Patent Application
20230382854
Disclosed herein are novel substituted 6,7-dihydro-5H-benzo[7]annulene derivatives, the processes for their preparation, as well as the therapeutic uses thereof, in particular as anticancer agents via selective antagonism and degradation of estrogen receptors.
The Estrogen Receptors (ER) belong to the steroid/nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation and in target tissues. ERs are in two forms: the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ) respectively encoded by the ESR1 and the ESR2 genes. ERα and ERβ are ligand-activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA/ER complex interacts with co-regulators to modulate the transcription of target genes.
ERα is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERα signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis.
ERα is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high level of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is well established and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority ERα-positive breast tumors. Currently, several strategies for inhibiting the estrogen axis in breast cancer exist, including: 1—blocking estrogen synthesis by aromatase inhibitors that are used to treat early and advanced ERα-positive breast cancer patients; 2—antagonizing estrogen ligand binding to ERα by tamoxifen which is used to treat ERα-positive breast cancer patients in both pre- and post-menopausal setting; 3—antagonizing and downregulating ERα levels by fulvestrant, which is used to treat breast cancer in patients that have progressed despite endocrine therapies such as tamoxifen or aromatase inhibitors.
Although these endocrine therapies have contributed enormously to reduction in breast cancer development, about more than one-third of ERα-positive patients display de novo resistance or develop resistance over time to such existing therapies. Several mechanisms have been described to explain resistance to such hormone therapies. For example, hypersensitivity of ERα to low estrogen level in treatment with aromatase inhibitors, the switch of tamoxifen effects from antagonist to agonist effects in tamoxifen treatments or multiple growth factor receptor signaling pathways. Acquired mutations in ERα occurring after initiation of hormone therapies may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the Ligand Binding Domain (LBD), result in the ability to bind to DNA in the absence of ligand and confer hormone independence in cells harboring such mutant receptors.
Most of the endocrine therapy resistance mechanisms identified rely on ERα-dependent activity. One of the new strategies to counterforce such resistance is to shut down the ERα signaling by removing ERα from the tumor cells using Selective Estrogen Receptors Degraders (SERDs). Clinical and preclinical data showed that a significant number of the resistance pathways can be circumvented by the use of SERDs.
There is still a need to provide SERDs with good degradation efficacy.
Documents WO2017/140669 and WO2018/091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs.
The inventors have now found novel compounds able to selectively antagonize and degrade the estrogen receptors (SERDs compounds), for use in cancer treatment.
Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof:
wherein:
The compounds of formula (I) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers.
The compounds of formula (I) may be present as well under tautomer forms.
The compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Hence, herein are provided compounds of formula (I) or pharmaceutically acceptable salts thereof.
These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided.
Among suitable salts of the compounds of formula (I), hydrochloride may be cited.
As used herein, the terms below have the following definitions unless otherwise mentioned throughout the instant specification:
In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R3 is —COOH.
In another embodiment, in the compounds of formula (I) as defined above, X represents —CH2—.
In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 represent independently from each other a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a —NH2 group or a —OH group; or R4 and R5 together form an oxo group, a ═NOCH3 group or a cyclopropyl group with the carbon atom to which they are attached or alternatively R4 and R7 together form a cyclopropyl group together with the bond to which they are attached, in particular both of R4 and R5 represent hydrogen atoms or a fluorine atom, or one of R4 and R5 represents a hydrogen atom and the other a fluorine atom or a —OH group, or one of R4 and R5 represents a methyl group and the other a hydroxy group or a fluorine atom, more particularly R4 and R5 both represent a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 represent a hydrogen atom, a —NH2 group, a methyl group, a methoxy group, an ethoxy group.
In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 both represent a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R7 represents a hydrogen atom, a —OH group, a methyl group or a fluorine atom, more particularly a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents R6 represents a phenyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a hydroxy methyl group, a 2-hydroxyethyl group, a fluoromethyl group, a difluoromethyl group, a 2,2-difluoroethyl group, a methoxy group, an ethoxy group, a cyano group, a cyanomethyl group, a trifluoromethylsulfonyl group, a methylsulfanyl group, a difluoromethylsulfanyl group, a methylsulfonyl group and a difluoromethoxy group.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a fused phenyl group, selected from a bicyclo[4.2.0]octa-trienyl group and an indanyl group, said groups being optionally substituted with one or two fluorine atoms.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cycloalkyl group selected from a cyclohexyl group, a cyclopentyl group, a cycloheptyl group, a cycloheptenyl group and a cyclohexenyl group, said cycloalkyl group being optionally substituted with 1 to 4 substituents independently selected from:
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a heterocycloalkyl group, and more particularly a tetrahydropyranyl group, said heterocycloalkyl group being optionally substituted with 1 to 3 substituents independently selected from: a (C1-C6)alkyl group, a fluorine atom and a —OH group.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a bicyclic group selected from
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a (C1-C6)alkyl group selected from an ethyl, an isobutyl group and an ethylbutyl, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group and a —OH group, and in particular optionally substituted with 1 or 3 fluorine atoms.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cis-1,3a,4,5,6,6a-hexahydropentalenyl group.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cyclobutylmethyl group.
In another embodiment, in the compounds of formula (I) as defined above, R6 represents a phenyl(C1-C2)alkyl group, in particular chosen from a phenylmethyl or a phenylethyl.
In another embodiment, in the compounds of formula (I) as defined above, R3′ and R3″ represent a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R8 independently represents a methyl group or a fluorine atom and n is 0, 1 or 2.
In another embodiment, in the compounds of formula (I) as defined above, Y represents —CH═, —C(CH3)═, —CF═ or —N═, and in particular —CH═ or —N═.
In another embodiment, in the compounds of formula (I) as defined above, R9 represents a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R10 and R10′ represent a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R11 represents a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, m is 1.
In another embodiment, in the compounds of formula (I) R3 is a COOH group and R6 is a phenyl group comprising two or three substitutions independently selected from a chlorine atom, a fluorine atom, a trifluoromethyl group and a methyl group, at least one of the substitutions comprising a halogen atom. In such embodiment, R3′ and R3″ are in particular hydrogen atoms. Still in such embodiment, R1, R2, R4; R5, R7, R9, R10, R10′ and R11 are hydrogen atoms. In such embodiment, Y is a —CH═ group and n is equal to 0. Still in such embodiment, X is a —CH2— group. Still in such embodiment, m is 1.
In addition to said embodiment, further embodiments are herein provided.
A further embodiment provides compounds of the formula (I′), or pharmaceutically acceptable salts thereof:
wherein:
The compounds of formula (I′) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers.
The compounds of formula (I′) may be present as well under tautomer forms.
The compounds of formula (I′) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Hence, herein are provided compounds of formula (I′) or pharmaceutically acceptable salts thereof.
These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I′) are also provided.
Among suitable salts of the compounds of formula (I′), hydrochloride may be cited.
In an embodiment, in the compound of formula (I′) as defined above, represents a single bond.
In another embodiment, in the compounds of formula (I′) as defined above, Rib and R2b are a hydrogen atom.
In another embodiment, in the compounds of formula (I) as defined above, R3b is —COOH.
In another embodiment, in the compounds of formula (I′) as defined above, Xb represents —CH2—.
In another embodiment, in the compounds of formula (I′) as defined above, R4b and R5b represent independently a hydrogen atom, a fluorine atom, a —NH2 group, a methyl group or a —OH group, in particular represent independently a hydrogen atom, a fluorine atom or a —OH group; or R4b and R5b together form an oxo group, in particular both of R4b and R5b represent hydrogen atoms or a fluorine atom, or one of R4b and R5b represents a hydrogen atom and the other a fluorine atom or a —OH group, more particularly R4b and R5b both represent a hydrogen atom.
In another embodiment, in the compounds of formula (I′) as defined above, R7b represents a hydrogen atom or a fluorine atom, more particularly a hydrogen atom.
In another embodiment, in the compounds of formula (I′) as defined above, R6b represents a phenyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a chlorine atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group and a difluoromethoxy group.
In another embodiment, in the compounds of formula (I′) as defined above, R6b represents a pyridyl group, said pyridyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom, a (C1-C6)alkyl group, a (C1-C6)haloalkyl group, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group and a —OH group, and more particularly selected from a methoxy group.
In another embodiment, in the compounds of formula (I′) as defined above, R6b represents a cycloalkyl group selected from a cyclohexyl group, a cyclopentyl group and a cyclohexenyl group, said cycloalkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom and a methyl group.
In another embodiment, in the compounds of formula (I′) as defined above, R6b represents a tetrahydropyran group, said tetrahydropyran group being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group and a —OH group.
In another embodiment, in the compounds of formula (I′) as defined above, R6b represents a spiro[3.3]hept-1-ene or a spiro[3.3]hept-2-ane group, said spiro[3.3]hept-1-ene or spiro[3.3]hept-2-ane group being optionally substituted with 1 to 4 substituents independently selected from: a (C1-C6)alkyl group, a fluorine atom, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group and a —OH group, and in particular optionally substituted with 1 or 2 fluorine atoms.
In another embodiment, in the compounds of formula (I′) as defined above, R6b represents an isobutyl group, said isobutyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group and a —OH group, and in particular optionally substituted with 1 to 3 fluorine atoms.
In another embodiment, in the compounds of formula (I′) as defined above, R8b independently represents a methyl group or a fluorine atom and n is 0, 1 or 2.
In another embodiment, in the compounds of formula (I′) as defined above, Yb represents —CH—, —C(CH3)—, —CF— or —N—, and in particular —CH— or —N—.
Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof:
Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as an inhibitor and degrader of estrogen receptors.
Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, especially breast cancer.
Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
Another embodiment is a method of treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
Another embodiment is a pharmaceutical composition comprising as active principle an effective dose of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
The compounds of the formula (I) can be prepared by the following processes.
The compounds of the formula (I) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known by the skilled person in the art. In addition, solvents, temperatures and other reaction conditions presented below may vary as deemed appropriate to the skilled person in the art.
General below methods for the preparation of compounds of formula (I) optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formula (I) as described below.
The following abbreviations and empirical formulae are used:
According to SCHEME 1a—Part—1 and Part—2, in which R3a is H, a carboxylic ester such as COOMe, COOEt, or protected OH as O-pivaloyl for example, R1, R2, R3, R3′, R3″, R4, R5, R6, R7, R8, R9, R10, R10′, R11, n, m, X and Y are defined as described above, compound 1A (prepared according to WO2017140669 when X═C), can be converted in STEP 1 to compound 1C by treatment with compound 1B in the presence of a palladium catalyst, for example bis (triphenylphosphine) palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine such as triphenylphosphine in solution in toluene by heating up to reflux of solvent in presence of a base such as KOPh.
Compound 1C can be converted in STEP 2 to compound 1E by treatment with compound 1D in a Suzuki coupling reaction using for example [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
Alternatively, compound 1E can be obtained in STEP 1′ by Suzuki coupling between compound 1A and compound 1D′ using for example [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
Compound 1E can be converted in STEP 3 to compound 1F by treatment for example with pyridinium tribromide in DCM or THF at room temperature.
This bromo derivative intermediate 1F can then be subjected in STEP 4 to a second Suzuki coupling with a suitable boronic reagent R6B(OR′)2, wherein —B(OR′)2 is a boronic acid or a pinacolate ester and R6 is defined as above, using for example Pd(dppf)Cl2, complex with DCM, as catalyst, in a mixture of dioxane and water as solvent and in the presence of a base, for example Cs2CO3, at room temperature or by heating up to reflux to give compound 1G. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced by hydrogenation with a catalyst such as Pd/C under hydrogen pressure (H2) around 5 bars for example at temperature up to 70° C. to give the corresponding saturated compound 1G.
Alternatively, compound 1F can be subjected to a photocatalyzed coupling reaction with R6Br, where R6 is an alkyl group, a cycloalkyl or a spiro bicyclic alkyl as defined above, using catalysts such as (Ir[dF(CF3)ppy]2(dtbpy))PF6 and nickel(II) chloride ethylene glycol dimethyl ether complex in presence of tris(trimethylsilyl)silane and bases such as 4,4′-di-tert-butyl-2,2′-bipyridine and sodium carbonate to give the corresponding compound 1G.
Compound 1G can be converted in STEP 5 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH).
Intermediate 1F can be converted in STEP 6 to compound 1Fa in the presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH).
