WO2018138739A1 - Nouveaux composés antiœstrogènes hétérocycliques - Google Patents

Nouveaux composés antiœstrogènes hétérocycliques Download PDF

Info

Publication number
WO2018138739A1
WO2018138739A1 PCT/IN2018/050040 IN2018050040W WO2018138739A1 WO 2018138739 A1 WO2018138739 A1 WO 2018138739A1 IN 2018050040 W IN2018050040 W IN 2018050040W WO 2018138739 A1 WO2018138739 A1 WO 2018138739A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
yloxy
dihydro
benzo
fluoro
Prior art date
Application number
PCT/IN2018/050040
Other languages
English (en)
Inventor
Biswajit Samanta
Nakul Pramodbhai AKOLKAR
Megha Shringesh DESAI
Poojan Kaushikbhai PATEL
Sairam V. V. M. Kalapatapu
Trinadha Rao Chitturi
Original Assignee
Sun Pharma Advanced Research Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharma Advanced Research Company Limited filed Critical Sun Pharma Advanced Research Company Limited
Publication of WO2018138739A1 publication Critical patent/WO2018138739A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids

Definitions

  • the present invention provides novel heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/ degraders and process for their preparation.
  • ER estrogen receptor
  • E2 BACKGROUND OF THE INVENTION Endogenous estrogen, 17 ?-estradiol
  • E2 shows a wide variety of biological activities in the reproductive systems, bone metabolism, and the cardiovascular systems, as well as the central nervous system.
  • the link between estrogen and breast cancer growth and development has been well established.
  • a number of strategies to inhibit the action of endogenous estrogen in estrogen receptor (ER) positive breast cancer are in practice.
  • SERMs selective ER modulators
  • SELD selective ER degraders
  • AI aromatase inhibitors
  • exemestane steroidal
  • anastrozole anastrozole
  • letrozole nonsteroidal
  • Bioorganic & Medicinal Chemistry Letters, 2005 (15), 3912-3916 discloses dihydrobenzoxathin as ligands for selective estrogen receptor alpha modulators.
  • US patent number 7138426 discloses pyrrolidinylethoxyphenyl benzoxanthins as estrogen receptor modulators.
  • WJ O application WO2016174551A1 discloses 2H-chromene derivatives and WO 2016097072A1 discloses tetrahydro-pyrido [3, 4-b] indole compounds as estrogen receptor modulators.
  • WJ O application WO 2016097071A1 discloses various compounds having azetidine or pyrrolidine ring in the side chain useful for the treatment of ER-related diseases or conditions.
  • WO 2012084711 Al discloses N-substituted azetidine derivatives as ER-a antagonists wherein the azetidine ring is attached to selective estrogen receptor modulator fragment.
  • the present invention provides a compound of Formula I
  • ring Z is a 5 to 10 membered mono- or bi-cyclic aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur; m and n are integer independently selected from 1 and 2;
  • A is selected from a group consisting of -0-, -NH-, -S-, -N(Ci_3alkyl)- and -N(C 3-6 cycloalkyl)-;
  • E is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of hydrogen, halogen, -COOH, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -CN, -Ci-3 haloalkyl, -Ci_ 3 alkyl, -OCi_ 3 haloalkyl and -OCi_ 3 alkyl;
  • R 2 at each occurrence, is independently selected from hydrogen, -C 1-6 alkyl, -C 1-6 haloalkyl, - C 3 _6 cycloalkyl and -C 3 _ 6 halocycloalkyl;
  • R 3 at each occurrence, is independently selected from hydrogen, -C 3-6 cycloalkyl and -C 1-6 alkyl;
  • Y is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R 5 , -OR 5 , halogen, -CN, -NR5COR5, -NR 5 S0 2 R 5 , -OC(0)R 5 , - OC(0)N(R 5 ) 2 , and -OC(0)ORs; wherein R5, at each occurrence, is independently selected from a group consisting of hydrogen, Ci_ 6 linear, branched or cyclic alkyl and Ci_ 6 linear, branched or cyclic haloalkyl;
  • L is selected from -0-, -NH-, -N(C 1-6 alkyl)-, -N(C 3 _ 6 cycloalkyl)-, -N(C 1-6 haloalkyl)- and - N(C 3 _6 halocycloalkyl)-;
  • ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;
  • D is a group selected from boronic acid and a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_ 3 alkyl group wherein the point of attachment of D to ring X is the boron atom;
  • R 7 and R 8 are independently selected from hydrogen, Ci_ 3 alkyl and Ci_ 3 haloalkyl.
  • the compounds of present invention are antagonists/degraders of estrogen receptor and can be used for the treatment of diseases which are related to modulation of ER.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention may be salts of inorganic acids such as hydrochloric acid, hydrobromic acid, fumaric acid, phosphoric acid, and the like or of organic acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartartic acid, amino acids such as glutamic acid or aspartic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, fumaric acid, phosphoric acid, and the like
  • organic acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, glycolic acid, lactic acid, fumaric acid, succinic acid,
  • suitable pharmaceutically acceptable basic salts are ammonium salts, or suitable organic amines, such as tertiary monoamines, e.g. triethylamine or tris(2-hydroxyethyl)amine etc., alkali metal salts such as sodium salts and potassium salts and alkaline earth metal salts such as magnesium salts and calcium salts.
  • suitable pharmaceutically acceptable basic salts are ammonium salts, or suitable organic amines, such as tertiary monoamines, e.g. triethylamine or tris(2-hydroxyethyl)amine etc., alkali metal salts such as sodium salts and potassium salts and alkaline earth metal salts such as magnesium salts and calcium salts.
  • suitable pharmaceutically acceptable basic salts are ammonium salts, or suitable organic amines, such as tertiary monoamines, e.g. triethylamine or tris(2-hydroxyethyl)amine etc., alkali metal salts such as sodium salt
  • aromatic ring or "aryl ring” refers to an aromatic radical having 6 to 10 carbon atoms, including monocyclic or bicyclic aromatic system.
  • the bicyclic aromatic ring or aryl ring includes an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic ring.
  • Typical aromatic ring or aryl ring includes, but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl.
  • heteroaryl ring refers to 5 to 10 membered aromatic heterocyclic ring radicals with one or more heteroatoms independently selected from nitrogen, oxygen or sulfur.
