WO2016196342A1 - Tetrasubstituted alkene compounds and their use - Google Patents

Tetrasubstituted alkene compounds and their use Download PDF

Info

Publication number
WO2016196342A1
WO2016196342A1 PCT/US2016/034774 US2016034774W WO2016196342A1 WO 2016196342 A1 WO2016196342 A1 WO 2016196342A1 US 2016034774 W US2016034774 W US 2016034774W WO 2016196342 A1 WO2016196342 A1 WO 2016196342A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
ethyl
reaction mixture
phenoxy
added
Prior art date
Application number
PCT/US2016/034774
Other languages
French (fr)
Inventor
Ming-Hong Hao
Manav KORPAL
Vijay Kumar Nyavanandi
Xiaoling Puyang
Susanta Samajdar
Peter Gerard Smith
John Wang
Guo Zhu Zheng
Ping Zhu
Original Assignee
Eisai R&D Management Co., Ltd.
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 Eisai R&D Management Co., Ltd. filed Critical Eisai R&D Management Co., Ltd.
Publication of WO2016196342A1 publication Critical patent/WO2016196342A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • tamoxifen has been shown to activate signaling activity in the endometrium leading to an increase in risk of endometrial cancers in the clinic (Fisher et al., (1994) J Natl Cancer Inst. Apr 6;86(7):527-37; van Leeuwen et al., (1994) Lancet Feb 19;343(8895):448-52).
  • fulvestrant since fulvestrant is a pure antagonist, it can lead to loss of bone density in post-menopausal women as ERa activity is critical for bone building.
  • clinical resistance is also beginning to emerge to these classes of ERa antagonists highlighting the need to develop next-generation compounds.
  • ESRl gene which encodes ERa protein
  • Described herein are novel compounds useful for treating cancer.
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-4
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-4
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5
  • R2 is selected from the group consisting of H and CH3;
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl;
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C6 alkoxy;
  • R5 are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl;
  • X is selected from the group consisting of H, -OH, halogen and NH2;
  • R8 and R9 are the same or different and are independently selected from the group consisting of H and methyl;
  • R6 and R7 are the same or different and are independently selected from the group consisting of H and C1-C6 alkyl, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 atom heterocyclic ring with
  • Rl is selected from the group consisting of ethyl and cyclobutyl
  • R2 is selected from the group consisting of H and -CH3
  • n is 0-1
  • R3 is selected from the group consisting of -CH3, -CI, -F and -OCH3
  • m is 0-2
  • R4 is selected from the group consisting of -CF3, F, - CH(CH3)2, -CH2CH3 and -CH3
  • R6 and R7 are the same or different and are independently selected from the group consisting of -CH3, -CH2CH2CF2CF3, -CH2(CH2)5CH3 and - CH2(CH2)4CF2CF3; or pharmaceutically acceptable salts thereof.
  • Embodiments may provide a compound selected from the group consisting of (E)-4-((2-(4- ((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2- enamide; (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)(methyl)amino)-N-methyl-N-(6,6,7,7,7-pentafluoroheptyl) but-2- enamide; (E)-N-heptyl-4-((2-(4-((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl) (methyl)amino)-N-methylbut-2-
  • Embodiments may provide compound selected from the group consisting of (E)-4-((2-(4- ((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2- enamide; (E)-4-((2-(4-((Z)-2-cyclobutyl- 1 -(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((Z)-l,2- diphenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((E)- l-(2-fluoro-4-hydroxyphenyl)-2-phenylbut-
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-3
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-3
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5
  • R2 is selected from the group consisting of H and CH3;
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl;
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C6 alkoxy;
  • R5 are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl;
  • X is selected from the group consisting of H, -OH, halogen and NH2;
  • R8 and R9 are the same or different and are independently selected from the group consisting of H and methyl;
  • R6 and R7 are the same or different and are independently selected from the group consisting of H and C1-C6 alkyl, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 atom heterocyclic ring
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-4
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl 1 is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-4
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5
  • R2 is selected from the group consisting of H and CH3;
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl;
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C6 alkoxy;
  • R5 are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl;
  • X is selected from the group consisting of H, -OH, halogen and NH2;
  • R8 and R9 are the same or different and are independently selected from the group consisting of H and methyl;
  • R6 and R7 are the same or different and are independently selected from the group consisting of H and C1-C6 alkyl, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 atom heterocyclic ring
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-4
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rll is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5; R
  • such novel compounds are described by Formula VI:
  • Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring
  • R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring
  • R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen
  • n is 0-4
  • R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring;
  • m is 0-5
  • the compounds of any of the above Formulas have the following permutations or combinations of permutations, when the substituent is present in the
  • Y is -C(0)NR6R7; Y and R9 are in "cis" configuration relative to each other; R6 and R7 are methyl; R8 and R9 are both H; Rl is ethyl or cyclobutyl; R2 is H or CH3; n is 1 and R3 is F; m is 1 and R4 is F; X is -OH; q is 1 ; m and n are both 0; m is 0 and n is 1 ; m is 1 and n is 0; R13, R14, R15 and R16 are H; r is 1 ; and wherein in Z is an oxygen atom.
  • such methods include administration to a subject in need thereof a therapeutically effective amount of any of the compounds of any of the above Formulas or pharmaceutically acceptable salts thereof.
  • use is made of the compounds of any of the above Formulas or pharmaceutically acceptable salts thereof for treating breast cancer.
  • the breast cancer is an ER-positive breast cancer.
  • the subject in need of treatment expresses a mutant ER-a protein.
  • the compounds disclosed herein are useful for inhibiting the cell culture growth of MCF7 ER-alpha (wildtype) and MCF7 ER-alpha (Y537S mutant) cells.
  • Other compounds e.g., tamoxifen, raloxifene and fulvestrant
  • the compounds disclosed herein are useful for treating ER-alpha expressing breast cancer in human patients, and are useful for treating Y537S mutant ER-alpha expressing breast cancer in human patients.
  • the compounds disclosed herein are useful for treating breast cancer.
  • the breast cancer is ER-a+.
  • the breast cancer expresses an ER-a mutation, which is L536Q (Robinson et al. Nat Genet. 2013 Dec;45(12)), L536R (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45), Y537S (Toy et al. Nat Genet. 2013
  • Figure 1 shows phenotypic resistance observed in mutant-bearing lines relative to control lines to existing clinical compounds, whereby MCF7 cells engineered to overexpress various ERa MUT showed partial resistance to various endocrine therapies.
  • alkyl As used herein, "alkyl”, "Ci, C 2 , C 3 , C 4 , C 5 or C 6 alkyl” or “Ci-C 6 alkyl” is intended to include Ci, C 2 , C 3 , C 4 , C 5 or C 6 straight chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5 or C 6 branched saturated aliphatic hydrocarbon groups.
  • Ci-C 6 alkyl is intended to include Ci, C 2 , C 3 , C 4 , C 5 and C alkyl groups.
  • alkyl examples include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C C 6 for straight chain, C 3 -C 6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • cycloalkyl refers to a saturated or unsaturated nonaromatic hydrocarbon ring having 3 to 7 carbon atoms (e.g., C 3 -C 7 ).
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • heterocycloalkyl refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic groups, 7-10 membered fused bicyclic groups having one or more heteroatoms (such as O, N, or S), unless specified otherwise.
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl,
  • tetrahydrofuranyl isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothiophene, dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, and the like.
  • heterocycloalkyl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
  • benzisothiazolyl benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,
  • optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
  • aminocarbonyl alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • arylalkyl or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g.,
  • alkylaryl is an aryl substituted with an alkyl (e.g., methylphenyl).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C2-C 6 includes alkenyl groups containing two to six carbon atoms.
  • C3-C 6 includes alkenyl groups containing three to six carbon atoms.
  • optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
  • aminocarbonyl alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
  • Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing two to six carbon atoms.
  • C 3 -C 6 includes alkynyl groups containing three to six carbon atoms.
  • alkynyl refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
  • aminocarbonyl alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
  • heterocycloalkyl examples include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.
  • Aryl includes groups with aromaticity, including “conjugated,” or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthalenyl, etc.
  • Heteroaryl groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.”
  • heteroaryl is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR' wherein R' is H or other substituents, as defined).
  • heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • aryl and heteroaryl include multicyclic aryl and heteroaryl groups, e.g., bicyclic.
  • Non-limiting example of such aryl groups include, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,
  • methylenedioxyphenyl quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
  • Aryl and heteroaryl groups may also be fused with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system
  • any variable e.g., Rl
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • Rj at each occurrence is selected independently from the definition of Ri.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • perhalogenated generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms.
  • haloalkyl or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.
  • Alkoxyalkyl “alkylaminoalkyl,” and “thioalkoxyalkyl” include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.
  • alkoxy or "alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,
  • alkylaminocarbonyl dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.
  • “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers.”
  • stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed
  • enantiomers or sometimes optical isomers.
  • a mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • a carbon atom bonded to four nonidentical substituents is termed a "chiral center.”
  • Chiral isomer means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Calm et al., Angew. Chem. Inter. Edit.
  • each incidence of a chiral center within a structural formula, such as the non-limiting example shown here: is meant to depict all possible stereoisomers.
  • R 3 and R 4 are in the plane of the paper, R ⁇ is above the plane of paper, and R 2 is behind the plane of paper).
  • “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • Tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds.
  • Tautomers exist as a mixture of a tautomeric set in solution.
  • keto- enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (--OH) in the same molecule to give it a cyclic (ring- shaped) form as exhibited by glucose.
  • tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine.
  • stractures and other compounds disclosed herein include all atropic isomers thereof, it being understood that not all atropic isomers may have the same level of activity.
  • “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • crystal polymorphs means crystal structures in which a compound (or a salt or solvate thereof) may crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility.
  • Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
  • Crystal polymorphs of the compounds may be prepared by crystallization under different conditions. It is understood that the compounds disclosed herein may exist in crystalline form, crystal form mixture, or anhydride or hydrate thereof.
  • the compounds disclosed herein include the compounds themselves, as well as their salts and solvates, if applicable.
  • a salt for example, may be formed between an anion and a positively charged group (e.g., amino) on an aryl- or heteroaryl-substituted benzene compound.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • pharmaceutically acceptable anion refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt may also be formed between a cation and a negatively charged group (e.g., carboxylate) on an aryl- or heteroaryl- substituted benzene compound.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethyl ammonium ion.
  • the aryl- or heteroaryl-substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
  • the compounds disclosed herein may exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • pharmaceutically acceptable salts refer to derivatives of the compounds disclosed herein wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1 ,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic,
  • hexylresorcinic hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.
  • amine acids e.g., glycine, alanine, phenylalanine, argin
  • salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt may be 1: 1, or any ratio other than 1:1, e.g., 3: 1, 2: 1, 1:2, or 1:3.
  • solvent addition forms that contain either stoichiometric or non
  • solvates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 0.
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of H hydrogen include tritium and deuterium
  • isotopes of C carbon include 13 C and I4 C.
  • treating means administering to a subject a pharmaceutical composition to ameliorate, reduce or lessen the symptoms of a disease.
  • treating or “treat” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” may also include treatment of a cell in vitro or an animal model.
  • Treating cancer may result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as "tumor regression."
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may result in a reduction in tumor volume.
  • tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Tumor volume may be measured by any reproducible means of measurement.
  • Treating cancer may result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • Treating cancer may result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • subject refers to any animal, such as mammals including rodents (e.g., mice or rats), dogs, primates, lemurs or humans.
  • rodents e.g., mice or rats
  • primates e.g., mice or rats
  • lemurs e.g., mice or rats
  • humans e.g., dogs, primates, lemurs or humans.
  • Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer may result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drag that is not a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound. Treating cancer may result in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate may be measured according to a change in tumor diameter per unit time.
  • Treating cancer may result in a decrease in tumor regrowth, for example, following attempts to remove it surgically.
  • tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • Treating or preventing a cell proliferative disorder may result in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • Treating or preventing a cell proliferative disorder may result in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells may be equivalent to the mitotic index.
  • Treating or preventing a cell proliferative disorder may result in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • the size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • Treating or preventing a cell proliferative disorder may result in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • An abnormal cellular morphology may be measured by microscopy, e.g., using an inverted tissue culture microscope.
  • An abnormal cellular morphology may take the form of nuclear pleiomorphism.
  • the term "alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased.
  • a sign or symptom may be alleviated without being eliminated.
  • the administration of pharmaceutical compositions disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required.
  • Effective dosages are expected to decrease the severity of a sign or symptom.
  • a sign or symptom of a disorder such as cancer, which may occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
  • severity is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state.
  • severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union against Cancer (UICC) and the Amerimay Joint Committee on Cancer (AJCC)) or by other art-recognized methods.
  • TNM system accepted by the International Union against Cancer (UICC) and the Amerimay Joint Committee on Cancer (AJCC)
  • UNM system International Union against Cancer
  • AJCC Amerimay Joint Committee on Cancer
  • Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes).
  • Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute,
  • severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized. Moreover, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe.
  • symptom is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by non-health- care professionals.
  • a "pharmaceutical composition” is a formulation containing a compound disclosed herein in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound disclosed herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a
  • pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that are required.
  • the phrase "pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • the present disclosure also provides pharmaceutical compositions comprising any compound disclosed herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition disclosed herein is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition disclosed herein may be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound disclosed herein may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state of the disease condition e.g., cancer, precancer, and the like
  • the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect may be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation may be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the disease or condition to be treated is cancer.
  • the disease or condition to be treated is a cell proliferative disorder.
  • the therapeutically effective amount may be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information may then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD5 0 (the dose lethal to 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it may be expressed as the ratio, LD50/ED50.
  • compositions that exhibit large therapeutic indices are preferred.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be
  • compositions containing active compounds disclosed herein may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that may be used pharmaceutically.
  • the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable earner. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials may be included as part of the composition.
  • the tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the active compounds may be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the compounds disclosed herein are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with embodiments described herein vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer.
  • Dosages may range from about 0.01 mg kg per day to about 5000 mg/kg per day. In preferred aspects, dosages may range from about 1 mg kg per day to about 1000 mg/kg per day.
  • the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m 2 , and age in years).
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.
  • the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • compositions may be included in a container, pack, or dispenser together with instructions for administration.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof may be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • Exemplary cancers that may be treated using one or more compounds disclosed herein include, but are not limited to, breast cancer, uterine endometrial, ovarian carcinoma, sarcoma, thyroid carcinoma, prostate, lung adenocarcinoma, and hepatocellular carcinoma.
  • the compounds disclosed herein may be useful for treating breast cancer.
  • the breast cancer is ER-a+.
  • the breast cancer expresses an ER-a mutation, which may be L536Q (Robinson et al. Not Genet. 2013 Dec;45(12)), L536R (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45), Y537S (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Robinson et al. Nat Genet. 2013 Dec;45(12); Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67), Y537N (Toy et al.
  • ESR1 mutations (Y537C/N) were recently discovered in 4 of 373 cases of endometrial cancers (Kandoth et al. Nature 2013 May 2;497(7447):67-73; Robinson et al. Nat Genet. 2013 Dec;45(12)). Since it has been shown that ESR1 mutations Y537C N significantly drive resistance to currently marketed SOC therapies, the compounds disclosed herein may be useful for treating ERa MUT endometrial cancers.
  • Exemplary cell proliferative disorders that may be treated using one or more compounds disclosed herein include, but are not limited to breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast.
  • Cell proliferative disorders of the breast may include hyperplasia, metaplasia, and dysplasia of the breast.
  • a breast cancer that is to be treated may arise in a male or female subject.
  • a breast cancer that is to be treated may arise in a premenopausal female subject or a postmenopausal female subject.
  • a breast cancer that is to be treated may arise in a subject 30 years old or older, or a subject younger than 30 years old.
  • a breast cancer that is to be treated has arisen in a subject 50 years old or older, or a subject younger than 50 years old.
  • a breast cancer that is to be treated may arise in a subject 70 years old or older, or a subject younger than 70 years old.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be used to treat or prevent a cell proliferative disorder of the breast, or to treat or prevent breast cancer, in a subject having an increased risk of developing breast cancer relative to the population at large, or used to identify suitable candidates for such purposes.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a female subject with a family history or personal history of breast cancer.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a female who is greater than 30 years old, greater than 40 years old, greater than 50 years old, greater than 60 years old, greater than 70 years old, greater than 80 years old, or greater than 90 years old.
  • a cancer that is to be treated may include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter.
  • a cancer that is to be treated may include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter.
  • a cancer that is to be treated may include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter.
  • a cancer that is to be treated may include a tumor that has been determined to be greater than 5 centimeters in diameter.
  • a cancer that is to be treated may be classified by microscopic appearance as well differentiated, moderately
  • a cancer that is to be treated may be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells).
  • a cancer that is to be treated may be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a cancer that is to be treated may be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance.
  • a cancer that is to be treated may be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy.
  • a cancer that is to be treated may be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • the compounds, or pharmaceutically acceptable salts thereof may be administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally.
  • One skilled in the art will recognize the advantages of certain routes of administration.
  • the dosage regimen utilizing the compounds may be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian may readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Step-1 To a suspension of zinc dust (36.6 g, 560 mmol) in dry THF (200 mL) at -10 °C was added TiCl 4 (50.4 g, 266 mmol) under nitrogen atmosphere. The contents were stirred there for 15 min, slowly allowed to warm to 23 °C and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C and a solution of bis(4-hydroxyphenyl)methanone (1, 46.7 mmol) and propiophenone (2, 140 mmol) in dry THF (20 mL) was added and the resulting mixture was heated at reflux for 2.5 h. The reaction mixture was cooled to 23 °C and quenched with saturated ammonium chloride solution.
  • the reaction mixture was extracted with ethyl acetate (500 mL x 3), the combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure.
  • the crude compound was purified over 230-400 mesh silica gel column chromatography using (3:7) ethyl acetate in n-hexane to afford 4,4'-(2-phenylbut-l-ene-l,l-diyl)diphenol (3, 40 mmol, 85%) as a brown colour solid.
  • Step-2 To a stirred solution of 4,4'-(2-phenylbut-l-ene-l,l-diyl)diphenol (3, 31.6 mmol) in acetone (100 mL) was added K 2 C0 3 (13.0 g, 94.8 mmol) at 23 °C and the contents were heated at 80 °C for 15 min. To this mixture, a solution of 2-iodoacetamide (4, 34.8 mmol) in 50 mL of acetone was added slowly over a period of 3 h at 80 °C and the contents were stirred for 1 h at 80 °C.
  • the reaction mixture was diluted with cold water (100 mL), extracted with ethyl acetate, organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure.
  • the crude material was purified by column chromatography over 230-400 mesh silica gel using (7:3) ethyl acetate in n-hexane an eluent to afford 2-(4-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)acetamide (5, 12.6 mmol, 40%) as a gummy solid.
  • Step-3 To a suspension of LiAlH 4 (6.18 g, 163 mmol) in dry THF (200 mL) at 0 °C was added A1C1 3 (6.27 g, 47 mmol) portion wise under nitrogen atmosphere. The contents were stirred for 15 min at room temperature, reaction mixture was re-cooled to 0 °C, and a solution of 2-(4-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)acetamide (5, 10 mmol) in 100 mL of dry THF was added.
  • reaction mixture was stirred for 5 h at room temperature, after completion of reaction, reaction mixture was quenched with saturated Na 2 S0 4 solution, filtered through sodium sulphate bed and washed with ethyl acetate. The combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na 2 S0 4 and concentrated under vacuum.
  • the crude compound was purified by column chromatography over 100-200 mesh silica gel using (1:9) methanol in dichloromethane as an eluent to afford 4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut- l-en-l-yl)phenol (6, 6.3 mmol, 63%) as a brown colour solid.
  • Step-4 To a stirred solution of 6 (1.07 mmol) in DMF (10 mL) were added at 0 °C, (E)-4- bromo-NN-dimethylbut-2-enamide (7, 1.6 mmol) and DIPEA (0.18 mL, 1.28 mmol). The reaction mixture was stirred for 2 h at 23 °C, was diluted with cold water (50 mL) extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-1 Zinc dust (31 g, 473 mmol) was suspended in dry THF (100 mL) and cooled this suspension to -10 °C. To this TiCl 4 (44 g, 230 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C, and a solution of lb (59.2 mmol) and propiophenone (2, 176 mmol) in dry THF (80 mL) were added and the contents were refluxed for 2.5 h. The reaction mixture was cooled to room temperature and quenched with 10% aqueous K 2 C0 3 solution and was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and
  • Step-2 To a solution of 3b (17 mmol) in acetonitrile (140 mL) was added potassium carbonate (7.1 g, 51 mmol) and l-bromo-2-chloro ethane (4b, 34 mmol). The reaction mixture was heated to 80 °C and maintained at this temperature for 24 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using (5:95) ethyl acetate in n-hexane to afford 5b (8.9 mmol, 52.5%) as a colourless gum.
  • Step-3 To a suspension of 5b (8 mmol) in methanol (100 mL) was added 40 % aq. methyl amine (150 mL). The reaction mixture was heated at 80 °C for 16 h in a sealed tube, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6b (7.0 mmol, 87.8 %) as a pale yellow gummy mass.
  • Step-4 To a stirred solution of 6b (1.29 mmol) in dichloromethane (36 mL) was added BBr 3 (1M solution in dichloromethane, 2.6 mL, 2.59 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the benzylated 6c (1.17 mmol, 91 %) as a gummy mass.
  • Step-5 To a stirred solution of 6c (1.07 mmol) in DMF (10 mL) were added at 0 °C, (E)-4- bromo-N,N-dimethylbut-2-enamide (7, 1.6 mmol) and DIPEA (0.18 mL, 1.28 mmol). The reaction mixture was stirred for 2 h at 23 °C, was diluted with cold water (50 mL) extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-1 To a stirred solution of 9 (10.989 mmol) in 30 mL of MeOH:DMA:H 2 0 (1: 1: 1) in a sealed tube, were added copper iodide (0.235 g, 1.098 mmol) and cesium carbonate (4.849 g, 15.3 mmol) at 23 °C. This mixture was degassed with three vacuum N 2 cycles, and were added 10 (22 mmol) followed by Pd(PPh 3 ) 2 Cl 2 (0.384 g, 0.5 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 X 50 mL).
  • Step-2 To a stirred solution of 11 (73.9 mmol) in 2-methyl THF (136 mL), was added bis(pinacolato) diboron (22.52 g, 88.6 mmol), tetrakis(triphenylphosphine)platinum(0) (919 mg, 0.739 mmol) under nitrogen atmosphere, reaction mixture was heated at 90 °C for 5 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure, to afford 13 (56 mmol, 76%).
  • Step-3 To a stirred solution of 13 (12.74 mmol), 4-iodophenol (14, 10.61 mmol), bis(triphenylphosphine)palladium(II) dichloride (372 mg, 0.530 mmol), cesium carbonate (6.9 g, 21.23 mmol) and 2-methyl THF (60 mL) were added. This mixture was degassed with nitrogen and water (5 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using MeOH in dichloromethane (1.6:98.4) to afford 16 (5.47 mmol, 43%).
  • Step-4 To a stirred solution of 16 (1.8 mmol) in 2-methyl THF (30 mL), iodobenzene (15, 1.8 mmol), 4M aqueous KOH (5 mL) and Pd(PPh 3 ) 2 Cl 2 (63 mg, 0.09 mmol) were added and the mixture was degassed with nitrogen for 15 min and heated at 90 °C for 8 h. Upon completion, the reaction mixture was diluted with EtOAc. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (2:8 EtOAc in n-hexane) to give a desired prodcut (18, 0.74 mmol, 41%).
  • Step-2, Step-3 and Step-4 To a stirred solution of 11 (13.78 mmol) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (12, 3.53 g, 13.94 mmol), tetrakis(triphenyl- phosphine)platinum(O) (130 mg, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 10 h.
  • reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude material was purified by column chromatography over 230-400 mesh silica gel using EtOAc in /r-hexane (2.5:7.5) to afford 18 (11.2 mmol, 81 %) as a white solid.
  • Step-5 To a solution of 11 (6.09 mmol), iodobenzene (15, 18.29 mmol), phenyl boronic acid (17, 18.29 mmol), in NN-dimethyl formamide/water (2: 1, 15 mL) was added K 2 C0 3 (2.52 g, 18.29 mmol). The contents were degassed with three vacuum/N 2 cycles, and then stirred for 1 h until the solution was homogeneous. A solution of Pd(PhCN) 2 Cl 2 (0.022 g, 0.0609 mmol) in N,N-dimethyl formamide (1 mL) was added and the resulting mixture was stirred at 45 °C for 12 h.
  • Step-1 To a solution of 18a (3.4 mmol) in DMF (30 mL), at 0 °C, were added sequentially potassium carbonate (1.4 g, 10.1 mmol) and te/t-butyl (2-bromoethyl)carbamate (19, 8.5 mmol). The reaction mixture was stirred at 80 °C for 16 h, was diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure.
  • Step-2 To a stirred solution of 18b (2.5 mmol) in ethanol (10 mL) was added at 0 °C, 2M HC1 in ether (10 mL). The reaction mixture was stirred for 16 h at 23 °C. After completion of reaction, reaction mixture was basified with saturated NaHC0 3) extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in DCM to afford the desire product (20, 1.25 mmol, 50%) as a brown coloured semi solid.
  • Step-3 To a stirred solution of 20 (1.24 mmol) in DMF (5 mL) was added at 0 °C, (E)-4- bromo-N,N-dimethylbut-2-enamide (7, 1.24 mmol) and DIPEA (0.321 g, 2.49 mmol). The reaction mixture was stirred for 48 h at 23 °C, was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give a crude mixture of 21.
  • Step-4 The crude material obtained from previous step was purified by preparative HPLC to afford pure isomer 22 (0.06 mmol, 5%) as a white solid. The 1H NMR, HPLC and MS data were collected.
  • Step-5 To a stirred solution of 21 (1.25 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (0.546 g, 2.5 mmol). The reaction mixture was stirred for 1 h at 23 °C, after completion of reaction, reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 2% MeOH in DCM to afford 18c (0.63 mmol, 50%) as a light brown semi-solid.
  • Step-6 To a stirred solution of 18c (0.622 mmol) in MeOH (5 mL) was added at 0 °C, 2M HC1 in ether (10 mL). The reaction mixture was stirred for 16 h at 23 °C. After completion of reaction, reaction mixture was basified with saturated NaHC0 3> extracted with 10% MeOH in DCM. Organic layer was concentrated under reduced pressure to obtain crude compound (15, 0.07 mmol) as an off-white solid. Crude compound was purified by preparative HPLC to afford desired pure isomer (22, 0.03 mmol, 4.1%) as an white solid. The 1H NMR, HPLC and MS data were collected.
  • Step-3 Br ⁇ / ⁇ ./ ⁇ N . 6
  • Step-1 To a stirred solution of 4-iodophenol (14a, 227 mmol) in DMF (750 mL) was added potassium carbonate (188 g, 1.363 mol) and stirred for 30 min at 23 °C, to the above mixture tert-butyl (2-bromoethyl)carbamate (19, 71.27 g, 318 mmol) was added. The contents were stirred at 70 °C for 12 h.
  • reaction mixture was poured onto ice cold water, solid separated was filtered and dried under reduced pressure to obtain desired compound tert-butyl (2-(4-iodophenoxy)ethyl)carbamate as an off-white solid (14b, 220 mmol, 97%).
  • Step-2 To a stirred solution of 14b (68.6 mmol) in ethanol (50 mL) was added at 0 °C, 2M HC1 in ether (250 mL). The reaction mixture was stirred for 12 h at 23 °C. After completion of reaction, reaction mixture was basified with saturated NaHC0 3, extracted with 10% MeOH in DCM. Organic layer was concentrated under reduced pressure and the crude material was used in next step without further purification (23, 60 mmol, 88%).
  • Step-3 To a stirred solution of 23 (60.6 mmol) in DMF (65 mL) was added at 0 °C, 4-bromo- N,N-dimethylbut-2-enamide (7, 42.4 mmol) and DIPEA (11.72 g, 90.9 mmol). The reaction mixture was stirred for 5 h at room temperature, was diluted with cold water (250 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (24, 50 mmol, 83%, crude).
  • Step-4 To a stirred solution of 24 (50.26 mmol) in dry dichloromethane (150 mL) was added DIPEA (6.4g, 50.2 mmol) at 0 °C, stirred for 15 min at 0 °C. To the above reaction mixture, was added di-tert-butyl dicarbonate (13.1 g, 60.3 mmol), resulting mixture was stirred at 23 °C for 12 h. Upon completion by TLC, the reaction mixture was cooled to 0 °C, quenched with ice cold water (500 mL) and extracted with dichloromethane (500 mL).
  • Step-1 To a stirred solution of but-2-enoic acid (25, 116.0 mmol) in benzene (150 mL) was added N-Bromo succinamide (31.4 g, 120.0 mmol) followed by Benzoyl peroxide (0.200 g, 1.4 mmol) at 23 °C. The reaction mixture was heated to reflux for 4 h, which resulted in precipitation of succinamide crystals. The crystals were filtered off and the filtrate was concentrated. The crude was recrystallized with minimum amount of hexane and washed with hexane to afford 4-bromobut-2-enoic acid (26, 42.5 mmol, 37 %) as a white solid.
  • Step-2 bromobut-2-enoic acid (26, 9 mmol) was taken in dichloromethane (30 mL) and cooled to 0 °C. To this solution oxalyl chloride (1.6 mL, 18 mmol), DMF (0.1 mL) were added and stirred for 0.5 h at 23 °C. The reaction mixture was concentrated under nitrogen atmosphere, residue was diluted with THF (30 mL), cooled to 0 °C and was basified with DIPEA (3.1 mL, 18 mmol). To this mixture, an amine (27, 9 mmol) was added slowly as a solution in dichloromethane and the contents were stirred at 23 °C for lh.
  • the reaction mixture was extracted with ethyl acetate (500 mL x 3), the combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure.
  • the crude compound was purified over 230-400 mesh silica gel column
  • Step-2 Synthesis of2-(4-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy) acetamide
  • the reaction mixture was diluted with cold water (100 mL), extracted with ethyl acetate, organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na 2 SC1 ⁇ 4 and concentrated under reduced pressure.
  • the crude material was purified by column chromatography over 230-400 mesh silica gel using (7:3) ethyl acetate in n-hexane an eluent to afford 2-(4-(l-(4-hydroxyphenyl)-2- phenylbut-1- en-l-yl)phenoxy)acetamide (4.8 g, 40%) as a gummy solid.
  • Step-3 Synthesis of 4-( l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol
  • reaction mixture was stirred for 5 h at room temperature, after completion of reaction, reaction mixture was quenched with saturated Na 2 S0 4 solution, filtered through sodium sulphate bed and washed with ethyl acetate. The combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na 2 S0 4 and concentrated under vacuum.
  • the crude compound was purified by column chromatography over 100-200 mesh silica gel using (1 :9) methanol in dichloromethane as an eluent to afford 4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (2.45 g, 63%) as a brown colour solid.
  • Step-5 Synthesis of ( E)-4-( (2-(4-( (Z)-l-( 4-hydroxyphenyl)-2-phenylbut-l-en-l - yl)phenoxy)ethyl)amino)-N,N-dimethylb t-2-enamide (Example 1 )
  • Example 1 1H-NMR (400 MHz, MeOH-d4) ⁇ 7.16-7.01 (m, 7H), 6.80-6.64 (m, 5H), 6.61- 6.58 (m, 3H), 3.99 (t, 2H), 3.50 (t, 2H), 3.11 (s, 3H), 2.99-2.94 (m, 5H), 2.50 (q, 2H), 0.92 (t, 3H); MS (ESI) 471 [M+H] + .
  • Step-2 Synthesis of 4-( l-(4-(benzyloxy)phenyl)-2-phenylbut-l -en-l-yl)phenol
  • Step-3 Synthesis of 1 -(Benzyloxy)-4-( 1 -(4-(2-chloroethoxy)phenyl)-2-phenylbut- 1-en-l- yl)benzene
  • Step-4 Synthesis of2-(4-(l-(4-(benzyloxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy) -N- methylethan-1 -amine
  • Step-5 Synthesis of ' 4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l- yl)phenol
  • Step-6 Synthesis of (E)-4-bromo-N-methyl-N-(6,6, 7, 7, 7-pentafluoroheptyl)but-2- enamide
  • Step-6.4 Synthesis of 6,6, 7 ,7 , 7-penta luoroheptan-l-ol
  • the reaction mixture was adjusted to pH 5 by slowly adding IN HC1 drop wise, and then extracted with ethyl acetate. The combined organics were washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dimethylsulphoxide (20 mL), and stirred at 170 °C for 18 h.
  • Step-6.6 Synthesis of 6, 6, 7, 7, 7-pentafluoro-N-methylheptan-l -amine
  • Step-6.7 Synthesis of ( E)-4-bromo-N-methyl-N-( 6, 6, 7, 7, 7-pentafluoroheptyl)but-2- enamide
  • the reaction mixture was concentrated under nitrogen atmosphere, residue was diluted with dichloromethane (10 mL) and was added to a mixture of 6,6,7,7,7-Pentafluoro- N-methylheptan-1- amine (0.17 g, 0.776 mmol) and DIPEA (0.74 mL, 2.18 mmol) in dichloromethane.
  • the reaction mixture was stirred at 0 °C, for 30 min and was diluted with water and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-7 Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en- 1- yl)phenoxy)ethyl) ( ? ⁇ iethyl)amino)-N-methyl-N-( 6, 6, 7, 7, 7-pentafluoroheptyl)b t-2-enamide (Example 2).
  • Step-2 Synthesis of ( E)-N-heptyl-4-( (2-(4-((Z)-l-( 4-hydroxyphenyl)-2-phenylbut-l- en-1 -yl ) phenoxy)ethyl) (methyl)amino)-N-methylbut-2-enamide (Example 3).
  • Example 4 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l- en-1- yl)phenoxy ) ethyl) ( methyl)amino )-N-methyl-N-(3, 3, 4, 4, 4-pentafluorobutyl)but-2-enamide
  • Step-1 Synthesis of(E)-4-bromo-N-methyl-N-(3,3,4,4,4-pentafluorobutyl)but-2- enamide
  • Step-1.1 Synthesis of 3, 3, 4, 4, 4-pentafluoro-N-methylbutan- 1 -amine
  • Step-1.2 Synthesis of4-bromo-N-methyl-N-(3,3,4,4,4-pentafluorobutyl)but-2- enamide l. (COCl) 2 / DMF /
  • Step-2 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydwxyphenyl)-2-phenylbut-l- en-1- yl)phenoxy)ethyl) (methyl)amino)-N-methyl-N-(3,3,4,4,4-pentafluorobutyl)but-2-enamide (Example 4)
  • Step-1.1 Synthesis of3-( ( tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol
  • Step-1.2 Synthesis of 3-( ( tetrahydro-2H-pyran-2-yl)oxy)propanal
  • Step-1.3 Synthesis of ethyl (E)-5-((tetrahydro-2H-pyran-2-yl)oxy)pen t-2-enoate
  • ethyl-2-(triphenyl-15-phosphanylidene)acetate 9.9 g, 28.6 mmol
  • Reaction mixture was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was concentrated under reduced pressure.
  • the crude material was purified by column chromatography over 230-400 mesh silica using (5:95) ethyl acetate in n- hexane as an eluent to afford title compound (4.6 g, 70%).
  • Step-1.5 Synthesis of (E)-N,N-dimethyl-5-( ( tetrahydro-2H-pyran-2-yl)oxy)pent-2- enamide
  • Step-1.7 Synthesis of ( E)-5-( dimethylamino )-5-oxopent-3-en-l-yl methanesulfonate
  • Step-2 Synthesis of (E)-5-( (2-(4-((Z)-l-( 4-hydroxyphenyl)-2-phenylbut-l-en-l - yl)phenoxy)ethyl)amino)-N,N-dimethylpent-2-enamide (Example 6)
  • Example-7 Synthesis of(E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l- en-1- yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide
  • Step-1.1 Synthesis of but-l-yn-l-yltrimethylsilane:
  • reaction mixture was quenched with water, extracted with ethyl acetate (1000 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product but-l-yn-l-yltrimethylsilane was distilled between 125-135 °C to afford the desired product (91 g, 61 %) as a colourless liquid.
  • Step- 1.2 Synthesis oftert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate
  • tert-butyl (5-bromopyridin-2-yl)carbamate 3 g, 10.989 mmol
  • MeOH:DMA:H 2 0 1:1: 1
  • copper iodide 0.235 g, 1.098 mmol
  • cesium carbonate 4.849 g, 15.3 mmol
  • Step-2 Synthesis oftert-butyl (E)-(5-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)pyridin-2- yl)carbamate
  • Step-3 Synthesis oftert-butyl (E)-(5-(l-(4-(2-( l,3-dioxoisoindolin-2-yl)ethoxy)- phenyl)-2- phenylbut-1 -en-1 -yl)pyridin-2-yl)carbatnate
  • Step-4 Synthesis of tert-butyl (E)-(5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut- 1-en-l- yl )pyridin-2 -yl )carbamate
  • Step-5 Synthesis of tert-butyl (5-((E)-l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2- en-1- yl)amino ) ethoxy )phenyl)-2-phenylbut-l -en-1 -yl )pyridin-2-yl )carbamate
  • Step-6 Synthesis of(E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide (Example 7)
  • Step-2 Synthesis of 4-(benzyloxy )-l-(but-l-yn-l -yl )-2-fluorobenzene
  • Step-3 Synthesis of tert -butyl (2-(4-iodophenoxy)ethyl)carba ate
  • Step-4 Synthesis of tert-butyl (2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut- 1-eti-l- yl)phenoxy) ethyl )carbamate
  • reaction mixture was stirred at 80 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude material was purified by column chromatography over 230-400 mesh silica gel using EtOAc in n-hexane (2.5:7.5) to afford tert-butyl (2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut- 1 -en- 1- yl)phenoxy)ethyl)carbamate (6.1 g, 81 %) as a white solid.
  • Step-5 Synthesis of2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut-l-en-l- yl jphenoxy )ethan-l -amine
  • Step-6 Synthesis of4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3-fluorophenol
  • Step-7 Synthesis of (2E)-4-((2-(4-(l-(2-fluoro-4-hydroxyphenyl)-2-phe?iylbut-l- en-1- yljphenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-8 Synthesis of tert-butyl ((E)-4-(dimethylomino)-4-oxobut-2-en-l-yl)(2-(4-(l- (2-fluoro- 4-hydroxyphenyl)-2-phenylbut-l-en-l -yl )phenoxy )ethyl )carbamate
  • (2E)-4-((2-(4-(l-(2-fluoro-4-hydroxyphenyl)-2-phenylbut- 1-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide 4.5 g, 9.2 mmol
  • dichloromethane 50 mL
  • boc anhydride 2.4 g, 11 mmol
  • reaction mixture was stirred for 5 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure.
  • Step-9 Synthesis of (E)-4-((2-(4-((E)-l-(2-fluoro-4-hydroxyphenyl)-2-phenylbut- 1-en-l- yl)phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide (Example 8)
  • LCMS 489.3 [M+H] + .
  • Step-1 Synthesis of tert-butyl (4-bromophenyl)carbamate
  • Step-2 Synthesis of tert-butyl (4-(but-l -yn-1 -yl)phenyl)carbamate
  • Step-3 Synthesis of tert-butyl (4-( 1 ,2-bis(4,4,5,5-tetramethyl-l ,3 2-dioxaborolan-2- yl)but-l- en-1 -yl )phenyl)carbamate
  • reaction mixture tetrakis(triphenylphosphine)platinum(0) (152 mg, 0.01 mmol) under nitrogen atmosphere, reaction mixture was heated at 90 °C for 5 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-4 Synthesis of tert-butyl (E)-(4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4- iodophenoxy) ethyl jcarbamate
  • Step-4.1 Synthesis of 2-(4-iodophenoxy)ethan-l -amine
  • Step-4.2 Synthesis of ( E)-4-( (2-( 4-iodophenoxy)ethyl)amino )-N,N-dimethylbut-2- enamide
  • Step-4.3 Synthesis of tert-butyl (E)-(4-(diniethylamino)-4-oxobut-2-en-l-yl)(2-(4- iodophenoxy) ethyl)carbamate
  • reaction mixture Upon completion by TLC, the reaction mixture was cooled to 0 °C, quenched with ice cold water (500 mL) and extracted with dichloromethane (500 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulphate and
  • Step-5 Synthesis of tert-butyl (2-(4-( 1 -(4-((tert-butoxycarbonyl)amino)phenyl)-2- (4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)but-l-en-l-yl)phenoxy)ethyl)((E)-4-(dimethylamm ⁇ oxobut-2-en-l -yl) carbamate
  • Step-6 Synthesis of tert-butyl (2-(4-(l-(4-((tert-butoxycarbonyl)amino)phenyl)-2- phenylbut- 1 -en-1 -yl )phenoxy )ethyl )( ( E)-4-( dimethylamino )-4-oxobut-2-en-l-yl )carbamate
  • Step-7 Synthesis of(E)-4-((2-(4-((Z)-l-(4-aminophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide ( Example 9)
  • LCMS 470.3 [M+H] + .
  • Example-10 Synthesis of(E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)
  • Step-2 Synthesis of tert-butyl (Z)-(2-(4-( 1 ,2-diphenylbut-l -en-1 -yl)phenoxy) ethyl)carbamate
  • Example 8 The same procedures as described in Example 7, Step-2, using tert-butyl (2-(4- iodophenoxy)ethyl) carbamate (Example 8, Step-3) and iodobenzene, to afford tert-butyl (Z)- (2-(4-(l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl) carbamate (2 g, 30%).
  • Step-3 Synthesis of (Z)-2-(4-( 1 ,2-diphenylbut-l -en-1 -yl)phenoxy)ethan-l -amine
  • Step-4 Synthesis of(E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N- di- methylbut-2-enamide
  • Step-5 Synthesis oftert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4- ((Z)-l,2- diphenylbut-1 -en-1 -yl)phenoxy)ethyl)carbamate
  • Step-6 Synthesis o (£)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl) amino)-N,7V- dimethylbut-2-enamide (Example 10)
  • Step-2 Synthesis of tert-butyl (2-(4-(2-phenyl-l-(pyridin-4-yl)but-l-en-l-yl)phenoxy) ethyl )carbamate i) Bis(pinacolato)diboron Pt(PPh 3 ) 4
  • Example 8 The same procedures as described in Example 7, Step-2, using tert-butyl (2-(4- iodophenoxy)ethyl) carbamate (Example 8, Step-3) and iodobenzene, to give a crude product, which was purified by combi-flash using 20-23% ethyl acetate in n-hexane to afford tert-butyl (2-(4-(2-phenyl-l-(pyridin-4-yl)but-l-en-l-yl)phenoxy) ethyl)carbamate (0.36 g, 7.2%).
  • Step-3 Synthesis of2-(4-( 2 -phenyl- 1 -(pyridin-4-yl)but-l -en-1 -yl )phenoxy)ethan-l - amine
  • Step-4 Synthesis of ( 2E)-N,N-dimethyl-4-( (2-( 4-( 2-phenyl-l-( pyridin-4-yl)but-l -en- 1 - yl )phenoxy ) ethyl )amino )but-2 -enamide
  • Step-5 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-(2- phenyl-1- ( pyridin-4-yl )but-l -en-1 -yl )phenoxy jethyl )carbamate
  • Step-6 Synthesis of (E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl) amino)-NN- dimethylbut-2-enamide (Example 11)
  • Example-12 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(3-(trifluoro- methyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enam
  • Step-2 Synthesis of 2- ⁇ 4- ⁇ hut-l -yn-1 -yl )phenoxy )tetrahydro-2H-pyran
  • Step-3 Synthesis of 4- ⁇ 1 ,2-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-l - en-1- yl)phenol
  • Step-4 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-(l- (4- hydroxyphenyl )-2-(3-( trtfluoromethyl )phenyl)but-l-en-l-yl )phenoxy)ethyl )- carbamate
  • Step-5 Synthesis of (E)-4-((2-(4-( (Z)-l-(4-hydroxyphenyl)-2-( 3-( trtfluoromethyl)- phenyl)but-l-en-l-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide 2,2,2-tri- fluoroacetate ⁇ Example 12) xamp e
  • LCMS 539.3[M+H] + .
  • Example- 13 Synthesis of (E)-4-( (2-( 4-( (Z)-l-( 4-hydroxyphenyl)-2-(4-isopropyl- phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of tert-butyl (E)-(2-(4-(l-(4-hydroxyphenyl)-2-(4,4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-2 Synthesis of tert-butyl (E)-(2-(4-(2-cyclobutyl-2-phenyl-l-(l-(tetrahydro-2H- pyran- 2-yl)-lH-indazol-5-yl)vinyl)phenoxy)ethyl)carbamate
  • Step-3 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-isopropylphenyl)but- 1-en-l- yl)phenol
  • Step-4 Synthesis of ( E)-4-( (2-( 4-( (Z)-l -( 4-hydroxyphenyl)-2-( 4-isopropylphenyl)- but-1 -en- 1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-5 Synthesis oftert-butyl ((E)-4-(dimethylammo)-4-oxobut-2-en-l-yl)(2-(4- ((Z)-l-(4- hydroxyphenyl )-2-( 4-isopropylphenyl )but-l -en-l-yl)phenoxy )ethyl )carba-mate
  • Step-6 Synthesis of (E)-4-( (2-( 4-( (Z)-l-( 4-hydroxyphenyl)-2-( 4-isopropylphenyl)- but-1 -en- 1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (Example 13)
  • LCMS 513.3[M+H] + .
  • Step-1 Synthesis of ( 4-iodophenyl )( 4-methoxyphenyl )methanone
  • 4-iodophenyl 4-methoxyphenyl
  • anisole (1.12 mL, 10.2 mmol) in dry dichloromethane (25 mL) at -10 °C
  • A1C1 3 1.5 g, 11 mmol
  • the resulting mixture was stirred at room temperature for 16 h.
  • the reaction mixture was quenched with ice cold water (50 mL) and IN HC1 (200 mL) and extracted with EtOAc (2 x 150 mL).
  • EtOAc 2 x 150 mL
  • the combined organic extracts were washed with water, brine and dried over anhydrous sodium sulphate and concentrated at 40 °C without reduced pressure to give a yellow colour liquid (2.4 g, 92%).
  • Step-2 Synthesis of l-iodo-4-(l-(4-methoxyphenyl)-2-phenylbut-l-en-l-yl)benzene
  • Step-3 Synthesis of 4- ⁇ l-(4-iodophenyl)-2-phenylbut-l-en-l-yl)phenol
  • Step-4 Synthesis of tert-butyl (2-(4-( 1 -(4-iodophenyl)-2-phenylbut-l -en-1 -yl)
  • Step-5 Synthesis of2-(4-(l-( 4-iodophenyl )-2-phenylbut-l-en-l-yl )phenoxy ) ethan-1 -amine
  • Step-6 Synthesis of (2E)-4-((2-(4-(l-( 4-iodophenyl)-2-phenylbut-l -en-1 -yl )phenoxy ) ethylamino)-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl (( E)-4-(dimethylamino)-4-oxobut-2-en-l -yl)(2-(4-( 1 - (4- iodophenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-8 Synthesis of (E)-4-((2-(4-((E)- 1 -(4-iodophenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (Example 14)
  • LCMS 581.2 [M+
  • Step-2 Synthesis of4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methylbenzene
  • Step-3 Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-methylphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
  • Step-4 Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l-amine
  • Step-5 Synthesis of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenol
  • Step-6 Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4- hydroxy-2-methylphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-8 Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-2 Synthesis of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-chlorobenzene
  • the pressure tube was sealed and heated at 90 °C for 12 h.
  • the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified over 230-400 mesh silica gel column chromatography using 3% EtOAc in n-hexane to afford 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-chlorobenzene (9.4 g, 80%).
  • Step-3 Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
  • Step-4 Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethan-l-amine
  • Step-5 Synthesis (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- chlorophenol
  • Step-6 Synthesis of (E)-4-((2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl (2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
  • Step-8 Synthesis of (E)-4-((2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of 4-(ben7 loxy)-l-bromo-2-methoxybenzene
  • Step-2 Synthesis of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methoxybenzene
  • the pressure tube was sealed and heated at 80 °C for 12 h.
  • the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified over 230-400 mesh silica gel column chromatography using 25% EtOAc in n-hexane to afford 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methoxybenzene (5 g, 78%).
  • Step-3 Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-methoxyphenyl)-2-phenylbut- l-en-l-yl)phenoxy)ethyl)carbamate 2-Methyl THF:H 2 O/RT/20 h
  • Step-4 Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethan-l -amine
  • Step-5 Synthesis (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methoxyphenol
  • Step-6 Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4- hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-8 Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of (E)-4-(l-(4-(benz loxy)phenyl)-2-(3,5-difluorophenyl)but-l-en-l- yl)phenol
  • Zinc dust (5.2 g, 78.6 mmol) was suspended in dry THF (50 mL) and cooled this suspension to -10 °C. To this TiCl 4 (4.4 mL, 39.3 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h.
  • Step-2 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benz loxy)phenyl)-2-(3,5- difluorophenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-3 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(3,5-difluorophenyl)but-l-en-l- yl)phenol
  • Step-4 Synthesis of (E)-4-((2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)amino) ⁇ N,N-dimethylbut-2-enamide
  • Step-5 Synthesis of tert-butyl (2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l- en-l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
  • Step-6 Synthesis of (E)-4-((2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Example 19 Example-107: Synthesis of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4- hydroxyphenyl)-2-phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of(E)-4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2-phenylvinyl)phenol
  • Zinc dust (5.16 g, 65.39 mmol) was suspended in dry THF (50 mL) and cooled this suspension to -10 °C. To this TiCl 4 (4.34 mL, 39.45 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h.
  • Step-2 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy )ethyl)carbamate
  • Step-3 Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy)ethan-l-amine
  • Step-4 Synthesis of (Z)-4-( l-(4-(2-aminoethoxy )phenyl)-2-cyclobutyl-2-phenylvinyl)phenol
  • Step-5 Synthesis of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-6 Synthesis of tert-butyl (2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
  • Step-7 Synthesis of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of tert-butyl (Z)-(2-(4-(2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy )ethyl)carbamate
  • Step-2 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-ethylphenyl)but-l-en-l- yl)phenol
  • Step-3 Synthesis of (E)-4-((2-(4-((Z)-2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-4 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-2-(4- ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-5 Synthesis of ((E)-4-((2-(4-((Z)-2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of (E)-4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol
  • Zinc dust (6.4 g, 98.57 mmol) was suspended in dry THF (100 mL) and cooled this suspension to -10 °C. To this TiCl 4 (5.4 mL, 49.28 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h.
  • Step-2 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy )ethyl)carbamate
  • Step-3 Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethan-l-amine
  • Step-4 Synthesis of(Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol
  • Step-5 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
  • Step-6 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(p-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-7 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy )ethyl)carbamate
  • reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(o-tolyl)but-l-en-l-yl)phenol
  • Step-3 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy )ethyl) mino )-N,N-dimethylbut-2-enamide
  • Step-4 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(o-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-5 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but-l- en-l-yl)phenoxy )ethan-l-amine
  • Step-3 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but- l-en-l-yl)phenol
  • Step-4 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2-
  • Step-5 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(2-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-6 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2-
  • Step-1 Synthesis of l-(benzyloxy)-4-bromo-2-fluorobenzene
  • Step-2 Synthesis of l-(benzyloxy)-4-(but-l-yn-l-yl)-2-fluorobenzene
  • the pressure tube was sealed and heated at 90 °C for 3 h.
  • the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified by combo-flash using 0.2% EtOAc in n-hexane to afford l-(benzyloxy)-4-(but-l-yn-l-yl)-2-fluorobenzene (2.88 g, 51.8%).
  • Step-3 Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
  • reaction mixture was stirred at 90 °C for 3 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-4 Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine
  • Step-5 Synthesis of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- fluorophenol
  • Step-6 Synthesis of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-8 Synthesis of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-2 Synthesis of tert-butyl (2-(4-iodo-3-methylphenoxy)ethyl)carbamate
  • Step-3 Synthesis of l-(benzyloxy)-4-bromobenzene
  • Step-4 Synthesis of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene
  • the pressure tube was sealed and heated at 90 °C for 12 h.
  • the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified by column chromatography using 1% EtOAc in n-hexane to afford l-(benzyloxy)-4-(but-l-yn-l- yl)benzene (1.6 g, 72%).
  • Step-3 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)carbamate
  • reaction mixture was stirred at 90 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-4 Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy )ethan-l -amine
  • Step-5 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenol
  • Step-6 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3-methylphenoxy)ethyl)carbamate
  • Step-8 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l en-l-yl)phenoxy)ethyl)carbamate
  • reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l-en-l- yl)phenoxy)ethan-l-amine
  • Step-3 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2 ⁇ (2-chlorophenyl)but-l-en-l- yl)phenol
  • Step-4 Synthesis of (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-5 Synthesis of tert-butyl (2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
  • Step-6 Synthesis of (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-1 Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(4- ( trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy )ethyl)carbamate
  • reaction mixture was stirred at 90 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-2 Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but-l- en-l-yl)phenoxy)ethan-l-amine
  • Step-3 Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but- l-en-l-yl)phenol
  • Step-5 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(4-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
  • Step-6 Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(4-)
  • Step-1 Synthesis of l-(benzyloxy)-3-bromobenzene
  • Step-2 Synthesis of l-(benzyloxy)-3-(but-l-yn-l-yl)benzene
  • the pressure tube was sealed and heated at 90 °C for 12 h.
  • the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified by column chromatography using 1% EtOAc in n-hexane to afford l-(benzyloxy)-3-(but-l-yn-l- yl)benzene (1.6 g, 72%).
  • Step-3 Synthesis of tert-butyl (E)-(2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)carbamate
  • reaction mixture was stirred at 90 °C for 8 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • Step-4 Synthesis of (E)-2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l-amine
  • Step-5 Synthesis of(E)-3-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol
  • Step-6 Synthesis of (E)-4-((2-(4-((E)-l-(3-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
  • Step-7 Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate

Abstract

Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and/or the subject in need of treatment may express a mutant ER-α protein.

Description

TETRASUBSTITUTED ALKENE COMPOUNDS AND THEIR USE
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to United States Provisional Patent Application No.
62/168,540, filed on May 29, 2015, and United States Provisional Patent Application No. 62/168,551, filed on May 29, 2015. Both of those applications are incorporated by reference herein.
BACKGROUND
Breast cancer is the most commonly diagnosed malignancy among women today with nearly 200,000/1.7 million new cases diagnosed in the US/worldwide each year respectively. Since about 70% of breast tumors are positive for the estrogen receptor alpha (ERa)— a key oncogenic driver in this subset of tumors— several classes of therapies have been developed to antagonize ERa function, including 1) selective estrogen receptor downregulators (SERDs) of which fulvestrant is an example, 2) selective estrogen receptor modulators (SERMs) of which tamoxifen is an example and 3) aromatase inhibitors that reduce systemic levels of estrogen. These therapies have been largely effective in the clinic reducing occurrence and progression of ERa+ breast tumors. However there are on-target liabilities associated with these different classes of compounds. For example, tamoxifen has been shown to activate signaling activity in the endometrium leading to an increase in risk of endometrial cancers in the clinic (Fisher et al., (1994) J Natl Cancer Inst. Apr 6;86(7):527-37; van Leeuwen et al., (1994) Lancet Feb 19;343(8895):448-52). In contrast, since fulvestrant is a pure antagonist, it can lead to loss of bone density in post-menopausal women as ERa activity is critical for bone building. In addition to on-target side effects, clinical resistance is also beginning to emerge to these classes of ERa antagonists highlighting the need to develop next-generation compounds.
Several mechanisms of resistance have been identified using in vitro and in vivo models of resistance to various endocrine therapies. These include increased ERa /HER2 "crosstalk" (Shou et al., (2004) J Natl Cancer Inst. Jun 16;96(12):926-35), aberrant expression of ERa coactivators/corepressors (Osborne et al., (2003) J Natl Cancer Inst. Mar 5;95(5):353-61) or loss of ERa altogether to allow ER-independent growth (Osborne CK, Schiff R (2011) Annu Rev Med 62: 233^7).
In the hopes of identifying clinically relevant mechanisms of resistance, great effort has also recently gone into deeply characterizing the genetics of endocrine-therapy resistant metastases isolated from patients. Several independent labs have recently published the multitude of genetic lesions observed in the resistant vs the primary tumors (Li et al, (2013) Cell Rep. Sep 26;4(6): 1116-30; Robinson et al, (2013) Nat Genet. Dec;45( 12): 1446-51; Toy et al, (2013) Nat Genet. 2013 Dec;45(12): 1439-45). Among these are the highly recurrent mutations in the ligand-binding domain of ESRl (gene which encodes ERa protein) found to be significantly enriched in about 20% of resistant tumors relative to endocrine therapy naive tumors (Jeselsohn et al., (2014) Clin Cancer Res. Apr 1;20(7): 1757-67; Toy et al, (2013) Nat Genet. 2013 Dec;45(12): 1439-45; Robinson et al., (2013) Nat Genet. Dec;45(12): 1446-51 ; Merenbakh-Lamin et al., (2013) Cancer Res. Dec l;73(23):6856-64; Yu et al., (2014) Science Jul l l;345(6193):216-20; Segal and Dowsett (2014), Clin Cancer Res Apr 1;20(7): 1724-6), suggesting the potential for these mutations to functionally drive clinical resistance. In contrast to the enrichment in ESRl mutations observed in therapy-resistant tumors, mutations in other cancer-related genes failed to show such a robust enrichment strongly implying the importance of ERa mutations in promoting resistance (Jeselsohn et al., (2014) Clin Cancer Res. Apr 1;20(7): 1757-67).
SUMMARY
Described herein are novel compounds useful for treating cancer.
In some embodiments, compounds are described be Formula VII:
Figure imgf000003_0001
VII
wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-4; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C4 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; R13, R14, Rj5, and R[6 are independently selected from the group consisting of -H, -CH3, -CH2CH3, propyl, isopropyl or butyl; r = 1-3; Z = O, S or is absent; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or - OH; or pharmaceutically acceptable salts thereof.
In embodiments, such novel compounds are described by Formula I:
Figure imgf000004_0001
I wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-4; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C4 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or -OH; or pharmaceutically acceptable salts thereof.
In more specific embodiments, such novel compounds are described by Formula I or Formula VII, wherein: R2 is selected from the group consisting of H and CH3; R3 are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C6 alkoxy; R5 are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl; X is selected from the group consisting of H, -OH, halogen and NH2; R8 and R9 are the same or different and are independently selected from the group consisting of H and methyl; R6 and R7 are the same or different and are independently selected from the group consisting of H and C1-C6 alkyl, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 atom heterocyclic ring with the N to which they are attached, optionally also containing an O atom.
In some embodiments, compounds are described by Formula VIII:
Figure imgf000006_0001
VIII
wherein: Rl is selected from the group consisting of ethyl and cyclobutyl; R2 is selected from the group consisting of H and -CH3; n is 0-1 ; R3 is selected from the group consisting of -CH3, -CI, -F and -OCH3; m is 0-2; R4 is selected from the group consisting of -CF3, F, - CH(CH3)2, -CH2CH3 and -CH3; R6 and R7 are the same or different and are independently selected from the group consisting of -CH3, -CH2CH2CF2CF3, -CH2(CH2)5CH3 and - CH2(CH2)4CF2CF3; or pharmaceutically acceptable salts thereof.
Embodiments may provide a compound selected from the group consisting of (E)-4-((2-(4- ((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2- enamide; (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)(methyl)amino)-N-methyl-N-(6,6,7,7,7-pentafluoroheptyl) but-2- enamide; (E)-N-heptyl-4-((2-(4-((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl) (methyl)amino)-N-methylbut-2-enamide; (E)-4-((2-(4-((Z)- 1 -(4-hydroxyphenyl)-2- phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)(methyl)amino)-N-methyl-N-(3 ,3 ,4,4,4- pentafluorobutyl)but-2-enamide; (E)-4-((2-(4-((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)(methyl)amino)-N,N-dimethylbut-2-enamide; (E)-5-((2-(4-((Z)-l-(4- hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy) ethyl)amino)-N,N-dimethylpent-2-enamide; (E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N- dimethylbut-2-enamide; (E)-4-((2-(4-((E)- 1 -(2-fluoro-4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((E)- 1 -(2-fluoro-4- hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((Z)-l-(4-aminophenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N- dimethylbut-2-enamide; (E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl)amino)- N,N -dimethylbut-2-enamide; (E)-N,N-dimethyl-4-((2-(4-((E)-2-phenyl-l-(pyridin-4-yl)but-
1- en-l-yl)phenoxy)ethyl) amino)but-2-enamide; (E)-4-((2-(4-((E)-l-(4- hydroxyphenyl)-2- (3-(trifluoiOmethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino) -N,N-dimethylbut-2- enamide; (E)-4-((2-(4-((Z)- 1 -(4-hydiOxyphenyl)-2-(4-isopropyl-phenyl)but- 1 -en- 1 - yl)phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide; and (2E)-4-((2-(4-(l-(4-iodophenyl)-
2- phenylbut- 1 -en- 1 -yl)-phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;
or pharmaceutically acceptable salts thereof
Embodiments may provide compound selected from the group consisting of (E)-4-((2-(4- ((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2- enamide; (E)-4-((2-(4-((Z)-2-cyclobutyl- 1 -(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((Z)-l,2- diphenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((E)- l-(2-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N- dimethylbut-2-enamide; (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; (E)-4-((2-(4-((Z)-l-(4- hydroxyphenyl)-2-(o-tolyl)but- 1 -en- 1 -yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2- enamide; (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(3-(trifluoromethyl) phenyl) but-l-en-1- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide; and (E)-5-((2-(4-((Z)-l-(4- hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylpent-2-enamide; or pharmaceutically acceptable salts thereof.
Embodiments may have the structure of Formula IX:
Figure imgf000008_0001
IX
wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-3; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C4 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; R13, RJ4, R15, and Ri6 are independently selected from the group consisting of -H, -CH3, -CH2CH3, propyl, isopropyl or butyl; r = 1-3; Z = O, S or is absent; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or - OH; or pharmaceutically acceptable salts thereof.
In embodiments, such novel compounds are described by Formula III:
Figure imgf000009_0001
III
wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-3; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C6 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or -OH; or pharmaceutically acceptable salts thereof.
In more specific embodiments, such novel compounds are described by Formula III or Formula IX, wherein: R2 is selected from the group consisting of H and CH3; R3 are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C6 alkoxy; R5 are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl; X is selected from the group consisting of H, -OH, halogen and NH2; R8 and R9 are the same or different and are independently selected from the group consisting of H and methyl; R6 and R7 are the same or different and are independently selected from the group consisting of H and C1-C6 alkyl, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 atom heterocyclic ring with the N to which they are attached, optionally also containing an O atom.
Figure imgf000010_0001
X
wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-4; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl 1 is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C4 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; Ri3, Rj4, R15, and Rj6 are independently selected from the group consisting of -H, -CH3, -CH2CH3, propyl, isopropyl or butyl; r = 1-3; Z = O, S or is absent; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or - OH; or pharmaceutically acceptable salts thereof.
In embodiments, such novel compounds are described by Formula V:
Figure imgf000011_0001
V
wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-4; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C6 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or -OH; or pharmaceutically acceptable salts thereof.
In more specific embodiments, such novel compounds are described by Formula V or Formula X, wherein: R2 is selected from the group consisting of H and CH3; R3 are the same or different, and are independently selected from the group consisting of H, halogen, methyl and ethyl; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C6 alkoxy; R5 are the same or different and are independently selected from the group consisting of H, halogen, methyl and ethyl; X is selected from the group consisting of H, -OH, halogen and NH2; R8 and R9 are the same or different and are independently selected from the group consisting of H and methyl; R6 and R7 are the same or different and are independently selected from the group consisting of H and C1-C6 alkyl, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 atom heterocyclic ring with the N to which they are attached, optionally also containing an O atom.
In embodiments, such novel compounds are described by Formula II:
Figure imgf000013_0001
II
wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-4; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rll is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C6 cycloalkoxy and a C4 heterocyclic ring; p is 0-4; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromefhane or trifluoromethane, or -OH; or pharmaceutically acceptable salts thereof.
In embodiments, such novel compounds are described by Formula IV:
Figure imgf000014_0001
IV
wherein: n is 0; Y is -C(0)NR6R7; and R6 and R7 are both -CH3. In embodiments, such novel compounds are described by Formula VI:
Figure imgf000014_0002
VI
wherein: n is 0; Y is -C(0)NR6R7; and R6 and R7 are both - Further embodiments may have the structure of Formula XI:
Figure imgf000014_0003
XI wherein: Rl is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and a 4- 6 membered heterocyclic ring; R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl and a 4-6 membered heterocyclic ring; R3 are the same or different, and are independently selected from the group consisting of H, halogen, C1-C6 alkyl and C1-C3 alkoxy optionally substituted with at least one halogen; n is 0-4; R4 are the same or different and are independently selected from the group consisting of H, halogen, C1-C6 alkyl, and OR11, wherein Rl l is selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring; m is 0-5; R5 are the same or different and are independently selected from the group consisting of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, C3-C4 cycloalkoxy and a C4 heterocyclic ring; p is 0-3; q is 1-2; X is selected from the group consisting of H, -OH, halogen, NH2 and NHR12, wherein R12 is selected from the group consisting of acyl, C1-C6 alkyl and C3-C6 cycloalkyl; R8 and R9 are the same or different and are independently selected from the group consisting of halogen, H and C1-C3 alkyl; Y is selected from the group consisting of -S(0)2R6, - S(0)2NR6R7, -C(0)NR6R7, -C(0)R6, -C(0)OR6 and -CN; or wherein Y and R8 both represent -CF3; R6 and R7 are the same or different and are independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and a 4-6 membered heterocyclic ring, wherein said alkyl is saturated or unsaturated or wherein R6 and R7 form a 4-6 membered heterocyclic ring with the N to which they are attached, optionally also containing an O atom; R13, Ri4, R15, and R|6 are independently selected from the group consisting of -H, -CH3, -CH2CH3, propyl, isopropyl or butyl; r = 1-3; Z = O, S or is absent; and wherein any carbon containing moiety of R1-R12 may be optionally substituted with one or more halogen atoms, fluoromethane, difluoromethane or trifluoromethane, or - OH; or pharmaceutically acceptable salts thereof.
In embodiments, the compounds of any of the above Formulas have the following permutations or combinations of permutations, when the substituent is present in the
Formula: Y is -C(0)NR6R7; Y and R9 are in "cis" configuration relative to each other; R6 and R7 are methyl; R8 and R9 are both H; Rl is ethyl or cyclobutyl; R2 is H or CH3; n is 1 and R3 is F; m is 1 and R4 is F; X is -OH; q is 1 ; m and n are both 0; m is 0 and n is 1 ; m is 1 and n is 0; R13, R14, R15 and R16 are H; r is 1 ; and wherein in Z is an oxygen atom.
Also disclosed herein are methods of using the novel compounds, for example, to treat breast cancer. In embodiments, such methods include administration to a subject in need thereof a therapeutically effective amount of any of the compounds of any of the above Formulas or pharmaceutically acceptable salts thereof. In embodiments, use is made of the compounds of any of the above Formulas or pharmaceutically acceptable salts thereof for treating breast cancer. In embodiments, the breast cancer is an ER-positive breast cancer. In embodiments, the subject in need of treatment expresses a mutant ER-a protein.
In embodiments, the compounds disclosed herein are useful for inhibiting the cell culture growth of MCF7 ER-alpha (wildtype) and MCF7 ER-alpha (Y537S mutant) cells. Other compounds (e.g., tamoxifen, raloxifene and fulvestrant) known to inhibit the cell culture growth of MCF7 ER-alpha (wildtype) cells are currently used to treat breast cancer in human patients. Hence, the compounds disclosed herein are useful for treating ER-alpha expressing breast cancer in human patients, and are useful for treating Y537S mutant ER-alpha expressing breast cancer in human patients.
In embodiments, the compounds disclosed herein are useful for treating breast cancer. In embodiments, the breast cancer is ER-a+. In embodiments, the breast cancer expresses an ER-a mutation, which is L536Q (Robinson et al. Nat Genet. 2013 Dec;45(12)), L536R (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45), Y537S (Toy et al. Nat Genet. 2013
Dec;45(12): 1439-45; Robinson et al. Nat Genet. 2013 Dec;45(12); Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67), Y537N (Toy et al. Nat Genet. 2013
Dec;45(12): 1439-45; Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67), Y537C (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67) and D538G (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Robinson et al. Nat Genet. 2013 Dec;45(12); Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67; Merenbakh-Lamin et al. Cancer Res. 2013 Dec l;73(23):6856-64), all of which are incorporated by reference in their entireties for their teachings of ER-a mutations.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows phenotypic resistance observed in mutant-bearing lines relative to control lines to existing clinical compounds, whereby MCF7 cells engineered to overexpress various ERaMUT showed partial resistance to various endocrine therapies.
DETAILED DESCRIPTION All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Where the text of this disclosure and the text of one or more documents incorporated by reference conflicts, this disclosure controls. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The embodiments described herein having now been described by way of written description, those of skill in the art will recognize that the embodiments described herein may be practiced in a variety of embodiments and that the description and examples provided herein are for purposes of illustration and not limitation of the claims.
As used herein, "alkyl", "Ci, C2, C3, C4, C5 or C6 alkyl" or "Ci-C6 alkyl" is intended to include Ci, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, Ci-C6 alkyl is intended to include Ci, C2, C3, C4, C5 and C alkyl groups. Examples of alkyl include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.
In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
As used herein, the term "cycloalkyl" refers to a saturated or unsaturated nonaromatic hydrocarbon ring having 3 to 7 carbon atoms (e.g., C3-C7). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
The term "heterocycloalkyl" refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic groups, 7-10 membered fused bicyclic groups having one or more heteroatoms (such as O, N, or S), unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl,
tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothiophene, dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, and the like.
Additional examples of heterocycloalkyl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.
The term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
An "arylalkyl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g.,
phenylmethyl(benzyl)). An "alkylaryl" moiety is an aryl substituted with an alkyl (e.g., methylphenyl).
"Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.
The term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
"Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms.
The term "optionally substituted alkynyl" refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Other optionally substituted moieties (such as optionally substituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.
"Aryl" includes groups with aromaticity, including "conjugated," or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthalenyl, etc.
"Heteroaryl" groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as "aryl heterocycles" or "heteroaromatics." As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR' wherein R' is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→0 and S(0)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
Furthermore, the terms "aryl" and "heteroaryl" include multicyclic aryl and heteroaryl groups, e.g., bicyclic. Non-limiting example of such aryl groups include, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,
methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
In the case of multicyclic aromatic rings, only one of the rings needs to be aromatic (e.g., 2,3- dihydroindole), although all of the rings may be aromatic (e.g., quinoline).
The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups may also be fused with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin,
methylenedioxyphenyl) . When a bond to a substituent is shown to cross a bond connecting two atoms in a ring (as shown by the examples below with substituent R), then such substituent may be bonded to any atom in the ring.
Figure imgf000022_0001
When any variable (e.g., Rl) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ri moieties, then the group may optionally be substituted with up to two Ri moieties and Rj at each occurrence is selected independently from the definition of Ri.
The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O".
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. The term "perhalogenated" generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl substituted with one or more halogen atoms.
"Alkoxyalkyl," "alkylaminoalkyl," and "thioalkoxyalkyl" include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.
The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.
"Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."
Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed
"enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."
A carbon atom bonded to four nonidentical substituents is termed a "chiral center."
"Chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Calm et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Calm et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
In the present specification, each incidence of a chiral center within a structural formula, such as the non-limiting example shown here:
Figure imgf000023_0001
is meant to depict all possible stereoisomers. In contrast, a chiral center drawn with hatches and wedges, such as the non-limiting exam le shown here:
Figure imgf000024_0001
is meant to depict the stereoisomer as indicated (here in this sp hybridized carbon chiral center, R3 and R4 are in the plane of the paper, R\ is above the plane of paper, and R2 is behind the plane of paper).
"Geometric isomer" means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
In the present specification, each incidence within a structural formula including a wavy line adjacent to a double bond as shown:
Figure imgf000024_0002
is meant to depict both geometric isomers. In contrast, such structures drawn without a wavy line is meant to depict a compound having the geometric configuration as drawn.
"Tautomer" is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds.
Tautomers exist as a mixture of a tautomeric set in solution. In solutions where
tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. Where the present specification depicts a compound prone to tautomerization, but only depicts one of the tautomers, it is understood that all tautomers are included as part of the meaning of the chemical depicted. It is to be understood that the compounds disclosed herein may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included, and the naming of the compounds does not exclude any tautomer form.
Of the various types of tautomerism that are possible, two are commonly observed. In keto- enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (--OH) in the same molecule to give it a cyclic (ring- shaped) form as exhibited by glucose.
Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine.
Furthermore, the stractures and other compounds disclosed herein include all atropic isomers thereof, it being understood that not all atropic isomers may have the same level of activity. "Atropic isomers" are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
The term "crystal polymorphs", "polymorphs" or "crystal forms" means crystal structures in which a compound (or a salt or solvate thereof) may crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility.
Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds may be prepared by crystallization under different conditions. It is understood that the compounds disclosed herein may exist in crystalline form, crystal form mixture, or anhydride or hydrate thereof. The compounds disclosed herein include the compounds themselves, as well as their salts and solvates, if applicable. A salt, for example, may be formed between an anion and a positively charged group (e.g., amino) on an aryl- or heteroaryl-substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt may also be formed between a cation and a negatively charged group (e.g., carboxylate) on an aryl- or heteroaryl- substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethyl ammonium ion. The aryl- or heteroaryl-substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
Additionally, the compounds disclosed herein, for example, the salts of the compounds, may exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds disclosed herein wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1 ,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic,
hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.
Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1: 1, or any ratio other than 1:1, e.g., 3: 1, 2: 1, 1:2, or 1:3.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.
"Solvate" means solvent addition forms that contain either stoichiometric or non
stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H20.
Chemicals as named or depicted are intended to include all naturally occurring isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of H hydrogen include tritium and deuterium, and isotopes of C carbon include 13C and I4C.
It will be understood that some compounds, and isomers, salts, esters and solvates thereof, of the compounds disclosed herein may exhibit greater in vivo or in vitro activity than others. It will also be appreciated that some cancers may be treated more effectively than others, and may be treated more effectively in certain species of subjects that others, using the compounds, and isomers, salts, esters and solvates thereof, of the compounds disclosed herein.
As used herein, "treating" means administering to a subject a pharmaceutical composition to ameliorate, reduce or lessen the symptoms of a disease. As used herein, "treating" or "treat" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term "treat" may also include treatment of a cell in vitro or an animal model.
Treating cancer may result in a reduction in size of a tumor. A reduction in size of a tumor may also be referred to as "tumor regression." Preferably, after treatment, tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
Treating cancer may result in a reduction in tumor volume. Preferably, after treatment, tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Tumor volume may be measured by any reproducible means of measurement.
Treating cancer may result in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
Treating cancer may result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified
magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
As used herein, "subject" or "subjects" refers to any animal, such as mammals including rodents (e.g., mice or rats), dogs, primates, lemurs or humans.
Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
Treating cancer may result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drag that is not a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof. Preferably, the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. A decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound. Treating cancer may result in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate may be measured according to a change in tumor diameter per unit time.
Treating cancer may result in a decrease in tumor regrowth, for example, following attempts to remove it surgically. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
Treating or preventing a cell proliferative disorder may result in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. The rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
Treating or preventing a cell proliferative disorder may result in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The proportion of proliferating cells may be measured by any reproducible means of
measurement. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. The proportion of proliferating cells may be equivalent to the mitotic index.
Treating or preventing a cell proliferative disorder may result in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. The size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
Treating or preventing a cell proliferative disorder may result in a decrease in the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment, the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement. An abnormal cellular morphology may be measured by microscopy, e.g., using an inverted tissue culture microscope. An abnormal cellular morphology may take the form of nuclear pleiomorphism.
As used herein, the term "alleviate" is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased. Importantly, a sign or symptom may be alleviated without being eliminated. In a preferred embodiment, the administration of pharmaceutical compositions disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required. Effective dosages are expected to decrease the severity of a sign or symptom. For instance, a sign or symptom of a disorder such as cancer, which may occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
As used herein, the term "severity" is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state. Alternatively, or in addition, severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union Against Cancer (UICC) and the Amerimay Joint Committee on Cancer (AJCC)) or by other art-recognized methods. Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes). Alternatively, or in addition, severity is meant to describe the tumor grade by art- recognized methods (see, National Cancer Institute, www.cancer.gov). Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute,
www.cancer.gov). Furthermore, severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, www.cancer.gov).
In another aspect of embodiments described herein, severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized. Moreover, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe. In these situations, prolonging the life expectancy of the subject and/or reducing pain, decreasing the proportion of cancerous cells or restricting cells to one system, and improving cancer stage/tumor grade/histological grade/nuclear grade are considered alleviating a sign or symptom of the cancer.
As used herein the term "symptom" is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by non-health- care professionals.
A "pharmaceutical composition" is a formulation containing a compound disclosed herein in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound disclosed herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
"Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient. The present disclosure also provides pharmaceutical compositions comprising any compound disclosed herein in combination with at least one pharmaceutically acceptable excipient or carrier.
A pharmaceutical composition disclosed herein is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
A compound or pharmaceutical composition disclosed herein may be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound disclosed herein may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
The term "therapeutically effective amount", as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect may be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation may be determined by routine experimentation that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.
For any compound, the therapeutically effective amount may be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information may then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it may be expressed as the ratio, LD50/ED50.
Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be
administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
The pharmaceutical compositions containing active compounds disclosed herein may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that may be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable earner. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
The active compounds may be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the compounds disclosed herein are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with embodiments described herein vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages may range from about 0.01 mg kg per day to about 5000 mg/kg per day. In preferred aspects, dosages may range from about 1 mg kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m2, and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.
The pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.
Techniques for formulation and administration of the compounds disclosed herein may be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, Pa. (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, may be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
Exemplary cancers that may be treated using one or more compounds disclosed herein include, but are not limited to, breast cancer, uterine endometrial, ovarian carcinoma, sarcoma, thyroid carcinoma, prostate, lung adenocarcinoma, and hepatocellular carcinoma.
In embodiments, the compounds disclosed herein may be useful for treating breast cancer. In embodiments, the breast cancer is ER-a+. In embodiments, the breast cancer expresses an ER-a mutation, which may be L536Q (Robinson et al. Not Genet. 2013 Dec;45(12)), L536R (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45), Y537S (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Robinson et al. Nat Genet. 2013 Dec;45(12); Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67), Y537N (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67), Y537C (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67) and D538G (Toy et al. Nat Genet. 2013 Dec;45(12): 1439-45; Robinson et al. Nat Genet. 2013 Dec;45(12); Jeselsohn et al. Clin Cancer Res. 2014 Apr 1;20(7): 1757-67; Merenbakh-Lamin et al. Cancer Res. 2013 Dec l;73(23):6856-64), all of which are incorporated by reference in their entireties for their teachings of ER-a mutations.
Thus, the compounds disclosed herein may be also useful for additional indications and genotypes. ESR1 mutations (Y537C/N) were recently discovered in 4 of 373 cases of endometrial cancers (Kandoth et al. Nature 2013 May 2;497(7447):67-73; Robinson et al. Nat Genet. 2013 Dec;45(12)). Since it has been shown that ESR1 mutations Y537C N significantly drive resistance to currently marketed SOC therapies, the compounds disclosed herein may be useful for treating ERaMUT endometrial cancers.
Exemplary cell proliferative disorders that may be treated using one or more compounds disclosed herein include, but are not limited to breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast. Cell proliferative disorders of the breast may include hyperplasia, metaplasia, and dysplasia of the breast.
A breast cancer that is to be treated may arise in a male or female subject. A breast cancer that is to be treated may arise in a premenopausal female subject or a postmenopausal female subject. A breast cancer that is to be treated may arise in a subject 30 years old or older, or a subject younger than 30 years old. A breast cancer that is to be treated has arisen in a subject 50 years old or older, or a subject younger than 50 years old. A breast cancer that is to be treated may arise in a subject 70 years old or older, or a subject younger than 70 years old.
A compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be used to treat or prevent a cell proliferative disorder of the breast, or to treat or prevent breast cancer, in a subject having an increased risk of developing breast cancer relative to the population at large, or used to identify suitable candidates for such purposes. A subject with an increased risk of developing breast cancer relative to the population at large is a female subject with a family history or personal history of breast cancer. A subject with an increased risk of developing breast cancer relative to the population at large is a female who is greater than 30 years old, greater than 40 years old, greater than 50 years old, greater than 60 years old, greater than 70 years old, greater than 80 years old, or greater than 90 years old.
A cancer that is to be treated may include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. A cancer that is to be treated may include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. A cancer that is to be treated may include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer that is to be treated may include a tumor that has been determined to be greater than 5 centimeters in diameter. A cancer that is to be treated may be classified by microscopic appearance as well differentiated, moderately
differentiated, poorly differentiated, or undifferentiated. A cancer that is to be treated may be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells). A cancer that is to be treated may be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells). A cancer that is to be treated may be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer that is to be treated may be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy. A cancer that is to be treated may be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
The compounds, or pharmaceutically acceptable salts thereof may be administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.
The dosage regimen utilizing the compounds may be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian may readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. EXAMPLES
Hereby are provided non-limiting examples of embodiments of compounds disclosed herein. If there is any discrepancy between a compound's depicted chemical structure and its chemical name, the depicted chemical structure will control.
Table 1
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
General Procedures
Scheme 1
Figure imgf000046_0002
Step-1: To a suspension of zinc dust (36.6 g, 560 mmol) in dry THF (200 mL) at -10 °C was added TiCl4 (50.4 g, 266 mmol) under nitrogen atmosphere. The contents were stirred there for 15 min, slowly allowed to warm to 23 °C and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C and a solution of bis(4-hydroxyphenyl)methanone (1, 46.7 mmol) and propiophenone (2, 140 mmol) in dry THF (20 mL) was added and the resulting mixture was heated at reflux for 2.5 h. The reaction mixture was cooled to 23 °C and quenched with saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (500 mL x 3), the combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified over 230-400 mesh silica gel column chromatography using (3:7) ethyl acetate in n-hexane to afford 4,4'-(2-phenylbut-l-ene-l,l-diyl)diphenol (3, 40 mmol, 85%) as a brown colour solid.
Step-2: To a stirred solution of 4,4'-(2-phenylbut-l-ene-l,l-diyl)diphenol (3, 31.6 mmol) in acetone (100 mL) was added K2C03 (13.0 g, 94.8 mmol) at 23 °C and the contents were heated at 80 °C for 15 min. To this mixture, a solution of 2-iodoacetamide (4, 34.8 mmol) in 50 mL of acetone was added slowly over a period of 3 h at 80 °C and the contents were stirred for 1 h at 80 °C. The reaction mixture was diluted with cold water (100 mL), extracted with ethyl acetate, organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using (7:3) ethyl acetate in n-hexane an eluent to afford 2-(4-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)acetamide (5, 12.6 mmol, 40%) as a gummy solid.
Step-3: To a suspension of LiAlH4 (6.18 g, 163 mmol) in dry THF (200 mL) at 0 °C was added A1C13 (6.27 g, 47 mmol) portion wise under nitrogen atmosphere. The contents were stirred for 15 min at room temperature, reaction mixture was re-cooled to 0 °C, and a solution of 2-(4-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)acetamide (5, 10 mmol) in 100 mL of dry THF was added. The reaction mixture was stirred for 5 h at room temperature, after completion of reaction, reaction mixture was quenched with saturated Na2S04 solution, filtered through sodium sulphate bed and washed with ethyl acetate. The combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under vacuum. The crude compound was purified by column chromatography over 100-200 mesh silica gel using (1:9) methanol in dichloromethane as an eluent to afford 4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut- l-en-l-yl)phenol (6, 6.3 mmol, 63%) as a brown colour solid.
Step-4: To a stirred solution of 6 (1.07 mmol) in DMF (10 mL) were added at 0 °C, (E)-4- bromo-NN-dimethylbut-2-enamide (7, 1.6 mmol) and DIPEA (0.18 mL, 1.28 mmol). The reaction mixture was stirred for 2 h at 23 °C, was diluted with cold water (50 mL) extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 3% methanol in dichloromethane to afford E/Z mixture, which was then separated by HPLC with a chiral column to give a pure desired isomer 8 (0.45 mmol, 28.3%).
Scheme 2:
Figure imgf000048_0001
Figure imgf000048_0002
Step-1: Zinc dust (31 g, 473 mmol) was suspended in dry THF (100 mL) and cooled this suspension to -10 °C. To this TiCl4 (44 g, 230 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C, and a solution of lb (59.2 mmol) and propiophenone (2, 176 mmol) in dry THF (80 mL) were added and the contents were refluxed for 2.5 h. The reaction mixture was cooled to room temperature and quenched with 10% aqueous K2C03 solution and was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and
concentrated. The crude material was purified by column chromatography over 230-400 mesh silica using (2:8) ethyl acetate in n-hexane to afford 3b (49 mmol, 83 %) as a colorless solid.
Step-2: To a solution of 3b (17 mmol) in acetonitrile (140 mL) was added potassium carbonate (7.1 g, 51 mmol) and l-bromo-2-chloro ethane (4b, 34 mmol). The reaction mixture was heated to 80 °C and maintained at this temperature for 24 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using (5:95) ethyl acetate in n-hexane to afford 5b (8.9 mmol, 52.5%) as a colourless gum.
Step-3: To a suspension of 5b (8 mmol) in methanol (100 mL) was added 40 % aq. methyl amine (150 mL). The reaction mixture was heated at 80 °C for 16 h in a sealed tube, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6b (7.0 mmol, 87.8 %) as a pale yellow gummy mass. Step-4: To a stirred solution of 6b (1.29 mmol) in dichloromethane (36 mL) was added BBr3 (1M solution in dichloromethane, 2.6 mL, 2.59 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the benzylated 6c (1.17 mmol, 91 %) as a gummy mass.
Step-5: To a stirred solution of 6c (1.07 mmol) in DMF (10 mL) were added at 0 °C, (E)-4- bromo-N,N-dimethylbut-2-enamide (7, 1.6 mmol) and DIPEA (0.18 mL, 1.28 mmol). The reaction mixture was stirred for 2 h at 23 °C, was diluted with cold water (50 mL) extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 3% methanol in dichloromethane to afford E/Z mixture of 8b, which was further purified by chiral HPLC to give the desired pure isomer 8b (0.30 mmol, 28.3%).
Scheme 3:
Figure imgf000049_0001
18 16
Step-1: To a stirred solution of 9 (10.989 mmol) in 30 mL of MeOH:DMA:H20 (1: 1: 1) in a sealed tube, were added copper iodide (0.235 g, 1.098 mmol) and cesium carbonate (4.849 g, 15.3 mmol) at 23 °C. This mixture was degassed with three vacuum N2 cycles, and were added 10 (22 mmol) followed by Pd(PPh3)2Cl2 (0.384 g, 0.5 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 X 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude product was purified over 230-400 mesh silica column chromatography using 5% EtOAc in n-hexane to afford 11 (9.67 mmol, 88%) as a white solid. Step-2: To a stirred solution of 11 (73.9 mmol) in 2-methyl THF (136 mL), was added bis(pinacolato) diboron (22.52 g, 88.6 mmol), tetrakis(triphenylphosphine)platinum(0) (919 mg, 0.739 mmol) under nitrogen atmosphere, reaction mixture was heated at 90 °C for 5 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure, to afford 13 (56 mmol, 76%).
Step-3: To a stirred solution of 13 (12.74 mmol), 4-iodophenol (14, 10.61 mmol), bis(triphenylphosphine)palladium(II) dichloride (372 mg, 0.530 mmol), cesium carbonate (6.9 g, 21.23 mmol) and 2-methyl THF (60 mL) were added. This mixture was degassed with nitrogen and water (5 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using MeOH in dichloromethane (1.6:98.4) to afford 16 (5.47 mmol, 43%).
Step-4: To a stirred solution of 16 (1.8 mmol) in 2-methyl THF (30 mL), iodobenzene (15, 1.8 mmol), 4M aqueous KOH (5 mL) and Pd(PPh3)2Cl2 (63 mg, 0.09 mmol) were added and the mixture was degassed with nitrogen for 15 min and heated at 90 °C for 8 h. Upon completion, the reaction mixture was diluted with EtOAc. Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (2:8 EtOAc in n-hexane) to give a desired prodcut (18, 0.74 mmol, 41%).
Combined Step-2, Step-3 and Step-4: To a stirred solution of 11 (13.78 mmol) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (12, 3.53 g, 13.94 mmol), tetrakis(triphenyl- phosphine)platinum(O) (130 mg, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 10 h. The solution was allowed to cool to 23 °C and iodobenzene 14 (13.78 mmol), bis(triphenylphosphine)palladium (II) dichloride (483 mg, 0.68 mmol), cesium carbonate (8.9 g, 27.55 mmol) and 2-methyl THF (30 mL) were added. This mixture was degassed with nitrogen and water (10 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (10 mL) and iodobenzene 15 (19.28 mmol) were added. Reaction mixture was stirred at 80 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using EtOAc in /r-hexane (2.5:7.5) to afford 18 (11.2 mmol, 81 %) as a white solid.
Step-5: To a solution of 11 (6.09 mmol), iodobenzene (15, 18.29 mmol), phenyl boronic acid (17, 18.29 mmol), in NN-dimethyl formamide/water (2: 1, 15 mL) was added K2C03 (2.52 g, 18.29 mmol). The contents were degassed with three vacuum/N2 cycles, and then stirred for 1 h until the solution was homogeneous. A solution of Pd(PhCN)2Cl2 (0.022 g, 0.0609 mmol) in N,N-dimethyl formamide (1 mL) was added and the resulting mixture was stirred at 45 °C for 12 h. Upon completion by TLC, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude material was purified over 230-400 mesh silica column chromatography using 20% ethyl acetate in n- hexane to afford 18 (8.6 mmol, 47%) as an off-white solid.
Scheme 4:
Figure imgf000051_0001
Step-1: To a solution of 18a (3.4 mmol) in DMF (30 mL), at 0 °C, were added sequentially potassium carbonate (1.4 g, 10.1 mmol) and te/t-butyl (2-bromoethyl)carbamate (19, 8.5 mmol). The reaction mixture was stirred at 80 °C for 16 h, was diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 15% ethyl acetate in n-hexane to afford the desired prodcut (18b, 1.8 mmol , 53%) as a light brown colour gummy mass. Step-2: To a stirred solution of 18b (2.5 mmol) in ethanol (10 mL) was added at 0 °C, 2M HC1 in ether (10 mL). The reaction mixture was stirred for 16 h at 23 °C. After completion of reaction, reaction mixture was basified with saturated NaHC03) extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in DCM to afford the desire product (20, 1.25 mmol, 50%) as a brown coloured semi solid.
Step-3: To a stirred solution of 20 (1.24 mmol) in DMF (5 mL) was added at 0 °C, (E)-4- bromo-N,N-dimethylbut-2-enamide (7, 1.24 mmol) and DIPEA (0.321 g, 2.49 mmol). The reaction mixture was stirred for 48 h at 23 °C, was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give a crude mixture of 21.
Step-4: The crude material obtained from previous step was purified by preparative HPLC to afford pure isomer 22 (0.06 mmol, 5%) as a white solid. The 1H NMR, HPLC and MS data were collected.
Step-5: To a stirred solution of 21 (1.25 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (0.546 g, 2.5 mmol). The reaction mixture was stirred for 1 h at 23 °C, after completion of reaction, reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 2% MeOH in DCM to afford 18c (0.63 mmol, 50%) as a light brown semi-solid.
Step-6: To a stirred solution of 18c (0.622 mmol) in MeOH (5 mL) was added at 0 °C, 2M HC1 in ether (10 mL). The reaction mixture was stirred for 16 h at 23 °C. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with 10% MeOH in DCM. Organic layer was concentrated under reduced pressure to obtain crude compound (15, 0.07 mmol) as an off-white solid. Crude compound was purified by preparative HPLC to afford desired pure isomer (22, 0.03 mmol, 4.1%) as an white solid. The 1H NMR, HPLC and MS data were collected.
Scheme 5:
Figure imgf000053_0001
(Rio=H)
0
Step-3 Br\ /^./^N. 6
R7
Boc 0 Step-4
Figure imgf000053_0002
Step-1: To a stirred solution of 4-iodophenol (14a, 227 mmol) in DMF (750 mL) was added potassium carbonate (188 g, 1.363 mol) and stirred for 30 min at 23 °C, to the above mixture tert-butyl (2-bromoethyl)carbamate (19, 71.27 g, 318 mmol) was added. The contents were stirred at 70 °C for 12 h. After completion of reaction, reaction mixture was poured onto ice cold water, solid separated was filtered and dried under reduced pressure to obtain desired compound tert-butyl (2-(4-iodophenoxy)ethyl)carbamate as an off-white solid (14b, 220 mmol, 97%).
Step-2: To a stirred solution of 14b (68.6 mmol) in ethanol (50 mL) was added at 0 °C, 2M HC1 in ether (250 mL). The reaction mixture was stirred for 12 h at 23 °C. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with 10% MeOH in DCM. Organic layer was concentrated under reduced pressure and the crude material was used in next step without further purification (23, 60 mmol, 88%).
Step-3: To a stirred solution of 23 (60.6 mmol) in DMF (65 mL) was added at 0 °C, 4-bromo- N,N-dimethylbut-2-enamide (7, 42.4 mmol) and DIPEA (11.72 g, 90.9 mmol). The reaction mixture was stirred for 5 h at room temperature, was diluted with cold water (250 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (24, 50 mmol, 83%, crude).
Step-4: To a stirred solution of 24 (50.26 mmol) in dry dichloromethane (150 mL) was added DIPEA (6.4g, 50.2 mmol) at 0 °C, stirred for 15 min at 0 °C. To the above reaction mixture, was added di-tert-butyl dicarbonate (13.1 g, 60.3 mmol), resulting mixture was stirred at 23 °C for 12 h. Upon completion by TLC, the reaction mixture was cooled to 0 °C, quenched with ice cold water (500 mL) and extracted with dichloromethane (500 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica using 3% MeOH in dichloromethane as an eluent to afford 14c (19 mmol, 37.8%).
Scheme 6:
Figure imgf000054_0001
Step-1: To a stirred solution of but-2-enoic acid (25, 116.0 mmol) in benzene (150 mL) was added N-Bromo succinamide (31.4 g, 120.0 mmol) followed by Benzoyl peroxide (0.200 g, 1.4 mmol) at 23 °C. The reaction mixture was heated to reflux for 4 h, which resulted in precipitation of succinamide crystals. The crystals were filtered off and the filtrate was concentrated. The crude was recrystallized with minimum amount of hexane and washed with hexane to afford 4-bromobut-2-enoic acid (26, 42.5 mmol, 37 %) as a white solid.
Step-2: bromobut-2-enoic acid (26, 9 mmol) was taken in dichloromethane (30 mL) and cooled to 0 °C. To this solution oxalyl chloride (1.6 mL, 18 mmol), DMF (0.1 mL) were added and stirred for 0.5 h at 23 °C. The reaction mixture was concentrated under nitrogen atmosphere, residue was diluted with THF (30 mL), cooled to 0 °C and was basified with DIPEA (3.1 mL, 18 mmol). To this mixture, an amine (27, 9 mmol) was added slowly as a solution in dichloromethane and the contents were stirred at 23 °C for lh. The volatiles were removed by concentration under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated. The crude material was purified by column chromatography over 230-400 mesh silica gel using 3-7% ethyl acetate in hexane to afford the desired amide (7, 0.85 mmol, 9.4%) as a brown colour liquid.
Example 1: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en- 1- yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of4,4'-( 2-phenylbut-l-ene-l,l-diyl)diphenol
Figure imgf000055_0001
To a suspension of zinc dust (36.6 g, 560 mmol) in dry THF (200 mL) at -10 °C was added TiCl4 (50.4 g, 266 mmol) under nitrogen atmosphere. The contents were stirred there for 15 min, slowly allowed to warm to room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C and a solution of bis(4-hydroxyphenyl)methanone (10 g, 46.7 mmol) and propiophenone (18.7 g, 140 mmol) in dry THF (20 mL) was added and the resulting mixture was heated at reflux for 2.5 h. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (500 mL x 3), the combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified over 230-400 mesh silica gel column
chromatography using (3:7) ethyl acetate in rc-hexane to afford 4,4'-(2-phenylbut-l-ene-l,l- diyl)diphenol (12.6 g, 85%) as a brown colour solid.
Step-2: Synthesis of2-(4-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy) acetamide
Figure imgf000055_0002
To a stirred solution of 4,4'-(2-phenylbut-l-ene-l,l-diyl)diphenol (10 g, 31.6 mmol) in acetone (100 mL) was added K2C03 (13.0 g, 94.8 mmol) at room temperature and the contents were heated at 80 °C for 15 min. To this mixture, a solution of 2-iodoacetamide (6.6 g, 34.8 mmol) in 50 mL of acetone was added slowly over a period of 3 h at 80 °C and the contents were stirred for 1 h at 80 °C. The reaction mixture was diluted with cold water (100 mL), extracted with ethyl acetate, organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2SC¼ and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using (7:3) ethyl acetate in n-hexane an eluent to afford 2-(4-(l-(4-hydroxyphenyl)-2- phenylbut-1- en-l-yl)phenoxy)acetamide (4.8 g, 40%) as a gummy solid.
Step-3: Synthesis of 4-( l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol
Figure imgf000056_0001
To a suspension of LiAlH4 (6.18 g, 163 mmol) in dry THF (200 mL) at 0 °C was added A1C13 (6.27 g, 47 mmol) portion wise under nitrogen atmosphere. The contents were stirred for 15 min at room temperature, reaction mixture was re-cooled to 0 °C, and a solution of 2-(4-(l- (4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)- acetamide (4 g, 10 mmol) in 100 mL of dry THF was added. The reaction mixture was stirred for 5 h at room temperature, after completion of reaction, reaction mixture was quenched with saturated Na2S04 solution, filtered through sodium sulphate bed and washed with ethyl acetate. The combined organic layers were washed with water, saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under vacuum. The crude compound was purified by column chromatography over 100-200 mesh silica gel using (1 :9) methanol in dichloromethane as an eluent to afford 4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (2.45 g, 63%) as a brown colour solid.
Step-4: Synthesis of ( E)-4-bromo-N,N-dimethylbut-2-enamide
Figure imgf000056_0002
Step-4.1: Synthesis of (E)-4-bromobut-2-enoic acid
Figure imgf000056_0003
To a stirred solution of (E)-but-2-enoic acid (10.0 g, 116.0 mmol) in benzene (150 mL) was added N-Bromosuccinamide (31.4 g, 120.0 mmol) followed by Benzoyl peroxide (0.200 g, 1.4 mmol) at 23 °C. The reaction mixture was heated to reflux for 4 h, which resulted in precipitation of succinamide crystals. The crystals were filtered off and the filtrate was concentrated. The crude was recrystallized with minimum amount of hexane and washed with hexane to afford (E)-4-bromobut-2-enoic acid (6.97 g, 37 %) as a white solid.
Step-4.2: Synthesis of ( E)-4-bromo-N,N-dimethylbut-2-enamide
Figure imgf000057_0001
(E)-4-bromobut-2-enoic acid (2 g, 12.2 mmol) was taken in dichloromethane (20 mL) and at 0 °C were added HATU (5.5 g, 14 mmol), triethyl amine (2.56 mL,18.4 mmol) and stirred for 10 min at RT. To this mixture N,N-dimethyl amine (9.2 mL, 18 mmol) was added slowly and the contents were stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated. The crude material was purified by column chromatography over 100-200 silica gel using 20% ethyl acetate in rc-hexane to afford (E)-4-bromo-7V,N-dimethylbut-2-enamide (0.4 g, 17 %) as a pale green colour liquid. MS (ESI) 192 [M+H]+
Step-5: Synthesis of ( E)-4-( (2-(4-( (Z)-l-( 4-hydroxyphenyl)-2-phenylbut-l-en-l - yl)phenoxy)ethyl)amino)-N,N-dimethylb t-2-enamide (Example 1 )
Figure imgf000057_0002
Example 1
A solution of 4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (200 mg, 0.56 mmol) and 4-bromo-but-2-enoic acid dimethylamide (110 mg, 0.56 mmol) in DMF (5 mL) was added DIEA (85 mg, 0.67 mmol). The resulting mixture was stirred at room temperature for 0.5 hours. LC-MS showed that the reaction was completed. Concentration and the residue was purified by Prep-HPLC to give a mixture of cis and trans isomers (21 mg, yield: 9%). The sample was combined with last batch and further separated by SFC to afford (£ -4-((2- (4-((Z)- 1 -(4-hydroxyphenyl)-2- phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N- dimethylbut-2-enamide (5.1 mg)
Example 1: 1H-NMR (400 MHz, MeOH-d4) δ 7.16-7.01 (m, 7H), 6.80-6.64 (m, 5H), 6.61- 6.58 (m, 3H), 3.99 (t, 2H), 3.50 (t, 2H), 3.11 (s, 3H), 2.99-2.94 (m, 5H), 2.50 (q, 2H), 0.92 (t, 3H); MS (ESI) 471 [M+H]+. Example 2: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy) ethyl)( methyl)amino )-N-methyl-N-( 6, 6, 7, 7, 7-pentafluoroheptyl) but-2- enamide
Step-1: Synthesis of 4-(Benzyloxyphenyl) (4-hydroxyphenyl) methanone
Figure imgf000058_0001
To a solution of bis (4-hydroxyphenyl)methanone (50 g, 234 mmol) in DMF (500 mL), were added potassium carbonate (35 g, 252 mmol) and benzyl bromide (43 g, 255 mmol) sequentially at 0 °C. The resulting mixture was heated at 60 °C for 24 h and the completion of the reaction monitored by TLC. The reaction mixture was cooled to room temperature, quenched by adding crushed ice (100 g) and stirred for 10 min. The precipitated solid was filtered, washed with ice cold water and dried under vacuum to afford 4- (benzyloxy)phenyl)(4-hydroxyphenyl) methanone (18 g, 25 %) as an off-white solid.
Step-2: Synthesis of 4-( l-(4-(benzyloxy)phenyl)-2-phenylbut-l -en-l-yl)phenol
Figure imgf000058_0002
The same procedure as described in Scheme 2, Step-1, to afford 4-(l-(4-(benzyloxy) phenyl)- 2-phenylbut-l-en-l-yl)phenol (20 g, 83 %) as a colorless solid.
Step-3: Synthesis of 1 -(Benzyloxy)-4-( 1 -(4-(2-chloroethoxy)phenyl)-2-phenylbut- 1-en-l- yl)benzene
Figure imgf000058_0003
To a solution of 4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (7 g, 17 mmol) in acetonitrile (140 mL) was added potassium carbonate (7.1 g, 51 mmol) and l-bromo-2- chloroethane (2.9 mL, 34 mmol). The reaction mixture was heated to 80 °C and maintained at this temperature for 24 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using (5:95) ethyl acetate in n-hexane to afford l-(benzyloxy)-4-(l-(4-(2- chloroethoxy)phenyl)-2- phenylbut-l-en-l-yl)benzene (4.2 g, 52.5%) as a colourless gum.
Step-4: Synthesis of2-(4-(l-(4-(benzyloxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy) -N- methylethan-1 -amine
Figure imgf000059_0001
To a suspension of l-(benzyloxy)-4-(l-(4-(2-chloroethoxyphenyl)-2-phenylbut-l-en- 1- yl)benzene (4.2 g, 8 mmol) in methanol (100 mL) was added 40 % aq. methyl amine (150 mL). The reaction mixture was heated at 80 °C for 16 h in a sealed tube, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(4-(l-(4- (benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy)-N-methylethan-l -amine (3.6 g, 87.8 %) as a pale yellow gummy mass.
Step-5: Synthesis of '4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l- yl)phenol
Figure imgf000059_0002
To a stirred solution of 2-(4-(l-(4-(benzyloxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy) -N- methylethan-1 -amine (0.6 g, 1.29 mmol) in dichloromethane (36 mL) was added BBr3 (1M solution in DCM, 2.6 mL, 2.59 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-(l-(4-(2-(methylamino) ethyl) phenyl)-2-phenylbut-l-en-l-yl)phenol (0.44 g, 91 %) as a gummy mass.
Step-6: Synthesis of (E)-4-bromo-N-methyl-N-(6,6, 7, 7, 7-pentafluoroheptyl)but-2- enamide
Figure imgf000060_0001
Step-6.1: Synthesis of 4,4,5,5,5-pentafluoropentyl methanesulfonate
Figure imgf000060_0002
To a stirred solution of 4,4,5,5,5-pentafluoropentan-l-ol (7.5 g, 42.13 mmol) in
dichloromethane (100 mL) at 0 °C was added triethylamine (7.1 mL, 50.56 mmol) and methane sulfonyl chloride (3.53 mL, 46.34 mmol). The reaction mixture was stirred for 1 h at RT and diluted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford 4,4,5,5,5- pentafluoropentyl methanesulfonate (6.0 g, 56%) as a brown colour liquid.
Step-6.2: Synthesis of 1,1,1, 2,2-pentafluoro-5-iodopentane
Figure imgf000060_0003
Sodiumiodide (9.7 g, 64.45 mmol) was added to a solution of 4,4,5,5,5- pentafluoropentyl methanesulfonate (6.0 g, 23.43 mmol) in acetone (100 mL) and the contents were heated under reflux for 12 h. After completion of reaction, the reaction mixture was filtered and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and was washed with water, brine solution and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give l,l,l,2,2-pentafluoro-5-iodopentane (4.8 g,
71.6%).
Step-6.3: Synthesis of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate
Figure imgf000060_0004
Sodium hydride (1.07 g, 29.9 mmol) was taken in anhydrous THF (50 mL) and at 0 °C, diethylmalonate (4.8 mL, 33.3 mmol) was added dropwise and the contents were stiixed for 1 h at room temperature. l,l,l,2,2-pentafluoro-5-iodopentane (4.8 g, 16.6 mmol) dissolved in anhydrous THF was then added drop wise to this reaction mixture and the reaction was continued for 12 h at room temperature. Water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by 230-400 mesh silica gel column
chromatography and elution with ethyl acetate/n-hexane, 1 :40 gave the desired Diethyl 2- (4,4,5,5,5-pentafluoropentyl) malonate (5.0 g, 90 %).
Step-6.4: Synthesis of 6,6, 7 ,7 , 7-penta luoroheptan-l-ol
Figure imgf000061_0001
A solution of potassium hydroxide (18.2 g, 325.0 mmol), in water (25 mL) was added to a solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (5.0 g, 16.25 mmol) and the contents were stirred at 60 °C for 16 h. The reaction mixture was adjusted to pH 5 by slowly adding IN HC1 drop wise, and then extracted with ethyl acetate. The combined organics were washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dimethylsulphoxide (20 mL), and stirred at 170 °C for 18 h. Water was added to the reaction mixture and was then extracted three times with ethyl acetate. The combined organic layers were washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (20 mL), cooled to -30 °C and borane-methyl sulphide complex (0.96 g, 9.69 mmol) was added drop wise and the contents were stiixed for 3 h at room temperature. The reaction was quenched with methanol, water was added to the reaction mixture and was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine solution and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was purified over 230-400 mesh silica gel column chromatography. Elution of the column with (1:20) ethyl acetate/n-hexane as an eluent afforded 6,6,7 ,7,7-pentafluoroheptan-l-ol (1.1 g, 78% over 2 steps). Step-6.5: Synthesis of 6, 6, 7, 7, 7-pentafluoroheptylmethanesulfonate
Figure imgf000062_0001
To a stirred solution of of 6,6,7,7,7-pentafluoroheptan-l-ol (1.1 g, 5.04 mmol) in
dichloromethane (20 mL) at 0 °C was added triethylamine (1.06 mL, 7.50 mmol) and methane sulfonyl chloride (0.53 mL, 5.54 mmol). The reaction mixture was stirred for 1 h at RT and diluted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous Na2S04 and concentrated to afford 6,6,7 ,7,7-pentafluoroheptyl
methanesulfonate (1.2 g, 83.9%) as a brown colour liquid.
Step-6.6: Synthesis of 6, 6, 7, 7, 7-pentafluoro-N-methylheptan-l -amine
Figure imgf000062_0002
A solution of 6,6,7,7 ,7-pentafluoroheptyl methanesulfonate (0.23 g, 0.80 mmol) in ethanol (10 mL) was added aqueous 40% methylamine (5 mL). The contents were heated at 60 °C under nitrogen for 2 h. After completion of reaction, reaction mixture was cooled to room temperature, the volatiles removed under vacuum and extracted with dichloromethane (30 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulphate to give 6,6,7,7,7-pentafluoro-N-methylheptan-l- amine, organic layer was directly used for next step.
Step-6.7: Synthesis of ( E)-4-bromo-N-methyl-N-( 6, 6, 7, 7, 7-pentafluoroheptyl)but-2- enamide
1) (COC1)2/DMF/DCM/0 "C-RT/l h
Figure imgf000062_0003
2) DIPEA/THF/ 0 "C-RT/1 h
To a solution of (E)-4-bromobut-2-enoic acid (0.180 g, 1.08 mmol, Example 1, Step-4.1) in dichloromethane (10 mL) at 0 °C were added oxalyl chloride (0.188 mL, 2.18 mmol) and DMF (0.1 mL) and the contents were stirred for 0.5 h at RT. The reaction mixture was concentrated under nitrogen atmosphere, residue was diluted with dichloromethane (10 mL) and was added to a mixture of 6,6,7,7,7-Pentafluoro- N-methylheptan-1- amine (0.17 g, 0.776 mmol) and DIPEA (0.74 mL, 2.18 mmol) in dichloromethane. The reaction mixture was stirred at 0 °C, for 30 min and was diluted with water and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified over 230-400 mesh silica gel column chromatography using ethyl acetate//?-hexane (1:20) to give (E)-4-bromo-N-methyl-N-(6,6,7,7,7-pentafluoroheptyl)but-2-enamide (0.14 g, 52 %).
Step-7: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en- 1- yl)phenoxy)ethyl) ( ?†iethyl)amino)-N-methyl-N-( 6, 6, 7, 7, 7-pentafluoroheptyl)b t-2-enamide (Example 2).
Figure imgf000063_0001
To a stirred solution of 4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut- 1-en-l- yl)phenol (0.240 g, 0.6434 mmol) in DMF (5 mL) at room temperature were added (E)-4- bromo-N-methyl-N-(6,6,7,7,7-pentafluoroheptyl)but-2-enamide (0.235 g, 0.6438 mmol) and DIPEA (0.332 mL, 1.930 mmol) at RT. The reaction mixture was stirred for 1 h at room temperature and was diluted with dichloromethane (50 mL), washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude was purified by column chromatography over 230-400 mesh silica gel, using (2:98) methanol in DCM to afford EfZ mixture of products, which was further purified by chiral HPLC to give pure isomer (E)-4- ((2-(4-((Z)-l- (4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)(methyl)amino)-N- methyl-N-(6,6,7,7,7-pentafluoroheptyl)but-2-enamide (0.200 g, 42%) as a gummy solid.