This compound 1Fa can be converted in STEP 7 to compound I through Suzuki conditions using a suitable boronic reagent R6B(OR′)2, wherein —B(OR′)2 is a boronic acid or a pinacolate ester and R6 is as above defined, using for example Pd(dppf)Cl2, complex with DCM, as catalyst, in a mixture of dioxane and water as solvent and in the presence of a base, for example Cs2CO3, at room temperature or by heating up to reflux of solvents. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced by hydrogenation with a catalyst, such as Pd/C under hydrogen (H2) pressure around 5 bars, for example at temperature up to 70° C., to give the corresponding saturated compound I.
When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, deprotection can be performed in STEP 5 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, extraction of the product could give the sodium salt of compound I. The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound I. The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound I.
Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1G
wherein R1, R2, R3″, R3″, R4, R5, R6, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as defined above and R3a is carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl for example, is converted to compound of formula (I), in presence of a source of hydroxide ions, such as NaOH in solution in methanol, said step being optionally preceded by a step for obtaining compound 1G, wherein a compound of formula 1F
wherein, R1, R2, R3″, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described above and R3a is as defined above, is subjected to a Suzuki coupling with a boronic reagent R6-B(OR′)2, wherein —B(OR′)2 is a boronic acid or a pinacolate ester and R6 is as defined above.
Herein is also provided a process for preparing a compound of formula (I) as described above, wherein a compound of formula 1Fa
wherein R1, R2, R3, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described above, is submitted to a Suzuki coupling with a boronic reagent R6-B(OR′)2, wherein —B(OR′)2 is a boronic acid or a pinacolate ester and R6 is defined above, said step being optionally preceded by a step for obtaining compound 1Fa, wherein a compound of formula 1F
wherein R1, R2, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described above and R3a is as defined above, is converted to a compound 1Fa in the presence of a source of hydroxide ions, such as NaOH in solution in methanol.
Herein are also provided the intermediate compounds selected from compounds of formula 1E, 1F, 1G and 1Fa, or any of its pharmaceutically acceptable salt,
wherein R1, R2, R3, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as defined above and R3a is carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl.
Herein is further provided the intermediate compound of formulas 1D and 1D′, or any of their pharmaceutically acceptable salt
wherein R1, R2, R4, R5, R7, R8, R9, R10, R10′, n and Y are as described above.
In another aspect, herein is also provided a process for the preparation of a compound of formula (I), wherein R3 is a —COOH group, comprising a deprotection step of a compound of formula IG as defined above, optionally followed by a purification step.
Said purification step may for example consist, as illustrated in step 2 of example 1 herein after, in an acidification step, for example with an aqueous solution of hydrochloric acid.
According to SCHEME 1b, in which R3a is H, a carboxylic ester such as COOMe, COOEt or protected OH with O-pivaloyl for example, and R11 is a hydrogen atom, R1, R2, R3, R3′, R3″, R4, R5, R6, R7, R8, R9, R10, R10′, n, m, X and Y are defined as described above, compound 1I can be converted in STEP 1 to compound 1J by treatment with aryl bromide or iodide in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), in solution in toluene by heating up to reflux of solvent, in presence of a base such as K2CO3 or Cs2CO3.
Compound 1J can be converted in STEP 2 to compound 1K by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of base such as DBU or NaH or KHMDS at −50° C. in a solvent such as MeTHF.
Compound 1K can be converted in STEP 3 to compound 1L by treatment for example with bis(pinacolato)diboron (compound 1B), and with a palladium catalyst, for example bis (triphenylphosphine) palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine such as triphenylphosphine in solution in toluene by heating up to reflux of solvent, in presence of a base such as KOPh.
Compound 1G can be prepared in a Suzuki coupling reaction between compounds 1L and 1D in STEP 4 using for example [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compound 1G can be converted in STEP 5 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a —COOH group, extraction of the product could give the sodium salt of compound I. The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound I. The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acide in the eluent could give the formate or trifluoroacetate salt of compound I.
Alternatively, compound 1L can be converted in STEP 4′ to compound 1N in a Suzuki coupling reaction with compound 1 M using for example [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
Compound 1N can be reduced to compound 10 in STEP 5′ by hydrogenation with a catalyst, such as PtO2 under hydrogen (H2) pressure, around 2 bars for example, at room temperature.
When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compound 1O can be converted in STEP 6′ to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a —COOH group, extraction of the product could give the sodium salt of compound I. The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound I. The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acide in the eluent could give the formate or trifluoroacetate salt of compound I.
Herein is further provided the intermediate compound of formula 1L, or any of its pharmaceutically acceptable salt
wherein R3a, R3′, R3″, X, m and R6 are as described above and R11 is a hydrogen atom.
According to SCHEME 1c, in which R3a is H, a carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl for example, and R11 is a hydrogen atom R1, R2, R3, R3′, R3″, R4, R5, R6, R7, R8, R9, R10, R10′, R11, n, m, X and Y are defined as described above, compound 1F can be converted in STEP 1 to compound 1H by treatment for example with bis(pinacolato)diboron (compound 1B) and with a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine such as triphenylphosphine in toluene by heating up to reflux of solvent in presence of a base such as KOPh.
Compound 1G wherein R6 is phenyl or heteroaryl can be prepared in a Suzuki coupling reaction between compounds 1H and either R6Br or R6I or R6OTf in STEP 2 using for example [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compound 1G can be converted in STEP 3 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a —COOH group, extraction of the product could give the sodium salt of compound I. The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound I. The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound I.
According to SCHEME 1d, in which X, m, R3′, R3″ and R11 are defined as described above, compound 1A could be commercially available or prepared as follows: compound 1Aa (commercially available or prepared according to WO2017140669 and WO2018091153), can be converted in STEP 1 to compound 1Ab by treatment with trifluoromethanesulfonic anhydride, in solution in DCM, in the presence of pyridine as a base.
Compound 1Ab can be converted in STEP 2 to compound 1Ac by carbonylation with carbon monoxide, in solution in DMF and MeOH, in the presence of a palladium catalyst, for example [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM.
Compound 1Ac can be converted in STEP 3 to compound 1A wherein R3a ═CO2Me by treatment with trifluoromethanesulfonic anhydride, in solution in DCM, in the presence of pyridine as a base.
According to SCHEME 1e, in which R3a is H, a carboxylic ester such as COOMe, COOEt or protected OH with O-pivaloyl for example, and R11 is a hydrogen atom R1, R2, R3, R3′, R3″, R4, R5, R6, R7, R8, R9, R10, R10′, R11, n, m, X and Y are defined as described above, compound 1K can be converted in STEP 1 to compound 1G by treatment with compound 1D′ in the presence of a palladium catalyst, for example [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compound 1G can be converted in STEP 2 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a —COOH group, extraction of the product could give the sodium salt of compound I. The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound I. The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound I.
According to SCHEME 1f, in which R3a is H, a carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl for example, R3′, R3″, R11, X and m are defined as described above, compound 1J could alternatively be prepared as follows: compound 1I can be converted in STEP 1 to compound 1Ia by treatment with pyridinium tribromide in DCM or THF at room temperature for example.
Compound 1Ia can be converted in STEP 2 to compound 1Ib by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.
Compound 1Ic can be prepared in STEP 3 in a Suzuki coupling reaction between compounds 1Ib and R6B(OR′)2 or R6BF3K using for example [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(I) (Pd(dppf)Cl2), complex with DCM, as catalyst, in a mixture of toluene and water and in the presence of a base, for example cesium carbonate (Cs2CO3), by heating up to reflux of solvent.
Compound 1Ic can be converted in STEP 4 to compound 1J by hydrolysis with aqueous HCl solution by heating in methanol and DCM for example.
The 1H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (6 in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.
The liquid chromatography/mass spectra (LC/MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210-400 nm and flash Acquity UPLC CSH C18 1.7 μm, dimension 2.1×30 mm, mobile phase H2O+0.1% HCO2H/CH3CN+0.1% HCO2H.
The following tables 1a and 1b comprise respectively specific compounds of formula (I) (name and structure) in accordance with the present disclosure as well their characterization (1H NMR and liquid chromatography/mass).
The examples which follow describe the preparation of some compounds of formula (I) described herein. The numbers of the compounds exemplified below match those given in the Table 1a above. All reactions are performed under inert atmosphere, unless otherwise stated.
In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds.
Method 1:
A suspension of 3-(4-bromobenzyl)azetidine, trifluoroacetic acid (4.5 g, 13.23 mmol) in DMF (45 ml), K2CO3 (5.67 g, 41.01 mmol) and 1-fluoro-3-iodopropane (2.49 g, 13.32 mmol) was heated to 70° C. for 2 hours. After cooling to room temperature, water (500 ml) was added and the reaction mixture was extracted three times with 200 ml of EtOAc. The organic phases were gathered, washed with water (150 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 2.3 g (61%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine as a viscous oil.
LC/MS (m/z, MH+): 286
Method 2:
A mixture of 3-(4-bromobenzyl)azetidine, trifluoroacetic acid (4 g, 11.76 mmol) in THF (20 ml), 1-fluoro-3-iodopropane (2.21 g, 11.76 mmol) and NaOH 5N (7.06 ml, 35.28 mmol) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (150 ml) and the reaction mixture was extracted three times with 150 ml of EtOAc. The organic phases were gathered, washed with water (150 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 1.58 g (47%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine as a viscous oil.
A mixture of Intermediate 1 (5 g, 17.47 mmol), bis(pinacolato)diboron (6.65 g, 26.21 mmol), KOAc (5.14 g, 52.41 mmol) and Pd(dppf)Cl2 (1.28 g, 1.75 mmol) in dioxane (50 mL) was degassed and purged 3 times with Ar and then the mixture was stirred at 80° C. for 12 hours under Ar atmosphere. The reaction mixture was filtered through celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 90/10, to give 4 g (69% yield) of 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine as a brown oil.
LC/MS (m/z, MH+): 334
A mixture of 3-(4-bromobenzyl)azetidine 4-methylbenzenesulfonate (19.39 g, 48.68 mmol), DMAP (17.98 g, 145.70 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (11.29 g, 58.30 mmol) and 3-fluoropropanoic acid (4.7 g, 48.50 mmol) in DMF (120 ml) was stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure. To the resulting residue obtained were added water (150 ml) and EtOAc (300 ml). After decantation, the organic phase was washed successively with NaOH 1N (50 ml), water (100 ml), HCl 1N (50 ml) and water (200 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 8.5 g (58%) of 1-(3-(4-bromobenzyl)azetidin-1-yl)-3-fluoropropan-1-one.
LC/MS (m/z, MH+): 299
To a mixture of 1-(3-(4-bromobenzyl)azetidin-1-yl)-3-fluoropropan-1-one (510 mg, 1.70 mmol) in diethyl ether (10 ml) at room temperature was added lithium aluminium deuteride (147 mg, 3.43 mmol). After 30 minutes, the reaction mixture was cooled to 4° C. After addition successively of EtOAc (1 ml), water (150 μl), NaOH 15% (150 μl) and water (450 μl), the white precipitate was filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 214 mg (44%) of 3-(4-bromobenzyl)-1-(1,1-dideuterio-3-fluoro-propyl)azetidine.
LC/MS (m/z, MH+): 287
A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (15 g, 42.82 mmol) (prepared according to WO2017140669), in toluene (150 ml), Pd(PPh3)2Cl2 (1.53 g, 2.14 mmol), PPh3 (673.87 mg, 2.57 mmol), bis(pinacolato)diboron (144.08 g, 52.67 mmol) and PhOK (8.04 g, 60.80 mmol) was heated to 75° C. during 1.5 hours. The yellow suspension becomes orange then brown. After cooling to room temperature, DCM (150 ml) and water (150 ml) were added, and decantation was done by hydrophobic column. The organic phase was concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of heptane/DCM: from 85/15 to 20/80 to give 10.1 g (72%) of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid.
LC/MS (m/z, MH+): 329
Intermediate 5 was prepared following a similar procedure to that of Intermediate 4 from methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2020/049153) to give 3.9 g (82%) of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid.