  • the heteroaryl ring may be a mono- or bi-cyclic ring system and includes fused ring systems (at least one of which is aromatic).
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring includes, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl.
  • halogen as used herein includes chloro, fluoro, bromo and iodo.
  • alkyl refers to a saturated hydrocarbon chain that includes carbon and hydrogen atoms in the backbone, either linear or branched, having from 1 to 20 carbon atoms, both inclusive unless defined otherwise.
  • the length of the chain may vary and is defined by the expression, for example, Ci_ 2 o which means an alkyl chain having 1 to 20 carbon atoms.
  • the term alkyl includes linear as well as branched alkyl.
  • the examples of alkyl chain are methyl, ethyl, ⁇ -propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (i-butyl).
  • alkyl groups described or claimed herein may be substituted or unsubstituted.
  • the numbers or the range written as subscript in terms like "Ci_6" refers to the number of carbon atoms in the group. Thus the referred group may have 1, 2, 3, 4, 5 or 6 carbon atoms.
  • haloalkyl refers to alkyl group substituted with one or more halogen radicals. The non-limiting examples of haloalkyl group includes fluoromethyl, difluromethyl, etc.
  • cycloalkyl or "cyclic alkyl” denotes a non-aromatic monocyclic ring.
  • the size of the ring is described by the expression, for example C 3 _ 4 which denotes that the ring may have 3 or 4 carbon atoms. Wherever the ring size is not defined, the cycloalkyl or cyclic alkyl ring may contain 3 to 8 carbon atoms.
  • the examples of cycloalkyl ring include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • halocycloalkyl refers to a cycloalkyl ring substituted with one or more halogen radicals.
  • the present invention provides a compound of Formula I
  • ring Z is a 5 to 10 membered mono- or bi-cyclic aromatic ring containing zero to 2 heteroatoms selected from nitrogen, oxygen and sulfur; m and n are integer independently selected from 1 and 2; A is selected from a group consisting of -0-, -NH-, -S-, -N(Ci_3alkyl)- and -N(C 3 _6 cycloalkyl)-;
  • E is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting hydrogen, halogen, -COOH, -NH 2 , -NH(Ci_ 3 alkyl), -N(C 1-3 alkyl) 2 , -CN, - Ci_ 3 haloalkyl, -Ci_ 3 alkyl, -OCi_ 3 haloalkyl and -OCi_ 3 alkyl;
  • R 2 at each occurrence, is independently selected from hydrogen, -Ci_ 6 alkyl, -Ci_ 6 haloalkyl, - C 3 _6 cycloalkyl and -C 3 _ 6 halocycloalkyl;
  • R 3 at each occurrence, is independently selected from hydrogen, -C 3 _6 cycloalkyl and -Ci_6 alkyl;
  • Y is mono-, di- or tri-substitution and at each occurrence is independently selected from a group consisting of -R 5 , -OR 5 , halogen, -CN, -NR 5 COR 5 ,-OS0 2 R 5 -NR 5 S0 2 R 5 , -OC(0)R 5 , - OC(0)N(R5) 2 , and -OC(0)ORs; wherein R5, at each occurrence, is independently selected from a group consisting of hydrogen, Ci_ 6 linear, branched or cyclic alkyl and Ci_ 6 linear, branched or cyclic haloalkyl;
  • L is selected from -0-, -NH-, -N(Ci_ 6 alkyl)-, -N(C _ 6 cycloalkyl)-, -N(Ci_ 6 haloalkyl)- and - N(C 3 _6 halocycloalkyl)-;
  • ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;
  • D is a group selected from boronic acid and a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more C 1-3 alkyl group wherein the point of attachment of D to ring X is the boron atom;
  • R 7 and R 8 are independently selected from hydrogen, -C 1-3 alkyl and -Ci_ 3 haloalkyl.
  • ring Z is a 5 or 6 membered aromatic ring containing 0 to 2 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the examples of ring Z includes, but not limited to phenyl, thiophenyl, pyridyl, pyrimidinyl etc.
  • ring Z is phenyl or pyridyl.
  • ring Z is phenyl.
  • the present invention provides a compound of Formula I, wherein A is selected from a group consisting of -0-, -NH-, -N(C 1-3 alkyl)- and -N(C 3-6 cycloalkyl)-.
  • A is -O- or -NH-.
  • A is -0-.
  • Z is a 6 membered aromatic ring
  • the substitution A on ring Z may be at 2, 3 or 4 position with respect to the point of attachment of ring Z to the rest of molecule.
  • Z is phenyl ring and A is attached at 3 or 4 position of the ring.
  • the present invention provides a compound of Formula I, wherein E is mono-, di- or tri-substitution.
  • E is mono- or di- or tri-substitution.
  • the ring Z can have one, two or three E groups substituted on it selected independently from each other.
  • E is tri-substitution.
  • E is di- substitution.
  • E is mono-substitution.
  • E at each occurrence is independently selected from a group consisting of hydrogen, halogen, -COOH, -NH 2 , -NH(Ci_ 3 alkyl), -N(Ci_ 3 alkyl) 2 , -CN, -C 1 -3 haloalkyl, -Ci_ 3 alkyl, -OCi_ 3 haloalkyl, and -OCi_ 3 alkyl.
  • E is hydrogen or halogen.
  • E is halogen.
  • E is fluoro.
  • alkyl chain optionally interrupted with one or more radicals means that the radicals is/are present in between the two carbon atoms of the alkyl chain. There may be more than one radicals present in the chain which can be placed adjacent to each other or separated by carbon atoms of the alkyl chain.
  • the group B can optionally be further substituted with one or more groups selected from halogen, -C 3 _ 6 cycloalkyl, -OR 4 , -N(R 4 ) 2 , -C(0)OCi_ 6 alkyl and phenyl unsubstituted or substituted with one or more groups selected from halogen, -Ci_ 6 alkyl and - OCi_ 6 alkyl; wherein, R 4 , at each occurrence, is a group selected from hydrogen and Ci_ 6 linear, branched or cyclic alkyl.
  • the group B can optionally be further substituted with one or more groups selected from halogen and -C 3 _ 6 cycloalkyl.
  • group B is substituted with one or more halogen.
  • B is Ci_ 6 linear or branched alkyl chain optionally substituted with one or more groups selected from halogen and -C 3 _ 6 cycloalkyl.
  • B is -Ci_ 3 alkyl or -Ci_ 3 haloalkyl.
  • B is n-propyl, 3- fluoropropyl, 2-fluoro-2-methylpropyl, 3,3,3-trifluoropropyl, n-hexyl, n-decyl or cyclopropylmethyl.
  • the present invention provides a compound of Formula I, wherein Y is mono-, di- or tri-substitution.
  • Y is mono- or di- or tri-substitution
  • Y is mono- or di- or tri-substitution