Example 2: 1H NMR (400 MHz, DMSO-< 6) δ 9.42 (s, 1H), 7.18-7.06 (m, 5H), 6.96 (d, J = 8.4 Hz, 2H), 6.74-6.68 (m, 4H), 6.57-6.52 (m, 4H), 3.90 (t, / = 4.8 Hz, 2H), 3.30 (s, 2H), 3.15 (d, J = 4.8 Hz, 2H), 2.96 (s, 1H), 2.82 (s, 2H), 2.66-2.61 (m, 2H), 2.39 (q, J = 7.3 Hz, 2H), 2.19 (s, 5H), 1.51-1.47 (m, 4H), 1.31-1.22 (m, 2H), 0.83 (t, 7 = 7.2 Hz, 3H). ES (MS) 659.3 [M+H]+. Example 3: Synthesis of(E)-N-heptyl-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2- phenylbut-1- en-l-yl)phenoxy) ethyl)(methyl)amino)-N-tnethylbut-2-enamide
Step-1: Synthesis of ( E)-4-bromo-N-heptyl-N-methylbut-2-enamide
Figure imgf000064_0001
2) DIPEA THF/ 0 °C-RT/1 h
The reaction was carried out according to Scheme 6, Step-2, using (E)-4-bromobut-2-enoic acid (Example 1, Step-4.1) and N-methylheptan-1 -amine, to give (E)-4-bromo-N-heptyl-N- methylbut-2-enamide (0.55 g, 43%).
Step-2 : Synthesis of ( E)-N-heptyl-4-( (2-(4-((Z)-l-( 4-hydroxyphenyl)-2-phenylbut-l- en-1 -yl ) phenoxy)ethyl) (methyl)amino)-N-methylbut-2-enamide (Example 3).
Figure imgf000064_0002
The reaction was carried out according to Scheme 2, Step-5, using (E)-4-bromobut-2-enoic acid (Example 1, Step-4.1), to give a crude product, which was purified by preparative HPLC to afford E/Z mixture, which was then purified by chiral HPLC to give a pure isomer of (E)-N-heptyl-4-((2-(4- ((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)(methyl)amino)-N-methylbut-2-enamide (0.09 g, 30 %) as a light brown colour sticky solid.
Example 3: Ή NMR (400 MHz, DMSO-<¾) δ 9.40 (s, 1H), 7.18-7.07 (m, 5H), 6.97 (d, / = 8.0 Hz, 2H), 6.74 (d, / = 8.4 Hz, 2H), 6.69 (d, / = 8.8 Hz, 2H), 6.58-6.53 (m, 4H), 3.90 (t, / = 5.0 Hz, 2H), 3.16 (d, J = 4.8 Hz, 2H), 2.95 (s, 1H), 2.90 (d, / = 7.2 Hz, 1H), 2.82 (s, 2H), 2.67-2.62 (m, 1H), 2.43-2.39 (m, 2H), 2.20 (s, 3H), 1.45-1.43 (m, 2H), 1.23-1.13 (m, 10H), 0.86-0.80 (m, 6H). ES (MS) 568.4 [M+H]+ .
Example 4: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l- en-1- yl)phenoxy ) ethyl) ( methyl)amino )-N-methyl-N-(3, 3, 4, 4, 4-pentafluorobutyl)but-2-enamide Step-1: Synthesis of(E)-4-bromo-N-methyl-N-(3,3,4,4,4-pentafluorobutyl)but-2- enamide
Figure imgf000065_0001
Step-1.1 : Synthesis of 3, 3, 4, 4, 4-pentafluoro-N-methylbutan- 1 -amine
Figure imgf000065_0002
To a stirred solution of l,l,l,2,2-pentafluoro-4-iodobutane (5 g,18 mmol) in THF (25 mL) at -78 °C was added methyl amine (2M in THF, 18mL, 36 mmol). The reaction mixture was slowly allowed to attain room temperature and stirred for 16 h at RT. The reaction mixture was diluted with dichloromethane (70 mL), washed with water (50 mL X 3) and dried over sodium sulphate and filtered. The resulting solution was directly used for next reaction (Note: Here the DCM solution of compound should be stored below 8 °C).
Step-1.2: Synthesis of4-bromo-N-methyl-N-(3,3,4,4,4-pentafluorobutyl)but-2- enamide l. (COCl)2 / DMF /
Figure imgf000065_0003
DIPEA / THF
0 °C - RT / lh
The reaction was carried out according Scheme 6, Step-2, using (E)-4-bromobut-2-enoic acid (Example 1, Step-4.1) to afford 4-bromo-N-methyl- N-(3,3,4,4,4-pentafluorobutyl)but-2- enamide (0.26 g, 9.4%) as a brown colour liquid.
Step-2: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydwxyphenyl)-2-phenylbut-l- en-1- yl)phenoxy)ethyl) (methyl)amino)-N-methyl-N-(3,3,4,4,4-pentafluorobutyl)but-2-enamide (Example 4)
Figure imgf000065_0004
Example 4
The same procedure as described in Scheme 2, Step-5, using 4-(l-(4-(2- (methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (Example 2, Step-5), to give a mixture, which was separated by chiral HPLC to give a pure isomer (0.13 g, 26.3%) as a light brown colour sticky solid.
Example 4: Ή NMR (400 MHz, DMSO-i 6) δ 9.39 (s, IH), 9.14 (s, IH), 7.16 (d, J = 6.8 Hz, 4H), 7.08 (d, 7 = 8.8 Hz, 8H), 6.98-6.91 (m, 4H), 6.75-6.63 (m, 4H), 6.60-6.55 (m, 8H), 6.39 (d, / = 8.4 Hz, 2H), 4.07 (s, 2H), 3.91 (s, 2H), 3.70-3.56 (m, 4H), 3.24 (d, J = 5.2 Hz, 2H), 3.17 (d, / = 5.2 Hz, 2H), 3.05 (d, 7 = 9.2 Hz, 4H), 2.97 (d, / = 5.6 Hz, 2H), 2.74 (s, 2H), 2.65 (d, 7 = 8.8 Hz, 4H), 2.43-2.33 (m, 6H), 2.27-2.20 (s, 6H), 0.84 (t, 7 = 7.2 Hz, 6H). ES (MS) 617 [M+H]+.
Example 5: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl) (methyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000066_0001
The same procedure as described in Scheme 2, Step-5, using 4-(l-(4-(2- (methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (Example 2, Step-5) and (E)-4- bromo-NN-dimethylbut-2-enamide (Example 1, Step-4.2), to give (2£)-4-((2-(4-(l-(4- hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)-ethyl)(methyl)- amino)-N,N-dimethylbut- 2-enamide (0.15 g, 28.3 %).
Example 5: 1H NMR (400 MHz, DMSO- ) δ 9.40 (s, IH), 9.14 (s, IH), 7.19-7.07 (m, 12H), 6.98-6.91 (m, 4H), 6.69-6.60 (m, 4H), 6.59-6.55 (m, 8H), 6.39 (d, / = 8.0 Hz, 2H), 4.07 (t, 7 = 5.6 Hz, 2H), 3.91 (t, 7 = 5.6 Hz, 2H), 3.23-3.15 (m, 4H), 3.02 (s, 3H), 2.99 (s, 3H), 2.86- 2.81 (m, 6H), 2.73 (t, 7 = 5.6 Hz, 2H), 2.63 (t, 7 = 5.6 Hz, 2H), 2.43-2.36 (m, 4H), 2.27-2.20 (bs, 6H), 0.84 (t, 7 = 7.2 Hz, 6H). ES (MS) 485 [M+H]+.
Example 6: Synthesis of(E)-5-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl) amino)-N,N-dimethylpent-2-enamide Step-1: Synthesis of ( E)-5-( dimethylamino)-5-oxopent-3-en-l-yl
Figure imgf000067_0001
Step-1.1: Synthesis of3-( ( tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol
Figure imgf000067_0002
45 oC/3 h
To a stirred solution of 1,3-propanediol (88 g, 1190 mmol) and dihydropyran (20 g, 238 mmol) in dichloromethane (200 mL) was added PPTS (100 mg) at 0 °C, mixture was stirred at room temperature for 3 h. After completion of reaction, reaction mixture was diluted with cold water (250 mL) and extracted with dichloromethane (500 mL), organic layer was washed with water, saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude material was used in next step without further purification (20 g, crude).
Step-1.2: Synthesis of 3-( ( tetrahydro-2H-pyran-2-yl)oxy)propanal
Figure imgf000067_0003
To a stirred solution of 3-((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol (20 g, 125 mmol) in dichloromethane (200 mL), PCC (40 g, 187.5 mmol), K2C03 (8.6 g, 62.5 mmol) and celite (10 g) were added at 0 °C, mixture was stirred at room temperature for 1 h. After completion of reaction, reaction mixture was filtered through celite, filterate was diluted with cold water (250 mL) and extracted with dichloromethane (500 mL), organic layer was washed with saturated NaCl solution and dried over anhydrous Na2S04, concentrated under reduced pressure. The crude material was used in next step without further purification (9 g, crude).
Step-1.3: Synthesis of ethyl (E)-5-((tetrahydro-2H-pyran-2-yl)oxy)pen t-2-enoate
Figure imgf000067_0004
To a stirred solution of 3-((tetrahydro-2H-pyran-2-yl)oxy)propanal (4.5 g, 28.6 mmol) in dichloromethane (100 mL), ethyl-2-(triphenyl-15-phosphanylidene)acetate (9.9 g, 28.6 mmol) was added. Reaction mixture was stirred at room temperature for 12 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica using (5:95) ethyl acetate in n- hexane as an eluent to afford title compound (4.6 g, 70%).
Step-1.4: Synthesis of (E)-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-2-enoic acid
Figure imgf000068_0001
To a solution of ethyl (E)-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-2-enoate (4.6 g, 20.8 mmol) in THF/H20 (75:25) (45 mL) at 0 °C, was added LiOH H20 (4.2 g, 100 mmol). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was concentrated under reduced pressure. Crude compound was diluted with water, acidified with acetic acid then extracted with ethyl acetate. Organic layer was washed with saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford desired compound, which was used in next step without further purification (4 g crude).
Step-1.5: Synthesis of (E)-N,N-dimethyl-5-( ( tetrahydro-2H-pyran-2-yl)oxy)pent-2- enamide
Figure imgf000068_0002
To a solution of (E)-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-2-enoic acid (4 g, 20 mmol) in dichloromethane (50 mL) at 0 °C were added NMP (2.4 mL, 22 mmol) followed by isobutyl chloroformate (2.86 mL, 22 mmol) and the contents were stirred for 1 h at 0 °C. To the above mixture dimethyl amine (25 mL, 50 mmol) was added at 0 °C, reaction mixture was stirred at RT for 16 h. After completion of reaction, diluted with water and extracted with
dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified over 230-400 mesh silica gel column chromatography using ethyl acetate in n- hexane (1: 1) to give title compound (1.7 g, 37 %).
Step-1.6: Synthesis of (E)-5-hydroxy-N,N-dimethylpent-2-enamide
Figure imgf000069_0001
To a stirred solution of (E)-N,N-dimethyl-5-((tetrahydro-2H-pyran-2-yl)oxy) pent-2-enamide (1.7 g, 7.48 mmol) in ethanol (50 mL) was added at 0 °C, PPTS (281 mg, 1.123 mmol). The reaction mixture was stilted for 2 h at RT. After completion of reaction, diluted with water and extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was used in next step without further purification (0.9 g, 84%).
Step-1.7: Synthesis of ( E)-5-( dimethylamino )-5-oxopent-3-en-l-yl methanesulfonate
Figure imgf000069_0002
To a stirred solution of (£ -5-hydroxy-N,N-dimethylpent-2-enamide (0.9 g, 6.29 mmol) in dichloromethane (20 mL) at 0 °C was added triethyl amine (1.06 mL, 7.54 mmol) and methanesulfonyl chloride (0.53 mL, 6.99 mmol). The reaction mixture was stirred for 1 h at room temperature and diluted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford (E)-5-(dimethylamino)-5-oxopent-3-en-l-yl methanesulfonate (0.9 g, 79%).
Step-2: Synthesis of (E)-5-( (2-(4-((Z)-l-( 4-hydroxyphenyl)-2-phenylbut-l-en-l - yl)phenoxy)ethyl)amino)-N,N-dimethylpent-2-enamide (Example 6)
Figure imgf000069_0003
A solution of (E)-5-(dimethylamino)-5-oxopent-3-en-l-yl methanesulfonate (0.9 g, 4.07 mmol) in DMF (15 mL) was added DIPEA (1.45 mL). To the above mixture 4-(l-(4-(2- aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (1.46 g, 4.07 mmol, Example 1, Step-3) was added. The contents were stirred at 23 °C under nitrogen for 72 h. After completion of reaction, reaction mixture was extracted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulphate to give crude (E)-5-((2-(4-((Z)-l-(4- hydroxyphenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-7V,N-dimethylpent-2-enamide, which was purified by preparative HPLC (12 mg, 0.6%).
Example 6: 1H NMR (400 MHz, DMSO-</6): δ 9.40 (s, 1H), 7.20-6.97 (m, 7H), 6.76-6.56 (m, 7H), 6.40 (d, / = 8.0 Hz, 1H), 3.85 (t, / = 5.6 Hz, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.79 (t, / = 5.6 Hz, 2H), 2.65 (t, / = 5.6 Hz, 2H), 2.40 (t, / = 5.6 Hz, 2H), 2.33 (t, J = 5.6 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H). ES (MS): 485 [M+H]+.
Example-7: Synthesis of(E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l- en-1- yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis oftert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate
Figure imgf000070_0001
Step-1.1: Synthesis of but-l-yn-l-yltrimethylsilane:
Figure imgf000070_0002
To a stirred solution of (trimethylsilyl)acetylene (116 g, 1.19 mol) in dry THF (400 mL) was added rc-BuLi (2.5M in THF, 500 mL) at -78 °C over 2 h. The resulting mixture was warmed to 0 °C for 10 min. The reaction mixture was again cooled to -78 °C, HMPA (234 g, 1.13 mol) was added to the above mixture and stirred at -78 °C for 30 min. To the above reaction mixture iodoethane (200 g, 1.28 mol) was added and the resulting mixture was stirred at room temperature for 16 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (1000 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product but-l-yn-l-yltrimethylsilane was distilled between 125-135 °C to afford the desired product (91 g, 61 %) as a colourless liquid.
Step- 1.2: Synthesis oftert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate
Figure imgf000070_0003
To a stirred solution of tert-butyl (5-bromopyridin-2-yl)carbamate (3 g, 10.989 mmol) in 30 mL of MeOH:DMA:H20 (1:1: 1) in a sealed tube, were added copper iodide (0.235 g, 1.098 mmol) and cesium carbonate (4.849 g, 15.3 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (2.76 g, 22 mmol) followed by Pd(PPh3)2Cl2 (0.384 g, 0.5 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 X 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude product was purified over 230-400 mesh silica column chromatography using 5% EtOAc in n-hexane to afford tert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate (2.5 g, 88%) as a white solid.
Step-2: Synthesis oftert-butyl (E)-(5-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)pyridin-2- yl)carbamate
Figure imgf000071_0001
To a solution of tert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate (1.5 g, 6.09 mmol), iodobenzene (3.73 g, 18.29 mmol), 4-hydroxyphenyl boronic acid (2.52 g, 18.29 mmol), in N,N-dimethyl formamide/water (2: 1, 15 mL) was added K2C03 (2.52 g, 18.29 mmol). The contents were degassed with three vacuum/N2 cycles, and then stirred for 1 h until the solution was homogeneous. A solution of Pd(PhCN)2Cl2 (0.022 g, 0.0609 mmol) in N,N- dimethyl formamide (1 mL) was added and the resulting mixture was stirred at 45 °C for 12 h. Upon completion by TLC, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude material was purified over 230-400 mesh silica column chromatography using 20% ethyl acetate in n-hexane to afford tert-butyl (E)-(5-( 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)pyridin-2-yl)carbamate (1.2 g, 47%) as an off-white solid.
Step-3: Synthesis oftert-butyl (E)-(5-(l-(4-(2-( l,3-dioxoisoindolin-2-yl)ethoxy)- phenyl)-2- phenylbut-1 -en-1 -yl)pyridin-2-yl)carbatnate
Figure imgf000072_0001
To a solution of (E)-(5-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin-2- yl)carbamate (0.5 g, 1.2 mmol) in DMF (12 mL), at 0 °C, were added sequentially potassium carbonate (0.663 g, 4.8 mmol) and 2-(2-bromoethyl)isoindoline-l,3-dione (1.52 g, 6 mmol). The reaction mixture was stirred at 80 °C for 12 h, was diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 20% ethyl acetate in n-hexane to afford tert-butyl (E)-(5-(l-(4-(2-(l,3-dioxoisoindolin-2- yl)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)-py- ridin-2-yl)carbamate (0.35 g, 50%) as a light brown colour gummy mass.
Step-4: Synthesis of tert-butyl (E)-(5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut- 1-en-l- yl )pyridin-2 -yl )carbamate
Figure imgf000072_0002
To a solution of (E)-(5-(l-(4-(2-(l,3-dioxoisoindolin-2-yl)ethoxy)phenyl)-2- phenylbut-l-en- l-yl)pyridin-2-yl)carbamate (0.5 g, 0.8488 mmol) in MeOH/DCM (2:1, 15 mL) was added hydrazine hydrate (10 mL) at room temperature. The reaction mixture was stirred at 70 °C for 2 h, quenched with NH4OH and extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 100-200 mesh silica gel using 10% methanol in DCM to afford tert-butyl (E)-(5-(l-(4-(2- aminoethoxy)phenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)carbamate (0.12 g, 30%) as an off- white solid.
Step-5: Synthesis of tert-butyl (5-((E)-l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2- en-1- yl)amino ) ethoxy )phenyl)-2-phenylbut-l -en-1 -yl )pyridin-2-yl )carbamate
Figure imgf000072_0003
To a stirred solution of tert-butyl (E)-(5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut- 1-en-l- yl)pyridin-2-yl)carbamate (0.120 g, 0.261 mmol) in DMF (10 mL) was added at 0 °C, (E)-4- bromo-N,N-dimethylbut-2-enamide (0.05 g, 0.261 mmol, Example 1, Step-4.2) and DIPEA (0.068 g, 0.522 mmol). The reaction mixture was stirred for 12 h at 23 °C, after completion of reaction, reaction mixture was diluted with cold water (50 mL) and extracted with
dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 100-200 mesh silica gel using 5% methanol in DCM to afford tert-butyl (5-((E)-l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2-en-l- yl)amino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.05 g, 33%) as an off-white solid.
Step-6: Synthesis of(E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide (Example 7)
Figure imgf000073_0001
To a stirred solution of tert-butyl (5-(l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2-en- 1- yl)amino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.1 g, 0.176 mmol) in ethanol (5 mL) was added at 0 °C, 2M HC1 in ether (10 mL). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with sat.NaHC03, extracted with 10% MeOH in DCM. Organic layer was
concentrated under reduced pressure and the crude material was purified by preparative HPLC to afford (£)-4-((2-(4-((E)-l- (6-aminopyridin-3-yl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (37 mg, 45%) as a white solid.
Example 7: Ή NMR (400 MHz, DMSO-<¾): δ 7.78 (d, / = 2 Hz, 1H), 7.19-7.15 (m, 2H), 7.11-7.07 (m, 4H), 6.73 (d, / = 8.8 Hz, 2H), 6.60 (d, / = 8.8 Hz, 2H), 6.57-6.51 (m, 2H), 6.43 (d, / = 8.4 Hz, 1H), 5.95 (s, 2H), 3.89 (d, J = 5.6 Hz, 2H), 3.36 (d, / = 4.8 Hz, 2H), 3.0 (s, 3H), 2.85 (s, 3H), 2.82-2.81 (m, 2H), 2.46-2.42 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). ES (MS): 471.2 [M+H]+. Example-8: Synthesis of (E)-4-((2-(4-((E)-l-(2-fluoro-4-hydroxyphenyl)-2-phenyl but-1- en-l-yl)phenoxy ) ethyl)amino )-N,N-dimethylbut-2-enamide
Step-1: Synthesis of 4-(benzyloxy)-l-bromo-2-fluorobenzene
Figure imgf000074_0001
To a solution of 4-bromo-3-fluorophenol (3 g, 15.7 mmol) in DMF (15 mL), were added potassium carbonate (4.3 g, 31.41 mmol) and benzyl bromide (3.2 g, 18.8 mmol) sequentially at room temperature. The resulting mixture was heated at 70 °C for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04) concentrated under reduced pressure. The crude compound was purified over 230- 400 mesh silica gel column chromatography using 10% EtOAc in n-hexane to afford 4- (benzyloxy)-l- bromo-2-fluorobenzene (4 g, 90%) as brown colour oil.
Step-2: Synthesis of 4-(benzyloxy )-l-(but-l-yn-l -yl )-2-fluorobenzene
Figure imgf000074_0002
sealed tube/90 "C/12 h
The reaction was carried out according to Scheme 3, Step-1, using but-l-yn-1- yltrimethylsilane (Example 7, Step-1.1) to afford 4-(benzyloxy)-l- (but-l-yn-l-yl)-2 fluorobenzene (6.5 g, 94%) as brown oil.
Step-3: Synthesis of tert -butyl (2-(4-iodophenoxy)ethyl)carba ate
Figure imgf000074_0003
To a stirred solution of 4-iodophenol (50 g, 0.227 mol) in DMF (750 mL) was added potassium carbonate (188 g, 1.363 mol) and stirred for 30 min at room temperature, to the above mixture tert-butyl (2-bromoethyl)carbamate (71.27 g, 0.318 mol) was added. The contents were stirred at 70 °C for 12 h. After completion of reaction, reaction mixture was poured onto ice cold water, solid separated was filtered and dried under reduced pressure to obtain desired compound tert-butyl (2-(4- iodophenoxy)ethyl)carbamate as an off-white solid (80 g, 97%).
Step-4: Synthesis of tert-butyl (2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut- 1-eti-l- yl)phenoxy) ethyl )carbamate
Figure imgf000075_0001
To a stirred solution of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-fluorobenzene (3.5 g, 13.78 mmol) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (3.53 g, 13.94 mmol), tetrakis(triphenylphosphine)platinum(0) (130 mg, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 10 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (5 g, 13.78 mmol), bis(triphenylphosphine)palladium (II) dichloride (483 mg, 0.68 mmol), cesium carbonate (8.9 g, 27.55 mmol) and 2-methyl THF (30 mL) were added. This mixture was degassed with nitrogen and water (10 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (10 mL) and iodobenzene (3.9 g, 19.28 mmol) were added. Reaction mixture was stirred at 80 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using EtOAc in n-hexane (2.5:7.5) to afford tert-butyl (2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut- 1 -en- 1- yl)phenoxy)ethyl)carbamate (6.1 g, 81 %) as a white solid.
Step-5: Synthesis of2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut-l-en-l- yl jphenoxy )ethan-l -amine
Figure imgf000075_0002
To a stirred solution of tert-butyl (2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)- 2-phenylbut-l-en- l-yl)phenoxy)ethyl)carbamate (11.5 g, 20.2 mmol) in ethanol (40 mL) was added at 0 °C, 2M HC1 in ether (120 mL). The reaction mixture was stirred for 5 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHCC^ extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (1:9) MeOH in dichloromethane to afford 2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2- phenylbut-1- en- l-yl)phenoxy)ethan-l -amine (9 g, 95%) as a brown colour oil.
Step-6: Synthesis of4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3-fluorophenol
Figure imgf000076_0001
To a stirred solution of 2-(4-(l-(4-(benzyloxy)-2-fluorophenyl)-2-phenylbut-l-en- 1- yl)phenoxy)ethan-l -amine (4.5 g, 9.6 mmol) in dichloromethane (45 mL) was added BBr3 (1M solution in dichloromethane, 48 mL, 48 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-(l-(4-(2-aminoefhoxy)phenyl)-2-phenylbut- l-en-l-yl)-3-fluorophenol (2.2 g, 61%) as a light brown solid.
Step-7: Synthesis of (2E)-4-((2-(4-(l-(2-fluoro-4-hydroxyphenyl)-2-phe?iylbut-l- en-1- yljphenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000076_0002
The reaction was carried out according to Scheme 4, Step-3, using (E)-4-bromo-/V,N- dimethylbut-2-enamide (Example 1, Step-4.2) to give a crude product, which was used in next step without further purification (4.5 g, crude).
Step-8: Synthesis of tert-butyl ((E)-4-(dimethylomino)-4-oxobut-2-en-l-yl)(2-(4-(l- (2-fluoro- 4-hydroxyphenyl)-2-phenylbut-l-en-l -yl )phenoxy )ethyl )carbamate
Figure imgf000076_0003
To a stirred solution of (2E)-4-((2-(4-(l-(2-fluoro-4-hydroxyphenyl)-2-phenylbut- 1-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (4.5 g, 9.2 mmol) in dichloromethane (50 mL) was added boc anhydride (2.4 g, 11 mmol). The reaction mixture was stirred for 5 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using (1:9) MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-(l-(2-fluoro-4- hydroxyphenyl)-2- phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.21 g, 3.8%) as a light brown fluffy solid.
Step-9: Synthesis of (E)-4-((2-(4-((E)-l-(2-fluoro-4-hydroxyphenyl)-2-phenylbut- 1-en-l- yl)phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide (Example 8)
Figure imgf000077_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l- yl)(2-(4- (l-(2- fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.21 g, 3.5 mmol) in EtOH (1 mL) was added at 0 °C, 2M HC1 in diethyl ether (4 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with ethyl acetate. Combined organic layers were dried over anhydrous a2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative TLC to afford desired compound (E)-4-((2-(4-((£)-l-(2-fluoro-4-hydroxy phenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (40 mg, 22.9%) as an off-white solid.
Example 8: Ή NMR (400 MHz, DMSO- 6): δ 9.86 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.14- 7.04 (m, 4H), 6.72 (d, / = 8.8 Hz, 2H), 6.65-6.55 (m, 5H), 6.5 (d, J = 15.2 Hz, 1H), 3.87 (t, / = 5.6 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.77 (t, 7 = 5.6, 2H), 2.5 (m, 2H), 2.3-2.28 (m, 2H), 0.79 (t, J = 7.6 Hz, 3H). LCMS: 489.3 [M+H]+. Example-9: Synthesis of (E)-4-((2-(4-((Z)-l-(4-aminophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (4-bromophenyl)carbamate
Figure imgf000078_0001
To a stirred solution of 4-bromoaniline (10 g, 58 mmol) in toluene (200 mL) was added boc anhydride (12.6 g, 58 mmol). The reaction mixture was stirred for 16 h at 70 °C, after completion of reaction (monitored by TLC), excess of toluene was removed under reduced pressure. Residue was diluted with water (250 mL) solid obtained was filtered and dried under reduced pressure to obtain desired compound (10.2 g, 64%).
Step-2: Synthesis of tert-butyl (4-(but-l -yn-1 -yl)phenyl)carbamate
Figure imgf000078_0002
The same procedure as described in Scheme 3, Step-1, using but-l-yn-l-yltrimethylsilane (Example 7, Step-1.1) to afford tert-butyl (4-(but-l-yn- l-yl)phenyl)carbamate (3.5 g, 77%).
Step-3: Synthesis of tert-butyl (4-( 1 ,2-bis(4,4,5,5-tetramethyl-l ,3 2-dioxaborolan-2- yl)but-l- en-1 -yl )phenyl)carbamate
Figure imgf000078_0003
To a stirred solution of tert-butyl (4-(but-l-yn-l-yl)phenyl)carbamate (3 g, 12 mmol) in 2- methyl THF (30 mL), was added bis(pinacolato)diboron (3.1 g, 12 mmol),
tetrakis(triphenylphosphine)platinum(0) (152 mg, 0.01 mmol) under nitrogen atmosphere, reaction mixture was heated at 90 °C for 5 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 15% EtOAc in n- hexane to afford tert-butyl (4-(l,2-bis(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)but-l-en- l-yl)phenyl)carbamate (3.5 g, 57%).
Step-4: Synthesis of tert-butyl (E)-(4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4- iodophenoxy) ethyl jcarbamate
Figure imgf000079_0001
Step-4.1: Synthesis of 2-(4-iodophenoxy)ethan-l -amine
Figure imgf000079_0002
To a stirred solution of tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (25 g, 68.6 mmol, Example 8, Step-3) in ethanol (50 mL) was added at 0 °C, 2M HC1 in ether (250 mL). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with 10% MeOH in DCM. Organic layer was concentrated under reduced pressure and the crude material was used in next step without further purification (16 g, 88%).
Step-4.2: Synthesis of ( E)-4-( (2-( 4-iodophenoxy)ethyl)amino )-N,N-dimethylbut-2- enamide
Figure imgf000079_0003
To a stirred solution of 2-(4-iodophenoxy)ethan-l -amine (16 g, 60.6 mmol) in DMF (65 mL) was added at 0 °C, (E)-4-bromo-N,N-dimethylbut-2-enamide (8.1 g, 42.4 mmol, Example-1, Step-4.2) and DIPEA (11.72 g, 90.9 mmol). The reaction mixture was stirred for 5 h at room temperature, was diluted with cold water (250 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (18.8 g, crude).
Step-4.3: Synthesis of tert-butyl (E)-(4-(diniethylamino)-4-oxobut-2-en-l-yl)(2-(4- iodophenoxy) ethyl)carbamate
Figure imgf000080_0001
To a stirred solution of (E)-4-((2-(4-iodophenoxy)ethyl)amino)-N,N-dimethylbut- 2-enamide (18.8 g, 50.26 mmol) in dry dichloromethane (150 mL) was added DIPEA (6.4g, 50.2 mmol) at 0 °C, stirred for 15 min at 0 °C. To the above reaction mixture, was added boc anhydride (13.1 g, 60.3 mmol), resulting mixture was stirred at room temperature for 12 h. Upon completion by TLC, the reaction mixture was cooled to 0 °C, quenched with ice cold water (500 mL) and extracted with dichloromethane (500 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The crude material was purified by column
chromatography over 230-400 mesh silica using 3% MeOH in dichloromethane as an eluent to afford tert-butyl (£)-(4-(dimethylamino)- 4-oxobut-2-en-l-yl)(2-(4- iodophenoxy)ethyl)carbamate (9 g, 37.8%).
Step-5: Synthesis of tert-butyl (2-(4-( 1 -(4-((tert-butoxycarbonyl)amino)phenyl)-2- (4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)but-l-en-l-yl)phenoxy)ethyl)((E)-4-(dimethylamm^ oxobut-2-en-l -yl) carbamate
Figure imgf000080_0002
To a stirred solution tert-butyl (4-(l,2-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)but-l- en-l-yl)phenyl)carbamate (2 g, 4 mmol), tert-butyl (E)-(4-(dimethyl amino)-4-oxobut-2-en-l- yl)(2-(4-iodophenoxy)ethyl)carbamate (1.89 g, 4 mmol),
bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.2 mmol), cesium carbonate (2.6 g, 8 mmol) and 2-methyl THF (20 mL) were added, degassed with nitrogen and water (0.2 mL) was added. The reaction mixture was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. The Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (2.8 g, crude).
Step-6: Synthesis of tert-butyl (2-(4-(l-(4-((tert-butoxycarbonyl)amino)phenyl)-2- phenylbut- 1 -en-1 -yl )phenoxy )ethyl )( ( E)-4-( dimethylamino )-4-oxobut-2-en-l-yl )carbamate
Figure imgf000081_0001
To a stirred solution of tert-butyl (2-(4-(l-(4-((tert-butoxycarbonyl)amino)phenyl)- 2- (4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)but- 1-en- 1 -yl)phenoxy)ethyl)((E)-4- (dimethylamino)-4-oxobut-2-en-l-yl)carbamate (2.8 g, 3 mmol) in 2-methyl THF (20 mL), iodobenzene (794 mg, 3 mmol), 4M aqueous KOH (2 mL) and Pd(PPh3)2Cl2 (136 mg, 0.1 mmol) were added and the mixture was degassed with nitrogen for 15 min and heated at 90 °C for 16 h. Upon completion, the reaction mixture was diluted with EtOAc. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2:8 EtOAc in rc-hexane) to give title compound (0.55 g, 21%).
Step-7: Synthesis of(E)-4-((2-(4-((Z)-l-(4-aminophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide ( Example 9)
Figure imgf000081_0002
xamp e
To a stirred solution of tert-butyl (2-(4-(l-(4-((tert-butoxycarbonyl)amino)phenyl)- 2- phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en- 1 -yl)carbamate (0.55 g, 0.82 mmol) in dichloromethane (10 mL) was added at 0 °C, trifluoroacetic acid (2 mL). The reaction mixture was stirred for 16 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired (E)-4-((2-(4-((Z)- 1 -(4-aminophenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.024 g, 3%) as an off-white solid.
Example 9: Ή NMR (400 MHz, OMSO-d6): δ 7.18-7.06 (m, 5H), 6.82 (d, / = 7.6 Hz, 2H), 6.7 (d, J = 8.8 Hz, 2H), 6.63-6.49 (m, 6H), 5.07 (bs, 2H), 3.87 (t, / = 5.2 Hz, 2H), 3.0 (s, 3H), 2.85 (s, 3H), 2.8 (t, J = 5.2Hz, 3H), 2.47-2.42 (m, 3H), 0.85 (t, J = 7.2 Hz, 3H). LCMS: 470.3 [M+H]+. Example-10: Synthesis of(E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)
ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of but-l-yn-l-ylbenzene
Figure imgf000082_0001
70 °C/12 h
sealed tube
The reaction was carried out according to Scheme 3, Step-1, using but-l-yn-1- yltrimethylsilane (Example 7, Step-1.1) to afford but-l-yn-l-ylbenzene (2 g, 83%).
Step-2: Synthesis of tert-butyl (Z)-(2-(4-( 1 ,2-diphenylbut-l -en-1 -yl)phenoxy) ethyl)carbamate
Figure imgf000082_0002
in) lodobenzeneM KOH
70 "C/4 h
The same procedures as described in Example 7, Step-2, using tert-butyl (2-(4- iodophenoxy)ethyl) carbamate (Example 8, Step-3) and iodobenzene, to afford tert-butyl (Z)- (2-(4-(l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl) carbamate (2 g, 30%).
Step-3: Synthesis of (Z)-2-(4-( 1 ,2-diphenylbut-l -en-1 -yl)phenoxy)ethan-l -amine
Figure imgf000082_0003
The reaction was carried out according to Scheme 4, Step-2, to give a crude compound, which was used in next step without further purification (1.3 g, crude).
Step-4: Synthesis of(E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N- di- methylbut-2-enamide
Figure imgf000083_0001
The reaction was carried out according to Scheme 4, Step-3, using (E)-4-bromo-N,N- dimethylbut-2-enamide (Example 1, Step-4.2) to give a crude product, which was used in next step without further purification (2 g, crude).
Step-5: Synthesis oftert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4- ((Z)-l,2- diphenylbut-1 -en-1 -yl)phenoxy)ethyl)carbamate
Figure imgf000083_0002
The reaction was carried out according to Scheme 4, Step-5, to give a crude compound, which was purified by column chromatography over 230-400 mesh silica-gel by eluting with 2% MeOH in dichloromethane as an eluent to afford tert-butyl ((E)-4-(dimethylamino)-4- oxobut-2-en-l-yl)(2-(4-((Z)-l,2-diphenylbut-l- en-l-yl)phenoxy)ethyl)carbamate (0.4 g, 16%).
Step-6: Synthesis o (£)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl) amino)-N,7V- dimethylbut-2-enamide (Example 10)
Figure imgf000083_0003
xamp e
The reaction was carried out according to Scheme 4, Step-6, to give a cmde product, which was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((Z)-l,2- diphenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (20 mg, 16%) as a brown colour semi solid.
Exxample 10: Ή NMR (400 MHz, OMSO-d6): δ 7.39-7.36 (m, 2H), 7.30-7.27 (m, 1H), 7.22-7.18 (m, 4H), 7.13-7.11 (m, 3H), 6.73 (d, 7 = 8.8 Hz, 2H), 6.63-6.57 (m, 3H), 6.51 (d, J = 14.1 Hz, 1H), 3.88 (t, / = 5.8 Hz, 2H), 3.33-3.31 (m, 3H), 2.99 (s, 3H), 2.85 (s, 3H), 2.79 (t, / = 5.4 Hz, 2H), 2.37 (q, / = 7.6 Hz, 2H), 0.84 (t, / = 7.6 Hz, 3H). LCMS: 455.3 [M+H]+. Example-11: Synthesis of (E)-N,N-dimethyl-4-( (2-(4-( (E)-2-phenyl-l-(pyridin-4- yl)but-l- en-l-yl) phenoxy)ethyl)amino)but-2-enamide
Step-1: Synthesis of 4-(but-l-yn-l-yl)pyridine
C1H.N
Figure imgf000084_0001
90 °C/S h/sealcd tube
The reaction was earned out according to Scheme 3, Step-1, using but-l-yn-1- yltrimethylsilane (Example 7, Step- 1.1), to give a crude product, which was purified by combiflash eluting with 5-10% EtOAc in n-hexane to afford 4-(but-l-yn-l-yl)pyridine (1.55 g, 65%) as light brown liquid.
Step-2: Synthesis of tert-butyl (2-(4-(2-phenyl-l-(pyridin-4-yl)but-l-en-l-yl)phenoxy) ethyl )carbamate i) Bis(pinacolato)diboron Pt(PPh3)4
Figure imgf000084_0002
ili) Iodol)cnzcnc/4M KOI I
70 °C/4 h
The same procedures as described in Example 7, Step-2, using tert-butyl (2-(4- iodophenoxy)ethyl) carbamate (Example 8, Step-3) and iodobenzene, to give a crude product, which was purified by combi-flash using 20-23% ethyl acetate in n-hexane to afford tert-butyl (2-(4-(2-phenyl-l-(pyridin-4-yl)but-l-en-l-yl)phenoxy) ethyl)carbamate (0.36 g, 7.2%).
Step-3: Synthesis of2-(4-( 2 -phenyl- 1 -(pyridin-4-yl)but-l -en-1 -yl )phenoxy)ethan-l - amine
Figure imgf000084_0003
The reaction was carried out according to Scheme 4, Step-2, to give a crude compound, which was used in next step without further purification (0.225 g, 81.2%) as a light brown solid.
Step-4: Synthesis of ( 2E)-N,N-dimethyl-4-( (2-( 4-( 2-phenyl-l-( pyridin-4-yl)but-l -en- 1 - yl )phenoxy ) ethyl )amino )but-2 -enamide