LC/MS (m/z, MH+): 473
Argon is bubbled for 10 minutes in a mixture of 1-bromo-2,4-difluoro-benzene (6.63 g, 34.37 mmol), methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (5 g; 22.91 mmol), K2CO3 (12.67 g, 91.66 mmol) in toluene (40 ml). After addition of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.32 g, 2.91 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.05 g, 1.15 mmol), the reaction mixture was heated to reflux for 72 hours. After cooling to room temperature, water (40 ml) and DCM (40 ml) were added. After decantation, the aqueous phase was washed three times with 40 ml of DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of Heptane/EtOAc from 100/00 to 90/10 to give 2.55 g (34%) of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 331
To a suspension of sodium hydride (545 mg, 13.62 mmol) in Me-THF (22 ml) cooled at 5° C. was added DBU (277 mg, 0.27 ml, 1.82 mmol) followed by a solution of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate (3 g, 9.08 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (4.2 g, 11.81 mmol) in THF. The cooling bath was removed to allow the temperature to warm up to room temperature. A mixture of acetic acid (0.4 ml) and water (32 ml) was dropwise added, followed by water (100 ml) and EtOAc (150 ml). After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure The residue obtained was purified by flash chromatography, eluting with DCM/heptane 50/50 to give 2.77 g (66%) of methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 463
Intermediate 6 was prepared following a similar procedure to that of Intermediate 4 from methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, to give 1.89 g (72%) of methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 473
A mixture of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) (17 g, 52.41 mmol), 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine (Intermediate 1) (15 g, 52.41 mmol), Pd(dppf)Cl2 complex with DCM (2.42 g, 3.14 mmol), Cs2CO3 (43.56 g, 134 mmol) in dioxane (120 ml) and water (50 ml) was heated to reflux for 1 hour. After cooling to room temperature, DCM (500 ml) and water (300 ml) were added, and decantation was done by hydrophobic column. The organic phase was concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 98/02 to give 16.19 g (90%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange viscous oil.
LC/MS (m/z, MH+): 408
To a mixture of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (19 g, 46.62 mmol) in DCM (150 ml) was added pyridinium tribromide (21.54 g, 60.61 mmol). The reaction mixture was stirred for 2 hours at room temperature. Water (100 ml) and DCM (150 ml) were added and pH was adjusted to 8 with concentrated solution of NaHCO3. The aqueous phase was washed 3 times with DCM and the gathered organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 7.48 g (33%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown viscous oil.
LC/MS (m/z, MH+): 486
A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (9.7 g, 20 mmol) in toluene (150 ml), Pd(PPh3)2Cl2 (1.5 g, 2 mmol), PPh3 (1 g, 4 mmol), bis(pinacolato)diboron (13 g, 50 mmol) and PhOK (7.9 g, 60 mmol) was heated to 100° C. for 3 hours. After cooling to room temperature, a saturated solution of Na2CO3 (50 ml) was added. After decantation, the organic phase was washed with water (25 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 8.2 g (75%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 534
To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepine-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO2018091153) and pyridine (2.82 g, 2.89 ml, 35.36 mmol) in DCM (120 ml) cooled at −20° C. was dropwise added trifluoromethanesulfonic anhydride (8.14 g, 6 ml, 28.28 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. Water (50 ml) was added. The organic phase was separated and washed with saturated solution of NaHCO3 (50 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 311
To a solution of compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-yl trifluoromethanesulfonate (7.4 g, 23.85 mmol) in DMF (30 mL) and MeOH (15 mL) was added DIEA (3.15 g, 4.16 ml, 23.85 mmol) and Pd(dppf)Cl2 complex with DCM (1.10 g, 1.43 mmol), the suspension was degassed and purged with CO 3 times. The mixture was stirred under CO (5 bars) at 75° C. for 2 hours. The reaction was filtered through celite. The filtrate was diluted with water (400 ml) and extracted with EtOAc (three times 300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography eluting with a gradient of heptane/ethyl acetate: from 85/15 to 80/20 to give 4.6 g (87.6%) methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate.
LC/MS (m/z, MH+): 221
To a mixture of methyl-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate (1.5 g, 6.811 mmol) and pyridine (812 mg, 0.826 ml, 10.22 mmol) in DCM (60 ml) cooled at 1.5° C., was dropwise added trifluoromethanesulfonic anhydride (3.92 g, 2.31 ml, 13.62 mmol). The reaction mixture was stirred at room temperature for 18 hours. Ice (25 g) and water (25 ml) were added. The organic phase was separated and washed with water (35 ml) and saturated solution of NaHCO3 (35 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/heptane: from 50/50 to 100/00 to give 2.06 g (86%) of methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.
LC/MS (m/z, MH+): 353
Step 4 of Intermediate 9 was prepared following a similar procedure to that of Intermediate 4 from methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-8-carboxylate to give 1.34 g (73%) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.
LC/MS (m/z, MH+): 331
Step 5 of Intermediate 9 was prepared following a similar procedure to that of step 1 of Intermediate 7 from methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate and 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine to give 230 mg (55%) methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.
LC/MS (m/z, MH+): 410
Step 6 of Intermediate 9 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate to give 111 mg (40.5%) of methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.
Step 1 of Intermediate 10 was prepared following a similar procedure to that of step 1 of Intermediate 9 from 8-hydroxy-3,4-dihydrobenzo[b]thiepine-5(2H)-one (prepared according to WO2018091153) to give 6.3 g (48%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 327
Step 2 of Intermediate 10 was prepared following a similar procedure to that of step 2 Intermediate 9 from 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-yl trifluoromethanesulfonate to give 6.36 g (94%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate.
LC/MS (m/z, MH+): 237
Step 3 of Intermediate 10 was prepared following a similar procedure to that of step 3 of Intermediate 9 from methyl-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate to give 1.84 g (79%) of methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate.
LC/MS (m/z, MH+): 369
Step 4 of Intermediate 10 was prepared following a similar procedure to that of Intermediate 4 from methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate to give 867 mg (50%) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate.
LC/MS (m/z, MH+): 347
Step 5 of Intermediate 10 was prepared following a similar procedure to that of step 1 Intermediate 7 from methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate and 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine to give 650 mg (86%) of methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate.
LC/MS (m/z, MH+): 410
Step 6 of Intermediate 10 was prepared following a similar procedure to that of step 2 Intermediate 7 from methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate to give 445 mg (84%) of methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate.
LC/MS (m/z, MH+): 504
To a solution of 1,4-dibromobenzene (290 g, 1.23 mol, 157 mL, 1.50 eq) in THF (1050 ml) was added n-BuLi (2.5 M, 491 ml, 1.50 eq) at −70° C. The mixture was stirred for 30 minutes before addition of 1-azetidinecarboxylic acid, 3-[(methoxymethylamino)carbonyl]-1,1-dimethylethyl ester (200 g, 819 mmol, 1.00 eq) in THF (420 mL) at −70° C. The mixture was stirred for 1.5 hours. The solution was warmed up to −25° C. and slowly quenched by aqueous saturated NH4Cl (2000 ml). The mixture was extracted twice with MTBE (800 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 10/1 to 0/1 to give 180 g (65%) of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate as a white solid.
LC/MS (m/z, MH+): 340
To a solution of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate (40 g, 117 mmol) in DCM (200 ml) was added TFA (88.6 g, 777 mmol, 57.5 ml). The mixture was stirred at 15° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 41.6 g (100%) of 3-azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid.
LC/MS (m/z, MH+): 240
Step 3 of Intermediate 11 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from 3-azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid to give 20 g (54%) of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone.
LC/MS (m/z, MH+): 300
To a solution of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate (40 g, 117 mmol) in DCM (200 ml) was added Deoxo-Fluor (260 g, 1.18 mol, 257 ml). The mixture was stirred at 40° C. for 48 hours. The mixture was poured into ice and aqueous saturated solution of NaHCO3 (1000 ml) and extracted with DCM (300 ml), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 98/02 to 00/100 to give 36 g (85%) of tert-butyl 3-((4-bromophenyl)difluoromethyl)azetidine-1-carboxylate as a yellow oil.
LC/MS (m/z, MH+): 362
Step 2 of Intermediate 12 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-((4-bromophenyl)difluoromethyl)azetidine-1-carboxylate to give 37.4 g (100%) of 3-[(4-bromophenyl)difluoromethyl]-azetidine, trifluoroacetic acid as a yellow solid.
LC/MS (m/z, MH+): 262
Step 3 of Intermediate 12 was prepared following a similar procedure to that of Intermediate 1 Method 2 from 3-[(4-bromophenyl)difluoromethyl]-azetidine, trifluoroacetic acid to give 13.3 g (41%) of 3-((4-bromophenyl)difluoromethyl)-1-(3-fluoropropyl)azetidine as a yellow oil.
LC/MS (m/z, MH+): 322
Step 1 of Intermediate 13 was prepared following a similar procedure to that of step 1 of Intermediate 7 from 3-((4-bromophenyl)difluoromethyl)-1-(3-fluoropropyl)azetidine (Intermediate 12) to give 3.5 g (99%) of methyl 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a yellow oil.
LC/MS (m/z, MH+): 444
Step 2 of Intermediate 13 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 3.48 g (84%) of methyl 8-bromo-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown oil.
LC/MS (m/z, MH+): 522
To a solution of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone Intermediate 11 (20.0 g, 66.6 mmol) in MeOH (100 ml) was added NaBH4 (5.04 g, 133 mmol) at 0° C. The mixture was stirred at 15° C. for 1 hour. The reaction mixture was slowly quenched by water (100 mL) and concentrated to remove MeOH. The aqueous layer was extracted three times with EtOAc (80 ml). After decantation, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM: MeOH from 98/02 to 90/10 to give 16.0 g (77%) of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol as mixture of two isomers.
LC/MS (m/z, MH+): 302
The mixture of two isomers of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol was separated by SFC (condition: flash DAICEL CHIRALPAK AD (250×50 mm, 10 μm); supercritical CO2 80%/MeOH 20%/[0.1% NH4OH MeOH] to give 5.3 g of isomer 1 and 5.2 g of isomer 2.
To a solution of racemic (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol (Intermediates 14 and 15) (30.0 g, 99.3 mmol) in DCM (150 ml) was added Deoxo-Fluor (26.4 g, 119 mmol, 26.1 ml) at −70° C. The mixture was stirred at 15° C. for 0.5 hour. The mixture was quenched by aqueous saturated solution of NaHCO3 (500 ml) and extracted with DCM (200 ml). After decantation, the organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 98/02 to 00/100 to give 10.5 g (32%) of 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine as mixture of two isomers.
LC/MS (m/z, MH+): 304
The mixture of two isomers of 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine was separated by SFC (condition: flash DAICEL CHIRALPAK AD (250×50 mm, 10 μm); supercritical CO2 60%/MeOH 40%/[0.1% NH4OH MeOH] to give 5.9 g of Isomer 1 and 6.3 g of Isomer 2.
Step 1 of Intermediate 18 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine Isomer 1 to give 1.18 g (84%) of methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1.
LC/MS (m/z, MH+): 426
Step 2 of Intermediate 18 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 to give 833 mg (60%) of methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1.
LC/MS (m/z, MH+): 504
Step 1 of Intermediate 19 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine Isomer 2 to give 2.59 g (92%) of methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 2.
LC/MS (m/z, MH+): 426
Step 2 of Intermediate 19 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 2 to give 1.03 g (36%) of methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 2.
LC/MS (m/z, MH+): 504
To a solution of (4-bromobenzyl)triphenylphosphonium bromide (79.2 g, 155 mmol) in DMF (400 ml) was added NaH (6.18 g, 155 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min. To this reaction mixture, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (24.1 g, 141 mmol) in DMF (160 ml) was added. The mixture was stirred at 20° C. for 9 hours. The reaction mixture was quenched by addition of NH4Cl (100 ml) at 0° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 60.0 g (crude) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a yellow solid.
LC/MS (m/z, MH+): 324
To a solution of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate (72.0 g, 222 mmol) in DCM (500 ml) was added m-CPBA (57.5 g, 266 mmol, 80% purity). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was quenched by addition of NaHSO3 aqueous solution (650 ml) at 0° C., and then diluted with EtOAc (500 ml) and extracted with EtOAc (300 ml×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of Petroleum ether/EtOAc from 00/100 to 90/10 to give 35.0 g (46.3%) of tert-butyl 2-(4-bromophenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylate as a yellow solid.