  • the phenyl ring can have one, two or three Y groups substituted on it.
  • Y is di-substitution.
  • Y is tri-substitution.
  • Y is mono-substitution.
  • Y at each occurrence is independently selected from a group consisting of -R 5 , -OR 5 , halogen, -CN, -NR 5 COR 5 , -NR 5 S0 2 R 5 , -OC(0)R 5 , - OC(0)N(R 5 ) 2 , -OS0 2 R5 and -OC(0)ORs; wherein R5, at each occurrence, is a group selected from hydrogen, Ci_ 6 linear, branched or cyclic alkyl and Ci_ 6 linear, branched or cyclic haloalkyl.
  • Y is -OH, halogen, -OCi_ 3 alkyl or -OCi_ 3 haloalkyl.
  • Y is -OH or -OCi_ 3 haloalkyl. In yet another preferred embodiment, Y is -OH.
  • the substitution Y on phenyl ring may be at 2, 3 or 4 position with respect to the point of attachment of phenyl ring to the rest of molecule. In a preferred embodiment, Y is a mono-substitution and is at 4 position on the phenyl ring.
  • the present invention provides a compound of Formula I, wherein L is selected from -0-, -NH-, -N(Ci_ 6 alkyl)-, -N(C 3 _ 6 cycloalkyl)-, -N(Ci_ 6 haloalkyl)- and - N(C 3 _ 6 halocycloalkyl)-.
  • L is -0-.
  • Ring X along with the two atoms of the central ring, is a 5 to 10 membered mono- or bi- cyclic ring containing 0 to 4 heteroatoms. Ring X can be aromatic or non-aromatic.
  • ring X is a 6 to 10 membered mono- or bi-cyclic ring containing zero to 3 heteroatoms selected from oxygen, nitrogen and sulfur.
  • ring X is selected from monocyclic ring such as phenyl, imidazolyl, pyrazolyl, thiophenyl, pyrazinyl and piperazinyl.
  • the present invention provides a compound of Formula I, wherein the ring X is a bicyclic ring selected from a group of
  • ring X is selected from
  • the ring X is phenyl. In another preferred embodiment, the ring X is
  • D is selected from -R 6 , -OR 6 , halogen, -OC(0)R 6 , -OC(0)N(R 6 ) 2 , -Ci_ 3 alkyl-N(R 6 ) 2 , -OP(0)(OH) 2 and 5 or 6 membered aryl or heteroaryl ring; wherein R 6 at each occurrence is independently selected from hydrogen and Ci_6 linear, branched or cyclic alkyl.
  • D is hydrogen or -OH.
  • D is -OH.
  • the phrase "D is mono- or di- or tri-substitution" means that the ring X can have one, two or three D groups substituted on it. In a preferred embodiment, D is mono-substitution.
  • D is a group selected from boronic acid and a 5 or 6 membered ring containing the C-O-Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_ 3 alkyl group wherein the point of attachment to ring X is the boron atom.
  • the present invention provides a compound of Formula I, wherein R 7 and R 8 are independently selected from hydrogen, Ci_ 3 alkyl and Ci_ 3 haloalkyl. In a preferred embodiment, R 7 and R 8 are hydrogen or Ci_ 3 alkyl. In another preferred embodiment, R 7 and R 8 are hydrogen. In another preferred embodiment, the present invention provides a compound of Formula I, wherein m and n are 1 thus forming an azetidinyl ring.
  • the present invention provides a compound of Formula la
  • the present invention provides a compound of Formula lb
  • the present invention provides the compounds selected from a group consisting of:
  • the present invention provides the compounds selected from a group consisting of:
  • the present invention provides the compounds selected from a group consisting of:
  • the compounds of the Formula I can be prepared by coupling a compound of Formula (1) wherein Q is a halogen and D, X & L are as defined earlier in the specification, with the compound of Formula (2) wherein W is - ⁇ or a suitable leaving group such as halogen, mesylate, tosylate, triflate or nosylate, P is a protecting group such as ie/t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethyloxycarbonyl (Fmoc) and Y, R 7 & R 8 are as defined earlier in the specification; to give a compound of Formula (3) wherein D, X, L, Q, P, Y, R 7 & R 8 are as defined earlier in the specification; which upon deprotection followed by intramolecular cyclization gives compound of Formula (4) wherein D, X, L, Y, R 7 & R 8 are as defined earlier in the specification.
  • W is - ⁇ or
  • the compound of Formula I can be prepared by following the procedure as depicted in Scheme 2.
  • Coupling of the compound of Formula (5) with compound of Formula (2) gives a compound of Formula (6) wherein W, P, Y, Z, E, A, B, R 7 , R 8 , m & n are as defined earlier in the specification.
  • Coupling of the compound of Formula (6) with a compound of Formula (1) gives an adduct of the Formula (7) wherein D, X, L, Q, P, Y, Z, E, A, B, R 7 , R 8 , m & n are as defined earlier in the specification; which upon deprotection followed by intramolecular cyclization gives the compound of Formula I.
  • the compound of Formula I can also be prepared by following the procedure as depicted in Scheme 3. Coupling of the compound of Formula (1) with compound of Formula (8) wherein W, Y, R 7 & R 8 are as defined earlier in the specification, gives compound of Formula (9) wherein D, X, L, Q, Y, R 7 & R 8 are as defined earlier in the specification. Reductive amination of the compound of Formula (9) gives a compound of Formula (10) wherein D, X, L, Q, Y, R 7 & R 8 are as defined earlier in the specification. Intramolecular cyclization of the compound of Formula (10) gives the compound of Formula (4). Buchwald reaction of the compound of Formula (4) with compound of Formula (5) gives the compound of Formula I.
  • the compound of Formula I can also be prepared by following the procedure as depicted in Scheme 4.
  • Coupling of the compound of Formula (8) with compound of Formula (12) gives an adduct of Formula (13) wherein D, X, L, Y, Z, E, A, B, R 7 , R 8 , m & n are as defined earlier in the specification, which upon intramolecular cyclization gives the compound of Formula I.
  • salts of the compound of Formula I may be prepared in a. manner known to those skilled in the art.
  • the acid addition salts of compounds of Formula I may be obtained by treating the compound of Formula ⁇ having a functional moiety capable of forming acid addition salt with an acid in a suitable solvent.
  • the compound of Formula I can be subjected to salt exchange, or treated with a suitable anion exchange reagent to obtain the desired acid addition salt.
  • Stereoisomeric mixtures can be separated into individual stereoisomers by means of suitable well known separation methods.