Figure imgf000085_0001
The reaction was carried out according to Scheme 4, Step-3, using (E)-4-bromo- V,N- dimethylbut-2-enamide (Example 1, Step-4.2) to give a crude product, which was used in next step without further purification (0.14 g, crude).
Step-5: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-(2- phenyl-1- ( pyridin-4-yl )but-l -en-1 -yl )phenoxy jethyl )carbamate
Figure imgf000085_0002
The reaction was carried out accroding to Scheme 4, Step-5, to give a cmde product, which was purified by combiflash eluting with 2-2.5% MeOH in ethyl acetate to afford tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-(2-phenyl-l- (pyridin-4-yl)but-l-en-l- yl)phenoxy)ethyl)carbamate (0.045 g, 26.5%) as a light brown semi solid.
Step-6: Synthesis of (E)-4-((2-(4-((Z)-l,2-diphenylbut-l-en-l-yl)phenoxy)ethyl) amino)-NN- dimethylbut-2-enamide (Example 11)
Figure imgf000085_0003
The reaction was carried out according to Scheme 4, Step-6, to give a crude compound, which was purified by preparative HPLC to afford desired (E)-N,N- dimethyl-4-((2-(4-((E)-2- phenyl-l-(pyridin-4-yl)but-l-en-l-yl)phenoxy)ethyl)amino)but-2-enamide (0.012 g, 33.3%). Example 11: Ή NMR (400 MHz, DMSO-<¾): δ 8.58-8.56 (m, 2H), 7.23-7.12 (m, 8H), 6.74 (d, J = 8.8 Hz, 2H), 6.64-6.49 (m, 4H), 3.88 (t, J = 5.6 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.78 (t, J = 5.2 Hz, 2H), 2.39-2.34 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H) LCMS: 456.3 [M+H]+.
Example-12: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(3-(trifluoro- methyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enam
trifluoroacetate
Step-1: Synthesis of2-(4-bromophenoxy)tetrahydro-2H-pyran
Figure imgf000086_0001
To a stirred solution of 4-bromophenol (15 g, 86 mmol) in dry dichloromethane (150 mL) at room temperature was added dihydro pyran (17.58 g, 173 mmol) followed by addition of pyridinium p-toluene sulfonate (50 mg). The resulting mixture was stirred at reflux temperature for 2 h. Upon completion by TLC, the reaction mixture was quenched with water (500 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic extracts were washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica using 6% ethyl acetate in n-hexane to afford 2-(4-bromophenoxy)tetrahydro-2H-pyran (20 g, 90%).
Step-2: Synthesis of 2-{4-{hut-l -yn-1 -yl )phenoxy )tetrahydro-2H-pyran
Figure imgf000086_0002
90 "C/5 h/sealed lube
The reaction was carried out according to Scheme 3, Step-1, using but- 1 -yn-1 - yltrimethylsilane (Example 7, Step-1.1) to give a crude product, which was purified by column chromatography over 230-400 mesh silica gel by eluting with 3% EtOAc in n-hexane to afford 2-(4-(but-l-yn-l- yl)phenoxy)tetrahydro-2H-pyran (17 g).
Step-3: Synthesis of 4-{ 1 ,2-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-l - en-1- yl)phenol
Figure imgf000087_0001
The reaction was carried out according to Scheme 3, Step-2, to afford 4-(l,2-bis(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)but-l-en-l-yl)phenol (21.5 g, 76%).
Step-4: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-(l- (4- hydroxyphenyl )-2-(3-( trtfluoromethyl )phenyl)but-l-en-l-yl )phenoxy)ethyl )- carbamate
Figure imgf000087_0002
To a stirred solution of 4-(l,2-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but- 1-en-l- yl)phenol (1.5 g, 3.9 mmol) in 2-methyl THF (10 mL), was added tert-butyl (E)-(4- (dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-iodophenoxy)ethyl)carbamate (0.864 g, 1.8 mmol, Example 9, Step-4), bis(triphenylphosphine)palladium(II) dichloride (91 mg, 0.13 mmol), cesium carbonate (1.69 g, 5.2 mmol) and 2-methyl THF (10 mL) were added. This mixture was degassed with nitrogen and water (2 mL) was added. Reaction mixture was stirred at room temperature for 5 days. After completion of reaction (monitored by TLC), l-iodo-3- (trifluoromethyl)benzene (738 mg, 2.71 mmol) and 4M aqueous KOH (4 mL) were added and the mixture was degassed with nitrogen and heated at 85 °C for 32 h. Upon completion (monitored by TLC), the reaction mixture was filtered through a celite/silicagel pad and washed with EtOAc. The filterate was washed with water, saturated NaCl solution and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over 230-400 mesh silica gel by eluting with 2% MeOH in dichloromethane to afford desired compound along with the starting material, which was used in next step (500 mg, crude).
Step-5 : Synthesis of (E)-4-((2-(4-( (Z)-l-(4-hydroxyphenyl)-2-( 3-( trtfluoromethyl)- phenyl)but-l-en-l-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide 2,2,2-tri- fluoroacetate {Example 12)
Figure imgf000088_0001
xamp e
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2- (4-(l-(4- hydroxyphenyl)-2-(3-(trifluoiOmethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)- carbamate (0.5 g, 0.78 mmol) in EtOH (2 mL) was added at 0 °C, 2M HC1 in diethyl ether (15 mL). The reaction mixture was stirred for 5 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with dichloromethane.
Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC using to afford desired (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(3-
(trifluoromethyl)phenyl)but- 1 -en- 1 -yl)- phenoxy)ethyl)amino)-N N-dimethylbut-2-enamide 2,2,2-trifluoroacetate (0.016 g).
Example 12: Ή NMR (400 MHz, DMSO-dg): δ 9.5 (s, 1H), 8.9 (bs, 1H), 7.45-7.41 (m, 3H), 7.37 (s, 1H), 7.0 (d, J = 8.8 Hz, 2H), 6.82-6.7 (m, 5H), 6.69 (d, J = 8.8 Hz, 2H), 6.6-6.53 (m, 1H), 4.08 (t, / = 4.8 Hz, 2H), 3.8 (d, / = 4.8 Hz, 2H), 3.28 (bs, 2H), 3.04 (s, 3H), 2.88 (s, 3H), 2.45-2.4 (m, 2H), 0.86 (t, J = 7.2 Hz, 2H). LCMS: 539.3[M+H]+.
Example- 13: Synthesis of (E)-4-( (2-( 4-( (Z)-l-( 4-hydroxyphenyl)-2-(4-isopropyl- phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (E)-(2-(4-(l-(4-hydroxyphenyl)-2-(4,4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000088_0002
The reaction was carried out according to Scheme 3, Step-3, using tert-butyl (2-(4- iodophenoxy)ethyl)carbamate (Example 8, Step-3) to give a crude product, which was purified by column chromatography over 230-400 mesh silica gel by eluting with 20% acetone in «-hexane to 5%MeOH in dichloromethane to afford desired compound (2 g, boronate ester, 1 g boronic acid).
Step-2: Synthesis of tert-butyl (E)-(2-(4-(2-cyclobutyl-2-phenyl-l-(l-(tetrahydro-2H- pyran- 2-yl)-lH-indazol-5-yl)vinyl)phenoxy)ethyl)carbamate
Figure imgf000089_0001
The reaction was carried out according to Scheme 3, Step-4, using 1-iodobenzene, to give a crude product, which was purified by silica gel chromatography (2:8 EtOAc in n-hexane) to give title compound (0.52 g, 41%).
Step-3: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-isopropylphenyl)but- 1-en-l- yl)phenol
Figure imgf000089_0002
The reaction was carried out according to Scheme 4, Step-2 to give a crude material, which was purified by column chromatography over 230-400 mesh silica gel using (2:98%) MeOH in dichloromethane to afford (Z)-4-(l-(4-(2-aminoethoxy)phenyl)- 2-(4-isopropylphenyl)but- l-en-l-yl)phenol (0.44 g).
Step-4: Synthesis of ( E)-4-( (2-( 4-( (Z)-l -( 4-hydroxyphenyl)-2-( 4-isopropylphenyl)- but-1 -en- 1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000089_0003
The reaction was carried out according to Scheme 4, Step-3, using (E)-4-bromo-N,N- dimethylbut-2-enamide (Example 1, Step-4.2) to afford (E)-4- ((2-(4-((Z)-l-(4- hydroxyphenyl)-2-(4-isopropylphenyl)but-l-en-l-yl)phenoxy)ethyl)-amino)-N,N- dimethylbut-2-enamide (0.5 g crude). Step-5: Synthesis oftert-butyl ((E)-4-(dimethylammo)-4-oxobut-2-en-l-yl)(2-(4- ((Z)-l-(4- hydroxyphenyl )-2-( 4-isopropylphenyl )but-l -en-l-yl)phenoxy )ethyl )carba-mate
Figure imgf000090_0001
The reaction was carried out according to Scheme 4, Step-5 to give a crude compound, which was purified by column chromatography eluting with 3% MeOH in dichloromethane to afford tert-butyl ((£)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2- (4-((Z)-l-(4- hydroxyphenyl)-2-(4-isopropylphenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.16 g, 27%).
Step-6: Synthesis of (E)-4-( (2-( 4-( (Z)-l-( 4-hydroxyphenyl)-2-( 4-isopropylphenyl)- but-1 -en- 1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (Example 13)
Figure imgf000090_0002
The reaction was carried out according to Scheme 4, Step-6 to give a crude compound, which was purified by preparative HPLC to afford desired (E)-4-((2-(4- ((Z)-l-(4-hydroxyphenyl)- 2-(4-isopropylphenyl)but- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.01 g, 7%).
Example 13: Ή NMR (400 MHz, DMSO-<¾): δ 9.38 (s, 1H), 7.05-6.99 (m, 4H), 6.96 (d, / = 8.8 Hz, 2H), 6.74 (d, / = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.63-6.59 (m, 3H), 6.50 (d, J = 15.2 Hz, 1H), 3.87 (t, J = 5.2 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.78 (t, / = 5.6 Hz, 2H), 2.40-2.35 (m, 3H), 1.15 (d, / = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H). LCMS: 513.3[M+H]+.
Example-14: Synthesis of(2E)-4-((2-(4-(l-(4-iodophenyl)-2-phenylbut-l-en-l-yl)- phenoxy )ethyl) amino )-N,N-dimethylbut-2-enamide
Step-1 : Synthesis of ( 4-iodophenyl )( 4-methoxyphenyl )methanone
Figure imgf000090_0003
To a stirred solution of 4-iodobenzoyl chloride (2.1 g, 7.8 mmol) and anisole (1.12 mL, 10.2 mmol) in dry dichloromethane (25 mL) at -10 °C was added A1C13 (1.5 g, 11 mmol). The resulting mixture was stirred at room temperature for 16 h. Upon completion by TLC, the reaction mixture was quenched with ice cold water (50 mL) and IN HC1 (200 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with water, brine and dried over anhydrous sodium sulphate and concentrated at 40 °C without reduced pressure to give a yellow colour liquid (2.4 g, 92%).
Step-2: Synthesis of l-iodo-4-(l-(4-methoxyphenyl)-2-phenylbut-l-en-l-yl)benzene
Figure imgf000091_0001
The reaction was carried out according to Scheme 2, Step-1, using propiophenone, to give a crude material, which was purified by column chromatography over 230-400 mesh silica gel by eluting with 5% EtOAc in n-hexane to afford l-iodo-4-(l-(4-mefhoxyphenyl)-2- phenylbut-l-en-l-yl)benzene (4 g, 50%) as a yellow colour sticky solid.
Step-3: Synthesis of 4-{ l-(4-iodophenyl)-2-phenylbut-l-en-l-yl)phenol
Figure imgf000091_0002
To a solution of l-iodo-4-(l-(4-methoxyphenyl)-2-phenylbut-l-en-l-yl)benzene (5 g, 11.36 mmol) in dichloromethane (50 mL) was added at -78 °C, BBr3 (1M solution in
dichloromethane, 68 mL, 68.16 mmol). The reaction mixture was stirred for 3 h at room temperature and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature, water was added (50 mL) and the layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound, crude material was purified by preparative HPLC to 4-(l-(4-iodophenyl)-2-phenylbut-l-en-l-yl)phenol as yellow colour semi solid (2.1 g, 43%).
Step-4: Synthesis of tert-butyl (2-(4-( 1 -(4-iodophenyl)-2-phenylbut-l -en-1 -yl)
phenoxy )ethyl )carbamate
Figure imgf000092_0001
The reaction was carried out according to Scheme 4, Step-1, using tert-butyl (2- bromoethyl)carbamate, to give a crude material, which was purified by combi-flash to afford tert-butyl (2-(4-(l-(4-iodophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)carbamate (1.7 g, 60%) as an off-white sticky solid.
Step-5: Synthesis of2-(4-(l-( 4-iodophenyl )-2-phenylbut-l-en-l-yl )phenoxy ) ethan-1 -amine
Figure imgf000092_0002
The reaction was carried out according to Scheme 4, Step-2 to give a crude compound, which was used in next step without further purification (1.2 g, 85%).
Step-6: Synthesis of (2E)-4-((2-(4-(l-( 4-iodophenyl)-2-phenylbut-l -en-1 -yl )phenoxy ) ethylamino)-N,N-dimethylbut-2-enamide
Figure imgf000092_0003
The reaction was carried out according to Scheme 4, Step-3, using (E)-4- bromo-7V,N- dimethylbut-2-enamide (Example 1, Step-4.2) to give a crude product was used in next step without further purification (0.88 g, crude).
Step-7: Synthesis of tert-butyl (( E)-4-(dimethylamino)-4-oxobut-2-en-l -yl)(2-(4-( 1 - (4- iodophenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000092_0004
The reaction was carried out according to Scheme 4, Step-5 to give a compound, which was purified by combiflash to afford tert-butyl ((E)-4-(dimethylamino)- 4-oxobut-2-en-l-yl)(2-(4- (l-(4-iodophenyl)-2-phenylbut-l-en-l-yl)-phenoxy)ethyl)- carbamate (0.48 g) as a yellow colour sticky solid.
Step-8: Synthesis of (E)-4-((2-(4-((E)- 1 -(4-iodophenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (Example 14)
Figure imgf000093_0001
The same procedure as described in Scheme 4, Step-6 to give the desired compound, (E)-4- ((2-(4-((E)-l-(4-iodophenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut- 2-enamide (0.12 g, 25%).
Example 14: Ή NMR (400 MHz, DMSO-d6): δ 7.73 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.22-1.20 (m, 4H), 7.19-7.09 (m, 9H), 7.11 (d, J = 8.4 Hz, 2H), 6.95 (d, / = 8.8 Hz, 2H), 6.71 (d, / = 9.2 Hz, 2H), 6.63-6.52 (m, 7H), 4.04 (t, J = 5.6 Hz, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.80 (d, / = 4.0 Hz, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.89-2.85 (m, 8H), 2.78 (t, J = 5.4 Hz, 2H), 2.46-2.32 (m, 4H), 0.87-.083 (m, 6H). LCMS: 581.2 [M+H]+.
Example 15: Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of 4-(benzyloxy)-l-bromo-2-methylbenzene
Figure imgf000093_0002
To a solution of 4-bromo-3-methylphenol (10 g, 53.4 mmol) in acetonitrile (200 mL), were added potassium carbonate (22.13 g, 160 mmol) and benzyl bromide (11.89 g, 69.5 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04> concentrated under reduced pressure to afford desired compound (13 g, 87%) as brown colour oil.
Step-2: Synthesis of4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methylbenzene
Figure imgf000094_0001
scaled tube/80 °C/12 h
To a stirred solution of 4-(benzyloxy)-l-bromo-2-methylbenzene (5 g, 18 mmol) in 50 mL of DMAin a sealed tube, were added copper iodide (0.344 g, 1.8 mmol) and cesium carbonate (8.79 g, 27 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimefhylsilane (6.9 g, 27.40 mmol, Example-16, Step- 2) followed by Pd(OAc)2 (0.540 g, 2.3 mmol). The pressure tube was sealed and heated at 80 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over 230-400 mesh silica gel column chromatography using 10% EtOAc in n-hexane to afford 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methylbenzene (4.52 g, 88%).
Step-3: Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-methylphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
2-Methyl THF:H20/RT/16 h
Figure imgf000094_0002
iii) /e/Y-butyl (2-(4-iodophenoxy)
ethyI)carbamate/4M KOH
85 "C/16 h
To a stirred solution of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methylbenzene (7.1 g, 29.55 mmol) in 2-methyl THF (72 mL), was added bis(pinacolato)diboron (7.58 g, 29.85 mmol), tetrakis(triphenylphosphine)platinum (0) (0.294 g, 0.236 mmol) under nitrogen atmosphere, reaction mixture was stin-ed at 85 °C for 8 h. After completion of reaction (monitored by TLC), solution was allowed to cool to room temperature, bis(triphenylphosphine)palladium (II) dichloride (0.483 g, 0.68 mmol), cesium carbonate (8.9 g, 27.55 mmol) and iodobenzene (3.9 g, 19.28 mmol) were added, reaction mixture was degassed with nitrogen and water (20 mL) was added, reaction mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (18 mL) and tert-butyl (2-(4- iodophenoxy)ethyl)carbamate (4.3 g, 11.88 mmol, Example-17, Step-2), and 2-methyl THF (30 mL) were added. Reaction mixture was stirred at 85 °C for 16 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5-10% EtOAc in n-hexane to afford tert-butyl (E)-(2-(4-(l-(4- (benzyloxy)-2-methylphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (3.2 g, 43 %).
Step-4: Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l-amine
Figure imgf000095_0001
To a stirred solution of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-methylphenyl)-2-phenylbut- l-en-l-yl)phenoxy)ethyl)carbamate (3.8 g, 6.74 mmol) in methanol (20 mL) was added at 0 °C, 2M HC1 in diethyl ether (40 mL). The reaction mixture was stirred for 5 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03j extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in dichloromethane to afford (E)-2-(4-(l-(4- (benzyloxy)-2-methylphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethan-l-amine (2.4 g, 77%).
Step-5: Synthesis of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenol
Figure imgf000095_0002
To a stirred solution of (E)-2-(4-(l-(4-(benzyloxy)-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine (2.4 g, 5.1 mmol) in dichloromethane (24 mL) was added BBr3 (1M solution in dichloromethane, 26 mL, 25 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was cooled to 0 °C, basified with saturated NaHC03 solution, slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3-methylphenol (0.9 g, 47%).
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
Figure imgf000096_0001
To a stirred solution of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenol (0.9 g, 2.4 mmol) in ΓΡΑ (10 mL) was added DIPEA (0.62 g, 4.8 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (£)-4-bromo-N,N- dimethylbut-2-enamide and (£ -4-chloro-N,N-dimethylbut-2-enamide mixture (0.368 g, 1.9 mmol, Example- 101, Step-7) in ΓΡΑ (5 mL) was added drop wise, reaction mixture was stined for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.29 g, crude).
Step-7: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4- hydroxy-2-methylphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000096_0002
To a stirred solution of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.29 g, 2.6 mmol) in dichloromethane (25 mL) was added boc anhydride (0.87 g, 4.01 mmol). The reaction mixture was stirred for 2 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4-hydroxy-2- methylphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.26 g, 16.8%).
Step-8: Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000097_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4- hydroxy-2-methylphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.26 g, 0.44 mmol) in EtOH (2 mL) was added at 0 °C, 2M HC1 in diethyl ether (4 mL). The reaction mixture was stirred for 16 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((E)- 1 -(4-hydroxy-2-methylphenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.15 g, 69.7%). Ή NMR (400 MHz, DMSO-i/6): δ 9.22 (s, 1H), 7.22-7.14 (m, 2H), 7.13-7.11 (m, 3H), 7.03 (d, J = 7.6 Hz, 1H), 6.72-6.64 (m, 2H), 6.61-6.47 (m, 6H), 3.86 (t, / = 5.6 Hz, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.77 (t, J = 5.6 Hz, 2H), 2.32-2.15 (m, 2H), 2.01 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H). LCMS: 485.4 [M+H]+
Example 16: Synthesis of (E)-4-((2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of 4-(benzyloxy)-l-bromo-2-chlorobenzene
Figure imgf000097_0002
To a solution of 4-bromo-3-chlorophenol (10 g, 48.3 mmol) in DMF (200 mL), were added potassium carbonate (19.99 g, 144 mmol) and benzyl bromide (6.93 mL, 57.97 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04j concentrated under reduced pressure to afford desired compound (13 g, 91%).
Step-2: Synthesis of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-chlorobenzene
Figure imgf000098_0001
sealed tube/90 "C/12 h
To a stirred solution of 4-(benzyloxy)-l-bromo-2-chlorobenzene (13 g, 43.91 mmol) in 130 mL of DMA in a sealed tube, were added copper iodide (0.833 g, 4.39 mmol) and cesium carbonate (28.63 g, 87.83 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (11 g, 87.83 mmol, Example-16, Step-2) followed by Pd(OAc)2 (1.079 g, 4.39 mmol) and dppf (2.4 g, 4.39 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over 230-400 mesh silica gel column chromatography using 3% EtOAc in n-hexane to afford 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-chlorobenzene (9.4 g, 80%).
Step-3: Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000098_0002
ethyl)carbamate/4M KOH
85 -C/16 h
To a stirred solution of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-chlorobenzene (4 g, 14.81 mmol) in 2-methyl THF (32 mL), was added bis(pinacolato)diboron (4.54 g, 17.87 mmol), tetrakis(triphenylphosphine)platinum (0) (0.185 g, 0.148 mmol) under nitrogen atmosphere, reaction mixture was stirred at 85 °C for 12 h. After completion of reaction (monitored by TLC), solution was allowed to cool to room temperature, bis(triphenylphosphine)palladium (II) dichloride (0.488 g, 0.66 mmol), cesium carbonate (8.51 g, 26.21 mmol) and iodobenzene (2.72 g, 13.35 mmol) were added, reaction mixture was degassed with nitrogen and water (1 mL) was added, reaction mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (3 g) and teri-butyl (2-(4- iodophenoxy)ethyl)carbamate (3.23 g, 8.9 mmol, Example-17, Step-2), and 2-niethyl THF (50 mL) were added. Reaction mixture was stirred at reflux temperature for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 25% EtOAc in n-hexane to afford tert- butyl (E)-(2-(4-( 1 -(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)carbamate (3.3 g, 46%).
Step-4: Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethan-l-amine
Figure imgf000099_0001
To a stirred solution of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate (3.34 g, 5.71 mmol) in ethanol (10 mL) was added at 0 °C, 2M HCl in diethyl ether (40 mL). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in dichloromethane to afford (E)-2-(4-(l-(4- (benzyloxy)-2-chlorophenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethan- 1 -amine (2.7 g) .
Step-5: Synthesis (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- chlorophenol
Figure imgf000099_0002
To a stirred solution of (E)-2-(4-(l-(4-(benzyloxy)-2-chlorophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine (2.7 g, 5.57 mmol) in dichloromethane (30 mL) was added BBr3 (1M solution in dichloromethane, 27.8 mL, 27.8 mmol) at -78 °C. The reaction mixture was stirred for 1.5 h and quenched with MeOH (5 mL). The resulting mixture was cooled to 0 °C, basified with saturated NaHC03 solution, slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3-chlorophenol (0.78 g, 35%).
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000100_0001
To a stirred solution of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- chlorophenol (0.78 g, 1.98 mmol) in DMF (16 mL) was added DIPEA (0.693 g, 3.97 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (£)-4-bromo-N,N- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.379 g, 1.98 mmol, Example- 101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.0 g, crude).
Step-7: Synthesis of tert-butyl (2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
Figure imgf000100_0002
To a stirred solution of (E)-4-((2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.0 g, 1.98 mmol) in dichloromethane (15 mL) was added boc anhydride (0.648 g, 2.97 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to obtain tert-butyl (2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.465 g, 39%).
Step-8: Synthesis of (E)-4-((2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000101_0001
To a stirred solution of tert-butyl (2-(4-((E)-l-(2-chloro-4-hydroxyphenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.44 g, 0.728 mmol) in dichloromethane (9 mL) was added at 0 °C, TFA (1 mL). The reaction mixture was stirred for 1.5 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03) extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (0.195 g, 53%). Ή NMR (400 MHz, DMSO-<¾): δ 9.85 (s, 1H), 7.23-7.11 (m, 6H), 6.87 (d, J = 1.6 Hz, 1H), 6.79 (dd, = 8.2 Hz, h = 1.8 Hz, 1H), 6.76 (d, / = 8.8 Hz, 2H), 6.62 (t, / = 5.2 Hz, 1H), 6.59-6.47 (m, 3H), 3.86 (t, J = 5.6 Hz, 2H), 3.25-3.31 (m, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.77 (t, J = 5.6 Hz, 2H), 2.29-2.21 (m, 2H), 2.19-2.05 (m, 1H), 0.77 (t, J = 7.4 Hz, 3H). LCMS: 505.3 [M+H]+
Example 17: Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of 4-(ben7 loxy)-l-bromo-2-methoxybenzene
Figure imgf000102_0001
To a solution of 4-bromo-3-methoxyphenol (10 g, 49.2 mmol) in acetone (100 mL), were added potassium carbonate (20.4 g, 147.7 mmol) and benzyl bromide (6.42 mL, 54.18 mmol) sequentially at room temperature. The resulting mixture was stirred at 60 °C for 5 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to afford desired compound (14 g, 95%).
Step-2: Synthesis of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methoxybenzene
Figure imgf000102_0002
sealed tube/80 °C/12 h
To a stirred solution of 4-(benzyloxy)-l-bromo-2-methoxybenzene (7 g, 23.89 mmol) in 70 mL of DMA in a sealed tube, were added copper iodide (0.45 g, 2.38 mmol) and cesium carbonate (11.64 g, 35.83 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles and were added but-l-yn-l-yltrimethylsilane (4.2 g, 33.44 mmol, Example-16, Step-2) followed by Pd(OAc)2 (0.54 g, 2.38 mmol) and dppf (1.34 g, 2.38 mmol). The pressure tube was sealed and heated at 80 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over 230-400 mesh silica gel column chromatography using 25% EtOAc in n-hexane to afford 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methoxybenzene (5 g, 78%).
Step-3: Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-methoxyphenyl)-2-phenylbut- l-en-l-yl)phenoxy)ethyl)carbamate 2-Methyl THF:H2O/RT/20 h
Figure imgf000103_0001
iii) /e/V-butyl (2-(4-iodophenoxy)
ethyl)carbamate/4M KOH
90 °C/16 h
To a stirred solution of 4-(benzyloxy)-l-(but-l-yn-l-yl)-2-methoxybenzene (5 g, 18.77 mmol) in 2-methyl THF (50 niL), was added bis(pinacolato)diboron (4.8 g, 18.96 mmol), tetrakis(triphenylphosphine)platinum (0) (0.186 g, 0.150 mmol) under nitrogen atmosphere, reaction mixture was stirred at 85 °C for 8 h. After completion of reaction (monitored by TLC), solution was allowed to cool to room temperature, bis(triphenylphosphine)palladium (II) dichloride (0.98 g, 1.39 mmol), cesium carbonate (18.16 g, 55.88 mmol) and iodobenzene (5.13 g, 25.14 mmol) were added, reaction mixture was degassed with nitrogen and water (20 mL) was added, reaction mixture was stirred at room temperature for 20 h. After completion of reaction, to the above reaction mixture 4M KOH (50 mL) and terf-butyl (2-(4- iodophenoxy)ethyl)carbamate (10.13 g, 27.90 mmol, Example-17, Step-2), and 2-methyl THF (50 mL) were added. Reaction mixture was stirred at 90 °C for 16 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5-10% EtOAc in n-hexane to afford tert- butyl (E)-(2-(4-( 1 -(4-(benzyloxy)-2-methoxyphenyl)-2-phenylbut- 1 -en- 1- yl)phenoxy)ethyl)carbamate (3.4 g, 31%).
Step-4: Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethan-l -amine
Figure imgf000103_0002
To a stirred solution of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-2-methoxyphenyl)-2- phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (3.4 g, 19.94 mmol) in methanol (15 mL) was added at 0 °C, 2M HC1 in diethyl ether (35 mL). The reaction mixture was stirred for 5 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03j extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in dichloromethane to afford (E)-2-(4-(l-(4- (benzyloxy)-2-methox phenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethan- 1 -amine (2.4 g).
Step-5: Synthesis (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methoxyphenol
Figure imgf000104_0001
To a stirred solution of (E)-2-(4-(l-(4-(benzyloxy)-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine (2.4 g, 5.01 mmol) in dichloromethane (15 mL) was added BBr (1M solution in dichloromethane, 28 mL, 25 mmol) at -78 °C. The reaction mixture was stirred for 30 min and quenched with MeOH (5 mL). The resulting mixture was cooled to 0 °C, basified with saturated NaHC03 solution, slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3-methoxyphenol (1.02 g, 51%).
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
Figure imgf000104_0002
To a stirred solution of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methoxyphenol (1 g, 2.5 mmol) in DMF (10 mL) was added DIPEA (0.66 g, 5.14 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4-bromo-N,N- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.39 g, 2.05 mmol, Example- 101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 16 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (2.3 g, crude).
Step-7: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4- hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000105_0001
To a stirred solution of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (2.3 g, 4.5 mmol) in dichloromethane (30 mL) was added boc anhydride (1.2 g, 5.5 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using 2-3% MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)- l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.43 g).
Step-8: Synthesis of (E)-4-((2-(4-((E)-l-(4-hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000105_0002
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(4- hydroxy-2-methoxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.43 g, 0.728 mmol) in ethanol (3 mL) was added at 0 °C, 2M HC1 in diethyl ether (5 mL). The reaction mixture was stin-ed for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03j extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (0.075 g, 13.9%). 1H NMR (400 MHz, DMSO-<¾): δ 9.38 (s, 1H), 7.24-7.07 (m, 5H), 6.89 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.62 (t, J = 5.0 Hz, 1H), 6.58 (t, J = 5.4 Hz, 1H), 6.55-6.52 (m, 2H), 6.48-6.35 (m, 2H), 3.85 (t, J = 5.6 Hz, 2H), 3.61 (s, 3H), 2.99 (s, 3H), 2.84 (s, 3H), 2.77 (t, J = 5.6 Hz, 2H), 2.24 (dd, Ji = 14.4 Hz, h = 7.2 Hz, 2H), 0.74 (t, / = 7.2 Hz, 3H). LCMS: 501.3 [M+H]+
Example 18: Synthesis of (E)-4-((2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but- l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of (E)-4-(l-(4-(benz loxy)phenyl)-2-(3,5-difluorophenyl)but-l-en-l- yl)phenol
Figure imgf000106_0001
Zinc dust (5.2 g, 78.6 mmol) was suspended in dry THF (50 mL) and cooled this suspension to -10 °C. To this TiCl4 (4.4 mL, 39.3 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C, and a solution of 4-(benzyloxy) phenyl)(4- hydroxyphenyl) methanone (4 g, 13.1 mmol) and l-(3,5-difluorophenyl)propan-l-one (2.35 g, 13.8 mmol) in dry THF (80 mL) were added and the contents were refluxed for 5 h. The reaction mixture was cooled to room temperature and quenched with 10% aqueous K2C03 solution and was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude material was purified by column chromatography over 230-400 mesh silica using (2:8) ethyl acetate in n- hexane to afford (E)-4-(l-(4-(benzyloxy)phenyl)-2-(3,5-difluorophenyl)but-l-en-l-yl)phenol (4.05 g, 69.8 %).
Step-2: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benz loxy)phenyl)-2-(3,5- difluorophenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000107_0001
To a solution of (E)-4-(l-(4-(benzyloxy)phenyl)-2-(3,5-difluorophenyl)but-l-en-l-yl)phenol (4 g, 9.04 mmol) in DMF (40 mL) was added potassium carbonate (12.5 g, 90.4 mmol) and tert-butyl (2-bromoethyl)carbamate (3.05 g, 13.5 mmol). The reaction mixture was heated to 70 °C and maintained at this temperature for 18 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 15% ethyl acetate in n-hexane to afford tert-butyl (Z)-(2-(4-( 1 -(4-(benzyloxy)phenyl)-2-(3 ,5-difluorophenyl)but- 1 -en- 1 - yl)phenoxy)ethyl)carbamate (4.5 g, 85%).
Step-3: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(3,5-difluorophenyl)but-l-en-l- yl)phenol
Figure imgf000107_0002
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(3,5- difluorophenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (4 g, 6.8 mmol) in dichloromethane (80 mL) was added BBr3 (1M solution in dichloromethane, 34.2 mL, 34.2 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (100 mL) and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound. The crude material was purified by column chromatography over 230-400 mesh silica gel using 10% MeOH in dichloromethane to afford desired compound (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(3,5- difluorophenyl)but-l-en-l-yl)phenol (1.35 g, 50 %). Step-4: Synthesis of (E)-4-((2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)amino)~N,N-dimethylbut-2-enamide
Figure imgf000108_0001
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(3,5-difluorophenyl)but-l-en- l-yl)phenol (1.5 g, 3.79 mmol) in DMF (15 mL) was added DIPEA (0.98 mL, 5.6 mmol) stirred for 15 min at room temperature. A solution of (E)-4-bromo-N,/V-dimethylbut-2- enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.51 g, 2.65 mmol, Example-101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 15 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.8 g, crude).
Step-5 : Synthesis of tert-butyl (2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l- en-l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
Figure imgf000108_0002
To a stirred solution of (E)-4-((2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.8 g, 3.55 mmol) in dichloromethane (20 mL) was added boc anhydride (1.16 g, 5.33 mmol). The reaction mixture was stilted for 1 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by combi-flash eluting with 100% EtOAc to obtain tert-butyl (2-(4- ((Z)-2-(3 ,5-difluorophenyl)- 1 -(4-hydroxyphenyl)but- 1 -en- 1 -yl)phenoxy)ethyl)((E)-4- (dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.47 g, 21.9%).
Step-6: Synthesis of (E)-4-((2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000109_0001