LC/MS (m/z, MH+): 340
To a solution of tert-butyl 2-(4-bromophenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (35.0 g, 103 mmol) in THF (200 ml) was added LiAlH4 (4.30 g, 113 mmol) at −70° C. The mixture was stirred at −70° C. for 2 hours. The reaction mixture was quenched by water (100 ml), and then extracted with EtOAc (100 ml). After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 99/01 to 90/10 to give 28 g (79.5%) of tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate as a white solid.
LC/MS (m/z, MH+): 342
To a solution of tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate (10.0 g, 29.2 mmol) in DCM (60.0 ml) was added deoxo fluor (5.65 g, 35.1 mmol, 4.63 ml) at −70° C. The mixture was stirred at −60° C. for 2 hours. The reaction mixture was quenched by water (60 ml). After decantation, the organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 99/01 to 95/05 to give 10 g (50%) of tert-butyl 3-(4-bromobenzyl)-3-fluoroazetidine-1-carboxylate as a white solid.
LC/MS (m/z, MH+): 344
Step 5 of Intermediate 20 was prepared following a similar procedure to that of step 2 of Intermediate 11 from 1-azetidinecarboxylic acid, 3-[(4-bromophenyl)methyl]-3-fluoro-1,1-dimethylethyl ester to give 9.80 g (94%) of 3-(4-bromobenzyl)-3-fluoroazetidine, trifluoroacetic acid as a crude product which was used into the next step without further purification.
LC/MS (m/z, MH+): 244
Step 6 of Intermediate 20 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from 3-(4-bromobenzyl)-3-fluoroazetidine, trifluoroacetic acid to give 5.10 g (61.3%) of 3-(4-bromobenzyl)-3-fluoro-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 304
Step 1 of Intermediate 21 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 3-(4-bromobenzyl)-3-fluoro-1-(3-fluoropropyl)azetidine to give 0.93 g (71%) of methyl 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 426
Step 2 of Intermediate 21 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 404 mg (59%) of methyl 8-bromo-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 504
Step 1 of Intermediate 22 was prepared following a similar procedure to that of Step 2 of Intermediate 11 from tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate to give 36.8 g (76%) of 3-(4-bromobenzyl)azetidin-3-ol, trifluoroacetic acid as a yellow solid.
LC/MS (m/z, MH+): 242
Step 2 of Intermediate 22 was prepared following a similar procedure to that of Method 1 of Intermediate 1 from 3-(4-bromobenzyl)azetidin-3-ol, trifluoroacetic acid to give 10 g (31%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol.
LC/MS (m/z, MH+): 302
A mixture of commercially available 3-(1-(4-bromophenyl)cyclopropyl)azetidine hydrochloride (0.3 g, 1.04 mmol), K2CO3 (0.36 g, 2.6 mmol) and 1-fluoro-3-iodopropane (108.5 μL, 1.06 mmol) in acetonitrile (20 mL) was stirred overnight at room temperature. It was then concentrated under reduced pressure. The residue was taken into EtOAc and water. The organic layer was separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 95/5 to 90/10 to give 0.1 g (31%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol as a brown oil.
LC/MS (m/z, MH+): 312
Intermediate 24 was prepared following a similar procedure to that of Intermediate 23 from commercially available 3-(4-bromobenzyl)-3-methylazetidine hydrochloride to give 295 mg (90%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)-3-methylazetidine as a yellow oil.
LC/MS (m/z, MH+): 300
To a solution of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 1 (1 g, 3.31 mmol) in DCM (40 mL) at 0° C. was slowly added thionyl chloride (0.48 mL, 6.62 mmol). The mixture was stirred at room temperature for 3 hours. DCM (75 mL) and saturated aqueous NaHCO3 (200 mL) were added. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1 g (94%) of 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine Isomer 1 as a yellow oil.
LC/MS (m/z, MH+): 320
To a solution of 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine Isomer 1 (0.65 g, 2.03 mmol) in DMF (20 mL) was added sodium azide (269 mg, 4.05 mmol). The mixture was stirred at 78° C. for 4 hours. Ether (100 mL) and water (100 mL) were added. The aqueous layer was separated and extracted three times with ether (100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/0 to 95/5 to give 0.55 g (83%) of 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine Isomer 1 as a colorless oil.
LC/MS (m/z, MH+): 327
Step 1 of Intermediate 26 was prepared following a similar procedure to that of step 1 of Intermediate 25 from (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 2 to give 1.1 g (95%) of 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine Isomer 2 as a yellow oil.
LC/MS (m/z, MH+): 320
Step 2 of Intermediate 26 was prepared following a similar procedure to that of step 2 of Intermediate 25 from 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine Isomer 2 to give 0.64 g (96%) of 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine Isomer 2 as a yellow oil.
LC/MS (m/z, MH+): 327
To a solution of 3,3-difluoropropan-1-ol (1 g, 10.41 mmol) and 2,6-lutidine (2.66 mL, 22.9 mmol) in DCM (20 mL) at 0° C. was dropwise added trifluoromethanesulfonic anhydride (1.93 mL, 11.45 mmol). The mixture was stirred at 0° C. for 30 minutes. Ether and water were added. The aqueous layer was separated and extracted three times with ether. The combined organic layers were twice washed with a 10% aqueous solution of citric acid then water and dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.06 g (86%) of 3,3-difluoropropyl trifluoromethanesulfonate which was used in the next step without further purification.
To a suspension of 3-(4-bromobenzyl)azetidine para-toluene sulfonate (5 g, 12.55 mmol), 3,3-difluoropropyl trifluoromethanesulfonate (3.44 g, 15.06 mmol) in DCM (100 mL) was added a 1N aqueous solution of sodium hydroxide (31.38 mL, 31.38 mmol). The mixture was stirred at room temperature for 4 hours. Water (100 mL) was added. The aqueous layer was separated and extracted twice with ether (100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/0 to 80/20 to give 1.71 g (45%) of 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine as a yellow oil.
LC/MS (m/z, MH+): 304
A solution of 4-methylbenzenesulfonohydrazide (2.01 g, 10.80 mmol) and tert-butyl-3-formylazetidine-1-carboxylate (2 g, 10.80 mmol) in 1,4-dioxane (40 ml) was stirred at 80° C. for two hours. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was then transferred in a separating funnel containing an aqueous saturated solution of NaCl. The mixture was extracted three times with EtOAc. The combined organic layers were then dried over MgSO4, filtered and concentrated to dryness to give 3.775 g (99%) of (tert-butyl(E)-3-((2-tosylhydrazono)methyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 354
To a solution of tert-butyl(E)-3-((2-tosylhydrazono)methyl)azetidine-1-carboxylate (623 mg, 1.76 mmol) in 1,4-dioxane (10 ml) were successively added K2CO3 (365.42 mg, 2.64 mmol) and (4-bromo-3-fluorophenyl)boronic acid (578.56 mg, 2.64 mmol). The reaction mixture was then refluxed for 16 hours. After cooling down to room temperature, the reaction mixture was transferred in a separating funnel containing an aqueous saturated solution of NH4Cl, extracted three times with EtOAc. The combined organic layers were, dried over MgSO4, filtered, and concentrated to dryness.
The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane/EtOAc 80/20 to give 335 mg (55%) of (tert-butyl 3-(4-bromo-3-fluorobenzyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 344
To a solution of tert-butyl 3-(4-bromo-3-fluorobenzyl)azetidine-1-carboxylate (326 mg, 947.06 μmol) in 1,4-dioxane (9 ml) was added dropwise 9.47 ml of a 4 M solution of HCl in 1,4-dioxane (37.88 mmol). The resulting reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated to dryness to give 266 mg of 3-(4-bromo-3-fluorobenzyl)azetidine hydrochloride which was engaged in the next step without further purification.
LC/MS (m/z, MH+): 244
Step 4 of Intermediate 28 was prepared following a similar procedure to that of Intermediate 23 from 3-(4-bromo-3-fluorobenzyl)azetidine hydrochloride to give 89 mg (18%) of (3-(4-bromo-3-fluorobenzyl)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 304
Step 1 of Intermediate 29 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (3-(4-bromo-3-fluorobenzyl)-1-(3-fluoropropyl)azetidine to give 1.28 g (100%) of methyl 9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 426
Step 2 of Intermediate 29 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 840 mg (55%) of methyl 8-bromo-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 504
Step 1 of Intermediate 30 was prepared following a similar procedure to that of step 2 of Intermediate 28 from (4-bromo-2-methylphenyl)boronic acid to give 593 mg (56%) of tert-butyl 3-(4-bromo-2-methylbenzyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 341
Step 2 of Intermediate 30 was prepared following a similar procedure to that of step 3 of Intermediate 28 from tert-butyl 3-(4-bromo-2-methylbenzyl)azetidine-1-carboxylate to give 480 mg (100%) of 3-(4-bromo-2-methylbenzyl)azetidine hydrochloride.
LC/MS (m/z, MH+): 241
Step 3 of Intermediate 30 was prepared following a similar procedure to that of Intermediate 23 from 3-(4-bromo-2-methylbenzyl)azetidine hydrochloride to give 86 mg (17%) of 3-(4-bromo-2-methylbenzyl)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 301
Step 1 of Intermediate 31 was prepared following a similar procedure to that of step 2 of Intermediate 28 from (4-bromo-2-fluorophenyl)boronic acid to give 126 mg (26%) of tert-butyl 3-(4-bromo-2-fluorobenzyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 344
Step 2 of Intermediate 31 was prepared following a similar procedure to that of step 3 of Intermediate 28 from tert-butyl 3-(4-bromo-2-fluorobenzyl)azetidine-1-carboxylate to give 320 mg (100%) of 3-(4-bromo-2-fluorobenzyl)azetidine hydrochloride.
LC/MS (m/z, MH+): 244
Step 3 of Intermediate 31 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from 3-(4-bromo-2-fluorobenzyl)azetidine hydrochloride to give 2.19 g (82%) of 3-(4-bromo-2-fluorobenzyl)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 304
Step 1 of Intermediate 32 was prepared following a similar procedure to that of step 1 of Intermediate 7 from 3-(4-bromo-2-fluorobenzyl)-1-(3-fluoropropyl)azetidine (Intermediate 31) to give 2.58 g (84%) of methyl 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 426
Step 2 of Intermediate 32 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 967 mg (82%) of methyl 8-bromo-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 504
Step 1 of Intermediate 33 was prepared following a similar procedure to that of step 2 of Intermediate 28 from (4-bromo-3-methylphenyl)boronic acid to give 850 mg (61%) of tert-butyl 3-(4-bromo-3-methylbenzyl)azetidine-1-carboxylate as a white solid.
Step 2 of Intermediate 33 was prepared following a similar procedure to that of step 3 of Intermediate 28 from tert-butyl 3-(4-bromo-3-methylbenzyl)azetidine-1-carboxylate to give 0.84 g (100%) of 3-(4-bromo-3-methylbenzyl)azetidine hydrochloride which was used in the next step without further purification.
LC/MS (m/z, MH+): 240
Step 3 of Intermediate 33 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from 3-(4-bromo-3-methylbenzyl)azetidine hydrochloride to give 63 mg (19%) of 3-(4-bromo-3-methylbenzyl)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 300
Intermediate 34 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from commercially available 3-(4-bromo-2,3-difluorobenzylidene)azetidine to give 0.65 g (34%) of 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine as an orange oil.
LC/MS (m/z, MH+): 320
To a solution of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol) in DCM (40 ml) and MeOH (10 ml) at 0° C. was portionwise added sodium borohydride (377 mg, 9.95 mmol). The reaction mixture was stirred at 0° C. for 1 hour then slowly quenched at 0° C. with a 1N aqueous solution of HCl. After stirring at 0° C. for 30 min, water was added and the mixture was transferred in a separating funnel and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated to dryness, triturated with pentane and filtered to give 1.83 g (91%) of (4-bromo-2,6-difluorophenyl)methanol as a pinkish solid.
LC/MS (m/z, MH+): 223
To a solution of (4-bromo-2,6-difluorophenyl)methanol (2.67 g, 11.99 mmol) in diethyl ether (60 ml) at 0° C. was dropwise added tribromophosphane (0.57 mL, 6 mmol). The reaction mixture was stirred for 12 hours at RT then slowly poured onto a saturated aqueous solution of NaHCO3 under stirring. After stirring for 30 minutes, the mixture was transferred in a separating funnel and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 3.04 g (88%) of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene as a colorless oil which was used in the next step without further purification.
