TW201710251A - Functionalised and substituted indoles as anti-cancer agents - Google Patents

Abstract

The present invention relates broadly to functionalised and substituted indoles, the preparation thereof and their use in the treatment of proliferative diseases such as cancer.

Description

Functionalization and replacement as an anticancer agent

The invention broadly relates to functionalized and substituted purines, their preparation and their use in the treatment of proliferative diseases such as cancer.

In the United States, cancer kills thousands of people and is the second leading cause of death. Significant breakthroughs have been made in the treatment or prevention of multiple cancers. For example, patients with breast cancer have benefited from early screening procedures and a variety of surgical techniques. However, these techniques often prove to be physically and emotionally debilitating. In addition, diseases of patients undergoing surgery and subsequent chemotherapy often experience relapse.

A potential new method for specifically attacking cancer cells is through the destruction of the cytoskeletal system of cancer cells, which are mainly composed of actin. The actin cytoskeleton is closely involved in cell division and cell migration. However, actin acts as an ubiquitous effect on the cytoskeleton of tumor cells and actin filaments in muscle sarcomere. Due to undesired off-target side effects, the difference in structural similarities makes actin a difficult target for drug development.

The present invention seeks to address one or more of the above mentioned problems and/or to improve cancer therapy.

In a first aspect, the invention provides a compound of formula (I),

Or a pharmaceutically acceptable salt, hydrate, derivative, solvate or prodrug thereof, wherein: R ¹ and R ^{2 are} independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl; R ³ -based NR ⁸ R ¹⁰ or 4 to 7 membered carbocyclic rings, wherein 1 to 3 carbons may be replaced by N, O, S or NR ^{6 as appropriate} , and wherein the ring is optionally substituted by R ⁷ ; R ⁴ is a 5 or 6 membered carbocyclic ring, Wherein 1 to 3 carbons may be replaced by N, O, S or NR ⁶ ; R ⁵ , wherein each Y is independently OH or C ₁ -C ₆ alkoxy and X is a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons may be replaced by N or NR ^{6 as appropriate} and wherein the ring is 3 substituents selected from the group consisting of halo and C ₁ -C ₆ alkyl, or R ⁵ , Wherein Z is OH or-based C ₁ -C ₆ alkoxy, and Q is selected from the group consisting of consisting of: halo, -SO ₂ C ₁ -C _{6 alkyl, - (CH 2) 0-5 COOH} , - (CH ₂ ) _0-5 COOC ₁ -C ₆ alkyl or a 5 or 6 membered carbocyclic ring, wherein 1 to 4 carbons may be optionally substituted by N or NR ⁶ ; R ^{6 is} selected from the group consisting of H and C ₁ -C ₆ alkyl; R ^{7 is} selected from the group consisting of H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, CN, CF ₃ and OCF ₃ ; R ⁸ and R ¹⁰ independently Selected from the group consisting of H and C ₁ -C ₆ alkyl; X ¹ is an alkanediyl group having 1 to 20 carbon atoms; and X ² and X ^{3 are} independently selected from the group consisting of: -O- , -NH-, -NC ₁ -C ₆ alkyl-, -C(O)-, -C(O)NH-, -NHC(O)- or an alkanediyl group having 1 to 20 carbon atoms, wherein One to three hydrogen atoms may be replaced by R ^{7 as appropriate} .

In a second aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) according to the first aspect, together with a pharmaceutically acceptable carrier, diluent or excipient.

In a third aspect, the invention provides a method of treating a proliferative disorder in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) according to the first aspect or according to a second aspect Pharmaceutical composition.

In a fourth aspect, the invention provides the use of a compound of formula (I) according to the first aspect for the manufacture of a medicament for the treatment of a proliferative disorder.

In a fifth aspect, the invention provides the use of a compound of formula (I) according to the first aspect or a pharmaceutical composition according to the second aspect for the treatment of a proliferative disorder in an individual.

In a sixth aspect, the invention provides a compound of formula (I) according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a proliferative disorder in an individual.

The proliferative disease can be a cancer, such as a solid tumor. In some embodiments, the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, uterine cancer, brain cancer, skin cancer, colon cancer, bladder cancer, melanoma, and neuroblastoma.

Cancer can be a recurrent cancer.

In a seventh aspect, the invention provides a method of reducing the incidence or risk of cancer recurrence in an individual considered to be at risk of cancer recurrence, the method comprising administering to the individual an effective amount of formula (I) according to the first aspect A compound or a pharmaceutical composition according to the second aspect.

In an eighth aspect, the invention provides the use of a compound of formula (I) according to a first aspect for the manufacture of a medicament for reducing the incidence or risk of cancer recurrence in an individual considered to be at risk of cancer recurrence.

In a ninth aspect, the invention provides a compound of formula (I) according to the first aspect, which is used to reduce the incidence or risk of cancer recurrence in an individual considered to be at risk of cancer recurrence.

In a tenth aspect, the invention provides the use of a compound of formula (I) according to the first aspect, for reducing the incidence of cancer recurrence in an individual considered to be at risk of cancer recurrence or risk.

The individual can be an individual with cancer relief.

In an eleventh aspect, the invention provides a combination comprising: (i) a compound of formula (I) according to the first aspect, and (ii) vincristine or paclitaxel .

This combination can be a synergistic combination.

In a twelfth aspect, the present invention provides a pharmaceutical composition comprising: (i) a compound of the formula (I) according to the first aspect, (ii) vincristine or paclitaxel, and (iii) a pharmaceutical An acceptable carrier, diluent or excipient.

The composition can be a synergistic composition.

In a thirteenth aspect, the present invention provides a kit comprising: (i) a pharmaceutical composition of a compound of the formula (I) according to the first aspect, and (ii) a vincristine or paclitaxel drug Compositions wherein the compositions are intended to be used simultaneously, in parallel, separately or sequentially.

In a fourteenth aspect, the invention provides a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) according to the first aspect and a therapeutically effective amount of Changchunxin Alkali or paclitaxel.

The cancer can be melanoma, lung cancer or prostate cancer.

The administration of the compound of formula (I) and vincristine or paclitaxel can be carried out simultaneously, in parallel, separately or sequentially.

In the eleventh to fourteenth aspects, the compound of the formula (I) may be selected from the group consisting of compounds 6, 8, 14, 16, 23, 24, 27, 31, 32, 38, 39, 47, 48, 51, 55. One or more of 58, 58, 60, 63, 67 and 68.

Other embodiments of the invention and other aspects of the aspects described in the preceding paragraphs will be apparent from the following description, taken in conjunction with the accompanying drawings.

definition

The following may be helpful in understanding some of the definitions of the description of the invention. The definitions are intended to be a general definition and are not intended to limit the scope of the invention to the individual terms, but rather to provide a better understanding of the following description.

The term "a" ("a" and "an") is used herein to mean one or more (ie, at least one) of the grammatical terms of the article. For example, "an element" means one element or more than one element.

Throughout the specification, unless the context requires otherwise, the words "comprise" or variations such as "comprises" or "comprising" are to be understood as implying the inclusion of such elements, integers or A step, or a group of elements, integers, or steps, but does not exclude any other elements, integers or steps, or groups of elements, integers, or steps. Thus, in the context of this specification, the term "comprising" means "including primarily, but not necessarily unique."

The term "alkyl" is used to mean a straight or branched monovalent saturated hydrocarbon group having the stated number of carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1,2 - dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methyl Pentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2- Trimethylpropyl, 1,1,2-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl , octyl, sulfhydryl and sulfhydryl.

The term "alkoxy" is used to mean an O-alkyl group, wherein the alkyl group is as defined herein. Righteousness. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, second butoxy and tert-butoxy.

The terms "halogen" and "halo" are synonymous and refer to fluoro, chloro, bromo or iodo.

The term "alkanediyl" is understood to mean according to formula of C _n H _2n divalent saturated branched or straight chain hydrocarbon group.

The term "carbocycle" refers to a ring structure in which all ring members are carbon atoms.

The term "pharmaceutically acceptable salts" means those salts which, within the scope of sound medical judgment, are suitable for exposure to human and animal tissues without undue toxicity, irritation, allergic reactions and the like, and which are commensurate with the reasonable benefit/risk ratio.

The term "prodrug" means a compound which can be converted in vivo to a compound of formula (I) by metabolic means, for example by hydrolysis, reduction or oxidation. For example, an ester prodrug of a compound of the invention containing a hydroxy group can be hydrolyzed in vivo to the parent molecule. Suitable esters such as acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleic acid Ester, methylene-bis-p-hydroxy naphthalate, gentisate, isethionate, di-p-tolylmethionate, methanesulfonate, ethanesulfonate, benzenesulfonic acid Ester, p-toluenesulfonate, cyclohexylaminosulfonate and quinic acid ester.

The term "treating", "treatment" and "prevention" are used for any and all purposes, which remedy a proliferative disease or its symptoms, prevent the establishment of a proliferative disease, or otherwise prevent, hinder, delay or reverse hyperplasia. Disease or progression of other undesired symptoms in any way. Therefore, the terms "treating", "preventing" and "prevention" and the like are intended to be considered in their broadest context. For example, treatment does not necessarily imply treatment of the individual until all recovery.

The term "therapeutically effective amount" includes a non-toxic but sufficient amount of the active compound to provide the desired therapeutic effect. Those skilled in the art should be aware that the exact amount of compound required will It varies based on a variety of factors, and therefore, an accurate "therapeutically effective amount" cannot be specified. However, for any given situation, an appropriate "therapeutically effective amount" can be determined by those skilled in the art.

The term "effective amount" includes a non-toxic but sufficient amount of the active compound to provide the effect. By reference to cancer recurrence, "effective amount" means the amount of a compound of formula (I) required to reduce the morbidity or risk of an individual undergoing cancer recurrence. Those skilled in the art will appreciate that the precise amount of the desired compound will vary based on a variety of factors, and thus it is not possible to specify an accurate "effective amount." However, for any given situation, an appropriate "effective amount" can be determined by those skilled in the art.

"Pharmaceutical carrier, diluent or excipient" includes, but is not limited to, any physiologically buffered (ie, about pH 7.0 to 7.4) medium comprising a suitable water-soluble organic vehicle, a conventional solvent, a dispersion medium, a filler, Solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Suitable water-soluble organic carriers include, but are not limited to, saline, dextrose, corn oil, dimethyl hydrazine, and gelatin capsules. Other conventional additives include lactose, mannitol, corn starch, potato starch, binders (eg crystalline cellulose, cellulose derivatives, gum arabic, gelatin), disintegrants (eg carboxymethyl-cellulose sodium) and lubricants (such as talc or magnesium stearate).

The term "individual" includes any human or non-human animal. Thus, the compounds of the invention may be used in veterinary treatment of mammals, including companion animals and farm animals such as, but not limited to, dogs, cats, horses, cows, sheep, and pigs, in addition to human therapy.

The term "relapse" when referring to cancer is understood to mean the recurrence of cancer cells and/or cancerous tumors after successful treatment of cancer cells and/or cancerous tumors.

The term "administering" and variations of the term (including "administer" and "administration") include contacting a compound or composition of the invention with an organism or by any suitable means. Surface, the compound or composition of the invention is applied, delivered or provided to a living organism or surface.

Figure 1: Imaging and quantification of actin filaments in SK-N-SH neuroblastoma cells treated with compounds (A) 50, (B) 51. Cells were stained with 488-Atto-Phallodin and DAPI to visualize actin filament bundles and nuclei. The top panel (enlarged insert bottom panel) shows representative grayscale immunofluorescence images from control (media only), 2.5 [mu]M and 5 [mu]M treated cells, which quantitatively overlap with linear features. Color lines indicate the detected actin filaments. The number of cells and the number of filaments/quantitative cells were also shown. Statistical analysis was performed using one-way ANNOVA-multiple comparisons in which each drug treated group was compared to a control. **** p<0.0001, **** p<0.001, *** p<0.01, ** p<0.1.

Figure 2: Imaging and quantification of actin filaments in SK-N-SH neuroblastoma cells treated with compounds (A) 50 and (B) 51. The cells were visualized to contain Tpm3 using γ9d primary antibody (MAb culture s/n pure line 2G10.2, 1:50), followed by 488-conjugated secondary antibody (goat anti-mouse 488, 1:1000) and DAPI staining. 1 filament bundle and core. The top panel (enlarged insert bottom panel) shows representative grayscale immunofluorescence images from control (media only), 2.5 [mu]M and 5 [mu]M treated cells, which quantitatively overlap with linear features. Color lines indicate the detected actin filaments. The number of cells and the number of filaments/quantitative cells were also shown. Statistical analysis was performed using one-way ANNOVA-multiple comparisons in which each drug treated group was compared to a control. **** p<0.0001, **** p<0.001, *** p<0.01, ** p<0.1.

Figure 3: Plate layout for drug combination analysis. Each screening plate contained up to six 6 x 6 dose matrices and analytical controls (thonzonium bromide and DMSO) as indicated. The remaining wells contain only cells. Individual dose within the matrix is based on _50-fold dilution steps used to establish the concentration of the two drugs of the IC. Each drug combination was tested in triplicate.

The present invention is based on the surprising discovery by the inventors that the compounds of formula (I) are effective in inhibiting tropomyosin, which produces unexpected changes in the treatment of proliferative diseases, in particular cancers. good.

The development of the actin cytoskeleton involves a variety of secondary control and regulatory proteins. The identification and specific targeting of actin regulatory proteins associated with the cytoskeleton of cancer cells provides an opportunity to develop cancer-specific drugs with no undesirable side effects.

The actin filaments are constructed by polymerization of globular actin protein monomers. Actin single system polar, with one end with a positive charge and the other end with a negative charge. Thus, actin filaments have all actin aligned in one direction. These filaments have secondary crimped proteins, tropomyosin associated therewith. Tropomyosin plays an integral role in regulating the function of actin filaments. The actin filaments are structurally composed of a polymeric actin monomer and a tropomyosin dimer in an alpha helix groove of actin filaments to form a homopolymer. There are more than 40 mammalian tropomyosin isoforms, each of which regulates specific actin filaments. There is a specific isoform of tropomyosin that regulates the cytoskeleton of cancer cells; the disruption of this interaction provides the basis for treating cancer cells with a high degree of specificity.

In one aspect, the invention provides a compound of formula (I),

Or a pharmaceutically acceptable salt, hydrate, derivative, solvate or prodrug thereof, wherein: R ¹ and R ^{2 are} independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl; R ³ -based NR ⁸ R ¹⁰ or 4 to 7 membered carbocyclic rings, wherein 1 to 3 carbons may be replaced by N, O, S or NR ^{6 as appropriate} , and wherein the ring is optionally substituted by R ⁷ ; R ⁴ is a 5 or 6 membered carbocyclic ring, Wherein 1 to 3 carbons may be replaced by N, O, S or NR ⁶ ; R ⁵ , wherein each Y is independently OH or C ₁ -C ₆ alkoxy and X is a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons may be replaced by N or NR ^{6 as appropriate} and wherein the ring is 3 substituents selected from the group consisting of halo and C ₁ -C ₆ alkyl, or R ⁵ , Wherein Z is OH or-based C ₁ -C ₆ alkoxy, and Q is selected from the group consisting of consisting of: halo, -SO ₂ C ₁ -C _{6 alkyl, - (CH 2) 0-5 COOH} , - (CH ₂ ) _0-5 COOC ₁ -C ₆ alkyl or a 5 or 6 membered carbocyclic ring, wherein 1 to 4 carbons may be optionally substituted by N or NR ⁶ ; R ^{6 is} selected from the group consisting of H and C ₁ -C ₆ alkyl; R ^{7 is} selected from the group consisting of H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, CN, CF ₃ and OCF ₃ ; R ⁸ and R ¹⁰ independently Selected from the group consisting of H and C ₁ -C ₆ alkyl; X ¹ is an alkanediyl group having 1 to 20 carbon atoms; and X ² and X ^{3 are} independently selected from the group consisting of: -O- , -NH-, -NC ₁ -C ₆ alkyl-, -C(O)-, -C(O)NH-, -NHC(O)- or an alkanediyl group having 1 to 20 carbon atoms, wherein One to three hydrogen atoms may be replaced by R ^{7 as appropriate} .

In one embodiment, R ¹ and R ^{2 are} independently selected from the group consisting of H and C ₁ -C ₃ alkyl.

In another embodiment, R ¹ and R ^{2 are} independently selected from the group consisting of H and methyl.

In still another embodiment, both R ¹ and R ² are methyl.

In still another embodiment, R ³ is a NR ⁸ R ¹⁰ or 4 to 7 membered carbocyclic ring, wherein 1 to 3 carbons are optionally replaced by N or NR ⁶ and wherein the ring is optionally substituted with R ⁷ .

In still another embodiment, R ³ is NR ⁸ R ¹⁰ or a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons are optionally replaced by N or NR ⁶ and wherein the ring is optionally substituted by C ₁ -C ₆ alkyl .

In yet another embodiment, R ³ is a NR ⁸ R ¹⁰ or 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons may optionally be replaced by N or NR ⁶ .

In yet another embodiment, R ³ is N(Me) ₂ , NH ₂ or a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons may optionally be replaced by N or NR ⁶ .

In still another embodiment, R ³ is N(Me) ₂ , NH ₂ or a 5 or 6 membered carbocyclic ring, wherein 1 or 2 carbons may optionally be replaced by N or NR ⁶ .

In still another embodiment, R ³ is an N(Me) ₂ , NH ₂ or 6 membered carbocyclic ring wherein one or two carbons are optionally replaced by N, NH or NMe.

In still another embodiment, R ³ is an N(Me) ₂ or 6 membered carbocyclic ring wherein one or two carbons are optionally replaced by N, NH or NMe.

In another embodiment, R ³ is N(Me) ₂ , NH ₂ or a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons are optionally replaced by N, S, O or NR ⁶ .

In the above examples for R ³ , the 4 to 7 membered carbocyclic ring and the 5 or 6 membered carbocyclic ring may be saturated or partially saturated.

In another embodiment, R ^{3 is} selected from the group consisting of N(Me) ₂ , NH ₂ and

In another embodiment, R ^{3 is} selected from the group consisting of N(Me) ₂ , NH ₂

In still another embodiment, R ^{3 is} selected from the group consisting of: N(Me) ₂ and

In another embodiment, R ⁴ is a 5 or 6 membered carbocyclic ring wherein 1 to 3 carbons are optionally replaced by N, NR ⁶ , O or S.

In still another embodiment, R ⁴ is a phenyl group or a 5 or 6 membered heteroaryl ring having from 1 to 3 heteroatoms selected from the group consisting of N, O and S.

In still another embodiment, R ⁴ is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 to 3 N heteroatoms.

In still another embodiment, R ⁴ is a phenyl group or a 6 membered heteroaryl ring having 1 to 3 N heteroatoms.

In still another embodiment, R ⁴ is a phenyl or a pyridyl group.

In still another embodiment, R ⁴ is a phenyl group.

In still another embodiment, R ⁴ is p-phenyl or meta-phenyl.

In one embodiment, the R ⁵ system , wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 to 3 hetero atoms selected from the group consisting of N, O and S, and wherein phenyl and heteroaryl The base ring may be optionally substituted with 1 or 2 substituents selected from the group consisting of halo, methyl, ethyl, propyl and isopropyl, or R ⁵ , wherein Z is OH or OMe and Q is selected from the group consisting of: halo, -SO ₂ Me, -(CH ₂ ) _0-5 COOH, -(CH ₂ ) _0-5 COOC ₁ -C ₆ alkyl, A phenyl group and a 5 or 6 membered heteroaryl ring having 1 to 4 N heteroatoms.

In another embodiment, the R ⁵ system Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 to 3 N heteroatoms, and wherein the phenyl and heteroaryl rings are optionally substituted with 1 or 2 halo groups Substituent, or R ⁵ Wherein Z is OH or OMe and Q is selected from the group consisting of halo, -SO ₂ Me, -(CH ₂ ) _1-5 COOH, phenyl and 5 or 6 members having 1 to 4 N heteroatoms Heteroaryl ring.

In yet another embodiment, the R ⁵ system Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl and heteroaryl ring are optionally substituted with a halo substituent, or R ⁵ series Wherein Z is OH or OMe and Q is selected from the group consisting of I, -SO ₂ Me, -(CH ₂ ) _1-3 COOH or a 5-membered heteroaryl ring having 1 to 4 N heteroatoms.

In still another embodiment, the R ⁵ system Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl and heteroaryl rings are optionally substituted with a fluorine substituent, or R ⁵ series Wherein Z is OH and Q is selected from the group consisting of I, -SO ₂ Me, -(CH ₂ ) ₂ COOH or a 5-membered heteroaryl ring having 1 to 4 N heteroatoms.

In yet another embodiment, the R ⁵ system Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl and heteroaryl rings are optionally substituted with a fluorine substituent, or R ⁵ series Wherein Z is OH and Q is selected from the group consisting of I, -SO ₂ Me, -(CH ₂ ) ₂ COOH, and tetrazolyl.

In yet another embodiment, X is selected from the group consisting of:

In still another embodiment, X is selected from the group consisting of:

In one embodiment, the R ⁵ system .

In some embodiments, the R ⁵ system .

In other embodiments, the R ⁵ system .

In other embodiments, the R ⁵ system .

In other embodiments, the R ⁵ system .

In some embodiments, R ^{6 is} selected from the group consisting of H, methyl, and ethyl.

In other embodiments, R ⁶ is selected from the group consisting of: H and methyl.

In one embodiment, X ¹ is an alkanediyl group having between 1 and 15 carbon atoms.

In another embodiment, X ¹ is an alkanediyl group having from 1 to 10 carbon atoms.

In still another embodiment, X ¹ is an alkanediyl group having 1 to 6 carbon atoms.

In still another embodiment, X ¹ is -(CH ₂ ) _1-6 - or -CH ₂ -CH(Me)-(CH ₂ )-.

In still another embodiment, X ¹ is -(CH ₂ ) _2-5 - or -CH ₂ -CH(Me)-(CH ₂ )-.

In one embodiment, X ² and X ^{3 are} independently selected from the group consisting of: -O-, -NH-, -NC ₁ -C ₆ alkyl-, -C(O)-, -C(O) NH-, -NHC(O)- and an alkanediyl group having 1 to 15 carbon atoms.

In another embodiment, X ² and X ^{3 are} independently selected from the group consisting of -O-, -NH-, -NMe, -C(O)NH-, -NHC(O)-, and having 1 to An alkanediyl group of 10 carbon atoms.

In another embodiment, X ² and X ^{3 are} independently selected from the group consisting of -O-, -NH-, -NMe, -C(O)NH-, -NHC(O)-, and having 1 to An alkanediyl group of 6 carbon atoms.

In still another embodiment, X ² and X ^{3 are} independently selected from the group consisting of -O-, -NH-, -C(O)NH-, -NHC(O)-, -CH ₂ CH ₂ CH ₂ -, CH ₂ CH ₂ - and -CH ₂ -.

In a further embodiment, X ² and X ³ are independently selected from the group consisting of: -O -, - NH -, - C (O) NH -, - NHC (O) - and CH _2.

In still another embodiment, X ^{2 is} selected from the group consisting of -O-, -NH-, and -CH ₂ -.

In yet another embodiment, the X ³ is -C(O)NH- or -NHC(O)-.

Exemplary compounds of formula (I) include the following:

In one embodiment, the compound is: N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(3) -(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-methyl)) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) A yl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (3,5-dihydroxy-4-(1 H -imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-methyl)) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) A yl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-methyl)) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy yl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1 H -imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-)4 -methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-methyl)) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy yl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-methyl)) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amine yl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-methyl)) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amine yl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide

N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-methyl-3-) 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-)4- Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

N- (2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-) 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl) methyl) - N - (4'- fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl amine

N- (3,5-dihydroxy-4-(1 H -imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(2-(4-methylhexahydro)) Pyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-(4-methylhexahydropyrazine)- 1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide

N- (2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-(4-methylhexahydropyridyl)) Pyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(4-(4-methylhexahydropyridyl)) Pyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(4-(4-methylhexahydropyrazine)- 1-yl)butyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(4-(4-methylhexahydropyridyl)) Pyrazin-1-yl)butyl)-1 H -indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(5-(4-methylhexahydropyridyl)) Pyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide

N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(5-(4-methylhexahydropyrazine)- 1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide

N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(5-(4-methylhexahydropyridyl)) Pyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide

4-((2,3-Dimethyl-1-(5-(4-methylhexahydropyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy) -N- (3-hydroxy-4- Iodophenyl)benzamide

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy) -N- (3-hydroxy-4- (methylsulfonyl)phenyl)benzamide

3-(4-(4-((1-(3-(dimethylamino))propyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzamide 2-hydroxyphenyl)propionic acid

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy) -N- (3-hydroxy-4- (2 H -tetrazol-5-yl)phenyl)benzamide

In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 9-12, 17-20, 22-24, 30-32, 44, 46-52, and 69-72.

In another embodiment, the compound of formula (I) is selected from the group consisting of compounds 1-12, 14-20, 26-28, 33-36, 38-40, 42-44, and 46-72.

In still another embodiment, the compound of formula (I) is selected from the group consisting of compounds 22-24 and 30-32.

In still another embodiment, the compound of formula (I) is selected from the group consisting of compounds 6, 8, 16, 23, 24, 47, 48, 51, 60 and 68.

The compound of formula (I) may include one or more chiral centers. The present invention includes all mirror image isomers and non-image isomers as well as mixtures thereof in any ratio. The invention also extends to isolated mirror image isomers or mirror image isomer pairs. Methods for separating mirror image isomers and non-image material isomers are well known to those skilled in the art. In some embodiments, the compound of formula (I) is a racemic mixture. In other embodiments, the compound of formula (I) is present in optically pure form.

Compounds of formula (I) are also employed to include hydrates and solvates. A solvate is a complex formed by association of a solvent molecule with a compound of formula (I). In the case where the compound of formula (I) is a solid, it will be apparent to those skilled in the art that such compounds may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention.