To a stirred solution of tert-butyl (2-(4-((Z)-2-(3,5-difluorophenyl)-l-(4-hydroxyphenyl)but- 1 -en- 1 -yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en- 1 -yl)carbamate (0.47 g, 0.775 mmol) in ethanol (5 mL) was added at 0 °C, 2M HCl in diethyl ether (15 mL). The reaction mixture was stirred for 5 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (0.042 g, 10.7%). 1H NMR (400 MHz, DMSO-i¾): δ 9.46 (s, 1H), 6.98- 6.93 (m, 3H), 6.80-6.74 (m, 6H), 6.68-6.61 (m, 3H), 6.60-6.40 (m, 1H), 3.91 (t, J = 5.4 Hz, 2H), 3.32-3.20 (m, 2H), 3.00 (s, 3H), 2.85-2.80 (m, 5H), 2.40 (q, J = 7.6 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). LCMS: 507.3 [M+H]+
Example 19: Example-107: Synthesis of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4- hydroxyphenyl)-2-phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of(E)-4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2-phenylvinyl)phenol
Figure imgf000109_0002
Zinc dust (5.16 g, 65.39 mmol) was suspended in dry THF (50 mL) and cooled this suspension to -10 °C. To this TiCl4 (4.34 mL, 39.45 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C, and a solution of 4-(benzyloxy) phenyl)(4-hydroxyphenyl) methanone (4 g, 13.15 mmol) and cyclobutyl(phenyl)methanone (5.71 g, 35.62 mmol) in dry THF (30 mL) were added and the contents were refluxed for 2.5 h. The reaction mixture was cooled to room temperature and quenched with 10% aqueous K2C03 solution and was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude material was purified by column chromatography over 230-400 mesh silica using 10% ethyl acetate in n-hexane to afford (E)-4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenol (4.91 g, 86 %).
Step-2: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy )ethyl)carbamate
Figure imgf000110_0001
To a solution of (E)-4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2-phenylvinyl)phenol (4.9 g, 11.34 mmol) in DMF (50 mL) was added potassium carbonate (4.6 g, 34.02 mmol) and tert- butyl (2-bromoethyl)carbamate (3.81 g, 17.01 mmol). The reaction mixture was heated to 70 °C and maintained at this temperature for 12 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 15% ethyl acetate in n-hexane to afford tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy)ethyl)carbamate (5.6 g, 86%).
Step-3: Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy)ethan-l-amine
Figure imgf000110_0002
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy)ethyl)carbamate (4.35 g, 7.56 mmol) in ethanol (15 mL) was added at 0 °C, 2M HC1 in diethyl ether (50 n L). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in dichloromethane to afford (Z)-2-(4-(l-(4- (benzyloxy)phenyl)-2-cyclobutyl-2-phenylvinyl)phenoxy)ethan-l-amine (2.87 g, 79.9%).
Step-4: Synthesis of (Z)-4-( l-(4-(2-aminoethoxy )phenyl)-2-cyclobutyl-2-phenylvinyl)phenol
Figure imgf000111_0001
To a stirred solution of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenoxy)ethan-l -amine (2.87 g, 6.04 mmol) in dichloromethane (30 mL) was added BBr3 (1M solution in dichloromethane, 30.2 mL, 30.2 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (100 mL) and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound. The crude material was purified by column chromatography over 230-400 mesh silica gel using 10% MeOH in dichloromethane to afford desired compound (0.725 g, 31%).
Step-5: Synthesis of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000111_0002
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-cyclobutyl-2- phenylvinyl)phenol (0.725 g, 1.88 mmol) in DMF (10 mL) was added DIPEA (0.492 mL, 2.52 mmol) stirred for 15 min at room temperature. A solution of (£)-4-bromo-JV,/V- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.269 g, 1.41 mmol, Example-101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 15 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (0.908 g, crude).
Step-6: Synthesis of tert-butyl (2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
Figure imgf000112_0001
To a stirred solution of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.908 g, 1.83 mmol) in dichloromethane (15 mL) was added boc anhydride (0.598 g, 2.74 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to afford desired compound (0.332 g, 30%).
Step-7: Synthesis of (E)-4-((2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000112_0002
To a stirred solution of tert-butyl (2-(4-((Z)-2-cyclobutyl-l-(4-hydroxyphenyl)-2- phenylvinyl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.332 g, 0.55 mmol) in ethanol (5 mL) was added at 0 °C, 2M HC1 in diethyl ether (10 mL). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (0.032 g, 11.59%). Ή NMR (400 MHz, OMSO-d6): 6 9.40 (s, 1H), 7.24- 7.20 (m, 2H), 7.15-7.13 (m, 1H), 7.02 (d, / = 6.8 Hz, 2H), 6.96 (d, / = 7.6 Hz, 2H), 6.76-6.71 (m, 4H), 6.62-6.57 (m, 1H), 6.55-6.48 (m, 3H), 3.83 (t, J = 5.6 Hz, 2H), 3.42-3.90 (m, 1H), 3.31-3.30 (m, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.76 (t, J = 5.6 Hz, 2H), 1.81-1.75 (m, 4H), 1.75-1.59 (m, 1H), 1.38-1.28 (m, 1H). LCMS: 497.3 [M+H]+
Example 20: Synthesis of (E)-4-((2-(4-((Z)-2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (Z)-(2-(4-(2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy )ethyl)carbamate
Figure imgf000113_0001
To a stirred solution of tert-butyl (E)-(2-(4-(l-(4-hydroxyphenyl)-2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)but-l-en-l-yl)phenoxy)ethyl)carbamate (1.3 g, 2.55 mmol, Example- 46, Step-1) in 2-methyl THF (15 mL), l-iodo-4-ethylbenzene (0.651 mg, 2.8 mmol), 4M aqueous KOH (2 mL) and Pd(PPh3)2Cl2 (89 mg, 0.127 mmol) were added and the mixture was degassed with nitrogen for 15 min and heated at 85 °C for 3 h. Upon completion, the reaction mixture was diluted with EtOAc. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2:8 EtOAc in n- hexane) to give title compound (0.5 g, 40%).
Step-2: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-ethylphenyl)but-l-en-l- yl)phenol
Figure imgf000113_0002
To a stirred solution of tert-butyl (Z)-(2-(4-(2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)carbamate (0.5 g, 1.03 mmol) in ethanol (2 mL) was added at 0 °C, 2M HC1 in diethyl ether (40 mL). The reaction mixture was stirred for 16 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03 solution, extracted with 10% MeOH in dichloromethane. The organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230- 400 mesh silica gel using (2:98%) MeOH in dichloromethane to afford (Z)-4-(l-(4-(2- aminoethoxy)phenyl)-2-(4-ethylphenyl)but- 1 -en- 1 -yl)phenol (0.39 g).
Step-3: Synthesis of (E)-4-((2-(4-((Z)-2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000114_0001
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-ethylphenyl)but-l-en-l- yl)phenol (0.39 g, 1 mmol) in DMF (2 mL) was added at 0 °C, DIPEA (0.27 mL, 1.5 mmol) and (E)-4-bromo-N,N-dimethylbut-2-enamide (0.144 g, 0.75 mmol, Example-101, Step-7). The reaction mixture was stirred for 16 h at room temperature, after completion of reaction, reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (E)-4-((2-(4-((Z)-2-(4- ethylphenyl)- 1 -(4-hydroxyphenyl)but- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2- enamide (0.15 g).
Step-4: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-2-(4- ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000114_0002
To a stirred solution of (E)-4-((2-(4-((Z)-2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.15 g, 0.3 mmol) in dichloromethane (5 mL) was added boc anhydride (0.065 mg, 0.3 mmol). The reaction mixture was stirred for 2 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude compound was purified by column chromatography eluting with 3% MeOH in dichloromethane to afford tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-2-(4-ethylphenyl)-l-(4- hydroxyphenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.13 g, 72%).
Step-5: Synthesis of ((E)-4-((2-(4-((Z)-2-(4-ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000115_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-2-(4- ethylphenyl)-l-(4-hydroxyphenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.13 g, 0.261 mmol) in EtOH (2 mL) was added at 0 °C, 2M HC1 in diethyl ether (10 mL). The reaction mixture was stirred for 6 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with dichloromethane. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((Z)-2-(4-ethylphenyl)- l-(4-hydroxyphenyl)but- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.075 g, 5%). 1H NMR (400 MHz, DMSO-rf6): δ 9.38 (s, 1H), 7.00-6.95 (m, 6H), 6.75-6.45 (m, 8H), 3.87 (t, / = 5.2 Hz, 2H), 3.40-3.39 (m, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.78 (t, / = 5.2 Hz, 2H), 2.40-2.32 (m, 4H), 1.13 (t, / = 7.6 Hz, 3H), 0.83 (t, / = 7.2 Hz, 3H). LCMS: 499.3 [M+H]+
Example 21: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of (E)-4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol
Figure imgf000115_0002
Zinc dust (6.4 g, 98.57 mmol) was suspended in dry THF (100 mL) and cooled this suspension to -10 °C. To this TiCl4 (5.4 mL, 49.28 mmol) was added slowly under nitrogen atmosphere, stirred there for 15 min, slowly allowed it to reach room temperature and heated to reflux for 2 h. The resulting mixture was cooled to 0 °C, and a solution of 4-(benzyloxy) phenyl)(4-hydroxyphenyl) methanone (5 g, 16.42 mmol) and l-(p-tolyl)propan-l-one (2.35 g, 13.8 mmol) in dry THF (100 mL) were added and the contents were refluxed for 2 h. The reaction mixture was cooled to room temperature and quenched with 10% aqueous K2C03 solution and was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The crude material was purified by column chromatography over 230-400 mesh silica using 10% ethyl acetate in n- hexane to afford (E)-4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol (4.5 g, 65.2 %).
Step-2: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy )ethyl)carbamate
Figure imgf000116_0001
To a solution of (E)-4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol (4.5 g, 10.71 mmol) in DMF (50 mL) was added potassium carbonate (14.8 g, 107 mmol) and tert- butyl (2-bromoethyl)carbamate (3.6 g, 16.07 mmol). The reaction mixture was heated to 70 °C and maintained at this temperature for 16 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5-20% ethyl acetate in n-hexane to afford tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)efhyl)carbamate (3.3 g).
Step-3: Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethan-l-amine
Figure imgf000117_0001
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethyl)carbamate (3 g, 5.32 mmol) in methanol (15 mL) was added at 0 °C, 2M HC1 in diethyl ether (60 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure and the crude material was purified by column chromatography over 230-400 mesh silica gel using (4-5%) MeOH in dichloromethane to afford (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(p- tolyl)but-l -en- l-yl)phenoxy)ethan-l -amine (2.3 g, 93.5%).
Step-4: Synthesis of(Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol
Figure imgf000117_0002
To a stirred solution of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethan-l -amine (2.3 g, 4.9 mmol) in dichloromethane (23 mL) was added BBr3 (1M solution in dichloromethane, 6.2 g, 24.84 mmol) at -78 °C. The reaction mixture was stirred for 2.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (100 mL) and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude compound. The crude material was purified by column chromatography over 230-400 mesh silica gel using 10% MeOH in dichloromethane to afford desired compound (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol (0.92 g, 40.8 %).
Step-5: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
Figure imgf000118_0001
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(p-tolyl)but-l-en-l-yl)phenol (0.92 g, 2.02 mmol) in DMF (5 mL) was added DIPEA (0.52 g, 4.04 mmol) stirred for 15 min at room temperature. A solution of (£)-4-bromo-N,N-dimethylbut-2-enamide and (E)-4- chloro-N,N-dimethylbut-2-enamide mixture (0.29 g, 1.51 mmol, Example-101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 16 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1 g, crude).
Step-6: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(p-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000118_0002
To a stirred solution of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1 g, 2.06 mmol) in dichloromethane (20 mL) was added boc anhydride (0.54 g, 2.47 mmol). The reaction mixture was stirred for 2 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 2-3% MeOH in dichloromethane to afford desired compound tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2- en- 1 -yl)(2-(4-((Z)- 1 -(4-hydroxyphenyl)-2-(p-tolyl)but- 1 -en- 1 -yl)phenoxy)ethyl)carbamate (0.27 g). Step-7: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(p-tolyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000119_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(p-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.27 g, 0.557 mmol) in ethanol (1.5 mL) was added at 0 °C, 2M HCI in diethyl ether (10 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (0.025 g, 11.2%). 1H NMR (400 MHz, DMSO-</6): δ 9.40 (s, 1H), 6.97-6.91 (m, 4H), 6.74- 6.72 (m, 4H), 6.69-6.41 (m, 6H), 3.88 (t, J = 5.4 Hz, 2H), 3.00 (s, 3H), 2.85 (s, 3H), 2.81- 2.67 (m, 2H), 2.55-2.50 (m, 2H), 2.45-2.35 (m, 2H), 2.21 (s, 3H), 0.83 (t, / = 7.2 Hz, 3H). LCMS: 485.3 [M+H]+
Example 22: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy )ethyl)carbamate
Figure imgf000119_0002
0 "C-RT/12 h
Hi) l-iodo-2-methylbenzene/4M OH
80 "C/12 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene (3 g, 12.7 mmol, Example- 125, Step-4) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (3.22 g, 12.7 mmol), tetrakis(triphenylphosphine)platinum (0) (0.13 g, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (4.29 g, 11.8 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.415 g, 0.59 mmol), cesium carbonate (7.71 g, 23.6 mmol) and 2-methyl THF (60 mL) were added. This mixture was degassed with nitrogen and water (1 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (2.31 g, 56 mmol) and l-iodo-2-methylbenzene (3.57 g, 15 mmol) were added. Reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5% EtOAc in n-hexane to afford tert-butyl (Z)-(2-(4-( 1 -(4-(benzyloxy)phenyl)-2-(o-tolyl)but- 1 -en- 1 - yl)phenoxy)ethyl)carbamate (1.7 g, 40%).
Step-2: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(o-tolyl)but-l-en-l-yl)phenol
Figure imgf000120_0001
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy)ethyl)carbamate (1 g, 2.07 mmol) in dichloromethane (10 mL) was added BBr3 (1M solution in dichloromethane, 10.35 mL, 10.35 mmol) at -78 °C. The reaction mixture was stirred for 30 min and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (Z)-4-(l-(4-(2- aminoethoxy)phenyl)-2-(o-tolyl)but-l-en-l-yl)phenol (0.5 g, 64%).
Step-3: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy )ethyl) mino )-N,N-dimethylbut-2-enamide
Figure imgf000120_0002
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(o-tolyl)but-l-en-l-yl)phenol (0.35 g, 0.938 mmol) in DMF (2.5 mL) was added DIPEA (0.242 g, 1.87 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4-bromo-/V,N- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.143 g, 0.75 mmol, Example-101, Step-7) in DMF (2.5 mL) was added drop wise, reaction mixture was stirred for 5 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (0.8 g, crude).
Step-4: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(o-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000121_0001
To a stirred solution of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.8 g, 1.65 mmol) in dichloromethane (10 mL) was added boc anhydride (0.72 g, 3.30 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(o-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.22 g, 22%).
Step-5: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l- yl)phenoxy )ethyl)amino )-N,N-dimethylbut-2-enamide
Figure imgf000121_0002
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(o-tolyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.2 g, 0.342 mmol) in dichloromethane (10 mL) was added at 0 °C, TFA (1.5 mL). The reaction mixture was stirred for 1 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2- (4-((Z)-l-(4-hydroxyphenyl)-2-(o-tolyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N- dimethylbut-2-enamide (0.030 g) as an off-white solid. Ή NMR (400 MHz, DMSO-< 6): δ 9.39 (s, 1H), 7.19-7.11 (m, 1H), 7.07 (dd, /; = 10.6 Hz, 72 = 1.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 2H), 7.03-7.00 (m, 2H), 6.77-6.68 (m, 4H), 6.62 (t, / = 5 Hz, 1H), 6.59-6.47 (m, 3H), 3.84 (t, J = 5.2 Hz, 2H), 3.31-3.30 (m, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.76 (t, J = 5.8 Hz, 2H), 2.31 (q, J = 7.4 Hz, 2H), 2.04 (s, 3H), 0.83 (t, J = 7.6 Hz, 3H). LCMS: 485.3 [M+H]+
Example 23: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2-
( trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy )ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000122_0001
0 "C-RT/12 h
Hi) l-iodo-2-(trifluoromethyl)benzene
4M KOH/80 °C/12 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene (2 g, 8.47 mmol, Example- 125, Step-4) in 2-methyl THF (20 mL), was added bis(pinacolato)diboron (2.15 g, 8.47 mmol), tetrakis(triphenylphosphine)platinum (0) (0.13 g, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (2 g, 5.51 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.276 g, 0.393 mmol), cesium carbonate (5.1 g, 15.74 mmol) and 2-methyl THF (20 mL) were added. This mixture was degassed with nitrogen and water (0.2 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (11 mL, 4.48 mmol) and l-iodo-2-(trifluoiOmethyl)benzene (3.2 g, 12.2 mmol) were added. Reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5% EtOAc in n- hexane to afford tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (2 g, 36%).
Step-2: Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but-l- en-l-yl)phenoxy )ethan-l-amine
Figure imgf000123_0001
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (2 g, 3.24 mmol) in EtOH (2 mL) was added at 0 °C, 2M HCl in ether (30 mL). The reaction mixture was stirred for 1 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03j extracted with EtOAc. Organic layer was concentrated under reduced pressure to afford (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but-l-en-l- yl)phenoxy)ethan-l -amine (1.5 g).
Step-3: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but- l-en-l-yl)phenol
Figure imgf000123_0002
To a stirred solution of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but- 1 -en- l-yl)phenoxy)ethan-l -amine (1.5 g, 2.9 mmol) in dichloromethane (20 mL) was added BBr3 (1M solution in dichloromethane, 14.5 mL, 14.5 mmol) at -78 °C. The reaction mixture was stirred for 1 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (Z)-4-(l-(4-(2- aminoethoxy)phenyl)-2-(2-(trifluoromethyl)phenyl)but-l-en-l-yl)phenol (0.8 g, 62%).
Step-4: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2-
(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enam
Figure imgf000124_0001
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(2- (trifluoromethyl)phenyl)but-l-en-l-yl)phenol (0.8 g, 1.87 mmol) in IPA (10 mL) was added DIPEA (0.67 mL, 3.74 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4-bromo-N,N-dimethylbut-2-enamide and (E)-4-chloro-7V,N-dimethylbut-2- enamide mixture (0.322 g, 1.87 mmol, Example-101, Step-7) in IPA (10 mL) was added drop wise, reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (0.9 g, crude).
Step-5: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(2-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000124_0002
To a stirred solution of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.9 g, 1.67 mmol) in dichloromethane (20 mL) was added boc anhydride (0.54 mL, 2.5 mmol). The reaction mixture was stirred for 1 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by combi-flash using 2% MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)- 1 -(4-hydroxyphenyl)-2-(2-(trifluoromethyl)phenyl)but- 1 -en- 1 -yl)phenoxy)ethyl)carbamate (0.2 g, 20%).
Step-6: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2-
(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylb
Figure imgf000125_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(2-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.2 g, 0.313 mmol) in EtOH (1 mL) was added at 0 °C, 2MHC1 in diethyl ether (10 mL). The reaction mixture was stirred for 1 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03j extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(2-(trifluoromethyl)phenyl)but- l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.12 g) as an off-white solid. 1H NMR (400 MHz, DMSO-< ): δ 9.41 (s, 1H), 7.58 (d, / = 7.6 Hz, 1H), 7.54-7.50 (m, 1H), 7.39-7.34 (m, 2H), 7.01-6.99 (m, 2H), 6.78-6.72 (m, 4H), 6.62-6.47 (m, 4H), 3.84 (t, / = 5.6 Hz, 2H), 3.31-3.25 (m, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 2.76 (t, / = 5.6 Hz, 2H), 2.33-2.17 (m, 2H), 0.82 (t, / = 7.6 Hz, 3H). LCMS: 539.3 [M+H]+
Example 24: Synthesis of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of l-(benzyloxy)-4-bromo-2-fluorobenzene
Figure imgf000125_0002
To a solution of 4-bromo-2-fluorophenol (10 g, 52.3 mmol) in DMF (70 mL), were added potassium carbonate (8.7 g, 62.8 mmol) and benzyl bromide (9.85 g, 57.5 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04i concentrated under reduced pressure. The crude compound was purified over 230-400 mesh silica gel column chromatography using 8% EtOAc in n-hexane to afford l-(benzyloxy)-4-bromo-2-fluorobenzene (12.7 g, 86.6%).
Step-2: Synthesis of l-(benzyloxy)-4-(but-l-yn-l-yl)-2-fluorobenzene
Figure imgf000126_0001
sealed tube/90 °C/3 h
To a stirred solution of l-(benzyloxy)-4-bromo-2-fluorobenzene (6 g, 21.4 mmol) in 60 mL of MeOH:DMA:H20 (1: 1 : 1) in a sealed tube, were added copper iodide (0.41 g, 2.14 mmol) and cesium carbonate (12.57 g, 38.5 mmol) at room temperature. This mixture was degassed with three vacuum/ 2 cycles, and were added but-l-yn-l-yltrimethylsilane (10.8 g, 85.7 mmol, Example- 16, Step-2) followed by Pd(PPh3)2Cl2 (0.752 g, 1.07 mmol). The pressure tube was sealed and heated at 90 °C for 3 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by combo-flash using 0.2% EtOAc in n-hexane to afford l-(benzyloxy)-4-(but-l-yn-l-yl)-2-fluorobenzene (2.88 g, 51.8%).
Step-3: Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000126_0002
iii) IodobenzeneMM KOH
90 °C/3 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)-2-fluorobenzene (2.85 g, 11.2 mmol) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (2.85 g, 11.2 mmol), tetrakis(triphenylphosphine)platinum (0) (0.106 g, 0.0852 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and terf-butyl (2-(4-iodophenoxy)ethyl)carbamate (2.85 g, 7.85 mmol, Example- 17, Step-2), bis(triphenylphosphine)palladium (II) dichloride (0.393 g, 0.56 mmol), cesium carbonate (7.315 g, 22.4 mmol) and 2-methyl THF (30 mL) were added. This mixture was degassed with nitrogen and water (10 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (15.4 mL, 61.6 mmol) and iodobenzene (1.38 mL, 12.3 mmol) were added. Reaction mixture was stirred at 90 °C for 3 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 12.5% EtOAc in tt-hexane to afford tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)carbamate (3.8 g, 59.7 %).
Step-4: Synthesis of (E)-2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine
Figure imgf000127_0001
To a stirred solution of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate (3.8 g, 6.7 mmol) in ethanol (10 mL) was added at 0 °C, 2M HC1 in ditheyl ether (30 mL). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with ethyl acetate. Organic layer was concentrated under reduced pressure to afford crude (E)-2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine (3.1 g crude).
Step-5: Synthesis of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- fluorophenol
Figure imgf000127_0002
To a stirred solution of (E)-2-(4-(l-(4-(benzyloxy)-3-fluorophenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine (3.1 g, 6.6 mmol) in dichloromethane (75 mL) was added BBr3 (1M solution in dichloromethane, 33.2 mL, 33.19 mmol) at -78 °C. The reaction mixture was stirred for 0.5 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2- phenylbut-l-en-l-yl)-2-fluorophenol (1.4 g, crude).
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000128_0001
To a stirred solution of (E)-4-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- fluorophenol (1.4 g, 3.7 mmol) in IPA (15 mL) was added DIPEA (1.28 mL, 7.4 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (£)-4-bromo-N,N- dimethylbut-2-enamide and (£)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.512 g, 2.9 mmol, Example- 101, Step-7) in IPA (5 mL) was added drop wise, reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (0.42 g, crude).
Step-7: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000128_0002
To a stirred solution of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.42 g, 0.86 mmol) in dichloromethane (10 mL) was added boc anhydride (0.375 g, 1.7 mmol). The reaction mixture was stirred for 2 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using (30%) acetone in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l- yl)(2-(4-((E)- 1 -(3 -fluoro-4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethyl)carbamate (0.15 g, crude).
Step-8: Synthesis of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000129_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.15 g, 0.25 mmol) in EtOH (0.2 mL) was added at 0 °C, 2M HCl in diethyl ether (2.5 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative TLC to afford desired compound (E)-4-((2-(4-((E)- 1 -(3 -fluoro-4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.006 g, 4.8%). Ή NMR (400 MHz, DMSO-<¾): δ 9.87 (s, 1H), 7.20-7.08 (m, 5H), 6.95 (t, J = 8.8 Hz, 1H), 6.88-6.81 (m, 2H), 6.74 (d, / = 8.0 Hz, 2H), 6.63-6.61 (m, 4H), 3.95-3.85 (m, 2H), 3.59-3.41 (m, 2H), 3.01 (s, 3H), 2.96-2.88 (m, 2H), 2.85 (s, 3H), 2.40 (q, J = 7 Hz, 2H), 0.85 (t, / = 7.2 Hz, 3H). LCMS: 489.3 [M+H]+
Example 25: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide Step-1: Synthesis of 4-iodo-3-methylphenol
3 M HCI/ J
Figure imgf000130_0001
To a solution of 4-amino-3-methylphenol (10 g, 81 mmol) in THF (45 mL) was added 3M HC1 (35 mL) at 0 °C over a period of 10 min followed by NaN02 (6.1 g, 89 mmol). To the above reaction mixture, potassium iodide (53.89 g, 166 mmol) in water (140 mL) was added dropwise and stirred at 0 °C for 15 min. After completion of reaction, reaction mixture was extracted with EtOAc. Organic layer was washed water followed by brine, concentared under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230-400 mesh silica gel using 10% EtOAc in n-hexane to give the title compound (9 g, 47%).
Step-2: Synthesis of tert-butyl (2-(4-iodo-3-methylphenoxy)ethyl)carbamate
Figure imgf000130_0002
To a solution of 4-iodo-3-methylphenol (8 g, 34.3 mmol) in DMF (80 mL) was added potassium carbonate (28.4 g, 206 mmol) and tert-butyl (2-bromoethyl)carbamate (15.38 g, 68.6 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford tert-butyl (2-(4-iodo-3- methylphenoxy)ethyl)carbamate (3.4 g, 28%).
Step-3: Synthesis of l-(benzyloxy)-4-bromobenzene
Figure imgf000130_0003
To a solution of 4-bromophenol (5 g, 28.9 mmol) in DMF (50 mL), were added potassium carbonate (11.9 g, 86.7 mmol) and benzyl bromide (5.9 g, 34.6 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04; concentrated under reduced pressure. The crude compound was purified over 230- 400 mesh silica gel column chromatography using 8% EtOAc in n-hexane to afford 1- (benzyloxy)-4-bromobenzene (6 g, 79%).
Step-4: Synthesis of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene
Figure imgf000131_0001
sealed tube/90 "C/12 h
To a stirred solution of l-(benzyloxy)-4-bromobenzene (2.5 g, 9.54 mmol) in 30 raL of MeOH:DMA:H20 (1 : 1: 1) in a sealed tube, were added copper iodide (0.181 g, 0.95 mmol) and cesium carbonate (4.3 g, 13.3 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (2.4 g, 19 mmol, Example-16, Step-2) followed by Pd(PPh3)2Cl2 (0.334 g, 0.479 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using 1% EtOAc in n-hexane to afford l-(benzyloxy)-4-(but-l-yn-l- yl)benzene (1.6 g, 72%).
Step-3: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)carbamate
Figure imgf000131_0002
0 "C-RT/12 h
Hi) lodobenzene/4M KOH
90 °C/7 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene (3 g, 12.7 mmol) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (3.22 g, 12.7 mmol), tetrakis(triphenylphosphine)platinum (0) (0.13 g, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodo-3-methylphenoxy)ethyl)carbamate (3.4 g, 8.99 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.315 g, 0.44 mmol), cesium carbonate (5.86 g, 17.9 mmol) and 2-methyl THF (30 mL) were added. This mixture was degassed with nitrogen and water (0.5 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (2.51 g, 44.8 mmol) and iodobenzene (1.66 g, 8.15 mmol) were added. Reaction mixture was stirred at 90 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 25% EtOAc in n-hexane to afford tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)carbamate (1.8 g, 40 %).
Step-4: Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy )ethan-l -amine
Figure imgf000132_0001
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)- 3-methylphenoxy)ethyl)carbamate (1.8 g, 3.19 mmol) in dichloromethane (10 mL) was added at 0 °C, 2M HC1 in ether (20 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure to afford (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)- 3-methylphenoxy)ethan-l-amine (1.5 g).
Step-5: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenol
Figure imgf000132_0002
To a stirred solution of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethan-l -amine (1.5 g, 3.2 mmol) in dichloromethane (15 mL) was added BBr3 (1M solution in dichloromethane, 16 mL, 16 mmol) at -78 °C. The reaction mixture was stirred for 2 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (Z)-4-(l-(4-(2-aminoethoxy)-2- methylphenyl)-2-phenylbut-l-en-l-yl)phenol (0.8 g, 66%).
Step-6: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000133_0001
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)-2-methylphenyl)-2-phenylbut-l-en-l- yl)phenol (0.8 g, 2.14 mmol) in DMF (6 mL) was added DIPEA (0.55 g, 4.2 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4-bromo-N,N- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.4 g, 2.14 mmol, Example- 101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 5 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.5 g, crude).
Step-7: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3-methylphenoxy)ethyl)carbamate
Figure imgf000133_0002
To a stirred solution of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.5 g, 3 mmol) in dichloromethane (20 mL) was added boc anhydride (1.35 g, 6.1 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)- l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3-methylphenoxy)ethyl)carbamate (0.35 g, 19%).
Step-8: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000134_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3-methylphenoxy)ethyl)carbamate (0.35 g, 0.599 mmol) in dichloromethane (5 mL) was added at 0 °C, TFA (1 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1-en- 1 -yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (4.2 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 7.13-7.09 (m, 2H), 7.05-7.01 (m, 3H), 6.98 (d, / = 8.8 Hz, 2H), 6.78 (d, / = 8.4 Hz, 1H), 6.71 (d, / = 8.4 Hz, 2H), 6.63-6.52 (m, 1H), 6.51- 6.46 (m, 3H), 3.86 (t, / = 6.0 Hz, 2H), 3.33-3.31 (m, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.78 (t, J = 5.6 Hz, 2H), 2.50-2.49 (m, 2H), 1.95 (s, 3H), 0.90 (t, J = 7.4 Hz, 3H). LCMS: 485.3 [M+H]+ Example-26: Synthesis of (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enainide
Step-1: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000135_0001
0 "C-RT/12 h
Hi) l-chloro-2-iodobenzene/4M KOH
80 "C/12 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene (3 g, 12.7 mmol, Example- 125, Step-4) in 2-methyl THF (30 mL), was added bis(pinacolato)diboron (3.22 g, 12.7 mmol), tetrakis(triphenylphosphine)platinum (0) (0.13 g, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (4.29 g, 11.8 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.415 g, 0.59 mmol), cesium carbonate (7.71 g, 23.6 mmol) and 2-methyl THF (60 mL) were added. This mixture was degassed with nitrogen and water (1 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (3.59 g, 64.2 mmol) and l-chloro-2-iodobenzene (5.56 g, 23.3 mmol) were added. Reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5% EtOAc in n- hexane to afford tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l-en-l- yl)phenoxy)ethyl)carbamate (3 g, 44%).
Step-2: Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l-en-l- yl)phenoxy)ethan-l-amine
Figure imgf000135_0002
To a stirred solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but- l-en-l-yl)phenoxy)ethyl)carbamate (3 g, 5.1 mmol) in dichloromethane (30 mL) was added at 0 °C, 2M HC1 in ether (30 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with 10% MeOH in dichloromethane. Organic layer was concentrated under reduced pressure to afford (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l- en-l-yl)phenoxy)efhan-l -amine (2.5 g).
Step-3: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2~(2-chlorophenyl)but-l-en-l- yl)phenol
Figure imgf000136_0001
To a stirred solution of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(2-chlorophenyl)but-l-en-l- yl)phenoxy)ethan-l -amine (2.5 g, 5.1 mmol) in dichloromethane (30 mL) was added BBr3 (1M solution in dichloromethane, 25.8 mL, 25.8 mmol) at -78 °C. The reaction mixture was stirred for 30 min and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (Z)-4-(l-(4-(2- aminoethoxy)phenyl)-2-(2-chlorophenyl)but-l-en-l-yl)phenol (1 g, 50%).