  • Enantiomers may be resolved by well-known techniques for example, through the formation of diastereomeric salts with enantiomerically pure chiral acid or a base; by derivatization with a suitable chiral derivatizing agent and separation such as by fractional crystallization, fractional distillation or by kinetic resolution such as enzymatic or chemical hydrolysis of the derivatized isomer.
  • the enantiomers may be resolved by means of chromatography, for example by chiral HPLC, using a chiral chromatographic stationary phase.
  • Table 1 provides few exemplary compounds of Formula I.
  • the compounds described herein, including compounds of Formula I can be prepared by reaction schemes depicted in Schemes 1, 2, 3 and 4. Furthermore, in the following examples, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as part of the present invention. The compounds obtained by using the general reaction scheme may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios.
  • the compounds can be converted into its acid addition salts or base addition salts as mentioned earlier in the specification, by dissolving the compounds in the appropriate solvent followed by the treatment with appropriate acid or base. All solvents and reagents were used as obtained from commercial sources unless otherwise indicated. 1H-NMR spectra were recorded on Bruker spectrometer operating at 400 MHz or
  • Step I (R)-N-(tert-Butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)-l-(4- benz loxyphenyl)ethylamine
  • Step II (/?)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-benzyloxy phenyl)ethylamine.
  • Trifluoroacetic acid (22 niL) was added to a stirred solution of ( ?)- V-(ie/ -butoxycarbonyl)- 2-(5-benzyloxy-2-bromophenoxy)- l-(4-benzyloxyphenyl)ethylamine (11 g, 0.018 mol) in dichloromethane (55 mL) at 0-5 °C and then stirred at ambient temperature for 1 hour. Reaction mixture was diluted with dichloromethane and made alkaline (pH ⁇ 9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Step IV 3-(4-Bromo-2-fluorophenoxy)azetidine-l-carboxylic acid tert-butyl ester
  • Diisopropyl azodicarboxylate (8.65 mL, 0.043 mol) was added dropwise to a stirred mixture of 3-hydroxyazetidine-l-carboxylic acid te/t-butyl ester (5.71 g, 0.032 mol), 4-bromo-2- fluorophenol (6.0 g, 0.031 mol) and triphenylphosphine (10.69 g, 0.041 mol) in a mixture (1: 1) of toluene (42 mL) and tetrahydrofuran (42 mL) under nitrogen atmosphere at room temperature. The resultant reaction mixture was then heated to reflux for 5 hours at 110 °C.
  • Trifluoroacetic acid (20 mL) was added to a stirred solution of 3-(4-bromo-2- fluorophenoxy)azetidine-l-carboxylic acid ieri-butyl ester (10.0 g, 0.031 mol) in dichloromethane (100 mL) at 0-5 °C and then stirred at room temperature for 1 hour 30 minutes.
  • the mixture was diluted with dichloromethane (30 mL) and made alkaline (pH ⁇ 9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with water followed by brine solution and dried over anhydrous sodium sulfate.
  • Glacial acetic acid (0.05 mL) was added to a mixture of 3-(4-bromo-2- fluorophenoxy)azetidine (0.5 g, 0.0022 mol) and propionaldehyde (0.237 mL, 0.0033 mol) in a mixture of dichloromethane (7 mL) and methanol (3 mL) at room temperature and stirred for lhr.
  • Sodium cyanoborohydride (0.314 g, 0.005 mol) was then added to the reaction mixture at room temperature and stirred for lhr. Reaction mixture was quenched with water and contents were concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane.
  • Step VII (/f)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro-4-(l-propylazetidin-3- loxy)phenyl] -3,4-dihydro-2H-benzo /,4/oxazine
  • Reaction mixture was heated at 105 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Step VIII (R)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)- 3,4-dihydro-2H-benzoA 4/oxazin-7-ol
  • Step II 2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine
  • Step III 7-Benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzoA , ⁇ 7oxazine
  • Potassium ie/t-butoxide (0.157 g, 0.0014 mol) was added to a stirred solution of 2-(5- benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine (0.415 g, 0.001 mol), tris(dibenzylidineacetone)dipalladium (0.046 g, 0.00005 mol) and 2,2'- bis(diphenylphosphino)-l, -binaphthyl (0.063 g, 0.0001 mol) in toluene (10 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for one and half hours.
  • Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 10:90) to get 7-benzylozy-3-(4-fluorophenyl)-3,4-dihydro-2H- benzo/7,4/oxazine.
  • Step IV 7-Benzyloxy-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phen l]-3,4-dihydro-2H-benzo/7,4/oxazine
  • reaction mixture Sodium ie/ -butoxide (0.060 g, 0.0006 mol) was added to reaction mixture and then heated at 105 °C for 1 hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate.
  • Step V 3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo/7,4/oxazin-7-ol
  • Reaction mixture was cooled to room temperature, filtered through celite bed and washed with a 1: 1 mixture of methanol and 1, 4- dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Combined organic layer washed with water followed by brine solution and dried over anhydrous sodium sulphate.
  • Example 3 Preparation of 4-
  • Step I 5-Bromo-l-(tetrahydropyran-2-yl)-6-(tetrahydropyan-2-yloxy)-/H-indazole.
  • Step II 5-Bromo-l- tetrahydropyran-2-yl)-/H-indazol-6-ol.
  • Step III ⁇ (/f)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-/H-indazol- 6- loxy]ethyl ⁇ carbamic acid tert butyl ester.
  • Step IV (/f)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-/H-indazol-6- yloxy]eth lamine.
  • Step V (R)-6-(4-Benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-l,5,6,7-tetrahydro-8- 1 ,2,5-triazac clopenta[Z> ] naphthalene.
  • Reaction mixture was heated at 100 °C for 1 hour 30 minutes. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n- hexane, 30:70) to get ( ?)-6-(4-benzyloxyphenyl)- l-(tetrahydropyran-2-yl)- l,5,6,7-tetrahydro- 8-oxa- 1 ,2,5-triazacyclopenta[ ]naphthalene.
  • Step VI (/f)-6-(4-Benzyloxyphenyl)-5-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l- (tetrahydropyran-2-yl)-l,5,6,7-tetrahydro-8-oxa-l,2,5-triazacyclopenta[6]naphthalene.
