhibitor, starting concentration 1000 nM) or a 10× serial dilution of the compound to the appropriate wells of a TC-treated assay plate. Add 32 μL of the cell suspension to the wells and pre-incubate in a humidified incubator at 37 °C / 5% CO2 for 30 minutes with the compound and control inhibitor titrations. Add 4 μL of 10× control activator TNF-alpha at a predetermined EC80 concentration to the wells containing the control inhibitor or the compound.

[0264] Incubate the plate in a humidified incubator at 37 °C / 5% CO2 for 5 hours. Add 8 μL of 1 μM substrate loading solution to each well and incubate the plate at room temperature for 2 hours. Read the plate on a fluorescence plate reader.

[0265] Oxidative stress - ARE - bla HepG2 - inhibitor screening, activated by tBHQ Thaw the ARE - bla HepG2 cells and resuspend them to a concentration of 375,000 cells per mL in assay medium (DMEM, 10% dialyzed FBS, 25 mM HEPES, pH 7.3, 0.1 mM NEAA, 100 U / mL / 100 μg / mL Pen / Strep). Add 32 μL of the cell suspension to each well of a 384 - well poly - D - lysine assay plate. Incubate the cells in the assay medium in the plate in a humidified incubator at 37°C / 5% CO2 for 16 to 24 hours. Add 4 μL of Ro - 31 - 8220 (control inhibitor, starting concentration 10,000 nM) or 10× serial dilutions of the compound to the appropriate wells of the plate and pre - incubate with the cells in a humidified incubator at 37°C / 5% CO2 for 30 minutes. Add 4 μL of 10× control activator tBHQ at a predetermined EC80 concentration to the wells containing the control inhibitor or the compound. Incubate the plate in a humidified incubator at 37°C / 5% CO2 for 5 hours. Add 8 μL of 1 μM substrate + solution D loading solution to each well and incubate the plate at room temperature for 2 hours. Read the plate with a fluorescence plate reader.

[0266] Toll - like receptor (TLR4) - NFκB - bla THP - 1 - inhibitor screening, activated by LPS Thaw NFκB-bla THP-1 cells and resuspend them in assay medium (RPMI, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U / mL / 100 μg / mL Pen / Strep) to a concentration of 625,000 cells per mL. Add 32 μL of the cell suspension to each well of a 384-well TC-treated assay plate. Incubate the cells in the assay medium in the plate in a humidified incubator at 37 °C / 5% CO2 for 16 to 24 hours. Add 4 μL of wissakerrin A (control inhibitor, starting concentration 10,000 nM) or 10× serial dilutions of the compound to appropriate wells of the plate and pre-incubate with the cells in a humidified incubator at 37 °C / 5% CO2 for 30 minutes. Add 4 μL of 10× control activator LPS at a predetermined EC80 concentration to the wells containing the control inhibitor or compound. Incubate the plate in a humidified incubator at 37 °C / 5% CO2 for 5 hours. Add 8 μL of 1 μM substrate loading solution to each well and incubate the plate at room temperature for 2 hours. Read the plate with a fluorescence plate reader.

[0267] Wnt / beta-catenin-LEF-TCF-bla HCT116-inhibitor screening, constitutively active Thaw LEF-TCF-bla HCT116 cells and resuspend them in assay medium (OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U / mL / 100 μg / mL Pen / Strep) to a concentration of 312,500 cells per mL. Add 32 μL of the cell suspension to each well of a 384-well poly-D-lysine assay plate. Incubate the cells in the assay medium in the plate in a humidified incubator at 37°C / 5% CO2 for 16 to 24 hours. Add 4 μL of ICG-001 (control inhibitor, starting concentration 25,000 nM) or 10× serial dilutions of the compound to the appropriate wells of the plate. Add 4 μL of assay medium to all wells to bring the final assay volume to 40 μL. Incubate the plate in a humidified incubator at 37°C / 5% CO2 for 5 hours. Add 8 μL of 1 μM substrate loading solution to each well and incubate the plate at room temperature for 2 hours. Read the plate with a fluorescence plate reader.