Step-4: Synthesis of (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000136_0002
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(2-chlorophenyl)but-l-en-l- yl)phenol (1 g, 2.5 mmol) in DMF (5 mL) was added DIPEA (0.9 mL, 5 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4-bromo-N,/V- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.437 g, 2.29 mmol, Example-101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 5 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.5 g, crude).
Step-5: Synthesis of tert-butyl (2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en- l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate
Figure imgf000137_0001
To a stirred solution of (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.5 g, 2.97 mmol) in dichloromethane (20 mL) was added boc anhydride (1.29 g, 5.95 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to obtain tert-butyl (2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.35 g, 23%).
Step-6: Synthesis of (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000137_0002
To a stirred solution of tert-butyl (2-(4-((Z)-2-(2-chlorophenyl)-l-(4-hydroxyphenyl)but-l- en-l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.35 g, 0.604 mmol) in dichloromethane (15 mL) was added at 0 °C, TFA (0.2 mL, 2.89 mmol). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((Z)-2-(2-chlorophenyl)- 1 -(4-hydroxyphenyl)but- 1-en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.045 g) as an off-white solid. 1H NMR (400 MHz, DMSO-i 6): δ 9.42 (s, 1H), 7.31 (d, / = 7.6 Hz, 1H), 7.19-7.13 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H), 7.78-7.75 (m, 4H), 6.67-6.57 (m, 3H), 6.50 (d, / = 15.2 Hz, 1H), 3.86 (t, J = 5.6 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.36 (q, J = 7.6 Hz, 2H), 0.86 (t, / = 7.6 Hz, 3H). LCMS: 505.3 [M+H]+
Example 27: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(4- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N^
Step-1: Synthesis of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(4- ( trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy )ethyl)carbamate
Figure imgf000138_0001
0 "C-RT/12 h
iii) l-iodo-4-(trinuoromethyl)benzene
4M KOH/90 °C/7 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene (2 g, 8.47 mmol, Example- 125, Step-4) in 2-methyl THF (20 mL), was added bis(pinacolato)diboron (2.15 g, 8.47 mmol), tetrakis(triphenylphosphine)platinum (0) (0.13 g, 0.104 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (2.67 g, 7.3 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.286 g, 0.41 mmol), cesium carbonate (5.32 g, 16.3 mmol) and 2-methyl THF (20 mL) were added. This mixture was degassed with nitrogen and water (0.5 mL) was added. This mixture was stirred at room temperature for 12 h. After completion of reaction, to the above reaction mixture 4M KOH (11 mL, 4.48 mmol) and l-iodo-4-(trifluoromethyl)benzene (3.2 g, 12.2 mmol) were added. Reaction mixture was stirred at 90 °C for 7 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 20% EtOAc in n- hexane to afford tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(4- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (3.2 g, 64%).
Step-2: Synthesis of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but-l- en-l-yl)phenoxy)ethan-l-amine
Figure imgf000139_0001
To a stin-ed solution of tert-butyl (Z)-(2-(4-(l-(4-(benzyloxy)phenyl)-2-(4- (trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (3.2 g, 5 mmol) in EtOH (15 mL) was added at 0 °C, 2M HCl in ether (30 mL). The reaction mixture was stin-ed for 1 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with EtOAc. Organic layer was concentrated under reduced pressure to afford (Z)-2-(4-( 1 -(4-(benzyloxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but- 1 -en- 1 - yl)phenoxy)ethan-l -amine (2.5 g, 93%).
Step-3: Synthesis of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but- l-en-l-yl)phenol
Figure imgf000139_0002
To a stirred solution of (Z)-2-(4-(l-(4-(benzyloxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but- 1 -en- l-yl)phenoxy)ethan-l -amine (2.5 g, 4.8 mmol) in dichloromethane (50 mL) was added BBr3 (1M solution in dichloromethane, 24.1 mL, 24.1 mmol) at -78 °C. The reaction mixture was stined for 1 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (Z)-4-(l-(4-(2- aminoethoxy)phenyl)-2-(4-(trifluoromethyl)phenyl)but-l-en-l-yl)phenol (0.785 g, 38%). Step-4: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(4-
(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enam
Figure imgf000140_0001
To a stirred solution of (Z)-4-(l-(4-(2-aminoethoxy)phenyl)-2-(4- (trifluoromethyl)phenyl)but-l-en-l-yl)phenol (0.78 g, 1.82 mmol) in IP A (5 mL) was added DIPEA (0.63 mL, 3.65 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4-bromo-N,N-dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2- enamide mixture (0.314 g, 1.82 mmol, Example-101, Step-7) in IPA (5 mL) was added drop wise, reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.15 g, crude).
Step-5: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(4-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000140_0002
To a stirred solution of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(4- (trifluoromethyl)phenyl)but- 1 -en- 1 -yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.12 g, 2 mmol) in dichloromethane (10 mL) was added boc anhydride (0.9 g, 4 mmol). The reaction mixture was stirred for 1 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by combi-flash using 3.5% MeOH in dichloromethane to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(4-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.07 g, 7.1%).
Step-6: Synthesis of (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(4-
(tnfiuoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethy
Figure imgf000141_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((Z)-l-(4- hydroxyphenyl)-2-(4-(trifluoromethyl)phenyl)but-l-en-l-yl)phenoxy)ethyl)carbamate (0.36 g, 0.564 mmol) in dichloromethane (10 mL) was added at 0 °C, TFA (2 mL). The reaction mixture was stirred for 2 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-(4-(trifluoromethyl)phenyl)but-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.055 g, 18%) as an off-white solid. 1H NMR (400 MHz, DMSO-< ): δ 9.45 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 2.0 Hz, 2H), 6.76 (d, J = 8.3 Hz, 2H), 6.73 (d, / = 3.0 Hz, 1H), 6.71 (d, / = 8.8 Hz, 1H), 6.64-6.57 (m, 3H), 6.49, (d, J = 15.2 Hz, 1H), 3.87 (t, J = 5.4 Hz, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 2.78 (t, / = 5.4 Hz, 2H), 2.50-2.44 (m, 2H), 2.06 (bs, 1H), 0.84 (t, J = 7.4 Hz, 3H). LCMS: 539.3 [M+H]+
Example 28: Synthesis of (E)-4-((2-(4-((E)-l-(3-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of l-(benzyloxy)-3-bromobenzene
BnBr/K2C03 DMF
HO Br RT/12 h BnO Br
To a solution of 3-bromophenol (5 g, 28.9 mmol)' in DMF (50 mL), were added potassium carbonate (11.9 g, 86.7 mmol) and benzyl bromide (5.9 g, 34.6 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04i concentrated under reduced pressure. The crude compound was purified over 230- 400 mesh silica gel column chromatography using 8% EtOAc in n-hexane to afford 1- (benzyloxy)-3-bromobenzene (6 g, 79%).
Step-2: Synthesis of l-(benzyloxy)-3-(but-l-yn-l-yl)benzene
Figure imgf000142_0001
sealed tubc/90 °C/12 h
To a stirred solution of l-(benzyloxy)-3-bromobenzene (2.5 g, 9.54 mmol) in 30 mL of MeOH:DMA:H20 (1: 1: 1) in a sealed tube, were added copper iodide (0.181 g, 0.95 mmol) and cesium carbonate (4.3 g, 13.3 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (2.4 g, 19 mmol, Example- 16, Step-2) followed by Pd(PPh3)2Cl2 (0.334 g, 0.479 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using 1% EtOAc in n-hexane to afford l-(benzyloxy)-3-(but-l-yn-l- yl)benzene (1.6 g, 72%).
Step-3: Synthesis of tert-butyl (E)-(2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy )ethyl)carbamate
Figure imgf000142_0002
iii) Iodobenzene/4M OH
90 "C/8 h
To a stirred solution of l-(benzyloxy)-3-(but-l-yn-l-yl)benzene (3.2 g, 13.55 mmol) in 2- methyl THF (30 mL), was added bis(pinacolato)diboron (3.4 g, 13.55 mmol), tetrakis(triphenylphosphine)platinum (0) (0.118 g, 0.094 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 8 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (4.2 g, 11.63 mmol, Example- 17, Step-2), bis(triphenylphosphine)palladium (II) dichloride (0.408 g, 0.58 mmol), cesium carbonate (7.5 g, 23.26 mmol) and 2-methyl THF (50 mL) were added. This mixture was degassed with nitrogen and water (1 mL) was added. This mixture was stirred at room temperature for 8 h. After completion of reaction, to the above reaction mixture 4M KOH (16 mL, 64.24 mmol) and iodobenzene (2.3 g, 11.68 mmol) were added. Reaction mixture was stirred at 90 °C for 8 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 2% MeOH in dichloromethane to afford tert-butyl (E)-(2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)carbamate (8 g, crude).
Step-4: Synthesis of (E)-2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l-amine
Figure imgf000143_0001
To a stirred solution of tert-butyl (E)-(2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)carbamate (8 g, 14.56 mmol) in ethanol (10 mL) was added at 0 °C, 2M HC1 in ditheyl ether (70 mL). The reaction mixture was stirred for 1 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with ethyl acetate. Organic layer was concentrated under reduced pressure to afford crude (E)-2-(4-( 1 -(3 -(benzyloxy)phenyl)-2-phenylbut- 1 -en- 1 -yl)phenoxy)ethan- 1 -amine (2.5 g) .
Step-5: Synthesis of(E)-3-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol
Figure imgf000143_0002
To a stirred solution of (E)-2-(4-(l-(3-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethan-l -amine (2.5 g, 5.56 mmol) in dichloromethane (50 mL) was added BBr3 (1M solution in dichloromethane, 27.8 mL, 27.8 mmol) at -78 °C. The reaction mixture was stirred for 2 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude (E)-3-(l-(4-(2-aminoethoxy)phenyl)-2- phenylbut-l-en-l-yi)phenol (1.1 g, crude).
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(3-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000144_0001
To a stirred solution of (E)-3-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol (1.1 g, 3.06 mmol) in DMF (20 mL) was added DIPEA (1.1 mL, 6.12 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (£)-4-bromo-N,N- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.42 g, 2.45 mmol, Example- 101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 12 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (1.4 g, crude).
Step-7: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000144_0002
To a stirred solution of (E)-4-((2-(4-((E)-l-(3-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (1.4 g, 2.97 mmol) in dichloromethane (20 mL) was added boc anhydride (0.97 g, 4.46 mmol). The reaction mixture was stirred for 1 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by combi-flash to obtain tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- hydroxyphenyl)-2-phenylbut- 1-en- 1 -yl)phenoxy)efhyl)carbamate (0.6 g).
Step-8: Synthesis of (E)-4-((2-(4-((E)-l-(3-fluoro-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000145_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-(4-((E)-l-(3- hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)carbamate (0.6 g, 1.05 mmol) in EtOH (3 mL) was added at 0 °C, 2M HC1 in diethyl ether (15 mL). The reaction mixture was stiffed for 1 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03i extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2- (4-((E)-l-(3-hydroxyphenyl)-2-phenylbut-l-en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut- 2-enamide (0.16 g). 1H NMR (400 MHz, DMSO-<¾): δ 9.34 (s, 1H), 7.20-7.09 (m, 6H), 6.73- 6.67 (m, 2H), 6.66-6.48 (m, 7H), 3.87 (t, J = 5.8 Hz, 2H), 3.32-3.31 (m, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 2.78 (t, / = 5.4 Hz, 2H), 2.39 (q, / = 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). LC MS: 471.3 [M+H]+
Example 29: Synthesis of (E)-4-((2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of2-(benzyloxy)-5-bromobenzonitrile
Figure imgf000145_0002
To a solution of 5-bromo-2-hydroxybenzonitrile (10 g, 50.5 mmol) in acetonitrile (100 mL), were added potassium carbonate (62.7 g, 454 mmol) and benzyl bromide (6.5 mL, 55 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was diluted with water, extracted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to afford 2-(benzyloxy)-5-bromobenzonitrile (13.8 g, 81%).
Step-2: Synthesis of2-(benzyloxy)-5-(but-l-yn-l-yl)benzonitrile
Figure imgf000146_0001
90 °C/S h
scaled tube
To a stirred solution of 2-(benzyloxy)-5-bromobenzonitrile (10 g, 29.8 mmol) in 90 mL of MeOH:DMA:H20 (1: 1 : 1) in a sealed tube, were added copper iodide (0.570 g, 2.98 mmol) and cesium carbonate (17.51 g, 53.7 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (7.52 g, 59 mmol, Example-16, Step-2) followed by Pd(PPh3)2Cl2 (1 g, 1.49 mmol). The pressure tube was sealed and heated at 90 °C for 5 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using 3% EtOAc in rc-hexane to afford 2-(benzyloxy)-5-(but-l-yn-l- yl)benzonitrile (6.8 g, 88%).
Step-3: Synthesis of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-cyanophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate
Figure imgf000146_0002
Hi) IodobenzeneMM KOH
90 °C/8 h
To a stirred solution of 2-(benzyloxy)-5-(but-l-yn-l-yl)benzonitrile (6.8 g, 26 mmol) in 2- methyl THF (60 mL), was added bis(pinacolato)diboron (6.61 g, 26 mmol), tetrakis(triphenylphosphine)platinum (0) (0.324 g, 0.26 mmol) under nitrogen atmosphere, reaction mixture was stirred at 90 °C for 12 h. The solution was allowed to cool to room temperature and tert-butyl (2-(4-iodophenoxy)ethyl)carbamate (9.44 g, 26 mmol, Example- 17, Step-2), bis(triphenylphosphine)palladium (II) dichloride (0.913 g, 1.3 mmol), cesium carbonate (16.96 g, 52 mmol) and 2-methyl THF (30 mL) were added. This mixture was degassed with nitrogen and water (2 mL) was added. This mixture was stirred at room temperature for 6 h. After completion of reaction, to the above reaction mixture 4M KOH (7.99 g, 142.7 mmol) and iodobenzene (7.41 g, 36.3 mmol) were added. Reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 5-6% EtOAc in rc-hexane to afford tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-cyanophenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)carbamate (6.3 g, 43%).
Step-4: Synthesis of (E)-5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- (benzyloxy)benzonitrile
Figure imgf000147_0001
To a stirred solution of tert-butyl (E)-(2-(4-(l-(4-(benzyloxy)-3-cyanophenyl)-2-phenylbut-l- en-l-yl)phenoxy)ethyl)carbamate (6.3 g, 10.9 mmol) in dichloromethane (60 mL) was added at 0 °C, 2M HC1 in ditheyl ether (30 mL). The reaction mixture was stirred for 3 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03, extracted with ethyl acetate. Organic layer was concentrated under reduced pressure to afford (E)-5-(l -(4-(2-aminoethoxy)phenyl)-2-phenylbut- 1 -en- 1 -yl)-2-
(benzyloxy)benzonitrile (4.6 g, 92%).
Step-5: Synthesis of (E)-5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- hydroxybenzonitrile
Figure imgf000147_0002
To a stirred solution of (E)-5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- (benzyloxy)benzonitrile (1 g, 2.1 mmol) in dichloromethane (10 mL) was added BBr3 (1M solution in dichloromethane, 10.5 mL, 10.5 mmol) at -78 °C. The reaction mixture was stirred for 2 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude (E)-5-(l-(4-(2-aminoethoxy)phenyl)-2- phenylbut-l-en-l-yl)-2-hydroxybenzonitrile (0.38 g, 47%).
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000148_0001
To a stirred solution of (E)-5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)-2- hydroxybenzonitrile (0.38 g, 0.989 mmol) in DMF (8 mL) was added DIPEA (0.255 g, 1.979 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (E)-4- bromo-N,N-dimethylbut-2-enamide and (£)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.188 g, 0.989 mmol, Example-101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 2 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (0.5 g, crude).
Step-7: Synthesis of tert-butyl (2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)((E)-4-(dimethy mino)-4-oxobut-2-en-l-yl)carbamate
Figure imgf000148_0002
To a stirred solution of (E)-4-((2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.5 g, 1.01 mmol) in dichloromethane (5 mL) was added boc anhydride (0.33 g, 1.5 mmol). The reaction mixture was stirred for 2 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by combi-flash to obtain tert-butyl (2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.08 g, 13.3%).
Step-8: Synthesis of (E)-4-((2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000149_0001
To a stirred solution of tert-butyl (2-(4-((E)-l-(3-cyano-4-hydroxyphenyl)-2-phenylbut-l-en- l-yl)phenoxy)ethyl)((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)carbamate (0.26 g, 0.436 mmol) in dichloromethane (10 mL) was added at 0 °C, 2M HC1 in diethyl ether (5 mL). The reaction mixture was stirred for 3 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03j extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-(4-((E)- l-(3-cyano-4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 - yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.025 g). Ή NMR (400 MHz, DMSO-i/6): δ 7.35 (d, J = 2.0 Hz, 1H), 7.29 (dd, J{ = 8.6 Hz, J2 = 2.2 Hz, 1H), 7.20-7.17 (m, 2H), 7.12-7.09 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.72 (d, / = 8.8 Hz, 2H), 6.64-6.48 (m, 4H), 3.87 (t, J = 5.6 Hz, 2H), 3.32-3.16 (m, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 2.78 (t, / = 5.8 Hz, 2H), 3.70 (q, / = 7.4 Hz, 2H), 0.85 (t, J = 7.6 Hz, 3H). LCMS: 496.3 [M+H]+
Example 30: Synthesis of (E)-4-((2-((5-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (Z)-(2-((5-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)oxy)ethyl)carbamate
Figure imgf000150_0001
0 "C-RT/16 h
iii) iodobenzene
4M KOH/90 °C/16 h
To a stirred solution of l-(benzyloxy)-4-(but-l-yn-l-yl)benzene (6.2 g, 26.2 mmol, Example- 125, Step-4) in 2-methyl THF (62 mL), was added bis(pinacolato)diboron (6.7 g, 26.5 mmol), tetrakis(triphenylphosphine)platinum (0) (0.32 g, 0.26 mmol) under nitrogen atmosphere, reaction mixture was stirred at 85 °C for 8 h. The solution was allowed to cool to room temperature and tert-butyl (2-((5-iodopyridin-2-yl)oxy)ethyl)carbamate (9.5 g, 26.5 mmol, Example-62, Step-1), bis(triphenylphosphine)palladium (II) dichloride (0.93 g, 1.3 mmol), cesium carbonate (17.06 g, 52.5 mmol) and 2-methyl THF (60 mL) were added. This mixture was degassed with nitrogen and water (2 mL) was added. This mixture was stirred at room temperature for 16 h. After completion of reaction, to the above reaction mixture 4M KOH (36 mL, 144 mmol) and iodobenzene (7.49 g, 36.7 mmol) were added. Reaction mixture was stirred at 90 °C for 16 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 10-15% EtOAc in n- hexane to afford tert-butyl (Z)-(2-((5-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)oxy)ethyl)carbamate (12.1 g, 78%).
Step-2: Synthesis of (Z)-4-(l-(6-(2-aminoethoxy)pyridin-3-yl)-2-phenylbut-l-en-l- yl)phenol
Figure imgf000150_0002
To a stirred solution of tert-butyl (Z)-(2-((5-(l-(4-(benzyloxy)phenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)oxy)ethyl)carbamate (7 g, 12.7 mmol) in dichloromethane (70 mL) was added BBr3 (1M solution in dichloromethane, 63.6 mL, 63.6 mmol) at -78 °C. The reaction mixture was stirred for 1 h and quenched with MeOH (5 mL). The resulting mixture was slowly warmed to room temperature; water was added (50 mL) and layers were separated. The organic layer was washed with saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain (Z)-4-(l-(6-(2- aminoethoxy)pyridin-3-yl)-2-phenylbut-l-en-l-yl)phenol (3.5 g, 76%).
Step-3: Synthesis of (E)-4-((2-((5-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin- 2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000151_0001
To a stirred solution of (Z)-4-(l-(6-(2-aminoethoxy)pyridin-3-yl)-2-phenylbut-l-en-l- yl)phenol (2 g, 5.55 mmol) in DMF (15 mL) was added DIPEA (1.43 g, 11 mmol) at room temperature, stirred for 15 min at same temperature. A solution of (£)-4-bromo-N,N- dimethylbut-2-enamide and (E)-4-chloro-N,N-dimethylbut-2-enamide mixture (0.94 g, 5.55 mmol, Example- 101, Step-7) in DMF (5 mL) was added drop wise, reaction mixture was stirred for 6 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was used in next step without further purification (3.2 g, crude).
Step-4: Synthesis of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-((5-((Z)-l-(4- hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)oxy)ethyl)carbamate
Figure imgf000151_0002
To a stirred solution of (E)-4-((2-((5-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide (3.2 g, 6.78 mmol) in dichloromethane (32 mL) was added boc anhydride (2.2 g, 10 mmol). The reaction mixture was stirred for 4 h at room temperature, after completion of reaction (monitored by TLC), reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water followed by saturated NaCl solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. Crude material was purified by combi-flash using 2-3% MeOH in dichloromethane to obtain tert-butyl ((E)-4- (dimethylamino)-4-oxobut-2-en- 1 -yl)(2-((5-((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 - yl)pyridin-2-yl)oxy)ethyl)carbamate (0.76 g).
Step-5: Synthesis of (E)-4-((2-((5-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin- 2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000152_0001
To a stirred solution of tert-butyl ((E)-4-(dimethylamino)-4-oxobut-2-en-l-yl)(2-((5-((Z)-l- (4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)oxy)ethyl)carbamate (0.75 g, 0.564 mmol) in EtOH (3.5 mL) was added at 0 °C, 2M HCl in diethyl ether (3.5 mL). The reaction mixture was stirred for 16 h at room temperature. After completion of reaction, reaction mixture was basified with saturated NaHC03> extracted with ethyl acetate. Combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. Crude compound was purified by preparative HPLC to afford desired compound (E)-4-((2-((5-((Z)- 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)pyridin-2- yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide (0.045 g, 7.3%) as an off-white solid. Ή NMR (400 MHz, DMSO- 6): δ 9.45 (s, 1H), 7.53 (s, 1H), 7.23-7.19 (m, 2H), 7.17-7.07 (m, 4H), 7.02-7.00 (m, 2H), 6.75 (d, J = 8.4 Hz, 2H), 6.63-6.59 (m, 1H), 6.50-6.47 (m, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.31-3.33 (m, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 2.77 (t, / = 5.6 Hz, 2H), 2.40 (q, J = 7.7 Hz, 2H), 0.84 (t, J = 7.7 Hz, 3H). LCMS: 472.3 [M+H]+
Example 31: Synthesis of (E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Step-1: Synthesis of tert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate
Figure imgf000152_0002
To a stirred solution of tert-butyl (5-bromopyridin-2-yl)carbamate (3 g, 10.989 mmol) in 30 mL of MeOH:DMA:H20 (1: 1: 1) in a sealed tube, were added copper iodide (0.235 g, 1.098 mmol) and cesium carbonate (4.849 g, 15.3 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (2.76 g, 22 mmol, Example-16, Step-2) followed by Pd(PPh3)2Cl2 (0.384 g, 0.5 mmol). The pressure tube was sealed and heated at 90 °C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 X 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude product was purified over 230-400 mesh silica column chromatography using 5% EtOAc in /i-hexane to afford tert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate (2.5 g, 88%) as a white solid.
Step-2: Synthesis of tert-butyl (E)-(5-( l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin- 2-yl)carbamate.
Figure imgf000153_0001
To a solution of tert-butyl (5-(but-l-yn-l-yl)pyridin-2-yl)carbamate (1.5 g, 6.09 mmol), iodobenzene (3.73 g, 18.29 mmol), 4-hydroxy phenyl boronic acid (2.52 g, 18.29 mmol), in Ν,Ν-dimethyl formamide/water (2: 1, 15 mL) was added K2C03 (2.52 g, 18.29 mmol). The contents were degassed with three vacuum/N2 cycles, and then stirred for 1 h until the solution was homogeneous. A solution of Pd(PhCN)2Cl2 (0.022 g, 0.0609 mmol) in N,N- dimethyl formamide (1 mL) was added and the resulting mixture was stirred at 45 °C for 12 h. Upon completion by TLC, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude material was purified over 230-400 mesh silica column chromatography using 20% ethyl acetate in n-hexane to afford tert-butyl (E)-(5-( 1 -(4-hydroxyphenyl)-2-phenylbut- 1 -en- 1 -yl)pyridin-2-yl)carbamate (1.2 g, 47%) as an off-white solid.
Step-3: Synthesis of tert-butyl (E)-(5-(l-(4-(2-(l,3-dioxoisoindolin-2-yl)ethoxy)phenyl)-2- phenylbut-l-en-l-yl)pyridin-2-yl)carbamate
Figure imgf000154_0001
To a solution of (E)-(5-(l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.5 g, 1.2 mmol) in DMF (12 mL), at 0 °C, were added sequentially potassium carbonate (0.663 g, 4.8 mmol) and 2-(2-bromoethyl)isoindoline-l,3-dione (1.52 g, 6 mmol). The reaction mixture was stirred at 80 °C for 12 h, was diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 230-400 mesh silica gel using 20% ethyl acetate in n-hexane to afford tert-butyl (E)-(5-(l-(4-(2-(l,3-dioxoisoindolin-2- yl)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.35 g, 50%) as a light brown colour gummy mass.
Step-4: Synthesis of tert-butyl (E)-(5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)carbamate
Figure imgf000154_0002
To a solution of (E)-(5-(l-(4-(2-(l,3-dioxoisoindolin-2-yl)ethoxy)phenyl)-2-phenylbut-l-en- l-yl)pyridin-2-yl)carbamate (0.5 g, 0.8488 mmol) in MeOH/DCM (2: 1, 15 mL) was added hydrazine hydrate (10 mL) at room temperature. The reaction mixture was stirred at 70 °C for 2 h, quenched with NH4OH and extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 100-200 mesh silica gel using 10% methanol in DCM to afford tert-butyl (E)-(5-(l-(4-(2- aminoethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.12 g, 30%) as an off- white solid.
Step-5: Synthesis of tert-butyl (5-((E)-l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2-en-l- yl)amino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate
Figure imgf000155_0001
To a stirred solution of tert-butyl (E)-(5-(l-(4-(2-aminoethoxy)phenyl)-2-phenylbut-l-en-l- yl)pyridin-2-yl)carbamate (0.120 g, 0.261 mmol) in DMF (10 mL) was added at 0 °C, (E)-4- bromo-N,N-dimethylbut-2-enamide (0.05 g, 0.261 mmol) and DIPEA (0.068 g, 0.522 mmol). The reaction mixture was stirred for 12 h at room temperature, after completion of reaction, reaction mixture was diluted with cold water (50 mL) and extracted with dichloromethane. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography over 100-200 mesh silica gel using 5% methanol in DCM to afford tert-butyl (5-((E)-l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2-en-l- yl)amino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.05 g, 33%) as an off-white solid.
Step-6: Synthesis of (E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
Figure imgf000155_0002
To a stirred solution of tert-butyl (5-((E)-l-(4-(2-(((E)-4-(dimethylamino)-4-oxobut-2-en-l- yl)amino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)pyridin-2-yl)carbamate (0.1 g, 0.176 mmol) in ethanol (5 mL) was added at 0 °C, 2M HQ in ether (10 mL). The reaction mixture was stirred for 12 h at room temperature. After completion of reaction, reaction mixture was basified with sat.NaHC03i extracted with 10% MeOH in DCM. Organic layer was concentrated under reduced pressure and the crude material was purified by preparative HPLC to afford (E)-4-((2-(4-((E)-l-(6-aminopyridin-3-yl)-2-phenylbut-l-en-l- yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide (37 mg, 45%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, / = 2 Hz, 1H), 7.19-7.15 (m, 2H), 7.11-7.07 (m, 4H), 6.73 (d, / = 8.8 Hz, 2H), 6.60 (d, / = 8.8 Hz, 2H), 6.57-6.51 (m, 2H), 6.43 (d, J = 8.4 Hz, 1H), 5.95 (s, 2H), 3.89 (d, J = 5.6 Hz, 2H), 3.36 (d, / = 4.8 Hz, 2H), 3.0 (s, 3H), 2.85 (s, 3H), 2.82-2.81 (m, 2H), 2.46-2.42 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). ES (MS): 471.2 [M+H]+
Example 32: Compounds That Inhibit ERa activity in vitro
Cell culture
MCF7 BUS cells (Coser, et al., (2003) PNAS 100(24): 13994-13999) were maintained in Dulbecco's Modified Eagle Medium supplemented with 10% FBS, 4 niM L-glutamine and lx non-essential amino acids. Lenti-X 293T cells (Clontech, Cat # 632180) were routinely cultured in Dulbecco's Modified Eagle Medium supplemented with 10% FBS.
Site-direct mutagenesis and cell line engineering
The QuikChange II XL Site-Directed Mutagenesis Kit (Agilent Technologies, Cat #200523) was used to generate Y537S, Y537C, Y537N and D538G mutations within the ERa exon 8. Wild-type ESR1 cDNA (GeneCopoeia Inc., Cat# GC-A0322, accession no. NM 000125) was used as a template with the following mutagenesis primers (where the underlined nucleotides represent site mutations); Y537S: F-AAG AAC GTG GTG CCC CTC TCT GAC CTG CTG CTG GAG ATG (SEQ ID NO: 1), R-CAT CTC CAG CAG CAG GTC AGA GAG GGG CAC CAC GTT CTT (SEQ ID NO: 2); Y537N: F-AAG AAC GTG GTG CCC CTC AAT GAC CTG CTG CTG GAG ATG (SEQ ID NO: 3), R-CAT CTC CAG CAG CAG GTC ATT GAG GGG CAC CAC GTT CTT (SEQ ID NO: 4); Y537C: F-AAG AAC GTG GTG CCC CTC TGT GAC CTG CTG CTG GAG ATG (SEQ ID NO: 5), R-CAT CTC CAG CAG CAG GTC ACA GAG GGG CAC CAC GTT CTT (SEQ ID NO: 6); D538G: F-AAC GTG GTG CCC CTC TAT GGC CTG CTG CTG GAG ATG CTG (SEQ ID NO: 7), R-CAG CAT CTC CAG CAG CAG GCC ATA GAG GGG CAC CAC GTT (SEQ ID NO: 8). WT and mutant ESR1 cDNAs were cloned into the designation lentiviral vector pLenti6.3/V5-Dest (Invitrogen, Cat #V533-06). To make lentivirus, DNAs (WT and mutant ESR1) were co- transfected with packaging plasmids into Lenti-X 293T cells using TransIT (Mirus, Cat #MIR 2700). 48h post-transfection, virus containing media was filtered and added to MCF7 cells in the presence of 8pg/ml polybrene overnight. Two days following infection, cells were placed under selection with 10 pg/ml blasticidin for 2 weeks for stable expression.
In vitro proliferation assays MCF7-WT and -Y537S cells were seeded at 1500 cells/well in black-walled 96- ell plates (assay plates, Costar, Cat #3904). In parallel, cells were also seeded in a separate 96-well plate (8 wells/cell line, control plate) for which a CTG (CellTiter-Glo® Luminescent Viability Assay, Promega, Cat #G7572) was measured the following day (day 0 reading). The day 0 reading was used for the GI50 calculation at the termination of the experiment. The day following seeding, compounds were added to assay plates. Briefly, a 1:4 serial dilution was prepared in DMSO at 200x final concentration for a total of 10 concentrations (9 dilutions containing compound and one is DMSO only). Serially diluted compounds were pipetted into medium to prepare a compound-medium mix at lOx final concentration. 10 μΐ of compound- medium mix was added to MCF7-WT and -Y537S cells at 3 wells/concentration (triplicate for each concentration). On day 3, media/compound was removed and replaced with fresh media/compound as described above. On day 6, CTG was measured and compared to day 0 readings from control plate to assess GI50.
Results
FIG. 1 shows that ectopic expression of ERaY537S N c> D538G in MCF7 cells conferred phenotypic resistance to currently marketed therapies tamoxifen (SERM), raloxifene (SERM) and fulvestrant (SERD). Similar observations were also recently published by several independent labs (Jeselsohn et al., (2014) Clin Cancer Res. Apr 1;20(7): 1757-67; Toy et al., (2013) Nat Genet. 2013 Dec;45(12): 1439-45; Robinson et al., (2013) Nat
Genet. Dec;45(12):1446-51; Merenbakh-Lamin et al., (2013) Cancer Res. Dec
l;73(23):6856-64; Yu et al., (2014) Science Jul l l;345(6193):216-20). Having confirmed that ERaMUT drive resistance to current endocrine therapies, identification of novel compounds that would reduce proliferation of the ERaMUT-bearing MCF7 cells more efficaciously than the corresponding clinical compound 4-hydroxytamoxifen was sought. Using the WT and mutant viability assay as a screening tool, compounds were identified that were more potent towards the Y537S-bearing MCF7 line relative to 4-hydroxytamoxifen. The results of the viability assay screen are shown in Table 1 above.
It will now be apparent that new, improved, and nonobvious compositions have been described in this specification with sufficient particularity as to be understood by one of ordinary skill in the art. Moreover, it will be apparent to those skilled in the art that modifications, variations, substitutions, and equivalents exist for features of the compositions which do not materially depart from the spirit and scope of the embodiments disclosed herein. Accordingly, it is expressly intended that all such modifications, variations, substitutions, and equivalents which fall within the spirit and scope of the invention as defined by the appended claims shall be embraced by the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A compound given by the following formula:
Figure imgf000159_0001
or a pharmaceutically acceptable salt thereof.
PCT/US2016/034774 2015-05-29 2016-05-27 Tetrasubstituted alkene compounds and their use WO2016196342A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562168551P 2015-05-29 2015-05-29
US201562168540P 2015-05-29 2015-05-29
US62/168,551 2015-05-29
US62/168,540 2015-05-29