The compound of formula (I) may be in the form of a pharmaceutically acceptable salt. Such salts are well known to those skilled in the art. The pharmaceutically acceptable salts are described in detail by SMBerge et al., J. Pharmaceutical Sciences, 1977 , 66: 1-19. The pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound of formula (I) or separately by reacting the free base compound with a suitable organic acid. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared from mineral acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids and sulfonic acid organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, apples. Acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, pyruvic acid, alkylsulfonic acid, arylsulfonic acid, aspartic acid, glutamic acid, benzoic acid, ortho-benzoic acid , methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, ambonic acid, pamoic acid, pantothenic acid, p-aminobenzenesulfonic acid, cyclohexylamine sulfonate Acid, stearic acid, alginic acid, beta-hydroxybutyric acid, galactosuccinic acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of the invention include those prepared from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc and from organic bases such as choline, diethanolamine, morpholine and the like. Organic salt. Or, from N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine An organic salt prepared from (procaine), an ammonium salt, a quaternary salt (for example, a tetramethylammonium salt), an amino acid addition salt (for example, a salt with glycine and arginine).

The compounds of formula (I) are also extended to include all derivatives having a physiologically dissociable cleavage group which can be cleaved in vivo to provide a compound of formula (I). Suitable exfoliating groups include sulfhydryls, phosphates, sulfates, sulfonates, and preferably mono-, di-, and per-indolyl-substituted compounds, wherein one or more pendant hydroxyl groups are derived from thiol groups. Jia Yiji) protection. Generally, the oxime-substituted compound is readily cleaved to the corresponding hydroxy-substituted compound.

The compound of the formula (I) or a salt, hydrate or solvate thereof can be obtained by a synthetic method known to those skilled in the art. In general, the compound of formula (I) can be synthesized from the following 5-substituted oxime:

As shown in Scheme 1 below, a compound of formula (II) can provide a compound of formula (I) wherein X ² is CH ₂ and X ³ is -C(O)NH- (referred to as a compound of formula (Ia)).

Scheme 1 Synthesis of a compound of formula (Ia)

Alternatively, the compound can (III) to produce a free acid hydrolysis and subsequent reaction with R ⁵ NH _2, after the 1-position of the indole functionalized to introduce a substituent X ¹ R ^3. This alternative synthetic route is shown in Scheme 2 below.

Scheme 2 Alternative Synthesis of Compounds of Formula (Ia)

As shown in Scheme 3 below, a compound of formula (VIII) can provide a compound of formula (I) wherein X ² is O and X ³ is -C(O)NH- (referred to as a compound of formula (Ib)).

Scheme 3 Synthesis of a compound of formula (Ib)

Alternatively, make compound (IX) to produce a free acid hydrolysis and then reacted with R ⁵ NH _2, after the 1-position of the indole functionalized to introduce a substituent X ¹ R ^3. This alternative synthetic route is shown in Scheme 4 below.

Scheme 4 Alternative Synthesis of Compounds of Formula (Ib)

As shown in Scheme 5 below, a compound of formula (XIV) can provide a compound of formula (I) wherein X ² is NH (referred to as a compound of formula (Ic)).

Scheme 5 Synthesis of compounds of formula (Ic)

The above methods of Schemes 1-5 may provide one or more advantages including high yield, stereochemistry control, minimal synthesis steps, and reaction conditions suitable for large scale manufacturing.

The above-described methods are merely representative and will be apparent to those skilled in the art, which are within the broad scope and scope of the invention. Those skilled in the art of synthetic organic chemistry will be aware of alternative methods of preparing compounds of formula (I).

The compounds of formula (I) are useful in the treatment or prevention of proliferative diseases such as cancer. The compounds and pharmaceutical compositions of the invention are useful in the treatment of a variety of cancers including, but not limited to, solid tumors such as breast cancer, lung cancer (NSCLC and SCLC), prostate cancer, ovarian cancer, uterine cancer, peritoneal cancer, brain cancer (including, for example) Glioma, such as glioblastoma, diffuse innate pons (DIPG) and medulloblastoma), skin cancer, colon cancer, bladder cancer, colorectal cancer, stomach cancer, liver cancer, pancreatic cancer, Head and neck cancer, melanoma, malignant abdomen Water, mesothelioma and neuroblastoma. In one embodiment, the cancer is selected from the group consisting of prostate cancer, lung cancer, breast cancer, colorectal cancer, melanoma, and neuroblastoma. In an alternate embodiment, the cancer can be leukemia.

Compounds of formula (I) have also been found to be useful in treating the recurrence of relapses and reducing the incidence or risk of cancer recurrence in individuals considered to be at risk of cancer recurrence, such as individuals with cancer remission. The individual can be relieved from a solid tumor as defined herein.

Advantageously, the compounds of formula (I) may have excellent pharmaceutical properties, for example, binding via glucuronyltransferase and other water-soluble transferases, such as sulphides, which can be expressed on proliferating cells, such as cancer cells. Improved resistance. This can advantageously confer superior pharmaceutical properties, such as enhanced pharmacokinetic properties via reduced binding and elimination.

Those skilled in the art will recognize that the compounds and pharmaceutical compositions of the present invention can be administered by any route that delivers an effective amount of the compound to the tissue or site to be treated. In general, the compounds and compositions can be administered parenterally (e.g., intravenously, intrathecally, subcutaneously, or intramuscularly), orally or topically. The administration can be for systemic, regional or topical administration. In one embodiment, the administration can be transrectal.

The particular route of administration to be used in any given situation will depend on a number of factors, including the nature of the cancer to be treated, the severity and extent of the cancer, the desired dosage of the particular compound to be delivered, and the potential side effects of the compound.

In general, suitable compositions may be prepared according to methods known to those skilled in the art and may include pharmaceutically acceptable carriers, diluents and/or excipients. The carrier, diluent and excipient should be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient.

Examples of pharmaceutically acceptable carriers or diluents are demineralized or distilled; aqueous saline solutions; plant based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil or coconut oil; polyoxygenated oils, Including polyoxyalkylene, such as methyl polyoxyalkylene, phenyl polyoxyalkylene and methylphenyl polyoxyalkylene; volatile polyoxo; mineral oil, such as liquid stone Wax, soft paraffin or squalane; cellulose derivatives such as methylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose or sodium hydroxypropylmethylcellulose; Cremaphor; Dextrin; lower alkanol, such as ethanol or isopropanol; lower aryl aryl alcohol; low carbon polyalkylene glycol or low carbon alkyl diol, such as polyethylene glycol, polypropylene glycol, ethylene glycol , propylene glycol, 1,3-butanediol or glycerol; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate; polyvinylpyrrolidone; agar; Carrageenan; tragacanth or gum arabic and petroleum glue. Typically, one or more carriers will comprise from 10% to 99.9% by weight of the composition.

The pharmaceutical composition of the present invention may be in a form suitable for administration by injection, in the form of a formulation suitable for oral ingestion (for example, capsules, lozenges, capsules, elixirs), suitable for topical administration. In the form of an ointment, cream or lotion, in a form suitable for delivery as an eye drop, in an aerosol form suitable for administration by inhalation (for example by intranasal or oral inhalation), suitably Parenteral administration (ie subcutaneous, intramuscular or intravenous).

For administration in the form of injectable solutions or suspensions, non-toxic parenterally acceptable diluents or carriers may include cyclodextrin (eg, Captisol®) Cremaphor, Ringer's solution, isotonic saline, Phosphate buffered saline, ethanol and 1,2 propanediol. To facilitate injection and delivery, compounds can also be added to PEGylated and non-pegylated liposomes with specific targeting tags (eg, RGD peptides or glutathione) attached to the PEG moiety or Microcells are used to help pass the blood-brain barrier.

Some examples of carriers, diluents, excipients and adjuvants suitable for oral use include cyclodextrin, Cremaphor, peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, arab Gum, tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatin and lecithin. Additionally, such oral formulations may contain suitable flavoring and coloring agents. When used in capsule form, the capsules can be coated with a compound which delays disintegration, such as glyceryl monostearate or glyceryl distearate.

Adjuvants usually include softeners, emulsifiers, thickeners, preservatives, bactericides, and Buffer.

The solid form for oral administration may contain binders, sweeteners, disintegrants, diluents, flavoring agents, coating agents, preservatives, lubricants and/or time acceptable in human and veterinary medicine practice. Delay agent. Suitable binders include gum arabic, gelatin, corn starch, tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methyl cellulose, polyvinyl pyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium citrate or calcium hydrogen phosphate. Suitable flavoring agents include peppermint oil, wintergreen oil, cherry, orange or raspberry flavoring agents. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or esters thereof, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

In addition to the above reagents, the liquid form for oral administration may contain a liquid carrier. Suitable liquid carriers include water, oil (such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, coconut oil), liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, Glycerin, fatty alcohol, triglyceride or a mixture thereof.

The suspension for oral administration may further comprise a dispersing agent and/or a suspending agent. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or ethoxylated alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitan monooleate or dioleate, stearate or -laurate, polyoxyethylene sorbes Alcoholic anhydride monooleate or dioleate, stearate or -laurate and the like.

The emulsion for oral administration may further comprise one or more emulsifiers. Suitable for emulsification The agent includes a dispersing agent or a natural gum as exemplified above, such as guar gum, gum arabic or tragacanth.

Methods for preparing compositions for parenteral administration are well known to those skilled in the art and are described in more detail, for example, in Remington's Pharmaceutical Science, 15th Edition, Mack Publishing Company, Easton, Pa. This is incorporated herein by reference.

The topical formulation may comprise the active ingredient together with one or more acceptable carriers and optionally any other therapeutic ingredient. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site in need of treatment, such as a liniment, lotion, cream, ointment or paste, and suitable for administration to the eye, Ear or nose drops.

Drops of the invention may comprise sterile aqueous or oily solutions or suspensions. Such drops may be prepared by dissolving the active ingredient in a bactericidal and/or fungicide and/or any other suitable preservative and, optionally, aqueous solutions including surfactants. The resulting solution can then be clarified by filtration, transferred to a suitable container and sterilized. Sterilization can be achieved by autoclaving at 90 ° C to 100 ° C for half an hour, or by filtration, followed by transfer to a container based on aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are nitric acid or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Solvents suitable for the preparation of oily solutions include glycerin, diluted alcohols and propylene glycol.

Lotions of the present invention include those suitable for application to the skin or the eye. The eye lotion may comprise a sterile aqueous solution containing a bactericide as appropriate, and may be prepared by a similar method as described above for the preparation of the drops. Lotions or liniments for application to the skin may also include agents (such as alcohol or acetone) that promote drying and cooling of the skin, and/or humectants such as glycerin or oils such as olive oil.

The creams, ointments or pastes of the present invention are useful as semi-solid formulations of externally applied active ingredients. It can be mixed with a fat-containing or fat-free matrix by a finely distributed or powdered form of the active ingredient, either alone or in a solution or suspension in an aqueous or non-aqueous liquid. To make it. The matrix may comprise a hydrocarbon, such as a hard, soft or liquid paraffin, glycerin, beeswax, metal soap; a sizing agent; an oil of natural origin, such as almond oil, corn oil, peanut oil, castor oil or olive oil; lanolin or a derivative thereof. Or a fatty acid (such as stearic acid or oleic acid) and an alcohol (such as propylene glycol or macrogol).

The composition may incorporate any suitable surfactant, such as an anionic, cationic or nonionic surfactant such as sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials (for example, cerium oxide containing cerium oxide) and other ingredients (for example, lanolin) may also be included.

In some embodiments, the composition is administered as a suppository for rectal administration of a compound of formula (I). The compositions are prepared by mixing a compound of formula (I) with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus will be melted in the rectum to release (I) a compound. Such materials include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

The composition may also be administered or delivered to the target cells in liposome form. Liposomes are typically derived from phospholipids or other lipid materials and are formed from mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Specific examples of liposomes for administration or delivery of a composition to a target cell are synthetic cholesterol (Sigma), phospholipid 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC); Avanti Polar Lipids), PEG lipid 3-N-[(-methoxypoly(ethylene glycol) 2000) amine carbaryl]-1,2-dimyristyloxy-propylamine (PEG-cDMA), and cation Lipid 1,2-di-o-octadecenyl-3-(N,N-dimethyl)aminopropane (DODMA) or 1,2-dilinoleyloxy-3-(N,N- Dimethyl)aminopropane (DLinDMA) with a molar ratio of 55:20:10:15 or 48:20:2:30, respectively PEG-cDMA, DODMA and DLinDMA. Liposomes can be derived from 1,2-distearyl-sn-glyceryl-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE PEG2000) and phospholipids derived from soybean Choline and 50-100% (for example) hydrogenated Soy PC-75 or Soy PC-100 are constructed. be usable Different MW PEGs are covalently bound to various specific targeting agents such as glutathione, RGD peptides or other recognition liposome targeting agents. Any physiologically acceptable and metabolizable non-toxic lipid that forms liposomes can be used. Compositions in liposome form may contain stabilizers, preservatives, excipients, and the like. Preferred are lipid-based phospholipids and phospholipids choline (lecithin), both natural and synthetic. Methods for forming liposomes are known in the art, and in this regard, reference is made in particular to Methods and Cell Biology, edited by Prescott, Volume XIV, Academic Press, New York, NY (1976), page 33, with reference to the following, This is incorporated herein by reference.

The compositions can also be administered in the form of microparticles or nanoparticles. Self-polylactic acid (PLA), polylactic acid-co-glycolide (PLGA) and ε-caprolactone ( Biodegradable microparticles formed from -caprolactone have been widely used as drug carriers to increase plasma half-life and thereby prolong efficacy (R. Kumar, M., 2000, J. Pharm. Pharmaceut. Sci. 3(2) 234-258). Microparticles are formulated to deliver a variety of drug candidates, including vaccines, antibiotics, and DNA. In addition, such formulations have been developed for a variety of delivery routes, including parenteral injections, intravenous injections, and inhalation.

The composition may incorporate a controlled release matrix comprised of a mixture of sucrose acetate isobutyrate (SAIB) and an organic solvent or organic solvent. A polymeric additive can be added to the vehicle as a release modifier to further increase viscosity and slow release rate. SAIB is a well-known food additive. It is a fully esterified sucrose derivative having a nominal hydrophobicity of 6 isobutyrate to 2 acetate groups. As a mixed ester, SAIB does not crystallize but exists as a clear viscous liquid. Mixing SAIB with a pharmaceutically acceptable organic solvent such as ethanol or benzyl alcohol will be sufficient to reduce the viscosity of the mixture to allow for injection. The active pharmaceutical ingredient can be added to the SAIB delivery vehicle to form a SAIB solution or suspension formulation. When the formulation is injected subcutaneously, the solvent is different from the matrix, allowing the SAIB-drug or SAIB-drug-polymer mixture to be set to form an accumulation in situ.

For the purposes of the present invention, compounds and groups can be administered therapeutically or prophylactically to an individual. Compound. In therapeutic applications, a composition that is already suffering from cancer is administered to a composition that is sufficient to cure or at least partially arrest the cancer and its complications. The compositions should provide a compound or agent in an amount sufficient to effectively treat the subject.

The therapeutically effective amount for any particular individual will depend on a number of factors, including: the cancer being treated and its severity; the activity of the compound administered; the composition in which the compound is present; the age, weight, general health, sex of the individual And diet; time of administration; route of administration; rate of capture of the compound; duration of treatment; drugs in combination or concurrent use with the compound, and other relevant factors well known in the art.

Those skilled in the art will be able to determine the effective non-toxic amount of a compound that will be required to treat or prevent a particular cancer by routine experimentation.

Generally, an effective dose is contemplated to be in the range of from about 0.0001 mg to about 1000 mg/kg body weight per 24 hours; typically from about 0.001 mg to about 750 mg/kg body weight per 24 hours; from about 0.01 mg to about 500 mg per kg body weight per 24 hours; From about 0.1 mg to about 500 mg/kg body weight per 24 hours; from about 0.1 mg to about 250 mg/kg body weight per 24 hours; from about 1.0 mg to about 250 mg/kg body weight per 24 hours. More typically, the effective dosage range is expected to be in the range of from about 1.0 mg to about 200 mg/kg body weight per 24 hours; from about 1.0 mg to about 100 mg/kg body weight per 24 hours; from about 1.0 mg to about 50 mg per kg body weight per 24 hours About 1.0 mg to about 25 mg/kg body weight / 24 hours; about 5.0 mg to about 50 mg / kg body weight / 24 hours; about 5.0 mg to about 20 mg / kg body weight / 24 hours; about 5.0 mg to about 15 mg / kg body weight / 24 hours.

Alternatively, the effective dose can be up to about 500 mg/m ² . Generally, it is contemplated that the effective dose is in the range of from about 25 mg/m ² to about 500 mg/m ² , preferably from about 25 mg/m ² to about 350 mg/m ² , more preferably from about 25 mg/m ² to about 300 mg/m ² , Still more preferably from about 25 mg/m ² to about 250 mg/m ² , even more preferably from about 50 mg/m ² to about 250 mg/m ² and still even more preferably from about 75 mg/m ² to about 150 mg/m ² .

Typically, in therapeutic applications, treatment can maintain the duration of the disease state.

In addition, those skilled in the art should be aware that the optimal amount and interval of individual doses can be borrowed. It is determined by the nature and extent of the cancer being treated, the form, route and site of administration, and the nature of the particular individual being treated. Again, these optimal conditions can be determined by conventional techniques.

The compounds of formula (I) may be used alone to treat cancer, or alternatively may be combined with radiation therapy and/or surgery and/or other therapeutic agents (eg, chemotherapeutic agents and immunostimulants) as part of a combination therapy. The compounds of formula (I) may sensitize cancer cells to other chemotherapeutic agents and/or radiation therapies.

The terms "combination therapy" and "additional therapy" are intended to encompass a plurality of therapeutic agents that are administered in a sequential manner in a regimen that would provide a beneficial effect and are intended to encompass the administration of such agents in a single formulation or in separate formulations.

Combination therapies may involve, in each case, the active agents being administered together, sequentially or at intervals, if appropriate. Combinations of active agents, including the compounds of the invention, can be synergistic.

Co-administration of a compound of formula (I) with other therapeutic agents can be achieved by a compound of formula (I) in the same unit dosage form as the other therapeutic agent, or the compound of formula (I) and other therapeutic agents can be present in parallel, depending on In separate or discrete unit dosage forms administered sequentially or separately. Administration of the compound of formula (I) alone is administered at different time points independently of the other therapeutic agents. It may be the case that the compound of formula (I) and other therapeutic agents are administered such that there is no overlap in the measurable blood content of the compound of formula (I) and other therapeutic agents. When administered separately, the compound of formula (I) and the other therapeutic agent may preferably be administered by the same route of administration, although this is not necessary. The sequential administration may be in any order that may be desired, and in the case of administration of a second or subsequent agent, particularly where a cumulative or synergistic effect is desired, the progressive physiological effects of the first or initial agent may be maintained.

According to various embodiments of the invention, one or more compounds of formula (I) may be included in combination therapy with surgery and/or radiation therapy and/or one or more chemotherapeutic agents.

There are a number of chemotherapeutic agents currently in use, for clinical evaluation and pre-clinical development that can be selected for the treatment of cancer in combination with a compound of formula (I). These agents belong to several major classes, namely, antibiotic-type agents, alkylating agents, antimetabolites, hormonal agents, immunopharmaceuticals, interferon-type agents, and a range of various agents. Alternatively, other chemical treatments can be used A therapeutic agent, such as a metal matrix protease (MMP) inhibitor. Suitable agents for use in combination therapies include those listed below: for example, Merck Index, An Encyclopaedia of Chemicals, Drugs and Biologicals, 12th Edition, 1996, the entire disclosure of which is incorporated herein by reference.

The compound of formula (I) can be administered with one or more of the following chemotherapeutic agents when used in the treatment of solid tumors: adriamycin, taxol, docetaxel, fluorouracil ( Fluorouracil), melphalan, cisplatin, alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide (etoposide), mBACOD (amine methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PROMACE/MOPP (Pray Pine, methotrexate (w/folic acid remedy), doxorubicin, cyclophosphamide, paclitaxel, etoposide/methyldichloroethylamine, vincristine, prednisone and procarbazine), Vincristine, vinblastine, angiostatin, TNP 470, pentosan polysulfate, platelet factor 4, angiostatin, LM 609, SU 101, CM 101, Techgalan, thalidomide ), SP-PG and the like.

The inventors have found that compositions comprising a compound of formula (I) and vincristine or paclitaxel are synergistic. Accordingly, the invention is also directed to a combination comprising a compound of formula (I) and vincristine or paclitaxel.

The invention further relates to pharmaceutical compositions comprising a compound of formula (I), vincristine or paclitaxel and a pharmaceutically acceptable carrier, diluent or excipient.

Further, the present invention is further directed to a kit comprising a pharmaceutical composition portion of a compound of the formula (I) and a pharmaceutical composition portion of vincristine or paclitaxel, wherein the composition is intended to be used simultaneously, in parallel, separately or sequentially. The kit may further comprise instructions for administering the compound of formula (I) and vincristine or paclitaxel to the individual.

The invention further relates to a method of treating cancer in an individual in need thereof, the method A method comprising administering to a subject a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of vincristine or paclitaxel. The cancer can be any cancer as described herein. The compound of formula (I) and vincristine or paclitaxel can be administered simultaneously, in parallel, separately or sequentially, as described above.

The invention further relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer, wherein the medicament is intended to be administered together with vincristine or paclitaxel. The cancer can be any of the cancers described herein. The compound of formula (I) and vincristine or paclitaxel can be administered simultaneously, in parallel, separately or sequentially, as described above.

The embodiments of the present invention will now be described in detail by reference to the accompanying examples, which are to

Example Example 1 - Synthesis of a compound Scheme 6. Preparation of Intermediate A.

Preparation of 1-(2,6-difluoro-4-nitrophenyl)-1 H -imidazole

A mixture of 1,2,3-trifluoro-5-nitrobenzene (45 g, 0.25 mol), imidazole (17.2 g, 0.25 mol) and triethylamine (35.6 mL, 0.25 mol) in acetonitrile (250 mL) Heat for 20 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, concentrated in vacuo and dried over Na ₂ SO _4, to yield 1- (2,6-difluoro-4-nitrophenyl) lH-imidazole (46g, 80%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05 (d, J = 10.0 Hz, 1.8 Hz, 2H), 7.85 (br s, 1H), 7.30-7.26 (m, 2H). LCMS: m/z 226.1 [M+H] ⁺ .

Preparation of 3,5-difluoro-4-(1 H -imidazol-1-yl)aniline

Add Fe powder to a solution of 1-(2,6-difluoro-4-nitrophenyl)-1H-imidazole (46 g, 0.20 mol) in ethanol:water (4: 1,500 mL) at room temperature ( 59 g, 1.1 mol) and NH ₄ Cl (16.2 g, 0.30 mol). The mixture was heated to 80 ° C for 5 hours. The reaction mixture was filtered through celite and evaporated. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sulfate and concentrated Na ₂ SO _4, to give crude product. The crude compound was purified by flash column chromatography to give 3,5-difluoro-4-(1H-imidazol-1-yl)aniline (38 g, 98%).

Preparation of intermediate A, 4-( 1H -imidazol-1-yl)-3,5-dimethoxyaniline

A solution of 3,5-difluoro-4-(1H-imidazol-1-yl)phenylamine (10 g, 51 mmol) and NaOMe (55.3 g, 1.02 mol) in methanol (100 mL) was heated to 120 ° C in a sealed tube. And keep it for 24 hours. After cooling, the reaction mixture was quenched with EtOAc EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give crude product. The crude compound was purified by flash column chromatography to afford 4-(1H-imidazol-1-yl)-3,5-dimethoxyaniline ( Intermediate A) (5.0 g, 44%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.39 (s, 1H), 6.93 (d, J = 17.6Hz, 2H), 5.97 (br s, 2H), 5.46 (br s, 2H), 3.61 ( s, 6H).

Scheme 7. Preparation of intermediates B, C and D.

Preparation of 4-bromo-3,5-dimethoxyaniline

To a solution of 3,5-dimethoxyaniline (10 g, 65 mmol) in dichloromethane (250 mL) was added EtOAc. The mixture was allowed to warm to room temperature and stirred for 5 hours. The mixture was poured into water and extracted with dichloromethane. The organic extracts were washed with water and brine, dried over anhydrous sulfate and concentrated Na ₂ SO _4, to give 4-bromo-3,5-dimethoxyaniline (3.2g, 21%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.97 (br s, 2H), 5.38 (br s, 2H), 3.73 (s, 6H). LCMS: m / z 232.0,234.0 [M + H] +.

Intermediate B,  Preparation of 3,5-dimethoxy-4-(pyridin-4-yl)aniline

Add Pd(PPh ₃ ) ₄ (5 mol%) and K ₃ PO _{4 to a} solution of 4-bromo-3,5-dimethoxyaniline (2.0 g, 8.6 mmol) in DMF (15 mL) at rt. (5.0 g, 24 mmol). The mixture was heated to 120 ° C for 16 hours. The reaction was concentrated, diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, the dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give solid 3,5-dimethoxy-4- (pyridin-4-yl) aniline (Intermediate B) (2.0 g, quantitative). LCMS: m/z 231.1 [M+H] ⁺ .

Other analogues prepared by this method:

Intermediate C, 2,6-dimethoxy-[1,1'-biphenyl]-4-amine (quantitative).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36-7.26 (m, 5H), 6.01 (s, 2H), 3.81-3.65 (m, 8H). LCMS: m/z 230.1 [M+H] ⁺ .

Intermediate D, 4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-amine (quantitative)

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.71-7.54 (m, 2H), 7.20-7.04 (m, 4H), 5.97 (s, 2H), 5.23 (br s, 2H), 3.58 (s, 6H). LCMS: m/z 248.1 [M+H] ⁺ .

Scheme 8. Preparation of Compounds 1-4

Preparation of 2,3-dimethyl-1 H -indole-5-formaldehyde

At -78 deg.] C solution of 5-bromo-2,3-dimethyl--1H- indole (5.6g, 25mmol) in dry THF (40mL) was added with stirring in the t -BuLi (50mL, 75mmol, 1.5M In THF). The resulting reaction mixture was stirred at the same temperature for 1 hour. Anhydrous DMF (5.0 mL, 65 mmol) was then added to the reaction mixture at -78. The mixture was stirred at this temperature for a further 2 hours. After the starting material was completely consumed, the reaction mass was quenched with a saturated aqueous solution of ammonium chloride at -40 ° C and extracted with ethyl acetate. The organic layer was washed with water and brine, the concentrated under reduced pressure and dried over anhydrous Na ₂ SO _4, to give a crude yellow solid -1H- indole-2,3-dimethyl-5-carbaldehyde (2.7 g, 62%) which was used in the next step without further purification. LCMS: m/z 174.1 [M+H] ⁺ .

