WO2017056115A1 - Novel n-aryl containing fused heterocyclic compounds - Google Patents
Novel n-aryl containing fused heterocyclic compounds Download PDFInfo
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- WO2017056115A1 WO2017056115A1 PCT/IN2016/050333 IN2016050333W WO2017056115A1 WO 2017056115 A1 WO2017056115 A1 WO 2017056115A1 IN 2016050333 W IN2016050333 W IN 2016050333W WO 2017056115 A1 WO2017056115 A1 WO 2017056115A1
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- Prior art keywords
- phenyl
- alkyl
- ring
- dihydro
- benzo
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- 0 C*c(c(*C)c1)cc2c1[n]nc2 Chemical compound C*c(c(*C)c1)cc2c1[n]nc2 0.000 description 3
- XTZYAKBJNRJPLO-UHFFFAOYSA-N CC(C)(C)OC(NC(CO)c(cc1)ccc1OCc1ccccc1)=O Chemical compound CC(C)(C)OC(NC(CO)c(cc1)ccc1OCc1ccccc1)=O XTZYAKBJNRJPLO-UHFFFAOYSA-N 0.000 description 1
- SRQNANYJLQIHSA-UHFFFAOYSA-N CC(C)(C)OC(NC(COc(cc(cc1)OCc2ccccc2)c1Br)c(cc1)ccc1OCc1ccccc1)=O Chemical compound CC(C)(C)OC(NC(COc(cc(cc1)OCc2ccccc2)c1Br)c(cc1)ccc1OCc1ccccc1)=O SRQNANYJLQIHSA-UHFFFAOYSA-N 0.000 description 1
- XHDMPUMBXNKDIA-UHFFFAOYSA-N CC(C1)N(C)Cc2c1cn[nH]2 Chemical compound CC(C1)N(C)Cc2c1cn[nH]2 XHDMPUMBXNKDIA-UHFFFAOYSA-N 0.000 description 1
- LXMFHNXEZJOMNW-UHFFFAOYSA-N CCc(c(C)c1)cc(CN2)c1C2=O Chemical compound CCc(c(C)c1)cc(CN2)c1C2=O LXMFHNXEZJOMNW-UHFFFAOYSA-N 0.000 description 1
- VKMIYNMPQVPVMK-UHFFFAOYSA-N CCc(c(C)c1)cc(OC2)c1NC2=O Chemical compound CCc(c(C)c1)cc(OC2)c1NC2=O VKMIYNMPQVPVMK-UHFFFAOYSA-N 0.000 description 1
- DTHUKAGSNUSBQR-UHFFFAOYSA-N CCc(c(C)c1)nc2c1[nH]cc2 Chemical compound CCc(c(C)c1)nc2c1[nH]cc2 DTHUKAGSNUSBQR-UHFFFAOYSA-N 0.000 description 1
- AHNLHEOXLSNWFP-UHFFFAOYSA-N CCc(c(CC)c1)cc(C2)c1NC2=O Chemical compound CCc(c(CC)c1)cc(C2)c1NC2=O AHNLHEOXLSNWFP-UHFFFAOYSA-N 0.000 description 1
- GBWUNVIXIJOBAE-UHFFFAOYSA-N CCc1cc(cn[nH]2)c2nc1C Chemical compound CCc1cc(cn[nH]2)c2nc1C GBWUNVIXIJOBAE-UHFFFAOYSA-N 0.000 description 1
- KCYQESSPXUYWAK-UHFFFAOYSA-N CCc1n[n]2nnnc2cc1C Chemical compound CCc1n[n]2nnnc2cc1C KCYQESSPXUYWAK-UHFFFAOYSA-N 0.000 description 1
- JSJWVMQXHQWPCG-UHFFFAOYSA-N Cc(c(C)c1)cc(CCN2)c1C2=O Chemical compound Cc(c(C)c1)cc(CCN2)c1C2=O JSJWVMQXHQWPCG-UHFFFAOYSA-N 0.000 description 1