Publications (1)

Publication Number Publication Date
WO2016196342A1 true WO2016196342A1 (en) 2016-12-08

Family

ID=57441719

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/034774 WO2016196342A1 (en) 2015-05-29 2016-05-27 Tetrasubstituted alkene compounds and their use

Country Status (1)

Country Link
WO (1) WO2016196342A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020055973A1 (en) 2018-09-12 2020-03-19 Xavier University Of Louisiana Estrogen receptor targeting antagonists
WO2020125640A1 (en) * 2018-12-17 2020-06-25 正大天晴药业集团股份有限公司 Estrogen receptor antagonist
WO2020253762A1 (en) 2019-06-19 2020-12-24 江苏恒瑞医药股份有限公司 Indazole derivative, preparation method therefor, and pharmaceutical application thereof
CN114644615A (en) * 2020-12-18 2022-06-21 江苏恒瑞医药股份有限公司 Crystalline form of indazole derivative and preparation method thereof
CN114644616A (en) * 2020-12-18 2022-06-21 江苏恒瑞医药股份有限公司 Pharmaceutically acceptable salt and crystal form of indazole derivative and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009120999A2 (en) * 2008-03-28 2009-10-01 Olema Pharmaceuticals, Inc. Use of an endoxifen prodrug for treatment of breast cancer
WO2011129837A1 (en) * 2010-04-16 2011-10-20 Olema Pharmaceuticals, Inc. Use of a 4-hydroxytoremifene prodrug for treatment of breast cancer
US8063249B1 (en) * 2008-04-25 2011-11-22 Olema Pharmaceuticals, Inc. Substituted triphenyl butenes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009120999A2 (en) * 2008-03-28 2009-10-01 Olema Pharmaceuticals, Inc. Use of an endoxifen prodrug for treatment of breast cancer
US8063249B1 (en) * 2008-04-25 2011-11-22 Olema Pharmaceuticals, Inc. Substituted triphenyl butenes
WO2011129837A1 (en) * 2010-04-16 2011-10-20 Olema Pharmaceuticals, Inc. Use of a 4-hydroxytoremifene prodrug for treatment of breast cancer

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020055973A1 (en) 2018-09-12 2020-03-19 Xavier University Of Louisiana Estrogen receptor targeting antagonists
CN113365641A (en) * 2018-09-12 2021-09-07 路易斯安那泽维尔大学 Estrogen receptor targeted antagonists
EP3849567A4 (en) * 2018-09-12 2022-09-28 Xavier University Of Louisiana Estrogen receptor targeting antagonists
WO2020125640A1 (en) * 2018-12-17 2020-06-25 正大天晴药业集团股份有限公司 Estrogen receptor antagonist
WO2020253762A1 (en) 2019-06-19 2020-12-24 江苏恒瑞医药股份有限公司 Indazole derivative, preparation method therefor, and pharmaceutical application thereof
CN114644615A (en) * 2020-12-18 2022-06-21 江苏恒瑞医药股份有限公司 Crystalline form of indazole derivative and preparation method thereof
CN114644616A (en) * 2020-12-18 2022-06-21 江苏恒瑞医药股份有限公司 Pharmaceutically acceptable salt and crystal form of indazole derivative and preparation method thereof
CN114644616B (en) * 2020-12-18 2023-11-14 江苏恒瑞医药股份有限公司 Pharmaceutically acceptable salt and crystal form of indazole derivative and preparation method thereof
CN114644615B (en) * 2020-12-18 2023-11-14 江苏恒瑞医药股份有限公司 Crystal form of indazole derivative and preparation method thereof

Similar Documents

Publication Publication Date Title
AU2016271126B2 (en) Tetrasubstituted alkene compounds and their use
WO2016196342A1 (en) Tetrasubstituted alkene compounds and their use
US20180141913A1 (en) Tetrasubstituted alkene compounds and their use
US20190337921A1 (en) Tetrasubstituted alkene compounds and their use
AU2021201705A1 (en) Ezh2 inhibitors for treating lymphoma
KR100250922B1 (en) Ethanolamine derivatives having sympathomimetic and anti-pollakiuria activities
US10519143B2 (en) Substituted-indole-compounds as estrogen receptor down-regulators
CN101781268B (en) Isothiazole ketone substituted benzene dicarboxylic acid derivative and usage thereof in preparation of beta-secretase inhibitor
WO2016016728A2 (en) Bcl-3 inhibitors
JP2018527324A (en) Substituted hydrophobic benzenesulfonamido thiazole compounds for use in treating cancer
TW201536775A (en) Benzothiophene compound
WO2019141095A1 (en) Amidine and guanidine derivative, preparation method therefor and medical use thereof

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: 16804151

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: 16804151

Country of ref document: EP

Kind code of ref document: A1