  • naphthalene (0.38 g, 0.00086 mol), 3-(4-bromo-2-fluorophenoxy)-l-propylazetidine (0.237 g, 0.00082 mol), palladium acetate (0.009 g, 0.000041 mol) and tii-tert butylphosphine (0.033 mL, 0.000082 mol, 50 % solution in toluene) in toluene (10 mL) under nitrogen atmosphere and then heated at 105 °C for 2 hours. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate.
  • Step VII 4-[(/f)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l-(tetrahydropyran-2- l)-l,5,6,7-tetrahydro-8-oxa-l,2,5-triazacyclopenta[6]naphthalen-6-yl]-phenol.
  • reaction mixture was heated at 70 °C for 30 minutes.
  • Reaction mixture was cooled to room temperature, filtered through celite bed and washed with a (1: 1) mixture of methanol and 1, 4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Combined organic layer washed with water followed by brine solution and dried over anhydrous sodium sulphate.
  • Step VIII 4-[(R)-5-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-l,5,6,7-tetrahydro-8- oxa-l,2,5-triazacyclopenta[6]naphthalen-6-yl]-phenol.
  • Step I (R)-tert-Butoxycarbonylamino-(4-fluoromethoxyphenyl)acetic acid methyl ester.
  • Step II [(/f)-l-(4-Fluoromethoxyphenyl)-2-hydroxyethyl]carbamic acid tert butyl ester.
  • Step III [(R)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluoromethoxyphenyl)- ethyl]carbamic acid tert butyl ester.
  • Step IV (R)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluoromethoxyphenyl) ethylamine.
  • Trifluoroacetic acid (15 mL) was added to a stirred solution of [( ?)-2-(5-benzyloxy-2- bromophenoxy)-l-(4-fluoromethoxyphenyl)-ethyl]carbamic acid tert-buty ⁇ ester (7.7 g,
  • Step V (/?)-7-Benzyloxy-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.
  • the resultant reaction mixture was stirred at room temperature and then heated to reflux for 2 hour 30 minutes at 110 °C.
  • the mixture was cooled to ambient temperature, concentrated and degassed under reduced pressure at 50 °C.
  • the mixture (20 mL) of n- hexane: ethyl acetate (85: 15) was added to the residue and contents were stirred vigorously for 30 minutes. Solid thus obtained was filtered under vacuum and washed with same mixture.
  • Step VII 3-(Azetidin-3-yloxy)-5-bromopyridine.
  • Trifluoroacetic acid (1.4 mL) was added to a stirred solution of 3-(4-bromo-2- fluorophenoxy)azetidine- l-carboxylic acid tert-butyX ester (0.67 g, 0.002 mol) in dichloromethane (8 mL) at 0-5 °C and then stirred at room temperature for 2 hours.
  • the mixture was diluted with dichloromethane (30 mL) and made alkaline (pH ⁇ 9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with water followed by brine solution and dried over anhydrous sodium sulfate.
  • Dichloromethane was removed under reduced pressure to get 3-(azetidin-3-yloxy)-5-bromopyridine.
  • Step VIII 3-Bromo-5-(l-propylazetidin-3-yloxy)pyridine.
  • Step IX (/f)-7-Benzyloxy-3-(4-fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3- yloxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[/,4]oxazine.
  • Reaction mixture was heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Step X (R)-3-(4-Fluoromethoxyphenyl)-4-[5-(l-propylazetidin-3-yloxy)pyridin-3 3,4-dihydro-2H-benzo[/,4]oxazin-7-ol.
  • Reaction mixture was cooled to room temperature, filtered through celite bed and washed with 1: 1 mixture of methanol and 1,4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate.
  • Example 5 Preparation of (3/?)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl1-3-(4- hvdroxyphenyl)-2-methyl-3,4-dihvdro-2H-benzo
  • Step I [(R)-(4-Benzyloxyphenyl)(methoxymethylcarbamoyl)methyl]carbamic acid tert butyl ester.
  • Step II [(R)-l-(4-Benzyloxyphenyl)-2-hydroxypropyl]carbamic acid tert butylester.
  • ketone derivative (2.4 g, 0.0067 mol) in methanol (25 mL) was added sodium borohydride (0.51 g, 0.0135 mol) slowly at -20 °C and stirred for 1 hour 30 minutes. The mixture was quenched with water and concentrated under reduced pressure at 35 °C. Aqueous layer was extracted with ethyl acetate.
  • Step III [(/f)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)propyl]carbamic acid tert butyl ester.
  • Reaction mixture was degassed under reduced pressure at 40 °C and 10 % ethyl acetate in n-hexane solution (20 mL) was added to the residue, stirred and filtered. The filterate was concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 10:90) to get [( ?)-2-(5-benzyloxy-2-bromophenoxy)- l-(4- benzyloxyphenyl)propyl]carbamic acid tert butyl ester.
  • Step IV (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2-methyl-3,4-dihydro-2H- benzo[/,4]oxazine.
  • Trifluoroacetic acid (1.4 mL) was added to a stirred solution of [( ?)-2-(5-benzyloxy-2- bromophenoxy)-l-(4-benzyloxyphenyl)propyl]carbamic acid tert-buty ⁇ ester (0.7 g, 0.0013 mol) in dichloromethane (7.0 mL) at 0-5 °C and then stirred at room temperature for 1 hour.
  • the mixture was diluted with dichloromethane (30 mL) and made alkaline (pH ⁇ 9) with aqueous saturated sodium bicarbonate solution at 0-5 °C. Aqueous layer was extracted with dichloromethane and combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Dichloromethane was removed under reduced pressure to get ( ?)-2-(5-benzyloxy-2-bromophenoxy)-l-(4- benzyloxyphenyl)propylamine.
  • Step V (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-fluoro-4-(l-propylazetidin-3 ylox henyl]-2-methyl-3,4-dihydro-2H-benzo/7,4/oxazine.
  • Reaction mixture was heated at 105 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Step VI (3/?)-4-[3-Fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4-hydroxyphenyl)-2- methyl-3,4-dihydro-2H-benzoA/,4/oxazin-7-ol.
  • Example 6 Preparation of 4-
  • Step I 5-Bromo-/H-indazol-4-ol.
  • Step III 5-Bromo-l-(tetrahydropyran-2-yl)-/H-indazol-4-ol.
  • Step IV [(/f)-2-[5-Bromo-l-(tetrahydropyran-2-yl)-/H-indazol-4-yloxy]-l-(4- fluoro henyl)ethyl]carbamic acid tert butyl ester.
  • Step V (/f)-2-[5-Bromo-l-(tetrahydropyran-2-yl)-/H-indazol-4-yloxy]-l-(4- fluorophenyl)ethylamine.
  • Reaction mixture was heated at 110 °C for 1 hour 40 minutes. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n- hexane, 20:80) to get ( ?)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9- oxa-2,3,6-triazacyclopenta[a]naphthalene.
  • Step VII (/?)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(4-fluorophenyl)-3- (tetrahydropyran-2-yl)-3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene.