- NXFZVNGILJWVEL-UHFFFAOYSA-N Cc(c(C)c1)cc(N2)c1SC2=O Chemical compound Cc(c(C)c1)cc(N2)c1SC2=O NXFZVNGILJWVEL-UHFFFAOYSA-N 0.000 description 1
- SRKHZQNEHYCJJC-UHFFFAOYSA-N Cc(c(C)c1)cc(N2)c1SCC2=O Chemical compound Cc(c(C)c1)cc(N2)c1SCC2=O SRKHZQNEHYCJJC-UHFFFAOYSA-N 0.000 description 1
- VQSHETACGYAGAQ-UHFFFAOYSA-N Cc(c(C)c1)cc2c1[nH]cc2 Chemical compound Cc(c(C)c1)cc2c1[nH]cc2 VQSHETACGYAGAQ-UHFFFAOYSA-N 0.000 description 1
- QMUXKZBRYRPIPQ-UHFFFAOYSA-N Cc(c(C)c1)cc2c1[s]cn2 Chemical compound Cc(c(C)c1)cc2c1[s]cn2 QMUXKZBRYRPIPQ-UHFFFAOYSA-N 0.000 description 1
- MVPKIPGHRNIOPT-UHFFFAOYSA-N Cc(c(C)c1)cc2c1nn[nH]2 Chemical compound Cc(c(C)c1)cc2c1nn[nH]2 MVPKIPGHRNIOPT-UHFFFAOYSA-N 0.000 description 1
- UMXSKHRHAWVRGJ-UHFFFAOYSA-N Cc1cc([nH]nc2)c2nc1C Chemical compound Cc1cc([nH]nc2)c2nc1C UMXSKHRHAWVRGJ-UHFFFAOYSA-N 0.000 description 1
- PNVFQKXTEZMZPM-UHFFFAOYSA-N Cc1cc(cc[nH]2)c2nc1C Chemical compound Cc1cc(cc[nH]2)c2nc1C PNVFQKXTEZMZPM-UHFFFAOYSA-N 0.000 description 1
- UXHFTHPRNDFYRO-UHFFFAOYSA-N Cc1cc2ccn[n]2cc1C Chemical compound Cc1cc2ccn[n]2cc1C UXHFTHPRNDFYRO-UHFFFAOYSA-N 0.000 description 1
- ABNFKDGIWHEMAA-UHFFFAOYSA-N Cc1nc([nH]nn2)c2nc1C Chemical compound Cc1nc([nH]nn2)c2nc1C ABNFKDGIWHEMAA-UHFFFAOYSA-N 0.000 description 1
- BHUJTGJQTRTOJT-UHFFFAOYSA-N Cc1nc(cn[nH]2)c2nc1C Chemical compound Cc1nc(cn[nH]2)c2nc1C BHUJTGJQTRTOJT-UHFFFAOYSA-N 0.000 description 1
- GINUPZNJWPYCBT-UHFFFAOYSA-N Oc(cc1OCC2c(cc3)ccc3F)ccc1N2c1cc(OCCNCCCCCCCCCCF)cc(F)c1 Chemical compound Oc(cc1OCC2c(cc3)ccc3F)ccc1N2c1cc(OCCNCCCCCCCCCCF)cc(F)c1 GINUPZNJWPYCBT-UHFFFAOYSA-N 0.000 description 1
- JFDUNGPDVYVZEE-UHFFFAOYSA-N Oc1cc(OCc2ccccc2)ccc1Br Chemical compound Oc1cc(OCc2ccccc2)ccc1Br JFDUNGPDVYVZEE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention provides novel N-aryl containing fused heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/ degraders and process for their preparation.
- ER estrogen receptor
- Endogenous estrogen, 17 ?-estradiol (E2) shows a wide variety of biological activities in the reproductive systems, bone metabolism, and the cardiovascular systems, as well as the central nervous system. The link between estrogen and breast cancer growth and development has been well established.