[0268] Inhibition of in vivo tumors A2058 tumor cells were maintained in vitro at 37°C in an atmosphere of 5% CO2 in air in DMEM medium supplemented with 10% fetal bovine serum and 1% Anti-Anti. The tumor cells were routinely passaged twice a week.

[0269] To the right flank of each Balb-c / nude mouse, inoculate subcutaneously A2058 melanoma tumor cells (5×10 6 + Matrigel) in 0.2 ml of PBS and develop the tumors. When the average tumor volume reached 74 mm 3 the animals were randomized to 10 animals per group. The test compound was prepared as a DMSO stock and diluted in the injection vehicle prior to dosing. The treatment was administered once every 2 days (QOD) as an injection around the tumor. The composition of the vehicle was 4% DMSO, 5% ethanol, 20% PEG200, 71% saline. The dosing volume was 5 mL / kg for all groups.

[0270] Body weight and clinical signs were monitored throughout the study.

[0271] The tumor volume was measured two - dimensionally twice a week using calipers, and the volume was expressed in mm using the formula: V = 0.5a×b 2 (where a and b are the major and minor axes of the tumor, respectively). Then, the tumor size was used for calculating the T / C value. The T / C value (in percentage) is an indicator of the antitumor effect. T and C are the average tumor volumes of the treatment group and the control group on a given day, respectively. 3 One - way ANOVA was performed to compare the tumor volumes between the treatment group and the vehicle group, and all data were analyzed using GraphPad Prism 5.0. p < 0.05 was considered statistically significant.

[0272] The tested cell lines are presented in Table 1.

[0273]

Table 18

[0274]

Table 18

[0275] Example 1. Activity of SND derivatives against various carcinomas As shown in Table 2A and Table 2B, SND470 and SND490 inhibited the growth of various solid cancers and hematological tumor cells.

[0276]

Table 19

[0277]

Table 20

[0278] As shown in Table 3, SND530 inhibited the growth of various solid cancers and hematological tumor cells.

[0279]

Table 21

[0280] As shown in Table 3B, SND477, SND478, and SND479 inhibited the growth of various solid cancer and hematological tumor cells.

[0281]

Table 22

[0282] As shown in Table 4A and Table 4B, SND540 to SND544B inhibited the growth of various solid cancer and hematological tumor cells.

[0283]

Table 23

[0284]

Table 24

[0285] As shown in Table 5A and Table 5B, SND550 to SND558 inhibited the growth of various solid cancer and hematological tumor cells.

[0286]

Table 25

[0287]

Table 26

[0288] Example 2. Apoptosis of cancer cells induced by SND derivatives SND470 was tested for induction of apoptosis in several cell lines, and the results are shown in Table 5.

[0289]

Table 27

[0290] Example 3. Inhibition of Signal Transduction of SND Derivatives SND470 and SND544 were evaluated for the inhibition of various signal transduction pathways that are most frequently deregulated in many cancers. The results are presented in Table 6.

[0291] [Table 28]

[0292] Example 4. In Vivo Activity of SND Derivatives SND470 and SND540 were evaluated for their in vivo activity in a xenograft model of nude mice with melanoma. The treatment and control vehicle were administered around the tumor, QOD, 6 injections for SND470 and 11 injections for SND540. The dose was 16 mg / kg for both derivatives. The treatment was generally well tolerated, and in all groups, some weight loss due to the tumor model itself was observed. Treatment with SND470 and treatment with SND540 caused some crust formation at the injection site, which dissipated after the cessation of treatment.

[0293] As shown in Table 7, both SND470 and SND540 showed significant activity regarding the inhibition of the A2058 melanoma cell line.

[0294] [Table 29]

[0295] Example 5. In Vivo Activity of SND477 and SND479 SND477 and SND479 were evaluated for their in vivo activity in a xenograft model of nude mice with melanoma.

[0296] As shown in Table 8, both SND477 and SND479 showed significant activity regarding the inhibition of A2058 melanoma cell line.