  • Step VIII (R)-6-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(4-fluorophenyl)- 3,6,7,8-tetrahydro-9-oxa-2,3,6-triazacyclopenta[a]naphthalene.
  • Step I [(/f)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethyl]carbamic acid tert-butyl ester.
  • Step II (R)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine.
  • Trifluoroacetic acid (5.2 niL) was added to a stirred solution of [( ?)-2-(5-benzyloxy-2- bromophenoxy)-l-(4-fluorophenyl)ethyl]carbamic acid ie/ -butyl ester (2.6 g, 0.0051 mol) in dichloromethane (13 niL) at 0-5 °C and then stirred at room temperature for 1 hour. Reaction mixture was cooled to 0-5 °C and diluted with dichloromethane and made alkaline (pH ⁇ 9) with aqueous 10% sodium hydroxide solution. Organic layer was separated, washed with brine solution and then dried over anhydrous sodium sulfate.
  • Step III (/?)-7-Benzyloxy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.
  • Reaction mixture was heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Step V (/?)-3-(4-Fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[/,4]oxazin-7-ol.
  • Reaction mixture was cooled to room temperature, filtered through celite bed and washed with an (1: 1) mixture of methanol and 1,4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer washed with brine solution and dried over anhydrous sodium sulphate.
  • Step I Di-tert-butyl [(/f)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7yl]phosphite.
  • Reaction mixture was degassed under reduced pressure at 40 °C to get di-ieri-butyl[( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazin-7-yl]phosphite, which was used for the next step without any further purification.
  • Step II Di-tert-butyl [(R)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7yl]phosphate.
  • ie/t-Butyl hydroperoxide (2.5 mL, 70% solution in water) was added slowly to a stirred solution of di-ie/ -butyl [( ?)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3- yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazin-7-yl]phosphite (1.0 g, 0.00159 mol) in tetrahydrofuran at ambient temperature. The mixture was stirred at room temperature for 1 hour. Reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step III ⁇ (R)-3-(4-fluorophenyl)-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3,4- dihydro-2H-benzo[/,4]oxazin-7-yl ⁇ dihydrogen phosphate.
  • Example 9 Preparation of (E)-4-(3-(2 ⁇ 6-Difluoro-4-r(R)-7-(4-fluorophenyl)-7 ⁇ 8- dihvdro-3H-9-oxa-2,3.i6-triazacvclopenta[a1naphthalen-6-yl1phenoxylazetidin-l-yl)but- 2-enoic acid dimethylamide (Compound No. 35).
  • Step-I 3-(4-Bromo-2,6-difluorophenoxy)azetidine-l-carboxylic acid tert butyl ester.
  • Step-II 3- ⁇ 2,6-Difluoro-4-[(R)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)-7,8-dihydro- 3H-9-oxa-2,3,6-triazacyclopenta[a]naphthalen-6-yl]phenoxy ⁇ azetidine-l-carboxylic acid tert-but l ester.
  • Step-III (R)-6-[4-(Azetidin-3-yloxy)-3,5-difluorophenyl]-7-(4-fluorophenyl)-3,6,7,8- tetrahydro-9-oxa-2 3,6-triazacyclopenta[a]naphthalene.
  • Trifluoroacetic acid (1.2 mL) was added slowly to a stirred solution of 3- ⁇ 2,6-difluoro-4- [( ?)-7-(4-fluorophenyl)-3-(tetrahydropyran-2-yl)-7,8-dihydro-3H-9-oxa-2,3,6- triazacyclopenta[(3]naphthalen-6-yl]phenoxy ⁇ azetidine-l-carboxylic acid ie/ -butyl ester (0.6 g, 0.00094 mol) in dichloromethane (5.0 mL) at 0-5 °C and then stirred at room temperature for 1 hour.
  • Step-IV (E)-4-(3- ⁇ 2,6-Difluoro-4-[(R)-7-(4-fluorophenyl)-7,8-dihydro-3H-9-oxa-2,3,6- triazacyclopenta[a]naphthalen-6-yl]phenoxy ⁇ azetidin-l-yl)but-2-enoic acid dimethylamide.
  • Example 10 Preparation of (/?)-8-dimethylaminomethyl-3-(4-fluorophenyl)-4-[3- fluoro-4-(l-propylazetidin-3-yloxy)phenyl1-3,4-dihvdro-2H-benzo[/,41oxazin-7-ol (Compound No. 36).
  • reaction mixture was heated at 75 °C for 15 minutes. Reaction mixture was cooled to room temperature and made alkaline (pH ⁇ 9) with aqueous saturated sodium bicarbonate solution. Aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. Combined organic layer was washed with brine solution and then dried over anhydrous sodium sulfate.
  • Step I (/f)-[(9H-Fluoren-9-ylmethoxycarbonylamino)]-(4-hydroxyphenyl)acetic acid methyl ester.
  • Step II (/f)-[(9H-Fluoren-9-ylmethoxycarbonylamino)]-[4-(tetrahydropyran-2-yloxy)- phenyl]acetic acid methyl ester.
  • Step III (R)-2-Amino-2-(4-tetrahydropyran-2-yloxyphenyl)ethanol.
  • Step IV ⁇ (/?)-2-hydroxy-l-[4-(tetrahydropyran-2-yloxy)phenyl]ethyl ⁇ carbamic acid 9H- fluoren-9-ylmethyl ester.
  • Solid thus obtained was purified by adding a solution of 15% ethylacetate in n-hexane (1200 mL) and stirred for 1 hour. Solid obtained was filtered and dried under reduced pressure at 55 °C to get ⁇ ( ?)-2-hydroxy- l-[4-(tetrahydropyran-2- yloxy)phenyl] ethyl jcarbamic acid 9H-fluoren-9-ylmethyl ester.
  • Step V ⁇ (R)-2-(5-Benzyloxy-2-bromophenoxy)-l-[4-(tetrahydropyran-2- loxy)phenyl]ethyl ⁇ carbamic acid 9H-fluoren-9-ylmethyl ester.
  • Step VI (R)-2-(5-benzyloxy-2-bromophenoxy)-l-(4-tetrahydropyran-2- yloxyphenyl)ethylamine.
  • Reaction mixture was degassed under reduced pressure to get residue, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 3:97) to get ( ?)-2-(5-benzyloxy-2-bromophenoxy)- l-[4-(tetrahydropyran-2- yloxy)phenyl]ethylamine.
  • Step VII (/f)-7-Benzyloxy-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H- benzo[/,4]oxazine.
  • Step VIII (/f)-7-Benzyloxy-4-[3,5-difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4- (tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazine.
  • Step IX (/?)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran- 2-yloxy)phenyl]-3,4-dihydro-2H-benzo[/,4]oxazin-7-ol.
  • reaction mixture was heated at 65 °C for 30 minutes.
  • Reaction mixture was cooled to room temperature, filtered through celite bed and washed with a (1: 1) mixture of methanol and 1, 4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with ethyl acetate. Combined organic layer washed with water followed by brine solution and dried over anhydrous sodium sulphate.
  • Step X (R)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-yloxy)phenyl]-3,4-dihydro-2H- benzo[i,4]oxazin-7-ol, which was used for the next step without further purification.
  • Step X (R)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-