Preparation of N '-((2,3-dimethyl-1 H -indol-5-yl)methylene)-4toluenesulfonate

Toluene sulfonate was added to a stirred solution of 2,3-dimethyl-1H-indole-5-carbaldehyde (2.7 g, 16 mmol) in anhydrous 1,4-dioxane (50 mL). 4.35g, 23.3 mmol). The temperature was increased to 80 ° C and maintained for 3 hours. The crude N '-((2,3-dimethyl-1H-indol-5-yl)methylene)-4-toluenesulfonate in the reaction mixture was used without isolation or purification.

Preparation of methyl 3-((2,3-dimethyl-1 H -indol-5-yl)methyl)benzoate

To a crude 2 N '-((2,3-dimethyl-1H-indol-5-yl)methylene)-4-toluenesulfonate cooled to 0 ° C in 1,4-dioxane K ₂ CO ₃ (3.2 g, 23 mmol) and (3-(methoxycarbonyl)phenyl) were added to the solution. Acid (4.2 g, 23 mmol). The reaction temperature was raised to 110 ° C and maintained for 5 hours. After the starting material was completely consumed, the reaction mixture was concentrated, diluted with water and ethyl acetate. The organic layer was washed with water and brine, the dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 5-10% ethyl acetate in petroleum ether as eluent to give 3-((2,3-dimethyl) as a brown oil. -1H-Indol-5-yl)methyl)benzoic acid methyl ester (2.4 g, 53%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.94 (br s, 1H), 7.85 (d, J = 7.6Hz, 1H), 7.63 (br s, 1H), 7.39 (d, J = 7.6Hz, 1H) , 7.31 (t, J = 7.6 Hz, 1H), 7.27 (br s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 4.11 ( s, 2H), 3.88 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H). LCMS: m/z 294.1 [M+H] ⁺ .

Preparation of 3-((1-(3-chloropropyl)-2,3-dimethyl-1 H -indol-5-yl)methyl)benzoic acid

Stirring solution of methyl 3-((2,3-dimethyl-1H-indol-5-yl)methyl)benzoate (2.4 g, 8.2 mmol) in DMF (20 mL) NaH (1.0 g, 42 mmol) was added portionwise. The mixture was stirred at this temperature for 30 minutes. 1-Bromo-3-chloropropane (1.6 mL, 16 mmol) was added dropwise to this mixture at 0 ° C and the mixture was stirred at room temperature for 3 hr. After the starting material was completely consumed, the reaction mixture was quenched with saturated aqueous ammonium chloride, diluted with ice cold water and then ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 15% ethyl acetate in petroleum ether as a solvent to give 3-((1-(3-chloropropyl)) as a brown liquid. -2,3-Dimethyl-1H-indol-5-yl)methyl)benzoic acid (1.8 g, crude). LCMS: m/z 356.0 [M+H] ⁺ .

Preparation of 3-((1-(3-chloropropyl)-2,3-dimethyl-1 H -indol-5-yl)methyl)benzoic acid methyl ester

3-((1-(3-Chloropropyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoic acid (1.8 g, 5.0 mmol) in methanol at 0 ° C Concentrated sulfuric acid (0.5 mL) was added to the solution in (20 mL). The mixture was heated to 80 ° C for 16 hours. After the starting material was completely consumed, the reaction mixture was concentrated and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ CH ₄ The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 5% ethyl acetate in petroleum ether as a solvent to give 3-((1-(3-chloropropyl) as a yellow liquid. -2,3-Dimethyl-1H-indol-5-yl)methyl)benzoic acid methyl ester (1.4 g, crude). LCMS: m/z 370.1 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl)benzoic acid Preparation of methyl ester

To 3-((1-(3-chloropropyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoic acid methyl ester (1.4 g, 3.8 mmol) at room temperature Sodium iodide (1.4 g, 9.3 mmol), sodium carbonate (1.2 g, 11 mmol) and then N -methylhexahydropyrazine (1.0 mL, 9.0 mmol) were added to a stirred solution of acetonitrile (15 mL). The reaction mixture was heated to 75 ° C for 16 hours. After the starting material was completely consumed, the reaction mixture was cooled to room temperature, concentrated under reduced pressure and diluted with ethyl acetate. The resulting solution was washed with water and saline solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on 50-200 mesh silica gel using 50% ethyl acetate in petroleum ether as eluent to give 3-((2,3-dimethyl-1) as a brown oil. -(3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid methyl ester (1.1 g, 67%). LCMS: m/z 434.3 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl)benzoic acid Preparation

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)) at 0 °C LiOH.H ₂ O (213 mg, 5.08 mmol) was added to a solution of methyl benzoate (1.1 g, 2.5 mmol) in THF:H ₂ O:MeOH (4:1:1, 36mL). The reaction mixture was stirred at room temperature for 16 hours. After the starting material was completely consumed, the reaction mass was concentrated, neutralized to pH about 7 and extracted with 30% isopropanol in chloroform. The organic layer was washed with water and a brine solution, then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 3-((2,3- dimethyl-1-(3-(4-methylhexahydro) Pyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid (798 mg, 76%). LCMS: m/z 420.3 [M+H] ⁺ .

N-(4-(1 H -imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1-(3-(4-methyl) Preparation of hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

To 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid (200 mg, 0.48 mmol) and a solution of Intermediate A (134 mg, 0.61 mmol. The mixture was stirred at room temperature for 10 minutes and then heated to 80 ° C for 2 hours. After the starting material was completely consumed, the reaction mass was concentrated, diluted with water and extracted with 30% isopropyl alcohol in chloroform. The organic layer was washed with water and brine, then dried and concentrated under reduced pressure to give N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-(( 2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (110 mg, 37%). LCMS: m/z 621.3 [M+H] ⁺ .

Other analogs prepared by this method: N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-() 3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (37%). LCMS: m/z 632.3 [M+ H] ⁺ .

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (44%). LCMS: m/z 631.3 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl) -N -(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (38%). LCMS: m/z 649.2 [M+H] ⁺ .

Compound 1 , N-(3,5-dihydroxy-4-(1 H -imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-) Preparation of hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

To N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1-(3-)() at 0 °C Stirring solution of 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (130 mg, 0.21 mmol) in dichloromethane (5 mL) Boron tribromide (1.0 mL, 1 M in DCM) was added. The mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform, washed with brine solution and dried over Na ₂ SO _4. The organic layer was concentrated under reduced pressure and the crude compound was purified by prep-HPLC, to give a brown solid N - (3,5- dihydroxy--4- (1H- imidazol-1-yl) phenyl) -3- ((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide ( Compound 1) (5 mg, 4%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.75 (br s, 1H), 7.71-7.68 (m, 2H), 7.46-7.38 (m, 2H), 7.29-7.24 (m, 2H), 7.14 (br) s, 1H), 7.07 (br s, 1H), 6.97-6.94 (m, 3H), 4.17 (t, J = 6.8 Hz, 2H), 4.13 (s, 2H), 2.71-2.40 (m, 8H), 2.39-2.32 (m, 5H), 2.19 (s, 3H), 2.15 (s, 3H), 1.95-1.79 (m, 2H). LCMS: m/z 593.3 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 2, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (18%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.46 (d, J = 4.8Hz, 2H), 7.75 (br s, 1H), 7.70 (br d, J = 7.2Hz, 1H), 7.53 (d, J = 4.8 Hz, 2H), 7.46 (br d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (br s, 1H), 7.26 (d, J = 8.4 Hz, 1H ), 6.96 (br d, J = 8.4 Hz, 1H), 6.89 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 4.13 (s, 2H), 3.07-2.35 (m, 16H), 2.20 (s, 3H), 1.92 (five peaks, J = 6.4 Hz, 2H). LCMS: m/z 604.3 [M+H] ⁺ .

Compound 3, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (16%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.74 (br s, 1H), 7.70 (brd, J = 6.8 Hz, 1H), 7.46-7.39 (m, 2H), 7.37-7.32 (m, 4H) , 7.28-7.23 (m, 3H), 6.96 (br d, J = 8.4 Hz, 1H), 6.84 (br s, 2H), 4.18-4.13 (m, 4H), 2.80-2.32 (m, 16H), 2.19 (s, 3H), 1.91 (five peaks, J = 6.8 Hz, 2H). LCMS: m/z 603.3 [M+H] ⁺ .

Compound 4, 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl) - N -(4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide (22%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.74 (br s, 1H), 7.70 (brd, J = 7.6 Hz, 1H), 7.64-7.30 (m, 6H), 7.29 (br s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 8.8 Hz, 2H), 6.96 (br d, J = 8.4 Hz, 1H), 6.84 (s, 2H), 4.17 (t, J = 6.8 Hz, 2H), 4.13 (s, 2H), 2.89-2.34 (m, 16H), 2.20 (s, 3H), 1.92 (five peaks, J = 7.2 Hz, 2H). LCMS: m/z 621.3 [M+H] ⁺ .

Scheme 9. Preparation of compound 5-8.

Preparation of 5-bromo-1-(3-chloro-2-methylpropyl)-2,3-dimethyl-1 H -indole

Add 5-bromo-2,3-dimethyl-1H-indole (5.0 g, 22 mmol) dropwise to a solution of NaH (2.8 g, 0.12 mol) in anhydrous DMF (50 mL) Solution in DMF (50 mL). The mixture was stirred for 30 minutes. To this mixture was added dropwise 1-bromo-3-chloro-2-methylpropane (11 g, 64 mmol) in anhydrous DMF (20 mL). The mixture was stirred at room temperature for 3 hours. After the starting material was completely consumed, the reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with ice cold water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford the crude compound. The crude product was purified by column chromatography on a 100-200 mesh silica gel using 2% ethyl acetate in petroleum ether as a solvent to give 5-bromo-1-(3-chloro-2-) as a yellow liquid. Methylpropyl)-2,3-dimethyl-1H-indole (6.8 g, crude). LCMS: m/z 314.0, 316.0 [M+H] ⁺ .

Preparation of 5-bromo-2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indole

Stirring to 5-bromo-1-(3-chloro-2-methylpropyl)-2,3-dimethyl-1H-indole (6.8 g, 22 mmol) in acetonitrile (50 mL) at rt. Sodium iodide (8.1 g, 54 mmol) and sodium carbonate (6.9 g, 65 mmol) were added to the solution, followed by N -methylhexahydropyrazine (5.4 g, 54 mmol). The reaction mixture was heated to 75 ° C for 16 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 5% methanol in dichloromethane as a solvent to give 5-bromo-2,3-dimethyl-1 as a yellow oil. (2-Methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole (1.4 g, 17%). LCMS: m/z 379.1, 381.1 [M+H] ⁺ .

Preparation of 2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indole-5-formaldehyde

5-Bromo-2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole at -78 °C (1.3 g, 3.4 mmol) n- BuLi (4.1 mL, 6.6 mmol, 1.6 M in THF). The resulting reaction mixture was stirred at this temperature for 15 minutes. Anhydrous DMF (1.5 mL) was then added to the reaction mixture at -78 °C. The mixture was stirred at this temperature for an additional hour. After the starting material was completely consumed, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, the dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 2% methanol in dichloromethane as a solvent to afford 2,3-dimethyl-1-(2-) 3-(4-Methylhexahydropyrazin-1-yl)propyl)-1 H -indole-5-carbaldehyde (890 mg, 80%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 9.87 (s, 1H), 7.88 (br s, 1H), 7.53 (dd, J = 8.4Hz, 1.6Hz, 1H), 7.19 (d, J = 8.4Hz, 1H), 4.18-4.12 (m, 1H), 3.67-3.61 (m, 1H), 2.30-2.05 (m, 20H), 0.74 (d, J = 6.4 Hz, 3H). LCMS: m/z 328.2 [M+H] ⁺ .

N' -((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) Preparation of methylene)-4-toluenesulfonate

To 2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5-carbaldehyde at room temperature ( To a stirred solution of 778 mg, 2.38 mmol, EtOAc (EtOAc m. The mixture was stirred at room temperature for 3 hours. Crude N '-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole in the reaction mixture -5-yl)methylene)-4-toluenesulfonate was used without isolation or further purification.

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl) Preparation of methyl benzoic acid methyl ester

To crude N' -((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- K ₂ CO ₃ (1.3 g, 9.4 mmol) and (3-(methoxycarbonyl)phenyl group were added to a solution of methylene)-4-toluenesulfonate in anhydrous 1,4-dioxane. ) Acid (642 mg, 3.6 mmol). The reaction temperature was raised to 110 ° C and maintained for 5 hours. After the starting material was completely consumed, the reaction mass was concentrated under reduced pressure to give a crude material. The crude compound was purified by column chromatography on 100-200 mesh silica eluting with 10% methanol in dichloromethane to afford 3-((2,3-dimethyl-1-) (2-Methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid methyl ester (300 mg, crude). LCMS: m/z 448.5 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl) Preparation of methyl)benzoic acid

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-) at 0 °C Addition of LiOH.H ₂ O (55 mg, 1.3 mmol) to a solution of 5-methyl)methyl)benzoic acid methyl ester (295 mg, 0.659 mmol) in THF:H ₂ O:MeOH (4:1:1, 12 mL) ). The reaction mixture was stirred at room temperature for 16 hours. After the starting material was completely consumed, the reaction mass was concentrated, neutralized to pH about 7 and extracted with 30% isopropanol in chloroform. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on 100-200 mesh silica gel using 10% methanol in dichloromethane as a solvent to give 3-((2,3-dimethyl-1-(2-) Methyl 3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid (148 mg, 52%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.78 (br s, 1H), 7.74 (br d, J = 7.6Hz, 1H), 7.51 (br d, J = 7.2Hz, 1H), 7.40 (t , J = 8.0 Hz, 1H), 7.27 (br s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 4.17-4.11 (m, 1H), 4.06 (s, 2H), 3.84-3.77 (m, 1H), 3.12-2.51 (m, 9H), 2.38-2.05 (m, 11H), 0.77 (d, J = 6.8 Hz, 3H). LCMS: m/z 434.07 [M+H] ⁺ .

N - (3, 5-Dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Preparation of methylhexahydropyrazin- 1-yl)propyl)-1 H -indol-5-yl)methyl)benzamide

To 4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid (300 mg, 0.69 mmol) and a solution of Intermediate B (200 mg, 0.87 mmol) in pyridine (4 mL). The mixture was stirred at 80 ° C for 3 hours. After the starting material was completely consumed, the reaction mass was concentrated, diluted with water and extracted with 30% isopropyl alcohol in chloroform. The organic layer was washed with water and brine, then dried and concentrated under reduced pressure to give crude. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 5-10% methanol in dichloromethane as a solvent to give a brown gum oily N- (3,5-dimethoxy). -4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)) Propyl)-1H-indol-5-yl)methyl)benzamide (300 mg, 67%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.31 (br s, 1H), 8.53 (d, J = 6.0Hz, 2H), 7.85 (br s, 1H), 7.81 (br d, J = 6.9Hz , 1H), 7.50-7.39 (m, 2H), 7.36 (s, 2H), 7.31-7.22 (m, 4H), 6.93 (dd, J = 8.1 Hz, 0.9 Hz, 1H), 4.17-4.05 (m, 7H), 3.82-3.77 (m, 1H), 3.69 (s, 6H), 2.49-2.08 (m, 16H), 0.73 (d, J = 6.3 Hz, 3H). LCMS: m/z 646.65 [M+H] ⁺ .

Other analogs prepared by this method: N -(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1) -(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (64%). LCMS: m/z 635.56 [M+H] ⁺ .

N- (2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-) 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (67%). LCMS: m/z 645.45 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) A N- (4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (69%). LCMS: m/z 663.67 [ M+H] ⁺ .

Compound 5, N-(3,5-dihydroxy-4-( 1H -imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3) Preparation of (4-methylhexahydropyrazine-l-yl)propyl)-1H -indol-5-yl)methyl)benzamide

To N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1-(2-)-A at 0 °C 3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (280 mg, 0.44 mmol) in dichloromethane (6 mL Boron tribromide (3.0 mL, 3.0 mmol, 1 M in DCM) was added to the stirred solution. The mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by prep-TLC using 2% methanol in dichloromethane to elute to give N-(3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl as an off white solid. -3((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) )methyl)benzamide (Compound 5) (14 mg, 5%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.13 (br s, 1H), 9.89 (br s, 2H), 7.80 (br s, 1H), 7.73 (br s, 7.2Hz, 1H), 7.53 ( Br s,1H), 7.45-7.38 (m, 2H), 7.28 (br s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.09 (br s, 1H), 7.02 (s, 2H), 6.95(br s,1H), 6.92 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 4.14 (dd, J = 14.8 Hz, 5.2 Hz, 1H), 4.08 (s, 2H), 3.78 (dd, J =14.8 Hz, 8.8 Hz, 1H), 2.43 - 2.12 (m, 20H), 0.72 (d, J = 6.4 Hz, 3H). LCMS : m/z 605.69 [MH] ^-

Other analogues prepared by this method:

Compound 6, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-)4 -Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (7%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.10 (br s, 1H), 9.53 (br s, 2H), 8.49 (d, J = 6.3Hz, 2H), 7.80 (br s, 1H), 7.73 (br d, J = 6.6 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.36 (d, J = 6.0 Hz, 2H), 7.28 (br s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.98 (s, 2H), 6.92 (dd, J = 8.7 Hz, 1.8 Hz, 1H), 4.14 (dd, J = 15.0 Hz, 4.8 Hz, 1H), 4.08 (s, 2H), 3.78 (dd , J = 15.3 Hz, 9.0 Hz, 1H), 2.41-2.12 (m, 20H), 0.72 (d, J = 6.3 Hz, 3H). LCMS: m/z 618.43 [M+H] ⁺ .

Compound 7, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-) (4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (5%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 7.80 (br s, 1H), 7.73 (br d, J = 6.6Hz, 1H), 7.44-7.17 (m, 9H), 6.95-6.89 (m, 3H ), 4.17-4.06 (m, 3H), 3.78 (dd, J = 14.7 Hz, 8.4 Hz, 1H), 2.37-2.09 (m, 20H), 0.73 (d, J = 6.0 Hz, 3H). LCMS: m/z 617.67 [M+H] ⁺ .

Compound 8, 3-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- yl) methyl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (22%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.76 (br s, 1H), 7.69 (brd, J = 7.6 Hz, 1H), 7.46-7.35 (m, 4H), 7.28 (br s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.95 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 6.84 (s, 2H), 4.18-4.06 ( m, 3H), 3.89-3.83 (m, 1H), 2.59-2.20 (m, 20H), 0.86 (d, J = 5.6 Hz, 3H). LCMS: m / z 635.56 [M + H] +.

Scheme 10. Preparation of Compounds 9-12 and 49-52

Preparation of methyl 4-((2,3-dimethyl-1 H -indol-5-yl)methyl)benzoate

To N -((2,3-dimethyl-1H-indol-5-yl)methylene)-4-toluenesulfonate (3.93 g, 11.5 mmol) at 1,4-2 at 80 °C K ₂ CO ₃ (1.7 g, 12 mmol) and (4-(methoxycarbonyl)phenyl) were added to the solution in methane (40 mL). Acid (2.07 g, 11.5 mmol). The reaction temperature was raised to 110 ° C and maintained for 4 hours. After the starting material was completely consumed, the reaction mixture was concentrated, diluted with water and ethyl acetate. The organic layer was washed with water and brine, the dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 20-25% ethyl acetate in petroleum ether eluting to afford 4-((2,3-dimethyl-1H-indole) as a brown solid. 5-Methyl)methyl)benzoic acid methyl ester (1.5 g, 45%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.55 (br s, 1H), 7.86 (d, J = 8.7Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.21 (br s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 4.05 (s, 2H), 3.82 (s, 3H), 2.27 (s, 3H) , 2.11 (s, 3H). LCMS: m/z 294.41 [M+H] ⁺ .

Preparation of 4-((1-(3-chloropropyl)-2,3-dimethyl-1 H -indol-5-yl)methyl)benzoic acid methyl ester

NaH (100 mg, 4.2 mmol) was added to dry DMF (5 mL). A solution of methyl 4-((2,3-dimethyl-1H-indol-5-yl)methyl)benzoate (240 mg, 0.81 mmol) in DMF (2 mL). The mixture was stirred at 0 ° C for 30 minutes. To this mixture was added dropwise bromochloropropane (0.16 mL, 1.6 mmol) in DMF (2 mL). The reaction mixture was stirred at this temperature for 3 hours. After the starting material was completely consumed, the reaction mixture was quenched with saturated aqueous ammonium chloride, diluted with ice cold water and then ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on 100-200 mesh silica gel using 3% ethyl acetate in petroleum ether to afford 4-((1-(3-chloropropyl)-2, Methyl 3-dimethyl-1H-indol-5-yl)methyl)benzoate (130 mg, crude).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.93 (d, J = 8.4Hz, 2H), 7.30-7.27 (m, 3H), 7.20 (d, J = 8.0Hz, 1H), 6.94 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 4.18 (s, 2H), 3.89 (s, 2H), 3.50 (t, J = 6.0 Hz, 2H), 2.35 (s) , 3H), 2.22-2.16 (m, 5H). LCMS: m/z 370.1 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid Preparation of base ester

To 4-((1-(3-chloropropyl)-2,3-dimethyl-1 H -indol-5-yl)methyl)benzoic acid methyl ester (130 mg, 0.35 mmol) at room temperature Sodium iodide (0.13 g, 0.87 mmol) and sodium carbonate (92 mg, 0.87 mmol) were added to a stirred solution of acetonitrile (3 mL), followed by N -methylhexahydropyrazine (88 mg, 0.88 mmol). The reaction mixture was heated to 85 ° C for 16 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a brown oil crude 4 ((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid methyl ester (180 mg, crude) which was used without further purification. LCMS: m/z 434.3 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl)benzoic acid Preparation

To 4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) A at room temperature yl) benzoic acid methyl ester (200mg, 0.46mmol) THF to: H ₂ O: was added _{LiOH.H 2 O (38mg, 0.91mmol)} 1,6mL) in the solution: 1: (4 MeOH. The reaction mixture was stirred for 16 hours. After the starting material was completely consumed, the reaction mass was concentrated, neutralized to pH about 7 and extracted with 30% isopropanol in chloroform. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a brown solid 4 - ((2,3-dimethyl-1- (3- (4-six Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid (160 mg, 83%). LCMS: m/z 420.3 [M+H] ⁺ .

Compound 49, N -(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(3-(4-) Preparation of methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide

To 4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) A at room temperature Ece. HCl (280 mg, 1.5 mmol) was added to a solution of benzoic acid (125 mg, 0.30 mmol) The mixture was stirred at 80 ° C for 1 hour. After the starting material was completely consumed, the reaction mass was diluted with ethyl acetate. The organic layer was washed with ammonium chloride solution, water and brine, then dried, concentrated and flash column chromatography by use of 4% methanol in dichloromethane eluted a purified liquid, to afford an off-white solid N - (4 -(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazine)- 1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (Compound 49) (125 mg, 68%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.86 (d, J = 8.4 Hz, 2H), 7.59 (br s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.30 (s, 2H) , 7.26 (br s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 10.0 Hz, 2H), 6.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 4.17- 4.11 (m, 4H), 3.79 (s, 6H), 2.58-2.28 (m, 16H), 2.19 (s, 3H), 1.95-1.87 (m, 2H). LCMS: m/z 621.3 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 50, N -(3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (37%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.46 (d, J = 6.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.40-7.36 (m, 4H), 7.26-7.22 (m) , 4H), 6.94 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 4.15-4.11 (m, 4H), 3.76 (s, 6H), 2.58-2.29 (m, 13H), 2.27 (s, 3H) , 2.19 (s, 3H), 1.95-1.87 (m, 2H). LCMS: m / z 630.4 [MH ] -.

Compound 51, N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (84%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.87 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.33-7.20 (m, 8H), 7.18 (s, 2H) ), 6.95 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 4.17 (t, J = 6.8 Hz, 2H), 4.13 (s, 2H), 3.71 (s, 6H), 2.94 - 2.48 (11H), 2.40-2.35 (m, 5H), 2.20 (s, 3H), 1.98-1.89 (m, 2H). LCMS: m/z 631.4 [M+H] ⁺ .

Compound 52, 4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl ) - N - (4'- fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (64%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.86 (d, J = 8.4Hz, 2H), 7.39 (d, J = 8.0Hz, 2H), 7.27-7.22 (m, 4H), 7.18 (s, 2H ), 7.04 (t, J = 8.8 Hz, 2H), 6.95 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 4.17 (t, J = 6.8 Hz, 2H), 4.13 (s, 2H), 3.72 ( s, 6H), 2.94-2.47 (m, 11H), 2.41-2.35 (m, 5H), 2.20 (s, 3H), 1.92 (five-peak, J = 6.8 Hz, 2H). LCMS: m/z 649.3 [M+H] ⁺ .

Compound 11, N-(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methyl) Preparation of hexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl)benzamide

To a stirred solution of compound 51 (80 mg, 0.13 mmol) in dichloromethane (5 mL)EtOAc. The mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by prep-TLC using 5% methanol in dichloromethane as a solvent to give N- (2,6-dihydroxy-[1,1'-biphenyl]-4- 4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl) Benzamide (Compound 11) (18 mg, 23%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.81 (d, J = 8.4 Hz, 2H), 7.36-7.32 (m, 6H), 7.27-7.22 (m, 3H), 6.94 (dd, J = 8.4 Hz , 1.6 Hz, 1H), 6.86 (s, 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.12 (s, 2H), 2.62-2.39 (m, 8H), 2.35-2.30 (m, 8H) , 2.19 (s, 3H), 1.90 (five peaks, J = 7.2 Hz, 2H). LCMS: m/z 603.3 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 9, N -(3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (4%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.80 (d, J = 8.4 Hz, 2H), 7.65 (br s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.25-7.22 (m, 2H), 7.13 (br s, 1H), 7.05 (br s, 1H), 6.96 (s, 2H), 6.93 (br d, J = 10.0 Hz, 1H), 4.15 - 4.10 (m, 4H), 2.69- 2.40 (m, 8H), 2.35 (s, 3H), 2.33-2.29 (m, 5H), 2.19 (s, 3H), 1.95-1.85 (m, 2H). LCMS: m/z 593.2 [M+H] ⁺ .