LC/MS (m/z, MH+): 285
A mixture of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (2.5 g, 8.74 mmol) and triethyl phosphite (2.25 ml, 13.12 mmol) was heated to 130° C. for 4 hours in a sealed tube. The resulting mixture was purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc from 100/0 to 80/20 to give 2.95 g (98%) of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate as a colorless oil.
LC/MS (m/z, MH+): 343
To a solution of diisopropylamine (1.35 mL, 9.62 mmol) in THF (15 ml) at −78° C. under Ar atmosphere was dropwise added a 2.5 M solution of n-butyllithium in hexanes (3.5 mL, 8.74 mmol). The reaction mixture was stirred for 5 minutes then a solution of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate (3 g, 8.74 mmol) in THF (15 ml) was added. After stirring for 45 minutes, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.65 g, 9.62 mmol) in THF (30 ml) was added. The reaction mixture was stirred allowing the temperature to warm up to RT until completion. It was then transferred in a separating funnel containing an aqueous saturated solution of NH4Cl, extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc from 100/0 to 50/50 to give 1.67 g (53%) of tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate as a colorless viscous oil.
LC/MS (m/z, MH+): 360
Step 5 of Intermediate 35 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate to give 1.65 g (98%) of 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid as a white solid.
LC/MS (m/z, MH+): 260
Step 6 of Intermediate 35 was prepared following a similar procedure to that of Method 1 of Intermediate 1 from 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid to give 79 mg (18%) of 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 320
Step 1 of Intermediate 36 was prepared following a similar procedure to that of step 1 of Intermediate 35 from 4-bromo-2,6-dimethylbenzaldehyde to give 1.86 g (92%) of (4-bromo-2,6-dimethylphenyl)methanol as a white solid.
LC/MS (m/z, MH+): 215
Step 2 of Intermediate 36 was prepared following a similar procedure to that of step 2 of Intermediate 35 from tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate to give 1.27 g (98%) of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene as a white solid.
LC/MS (m/z, MH+): 277
Step 3 of Intermediate 36 was prepared following a similar procedure to that of step 3 of Intermediate 35 from 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene to give 1.16 g (86%) of diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate as a colorless oil.
LC/MS (m/z, MH+): 335
Step 4 of Intermediate 36 was prepared following a similar procedure to that of step 4 of Intermediate 35 from diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate to give 0.86 g (27%) of tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate as a colorless viscous oil.
LC/MS (m/z, MH+): 352
Step 5 of Intermediate 36 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate to give 0.77 g (86%) of 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid as a white solid.
LC/MS (m/z, MH+): 252
Step 6 of Intermediate 36 was prepared following a similar procedure to that of Method 1 of Intermediate 1 from 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid to give 0.7 mg (50%) of 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 312
Step 1 of Intermediate 37 was prepared following a similar procedure to that of step 3 of Intermediate 35 from commercially available 1-bromo-4-(bromomethyl)-2,5-difluorobenzene to give 6.48 g (87%) of diethyl (4-bromo-2,5-difluorobenzyl)phosphonate as a colorless oil.
LC/MS (m/z, MH+): 343
Step 2 of Intermediate 37 was prepared following a similar procedure to that of step 4 of Intermediate 35 from diethyl (4-bromo-2,5-difluorobenzyl)phosphonate to give 1.16 g (73%) of tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate as a white solid.
LC/MS (m/z, MH+): 360
Step 3 of Intermediate 37 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate to give 1.07 g (89%) of 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid as a white solid.
LC/MS (m/z, MH+): 260
Step 4 of Intermediate 37 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid to give 0.7 g (76%) of 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 320
To a solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (500 mg, 2.63 mmol) and NBS (468 mg, 2.63 mmol) in H2O (5 ml) was added a solution of concentrated H2SO4 (286 μl, 5.26 mmol) in H2O (0.5 ml) and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was extracted with EtOAc (30 mL) and after decantation, the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a 0-15% Ethyl acetate gradient in Petroleum ether to give 260 mg (37%) of 1-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 130 mg (18%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 268
A mixture 1-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1 g, 3.72 mmol) in a mixture of dioxane (20 ml) and H2O (5 ml) was purged with Ar for 15 minutes. K2CO3 (1.54 g, 11.15 mmol), MeB(OH)2 (266.90 mg, 4.46 mmol) and Pd(PPh3)4 (214.68 mg, 185.78 μmol) were added sequentially under N2 atmosphere. The reaction mixture was sealed and heated to 100° C. for 2 hours. The mixture was poured into water (20 ml) and extracted three times with EtOAc (20 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-15% gradient of Ethyl acetate in Petroleum ether to give 880 mg (100%) of 2-methoxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 205
A mixture of 2-methoxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (760 mg, 3.72 mmol) in DCM (10 ml) was cooled to −60° C., BBr3 (1.08 ml, 11.16 mmol) was added slowly. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by addition of H2O (10 ml) and extracted twice with EtOAc (10 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a 0-35% gradient of ethyl acetate in petroleum ether to give compound 500 mg (71%) of 2-hydroxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 191
Step 4 of Intermediate 38 was prepared following a similar procedure to that of Step 1 of Intermediate 9 from 2-hydroxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 610 mg (100%) of 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 323
Step 5 of Intermediate 38 was prepared following a similar procedure to that of Step 2 of Intermediate 9 from 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate to give 70 mg (97%) of methyl 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 233.
Step 6 of Intermediate 38 was prepared following a similar procedure to that of Step 3 of Intermediate 9 from methyl 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 480 mg (93%) of methyl 4-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 365
To a solution of methyl 4-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (480 mg, 1.32 mmol), Cs2CO3 (1.5 M, 1.76 ml) and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine (Intermediate 2) (571 mg, 1.71 mmol) in dioxane (10 ml) was added Pd(dppf)Cl2 (96.40 mg, 131.75 μmol). The mixture was stirred at 60° C. for 1 hour under Ar atmosphere. The residue was poured into water (20 ml) and extracted three times with EtOAc (20 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-10% gradient of DCM in MeOH to give 610 mg (91%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 422
Step 8 of Intermediate 38 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 400 mg (77% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 500
Step 1 of Intermediate 39 was prepared following a similar procedure to that of Step 2 of Intermediate 38 from 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 183 mg (73%) of 2-methoxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 205
To a solution of 2-methoxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (310 mg, 1.52 mmol) in toluene (3 ml) was added AlCl3 (1.01 g, 7.59 mmol) and the mixture was stirred at 80° C. for 3 hours. The residue was poured into water (10 ml) and extracted three times with EtOAc (10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-50% gradient of Ethyl acetate in Petroleum ether to give 319 mg (99%) of 2-hydroxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 191
Step 3 of Intermediate 39 was prepared following a similar procedure to that of Step 1 of Intermediate 9 from 2-hydroxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 437 mg (80%) of 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 323
Step 4 of Intermediate 39 was prepared following a similar procedure to that of Step 2 of Intermediate 9 from 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate to give 300 mg (95%) of methyl 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 233
Step 5 of Intermediate 39 was prepared following a similar procedure to that of Step 3 of Intermediate 9 from methyl 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give compound 315 mg (67%) of methyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 365
Step 6 of Intermediate 39 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 439 mg (96%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 422
Step 7 of Intermediate 39 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 349 mg (72%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 500
To a solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (10 g, 52.57 mmol) and N-chlorosuccinimide (7.72 g, 57.82 mmol) in H2O (100 ml) was added H2SO4 (5.72 ml, 105.13 mmol, 98% purity) in H2O (20 ml) and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was extracted twice with EtOAc (200 ml) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a 0-15% gradient of Ethyl acetate in Petroleum ether to give 5.3 g (45%) of 1-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 4.8 g (20%) of 3-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 225
Step 2 of Intermediate 40 was prepared following a similar procedure to that of Step 2 of Intermediate 39 from 1-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 1.8 g (crude) of 1-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 211
To a solution of 1-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.8 g, 8.54 mmol) in DCM (20 ml) was added TEA (2.16 g, 21.36 mmol, 2.97 ml). Then SO2F2 (gas) was introduced by needle from a balloon filled with the gas and the mixture was stirred at 25° C. for 1 hour. The residue was poured into H2O (10 ml) and extracted with DCM (40 ml). The organic phase was washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography with 0-30% Ethyl acetate in Petroleum ether gradient to give 2 g (80%) of 1-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene.
LC/MS (m/z, MH+): 292
Step 4 of Intermediate 40 was prepared following a similar procedure to that of Step 2 of Intermediate 9 from 1-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene to give 900 mg (52%) of methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 253
To a solution of methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (200 mg, 791 μmol) in THF (3 ml) was added NaHMDS (1 M, 950 μl) at −78° C. under Ar atmosphere. The mixture was stirred for 30 minutes and a mixture of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (368 mg, 1.03 mmol) in THF (1 ml) was added to the resulting mixture. The reaction mixture was slowly warmed up to 20° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (5 ml), then diluted with H2O (15 ml) and extracted twice with EtOAc (20 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography with a 0-25% gradient of Ethyl acetate in Petroleum ether to give 250 mg (82%) of methyl 4-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 385
Step 6 of Intermediate 40 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 4-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 280 mg (93%) of methyl 4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 422
Step 7 of Intermediate 40 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 290 mg (83%) of methyl 8-bromo-4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 522
Step 1 of Intermediate 41 was prepared following a similar procedure to that of Step 2 of Intermediate 39 from 3-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 650 mg (69.33%) of 3-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 211
Step 2 of Intermediate 41 was prepared following a similar procedure to that of Step 3 of Intermediate 40 from 3-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 1.4 g (92%) of 3-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene
LC/MS (m/z, MH+): 292
Step 3 of Intermediate 41 was prepared following a similar procedure to that of Step 2 of Intermediate 9 from 3-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene to give 700 mg (58%) of methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 253
Step 4 of Intermediate 41 was prepared following a similar procedure to that of Step 5 of Intermediate 40 from methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 40 mg (53%) of methyl 2-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 385
Step 5 of Intermediate 41 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 2-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 300 mg (crude) of methyl 2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 442
Step 6 of Intermediate 41 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 260 mg (crude) of methyl 8-bromo-2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 522
To a solution of methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (2.1 g, 8.31 mmol), Zn (163 mg, 2.49 mmol), Zn(CN)2 (976 mg, 8.31 mmol) and dppf (461 mg, 831 μmol) in DMA (25 ml) was added Pd2(dba)3 (761 mg, 0.83 mmol). The mixture was stirred at 150° C. for 2 hours. The residue was poured into H2O (20 ml) and extracted three times with EtOAc (30 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-40% gradient of Ethyl acetate in Petroleum ether to give 750 mg (37%) of methyl 1-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 244
Step 2 of Intermediate 42 was prepared following a similar procedure to that of Step 5 of Intermediate 40 from methyl 1-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 500 mg (88%) of methyl 4-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 376
Step 3 of Intermediate 42 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 4-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 350 mg (80%) of methyl 4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 433
Step 4 of Intermediate 42 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 440 mg (91%) of methyl 8-bromo-4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 513
Step 1 of Intermediate 43 was prepared following a similar procedure to that of Step 1 of Intermediate 42 from methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 360 mg (36%) of methyl 3-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 244
Step 2 of Intermediate 43 was prepared following a similar procedure to that of Step 5 of Intermediate 40 from methyl 3-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 200 mg (47%) of methyl 2-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 376
Step 3 of Intermediate 43 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 2-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 200 mg (crude) of methyl 2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 433
Step 4 of Intermediate 43 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 100 mg (64%) of methyl 8-bromo-2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 513
Step 1 of Intermediate 44 was prepared following a similar procedure to that of step 1 of Intermediate 9 from 3-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 4.2 g (81%) of 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 327
Step 2 of Intermediate 44 was prepared following a similar procedure to that of step 2 Intermediate 9 from 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate to give 2.9 g (95%) of methyl 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 237
Step 3 of Intermediate 44 was prepared following a similar procedure to that of Step 3 of Intermediate 9 from methyl 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 3.6 g (80%) of methyl 2-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 369
Step 4 of Intermediate 44 was prepared following a similar procedure to that of Intermediate 4 from methyl 2-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 4.3 g (100% yield) of methyl 2-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 347
Step 5 of Intermediate 44 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from methyl 2-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 827 mg (38% yield) of methyl 2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 426
Step 6 of Intermediate 44 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 405 mg (41% yield) of methyl 8-bromo-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 504
Step 1 of Intermediate 45 was prepared following a similar procedure to that of Intermediate 4 from methyl 4-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) to give 3.1 g (67% yield) of methyl 4-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 347
Step 2 of Intermediate 45 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from methyl 4-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.9 g (40% yield) of methyl 4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 426
Step 3 of Intermediate 45 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.24 g (55% yield) of methyl 8-bromo-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 504
To a solution of [3-(ethoxycarbonyl)propyl]triphenylphosphonium bromide (5.42 g, 11.5 mmol) in THF (40 mL) at −78° C. was slowly added a 1 M solution of potassium bis(trimethylsilyl)amide THF (11.5 mL, 11.5 mmol). The reaction mixture was stirred 1 hour at −78° C. and a solution of 2,4-difluoro-3-methoxybenzaldehyde (1 g, 5.75 mmol) in THF (5 mL) was added. The reaction mixture was stirred at −78° C. for 1 h and then allowed to reach room temperature overnight under stirring. The mixture was poured into water and extracted with DCM. The aqueous layer was separated and extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/ethyl acetate: from 100/0 to 90/10 to give 1.1 g (71%) of ethyl (Z)-5-(2,4-difluoro-3-methoxyphenyl)pent-4-enoate.