  • Triflic anhydride (0.2 mL, 0.0012 mol) was added to a stirred solution of ( ?)-4-[3,5-difluoro- 4-(l-propylazetidin-3-yloxy)phenyl]-3-[4-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H- benzo[l,4]oxazin-7-ol (0.55 g, 0.000995 mol) in dichloromethane (10 mL) and pyridine (0.47 mL, 0.006 mol) at 0-5 °C. The mixture was allowed to stir at ambient temperature for 1 hour, and quenched with water and extracted with dichloromethane.
  • Step XI 4-[(R)-4-[3,5-Difluoro-4-(l-propylazetidin-3-yloxy)phenyl]-7-(lH-pyrazol-4-yl)- 3,4-dihydro-2H-benzo[/,4]oxazin-3-yl]phenol.
  • Residue was basified to pH ⁇ 8 using saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude, which was purified by column chromatography (silica gel 230-400 mesh, methanol: dichloromethane, 08: 92) to get 4-[(R)-4-[3,5-difluoro-4-(l- propylazetidin-3-yloxy)phenyl]-7-(iH-pyrazol-4-yl)-3,4-dihydro-2H-benzo[i,4]oxazin-3- yl]phenol (Compound No. 38). It was dissolved in appropriate solvent and treated with hydrochloric acid to obtain hydrochloride salt of compound no. 38.
  • Step I [(/f)-2-(2-Bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethyl]carbamic acid tert butyl ester.
  • Step II (/?)-2-(2-Bromo-5-fluorophenoxy)-l-(4-methoxyphenyl)ethylamine.
  • Trifluoroacetic acid (2.2 mL) was added to a stirred solution of [(7?)-2-(2-bromo-5- fluorophenoxy)-l-(4-methoxyphenyl)ethyl]carbamic acid ie/ -butyl ester (1.1 g, 0.0025 mol) in dichloromethane (11 mL) at 0-5 °C and then stirred at ambient temperature for 1 hour. Reaction mixture was diluted with dichloromethane and made alkaline (pH ⁇ 9) with aqueous saturated sodium bicarbonate solution. Organic layer was separated, washed with brine solution and then dried over anhydrous sodium sulfate.
  • Step IV (/f)-7-Fluoro-4-[3-fluoro-4-(l-propylazetidin-3-yloxy)phenyl]-3-(4- methoxyphenyl)-3,4-dihydro-2H-benzo[/,4]oxazine.
  • Reaction mixture was heated at 105 °C for 25 minutes under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Example 13 Preparation of 4-
  • Step I (R )-3-(4-Bromo-2-fluorophenoxy)pyrrolidine-l-carboxylic acid tert butyl ester.
  • Step II (R)-3-(4-Bromo-2-fluorophenoxy)pyrrolidine hydrochloride.
  • Step III (R)-3-(4-Bromo-2-fluorophenoxy)-l-(3-fluoropropyl)pyrrolidine.
  • Ammonium acetate (8.65 g, 0.1123 mol) was added to a solution of 2-(5-benzyloxy-2- bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)ethanone (5.0 g, 0.011 mol) in a mixture of methanol (50.0 mL) and dichloromethane (20.0 mL) at room temperature and stirred for 1 one hour at ambient temperature.
  • Sodium cyanoborohydride (1.41 g, 0.022 mol) was added to reaction mixture and heated at 60 °C for 5 hours. Reaction mixture was concentrated under reduced pressure at 40 °C. Residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • Step VI 7-Benzyloxy-3-(3-fluoro-4-methoxyphenyl)-3,4-dihydro-2H-benzo
  • Potassium ie/t-butoxide (1.02 g, 0.0091 mol) was added to a stirred solution of 2-(5- benzyloxy-2-bromophenoxy)-l-(3-fluoro-4-methoxyphenyl)ethylamine (2.9 g, 0.0065mol), tris(dibenzylidineacetone)dipalladium (0.3 g, 0.000325 mol) and 2,2'- bis(diphenylphosphino)- l, -binaphthyl (0.41 g, 0.00065 mol) in toluene (29 mL) at room temperature under nitrogen atmosphere and then heated at 105 °C for one hour.
  • Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Ethyl acetate was removed under reduced pressure to give crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethylacetate: n-hexane, 15: 85) to get 7-benzylozy-3-pyridin-4-yl-3,4-dihydro-2H-benzo/7,4/oxazine.
  • Step VII 7-Benzyloxy-4- ⁇ 3-fluoro-4-[(/f)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl ⁇ - 3-(3-fluoro-4-methox henyl)-3,4-dihydro-2H-benzo[/,4]oxazine.
  • Reaction mixture was heated at 105 °C for 1 hour under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and then dried over anhydrous sodium sulfate.
  • Step VIII 4- ⁇ 3-Fluoro-4-[(/f)-l-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl ⁇ -3-(3-fluoro- 4-methoxyphenyl)-3,4-dihydro-2H-benzo[/,4]oxazin-7-ol.
  • reaction mixture was heated at 70 °C for 1 hour.
  • Reaction mixture was cooled to room temperature, filtered through celite bed and washed with an (1 : 1) mixture of methanol and 1,4-dioxane. Combined filtrate was concentrated at 50 °C under reduced pressure. Water was added to the residue and extracted with dichloromethane. Combined organic layer washed with brine solution and dried over anhydrous sodium sulphate.
  • MCF-7 cells were plated in 96 well plate in the presence of estradiol (1 nM) and incubated overnight. After 24 hours test compound was added at various concentrations and incubated for five days. On the fifth day, cell viability was evaluated using Presto Blue ® Cell Viability Reagent. Percentage growth inhibition was calculated as follows: 100 - [(O.D. of sample)* 100/ O.D. of vehicle control] wherein O.D. is Optical Density.
  • Compounds of Formula I showed growth inhibition of about 50 % or more at 3 micromolar concentration.
  • MCF-7 WT cells were seeded at density of 40000 cells/well in 48-well plate. The cells were plated in phenol red free RPMI1640 medium supplemented with 5% CS-FBS and incubated overnight. Next day, the cells were treated with varying concentrations of test molecule in the range of 1000 nM to 0.01 nM and vehicle control (0.1 % DMSO) for 4 days. The cells were lysed and the lysate was analysed for detecting ER-a by Western blot. The compound of Formula I showed degradation of ER-a in the range of 90 % to 100 % when studied at a concentration of about 10 nM to 100 nM. Table 4 provides percentage of ER-a remained at 30 nM concentration of some of the representative compounds in ER-a degradation assay in MCF-7 WT cell lines. Table 4:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés hétérocycliques de formule I dans laquelle A, B, E, cycle Z, Y, L, cycle X, D, m, n, R7 et R8 sont tels que définis dans la description en tant qu'antagonistes/agents de dégradation du récepteur des œstrogènes. Le composé de formule I peut être utilisé pour le traitement de cancers induits par les récepteurs des œstrogènes. (Formule I ).
PCT/IN2018/050040 2017-01-27 2018-01-25 Nouveaux composés antiœstrogènes hétérocycliques WO2018138739A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201721003143 2017-01-27
IN201721003143 2017-01-27