Compound 10, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (1%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.45 (d, J = 6.0Hz, 2H), 7.80 (d, J = 8.0Hz, 2H), 7.53 (d, J = 6.0Hz, 2H), 7.36 ( d, J = 8.4 Hz, 2H), 7.25 (br s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.93 (br d, J = 8.4 Hz, 1H), 6.90 (s, 2H), 4.20-4.11 (m, 4H), 2.85-2.28 (m, 16H), 2.19 (s, 3H), 1.97-1.85 (m, 2H). LCMS: m/z 604.3 [M+H] ⁺ .

Compound 12, 4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl) - N -(4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide (23%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.96 (br s, 1H), 9.20 (br s, 2H), 7.82 (d, J = 8.0Hz, 2H), 7.39-7.31 (m, 4H), 7.28-7.25 (m, 2H), 7.12 (t, J = 8.8 Hz, 2H), 6.93-6.90 (m, 3H), 4.08-4.04 (m, 4H), 2.38-2.14 (m, 19H), 1.78- 1.71 (m, 2H). LCMS: m/z 621.3 [M+H] ⁺ .

Scheme 11. Preparation of Compounds 14-16 and 53-56

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl) Preparation of methyl benzoic acid methyl ester

To 2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5-carbaldehyde at room temperature ( To a stirred solution of 2.7 g, 8.2 mmol, EtOAc (EtOAc m. The mixture was stirred at room temperature for 3 hours. To this solution was added K ₂ CO ₃ (4.5 g, 33 mmol) and (4-(methoxycarbonyl)phenyl) Acid (2.2 g, 12 mmol). The reaction temperature was raised to 110 ° C and maintained for 5 hours. After the starting material was completely consumed, the reaction mass was concentrated under reduced pressure to give a crude material. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 10% methanol in dichloromethane to afford 4-((2,3- dimethyl-1-(2-) 3- (4-methyl-piperazine-1-yl) propyl) -1 H - indol-5-yl) methyl) benzoic acid methyl ester (1.4g, 38%). LCMS: m/z 448.5 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl) Preparation of methyl)benzoic acid

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole- at 0 °C 5- yl) methyl) benzoic acid methyl ester (1.4g, 3.1mmol) in _{THF: H 2 O: 1:} : (4 MeOH 1,12mL) of the 2N NaOH solution was added (4mL). The reaction mixture was stirred at room temperature for 16 hours. After the starting material was completely consumed, the reaction mass was concentrated, neutralized to pH about 7 and extracted with 30% isopropanol in chloroform. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 10% methanol in methylene chloride as eluent to afford 4-((2,3-dimethyl-1-) (2-Methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzoic acid (1.0 g, 74%). LCMS: m/z 434.42 [M+H] ⁺ .

Compound 53, N -(4-(1 H -imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-methyl) Preparation of amines of -3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)methyl)benzamide

To 4-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) EDC.HCl (660 mg, 3.4 mmol) was added to a solution of EtOAc (EtOAc, EtOAc, EtOAc. The mixture was stirred at room temperature for 10 minutes, then heated to 80 ° C and stirred for 3 hours. After the starting material was completely consumed, the reaction mass was concentrated, diluted with water and extracted with 30% isopropyl alcohol in chloroform. The organic layer was washed with water and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 5-10% methanol in methylene chloride as eluent to afford N- (4-(1H-imidazole-1-) -3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)) )propyl)-1H-indol-5-yl)methyl)benzamide (Compound 53) (200 mg, 55%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.29 (br s, 1H), 7.90 (d, J = 8.4Hz, 2H), 7.54 (br s, 1H), 7.43-7.38 (m, 4H), 7.28(br, s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.09 (br s, 1H), 6.98 (br s, 1H), 6.92 (dd, J = 8.4 Hz, 1.6 Hz, 1H) ), 4.14 (dd, J = 15.2 Hz, 4.8 Hz, 1H), 4.08 (s, 2H), 3.82-3.76 (m, 1H), 3.72 (s, 6H), 2.49-2.11 (m, 20H), 0.73 (d, J = 6.4 Hz, 3H). LCMS: m/z 633.21.[M+H] ⁺ .

Other analogues prepared by this method:

Compound 54, N -(3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-) (4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (19%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.34 (br s, 1H), 8.53 (d, J = 5.4Hz, 2H), 7.90 (d, J = 8.4Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.36 (s, 2H), 7.28-7.22 (m, 4H), 6.92 (br d, J = 7.5 Hz, 1H), 4.14 (dd, J = 14.7 Hz, 6.4 Hz, 1H) , 4.08(s, 2H), 3.79 (dd, J = 14.7 Hz, 8.4 Hz, 1H), 3.69 (s, 6H), 2.49-2.14 (m, 20H), 0.73 (d, J = 6.3 Hz, 3H) . LCMS: m/z 644.76 [M+H] ⁺ .

Compound 55, N -(2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-)- 3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (21%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.19 (br s, 1H), 7.89 (d, J = 8.1Hz, 2H), 7.41 (d, J = 8.1Hz, 2H), 7.39-7.19 (m , 9H), 6.93 (br d, J = 8.7 Hz, 1H), 4.14 (dd, J = 14.4 Hz, 4.2 Hz, 1H), 4.08 (s, 2H), 3.79 (dd, J = 14.7 Hz, 8.7 Hz , 1H), 3.65 (s, 6H), 2.49-2.12 (m, 20H), 0.73 (d, J = 6.3 Hz, 3H). LCMS: m/z 645.64 [M+H] ⁺ .

Compound 56, 4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indole-5 - yl) methyl) - N - (4'- fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (47%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.19 (br s, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.41 (d, J = 8.7Hz, 2H), 7.32 (s, 2H ), 7.30-7.22 (m, 6H), 7.16 (t, J = 9.3 Hz, 2H), 6.92 (br d, J = 8.4 Hz, 1H), 4.14 (dd, J = 15.0 Hz, 4.8 Hz, 1H) , 4.08(s, 2H), 3.79 (dd, J = 14.7 Hz, 8.7 Hz, 1H), 3.66 (s, 6H), 2.49-2.12 (m, 20H), 0.73 (d, J = 6.3 Hz, 3H) . LCMS: m/z 663.60 [M+H] ⁺ .

Compound 14 , N-(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-)4 Preparation of -methylhexahydropyrazin- 1-yl)propyl)-1 H -indol-5-yl)methyl)benzamide

To a stirred solution of compound 54 (50 mg, EtOAc) (EtOAc)EtOAc. The mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was washed with water and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by prep-TLC using 5% methanol in dichloromethane to elute to give N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl) as an off white solid. -4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) Methyl)benzamide (Compound 14) (17 mg, 35%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.03 (br s, 1H), 9.48 (br s, 2H), 8.48 (d, J = 6.0Hz, 2H), 7.83 (d, J = 8.1Hz, 2H), 7.40-7.34 (m, 4H), 7.27 (br s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.98 (s, 2H), 6.91 (br d, J = 8.1 Hz, 1H) ), 4.14 (dd, J = 14.4 Hz, 4.8 Hz, 1H), 4.07 (s, 2H), 3.79 (dd, J = 13.8 Hz, 8.7 Hz, 1H), 2.49-2.05 (m, 20H), 0.73 ( d, J = 6.3 Hz, 3H). LCMS: m/z 618.46 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 15, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-) (4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)methyl)benzamide (43%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.96 (br s, 1H), 9.13 (br s, 2H), 7.83 (d, J = 8.1Hz, 2H), 7.38 (d, J = 8.1Hz, 2H), 7.33-7.20 (m, 7H), 6.94-6.89 (m, 3H), 4.18-4.04 (m, 3H), 3.83-3.74 (m, 1H), 2.42-2.07 (m, 20H), 0.73 ( d, J = 6.0 Hz, 3H). LCMS: m/z 617.44 [M+H] ⁺ .

Compound 16, 4-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- yl) methyl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (17%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.96 (br s, 1H), 9.21 (br s, 2H), 7.82 (d, J = 8.1Hz, 2H), 7.38 (d, J = 8.4Hz, 2H), 7.33 (dd, J = 8.7 Hz, 5.7 Hz, 2H), 7.27 (br s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 8.7 Hz, 2H), 6.94-6.89 (m, 3H), 4.14 (dd, J = 14.7 Hz, 4.5 Hz, 1H), 4.06 (s, 2H), 3.78 (s, J = 14.7 Hz, 9.0 Hz, 1H), 2.45-2.07 ( m, 20H), 0.72 (d, J = 6.0 Hz, 3H). LCMS: m/z 636.40 [M+H] ⁺ .

Scheme 12. Preparation of Compound 17-20.

Preparation of 5-methoxy-2,3-dimethyl-1H-indole

2-butanone (19.3 mL, 0.215 mol) was added to a stirred solution of 4-methoxyindole hydrochloride (25.0 g, 0.143 mol) in acetic acid (250 mL), followed by heating at 130 ° C for 3 hours. After the starting material was completely consumed, the reaction mixture was quenched with water and stirred at room temperature for 30 min. The resulting precipitate was collected by filtration and dried for 1 hour to give 5-methoxy-2,3-dimethyl- 1H -indole (22 g, 88%) as a brown solid. LCMS: m/z 176.1 [M+H] ⁺ .

Preparation of 2,3-dimethyl-1 H -indole-5-ol

Add BBr ₃ (142 mL, 1.0 M) to a stirred solution of 5-methoxy-2,3-dimethyl-1H-indole (10.0 g, 57.1 mmol) in dichloromethane (200 mL). In DCM). The temperature was maintained at 0 ° C to 5 ° C for 3 hours. After complete consumption of the starting material, the reaction mixture, followed by extraction with dichloromethane and basified with saturated NaHCO _3. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 10% ethyl acetate in petroleum ether eluting to afford 2,3-dimethyl-1H-indole-5-ol as a brown solid (8.2 g) , 89%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.26 (s, 1H), 8.44 (s, 1H), 6.98 (d, J = 8.4Hz, 1H), 6.64 (d, J = 2.4Hz, 1H) , 6.47 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 2.24 (s, 3H), 2.05 (s, 3H). LCMS: m/z 162.2 [M+H] ⁺ .

Preparation of 3-hydroxy-2,3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

To a stirred solution of 2,3-dimethyl-1H-indol-5-ol (8.2 g, 51 mmol) in acetonitrile (80 mL) was added Boc-anhydride (32.9 g, 151 mmol) and DMAP ( 0.61 g, 5.0 mmol). The reaction was stirred at room temperature for 16 hours. After the starting material was completely consumed, acetonitrile was concentrated under reduced pressure. The residue was redissolved in methanol (200mL), add _{K 2 CO 3 (20.7g, 150mmol} ) and the resulting mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 13% ethyl acetate in petroleum ether as eluent to give 5-hydroxy-2,3-dimethyl-1H as a yellow solid. - 吲哚-1-carboxylic acid tert-butyl ester (11.2 g, 84%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.93 (d, J = 8.8Hz, 1H), 6.83 (d, J = 2.4Hz, 1H), 6.73 (dd, J = 8.8Hz, 2.8Hz, 1H), 4.77 (s, 1H), 2.50 (s, 3H), 2.12 (s, 3H), 1.66 (br s, 9H). LCMS: m/z 2621. [M+H] ⁺ .

Preparation of 3-(3-(methoxycarbonyl)phenoxy)-2,3-dimethyl-1 H -indole-1-carboxylic acid tert-butyl ester

Add 3-(methoxy) to a stirred solution of 5-hydroxy-2,3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (5.0 g, 19 mmol) in dichloromethane (150 mL) Carboxyl)phenyl) Acid (10.3 g, 57.2 mmol). Cu(OAc) ₂ (8.7 g, 48 mmol) was then added followed by triethylamine (13.3 mL, 95 mmol) and the system was then evaporated with &lt The entire reaction mass was stirred for an additional 16 hours under an oxygen atmosphere. After the starting material was completely consumed, the reaction mass was filtered through a bed of diatomaceous earth. The filtrate was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on 100-200 mesh silica gel using 3% ethyl acetate in petroleum ether as a solvent to give 5-(3-(methoxycarbonyl) as a brown liquid. Phenoxy)-2,3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (3.5 g, 46%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.08 (d, J = 8.8Hz, 1H), 7.22 (dt, J = 7.6Hz, 1.2Hz, 1H), 7.60 (dd, J = 2.4Hz, 1.6Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.19-7.15 (m, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 8.8 Hz, 1.6 Hz, 1H) , 3.87 (s, 3H), 2.53 (s, 3H), 2.13 (s, 3H), 1.68 (s, 9H). LCMS: m/z 396.1 [M+H] ⁺ .

Preparation of 3-((2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid methyl ester

To a solution of 5-(3-(methoxycarbonyl)phenoxy)-2,3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (3.5 g, 20.8 mmol) at 0 ° C To a stirred solution of dichloromethane (10 mL) was added 1,4-dioxane hydrochloride (25 mL, 4.0 M dichloromethane). The mixture was warmed to room temperature and stirred for 20 hours. After complete consumption of the starting material, reaction mixture was concentrated in vacuo, basified with aqueous NaHCO ₃ to pH 10 and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a brown liquid 3 - ((2,3-dimethyl--1H- indol-5-yl) oxy) methyl-benzoic acid Ester (2.5 g, 96%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.75 (br s, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.60 (t, J = 2.4Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.17-7.13 (m, 2H), 6.84 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 3.86 (s, 3H), 2.38 ( s, 3H), 2.17 (s, 3H). LCMS: m/z 296.1 [M+H] ⁺ .

Preparation of 3-((1-(3-chloropropyl)-2,3-dimethyl-1 H -indol-5-yl)oxy)benzoic acid methyl ester

3-((2,3-Dimethyl-1H-indol-5-yl)oxyl was added dropwise to a stirred suspension of NaH (1.17 g, 49 mmol) in anhydrous DMF (10 mL). A solution of methyl benzoate (2.4 g, 8.1 mmol) in DMF (10 mL). The mixture was allowed to warm to room temperature and held for 30 minutes. To this mixture was added dropwise bromochloropropane (1.6 mL, 16 mmol) at 0 °C. The mixture was stirred for 2 hours. After the starting material was completely consumed, ice-cold water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with chilled aqueous ammonium chloride solution and salt, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using 4% ethyl acetate in petroleum ether eluting to afford 3-((1-(3-chloropropyl)-2, 3- Methyl-1H-indol-5-yl)oxy)benzoic acid methyl ester (600 mg, 20%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.69 (dt, J = 7.6Hz, 1.2Hz, 1H), 7.60 (t, J = 2.0Hz, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.26-7.18 (m, 1H), 7.17-7.14 (m, 2H), 6.87 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 4.26 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H) ), 3.55 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.25-2.19 (m, 5H). LCMS: m/z 3721. [M+H] ⁺ .

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzoic acid Preparation of methyl ester

3-((1-(3-Chloropropyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid methyl ester (600 mg, 1.6 mmol) at room temperature Sodium iodide (600 mg, 4.0 mmol) and sodium carbonate (420 mg, 3.9 mmol) were added to a stirred solution of acetonitrile (10 mL), and then N -methylhexahydropyrazine (400 mg, 4.0 mmol) was added. The reaction mixture was heated to 85 ° C for 16 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 5% methanol in dichloromethane as a solvent to afford 3-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzoic acid methyl ester (380 mg, 44%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.68 (dt, J = 7.6Hz, 1.2Hz, 1H), 7.59 (t, J = 2.4Hz, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.26-7.18(m,1H), 7.17-7.14(m,2H), 6.85 (dd, J =8.8Hz, 2.4Hz, 1H), 4.13(t, J =7.2Hz, 2H), 3.86(s,3H) ), 2.75-2.39 (m, 8H), 2.38-2.20 (m, 8H), 2.17 (s, 3H), 1.95-1.88 (m, 2H). LCMS: m/z 436.3 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy) benzoic acid Preparation

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy) at room temperature yl) benzoic acid methyl ester (380mg, 0.87mmol) in _{THF: H 2 O: 1:} : (4 MeOH 1,10mL) was added in the _{LiOH.H 2 O (360mg, 8.6mmol)} . The reaction mixture was stirred for 16 hours. After the starting material was completely consumed, the reaction material was concentrated, cooled to 0 ° C, acidified to pH 2 with 1 N HCl and extracted with 30% isopropyl alcohol in chloroform. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to give the crude product. The crude compound was purified by trituration with n-pentane to give 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl) as a brown solid. Base-1-1 H -indol-5-yl)oxy)benzoic acid (320 mg, 87%). LCMS: m/z 4221. [M+H] ⁺ .

N-(3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Preparation of pyrazin- 1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzoic acid (97 mg, 0.23 mmol) and Intermediate B (69 mg, 0.30 mmol. The mixture was stirred at room temperature for 10 minutes, then heated to 80 ° C for 1 hour. After the starting material was completely consumed, the reaction mass was concentrated, cooled to 0 ° C, diluted with water and extracted with 30% isopropyl alcohol in chloroform. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using ethyl acetate and 5% methanol in dichloromethane as a solvent to give N- (3,5-dimethoxy) as a brown solid. 4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-) 1H-Indol-5-yl)oxy)benzamide (50 mg, 34%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.32 (br s, 1H), 8.53 (dd, J = 8.4 Hz, 1.6 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.51 7.42 (m, 3H), 7.34 (s, 2H), 7.25 (dd, J = 8.4 Hz, 1.6 Hz, 2H), 7.15-7.12 (m, 2H), 6.83 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.68 (s, 6H), 2.46-2.15 (m, 19H), 1.80 (five-peak, J = 6.8 Hz, 2H). LCMS: m/z 634.3 [M+H] ⁺ .

Other analogs prepared by this method: N -(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1) -(3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (41%). LCMS: m/z 623.3 [ M+H] ⁺ .

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide (66%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.27 (br s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.51-7.43 (m, 3H), 7.35-7.30 (m, 4H) , 7.26-7.12 (m, 5H), 6.83 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 4.14 (br s, 2H), 3.64 (s, 6H), 2.46-2.14 (m, 19H), 1.81 (br s, 2H).

3-((2,3 Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy) -N - (4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (35%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.27 (br s, 1H), 7.68 (d, J = 7.6Hz, 1H), 7.51-7.43 (m, 3H), 7.25-7.21 (m, 2H) , 7.17-7.12 (m, 4H), 6.84 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.65 (s, 6H), 2.81-2.24 (m, 16H), 2.15 (s, 3H), 1.88-1.77 (m, 2H). LCMS: m/z 651.3 [M+H] ⁺ .

Compound 19, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methyl) Preparation of hexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-)() at 0 °C Stirring of 4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide (110 mg, 0.17 mmol) in dichloromethane (2 mL) Boron tribromide (0.50 mL, 5.3 mmol) was added to the solution. The mixture was stirred at this temperature for 10 minutes, then warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by prep-TLC using 2.5% methanol in dichloromethane as a solvent to give N- (2,6-dihydroxy-[1,1'-biphenyl]-4- 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy) Benzoguanamine (Compound 19) (20 mg, 19%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.54 (d, J = 7.6Hz, 1H), 7.45-7.34 (m, 7H), 7.28-7.23 (m, 1H), 7.16-7.12 (m, 2H) , 6.85 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.81 (s, 2H), 4.24 (t, J = 6.8 Hz, 2H), 3.21-2.32 (m, 16H), 2.19 (s, 3H) , 1.97 (five peaks, J = 6.8 Hz, 2H). LCMS: m/z 605.3 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 17, N -(3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (5%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.64 (br s, 1H), 7.54 (br d, J = 8.0Hz, 1H), 7.45-7.39 (m, 2H), 7.36 (d, J = 8.4Hz , 1H), 7.14-7.10 (m, 3H), 7.05 (br s, 1H), 6.87 (s, 2H), 6.84 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 4.19 (t, J = 6.8 Hz, 2H), 2.75-2.41 (m, 8H), 2.38 (s, 3H), 2.34-2.30 (m, 5H), 2.19 (s, 3H), 1.97-1.86 (m, 2H). LCMS: m/z 595.3 [M+H] ⁺ .

Compound 18, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (21%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.45 (d, J = 5.6Hz, 2H), 7.56-7.50 (m, 3H), 7.44-7.39 (m, 2H), 7.36 (d, J = 8.8Hz , 1H), 7.13-7.10 (m, 2H), 6.87 (s, 2H), 6.83 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 4.20 (t, J = 6.8 Hz, 2H), 2.74-2.41 (m, 8H), 2.38 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 1.94 (five peaks, J = 7.2 Hz, 2H). LCMS: m/z 606.3 [M+H] ⁺ .

Compound 20, 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy ) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine (12%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.53 (d, J = 8.0Hz, 1H), 7.45-7.33 (m, 5H), 7.13-7.09 (m, 2H), 7.06 (t, J = 8.8Hz , 2H), 6.85-6.82 (m, 3H), 4.20 (t, J = 6.8 Hz, 2H), 2.98-2.40 (m, 8H), 2.38 (s, 3H), 2.36-2.31 (m, 5H), 2.19 (s, 3H), 1.94 (five peaks, J = 6.8 Hz, 2H). LCMS: m/z 623.3 [M+H] ⁺ .

Scheme 13. Preparation of Compound 22-24

Preparation of 5-methoxy-2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indole

Add 5-methoxy-2,3-dimethyl-1H-indole (15 g) to a stirred suspension of NaH (6.1 g, 265 mmol) in DMF (50 mL). , 86 mmol) in DMF (50 mL). The mixture was stirred for 30 minutes. To this mixture was added dropwise 1-bromo-3-chloro-2-methylpropane (20 mL, 171 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 hours. After the starting material was completely consumed, ice-cold water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with chilled solution of ammonium chloride, then brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using petroleum ether as a solvent to give 5-bromo-1-(3-chloro-2-methylpropyl)-2 as a yellow liquid. , 3-dimethyl-1H-indole (6 g, crude).

Sodium iodide (8.45 g, 56.4 mmol), sodium carbonate (5.97 g, 56.3 mmol), and subsequently N -methyl-6 were added to a stirred solution of the crude intermediate (6 g) in acetonitrile (100 mL). Hydropyrazine (5.65 g, 56.4 mmol). The reaction mixture was heated to 85 ° C for 12 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 4% methanol in dichloromethane as a solvent to give 5-methoxy-2,3-dimethyl- as a yellow liquid. 1-(2-Methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole (1.75 g, 6%). LCMS: m/z 330.30 [M+H] ⁺ .

Preparation of 2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indole-5-ol

5-methoxy-2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H- at -78 °C Boron tribromide (18.6 mL, 18.6 mmol, 1 M in DCM) was added to a stirred solution of EtOAc (EtOAc). The mixture was stirred at this temperature for 2 hours, then slowly warmed to room temperature and stirred for additional 2 hours. The reaction mixture was quenched with ice cold saturated NaHCO ₃ solution, followed by extraction with ethyl acetate. The organic layer was washed with chilled saline solution, and dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 6% methanol in methylene chloride as a solvent to afford 2,3-dimethyl-1-(2-) 3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5-ol (2.1 g, 53%). LCMS: m/z 316.29 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy Preparation of benzonitrile

At 0 ℃ was added dropwise 2,3-dimethyl-1 in the N ₂ atmosphere NaH (130mg, 5.4mmol) in DMF (5mL) in a stirred solution of (2-methyl-3- (4 A solution of -methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-ol (1.00 g, 3.17 mmol) in DMF (5 mL). 3-Chlorobenzonitrile (77 mg, 0.48 mmol) was added at 0 °C. The mixture was heated to 100 ° C and stirred at this temperature for 12 hours. After the starting material was completely consumed, the reaction mass was cooled to 0 ° C, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 3% methanol in methylene chloride as eluent to give 3-((2,3-dimethyl-1) as a brown gum solid. - (2-methyl-3- (4-methyl-piperazine-1-yl) propyl) -1 H - indol-5-yl) oxy) benzonitrile (850mg, 65%). LCMS: m/z 417.33 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl) Preparation of oxy)benzoic acid

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-) at 0 °C A solution of 5-N-oxy)benzonitrile (900 mg, 2.1 mmol) in EtOAc (15 mL) was evaporated. The reaction mixture was heated to 100 ° C for 12 hours. After the starting material was completely consumed, the reaction mass was concentrated and acidified with 6N HCl. The residue was extracted with 30% of isopropanol in chloroform, dried Na ₂ SO ₄ and concentrated under reduced pressure, dried over anhydrous, to afford an off-white solid 3 - ((2,3-dimethyl-1- (2- Methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzoic acid (800 mg, 85%). LCMS: m/z 436.38 [M+H] ⁺ .

N - (3, 5-Dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Preparation of methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To 3-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) EDC.HCl (527 mg, 2.75 mmol) was added to a solution of EtOAc (EtOAc, EtOAc, EtOAc. The mixture was stirred at room temperature for 10 minutes, then heated to 100 ° C for 2 hours. After the starting material was completely consumed, the reaction mixture was concentrated, diluted with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 3% methanol in methylene chloride as a solvent to afford N- (3,5-dimethoxy-4- (pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl) -1H-Indol-5-yl)oxy)benzamide (200 mg, 68%). LCMS: m/z 647.33 [MH] ^- .

Other analogs prepared by this method: N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1) -(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (68%). LCMS: m/z 647.47 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy -N-(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (66%). LCMS: m/z 665.41 [ M+H] ⁺ .