LC/MS (m/z, MH+): 271
To a solution of ethyl (Z)-5-(2,4-difluoro-3-methoxyphenyl)pent-4-enoate (8.4 g, 31 mmol) in ethanol (40 mL) was added Pd/C 10% (0.33 g). The black suspension was hydrogenated in an autoclave at room temperature under 3.5 bars of hydrogen for 1 hour. The mixture was filtered with ethanol washes then the filtrate was concentrated under reduced pressure to give 8.4 g (99%) of ethyl 5-(2,4-difluoro-3-methoxyphenyl)pentanoate as a colorless oil.
LC/MS (m/z, MH+): 273
To a solution of ethyl 5-(2,4-difluoro-3-methoxyphenyl)pentanoate (5.7 g, 20.9 mmol) in ethanol (15 mL) were added aqueous NaOH (8.8 mL, 44 mmol). The reaction mixture was stirred for 40 minutes at 50° C. After cooling to room temperature, ice was added then the reaction mixture was acidified with 1 M aqueous HCl to pH 3 and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 5.1 g (99%) of 5-(2,4-difluoro-3-methoxyphenyl)pentanoic acid.
LC/MS (m/z, MH+): 245
A mixture of 5-(2,4-difluoro-3-methoxyphenyl)pentanoic acid (5.5 g, 22.5 mmol) and Eaton's reagent (143 mL, 0.9 mol) was stirred at room temperature for 12 hours then ice was added. Saturated aqueous solution of NaHCO3 and DCM were added. The organic layer was separated and the aqueous layer extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 5 g (98%) of 1,3-difluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 227
To 1,3-difluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (6.79 g, 30 mmol) was slowly added a 33% solution of hydrobromic acid in acetic acid (34 mL, 0.6 mol). The brown reaction mixture was heated at 75° C. overnight. An additional 33% solution of hydrobromic acid in acetic acid (17 mL, 0.3 mol) was added and the mixture was heated at 75° C. for 2 days. After cooling down to room temperature, the mixture was poured onto ice. Saturated aqueous solution of NaHCO3 and ethyl acetate were added. The organic layer was separated and the aqueous layer extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/ethyl acetate: from 95/5 to 50/50 to give 4.2 g (66%) of 1,3-difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one as a yellow solid.
LC/MS (m/z, M-H−): 211
Step 6 of Intermediate 46 was prepared following a similar procedure to that of step 1 of Intermediate 9 from 1,3-difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 6.1 g (89%) of 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate as a yellow oil.
LC/MS (m/z, MH+): 345
Step 7 of Intermediate 46 was prepared following a similar procedure to that of step 2 Intermediate 9 from 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate to give 3 g (66%) of methyl 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a colorless oil.
LC/MS (m/z, MH+): 255
Step 8 of Intermediate 46 was prepared following a similar procedure to that of Step 3 of Intermediate 9 from methyl 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 1 g (37%) of methyl 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
Step 9 of Intermediate 46 was prepared following a similar procedure to that of Intermediate 4 from methyl 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 0.75 g (80% yield) of methyl 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 365
Step 10 of Intermediate 46 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from methyl 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.28 g (93% yield) of methyl 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 444
Step 11 of Intermediate 46 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 0.67 g (46% yield) of methyl 8-bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brownish foam.
LC/MS (m/z, MH+): 522
Intermediate 47 was prepared following a similar procedure to that of Method 2 of Intermediate 1 from 3-(4-bromobenzylidene)azetidine hydrochloride to give 0.34 g (40%) of 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine
LC/MS (m/z, MH+): 284
To a solution of tert-butyl 3-methyleneazetidine-1-carboxylate (2.54 g, 15 mmol) in anhydrous THF (30 mL) under Ar atmosphere was added 9-BBN (33 mL, 16.5 mmol). The resulting mixture was heated to 75° C. for 2 hours. After allowing the temperature to cool down to room temperature, 2-bromo-5-iodopyridine (3.84 g, 13.5 mmol), K2CO3 (910 mg, 6.58 mmol), anhydrous DMF (21 mL) and Pd(dppf)Cl2 (0.33 g, 0.45 mmol) were added and the mixture was heated to 60° C. overnight under Ar atmosphere. After allowing the temperature to cool down to room temperature, EtOAc and water were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc from 100/00 to 50/50 to give 2.07 g (42%) of tert-butyl 3-((6-bromopyridin-3-yl)methyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 327
Step 2 of Intermediate 48 was prepared following a similar procedure to that of step 1 of Intermediate 7 from tert-butyl 3-((6-bromopyridin-3-yl)methyl)azetidine-1-carboxylate to give 0.4 g (58%) of tert-butyl 3-((6-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate as a brownish foam.
LC/MS (m/z, MH+): 449
Step 3 of Intermediate 48 was prepared following a similar procedure to that of step 2 of Intermediate 7 from tert-butyl 3-((6-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate to give 60 mg (27%) of tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate as a yellowish foam.
LC/MS (m/z, MH+): 527
Step 1 of Intermediate 49 was prepared following a similar procedure to that of step 1 of Intermediate 7 from 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (prepared according to WO2018091153) and 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine to give 1.27 g (70%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.
LC/MS (m/z, MH+): 450
Step 2 of Intermediate 49 was prepared following a similar procedure to that of step 2 of Intermediate 7 from 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate to give 1.7 g (89%) of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.
LC/MS (m/z, MH+): 528
To a solution of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (0.8 g, 1.51 mmol) in MeOH (15 mL) was added a solution of NaOH (1.51 mL, 1 M) and the reaction mixture was heated to 50° C. for 1 hour. After cooling, EtOAC and water were added and pH was adjusted to 4 with HCl 5N. After separation, the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.6 g (90%) of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as a brown solid.
LC/MS (m/z, MH+): 444
Intermediate 50 was prepared following a similar procedure to that of step 2 of Intermediate 27 from 2,3-difluoropropyl trifluoromethanesulfonate to give 211 mg (40%) of 3-(4-bromobenzyl)-1-(2,3-difluoropropyl)azetidine.
LC/MS (m/z, MH+): 304
Step 1 of Intermediate 51 was prepared following a similar procedure to that of Intermediate 23 from 3-(4-bromobenzyl)azetidine, 4-methylbenzenesulfonic acid and 1,1,1-trifluoro-3-iodopropane to give 0.8 g (49%) of 3-(4-bromobenzyl)-1-(3,3,3-trifluoropropyl)azetidine.
LC/MS (m/z, MH+): 322
Step 2 of Intermediate 51 was prepared following a similar procedure to that of step 1 of Intermediate 7 from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) and 3-(4-bromobenzyl)-1-(3,3,3-trifluoropropyl)azetidine to give 1.4 g (86%) of methyl 9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 444
Step 3 of Intermediate 51 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.2 g (73%) of methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown foam.
LC/MS (m/z, MH+): 522
Step 1 of Intermediate 52 was prepared following a similar procedure to that of step 1 of Intermediate 6 from methyl 1-oxotetralin-6-carboxylate to give 459 mg (19%) of methyl 6-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate.
LC/MS (m/z, MH+): 349
To a solution of methyl 6-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.29 g, 0.83 mmol) in THF (5 mL) at −78° C. under Ar atmosphere was added N,N-bis(trifluoromethylsulfonyl)aniline (0.39 g, 1.08 mmol) followed by KHMDS (1 M, 1.08 mL, 1.08 mmol). The reaction mixture was stirred for 5 hours allowing the temperature to warm up to −10° C. then it was poured into brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography with a 0-10% gradient of Ethyl acetate in cyclohexane to give 0.33 g (82%) of methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate.
LC/MS (m/z, MH+): 481
To a suspension of 1,3-difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (step 5 of Intermediate 46) (2.3 g, 10.84 mmol) and K2CO3 (3.75 g, 27.1 mmol) in acetone (150 mL) was dropwise 2,2-dimethylpropanoyl chloride (3.18 mL, 23.85 mmol). The reaction mixture was stirred at RT for 20 minutes. Water was added and the reaction mixture was extracted three times with EtOAc. The organic phases were gathered, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 97/03 to give 3 g (93%) of 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate as a yellow oil.
LC/MS (m/z, MH+): 297
Step 2 of Intermediate 53 was prepared following a similar procedure to that of step 3 of Intermediate 9 from 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate to give 1.35 g (31%) of 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.
LC/MS (m/z, MH+): 429
Step 3 of Intermediate 53 was prepared following a similar procedure to that of Intermediate 4 from 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate to give 310 mg (63%) of 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.
LC/MS (m/z, MH+): 407
Step 4 of Intermediate 53 was prepared following a similar procedure to that of step 1 of Intermediate 7 from 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate to give 180 mg (43%) of 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.
LC/MS (m/z, MH+): 486
Step 5 of Intermediate 53 was prepared following a similar procedure to that of step 2 of Intermediate 7 from 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate to give 210 mg (76%) of 8-bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.
LC/MS (m/z, MH+): 564
Step 1 of Intermediate 54 was prepared following a similar procedure to that step 1 of Intermediate 53 from 3-hydroxy-2-methoxy-benzaldehyde to give 11.5 g (74%) of 3-formyl-2-methoxyphenyl pivalate.
LC/MS (m/z, MH+): 237
Step 2 of Intermediate 54 was prepared following a similar procedure to that step 1 of Intermediate 46 from 3-formyl-2-methoxyphenyl pivalate to give 11 g (67%) of ethyl (Z)-5-(2-methoxy-3-(pivaloyloxy)phenyl)pent-4-enoate.
LC/MS (m/z, MH+): 335
Step 3 of Intermediate 54 was prepared following a similar procedure to that step 2 of Intermediate 46 from ethyl (Z)-5-(2-methoxy-3-(pivaloyloxy)phenyl)pent-4-enoate to give 11 g (99%) of ethyl 5-(2-methoxy-3-(pivaloyloxy)phenyl)pentanoate.