Publications (1)

Publication Number Publication Date
WO2018138739A1 true WO2018138739A1 (fr) 2018-08-02

Family

ID=61258574

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2018/050040 WO2018138739A1 (fr) 2017-01-27 2018-01-25 Nouveaux composés antiœstrogènes hétérocycliques

Country Status (1)

Country Link
WO (1) WO2018138739A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115073493A (zh) * 2021-03-15 2022-09-20 深圳福沃药业有限公司 雌激素受体调节剂

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7015219B2 (en) 2001-12-19 2006-03-21 Bristol-Myers Squibb Company 3-aryl-hydroxybenzoxazines and 3, 4-dihydro-3-aryl-hydroxybenzoxazines as selective estrogen receptor beta modulators
US7138426B2 (en) 2002-04-24 2006-11-21 Merck & Co., Inc. Estrogen receptor modulators
WO2012084711A1 (fr) 2010-12-24 2012-06-28 Msd Oss B.V. Dérivés d'azétidine n-substitués
WO2016097072A1 (fr) 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indole et utilisations associées
WO2016097071A1 (fr) 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs du récepteur des œstrogènes et leurs utilisations
US20160311805A1 (en) * 2015-04-27 2016-10-27 Pfizer Inc. Anti-estrogenic compounds
WO2017056115A1 (fr) * 2015-10-03 2017-04-06 Sun Pharma Advanced Research Company Limited Nouveaux composés hétérocycliques fusionnés contenant n-aryle

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7015219B2 (en) 2001-12-19 2006-03-21 Bristol-Myers Squibb Company 3-aryl-hydroxybenzoxazines and 3, 4-dihydro-3-aryl-hydroxybenzoxazines as selective estrogen receptor beta modulators
US7138426B2 (en) 2002-04-24 2006-11-21 Merck & Co., Inc. Estrogen receptor modulators
WO2012084711A1 (fr) 2010-12-24 2012-06-28 Msd Oss B.V. Dérivés d'azétidine n-substitués
WO2016097072A1 (fr) 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indole et utilisations associées
WO2016097071A1 (fr) 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs du récepteur des œstrogènes et leurs utilisations
US20160311805A1 (en) * 2015-04-27 2016-10-27 Pfizer Inc. Anti-estrogenic compounds
WO2016174551A1 (fr) 2015-04-27 2016-11-03 Pfizer Inc. Composés anti-œstrogéniques
WO2017056115A1 (fr) * 2015-10-03 2017-04-06 Sun Pharma Advanced Research Company Limited Nouveaux composés hétérocycliques fusionnés contenant n-aryle

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 2005, pages 3912 - 3916
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 14, 2006, pages 3455 - 3466
JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, 2003, pages 2945 - 2957

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115073493A (zh) * 2021-03-15 2022-09-20 深圳福沃药业有限公司 雌激素受体调节剂

Similar Documents

Publication Publication Date Title
CN110049984B (zh) 苯基丙酸衍生物及其用途
EP1611129B1 (fr) Sulfamides cycliques en tant qu'inhibiteurs de la gamma-secretase
CN101842369B (zh) 用于治疗周围和中枢神经系统疾病的作为α2C拮抗剂的2，3-二氢苯并[1，4]二*英-2-基甲基衍生物
EP2897956B1 (fr) Nouveaux pyridones bicyliques
CN115003295A (zh) 具有雌激素受体降解活性的新型色满衍生物及其用途
CN111285850A (zh) 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
AU2015242330B2 (en) Chromene and 1,1 a,2,7b-tetrahydrocyclopropa[c]chromene pyridopyrazinediones as gamma-secretase modulators
CA2883545A1 (fr) Derives d'imidazoline, leurs procedes de preparation et leurs applications en medecine
EP2906566B1 (fr) Procédé de préparation de composés de thiénopyrimidine
US20170362210A1 (en) Anti-estrogenic compounds
JP2009051843A (ja) ピラゾロ［１，５−ａ］ピリジン化合物およびその医薬
CN108884093B (zh) 一种多巴胺d3配体化合物
EP3969457A1 (fr) Procédés de préparation d'indoles macrocycliques
WO2021026672A1 (fr) Inhibiteurs hétérocycliques de wdr5 utilisés en tant que composés anticancéreux
US9975856B2 (en) Process for the preparation of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
CN114805361B (zh) 一类氨基取代的芳香杂环并吡唑类化合物、制备方法和用途
ES2818806T3 (es) Novedosas ciclopropabenzofuranil piridopirazindionas
WO2017056115A1 (fr) Nouveaux composés hétérocycliques fusionnés contenant n-aryle
EP4228757B1 (fr) Composés 6,7-dihydro-5h-benzo[7]annulène et leurs dérivés, leurs procédés de préparation et leurs utilisations thérapeutiques
JP2024514251A (ja) 二環式化合物の製造方法及び抗菌剤としての使用
CN105294554B (zh) 苯基哌嗪衍生物及其使用方法和用途
WO2018138739A1 (fr) Nouveaux composés antiœstrogènes hétérocycliques
CN113620931A (zh) 一种雄激素受体抑制剂及其用途
WO2021080929A1 (fr) Dérivés de n-hétéroaryl indazole utilisés en tant qu'inhibiteurs de lrrk2, compositions pharmaceutiques et leurs utilisations
KR102377981B1 (ko) 폐 섬유증 치료용 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18706871

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18706871

Country of ref document: EP

Kind code of ref document: A1