Compound 23, N-(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-) Preparation of (4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-)-A at 0 °C 3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (200 mg, 0.31 mmol) in dichloromethane (6 mL Boron tribromide (2.0 mL, 2.0 mmol, 1.0 M in DCM) was added to the stirred solution. The mixture was stirred at this temperature for 10 minutes, then warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford crude. The crude compound was purified by prep-TLC using 5% methanol in dichloromethane as a solvent to afford N- (2,6-dihydroxy-[1,1'-biphenyl]-4- Benzyl-3-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- Benzyloxy)benzamide (Compound 23) (40 mg, 21%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.06 (br s, 1H), 9.14 (br s, 2H), 7.60 (d, J = 8.0Hz, 1H), 7.45-7.43 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.30-7.28 (m, 4H), 7.25-7.17 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.0 Hz) , 2.0 Hz, 1H), 6.92 (s, 2H), 6.82 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 4.18 (dd, J = 14.8 Hz, 4.8 Hz, 1H), 3.86 (dd, J = 14.4 Hz, 8.8 Hz, 1H), 2.52-2.08 (m, 20H), 0.78 (d, J = 6.4 Hz, 3H). LCMS: m/z 619.45 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 22, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-)4 -methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (7%)

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.12 (br s, 1H), 9.55 (br s, 2H), 8.49 (d, J = 6.0Hz, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.47-7.34 (m, 5H), 7.12 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.97 (s, 2H), 6.82 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 4.18 (dd, J = 14.8 Hz, 4.4 Hz, 1H), 3.95 (dd, J = 14.4 Hz, 8.4 Hz, 1H), 2.52-2.14 (m, 20H), 0.78 (d, J = 6.4 Hz, 3H). LCMS: m/z 620.39 [M+H] ⁺ .

Compound 24, 3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- yl) oxy) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (31%)

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.07 (br s, 1H), 9.22 (br s, 2H), 7.60 (d, J = 8.0Hz, 1H), 7.46-7.42 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.34-7.30 (m, 2H), 7.15-7.10 (m, 3H), 7.07 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.93 (s, 2H) ), 6.82 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 4.19 (dd, J = 14.4 Hz, 4.4 Hz, 1H), 3.95 (dd, J = 14.4 Hz, 8.4 Hz, 1H), 2.52-2.09 (m, 20H), 0.78 (d, J = 5.6 Hz, 3H). LCMS: m/z 637. 46 [M+H] ⁺ .

Scheme 14. Preparation of Compounds 26-28

Preparation of 3-(4-(methoxycarbonyl)phenoxy)-2,3-dimethyl-1 H -indole-1-carboxylic acid tert-butyl ester

Add 4-(methoxy) to a stirred solution of 5-hydroxy-2,3-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (6.0 g, 23 mmol) in dichloromethane (300 mL) Carboxyl)phenyl) Acid (12.4 g, 68.9 mmol). Cu(OAc) ₂ (10.4 g, 57.3 mmol) was then added followed by triethylamine (9.6 mL, 69 mmol) and the system was then evaporated with EtOAc. The entire reaction mass was stirred under an oxygen atmosphere for a total of 16 hours. After the starting material was completely consumed, the reaction mass was filtered through a bed of diatomaceous earth. The filtrate was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 10% ethyl acetate in petroleum ether as eluent to give 5-(4-(methoxycarbonyl)phenoxy 2,3-Dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (6.0 g, 66%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.10 (d, J = 8.8Hz, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.11 (d, J = 2.0Hz, 1H), 6.97-6.93 (m, 3H), 3.89 (s, 3H), 2.53 (s, 3H), 2.14 (s, 3H), 1.68 (s, 9H). LCMS: m/z 396.1 [M+H] ⁺ .

Preparation of 4-((2,3-dimethyl-1 H -indol-5-yl)oxy)benzoic acid methyl ester

To a solution of 5-(4-(methoxycarbonyl)phenoxy)-2,3-dimethyl-1 H -indole-1-carboxylic acid tert-butyl ester (6.0 g, 15 mmol) at 0 ° C 1,4-Dioxane hydrochloride (25 mL, 4.0 M in DCM) was added dropwise to a stirred solution in dichloromethane (100 mL). The mixture was warmed to room temperature and stirred for 20 hours. The reaction mixture was concentrated in vacuo, basified with aqueous NaHCO ₃ to pH 10 and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford an off-white solid 4 - ((2,3-dimethyl--1H- indol-5-yl) oxy) methyl-benzoic acid Ester (4.2 g, 94%). LCMS: m/z 296.1 [M+H] ⁺ .

Preparation of 4-((1-(3-chloropropyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid methyl ester

Add 4-((2,3-dimethyl-1H-indol-5-yl)oxy) dropwise to a stirred suspension of NaH (1.7 g, 71 mmol) in DMF (20 mL) A solution of methyl benzoate (4.2 g, 14 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 30 minutes and then cooled to 0 °C. To this mixture was added bromochloropropane (3.2 mL, 32 mmol) dropwise. The mixture was stirred for 2 hours. After the starting material was completely consumed, ice-cold water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with chilled solution of ammonium chloride, then brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 4% ethyl acetate in petroleum ether eluting to afford 4-((1-(3-chloropropyl)-2, 3- Methyl-1H-indol-5-yl)oxy)benzoic acid methyl ester (2.5 g, 48%). LCMS: m/z 3721. [M+H] ⁺ .

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzoic acid Preparation of methyl ester

4-((1-(3-Chloropropyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid methyl ester (2.0 g, 5.4 mmol) at room temperature Sodium iodide (2.1 g, 14 mmol) and sodium carbonate (1.5 g, 14 mmol) were added to a stirred solution of acetonitrile (20 mL), and then N -methylhexahydropyrazine (1.6 mL, 14 mmol) was added. The reaction mixture was heated to 85 ° C for 16 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 5% methanol in dichloromethane as a solvent to afford 4-((2,3-dimethyl-1-(3-(4-)) Methyl hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzoic acid methyl ester (1.1 g, 47%). LCMS: m/z 436.3 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzoic acid Preparation

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy) at 0 °C yl) benzoic acid methyl ester (1.1g, 2.5mmol) in _{THF: MeOH: H 2 O (} 4: 1: in the 1,16mL), was added aqueous 2N NaOH (8mL). The reaction mixture was warmed to room temperature and stirred for 16 h. After the starting material was completely consumed, the reaction was concentrated in vacuo, cooled to 0 <0> C, acidified to EtOAc EtOAc EtOAc The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to afford an off-white solid 4 - ((2,3-dimethyl-1- (3- (4-hexahydropyrazino -1 -yl)propyl)-1H-indol-5-yl)oxy)benzoic acid (0.80 g, 75%). LCMS: m/z 4221. [M+H] ⁺ .

N-(3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Preparation of pyrazin- 1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To 4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzoic acid (150 mg, 0.36 mmol) and Intermediate B (110 mg, 0.48 mmol), EtOAc (EtOAc) The mixture was stirred at room temperature for 10 minutes, then heated to 80 ° C for 1 hour. After the starting material was completely consumed, the reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 4% methanol in dichloromethane to elute to afford N- (3,5-dimethoxy-4- (pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole -5-yl)oxy)benzamide (100 mg, 44%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.60 (d, J = 4.4Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.30-7.21 (m, 4H), 7.06 (br s, 2H ), 7.01 (d, J = 8.4 Hz, 2H), 6.88 (br d, J = 8.4 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H), 3.78 (s, 6H), 2.83 - 2.27 ( m, 16H), 2.21 (s, 3H), 1.98-1.84 (m, 2H). LCMS: m/z 634.37 [M+H] ⁺ .

Other analogs prepared by this method: N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1) -(3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (44%). LCMS: m/z 633.48 [ M+H] ⁺ .

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy) -N -(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (39%). LCMS: m/z 651.3 [M+H] ⁺ .

Compound 26 , N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Preparation of pyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-)4- at 0 °C a stirred solution of methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide (100 mg, 0.16 mmol) in dichloromethane (5 mL) A solution of boron tribromide (0.5 mL, 5 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was washed with brine, dried over anhydrous sulfate and concentrated Na ₂ SO _4, to give crude product. The crude compound was purified by prep-TLC using 5% methanol in dichloromethane to elute to give N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl) as a brown solid. 4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzene Indoleamine (Compound 26) (28 mg, 29%).

_{^{1 H NMR (300MHz, CD 3}} OD): δ 8.46 (d, J = 6.3Hz, 2H), 7.87 (d, J = 8.7Hz, 2H), 7.53 (d, J = 6.3Hz, 2H), 7.38 ( d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.90 (s, 2H), 6.83 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 2.54 (br s, 8H), 2.40-2.33 (m, 5H), 2.31 (s, 3H), 2.19 (s, 3H), 1.94 (Five peaks, J = 6.9 Hz, 2H). LCMS: m/z 606.53 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 27, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (19%).

_{^{1 H NMR (300MHz, CD 3}} OD): δ 7.87 (d, J = 8.7Hz, 2H), 7.40-7.32 (m, 5H), 7.28-7.23 (m, 1H), 7.12 (d, J = 2.1Hz , 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.87-6.81 (m, 3H), 4.20 (t, J = 6.9 Hz, 2H), 2.65-2.32 (m, 16H), 2.19 (s, 3H), 1.94 (five peaks, J = 7.2 Hz, 2H). LCMS: m/z 564.57 [M+H] ⁺ .

Compound 28, 4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy ) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine (7%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.86 (d, J = 8.8Hz, 2H), 7.39-7.35 (m, 3H), 7.17 (d, J = 2.0Hz, 1H), 7.07 (t, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.86-6.81 (m, 3H), 4.21 (t, J = 6.8 Hz, 2H), 2.71-2.32 (m, 16H), 2.19 (s, 3H), 2.00-1.91 (m, 2H). LCMS: m/z 623. 46 [M+H] ⁺ .

Scheme 15. Preparation of Compound 30-32.

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5- yl) Preparation of oxy)benzonitrile

To 2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-ol under argon atmosphere ( 450mg, 1.43mmol) was added _{K 2 CO 3 (0.99g, 7.2mmol} ) and 4-fluorobenzonitrile (0.51g, 4.2mmol) (10mL) in the solution in degassed DMF. The mixture was stirred at 120 ° C for 16 hours. After the starting material was completely consumed, the reaction mixture was cooled to 0 ° C, quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to give crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 3% methanol in dichloromethane as a solvent to give 4-((2,3-dimethyl-1-) as a yellow liquid. (2-Methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzonitrile (0.55 g, 92%). LCMS: m/z 417.31 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy Preparation of benzoic acid

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole- at 0 °C A stirred solution of 5-N-oxy)benzonitrile (0.55 g, 1.3 mmol) in EtOAc (EtOAc) The reaction mixture was heated to 100 ° C and stirred at this temperature for 16 hours. After the starting material was completely consumed, the reaction material was concentrated, acidified with 6N HCl and extracted with 30% isopropyl alcohol in chloroform. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a brown solid 4 - ((2,3-dimethyl-1- (2-methyl-3- (4-methylhexahydrophthalic Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzoic acid (0.44 g, 76%). LCMS: m/z 436.32 [M+H] ⁺ .

N - ( 2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-) Preparation of 4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To 4-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) EDC.HCl (211 mg, 1.1 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc, EtOAc. The mixture was stirred at room temperature for 10 minutes, then heated to 100 ° C for 2 hours. After the starting material was completely consumed, the reaction mixture was concentrated, diluted with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 4% methanol in dichloromethane as a solvent to afford N- (2,6-dimethoxy-[1 ,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propane Base)-1H-indol-5-yl)oxy)benzamide (80 mg, 67%). LCMS: m/z 647.44 [M+H] ⁺ .

Other analogs prepared by this method: N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-() 2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (46%). LCMS: m/ z 647.01[MH] ^- .

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H-indol-5-yl) Oxy)-N-(4'-fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (45%). LCMS: m/z 665.48 [M+H] ⁺ .

Compound 31 , N-(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-) Preparation of (4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)oxy)benzamide

To N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-)-A at 0 °C 3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (80 mg, 0.12 mmol) in dichloromethane (6 mL Boron tribromide (2.0 mL, 2.0 mmol, 1.0 M in DCM) was added to the stirred solution. The mixture was stirred at this temperature for 10 minutes, then warmed to room temperature and stirred for 12 hours. After complete consumption of the starting material, the reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to give crude product. The crude compound was purified by prep-TLC using 8% methanol in DCM as a solvent to give N- (2,6-dihydroxy-[1,1'-biphenyl]-4-yl) as a white solid. -4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) Oxy)benzamide (Compound 31) (28 mg, 38%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.94 (br s, 1H), 9.13 (br s, 2H), 7.92 (d, J = 8.8Hz, 2H), 7.41 (d, J = 8.8Hz, 1H), 7.31-7.30 (m, 4H), 7.22-7.18 (m, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.94 (s, 2H) ) 6.83 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 4.19 (dd, J = 14.8 Hz, 4.8 Hz, 1H), 3.88 (dd, J = 15.2 Hz, 9.2 Hz, 1H), 2.66-2.15 ( m, 20H), 0.79 (d, J = 6.4 Hz, 3H). LCMS: m/z 619.43 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 30, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-)4 -methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)oxy)benzamide (24%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.01 (br s, 1H), 9.48 (s, 2H), 8.49 (d, J = 6.0Hz, 2H), 7.92 (d, J = 8.8Hz, 2H ), 7.40 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 6.0 Hz, 2H), 7.14 (d, J = 2.4 Hz, 1H), 6.996.96 (m, 4H), 6.82 (dd) , J = 8.4 Hz, 2.4 Hz, 1H), 4.19 (dd, J = 14.8 Hz, 4.4 Hz, 1H), 3.86 (dd, J = 14.8 Hz, 8.8 Hz, 1H), 2.46-2.15 (m, 20H) , 0.78 (d, J = 5.6 Hz, 3H). LCMS: m/z 620.31 [M+H] ⁺ .

Compound 32, 4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- yl) oxy) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (66%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.94 (br s, 1H), 9.21 (br s, 2H), 7.91 (d, J = 8.8Hz, 2H), 7.40 (d, J = 8.8Hz, 1H), 7.33 (dd, J = 8.8 Hz, 6.0 Hz, 2H), 7.15-7.10 (m, 3H), 6.97 (d, J = 8.8 Hz, 2H), 6.94 (s, 2H), 6.82 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 4.19 (dd, J = 14.8 Hz, 4.4 Hz, 1H), 3.87 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 2.19-2.15 (m, 20H), 0.78 (d, J = 5.6 Hz, 3H). LCMS: m/z 637.39 [M+H] ⁺ .

Scheme 16. Preparation of Compounds 33-36 and 38-40.

Preparation of N-(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-nitrobenzamide

DIPEA (1.06 mL, 6.09 mmol) was added to a stirred solution of 3-nitrobenzoic acid (350 mg, 2.1 mmol) in DMF (10 mL). Intermediate A (505 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the starting material was completely consumed, the reaction mass was diluted with ice water. The resulting precipitate was collected by filtration to give N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-nitrobenzamide (0.60 g) as a brown solid. , 78%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.72 (br s, 1H), 8.83 (br s, 1H), 8.48-8.42 (m, 2H), 7.88 (t, J = 8.0Hz, 1H), 7.57 (s, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 7.00 (s, 1H), 3.76 (s, 6H). LCMS: m/z 369.1 [M+H] ⁺ .

Other analogs prepared by this method: N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-3-nitrobenzamide (82%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.70 (br s, 1H), 8.84 (br s, 1H), 8.56 (d, J = 5.7Hz, 2H), 8.49-8.42 (m, 2H), 7.88 (t, J = 8.1 Hz, 1H), 7.36 (s, 2H), 7.28 (d, J = 6.0 Hz, 2H), 3.72 (s, 6H). LCMS: m/z 380.1 [M+H] ⁺ .

N- (2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-3-nitrobenzamide (72%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.64 (br s, 1H), 8.84 (t, J = 2.0Hz, 1H), 8.48-8.43 (m, 2H), 7.88 (t, J = 8.0Hz , 1H), 7.37-7.32 (m, 4H), 7.28-7.22 (m, 3H), 3.68 (s, 6H). LCMS: m/z 379.1 [M+H] ⁺ .

N -(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-3-nitrobenzamide (84%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.64 (br s, 1H), 8.83 (br s, 1H), 8.49-8.42 (m, 2H), 7.87 (t, J = 8.0Hz, 1H), 7.33 (s, 2H), 7.26 (dd, J = 8.4 Hz, 5.6 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 3.69 (s, 6H). LCMS: m/z 397.1 [M+H] ⁺ .

Preparation of N-(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-aminobenzimidamide

To N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-nitrobenzamide (600 mg, 1.8 mmol) in ethanol (30 mL) Powder (182 mg, 3.26 mmol) and NH ₄ Cl (435 mg, 8.14 mmol) were added to a stirred solution in water (30 mL). The reaction mixture was heated at reflux for 3 h. After the starting material was completely consumed, the mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The obtained precipitate was collected by filtration and dried to give N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-aminobenzimidamide as a brown solid. 400 mg, 73%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.28 (br s, 1H), 7.58-7.34 (m, 3H), 7.27-7.04 (m, 5H), 6.78 (d, J = 7.2Hz, 1H) , 3.76 (s, 6H). LCMS: m/z 339.1 [M+H] ⁺ .

Other analogs prepared by this method: 3-amino- N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)benzamide (99%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 8.54 (br s, 2H), 7.37 (br s, 2H), 7.29 (br s, 2H), 7.21-7.05 (m, 4H), 6.77 (d, J = 6.4 Hz, 1H), 5.40 (br s, 2H), 3.69 (s, 6H). LCMS: m/z 350.1 [M+H] ⁺ .

3-amino- N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (72%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.11 (br s, 1H), 7.35-7.32 (m, 4H), 7.26-7.14 (m, 4H), 7.11-7.04 (m, 2H), 6.76 ( Br d, J = 8.0 Hz, 1H), 5.35 (br s, 2H), 3.65 (s, 6H). LCMS: m/z 349.1 [M+H] ⁺ .

3-amino- N- (4'-fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (500 mg, 77%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.09 (br s, 1H), 7.33 (s, 2H), 7.26-7.22 (m, 2H), 7.17-7.07 (m, 5H), 6.76 (br d , J = 8.0Hz, 1H), 5.31 (br s, 2H), 3.72 (s, 6H). LCMS: m/z 367.1 [M+H] ⁺ .

Preparation of 5-bromo-1-(3-chloropropyl)-2,3-dimethyl-1 H -indole

NaH (1.8 g, 75 mmol) was added portionwise to a stirred solution of 5-bromo-2,3-dimethyl-1H-indole (5.0 g, 22 mmol). The mixture was allowed to warm to room temperature and held for 30 minutes. To this mixture, bromochloropropane (11.7 mL, 11.8 mmol) was added dropwise at 0 ° C and the mixture was stirred at room temperature for 3 hr. After the starting material was completely consumed, ice-cold water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude product. The crude compound was purified by flash column chromatography using 5% ethyl acetate in petroleum ether eluting to afford 5-bromo-1-(3-chloropropyl)-2,3- Methyl-1H-indole (2.6 g, 39%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.59 (d, J = 2.0Hz, 1H), 7.21 (dd, J = 8.4Hz, 1.6Hz, 1H), 7.16 (d, J = 8.4Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.30-2.15 (m, 5H). LCMS: m/z 301.2, 3021. [M+H] ⁺ .

Other analogues prepared by this method: 5-bromo-1-(3-chloro-2-methylpropyl)-2,3-dimethyl-1H-indole (61%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.59 (d, J = 2.0Hz, 1H), 7.17 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.03 (d, J = 8.4Hz, 1H), 4.21-4.17(m,1H),3.91-3.83(m,1H),3.62-3.49(m,2H), 2.36(s,3H), 2.30-2.25(m,4H),1.02(d, J =6.4 Hz, 3H). LCMS: m/z 315.1, 316.0 [M+H] ⁺ .

Preparation of 5-bromo-2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole

Addition of iodinated to a stirred solution of 5-bromo-1-(3-chloropropyl)-2,3-dimethyl-1H-indole (9.0 g, 30 mmol) in acetonitrile (20 mL) Sodium (11.2 g, 74.7 mmol), sodium carbonate (7.93 g, 74.8 mmol) and subsequently N -methylhexahydropyrazine (7.4 g, 73.9 mmol). The reaction mixture was heated to 75 ° C for 16 hours. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 5% methanol in dichloromethane as a solvent to give 5-bromo-2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indole (3.2 g, 30%). LCMS: m / z 364.0,366.0 [M + H] +.

Other analogs prepared by this method: 5-bromo-2,3-dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)- 1H-吲哚 (17%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.58 (d, J = 1.6Hz, 1H), 7.17 (dd, J = 8.4Hz, 1.6Hz, 1H), 7.11 (d, J = 8.4Hz, 1H), 4.22-4.17(m,1H), 3.76-3.70(m,1H), 2.65-2.40(m,6H), 2.38(s,3H), 2.33(s,3H), 2.29-2.22(m,2H), 2.21-2.14 (m, 4H), 1.29-1.25 (m, 2H), 0.87 (d, J = 6.2 Hz, 3H). LCMS: m/z 378.1, 380.1 [M+H] ⁺ .

N-(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1-(3-(4-methyl) Preparation of Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

To 5-bromo-2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole (200 mg) under argon at room temperature , 0.55 mmol) NaO t Bu (159 mg, 1.65 mmol), Pd ₂ (dba) ₃ (56 mg, 0.061 mmol), Dave Phos (108 mg, 0.27) were added to a stirred solution of 1,4-dioxane (20 mL). Methyl) and N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-aminobenzimidamide (185 mg, 0.55 mmol). The reaction mixture was heated to 100 ° C in a sealed tube and held for 12 hours. After the starting material was completely consumed, the reaction mixture was diluted with ethyl acetate and filtered over Celite. The organic layer was washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by prep-TLC using 5% methanol in dichloromethane as a solvent to afford N- (4-(1H-imidazol-1-yl)-3,5-dimethoxy Phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amine Benzobenzamide (80 mg, 23%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.27 (br s, 1H), 8.00 (br s, 1H), 7.57-7.48 (m, 1H), 7.43-7.39 (m, 3H), 7.35-7.17 (m, 4H), 7.11-7.05 (m, 2H), 7.00-6.93 (m, 1H), 6.90 (br d, J = 8.0 Hz, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.71 (s, 6H), 2.39-2.13 (m, 19H), 1.82-1.75 (m, 2H). LCMS: m/z 622.3 [M+H] ⁺ .

Other analogs prepared by this method: N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-() 3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (99%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.22 (br s, 1H), 8.53 (d, J = 5.2Hz, 2H), 7.99 (br s, 1H), 7.41 (br s, 1H), 7.36 -7.32 (m, 3H), 7.28-7.23 (m, 4H), 7.18 (br s, 1H), 7.08 (br d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.68 (s, 6H), 2.38-2.20 (m, 13H), 2.15 (s, 6H), 1.79 (five-peak, J = 6.8 Hz, 2H). LCMS: m/z 633.3 [M+H] ⁺ .

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (26%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.16 (br s, 1H), 7.98 (br s, 1H), 7.41-7.18 (m, 10H), 7.08-6.89 (m, 4H), 4.10 (t , J = 6.6 Hz, 2H), 3.64 (s, 6H), 2.41-2.15 (m, 19H), 1.81-1.74 (m, 2H). LCMS: m/z 632.4 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)amino) -N -(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (25%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.18 (br s, 1H), 7.96 (br s, 1H), 7.41 (br s, 1H), 7.34-7.29 (m, 3H), 7.27-7.21 ( m, 4H), 7.18 (d, J = 1.6 Hz, 1H), 7.15 (t, J = 9.2 Hz, 2H), 7.07 (br d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8 Hz) , 2.0 Hz, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.65 (s, 6H), 2.38-2.14 (m, 19H), 1.79 (five-peak, J = 7.2 Hz, 2H). LCMS: m/z 650.3 [M+H] ⁺ .

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-(4-) Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (44%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.21 (br s, 1H), 8.54 (d, J = 5.4Hz, 2H), 7.99 (br s, 1H), 7.41 (br s, 1H), 7.37 (s, 2H), 7.36-7.18 (m, 6H), 7.10-7.04 (m, 1H), 6.88 (br d, J = 7.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.19 -4.11 (m, 1H), 3.87-3.76 (m, 1H), 3.68 (s, 6H), 2.50-2.04 (m, 20H), 0.78 (d, J = 6.0 Hz, 3H). LCMS: m/z 647.6 [M+H] ⁺ .

N- (2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-) 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (72%). LCMS: m/z 646.4 [M+H] ⁺ .

3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amine yl) - N - (4'- fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (26%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.17 (br s, 1H), 7.78 (br s, 1H), 7.42 (br s, 1H), 7.31-7.22 (m, 7H), 7.18-7. m, 3H), 7.07 (br d, J = 12 Hz, 1H), 6.90 (br d, J = 8.8 Hz, 1H), 4.19-4.12 (m, 1H), 3.86-3.78 (m, 1H), 3.65 (s, 6H), 2.41-2.12 (m, 20H), 0.93 (d, J = 6.8 Hz, 3H). LCMS: m/z 664.3 [M+H] ⁺ .

Compound 33 , N-(3,5-Dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Preparation of pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide

To N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-3-((2,3-dimethyl-1-(3-)() at 0 °C Stirring solution of 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (50 mg, 0.080 mmol) in dichloromethane (3 mL) Boron tribromide (1.0 mL, 1 M dichloromethane solution) was added. The mixture was stirred at this temperature for 10 minutes, then warmed to room temperature and stirred for 12 hours. The reaction mixture was diluted with water and basified with saturated NaHCO ₃ to pH 9. The resulting precipitate was collected by filtration to obtain a crude product. The crude compound was purified by prep-HPLC to give N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-3-((2,3-dimethyl) as an off white solid. 1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)amino)benzamide (Compound 33) (10 mg, 21%) ).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.47 (br s, 3H), 7.85 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (br s, 1H) ), 7.48-7.41 (m, 1H), 7.38 (br s, 1H), 7.35-7.29 (m, 2H), 7.27-7.23 (m, 2H), 7.18-7.15 (m, 2H), 7.11-7.06 ( m, 2H), 6.98 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.93 (s, 2H), 4.19 (t, J = 6.8 Hz, 2H), 2.95-2.53 (m, 11H), 2.42- 2.37 (m, 5H), 2.20 (s, 3H), 1.95 (five peaks, J = 6.8 Hz, 2H). LCMS: m/z 594.40 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 34, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (8%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.46 (d, J = 6.4Hz, 2H), 7.54 (d, J = 5.6Hz, 2H), 7.38 (br s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.27-7.21 (m, 2H), 7.17 (br d, J = 7.2 Hz, 1H), 7.08 (br d, J = 7.6 Hz, 1H), 6.99 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 6.87 (s, 2H), 4.20 (t, J = 6.8 Hz, 2H), 2.96 (br s, 8H), 2.64 (s, 3H), 2.42 (t, J = 6.8 Hz, 2H) ), 2.37 (s, 3H), 2.20 (s, 3H), 1.96 (five peaks, J = 6.8 Hz, 2H). LCMS: m/z 564.46 [M+H] ⁺ .