- SERMs selective ER modulators
- SELD selective ER degraders
- AI aromatase inhibitors
- exemestane steroidal
- anastrozole anastrozole
- letrozole nonsteroidal
- WO 2015092634 discloses 1,2,3,4- tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders.
- Journal of Medicinal Chemistry 2003 (46), 2945-2957 discloses ERa-selective tetrahydroisoquinoline ligands as estrogen receptor modulators.
- US patent No. 7015219 discloses 3-aryl-hydroxybenzoxazines and 3,4-dihydro-3-aryl-hydroxybenzoxazines as selective estrogen receptor beta modulators.
- Bioorganic & Medicinal Chemistry, 2006 (14), 3455-3466 discloses hydroxybenzoyl-3,4-dihydroquinoxalin-2(iH)-ones as ligands for estrogen receptors.
- ring Z is a 5 to 10 membered aromatic ring optionally containing 1 or 2 heteroatoms selected from N, O and S;
- A is selected from a group comprising -0-, -NH-, -S-, -N(Ci_3 alkyl)-, -N(C3_6 cycloalkyl)- or
- n and n are integer independently selected from 1 or 2;
- J is -CH- or -N-;
- E is mono- or di-substitution and is selected from hydrogen, halogen, -COOH, -NH 2 , -NH(Ci_ 3 alkyl), -N(C 1-3 alkyl) 2 , -CN, -C 1-3 haloalkyl, -C 1-3 alkyl and -OC 1-3 alkyl;
- B is hydrogen or a Ci_2o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR , -S-, -SO-,-S(0) 2 -, -CR ⁇ CRr, -C ⁇ C-, -NRjCO-, - CONRj-, -NR J CONR J -, NRjC(0)0-, -OC(0)0- or a group represented by formula N Q
- g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-; wherein, Rj, at each occurrence, is selected from hydrogen, C 3 _6 cycloalkyl or Ci_6 alkyl;
- B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R 2 ) 2 and -C(0)OQ_6 alkyl wherein, R 2 , at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched and cyclic alkyl;
- Y is mono or di substitution and is a group selected from -R 3 , -OR 3 , halogen, -CN, - NR 3 COR 3 , NR 3 S0 2 R , -OC(0)R 3 , -OC(0)N(R 3 ) 2 , -S0 2 C 1 alkyl, -N(R 3 ) 2 and -OC(0)OR 3 ; wherein R 3 , at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched or cyclic alkyl and Ci_6 linear, branched or cyclic haloalkyl;
- L is selected from -0-, -N (d_ 6 alkyl)-, -N (C 3 _ 6 cycloalkyl)-, -N (d_ 6 haloalkyl)-, -N (C 3 _ 6 halocycloalkyl)- and -S-;
- ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;
- D is a group selected from boronic acid or a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_3 alkyl group wherein the point of attachment to ring X is the boron atom.
- the compounds of present invention are modulators of estrogen receptors and can be used for the treatment of diseases which are related to modulation of ER.
- aromatic ring or "aryl ring” refers to monocyclic and bicyclic conjugated ring systems containing 4n+2 pi electrons, where n is an integer.
- the aromatic ring may contain between 6 to 10 carbon atoms unless specified otherwise.
- the non-limiting examples of aromatic ring or aryl ring are phenyl, naphthyl etc. Wherever specified, the aromatic ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur to form heteroaryl ring.
- heteroaryl ring examples include, but not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl.
- alkyl refers to a linear or branched saturated monovalent hydrocarbon radical that includes carbon and hydrogen atoms in the backbone.
- the alkyl group may have 1 to 20 carbon atoms, both inclusive, unless specified otherwise and is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, w-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl, and 1,1-dimethylethyl (i-butyl).
- all alkyl groups described or claimed herein may be substituted or unsubstituted.
- cycloalkyl or "cyclic alkyl” denotes a non-aromatic monocyclic ring of 3 to about 8 carbon atoms, unless specified otherwise.
- the cycloalkyl ring may be saturated or unsaturated.