[0297]

Table 30

Claims

1. Formula (1): 【Chemistry 1】 (In the formula, V is -R3 and W is 【Chemistry 2】 or W is -R3 and V is 【Transformation 3】 or Z is -[P(R ５ ) ３ ]X, X is a counter anion, R １ and R ２ are independently —H, —C １～４ Alkyl, —C(O)R ４ , —C(O)NHR ４ , and —C(O)N(R ４ ) ２ or R １ and R ２ Let's get together and C １～４ Forming an alkylene group, R ３ is H, halo, -CN, -NO ２ , -R β , —OH, —OR β , -SH, -SR β , -SOR β , -SO ２ H, -SO ２ R β , -SO ２ NH ２ , -SO ２ NHR β , -SO ２ N (R β ) ２ , -NH ２ , -NHR β , -N(R β ) ２ , -CHO, -COR β , -COOH, -COOR β , and -OCOR β is selected from Each -R β are independently １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl or C ３ ~C １４ cyclic groups, and any -R β is one or more C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ７ cycloalkyl, —O(C １ ~C ４ alkyl), —O(C １ ~C ４ haloalkyl), —O(C ３ ~C ７ cycloalkyl), halo, —OH, —NH ２ , -CN, -NO ２ , -C≡CH, -CHO, -CON(CH ３ ) ２ or oxo (=O) group, Each -R ４ are independently １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３～１４ Cyclic groups, halo, -NO ２ , -CN, -OH, -NH ２ , mercapto, formyl, carboxy, carbamoyl, C １～６ Alkoxy, C １～６ Alkylthio, -NH(C １～６ alkyl), -N(C １～６ alkyl) ２ , C １～６ Alkylsulfinyl, C １～６ alkylsulfonyl, or arylsulfonyl; R ５ are independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ３ ~C １４ an aryl group, or C ３ ~C １４ an aliphatic cyclic group, and any —R ５ is one or more C １ ~C ４ Alkyl, halo, -CF ３ , —OH, —NH ２ , -CN, -C≡CH or oxo (=O) group; and n is an integer from 1 to 10, or a pharmaceutically acceptable salt, double salt, or solvate thereof.

2. Formula (2), Formula (2A), Formula (2B), Formula (3), Formula (3A) or Formula (3B): 【Chemistry 4】 【change】 (In the formula, R １ , R ２ , R ３ , Z and n are as defined in claim 1.

3. R １ and R ２ are independently —H and —CH ３ 3. The compound according to claim 1 or 2, selected from:

4. R ３ But -CH ３ , —Cl, —F, and —OCH ３ 2. The compound of claim 1 selected from:

5. R ３ The compound of claim 1 , wherein is —H.

6. 2. The compound of claim 1, wherein X is fluoride, chloride, bromide, or iodide.

7. 7. The compound of claim 6, wherein X is bromide or chloride.

8. Each -R ５ But independently, C ３ ~C １４ is an aryl group, and any —R ５ But one or more C １ ~C ４ Alkyl, halo, —OH, —NH ２ , -CN, -C≡CH or oxo (=O) group, or each -R ５ are phenyl groups, and each phenyl group is one or more C １ ~C ４ Alkyl, halo, —OH, —NH ２ , -CN, -C≡CH or oxo (=O) group.

9. Each R ５ The compound of claim 8 , wherein is a phenyl group.

10. Each -R ５ But, -CF ３ 2. The compound of claim 1, wherein the phenyl is optionally substituted with

11. 2. The compound of claim 1, wherein n is an integer from 2 to 10.

12. 12. The compound of claim 11, wherein n is 3, 4, or 5.

13. 2. The compound of claim 1, wherein the compound of formula (1) is selected from the following, and X is a counter anion: Table 1

14. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, double salt, or solvate thereof, and a pharmaceutically acceptable excipient.

15. 15. A compound according to claim 1, or a pharmaceutically acceptable salt, double salt, or solvate thereof, for use in medicine, or a pharmaceutical composition according to claim 14.

16. 15. A compound according to claim 1, or a pharmaceutically acceptable salt, double salt, or solvate thereof, or a pharmaceutical composition according to claim 14, for use in the treatment or prevention of cancer.

Images