Compound 35, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (12%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.38-7.21 (m, 9H), 7.17 (br d, J = 7.6Hz, 1H), 7.08 (br d, J = 9.2Hz, 1H), 6.99 (dd , J = 8.4 Hz, 2.0 Hz, 1H), 6.83 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 2.82-2.33 (m, 16H), 2.20 (s, 3H), 1.97-1.91 (m, 2H). LCMS: m/z 604.3 [M+H] ⁺ .

Compound 36, 3-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)amino ) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine (6%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.39-7.34 (m, 3H), 7.29 (d, J = 8.8Hz, 1H), 7.26-7.22 (m, 2H), 7.17 (br s, J = 8.0 Hz, 1H), 7.08-7.03 (m, 3H), 6.97 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 6.83 (s, 2H), 4.17 (t, J = 6.8 Hz, 2H), 2.62 2.31 (m, 13H), 2.27 (s, 3H), 2.19 (s, 3H), 1.92 (five-peak, J = 6.8 Hz, 2H). LCMS: m/z 622.51 [M+H] ⁺ .

Compound 38, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-1-(2-methyl-3-)4 -methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (24%).

_{^{1 H NMR (300MHz, CD 3}} OD): δ 8.46 (d, J = 6.3Hz, 2H), 7.53 (d, J = 6.3Hz, 2H), 7.39 (br s, 1H), 7.29-7.23 (m, 3H), 7.17 (br d, J = 7.5 Hz, 1H), 7.09 (br d, J = 6.6 Hz, 1H), 6.98 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.87 (s, 2H) , 4.19-4.13 (m, 1H), 3.99-3.92 (m, 1H), 2.78 (br s, 8H), 2.59 (s, 3H), 2.39-2.32 (m, 6H), 2.21 (s, 3H), 0.93 (d, J = 5.7 Hz, 3H). LCMS: m/z 619.45 [M+H] ⁺ .

Compound 39, N -(2,6-Dihydroxy-[1,1'-biphenyl]-4-yl)-3-((2,3-dimethyl-1-(2-methyl-3-) (4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (17%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.95 (br s, 1H), 9.12 (br s, 2H), 8.17 (br s, 1H), 7.96 (br s, 1H), 7.39 (br s, 1H), 7.31-7.16 (m, 8H), 7.05 (br d, J = 8.4 Hz, 1H), 6.92 (s, 2H), 6.89 (dd, J = 8.7 Hz, 1.8 Hz, 1H), 4.19-4.11 (m, 1H), 3.80 (dd, J = 14.7 Hz, 8.4 Hz, 1H), 2.45-2.13 (m, 20H), 0.77 (d, J = 6.0 Hz, 3H). LCMS: m/z 618.48 [M+H] ⁺ .

Compound 40, 3-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole-5- yl) amino) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine (3%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.39-7.34 (m, 3H), 7.26-7.21 (m, 3H), 7.16 (br d, J = 6.4Hz, 1H), 7.09-7.03 (m, 3H ), 6.96 (br d, J = 8.8 Hz, 1H), 6.83 (s, 2H), 4.20 - 4.16 (m, 1H), 3.86 (dd, J = 14.4 Hz, 5.6 Hz, 1H), 2.53-2.32 ( m, 11H), 2.35-2.25 (m, 6H), 2.15 (s, 3H), 0.88 (d, J = 6.4 Hz, 3H). LCMS: m/z 636.3 [M+H] ⁺ .

Scheme 17. Preparation of Compound 41-48.

Preparation of N - ( 2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-nitrobenzamide

Add HATU (1.5 g, 3.9 mmol), DIPEA (1.12 mL, 6.43 mmol) and Intermediate C (yield) to a stirred solution of 4-nitrobenzoic acid (350 mg, 2.1 mmol) in DMF (10 mL) 528 mg, 2.30 mmol). The reaction mixture was stirred at this temperature for 16 hours. After the starting material was completely consumed, the reaction mass was diluted with ice water. The resulting precipitate was collected by filtration to give N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-nitrobenzamide as an off-white solid (600 mg, 76%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.62 (br s, 1H), 8.40 (d, J = 8.8Hz, 2H), 8.22 (d, J = 8.8Hz, 2H), 7.38-7.31 (m , 4H), 7.28-7.21 (m, 3H), 3.67 (s, 6H). LCMS: m/z 379.0 [M+H] ⁺ .

Other analogs prepared by this method: N -(4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-nitrobenzamide (73%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.72 (br s, 1H), 8.41 (d, J = 8.8Hz, 2H), 8.22 (d, J = 8.8Hz, 2H), 7.57 (s, 1H ), 7.39 (s, 2H), 7.12 (s, 1H), 6.99 (s, 1H), 3.75 (s, 6H). LCMS: m/z 369.1 [M+H] ⁺ .

N- (3,5-Dimethoxy-4-(pyridin-4-yl)phenyl)-4-nitrobenzamide (56%). LCMS: m/z 380.1 [M+H] ⁺ .

N -(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-nitrobenzamide (84%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 10.61 (br s, 1H), 8.40 (d, J = 8.7Hz, 2H), 8.21 (d, J = 8.7Hz, 2H), 7.32 (s, 2H ), 7.26 (dd, J = 8.7 Hz, 6.0 Hz, 2H), 7.17 (t, J = 9.0 Hz, 2H), 3.68 (s, 6H). LCMS: m/z 397.1 [M+H] ⁺ .

Preparation of 4-amino-N-(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide

To N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-nitrobenzimidamide (600 mg, 1.58 mmol) in ethanol (15 mL) Fe powder (177 mg, 3.17 mmol) and NH ₄ Cl (423 mg, 7.91 mmol) were added to the stirred solution in water (15 mL). The reaction mixture was heated at reflux for 3 h. After the starting material was completely consumed, the mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The resulting precipitate was collected by filtration and dried to give 4-amino- N- (2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide as an off-white solid. 400 mg, 72%). LCMS: m/z 349.1 [M+H] ⁺ .

Other analogs prepared by this method: N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-aminobenzamide (73%). LCMS: m/z 339.1 [M+H] ⁺ .

4- amino - N - (3,5- dimethoxy-4- (pyridin-4-yl) phenyl) benzoyl-amine (81%) LCMS: m / z 350.1 [M + H] + .

4-amino- N- (4'-fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (400 mg, 62%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.80 (br s, 1H), 7.74 (d, J = 7.6Hz, 2H), 7.32 (s, 2H), 7.25-7.13 (m, 4H), 6.61 (d, J = 8.0 Hz, 2H), 5.79 (br s, 2H), 3.66 (s, 6H). LCMS: m/z 367.1 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)amino)-N -(4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide

To 5-bromo-2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indole (200 mg, 0.55 mmol) at room temperature NaO t Bu (159 mg, 1.65 mmol), Pd ₂ (dba) ₃ (56 mg, 0.061 mmol), Dave Phos (108 mg, 0.27 mmol) and 4- were added to a solution of 1,4-dioxane (20 mL). Amino- N- (4'-fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (200 mg, 0.55 mmol). The reaction mixture was heated to 100 ° C in a sealed tube and held for 12 hours. After the starting material was completely consumed, the reaction mixture was diluted with ethyl acetate and filtered thru EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by prep-TLC using 5% methanol in methylene chloride as a solvent to afford 4-((2,3- dimethyl-1-(3-(4-) yl piperazine-1-yl) propyl) lH-indol-5-yl) amino) - N - (4'- fluoro-2,6-dimethoxy - [1,1'- Biphenyl]-4-yl)benzamide (120 mg, 34%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.90 (br s, 1H), 8.38 (br s, 1H), 7.83 (d, J = 8.8Hz, 2H), 7.38-7.33 (m, 3H), 7.26-7.20(m,3H), 7.16(t, J = 8.8Hz, 2H), 6.94-6.91(m,3H), 4.11(t, J = 6A Hz, 2H), 3.66(s,6H), 2.46 -2.15 (m, 19H), 1.83-1.75 (m, 2H). LCMS: m / z 650.2 [M + H] +.

Other analogs prepared by this method: N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1) -(3-(4-Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (21%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.98 (br s, 1H), 8.39 (br s, 1H), 7.85 (d, J = 8.7Hz, 2H), 7.54 (s, 1H), 7.42 ( s, 2H), 7.36 (d, J = 8.7 Hz, 1H), 7.21 (br s, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.95-6.90 (m, 3H), 4.11 ( t, J = 6.6 Hz, 2H), 3.72 (s, 6H), 2.43 - 2.14 (m, 19H), 1.85-1.73 (m, 2H). LCMS: m/z 622.2 [M+H] ⁺ .

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydropyridyl)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (23%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.94 (br s, 1H), 8.53 (d, J = 5.4Hz, 2H), 8.38 (br s, 1H), 7.83 (d, J = 8.7Hz, 2H), 7.40-7.35 (m, 3H), 7.27 (d, J = 5.7 Hz, 2H), 7.21 (br s, 1H), 6.96-6.89 (m, 3H), 4.11 (t, J = 6.9 Hz, 2H), 3.69 (s, 6H), 2.48-2.14 (m, 19H), 1.84-1.72 (m, 2H). LCMS: m/z 633.5 [M+H] ⁺ .

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (23%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.88 (br s, 1H), 8.36 (br s, 1H), 7.83 (d, J = 8.7Hz, 2H), 7.38-7.31 (m, 5H), 7.27-7.19 (m, 4H), 6.95-6.89 (m, 3H), 4.11 (t, J = 6.6 Hz, 2H), 3.65 (s, 6H), 2.45-2.14 (m, 19H), 1.80 (five weights) Peak, J = 6.6 Hz, 2H). LCMS: m/z 632.4 [M+H] ⁺ .

N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-methyl-3-) 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (20%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.99 (br s, 1H), 8.38 (br s, 1H), 7.83 (d, J = 8.7Hz, 2H), 7.54 (br s, 1H), 7.42 (s, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 1H), 7.09 (br s, 1H), 6.98-6.89 (m, 4H), 4.22-4.14 (m, 1H) ), 3.88-3.76 (m, 1H), 3.72 (s, 6H), 2.42-2.14 (m, 20H), 0.78 (d, J = 6.0 Hz, 3H). LCMS: m/z 636.4 [M+H] ⁺ .

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-)4- Methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (16%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.94 (br s, 1H), 8.55 (d, J = 5.6Hz, 2H), 8.38 (br s, 1H), 7.82 (d, J = 8.8Hz, 2H), 7.39 (s, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 5.6 Hz, 2H), 7.22 (d, J = 2.0 Hz, 1H), 6.97-6.92 ( m, 3H), 4.20-4.14 (m, 1H), 3.86-3.79 (m, 1H), 3.69 (s, 6H), 2.49-2.05 (m, 20H), 0.79 (d, J = 6.4 Hz, 3H) . LCMS: m/z 647.4 [M+H] ⁺ .

N- (2,6-Dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-) 4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (35%).

^{1 H NMR (300MHz, DMSO-} d 6): δ 9.88 (br s, 1H), 8.35 (br s, 1H), 7.83 (d, J = 8.7Hz, 2H), 7.40-7.28 (m, 5H), 7.27-7.19 (m, 4H), 6.96-6.89 (m, 3H), 4.17 (dd, J = 14.7 Hz, 4.2 Hz, 1H), 3.83 (dd, J = 13.5 Hz, 8.1 Hz, 1H), 3.65 ( s, 6H), 2.46-2.12 (m, 20H), 0.78 (d, J = 6.0 Hz, 3H). LCMS: m/z 646.4 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amine yl) - N - (4'- fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (34%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.89 (br s, 1H), 8.36 (br s, 1H), 7.83 (d, J = 8.8Hz, 2H), 7.39-7.30 (m, 3H), 7.26-7.21(m,3H), 7.16(t, J = 8.8Hz, 2H), 6.94-6.90(m,3H), 4.16(dd, J = 14.8Hz, 4.4Hz, 1H), 3.83(dd, J =14.8 Hz, 8.4 Hz, 1H), 3.66 (s, 6H), 2.46-2.15 (m, 20H), 0.78 (d, J = 6.4 Hz, 3H). LCMS: m/z 664.3 [M+H] ⁺ .

Compound 44,  4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)-N- Preparation of (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

4-((2,3-Dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amine at 0 °C yl) - N - (4'- fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl amine (120mg, 0.18mmol) in dichloromethane (3mL Boron tribromide (1.0 mL, 1 M dichloromethane solution) was added to the stirred solution. The mixture was stirred at this temperature for 10 minutes, then warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated, diluted with water and then basified with saturated NaHCO ₃ to pH 9. The resulting precipitate was collected by filtration to give a crude product. The crude compound was purified by prep-HPLC to give 4-((2,3-dimethyl-1-(3-(4-methylhexahydropyrazin-1-yl)propyl)-1 as a brown solid. H - indol-5-yl) amino) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl amine (compound 44) (20 mg, 18%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.74 (d, J = 8.8 Hz, 2H), 7.37 (dd, J = 8.8 Hz, 5.6 Hz, 2H), 7.31 (d, J = 8.8 Hz, 1H) , 7.25 (d, J = 2.0 Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.97 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H) ), 6.83 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 2.68-2.30 (m, 16H), 2.20 (s, 3H), 1.94 (five peaks, J = 7.2 Hz, 2H) . LCMS: m/z 622.3 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 41, N -(3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1 H -indol-5-yl)amino)benzamide (4%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.78 (br s, 3H), 8.33 (br s, 1H), 7.79 (d, J = 8.0Hz, 2H), 7.53 (br s, 1H), 7.35 (s, J = 8.8 Hz, 1H), 7.20 (br s, 1H), 7.09 (s, 1H), 7.04 (s, 2H), 6.95-6.89 (m, 4H), 4.12 (br s, 2H), 2.49-2.14 (m, 19H), 1.87-1.72 (m, 2H). LCMS: m/z 594.3 [M+H] ⁺ .

Compound 42, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(3-(4-methylhexahydro)) Pyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (6%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.46 (d, J = 5.6 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 6.0 Hz, 2H), 7.31 ( d, J = 8.8 Hz, 1H), 7.25 (br s, 1H), 6.97 (br d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.88 (s, 2H), 4.18 (t, J = 7.2 Hz, 2H), 2.65-2.33 (m, 13H), 2.30 (s, 3H), 2.20 (s, 3H), 1.94 (five peaks, J = 12 Hz, 2H). LCMS: m/z 605.3 [M+H] ⁺ .

Compound 43, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(3-(4-methyl) Hexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (26%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.66 (br s, 1H), 9.08 (br s, 2H), 8.30 (br s, 1H), 7.79 (d, J = 8.4Hz, 2H), 7.37 -7.08 (m, 7H), 6.94-6.90 (m, 5H), 4.11 (t, J = 6.8 Hz, 2H), 2.50-2.14 (m, 19H), 1.86-1.74 (m, 2H). LCMS: m/z 604.4 [M+H] ⁺ .

Compound 45, N -(3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-) (4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (4%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.74 (d, J = 8.8Hz, 2H), 7.68 (br s, 1H), 7.29-7.25 (m, 2H), 7.14 (br s, 1H), 7.06 (br s,1H), 6.98-6.90 (m, 5H), 4.20 (dd, J = 16.0 Hz, 5.2 Hz, 1H), 3.91 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 2.69-2.44 ( m, 11H), 2.40-2.28 (m, 6H), 2.21 (s, 3H), 0.90 (d, J = 5.6 Hz, 3H). LCMS: m/z 606.4 [MH] ^- .

Compound 46, N -(3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-methyl-3-)4 -methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (6%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.45 (d, J = 6.0Hz, 2H), 7.75 (d, J = 8.8Hz, 2H), 7.54 (d, J = 5.6Hz, 2H), 7.28- 7.25 (m, 2H), 6.96 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.88 (s, 2H), 4.15 (dd, J = 13.6 Hz, 4.0Hz, 1H), 3.90 (dd , J = 14.0Hz, 8.0Hz, 1H), 2.65-2.39 (m, 8H), 2.37 (s, 3H), 2.35 (s, 3H), 2.32-2.26 (m, 3H), 2.21 (s, 3H), 0.89 (d, J = 5.6 Hz, 3H). LCMS: m / z 617.4 [MH ] -.

Compound 47, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-methyl-3-) (4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl)amino)benzamide (22%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.75 (d, J = 8.8 Hz, 2H), 7.38-7.31 (m, 4H), 7.28-7.22 (m, 3H), 6.96 (dd, J = 8.0 Hz , 2.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.84 (s, 2H), 4.20 (dd, J = 14.4 Hz, 5.2 Hz, 1H), 3.80 (dd, J = 14.8 Hz, 6.8 Hz, 1H), 2.62-2.38 (m, 8H), 2.37 (s, 3H), 2.33 (s, 3H), 2.31-2.26 (m, 3H), 0.89 (d, J = 6.0 Hz, 3H). LCMS: m / z 616.4 [MH ] -.

Compound 48, 4((2,3-Dimethyl-1-(2-methyl-3-(4-methylhexahydropyrazin-1-yl)propyl)-1H-indol-5-yl) ) amino) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (22%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.74 (d, J = 8.8Hz, 2H), 7.37 (dd, J = 8.8Hz, 6.0Hz, 2H), 7.28-7.24 (m, 2H), 7.06 ( t, J = 8.8 Hz, 2H), 6.96 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.83 (s, 2H), 4.20 (dd, J = 14.8Hz, 4.8Hz, 1H), 3.87 (dd, J = 14.8Hz, 8.4Hz, 1H), 2.56-2.34 (m, 11H), 2.33-2.25 (m, 6H), 2.21 (s, 3H), 0.88 (d, J = 6.0 Hz, 3H). LCMS: m/z 634.4 [MH] ^- .

Scheme 18. Preparation of Compound 57-60.

Preparation of 5-bromo-1-(2-chloroethyl)-2,3-dimethyl-1 H -indole

KOH (3.1 g, 55 mmol) was added to a solution of 5-bromo-2,3-dimethyl-1H-indole (3.0 g, 13 mmol) in dimethylhydrazine (30 mL). The mixture was allowed to warm to room temperature and stirred for 20 minutes, then cooled to 0 °C. 2-Chloroethyl 4-toluenesulfonate (9.0 g, 38 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. After the starting material was completely consumed, ice-cold water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica eluting with 1% ethyl acetate in petroleum ether to afford a 5-bromo-1-(2-chloroethyl) as a yellow solid. -2,3-Dimethyl-1H-indole (1.28 g, 33%). LCMS: m/z 285.9, 287.9 [M+H] ⁺ .

Preparation of 5-bromo-2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1 H -indole

Addition of iodinated to a stirred solution of 5-bromo-1-(2-chloroethyl)-2,3-dimethyl-1H-indole (5.2 g, 18 mmol) in acetonitrile (50 mL) sodium (8.2g, 55mmol), sodium carbonate (5.7g, 54mmol) was added followed by N - methyl-piperazine (5.4g, 54mmol). The reaction mixture was stirred at 90 ° C for 16 hours. After the starting material was completely consumed, the reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 6% methanol in dichloromethane as a solvent to give 5-bromo-2,3-dimethyl-1 as a yellow semi solid. -(2-(4-Methylhexahydropyrazin-1-yl)ethyl)-1H-indole (3.3 g, 52%). LCMS: m/z 350.36, 352.36 [M+H] ⁺ .

Preparation of 2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1 H -indole-5-formaldehyde

5-Bromo-2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indole (3.3 g, 9.4) at -78 °C Methyl) n- BuLi (11.3 mL, 28.5 mmol, 2.5 M in THF). Anhydrous DMF (3.0 mL) was then added to the reaction mixture and the obtained mixture was stirred at -78 ° C for 30 min. After the starting material was completely consumed, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride solution and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a yellow semi-solid crude 2,3-dimethyl-1- (2- (4 Methylhexahydropyrazin-1-yl)ethyl)-1H-indole-5-carboxaldehyde (3.1 g, crude) was used in the next reaction without any further purification. LCMS: m/z 300.3 [M+H] ⁺ .

N '-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methylene)- Preparation of 4-toluenesulfonate

To 2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1 H -indole-5-carbaldehyde (3.5 g, 12 mmol) at room temperature To a stirred solution of anhydrous 1,4-dioxane (80 mL) was added toluenesulfonate (3.3 g, 18 mmol). The mixture was stirred at room temperature for 4 hours. The crude N-((2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)) Methyl)-4-toluenesulfonate is used without isolation or further purification.

4-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1 H -indol-5-yl)methyl)benzoic acid Preparation of methyl ester

To the crude N '- ((2,3- dimethyl-1- (2- (4-methyl-piperazine-1-yl) ethyl) lH-indol-5-yl) methylene Add K ₂ CO ₃ (4.8 g, 25 mmol) and (4-(methoxycarbonyl)phenyl) to a solution of 4-toluenesulfonate in anhydrous 1,4-dioxane (80 mL) Acid (3.16 g, 17.6 mmol). The reaction temperature was raised to 110 ° C and maintained for 5 hours. After the starting material was completely consumed, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride solution and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 4% methanol in dichloromethane as a solvent to afford 4-((2,3-dimethyl-1-) (2-(4-Methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzoic acid methyl ester (2.2 g, 44%). LCMS: m/z 420.38 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzoic acid preparation

4-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)) at 0 °C A 2N aqueous NaOH solution (20 mL) was added dropwise to a stirred solution of EtOAc (EtOAc) (EtOAc) The reaction mixture was allowed to warm to room temperature and stirred for 16 h. After the starting material was completely consumed, the reaction mass was concentrated and then partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 2 with 2N HCl and extracted with 30% isopropyl alcohol in chloroform. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford an off-white solid 4 - ((2,3-dimethyl-1- (2- (4- Hexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzoic acid (1.1 g, 52%). LCMS: m/z 406.38 [M+H] ⁺ .

N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-(4-methyl-6) Preparation of amines of hydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide

To 4-((2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzoic acid (250 mg, 0.62 mmol) and a solution of Intermediate A ( 175 mg, EtOAc. The mixture was stirred at room temperature for 10 minutes and then at 80 ° C for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 4% methanol in methylene chloride as a solvent to give N- (4-(1H-imidazol-1-yl) as a brown solid. -3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H- Indole-5-yl)methyl)benzamide (230 mg, 62%). LCMS: m/z 607.56 [M+H] ⁺ .

Other analogs prepared by this method: N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-() 2-(4-Methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide (47%). LCMS: m/z 616.49 [MH] ^- .

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-(4-methyl-6) Hydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide (52%). LCMS: m/z 617.47 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl) -N - (4'-fluoro-2,6-dimethoxy - [1,1'-biphenyl] -4-yl) benzoyl amine (51%) LCMS:. m / z 635.47 [m + H] + .

Compound 57 , N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(2-(4-methyl)) Preparation of hexahydropyrazin-1-yl)ethyl)-1H-indole-5-yI)methyl)benzamide

To N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(2-)) at 0 °C Stirring solution of 4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide (230 mg, 0.38 mmol) in dichloromethane (5 mL) A solution of boron tribromide (0.50 mL, 5.3 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at this temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. After complete consumption of the starting material, the reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude product. The crude compound was purified by prep-TLC using 7% methanol in dichloromethane as a solvent to give N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)benzene as a brown solid. 4-((2,3-dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl) Benzamide (Compound 57) (55 mg, 25%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.80 (d, J = 8.0 Hz, 2H), 7.65 (br s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.25 (br s, 1H) ), 7.22 (d, J = 8.8 Hz, 1H), 7.13 (br s, 1H), 7.05 (br s, 1H), 6.97-6.93 (m, 3H), 4.22 (t, J = 6.8 Hz, 2H) , 4.12 (s, 2H), 2.64 - 2.43 (m, 10H), 2.36 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H). LCMS: m/z 579.45 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 58, N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(2-(4-methylhexahydro)) Pyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide (42%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.45 (d, J = 6.4Hz, 2H), 7.80 (d, J = 8.4Hz, 2H), 7.52 (d, J = 6.0Hz, 2H), 7.35 ( d, J = 8.4 Hz, 2H), 7.25 (br s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.90 (s, 2H) ), 4.21 (t, J = 7.2 Hz, 2H), 4.11 (s, 2H), 2.65-2.49 (m, 10H), 2.36 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H) . LCMS: m / z 588.56 [MH ] -.

Compound 59, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(2-(4-methyl) Hexahydropyrazin-1-yl)ethyl)-1H-indol-5-yl)methyl)benzamide (16%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.80 (d, J = 8.0 Hz, 2H), 7.38-7.32 (m, 6H), 7.26-7.20 (m, 3H), 6.95 (dd, J = 8.4 Hz , 1.6 Hz, 1H), 6.86 (s, 2H), 4.22 (t, J = 7.2 Hz, 2H), 4.11 (s, 2H), 2.65-2.42 (m, 10H), 2.36 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H). LCMS: m/z 589.484 [M+H] ⁺ .

Compound 60, 4-((2,3-Dimethyl-1-(2-(4-methylhexahydropyrazin-1-yl)ethyl)-1 H -indol-5-yl)methyl ) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (29%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.80 (d, J = 7.6Hz, 2H), 7.39-7.34 (m, 4H), 7.25 (br s, 1H), 7.21 (d, J = 8.0Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.94 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.85 (s, 2H), 4.21 (t, J = 7.2 Hz, 2H), 4.11 (s, 2H), 2.62-2.40 (m, 10H), 2.36 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H). LCMS: m/z 607.16 [M+H] ⁺ .