- Monocyclic rings include, but are not limited to cylcopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
- halogen as used herein includes chloro, fluoro, bromo and iodo.
- haloalkyl refers to alkyl group substituted with one or more halogen radicals.
- the present invention provides a compound of Formula I
- ring Z is selected from 5 to 10 membered aromatic ring optionally containing 1 or heteroatoms selected from N, O and S;
- A is selected from a group comprising -0-, -NH-, -S-, -N(Ci_3 alkyl)-, -N(C3_6 cycloalkyl)-
- n and n are integer independently selected from 1 or 2;
- J is -CH- or -N-; and ' ⁇ ' indicates the point of attachment to ring Z;
- E is mono- or di-substitution and is selected from hydrogen, halogen, -COOH, -NH2, -NH(Ci_ 3 alkyl), -N(d_ 3 alkyl) 2 , -CN, -d_ 3 haloalkyl, -d_ 3 alkyl and -Od_ 3 alkyl;
- B is hydrogen or a Ci_2o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR , -S-, -SO-,-S(0) 2 -, -CR ⁇ CRr, -C ⁇ d, -NRjCO-, - CONRj-, -NRJCONRJ-, NRjC(0)0-, -OC(0)0- or a group represented by formula
- g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-;
- Rj at each occurrence, is hydrogen, C3_6 cycloalkyl or Ci_6 alkyl
- B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R 2 ) 2 and -C(0)OCi_6 alkyl wherein, R 2 , at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched and cyclic alkyl;
- Y is mono- or di-substitution and is a group selected from -R3, -OR 3 , halogen, -CN, - NR 3 COR 3 , NR 3 SO2R 3 , -OC(0)R 3 , -OC(0)N(R 3 ) 2 , -SO2Q4 alkyl, -N(R 3 ) 2 and -OC(0)OR 3 ; wherein R3, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched or cyclic alkyl and Ci_6 linear, branched or cyclic haloalkyl;
- L is selected from -0-, -N (d_ 6 alkyl)-, -N (C 3 _ 6 cycloalkyl)-, -N (d_ 6 haloalkyl)-, -N (C 3 _ 6 halocycloalkyl)- and - or -S-;
- ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms;
- D is a group selected from boronic acid or a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_3 alkyl group wherein the point of attachment to ring X is the boron atom.
- ring Z is a 5 or 6 membered aromatic ring optionally containing lor 2 heteroatoms selected from N, O and S.
- the examples of ring Z are, but not limited to, phenyl, thiazolyl, imidazolyl, thiophenyl, pyridyl, pyrimidinyl etc.
- ring Z is phenyl.
- the present invention provides a compound of Formula I wherein, A is selected from a group comprising -0-, -NH-, -S-, -N(Q_3 alkyl)-, -N(C3_6 cycloalkyl)- or bV J" wherein, m and n are integer independently selected from are 1 or 2; J is -CH- or -N-; and ' ⁇ ' indicates the point of attachment of ring Z. Examples of moieties representing the group
- A is -O- or -NH-. In another preferred embodiment A is -0-.
- substitution A on ring Z may be at 2, 3 or 4 position with respect to the point of attachment of ring Z to the rest of molecule.
- Z is phenyl ring and A ia attached at 3-position of the ring.
- the present invention provides a compound of Formula I wherein, E is mono- or di-substitution and is selected from hydrogen, -C1-3 haloalkyl and halogen.
- E is mono- or di-substitution
- the phrase "E is mono- or di-substitution” means that the ring Z can have one or two E groups substituted on it.
- the present invention provides a compound of Formula I wherein, L is -0-.
- the present invention provides a compound of Formula I wherein, B is interrupted by a group
- group B can be further substituted with one or more groups selected from halogen, -OR2, -N(R 2 ) 2 and - C(0)OCi_6 alkyl wherein, R 2 , at each occurrence, is hydrogen or Ci_6 linear, branched or cyclic alkyl.
- group B is substituted with one or more halogen.