LC/MS (m/z, MH+): 337
Step 4 of Intermediate 54 was prepared following a similar procedure to that step 4 of Intermediate 46 from ethyl 5-(2-methoxy-3-(pivaloyloxy)phenyl)pentanoate to give 3.6 g (53%) of 2-hydroxy-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
LC/MS (m/z, MH+): 207
Step 5 of Intermediate 54 was prepared following a similar procedure to that of step 1 of Intermediate 9 from 2-hydroxy-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 4.6 g (70%) of 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 339
Step 6 of Intermediate 54 was prepared following a similar procedure to that of step 2 Intermediate 9 from 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate to give 2.4 g (70%) of methyl 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 249
Step 7 of Intermediate 54 was prepared following a similar procedure to that of step 3 of Intermediate 9 from methyl 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 3.8 g (100%) of methyl 4-methoxy-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 381
Step 8 of Intermediate 54 was prepared following a similar procedure to that of Intermediate 4 from methyl 4-methoxy-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 2 g (56%) of methyl 4-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 359
Step 9 of Intermediate 54 was prepared following a similar procedure to that of step 1 of Intermediate 7 from methyl 4-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 180 mg (43%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 438
Step 10 of Intermediate 54 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 576 mg (62%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 516
Step 1 of Intermediate 55 was prepared following a similar procedure to that of step 1 of Intermediate 7 from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) and 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine (Intermediate 27) to give 4.7 g (98%) of methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 426
Step 2 of Intermediate 55 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 3.4 g (61%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 504
Intermediate 56 was prepared following a similar procedure to that of Intermediate 8 from methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 55) to give 164 mg (50%) of methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 552
Step 1 of Intermediate 57 was prepared following a similar procedure to that of step 3 of Intermediate 9 from 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one to give 1.68 g (85%) of 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 293
Step 2 of Intermediate 57 was prepared following a similar procedure to that of Intermediate 4 from 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate to give 91 mg (65%) of 2-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
LC/MS (m/z, MH+): 271
Step 3 of Intermediate 57 was prepared following a similar procedure to that of step 1 of Intermediate 7 from 2-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine (Intermediate 27) to give 782 mg (59%) of 3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 350
Step 4 of Intermediate 57 was prepared following a similar procedure to that of step 2 of Intermediate 7 from 3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine to give 211 g (86%) of 3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine.
LC/MS (m/z, MH+): 428
To a mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (9.42 g, 43.2 mmol) in DCM (400 mL) was portionwise added pyridinium tribromide (16.12 g, 45.4 mmol). The reaction mixture was stirred overnight at room temperature. Water (500 ml) and ether (1 L) were added. The organic phase was separated and washed twice with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 297
To a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (10 g, 33.66 mmol) in acetonitrile (100 mL) was added DABCO (7.4 mL, 67.32 mmol). The reaction mixture was heated to 55° C. for 2.5 hours under Ar. Ether and 1N HCl were added. The organic phase was separated and washed twice with water, with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane/EtOAc 85/15 to give 1.88 g (26%) of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 217
To a solution of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate (1.88 g, 8.6 mmol) in THF (30 mL) under Ar at 0° C. was added a 0.328 M cuprate solution (35 mL, 11.5 mmol) prepared by addition of 15 mL of a 1.6N solution of methyl lithium in ether to a suspension of 2.5 g of CuI (13 mmol) in 25 mL of ether under Ar at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. Ether (200 mL) and 1N HCl (200 mL) were added. The organic phase was separated and the aqueous phase extracted with ether. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane/EtOAc 95/5 to give 1.95 g (86%) of methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 233
Step 4 of Intermediate 58 was prepared following a similar procedure to that of step 3 of Intermediate 9 from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) to give 2.5 g (86%) of methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 365
Step 5 of Intermediate 58 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 1.1 g (95%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 422
Step 6 of Intermediate 58 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 1.4 g (100% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 500
The mixture of two isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by SFC (conditions: column DAICEL IH (250×50 mm, 5 μm); supercritical CO2 87%/MeOH 13%/[0.1% Et3N in EtOH]; 40° C.; 100 bars) to give 217 mg of isomer 1 and 174 mg of isomer 2.
To a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (7.4 g, 25 mmol) in THF (80 mL) at −78° C. under Ar atmosphere was added LiHMDS (1 M, 27 mL). The mixture was stirred for 2 hours then treated with acetic anhydride (8.8 mL, 75 mmol) allowing the temperature to warmed up to 0° C. After pouring onto diisopropyl ether and water, the aqueous layer was separated and extracted with diisopropyl ether. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography with a 0-50% gradient of ethyl acetate in cyclohexane to give 6.97 g (83%) of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 339
A mixture of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (300 mg, 0.89 mmol), potassium benzyltrifluoroborate (193 mg, 0.97 mmol), Cs2CO3 (874 mg, 2.63 mmol), and Pd(dppf)Cl2, complex with DCM (74 mg, 88 μmol) in toluene (9 mL) and water (3 mL) was heated to 90° C. in a sealed tube for 30 minutes. After cooling to room temperature, the reaction mixture was extracted with EtOAc (200 mL). The organic layer were washed twice with water (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography with a 0-100% gradient of ethyl acetate in cyclohexane to give 285 mg (92%) of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 351
To a solution of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (285 mg, 0.81 mmol) in methanol (8 mL) and DCM (4 mL) was added a 12N solution of HCl (0.44 mL, 5.29 mmol). The resulting reaction mixture was heated to reflux for 7 hours then stirred overnight at room temperature. After pouring onto diisopropyl ether and water, the aqueous layer was separated and extracted with diisopropyl ether. The combined organic layers were washed with water, a 5% aqueous solution of Na2CO3 and water then dried over Na2SO4, filtered, and concentrated under reduced pressure to give 220 mg (88%) of methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate which was used in the next step without further purification.
LC/MS (m/z, MH+): 309
Step 4 of Intermediate 59 was prepared following a similar procedure to that of step 2 of Intermediate 52 from methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 249 mg (79%) of methyl 8-benzyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 441
Step 1 of Intermediate 60 was prepared following a similar procedure to that of step 1 of Intermediate 9 from 7-hydroxythiochroman-4-one (prepared according to WO2018091153) to give 1.14 g (33%) of 4-oxothiochroman-7-yl trifluoromethanesulfonate.
LC/MS (m/z, MH+): 313
Step 2 of Intermediate 60 was prepared following a similar procedure to that of step 2 of Intermediate 9 from 4-oxothiochroman-7-yl trifluoromethanesulfonate to give 0.61 g (76%) of methyl 4-oxothiochromane-7-carboxylate.
LC/MS (m/z, MH+): 223
Step 3 of Intermediate 60 was prepared following a similar procedure to that of step 2 of Intermediate 52 from methyl 4-oxothiochromane-7-carboxylate to give 199 mg (41%) of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate.
LC/MS (m/z, MH+): 355
Step 4 of Intermediate 60 was prepared following a similar procedure to that of step 7 of Intermediate 38 from methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate to give 72 mg (62%) of methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate.
LC/MS (m/z, MH+): 412
Step 5 of Intermediate 60 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate to give 923 mg (80%) of methyl 3-bromo-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate.
LC/MS (m/z, MH+): 490
Step 1 of Intermediate 61 was prepared following a similar procedure to that of Step 3 of Intermediate 58 from methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate and lithium diethylcopper to give 0.4 g (80%) of methyl 7-ethyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 247
Step 2 of Intermediate 61 was prepared following a similar procedure to that of step 3 of Intermediate 9 from methyl 7-ethyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) to give 0.62 g (98%) of methyl 7-ethyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 379
Step 3 of Intermediate 61 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 7-ethyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 0.67 g (94%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 436
Step 4 of Intermediate 61 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 0.66 g (100% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 514
The mixture of two isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral HPLC (conditions: column CHIRALPACK AD (350×76.5 mm, 20 μm); Heptane 90%/EtOH 10%/[0.1% Et3N in MeOH]; 400 mL/min) to give 220 mg of isomer 1 and 220 mg of isomer 2.
Intermediate 62: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2
Step 1 of Intermediate 62 was prepared following a similar procedure to that of Step 3 of Intermediate 58 from methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate and lithium diisopropylcopper to give 0.37 g (77%) of methyl 7-isopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 261
Step 2 of Intermediate 62 was prepared following a similar procedure to that of step 3 of Intermediate 9 from methyl 7-isopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) to give 0.56 g (100%) of methyl 7-isopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 393
Step 3 of Intermediate 62 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 7-isopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 0.507 g (79%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 450
Step 4 of Intermediate 62 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 0.453 g (76% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 528
The mixture of two isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by SFC (conditions: column CHIRALCEL OD-H (250×30 mm, 5 μm); supercritical CO2 85%/MeOH 15%/[0.1% Et3N in MeOH]; 120 mL/min; 40° C.; 100 bars) to give 99 mg of isomer 1 and 100 mg of isomer 2.
Step 1 of Intermediate 63 was prepared following a similar procedure to that of Step 3 of Intermediate 58 from methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate and lithium dicyclopropylcopper to give 0.175 g (37%) of methyl 7-cyclopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 259
Step 2 of Intermediate 63 was prepared following a similar procedure to that of step 3 of Intermediate 9 from methyl 7-cyclopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) to give 0.16 g (61%) of methyl 7-cyclopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 391
Step 3 of Intermediate 63 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 7-cyclopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 0.145 g (100%) of methyl 7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 448
Step 4 of Intermediate 63 was prepared following a similar procedure to that of Step 2 of Intermediate 7 from methyl 7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) to give 0.268 g (82% yield) of methyl 8-bromo-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.
LC/MS (m/z, MH+): 526
Step 1 of Intermediate 64 was prepared following a similar procedure to that of Step 7 of Intermediate 38 from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.07 g (99%) of methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 367
A mixture of methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (1.07 g, 2.92 mmol) and Pd/C 10% (50 mg, 4.68 mmol) in EtOAc (10 ml) was hydrogenated at room temperature and 3.5 bars of H2 for 4 hours. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of EtOAc in cyclohexane (99/01 to 90/10, v/v) to give 580 mg (54%) of methyl 9-acetoxy-8-(bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 369
Step 3 of Intermediate 64 was prepared following a similar procedure to that of Step 3 of Intermediate 59 from methyl 9-acetoxy-8-(bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 509 mg (99%) of methyl 6-(bicyclo[3.2.1]octan-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.
LC/MS (m/z, MH+): 327
Step 4 of Intermediate 64 was prepared following a similar procedure to that of step 2 of Intermediate 52 from methyl 6-(bicyclo[3.2.1]octan-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 480 mg (67%) of methyl 8-(bicyclo[3.2.1]octan-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 459
Method A:
A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (103 mg, 212.45 μmol), phenyl-boronic acid (37.14 mg, 298.51 μmol), Cs2CO3 (224 mg, 673.75 μmol), and Pd(dppf)Cl2, complex with DCM (13.15 mg, 15.46 μmol) in dioxane (1 ml) and water (0.4 ml) was microwaved at 80° C. for 30 minutes. Water (2 ml) and DCM (5 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was treated on SCX column. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 41 mg (40%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 484
To a solution of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (40.8 mg, 84.45 μmol) in MeOH (1.5 ml) was added a solution of NaOH (300 μl, 1 M) and the reaction mixture was heated to reflux for 50 minutes. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 30 mg (70.8%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.
Step 1 of Example 2 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and 2,4-dichlorophenyl-boronic acid to give 100 mg (62%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 552
To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (100 mg, 181 μmol) in MeOH (3 ml) was added a solution of NaOH (250 μl, 1 M) and the reaction mixture was heated to reflux for 2.5 hours. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 5 with HCl 1N. After hydrophobic Column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 48 mg (49%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.
Method B:
Step 1 of Example 148 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 8) and 2-bromo-5-chloro-3-methyl-pyridine to give 71 mg (47%) of methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 533
Step 2 of example 148 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 21 mg (30%) of 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.
Method C:
Step 1 of Example 4 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and (4,4-difluorocyclohex-1-en-1-yl)boronic acid to give 55 mg (347%) of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 524.
A mixture of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (55 mg, 105 μmol), Pd/C 10% (18.67 mg, 175 μmol) in MeOH (3 ml) and EtOAc (2 ml) was hydrogenated at 50° C. and 5 bars of H2 for 15 hours. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 55 mg (99%) of methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 526
Step 3 of Example 4 was prepared following a similar procedure to that of step 2 of Example 1 from methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 46 mg (80.6%) of 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.
Method D:
Step 1 of Example 39 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and (4-bromobenzyl)(1-(3-fluoropropyl)azetidin-3yl)methanone (Intermediate 11) to give 111 mg (46%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange viscous oil.
LC/MS (m/z, MH+): 566
Step 2 of Example 39 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 69 mg (63%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.
Method E:
To a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (50 mg, 103 μmol) in THF (1 ml) were added nickel(II) chloride ethylene glycol dimethyl ether complex (1 mg, 5 μmol), 4,4′-di-tert-butyl-2,2′-bipyridine (1.38 mg, 5.14 μmol), sodium carbonate (21.79 mg, 205.58 μmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.15 mg, 1.03 μmol), 3-(bromomethyl)pentane (63 μl, 308 μmol) and tris(trimethylsilyl)silane (30 μl, 150 μmol). The degassed reaction mixture was irradiated under LED blue light (Photoreactor Penn OC ml) for 2 hours. Potassium fluoride 1 M (2 ml) and EtOAc were added. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/EtOAc/MeOH from 100/0/0 to 50/45/05 to give 21 mg (42%) of methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 492
Step 2 of Example 231 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 17 mg (87%) of 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.