Scheme 19. Preparation of Compound 61-68

Preparation of 4-((1-(4-chlorobutyl)-2,3-dimethyl-1 H -indol-5-yl)methyl)benzoic acid

Stirring solution of methyl 4-((2,3-dimethyl-1H-indol-5-yl)methyl)benzoate (0.80 g, 2.7 mmol) in DMF (5 mL) A suspension of NaH (0.32 g, 13 mmol) in anhydrous DMF (5 mL) The mixture was stirred at this temperature for 30 minutes. 1-Bromo-4-chlorobutane (1.0 mL, 8.7 mmol) was added dropwise at 0 ° C and the mixture was stirred for 1 hour. After the starting material was completely consumed, the reaction was quenched with saturated aqueous ammonium chloride, diluted with ice cold water and ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a crude brown liquid 4 - ((1- (4-chlorobutyl) -2,3-dimethyl - 1H-Indol-5-yl)methyl)benzoic acid (0.8 g, crude) was used for subsequent work without further purification. LCMS: m/z 370.1 [M+H] ⁺ .

Other analogs prepared by this method: 4-((1-(5-chloropentyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoic acid (80%, Crude). LCMS: m/z 384.1 [M+H] ⁺ .

Preparation of 4-((1-(4-chlorobutyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoic acid methyl ester

4-((1-(4-Chlorobutyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoic acid (0.80 g, 2.2 mmol) in methanol at 0 °C Concentrated sulfuric acid (0.5 mL) was added dropwise to the solution in (20 mL). The mixture was heated to 80 ° C for 16 hours. After the starting material was completely consumed, the reaction mixture was concentrated and then diluted with ethyl acetate. The organic layer was evaporated and washed with saturated NaHCO ₃ solution, water and brine, dried over anhydrous Na ₂ SO ₄ in vacuo to give a brown liquid 4 - ((1- (4-chlorobutyl) -2,3- Methyl dimethyl-1H-indol-5-yl)methyl)benzoate (0.8 g, crude) was used in the next reaction without purification. LCMS: m/z 384.1 [M+H] ⁺ .

Other analogs prepared by this method: 4-((1-(5-chloropentyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoate (81 %, crude). LCMS: m/z 398.1 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzoic acid Preparation of base ester

4-((1-(4-Chlorobutyl)-2,3-dimethyl-1H-indol-5-yl)methyl)benzoic acid methyl ester (0.80 g, 2.1 mmol) at room temperature Sodium iodide (0.78 g, 5.2 mmol), sodium carbonate (0.40 g, 3.8 mmol) and then N -methylhexahydropyrazine (0.38 mL, 3.4 mmol) were added to a stirred solution of acetonitrile (20 mL). . The reaction mixture was heated to 85 ° C for 16 hours. After the starting material was completely consumed, the reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude compound was purified by flash column chromatography using 100-200 mesh silica gel using 4% methanol in dichloromethane as a solvent to give 4-((2,3-dimethyl-1-) as a yellow liquid. (4-(4-Methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzoic acid methyl ester (0.56 g, 60%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.93 (d, J = 8.0Hz, 2H), 7.28 (d, J = 8.0Hz, 2H), 7.25 (br s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.92 (br d, J = 9.6 Hz, 1H), 4.12 (s, 2H), 4.03 (t, J = 12 Hz, 2H), 3.89 (s, 3H), 2.63-2.22 (m, 16H), 2.20 (s, 3H), 1.75-1.57 (m, 4H). LCMS: m/z 448.3 [M+H] ⁺ .

Other analogues prepared by this method: 4-((2,3-Dimethyl-1-(5-(4-methylhexahydropyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzoic acid Base ester (66%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.93 (d, J = 8.0Hz, 2H), 7.28 (d, J = 8.0Hz, 2H), 7.25 (br s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.92 (br d, J = 9.2 Hz, 1H), 4.12 (s, 2H), 4.02 (t, J = 7.2 Hz, 2H), 3.89 (s, 3H), 2.99-2.41 (m, 11H), 2.32 (s, 3H), 2.21 (s, 3H), 1.75-1.70 (m, 2H), 1.55-1.46 (m, 4H), 1.37-1.25 (m, 2H). LCMS: m/z 462.3 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzoic acid preparation

4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)) at 0 °C A solution of methyl benzoate (0.56 g, 1.3 mmol) in THF:MeOH (4:1, 10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. After the starting material was completely consumed, the reaction material was concentrated, neutralized with 2N HCl and extracted with 30% isopropyl alcohol in dichloromethane. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a brown solid 4 - ((2,3-dimethyl-1- (4- (4-methylhexahydrophthalic Hydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzoic acid (0.46 g, 85%). LCMS: m/z 434.2 [M+H] ⁺ .

Other analogs prepared by this method: 4-((2,3-dimethyl-1-(5-(4-methylhexahydropyrazin-1-yl)pentyl)-1 H -indole -5-yl)methyl)benzoic acid (93%). LCMS: m/z 448.3 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)-N- Preparation of (4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide

To 4-((2,3-dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzoic acid (150 mg, 0.35 mmol) and Intermediate D (113 mg, 0.46 mmol. The mixture was stirred at room temperature for 10 minutes and then at 80 ° C for 1 hour. After the starting material was completely consumed, the reaction mixture was concentrated, diluted with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude product. The crude compound was purified by column chromatography on a 100-200 mesh silica gel using 4% methanol in dichloromethane as the eluent to give 4-((2,3-dimethyl-1-(4-) (4-methyl-piperazine-1-yl) butyl) lH-indol-5-yl) methyl) - N - (4'- fluoro-2,6-dimethoxy - [1 , 1 '-biphenyl]-4-yl)benzamide (142 mg, 61%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 10.21 (br s, 1H), 7.90 (d, J = 8.0Hz, 2H), 7.41 (d, J = 8.4Hz, 2H), 7.33 (s, 2H ), 7.29-7.22 (m, 4H), 7.16 (t, J = 9.2 Hz, 2H), 6.94 (br d, J = 8.8 Hz, 1H), 4.094.03 (m, 4H), 3.72 (s, 6H) ), 2.50-2.15 (m, 17H), 1.64-1.53 (m, 2H), 1.51-1.39 (m, 2H), 1.29-1.20 (m, 2H). LCMS: m/z 663.4 [M+H] ⁺ .

Other analogs prepared by this method: N- (4-(1H-imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1) -(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzamide (81%, crude). LCMS: m/z 633.48[MH] ^- .

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(4-(4-methylhexahydropyridyl)) 1-yl) butyl) lH-indol-5-yl) methyl) benzoyl-amine (63%) LCMS:. m / z 644.4 [MH] -.

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(4-(4-methyl) piperazine-1-yl) butyl) lH-indol-5-yl) methyl) benzoyl-amine (68%) LCMS:. m / z 643.4 [MH] -.

N -(4-(1 H -imidazol-1-yl)-3,5-dimethoxyphenyl)-4-((2,3-dimethyl-1-(5-(4-methyl) piperazine-1-yl) pentyl) lH-indol-5-yl) methyl) benzoyl-amine (66% crude) .LCMS: m / z 649.48 [ m + H] +.

N- (3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(5-(4-methylhexahydropyridyl)) Pyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide (61%). LCMS: m/z 660.4 [M+H] ⁺ .

N -(2,6-dimethoxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(5-(4-methyl-6) Hydropyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide (70%). LCMS: m/z 659.4 [M+H] ⁺ .

4-((2,3-Dimethyl-1-(5-(4-methylhexahydropyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl) -N - (4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (62%). LCMS: m/z 677.4 [M+H] ⁺ .

Compound 64,  4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)-N- Preparation of (4'-Fluoro-2,6-dihydroxy-[1,1'-biphenyl]-4-yl)benzamide

4-((2,3-Dimethyl-1-(4-(4-methylhexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)) at 0 °C N- (4'-Fluoro-2,6-dimethoxy-[1,1'-biphenyl]-4-yl)benzamide (140 mg, 0.21 mmol) in dichloromethane (6 mL Boron tribromide (2.0 mL, 1 M dichloromethane solution) was added to the stirred solution. The mixture was stirred at this temperature for 10 minutes, then warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with saturated NaHCO _3, followed by extraction with 30% of isopropanol in chloroform. The organic layer was dried over anhydrous Na _{2 4} SO and concentrated under reduced pressure to give crude product. The crude compound was purified by prep-TLC using 10% methanol in dichloromethane to elute to afford 4-((2,3-dimethyl-1-(4-(4-methyl) piperazine-1-yl) butyl) -1 H - indol-5-yl) methyl) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl ]-4-yl)benzamide (Compound 64) (34 mg, 26%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.81 (d, J = 8.0 Hz, 2H), 7.39-7.34 (m, 4H), 7.25 (br s, 1H), 7.21. (d, J = 8.4 Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.93 (br d, J = 8.4 Hz, 1H), 6.85 (s, 2H), 4.19-4.05 (m, 4H), 2.70-2.25 (m, 16H), 2.19 (s, 3H), 1.74-1.67 (m, 2H), 1.52-1.44 (m, 2H). LCMS: m/z 635.4 [M+H] ⁺ .

Other analogues prepared by this method:

Compound 61, N -(3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl- 1-(4-(4-methyl) Hexahydropyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzamide (14%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.81 (d, J = 8.0 Hz, 2H), 7.65 (br s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (br s, 1H) ), 7.21 (d, J = 8.4 Hz, 1H), 7.13 (br s, 1H), 7.05 (br s, 1H), 6.97-6.92 (m, 3H), 4.15-4.11 (m, 4H), 2.64 2.32 (m, 16H), 2.19 (s, 3H), 1.75-1.69 (m, 2H), 1.53-1.46 (m, 2H). LCMS: m/z 607.3 [M+H] ⁺ .

Compound 62, N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(4-(4-methylhexahydro)) Pyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzamide (23%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.45 (d, J = 6.4Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.53 (d, J = 6.4Hz, 2H), 7.36 ( d, J = 8.4 Hz, 2H), 7.26 (br s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.90 (s, 2H) ), 4.14-4.10 (m, 4H), 2.63-2.28 (m, 16H), 2.19 (s, 3H), 1.76-1.69 (m, 2H), 1.52-1.44 (m, 2H). LCMS: m / z 616.23 [MH ] -.

Compound 63, N -(2,6-dihydroxy-[1,1'-biphenyl]4-yl)4-((2,3-dimethyl-1-(4-(4-methylhexahydro)) Pyrazin-1-yl)butyl)-1H-indol-5-yl)methyl)benzamide (24%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.81 (d, J = 8.0Hz, 2H), 7.40-7.33 (m, 6H), 7.29-7.20 (m, 3H), 6.93 (br d, J = 8.4 Hz, 1H), 6.86 (s, 2H), 4.14 - 4.09 (m, 4H), 2.72 - 2.33 (m, 16H), 2.19 (s, 3H), 1.77-1.69 (m, 2H), 1.52-1.44 ( m, 2H). LCMS: m/z 617.3 [M+H] ⁺ .

Compound 65, N- (3,5-dihydroxy-4-(1H-imidazol-1-yl)phenyl)-4-((2,3-dimethyl-1-(5-(4-methyl) Hexahydropyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide (15%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.81 (d, J = 8.0 Hz, 2H), 7.65 (br s, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.25 (br s, 1H) ), 7.19 (d, J = 8.0 Hz, 1H), 7.13 (br s, 1H), 7.05 (br s, 1H), 6.96 (s, 2H), 6.93 (dd, J = 8.4 Hz, 1.6 Hz, 1H) ), 4.2-4.07 (m, 4H), 2.50 (br s, 8H), 2.34-2.30 (m, 8H), 2.19 (s, 3H), 1.72 (five peaks, J = 7.2 Hz, 2H), 1.47 - 1.43 (m, 2H), 1.35-1.29 (m, 2H). LCMS: m/z 619.27 [MH] ^- .

Compound 66, N- (3,5-dihydroxy-4-(pyridin-4-yl)phenyl)-4-((2,3-dimethyl-1-(5-(4-methylhexahydro)) Pyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide (17%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 8.45 (d, J = 6.0Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.53 (d, J = 6.0Hz, 2H), 7.37 ( d, J = 8.4 Hz, 2H), 7.25 (br s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.96-6.88 (m, 3H), 4.12-4.07 (m, 4H), 2.50 ( Br s,8H), 2.39-2.30 (m,8H), 2.19 (s,3H), 1.74 (five peaks, J = 7.2 Hz, 2H), 1.51-1.43 (m, 2H), 1.35-1.28 (m , 2H). LCMS: m / z 630.28 [MH ] -.

Compound 67, N -(2,6-dihydroxy-[1,1'-biphenyl]-4-yl)-4-((2,3-dimethyl-1-(5-(4-methyl) Hexahydropyrazin-1-yl)pentyl)-1H-indol-5-yl)methyl)benzamide (28%)

¹ H NMR (400 MHz, CD ₃ OD): δ 7.81 (d, J = 8.4 Hz, 2H), 7.37-7.33 (m, 6H), 7.27-7.23 (m, 2H), 7.19 (d, J = 8.4 Hz) , 1H), 6.93 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.86 (s, 2H), 4.12-4.06 (m, 4H), 2.62-2.27 (m, 16H), 2.19 (s, 3H) , 1.73 (five peaks, J = 12 Hz, 2H), 1.50-1.42 (m, 2H), 1.35-1.28 (m, 2H). LCMS: m/z 631.3 [M+H] ⁺ .

Compound 68, 4-((2,3-Dimethyl-1-(5-(4-methylhexahydropyrazin-1-yl)pentyl)-1 H -indol-5-yl)methyl ) - N - (4'- fluoro-2,6-dihydroxy - [1,1'-biphenyl] -4-yl) benzoyl-amine (24%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.81 (d, J = 8.0Hz, 2H), 7.39-7.35 (m, 4H), 7.25 (br s, 1H), 7.19 (d, J = 8.4Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.93 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.86 (s, 2H), 4.11-4.07 (m, 4H), 2.54 (br s , 8H), 2.37-2.32 (m, 8H), 2.19 (s, 3H), 1.74 (five peaks, J = 7.2 Hz, 2H), 1.51-1.43 (m, 2H), 1.36-1.28 (m, 2H) ). LCMS: m/z 647.26 [MH] ^- .

Scheme 20. Preparation of Compound 69.

Preparation of 5-methoxy-2,3-dimethyl-1 H -indole

A mixture of (4-methoxyphenyl)hydrazine hydrochloride (10.5 g, 60 mmol) and butan-2-one (10.7 mL, 120 mmol) Upon cooling, the acetic acid is removed and the residue was dissolved in ethyl acetate (200mL) in, washed with saturated NaHCO ₃ and dried with brine and Na ₂ SO ₄ and concentrated in vacuo to yield a yellow solid 5-methoxy Base-2,3-dimethyl-1H-indole (9.80 g, 94%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.58 (br s, 1H), 7.14 (d, J = 8.8Hz, 1H), 6.92 (d, J = 1.2Hz, 1H), 6.76 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 3.86 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H). LCMS: m/z 176.1 [M+H] ⁺ .

Preparation of 3-(5-methoxy-2,3-dimethyl-1H-indol-1-yl) -N,N -dimethylpropan-1-amine

Add 5-methoxy-2,3-dimethyl-1H-indole (317 mg, 1.81 mmol) in anhydrous DMF (1 mL) EtOAc. Solution. The mixture was stirred at room temperature for 30 minutes. 3-Chloro- N,N -dimethylpropan-1-amine hydrochloride (572 mg, 3.62 mmol) was then added in portions. After the addition, the mixture was stirred at 100 ° C for 1 hour. Upon cooling, the solution was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over Na ₂ SO ₄ and concentrated in vacuo to yield an oil of 3- (5-methoxy-2,3-dimethyl -1H- indol-1-yl) - N ,N -Dimethylpropan-1-amine (350 mg, 77%). LCMS: m/z 261.1 [M+H] ⁺ .

Preparation of 1-(3-(dimethylamino)propyl)-2,3-dimethyl-1 H -indole-5-ol

To 3-(5-methoxy-2,3-dimethyl-1H-indol-1-yl) -N,N -dimethylpropan-1-amine (780 mg, 3 mmol) at 0 ° C BBr ₃ (0.5 mL, excess) was added to a stirred solution of dichloromethane (10 mL). The mixture was stirred at room temperature overnight. Ice water (10 mL) was added dropwise, followed by saturated Na ₂ CO ₃ (40 mL). The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated in vacuo to give 1-(3-(dimethylamino)propyl)-2,3-dimethyl-1H-indole-5-ol (1.1 g, >100% yield: contaminated with inorganic salts). The crude compound was used in the next step without further purification.

Preparation of 4-((1-(3-(dimethylamino)propyl)-2,3-dimethyl-1 H -indol-5-yl)oxy)benzoic acid

1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-ol (100 mg, 0.407 mmol), Cs ₂ CO ₃ (400 mg, 1.22 mmol) A mixture of 4-fluorobenzoic acid methyl ester (125 mg, 0.814 mmol) in N -methyl-2-pyrrolidone (4 mL) was stirred at 140 ° C overnight. After cooling to room temperature, the mixture was poured into aq. EtOAc (1 M, 5 mL), and then stirred at room temperature for 1 hour and then acidified to pH=4 with 1M HCl. Remove water in a vacuum. One half of the residue was purified by reverse phase combi-quick chromatography to give 4-((1-(3-(dimethylamino)propyl)-2,3-dimethyl-1H-indole-5- Benzyloxy)benzoic acid (14 mg, 9%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.95 (d, J = 12 Hz, 2H), 7.40 (brd, J = 3.6 Hz, 1H), 7.15 (br s, 1H), 6.93 - 6.85 (m) , 3H), 4.27 (br s, 2H), 3.17 (br s, 2H), 2.87 (s, 6H), 2.42 (s, 3H), 2.20 (br s, 5H). LCMS: m/z 367.2 [M+H] ⁺ .

Preparation of 2-iodo-5-nitrophenol

At -78 deg.] C solution of 1-iodo-2-methoxy-4-nitrobenzene (1.0g, 3.6mmol) was added BBr ₃ solution in dichloromethane of the solution (1M, 10mL). The solution was stirred at this temperature for 2 hours and then allowed to warm to room temperature overnight. Water was added and the mixture was stirred at 0 ℃ extracted with ethyl acetate, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc) LCMS: m/z 263.8 [MH] ^- .

Preparation of 5-amino-2-iodophenol

Fe powder (253 mg, 4.5 mmol) was added to a solution of 2-iodo-5-nitrophenol (300 mg, 1.1 mmol) in ethanol (10 mL), then concentrated HCl (1 mL). The reaction was stirred at room temperature for 1 hour. The mixture was filtered and the solution was concentrated to give 5-amino-2-iodophenol (180 mg, 70%). LCMS: m/z 236.0 [M+H] ⁺ .

Compound 69, 4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1 H -indol-5-yl)oxy) -N- (3- Preparation of hydroxy-4-iodophenyl)benzamide

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid (114 mg, 0.31 mmol) A solution of DIPEA (120 mg, 0.93 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then HATU (236 mg, 0.62 mmol). The mixture was stirred for 10 minutes, then 5-amino-2-iodophenol (73 mg, 0.31 mmol) was added. The resulting mixture was stirred overnight at room temperature. It was then concentrated under vacuum and the residue was partitioned between 1N EtOAc andEtOAc. The organic layer was separated and concentrated under vacuum. The residue was purified by prep-TLC to afford 4-((1-(3-(dimethylamino)propyl)-2,3-dimethyl-1H-indole-5-yl) as a solid. yloxy) - N - (3- hydroxy-4-iodo-phenyl) benzoyl-amine (compound 69) (5mg, 3%) .

_{^{1 H NMR (400MHz, CD 3}} OD): δ 7.88 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.8Hz, 1H), 7.52 (br s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.16 (br s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.90-6.86 (m, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.21-3.16 (m, 2H), 2.92 (s, 6H), 2.43 (s, 3H), 2.21-2.17 (m, 5H).

Scheme 21. Preparation of Compound 70.

Preparation of (2-methoxy-4-nitrophenyl)(methyl)sulfane

1-iodo-2-methoxy-4-nitrobenzene (1.9 g, 6.8 mmol), NaSMe (500 mg, 7.1 mmol), Pd ₂ (dba) ₃ (156 mg), Xantphos (197 mg) and TEA (1.18) The mixture was stirred with argon and heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc/EtOAcEtOAcEtOAcEtOAc (400 mg, 30%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.66 (d, J = 2.4Hz, 1H), 7.15 (d, J = 8.8Hz, 1H), 4.00 (s, 3H), 2.51 (s, 3H).

Preparation of 2-methoxy-1-(methylsulfonyl)-4-nitrobenzene

(2-Methoxy-4-nitrophenyl)(methyl)sulfane (400 mg, 2.0 mmol) was dissolved in methanol (5 mL) and EtOAc (5 mL). A solution of ozone (1.9 g, 12 mmol) in water (10 mL). The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a yellow solid 2-methoxy-1- (sulfonic acyl methyl) -4-nitrobenzene (368mg, 79%) . The product was used in the next step without further purification.

Preparation of 3-methoxy-4-(methylsulfonyl)aniline

Mixture of 2-methoxy-1-(methylsulfonyl)-4-nitrobenzene (368 mg, 1.59 mmol) and SnCl ₂ (1 g) in ethanol (10 mL) with argon and heated to reflux 1 hour. TLC showed complete consumption of the starting material and the formation of new spots. The reaction mixture was quenched with cold NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ dried and concentrated under reduced pressure to yield a yellow solid of 3-methoxy-4- (sulfonic acyl methyl) aniline (300mg, 94%). The product was used in the next step without further purification. LCMS: m/z 2021. [M+H] ⁺ .

Preparation of 5-amino-2-(methylsulfonyl)phenol

Was added BBr ₃ (1mL, excess) was added to the group of 3-methoxy-4- (sulfonic acyl methyl) aniline (300mg, 1.5mmol) in DCM (10mL) was stirred solution at 0 ℃. The mixture was stirred at room temperature overnight. Ice water (15 mL) was added dropwise, followed by saturated Na ₂ CO ₃ (50 mL). The aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated and dried over Na ₂ SO ₄ in vacuo to yield 5-amino-2- (acyl sulfo methyl) phenol (200mg, 71%). The crude compound was used in the next step without further purification.

Compound 70,  4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy)-N-(3-hydroxy-4- Preparation of (methylsulfonyl)phenyl)benzamide

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid (114 mg, 0.31 mmol) A solution of DIPEA (120 mg, 0.93 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then HATU (236 mg, 0.62 mmol). The mixture was stirred for 10 minutes, after which 5-amino-2-(methylsulfonyl)phenol (58 mg, 0.31 mmol) was added. The resulting mixture was stirred overnight at room temperature. It was then concentrated under vacuum and the residue was partitioned between 1N EtOAc andEtOAc. The organic layer was separated and concentrated under vacuum. The residue was purified by prep-TLC to afford 4-((1-(3-(dimethylamino)propyl)-2,3-dimethyl-1H-indole-5-yl) as a solid. yloxy) - N - (3- hydroxy-4- (sulfonic acyl methyl) phenyl) benzoyl-amine (compound 70) (7mg, 4%) .

^{1 H NMR (400MHz, DMSO-} d 6): δ 8.09 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.8Hz, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.22 (br s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.90 (br d, J = 8.4 Hz, 1H), 6.57 (br d, J = 8.8 Hz, 1H), 6.48 (br s, 1H), 6.35 (br s, 2H), 4.16 (t, J = 6.8 Hz, 2H), 3.10 (s, 3H), 2.36 (br s, 5H), 2.26 (br s, 6H), 2.16 (s, 3H), 1.86-1.79 (m, 2H).

Scheme 22. Preparation of Compound 71.

Preparation of (E)-3-(2-methoxy-4-nitrophenyl)acrylic acid methyl ester

1-iodo-2-methoxy-4-nitrobenzene (2.0 g, 7.16 mmol), methyl acrylate (2.0 mL, 22.2 mmol), Pd(OAc) ₂ (100 mg) and PPh ₃ (200 mg) The mixture in DMF (20 mL) was swept with argon and heated to 70 &lt;0&gt;C overnight. TLC showed complete consumption of the starting material and the formation of new spots. The reaction mixture was diluted with ethyl acetate and the catalyst was removed by filtration. The organic layer was washed with brine, dried over Na ₂ CH ₄ By silica gel column (100% petroleum ether) to give the residue, to yield a yellow solid (E) -3- (2- methoxy-4-nitrophenyl) acrylic acid methyl ester (500mg, 31%) .

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.96 (d, J = 16.0Hz, 1H), 7.84 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.77 (d, J = 2.0Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 16.4 Hz, 1H), 4.00 (s, 3H), 3.83 (s, 3H).

7-nitro-2 H - Preparation of ene-2-one

To a solution of methyl ( E )-3-(2-methoxy-4-nitrophenyl) acrylate (500 mg, 2.1 mmol) in dichloromethane (5 mL) BBr ₃ (1 mL, excess) was added dropwise. The resulting mixture was heated to 50 ° C overnight. The cooled reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ CH ₄ The residue was purified by a hydrazine column (petroleum ether: ethyl acetate = 2:1, v/v) to yield 7-nitro- 2H . Alken-2-one (150 mg, 40%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.18 (d, J = 2.0Hz, 1H), 8.14 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.78 (d, J = 9.2Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H).

7-amino group Preparation of indole-2-one

Will 7-nitro-2 H - A mixture of ene-2-one (315 mg, 1.65 mmol), Pd/C (70 mg) and ethyl acetate (25 mL) was stirred at room temperature under hydrogen pressure of 1.2 MPa overnight. The mixture was then filtered and the filtrate was acidified with EtOAc /EtOAc. The resulting precipitate was collected by filtration and dried to give a 7-amino group. Indole-2-one (105 mg, 40%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.80 (br s, 2H), 7.35 (d, J = 8.4Hz, 1H), 7.04 (dd, J = 8.0Hz, 2.0Hz, 1H), 6.98 ( d, J = 2.0 Hz, 1H), 2.98 (t, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H).

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1 H -indol-5-yl)oxy) -N-(2-sideoxy Preparation of 唍-7-yl)benzamide

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid (114 mg, 0.31 mmol) A solution of DIPEA (120 mg, 0.93 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then HATU (236 mg, 0.62 mmol). The mixture was stirred for 10 minutes, after which 5-amino-2-(methylsulfonyl)phenol (51 mg, 0.31 mmol) was added. The resulting mixture was stirred overnight at room temperature. It was then concentrated under vacuum and the residue was partitioned between 1N EtOAc andEtOAc. The organic layer was separated and concentrated under vacuum. The residue was purified by prep-TLC to afford 4-((1-(3-(dimethylamino)propyl)-2,3-dimethyl-1H-indole-5-yl) as a solid. yloxy) - N - (2- oxoalkyl 唍-7-yl)benzamide (19 mg, 12%).