- group B is C3 4 alkyl chain optionally interrupted with groups selected from -NRi-, -S- or -SO-.
- Ring X is a 5 tolO membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms. Ring X can be aromatic or non-aromatic. In an embodiment ring X is selected from monocyclic ring such as imidazolyl, thiophenyl, indazolyl, phenyl, pyrazinyl pyrazine or piperaznyl. In another embodiment, the present invention provides a compound of Formula I wherein, the
- ring X is selected from
- the ring X is phenyl.
- D is selected from -OH, NR 4 S(3 ⁇ 4R 4 , - NR 4 CHO, -NR 4 COR 4 , -OC(0)R 4 , -OC(0)N(R 4 ) 2 , and -OC(0)OR 4 or -R 4 .
- D is -OH group.
- D is a group selected from boronic acid or a 5 or 6 membered ring containing the C-O-Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_3 alkyl group wherein the point of attachment to ring X is the boron atom.
- B is a Ci-2 0 linear or branched alkyl chain interrupted with one or more radicals selected from -NRj, -S- or a group represented by a formula -N Q-
- g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-; and is optionally further substituted with halogen.
- the present invention provides a compound of Formula lb
- the compounds of the Formula I can be prepared by coupling a compound of Formula ( 1 ) with the compound of Formula (2) to give a compound of Formula (3), which upon intramolecular cyclization gives compound of Formula (4).
- Buchwald reaction of Formula (4) with the compound of Formula (5) gives compound of formula (I). The process can be depicted as in Scheme 1.
- compound of the Formula I can be prepared by following the procedure as depicted in Scheme 2.
- Displacement reaction of compound of Formula (5) with compound of Formula (2a) gives compound of Formula (6).
- Coupling reaction of compound of Formula (6) with a compound of Formula ( 1) gives adduct of the Formula (7), which upon intramolecular cyclization reaction gives compound of Formula L
- compound of the Formula 1 can also be prepared by following the procedure as depicted in Scheme 3. Displacement reaction of compound of Formula (5) with compound of Formula ( 1 ) gives compound of Formula (8). Coupling reaction of compound of Formula (8) with a compound of Formula ( 10) gives adduct of Formula (9), which upon intramolecu
- Table 1 provides few exemplary compounds of Formula I.
- the compounds described herein, including compounds of Formula I can be prepared by reaction schemes depicted in Schemes 1, 2 and 3. Furthermore, in the following examples, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as part of the present invention. The compounds obtained by using the general reaction scheme may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios.
- Step I (/?)-N-(tert-Butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)-l-(4-
- Diisopropylazodicarboxylate (20 mL, 0.102 mol) was added to a stirred mixture of (R)-2- (teri-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (25 g, 0.073 mol), 5-benzyloxy-2- bromophenol (20.3 g, 0.073 mol) and triphenylphosphine (24.8 g, 0.094 mol) in tetrahydrofuran (375 mL) under nitrogen atmosphere. Reaction mixture is stirred for further 4 hours at room temperature. Diisopropylazodicarboxylate (4.3 mL, 0.022 mol) was added and stirring continued for additional 12 hours at room temperature.
- Trifluoroacetic acid 22 mL was added to a stirred solution of (R)-N-(ieri-butoxycarbonyl)- 2-(5-benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)ethylamine (11 g, 0.018 mol) in dichloromethane (DCM) (55 mL) at 0-5 °C and then stirred at room temperature for 1 hour. Reaction mixture was diluted with DCM, aqueous saturated sodium bicarbonate solution is added to adjust pH ⁇ 8.
- DCM dichloromethane
- Step IV (2- ⁇ 3-[( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[i,4]oxazine-4- yl]phenoxy ⁇ ethyl)dimethylamine
- Reaction mixture was then heated at 100 °C for 3 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water is added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol, 95:5) to get (2- ⁇ 3-[(R)-7-benzyloxy-3-(4-benzyloxyphenyl)-2,3- dihydrobenzo [i, 4] oxazine-4-yl] phenoxy ⁇ ethyl)dimethylamine.