Method F
Step 1 of Example 115 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 34) to give 215 mg (58%) of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange oil.
LC/MS (m/z, MH+): 586
To a solution of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (165 mg, 0.281 mmol) in ethanol (30 mL) was added PtO2 (32 mg, 0.14 mmol). The suspension was hydrogenated in an autoclave at room temperature under 2 bars of hydrogen for 2 hours. The mixture was filtered with ethanol washes then the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM/MeOH: 90/10 to give 140 mg (84%) of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
To a solution of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (140 g, 0.238 mmol) in methanol (2 mL), THF (1 mL) and water (0.5 mL) was added LiOH (59 mg, 2.38 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, taken into water and acidified with 1N aqueous HCl to pH 3. The resulting precipitate was filtered and dried to give 44 mg (30%) of 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride as a white solid.
Method G:
Step 1 of Example 262 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate (Intermediate 52) and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine (Intermediate 2), to give 48 mg (43%) of methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate.
LC/MS (m/z, MH+): 538
Step 2 of Example 262 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate to give 22 mg (47%) of 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride.
Method H:
Step 1 of Example 77 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 47) to give 101 mg (86%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 550
To a solution of diethylzinc (1.13 mL, 1.13 mmol, 1 M in hexanes) at 0° C. under Argon atmosphere was added a solution of diiodomethane (90 μL, 1.13 mmol) in DCM (1 mL). The mixture was stirred at 0° C. for 30 minutes then a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (310 mg, 0.563 mmol) in DCM (6 mL) was dropwise added. The resulting mixture was stirred overnight allowing the temperature to warm up to room temperature then quenched with a 1N aqueous HCl solution (10 mL) and diluted with water. The aqueous layer was separated and extracted three times with DCM. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 80/20, v/v) to give 132 mg (33%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a mixture of two isomers.
LC/MS (m/z, MH+): 550
The mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral HPLC (conditions: flash Chiralcel OD-H 250×30 mm, 5 μm; Heptane 95%/Isopropanol 5%/TEA 0.1%; 45 mL/min) to give 54 mg of isomer 1 and 43 mg of isomer 2.
To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (43 mg, 80 μmol) in methanol (9 mL)/THF (3 mL)/water (3 mL) was added LiOH (30.5 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight then quenched with 1N aqueous HCl to pH 1 and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 31 mg (74%) of 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 1 as a white solid.
Example 78 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 41 mg (78%) of 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 2 as a white solid.
Step 1 of Example 105 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and 2-cyanopyridine-4-boronic acid pinacol ester to give 227 mg (44%) of methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 510
To a solution of methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (227 mg, 445 μmol) in MeOH (10 ml) was added a 1 M solution of NaOH (2.8 ml, 2.8 mmol) and the reaction mixture was heated to reflux for 1 hour. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 94 mg (41%) of 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.
Step 1 of Example 110 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and N-Boc-2-pyrroleboronic acid to give 223 mg (89%) of tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate.
LC/MS (m/z, MH+): 573
To a solution of tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate (93 mg, 162 μmol) in MeOH (10 ml) was added a solution of NaOH (1.02 ml, 1.02 mmol) and the reaction mixture was heated to reflux for 1 hour. After cooling, water (5 ml) and DCM (5 ml) were added, and pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 30 mg (32%) of 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride and 12 mg (16%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride.
To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Step 1 of Example 235) (200 mg, 343 μmol) in DCM (5 mL) at −78° C. was added diethylaminosulfur trifluoride (90 μl, 0.69 mmol). The mixture was stirred for 1 hour at −78° C. then for 6 hours allowing the temperature to warm up to room temperature. Saturated aqueous solution of NaHCO3 and DCM were added. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of gradient of DCM/MeOH/NH4OH from 100/0/0 to 90/10/1 to give 153 mg (77%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as mixture of two isomers.
LC/MS (m/z, MH+): 584
The mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral SFC (conditions: flash Chiralcel OD-H (250×30 mm, 5 μm); supercritical CO2 80%/[0.1% TEA/MeOH] 20%; 3 mL/min) to give 35 mg of isomer 1 and 37 mg of isomer 2.
Example 175 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 31 mg (82%) of 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 1.
Example 176 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 26 mg (75%) of 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 2.
To a solution of 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (Step 1 of Example 39) (100 mg, 176 μmol) in THF (5 mL) at −10° C. was added a 3 M solution of methyl magnesium bromide in ether (180 μL, 530 μmol). The mixture was stirred at −10° C. for 45 minutes. The reaction mixture was slowly quenched by addition of a saturated aqueous solution of NH4Cl and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 102 mg (99%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as mixture of two isomers.
LC/MS (m/z, MH+): 582
The mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral HPLC (conditions: flash Chiralpak AY-H 250×4.6 mm, 5 μm; Heptane 89/EtOH 10/MeOH 1/TEA 0.2; 45 mL/min) to give 20 mg of isomer 1 and 19 mg of isomer 2.
Example 235 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 4 mg (21%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 1.
Example 236 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 7 mg (35%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 2.
Step 1 of Example 194 Isomer 1 and Isomer 2 were prepared following a similar procedure to that of step 1 of Example 1 from 3-(4-bromobenzyl)-1-(2,3-difluoropropyl)azetidine (Intermediate 50) and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) to give 278 mg (66%) as a mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and Isomer 2.
The mixture of two isomers was separated by chiral chromatography (condition: flash Chiralpak IF 5 m (250×30 mm), eluent: Heptane 95 EtOH 5 TEA 0.1 to give 91 mg of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and 94 mg of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.
LC/MS (m/z, MH+): 570
Step 2 of Example 194 Isomer 1 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 75 mg (84%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.
Example 195 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 to give 90 mg (98%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.
Step 1: Methyl(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate acid (Step 1 of Example 39) (500 mg, 882 μmol) and O-methylhydroxylamine hydrochloride (184 mg, 2.21 mmol) in pyridine (5 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The 2 isomers were separated by SFC (condition: flash Chiralpak IG 5 μm (3×25 cm), eluent CO2/11% (MeOH+0.1% DEA) to give 111 mg (21%) of methyl(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 34 mg (6%) of methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 595
Step 2 of Example 196 isomer 1 was prepared following a similar procedure to that of step 2 of Example 2 from methyl(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 86 mg (66%) of (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid.
Example 197 was prepared following a similar procedure to that of step 2 of Example 2 from methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 12 mg (30%) of (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acetate.
Step 1 of Example 227 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 1 (Intermediate 14) to give 191 mg (64%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1.
LC/MS (m/z, MH+): 568
To a solution of methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (100 mg, 170 μmol) in methanol (5 mL) and water (1 mL) was added LiOH (12 mg, 511 μmol). The reaction mixture was stirred at room temperature for 3 hours then quenched with 1N aqueous HCl to pH 6-7 and extracted three times with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 95/05 to give 28 mg (29%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.
Step 1 of Example 228 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 2 (Intermediate 15) to give 186 mg (62%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.
LC/MS (m/z, MH+): 568
Step 2 of Example 228 was prepared following a similar procedure to that of step 2 of Example 227 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 175 mg (91%) of methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.
LC/MS (m/z, MH+): 586
Step 3 of Example 228 was prepared following a similar procedure to that of step 3 of Example 227 from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 25 mg (26%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.
Example 229 was prepared following a similar procedure to that of step 3 of Example 227 from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and EtOH to give 15 mg (30%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.
Example 230 was prepared following a similar procedure to that of step 3 of Example 227 from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 and EtOH to give 34 mg (34%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.
Step 1 of Example 243 was prepared following a similar procedure to that of step 1 of Example 1 from 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine Isomer 1 (Intermediate 25) and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) to give 500 mg (99%) of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1.
LC/MS (m/z, MH+): 593
A mixture of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (300 mg, 505 μmol) and triphenylphosphine (132 mg, 505 μmol) in THF (4 ml) was stirred at room temperature for 24 hours. DCM (100 ml) and water (100 ml) were added. After decantation, the organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 to give 44 mg (15%) of methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1.
LC/MS (m/z, MH+): 567
Step 3 of Example 243 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 33 mg (79%) of 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.
Step 1 of Example 244 was prepared following a similar procedure to that of step 1 of Example 1 from 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 2 (Intermediate 26) and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) to give 550 mg (97%) of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.
LC/MS (m/z, MH+): 593
Step 2 of Example 244 was prepared following a similar procedure to that of step 2 of Example 243 from methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 140 mg (44%) of methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.
LC/MS (m/z, MH+): 567
Step 3 of Example 244 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 22 mg (52%) of 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.
Step 1 of Example 252 was prepared following a similar procedure to that of step 1 of Example 1 from tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate (Intermediate 48) and (2-chlorophenyl)boronic acid to give 87 mg (41%) of tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 559
Step 2 of Example 252 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate to give methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid which was used in the next step without further purification.
Step 3 of Example 252 was prepared following a similar procedure to that of step 4 of Intermediate 28 from methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give 35 mg (43%) of methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 519
Step 4 of Example 252 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 32 mg (44%) of 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.
Step 1 of Example 253 was prepared following a similar procedure to that of step 1 of Example 1 from tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate (Intermediate 48) and (2,4-dichlorophenyl)boronic acid to give 105 mg (47%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate.
LC/MS (m/z, MH+): 593
Step 2 of Example 253 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate to give methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid which was used in the next step without further purification.
Step 3 of Example 253 was prepared following a similar procedure to that of step 4 of Intermediate 28 from methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.
LC/MS (m/z, MH+): 553
Step 4 of Example 253 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 17 mg (18% for two last steps) of 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.
Example 254 was prepared following a similar procedure to that of step 1 of Example 1 from 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Intermediate 49) and 2,4-dichlorophenyl-boronic acid to give 120 mg (52%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as an off-white solid.
Example 255 was prepared following a similar procedure to that of step 1 of Example 1 from 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Intermediate 49) and 2-chlorophenyl-boronic acid to give 130 mg (61%) of 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as a brownish solid.
The compounds according to Table 1a above were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.
Test: Estrogen Receptor Degradation Activity
Said test involves measuring the in vitro degradation activity of the compounds of the Table 1a.
The measurements of the degradation activities were made using a breast cancer cell ERα in cell western assay as described hereunder.
MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/30 μL per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound was added to the cells in 2.5p L at final concentrations ranging from 0.3-0.0000018 μM (in table 2), or 0.1 μM for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 μL anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking buffer but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37° C. for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 μM final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech). Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ERα and DNA respectively.
The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC50) in nM.
The % of ERα levels decrease were determined as follows: % inhibition=100*(1−(sample−fulvestrant: DMSO−fulvestrant)).
The Table 2 below indicates the estrogen receptor degradation activity results for the compounds of Table 1a tested at 0.3 μM, and demonstrates that said compounds have a significant degradation activity on estrogen receptors.
It is therefore apparent that the tested compounds have degradation activities for estrogen receptors, with IC50 less than 1 μM and with degradation levels greater than 50%. The compounds of formula (I) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors.
Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.
Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use as medicines.
Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors.
Herein are also provided the compounds of formula (I) defined above, or a pharmaceutically acceptable salts thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.
A particular aspect is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
In an embodiment, the cancer is a hormone dependent cancer.
In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.
In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.
In another embodiment, the metastasis is a cerebral metastasis.
In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERα positive breast cancer).
In another embodiment, the cancer is resistant to anti-hormonal treatment.
In a further embodiment, the compound of formula (I) is as used as single agent or in combination with other agents such as CDK4/6, mTOR or PI3K inhibitors.
According to another aspect, herein is provided a method of treating the pathological conditions indicated above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.
Herein is also provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer.
Herein are also provided the pharmaceutical compositions comprising as active principle a compound of formula (I). These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.
In the pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.
The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants. For topical application it is possible to use the compounds of formula (I) in creams, gels, ointments or lotions.
As an example, a unit administration form of a compound of formula (I) in tablet form may comprise the following components:
There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20306236.9 | Oct 2020 | EP | regional |
| 21306281.3 | Sep 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/078883 | 10/19/2021 | WO |