Compound 71 , 3-(4-(4-((1-(3-(dimethylamino))propyl)-2,3-dimethyl-1 H -indol-5-yl) oxy) Preparation of benzamidine)-2-hydroxyphenyl)propionic acid

4 - ((1- (3- (dimethylamino) propyl) -2,3-dimethyl--1H- indol-5-yl) oxy) - N - (2- oxoalkyl A solution of hydrazine-7-yl)benzamide (19 mg, 0.04 mmol) in THF (5 mL). The mixture was stirred at room temperature for 3 hr then EtOAc (EtOAc)EtOAc. The organic layers were combined, dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure to yield a solid 3- (4- (4 - ((1- (3- (dimethylamino) propyl) - 2,3-Dimethyl-1H-indol-5-yl)oxy)benzhydrylamino)-2-hydroxyphenyl)propanoic acid (Compound 71) (5 mg, 26%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.89 (br s, 1H), 7.91 (d, J = 8.4Hz, 2H), 7.43 (d, J = 8.8Hz, 1H), 7.39 (br s, 1H), 7.14 (d, J = 1.6 Hz, 1H), 7.02-6.95 (m, 4H), 6.86 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H) , 2.73-2.68 (m, 2H), 2.46-2.42 (m, 2H), 2.35 (br s, 5H), 2.24 (s, 6H), 2.14 (s, 3H), 1.85-1.79 (m, 2H). LCMS: m/z 530.3 [M+H] ⁺ .

Scheme 23. Preparation of Compound 72.

Preparation of 2-methoxy-4-nitrobenzonitrile

Add 1-iodo-2-methoxy-4-nitrol to a mixture of CuCN (322 mg, 3.6 mmol) and L -proline (415 mg, 3 mmol) in DMF (15 mL) Benzene (837 mg, 3 mmol). The mixture was stirred at 80 ° C for 45 hours. The resulting suspension was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water. Dried over Na ₂ SO ₄ and the organic phase was concentrated. The residue was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc)

Preparation of 5-(2-methoxy-4-nitrophenyl)-2 H -tetrazole

The mixture of 2-methoxy-4-nitrobenzonitrile _{(510mg, 2.76mmol), NaN 3} (719mg, 11.06mmol) and ZnBr ₂ (2.50g, 11.06mmol) in water (5mL) at 160 ℃ in the Heat under microwave conditions for 30 minutes. Purified by chromatography to give 5- (2-methoxy-4-nitrophenyl) -2 H - tetrazole (450mg, 75%).

Preparation of 5-nitro-2-(2H-tetrazol-5-yl)phenol

(10 mL) was added dropwise in the tetrazole (200mg, 0.90mmol) in dichloromethane - at -78 deg.] C under stirring solution of 5- (2-methoxy-4-nitrophenyl) -2 H BBr ₃ /CH ₂ Cl ₂ (0.5 mL, excess) was added. The resulting mixture was stirred at room temperature for 1 hour and then treated with ice water and extracted with dichloromethane. The organic layer was dried over anhydrous Na ₂ SO _4, concentrated and purified by prep-TLC in vacuo to give 5-nitro -2- (2 H - tetrazol-5-yl) phenol (120mg, 64%) .

Preparation of 5-amino-2-( 2H -tetrazol-5-yl)phenol

-2- (2 H - tetrazol-5-yl) solution of 5-nitrophenol (120mg, 0.58mmol) and Pd / C (30mg) in MeOH (5mL) was charged in a mixture of H ₂ at room Stir under overnight. After purification by chromatography, 5-amino-2-( 2H -tetrazol-5-yl)phenol (87 mg, 84%) was obtained.

Compound 72 , 4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1 H -indol-5-yl)oxy)-N-(3- Preparation of hydroxy-4-( 2H -tetrazol-5-yl)phenyl)benzamide

4-((1-(3-(Dimethylamino)propyl)-2,3-dimethyl-1H-indol-5-yl)oxy)benzoic acid (114 mg, 0.31 mmol) A solution of DIPEA (120 mg, 0.93 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then HATU (236 mg, 0.62 mmol). The mixture was stirred for 10 minutes, then 5-amino-2-iodophenol (55 mg, 0.31 mmol) was added. The resulting mixture was stirred overnight at room temperature. It was then concentrated under vacuum and the residue was partitioned between 1N EtOAc andEtOAc. The organic layer was separated and concentrated under vacuum. The residue was purified by prep-TLC to afford 4-((1-(3-(dimethylamino)propyl)-2,3-dimethyl-1H-indole-5-yl) as a solid. Oxy) -N- (3-hydroxy-4-( 2H -tetrazol-5-yl)phenyl)benzamide (Compound 72) (6 mg, 4%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.04 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.85 (br s, 1H), 7.43-7.40 (m, 2H), 7.18 (br s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.94-6.88 (m, 2H), 4.28 (t, J = 6.8 Hz, 2H), 3.21-3.16 (m, 2H), 2.89 (s, 6H), 2.44 (s, 3H), 2.22 - 2.14 (m, 5H). LCMS: m/z 526.4 [M+H] ⁺ .

Example 2 - Activity of an antigenic myosin compound as a monotherapy

Computer modeling has identified binding sites on tropomyosin Tpm3.1 to produce a range of tropomyosin inhibitors of the invention. Inhibition of Tpm3.1 in tumor cells causes disruption of the actin cytoskeleton and ultimately cell death. The ability of compounds 50 and 51 to disrupt the total actin cytoskeleton (Fig. 1) and specific targeting of actin filaments containing Tpm3.1 (Fig. 2) was evaluated in vitro using microfilament destruction assay.

Briefly, SK-N-SH neuroblastoma cells were seeded at 30 x 10 ³ cells/well in a volume of 1000 μL with complete medium onto a 12-well plate containing 19 mm coverslips and plated prior to treatment. Leave for 24 hours. Cells were then treated with 0 [mu]M, 2.5 [mu]M and 5 [mu]M test compounds. 24 hours after treatment, cells were fixed with 4% paraformaldehyde (PBS) and stained with 488-Atto-Phallodin and DAPI to visualize actin filament bundles and nuclei, or with gamma 9d primary antibody (MAb culture s/n pure line) 2G10.2, 1:50), followed by 488-conjugated secondary antibody (goat anti-mouse 488, 1:1000) and DAPI staining to visualize fibril bundles and nuclei containing Tpm3.1, respectively. A single planar image was obtained on a Perkin Elmer Opera confocal microscope using a 20x objective. Imaging 12 fields per condition was imaged. The images were then exported and the changes in the organization and number of actin filaments in the cells were quantified using a linear feature detection algorithm developed by the Commonwealth Scientific and Industrial Research Organisation (CSIRO). This algorithm detects the "ridge" or "peak" in the local pixel intensity in the cell image. These "ridges" correspond to actin filament bundles and allow quantification of the number of filaments per cell.

The data demonstrates that both compounds 50 and 51 disrupted the total actin cytoskeleton and actin filaments containing Tpm3.1 in a dose dependent manner.

Evaluation of compounds 1-12, 14-20, 26-28, 33-36, 38-40, and 42-68 inhibited neuroblastoma, melanoma, prostate cancer, colorectal cancer, non-small cell lung cancer, and triple-negative breast cancer The ability of cancer cells to proliferate (see Table 1). These studies were carried out by a fiduciary study (GVK-BIO). Briefly, a predetermined number of cells, as calculated from cell growth assays for each cell line used, were seeded into their respective culture media (using ATCC media parameters - http://www.atcc.org) and at 37 °C. The cells were cultured in a 96-well culture plate for 24 hours under 5% CO ₂ . After attachment, each cell line was subsequently exposed to each of the different analogs (30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, and 0.1 μM) for a further 72 h and cell-titre luminescent reagent (100 μL) / hole) exposed for another 30min. The luminescence was captured using an EnVision multi-label reader and the data for each analog concentration was compared for untreated controls. The cell viability was normalized to the control (vehicle only) and a dose - response curves, and using Graph Pad Prism 6 (S-shaped dose-linear regression - Reaction variable slope) measuring the half maximal effective concentration (EC ₅₀₎ values.

The antiproliferative activity of Compound 69-72 against SHEP neuroblastoma and SK-Mel-28 melanoma cells was also evaluated. The SHEP and SK-Mel-28 cell lines were maintained as a monolayer in Dulbeccos Modified Eagles medium (DMEM-Invitrogen) supplemented with 10% fetal bovine serum (FBS) and at 37 ° C. It is grown in a humidified atmosphere with 5% CO ₂ . For cytotoxicity assays, 2 x 10 ³ cells were plated in 96-well plates and treated with serial dilutions of the drug (1:2 starting concentration of 200 μM) and viability was measured after 48 hours using standard MTS assays. The cell viability was normalized to the control (vehicle only) and a dose response curve using Graph Pad Prism 5 - Determination of EC ₅₀ values (Table 2) (S-shaped dose response non-linear regression variable slope).

Example 3 - Activity of a compound of formula (I) in combination with vincristine and paclitaxel

The study was conducted to determine the combined cytotoxic agents vincristine and paclitaxel with compounds 6, 8, 14, 16, 23, 24, 27, 31, 32, 38, 39, 47, 48, 51, 55, 58, 60 Synergistic drug interactions between A375 (malignant melanoma), A549 (lung cancer), and DU145 (prostate cancer) cell lines between 63, 67, and 68.

3.1 Materials and methods Compound

A stock solution (10 mM) was prepared by dissolving the compound in 100% sterile DMSO. Vincristine and paclitaxel were further diluted to 0.1 mM for the experiment. Small aliquots (20 μl) were prepared and stored at -30 ° C with minimal light. For each experiment, only the stock solution was thawed once.

Cell line

All cell lines (A375, A549 and DU145) were tested for mycoplasma contamination and tested negative.

Cell expansion and culture conditions

A549 and A375 cells were cultured in DMEM cell culture medium supplemented with 10% (v/v) FBS and DU145 cells were cultured in RPMI cell culture medium supplemented with 10% (v/v) FBS. All cell lines were cultured for no more than 10 generations in the absence of antibiotics. The cells were harvested by trypsinization (passage +111 (A549), passage +20 (A375) and passage 8 (DU145) at about 80% confluence. The cells were then washed, counted, and plated in 384 well plates.

In vitro growth inhibition analysis

In vitro growth inhibition assays were performed in triplicate in two separate experiments and cell viability was assessed by alamar blue assay reads. Briefly, cells in log phase growth were seeded in 384 well plates at a 50 [mu]L/well assay volume. Cells were seeded at 250 cells/well for A549 using Multidrop 384 (Thermo Scientific), 400 cells/well for A375 and 500 cells/well for DU145, and allowed to accumulate at 37 °C with 5% CO ₂ Adhesive in a wet atmosphere (LiCONiC incubator). After 24 hours of incubation, test compounds, positive control (20 μM guanzolam bromide, 100% kill) and only the wells were added to the wells of each assay plate in triplicate using minimal technique using a Tecan HP D300 digital dispenser. Vehicle (0.4% DMSO). After 72 hours of drug exposure, 10% (v/v) Alamar Blue reagent was added to each assay well to detect metabolic activity by using a Multidrop Combi (Thermo Scientific), and by using an EnSpire (Perkin Elmer) plate reader The fluorescence intensity (excitation 555 nm, emission 585 nm) was measured to determine metabolic activity. Reading was carried out at 0 hours (background) and after 6 hours of Alamar blue incubation at 37 °C.

IC ₅₀ Determination

Using a growth inhibition assay using triplicate drug exposure for 72h alamar Blue assay readout compounds vincristine and paclitaxel as a single agent and concentration for all cell lines IC ₅₀ in two separate experiments. Each drug test was a 10-point concentration series in which each drug was serially diluted twice. For two separate experiments, the concentration series for the compounds of all cell lines tested were 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.156 μM, 0.078 μM, and 0.039 μM. The concentration series of vincristine and paclitaxel were 100 nM, 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.125 nM, 1.5625 nM, 0.781 nM, 0.391 nM and 0.195 nM. Toluidine bromide (20 μM) and 0.4% DMSO were used as positive and vehicle controls, respectively. IC50 values were calculated by deriving a best fit line using a sigmoidal dose response model (Activity Base Suite, IDBS).

Drug combination screening

Each drug combination was tested for A275, A549, and DU145 cells using a 6x6 dose matrix based on the calculated IC50 values using a 2-fold dilution step using a growth inhibition assay using 72h drug exposure in a 384 well format. Two drugs in each combination matrix were assigned using a Tecan HP D300 digital dispenser. The arrangement of each screening plate is shown in Figure 3. Analysis was performed in triplicate for each drug combination (ATM/Vincristine and ATM/Pacific Paclitaxel combination). Synergistic drug interactions were calculated from average cell viability data using the methods described below.

3.2 Data Analysis

Data analysis was performed using the Activity Base suite of software (IDBS, version 8.3.0.175). Cell survival is expressed as a percentage of viable cells. By using S-shaped dose-response model using a technique derived from triplicate data points best fit line ₅₀ is calculated concentration IC.

Computational method of synergistic drug interaction

Synergistic drug interactions were determined for each pair of drug combinations by applying a Bliss-independence model that assumes the independence of the drug mechanism. Prior to analysis, the cell viability (CV) % of the combined data was converted to a cell growth inhibition (GI) score by the following formula: GI = 1 - (CV / 100)

Reactions A and B (using GI values) were used to calculate the predicted combined reaction C for the two single agents using the Bliss additivism model as follows: C=A+B-(A×B)

Experimental observations exceeding the predicted additive value for each combination exhibited a synergistic effect, while values below the predicted additive value exhibited an antagonistic effect against inhibition of cell viability of only a single agent. The final score report for any combination is normalized to 100 by the difference between the value predicted by the additive model and the experimental observation. Using the GI value, the maximum possible synergy score was 100, with 0 indicating no synergy and a negative indicating possible antagonism. The scores are also reported as the "maximum synergy" score (which is the highest individual synergy score for each combination matrix) and the "total synergy" score (which is obtained by summation of each individual synergistic score of the matrix).

3.3 Results IC ₅₀ Determination

Such that the dose of 6 × 6 matrix of combinations can be generated for A375, A549 and DU145 cell growth inhibition assay using Alamar Blue cell viability was measured by reading out the compound as a single agent, the ₅₀ concentration of paclitaxel and vincristine IC. Data listed as technique of two independent experiments in triplicate average value of IC ₅₀ in Table 3. IC ₅₀ then uses the average concentration of a single agent in the synergy of two experiments to generate dose 6 × 6 matrix.

Drug combination screening

Compounds in combination with vincristine and paclitaxel were tested in triplicate for each cell line in a 6 x 6 dose matrix. The synergy score for each drug combination was calculated by the Bliss-independence model. The maximum synergy and total synergy score for each combination of all tested cell lines are listed in Tables 4-6 below.

The highest individual synergy score for each combination matrix of the same function; the sum of each individual synergy score for the total synergy matrix.

* Maximum and total synergy scores were determined for each drug combination matrix. The maximum synergy is the highest individual synergy score for each combination matrix; the sum of each individual synergy score for the total synergy matrix.

The combination of vincristine with the compound of formula (I) produced a synergistic enhancement to the highest degree of cell death in A375, A549 and DU145 cells, with the highest degree of synergy observed for DU145 cells. In the case of a combination of a compound of formula (I) and paclitaxel, a higher synergistic score was observed in A375 cells compared to the other two test cell lines.

References in this specification to any prior publication (or information derived from it) or anything known are not and should not be construed as endorsing or recognizing or implying in any way that the prior publication (or originating from it) Information) or known things form part of the common sense in the field to which this specification is intended.

It will be appreciated by those skilled in the art that the present invention described herein is susceptible to variations and modifications. It is to be understood that the invention includes all such variations and modifications. The present invention also includes any and all of the steps, features, compositions and compounds, and any and all of the steps, features, compositions and compounds, individually or collectively referred to in the specification. combination.

Claims (51)

a compound of formula (I), Or a pharmaceutically acceptable salt, hydrate, derivative, solvate or prodrug thereof, wherein: R ¹ and R ^{2 are} independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl; R ³ -based NR ⁸ R ¹⁰ or 4 to 7 membered carbocyclic rings, wherein 1 to 3 carbons may be replaced by N, O, S or NR ⁶ and wherein the ring is optionally substituted by R ⁷ ; R ⁴ is a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons may be replaced by N, O, S or NR ⁶ ; R ⁵ , wherein each Y is independently OH or C ₁ -C ₆ alkoxy and X is a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons may be replaced by N or NR ^{6 as appropriate} and wherein the ring is 3 substituents selected from the group consisting of halo and C ₁ -C ₆ alkyl, or R ⁵ , Wherein Z is OH or-based C ₁ -C ₆ alkoxy, and Q is selected from the group consisting of consisting of: halo, -SO ₂ C ₁ -C _{6 alkyl, - (CH 2) 0-5 COOH} , - (CH ₂ ) _0-5 COOC ₁ -C ₆ alkyl or a 5 or 6 membered carbocyclic ring, wherein 1 to 4 carbons may be optionally substituted by N or NR ⁶ ; R ^{6 is} selected from the group consisting of H and C ₁ -C ₆ alkyl; R ^{7 is} selected from the group consisting of H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, CN, CF ₃ and OCF ₃ ; R ⁸ and R ¹⁰ independently is selected from the group consisting of: H and C ₁ -C ₆ alkyl group; X ¹ based alkanediyl group having 1 to 20 carbon atoms; and X ² and X ³ are independently selected from the group consisting of: -O- , -NH-, -NC ₁ -C ₆ alkyl-, -C(O)-, -C(O)NH-, -NHC(O)- or an alkanediyl group having 1 to 20 carbon atoms, wherein One to three hydrogen atoms may be replaced by R ^{7 as appropriate} . The compound of claim 1, wherein R ¹ and R ^{2 are} independently selected from the group consisting of H and C ₁ -C ₃ alkyl. The compound of claim 2, wherein both R ¹ and R ² are methyl. The compound of any one of claims 1 to 3, wherein R ³ is a NR ⁸ R ¹⁰ or a 4 to 7 membered carbocyclic ring, wherein 1 to 3 carbons are optionally replaced by N or NR ⁶ and wherein the cyclic condition is R ⁷ replaced. The compound of claim 4, wherein R ³ is NR ⁸ R ¹⁰ or 5 or 6 membered carbocyclic rings, wherein 1 to 3 carbons are optionally replaced by N or NR ⁶ . The compound of claim 5, wherein R ³ is N(Me) ₂ , NH ₂ or a 5 or 6 membered carbocyclic ring, wherein 1 or 2 carbons are optionally replaced by N or NR ⁶ . The compound of claim 6, wherein R ³ is an N(Me) ₂ or 6 membered carbocyclic ring, wherein 1 or 2 carbons are optionally replaced by N, NH or NMe. The compound of claim 4, wherein R ³ is N(Me) ₂ or a saturated 6 membered carbocyclic ring, wherein 1 or 2 carbons are optionally replaced by N, NH or NMe. The compound of any one of claims 1 to 3, wherein R ^{3 is} selected from the group consisting of N(Me) ₂ , NH ₂ and The compound of any one of claims 1 to 3, wherein R ^{3 is} selected from the group consisting of: N(Me) ₂ and . The compound of any one of claims 1 to 10, wherein R ⁴ is a 5 or 6 membered carbocyclic ring, wherein 1 to 3 carbons are optionally replaced by N, NR ⁶ , O or S. The compound of claim 11, wherein R ⁴ is a phenyl group or a 5- or 6-membered heteroaryl ring having 1 to 3 hetero atoms selected from the group consisting of N, O and S. A compound according to claim 12, wherein R ⁴ is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 to 3 N heteroatoms. The compound of claim 13, wherein R ⁴ is a phenyl or a pyridyl group. The compound of claim 14, wherein R ⁴ is a phenyl group. The compound of claim 15 wherein R ⁴ is p-phenyl or m-phenyl. The compound of any one of claims 1 to 16, wherein the R ⁵ is , wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 to 3 hetero atoms selected from the group consisting of N, O and S, and wherein the phenyl group and the The heteroaryl ring may optionally be substituted with 1 or 2 substituents selected from the group consisting of halo, methyl, ethyl, propyl and isopropyl, or R ⁵ , wherein Z is OH or OMe and Q is selected from the group consisting of: halo, -SO ₂ Me, -(CH ₂ ) _0-5 COOH, -(CH ₂ ) _0-5 COOC ₁ -C ₆ alkyl, A phenyl group and a 5 or 6 membered heteroaryl ring having 1 to 4 N heteroatoms. The compound of claim 17, wherein the R ⁵ is Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 to 3 N heteroatoms, and wherein the phenyl group and the heteroaryl ring may optionally have 1 or 2 halo groups. Substituent substitution, or R ⁵ Wherein Z is OH or OMe and Q is selected from the group consisting of halo, -SO ₂ Me, -(CH ₂ ) _1-5 COOH, phenyl and 5 or 6 members having 1 to 4 N heteroatoms Heteroaryl ring. The compound of claim 18, wherein the R ⁵ is Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl group and the heteroaryl ring are optionally substituted with a halo substituent, Or R ⁵ series Wherein Z is OH or OMe and Q is selected from the group consisting of I, -SO ₂ Me, -(CH ₂ ) _1-3 COOH or a 5-membered heteroaryl ring having 1 to 4 N heteroatoms. The compound of claim 19, wherein the R ⁵ is Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl group and the heteroaryl ring are optionally substituted with a fluorine substituent, or R ⁵ series Wherein Z is OH and Q is selected from the group consisting of I, -SO ₂ Me, -(CH ₂ ) ₂ COOH or a 5-membered heteroaryl ring having 1 to 4 N heteroatoms. The compound of claim 20, wherein the R ⁵ is Wherein Y is OH or OMe and X is a phenyl group or a 5 or 6 membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl group and the heteroaryl ring are optionally substituted with a fluorine substituent, or R ⁵ series Wherein Z is OH and Q is selected from the group consisting of I, -SO ₂ Me, -(CH ₂ ) ₂ COOH, and tetrazolyl. The compound of claim 21, wherein X is selected from the group consisting of: The compound of claim 21, wherein X is selected from the group consisting of: The compound of any one of claims 1 to 23, wherein the R ⁵ is or The compound of any one of claims 1 to 23, wherein the R ⁵ is . The compound of any one of claims 1 to 25, wherein X ¹ is an alkanediyl group having 1 to 10 carbon atoms. The compound of claim 26, wherein X ¹ is an alkanediyl group having from 1 to 6 carbon atoms. The compound of claim 27, wherein X ¹ is -(CH ₂ ) _1-6 - or -CH ₂ -CH(Me)-(CH ₂ )-. The compound of any one of claims 1 to 28, wherein X ² and X ^{3 are} independently selected from the group consisting of -O-, -NH-, -NMe, -C(O)NH-, -NHC ( O)- and an alkanediyl group having 1 to 10 carbon atoms. The compound of claim 29, wherein X ² and X ^{3 are} independently selected from the group consisting of -O-, -NH-, -NMe, -C(O)NH-, -NHC(O)- and having 1 An alkanediyl group of up to 6 carbon atoms. The compound of claim 30, wherein X ² and X ^{3 are} independently selected from the group consisting of -O-, -NH-, -C(O)NH-, -NHC(O)-, and CH ₂ . The compound of any one of claims 1 to 28, wherein X ^{2 is} selected from the group consisting of -O-, -NH-, and -CH ₂ -. The compound of any one of claims 1 to 28, wherein X ³ is -C(O)NH- or -NHC(O)-. The compound of claim 1, wherein the compound is selected from the group consisting of: The compound of claim 34, wherein the compound is selected from the group consisting of compounds 6, 8, 16, 23, 24, 47, 48, 51, 60 and 68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35 together with a pharmaceutically acceptable carrier, diluent or excipient. A method of treating a proliferative disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 to 35 or a pharmaceutical composition according to claim 36. The method of claim 37, wherein the proliferative disease is cancer. The method of claim 38, wherein the cancer is breast cancer, lung cancer, prostate cancer, colon cancer, melanoma or neuroblastoma. The method of claim 38 or 39, wherein the cancer has relapsed. Use of a compound according to any one of claims 1 to 35 for the manufacture of a medicament for the treatment of a proliferative disease. A method of reducing the incidence or risk of cancer recurrence in an individual considered to be at risk of cancer recurrence, the method comprising administering to the individual an effective amount of a compound according to any one of claims 1 to 35 or a medicament according to claim 36 combination. Use of a compound of formula (I) according to any one of claims 1 to 35 for the manufacture of a medicament for reducing the incidence or risk of cancer recurrence in an individual considered to be at risk of cancer recurrence. The method of claim 42, wherein the system is a subject of cancer relief. A combination comprising: (i) a compound of formula (I) according to any one of claims 1 to 34, and (ii) vincristine or paclitaxel. A pharmaceutical composition comprising: (i) a compound of formula (I) according to any one of claims 1 to 34, (ii) vincristine or paclitaxel, and (iii) a pharmaceutically acceptable carrier Agent, diluent or excipient. A kit comprising: (i) a pharmaceutical composition of a compound of formula (I) according to any one of claims 1 to 34, and (ii) a pharmaceutical composition of vincristine or paclitaxel, wherein Compositions are intended to be used simultaneously, in parallel, separately or sequentially. A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 34, and a therapeutically effective amount of vincristine or paclitaxel . The method of claim 48, wherein the cancer is melanoma, lung cancer or prostate cancer. A combination of claim 45, such as the composition of claim 46 or the kit of claim 47, wherein the compound of formula (I) is selected from the group consisting of compounds 6, 8, 14, 16, 23, 24, 27, 31 One or more of 32, 38, 39, 47, 48, 51, 55, 58, 60, 63, 67 and 68. The method of claim 48 or 49, wherein the compound of the formula (I) is selected from the group consisting of compounds 6, 8, 14, 16, 23, 24, 27, 31, 32, 38, 39, 47, 48, 51, 55 One or more of 58, 58, 60, 63, 67 and 68.