- Step V (/?)-4-[3-(2-Dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro- -benzo[i,4]oxazin-7-ol
- Step I (/?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4- ⁇ 3-[2-(4-nonylpiperazin-l-yl)ethoxy]
- Step II ( ?)-3-(4-Hydroxyphenyl)-4- ⁇ 3-[2-(4-nonylpiperazin-l-yl)ethoxy]phenyl ⁇ -3,4- ihydro-2H-benzo[i,4]oxazin-7-ol
- Step I ( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-(tetrahydropyran-2-yloxy)phenyl]- 3 4-dihydro-2H-benzo[i,4]oxazine
- Step II 3-[( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl] phenol
- Step III ( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4- ⁇ 3-[9-(4,4,5,5,5-pentafluoropentyl
- Potassium carbonate (0.1 g, 0.0007 mol) was added to a solution of 3-[(R)-7-benzyloxy-3-(4- benzyloxy phenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl]phenol (0.15 g, 0.00029 mol) in N,N- dimethylformamide (5 mL) at room temperature and stirred for 30 minutes.
- l-Bromo-9- (4,4,5,5, 5-pentafluoropentylsulfanyl)nonane (0.13 g, 0.0004 mol) was added to the reaction mixture and then heated for 1 hour at 70 °C.
- Step IV (/?)-3-(4-Hydroxyphenyl)-4- ⁇ 3-[9-(4,4,5,5,5-pentafluoropentylsulfanyl) nonyloxy]phenyl ⁇ -3,4-dihydro-2H-benzo[i,4]oxazin-7-ol
- Step III 2-(5-Benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine
- Step V (2- ⁇ 3-[7-Benzyloxy-3-(4-fluorophenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl]-5- fluoro henoxy)ethyl)-(lO-fluorodecyl)
- reaction mixture Sodium teri-butoxide (0.08 g, 0.0008 mol) was added to reaction mixture and heated at 105 °C for one hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (3x30 mL). Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate.
- Step VI (10-Fluorodecyl)-(2- ⁇ 3-fluoro-5-[3-(4-fluorophenyl)-7-hydroxy-2,3-dihydro
- Reaction mixture was cooled to room temperature, filtered through celite bed and washed with mixture of methanol and 1,4- dioxane (1 : 1). Combined filtrate was concentrated at 50 °C under reduced pressure. Residue was dissolved in ethyl acetate, washed with water, brine solution and dried over anhydrous sodium sulphate.
- Step VII 4- ⁇ 3-Fluoro-5-[2-(10-fluorodecylamino)ethoxy]phenyl ⁇ -3-(4-fluorophenyl)-3,4-
- Step I 5-Bromo-l Methane sulfonic acid (0.12 mL, 0.0019 mol) was added to a stirred solution of 5-bromo-iH- indazol-6-ol (2.0 g, 0.0094 mol) and 3,4-dihydro-2H-pyran (4.25 mL, 0.047 mol) in a mixture (40 mL) of DCM and tetrahydrofuran (1 : 1) at room temperature and stirred for 1 hour. Reaction mixture was cooled to 0-5 °C, quenched with saturated sodium bicarbonate solution and extracted with DCM.
- Step II ⁇ (/?)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6- yloxy]ethyl ⁇ carbamic acid tert-but l ester.
- Diisopropylazodicarboxylate (1.0 ml, 0.0048 mol) was added to a stirred mixture of [(R)-l- (4-benzyloxyphenyl)-2-hydroxyethyl]carbamic acid teri-butyl ester (1.18 g, 0.0034 mol), 5- bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-ol (1.0 g, 0.0034 mol) and triphenylphosphine (1.17 g, 0.0044 mol) in a mixture of tetrahydrofuran (4 mL) and toluene (16 mL) under nitrogen atmosphere at room temperature and stirred for 1 hour.
- Reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 45 °C to get crude viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 15:85) to get the title compound.
- Step III (/?)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6- loxyjethylamine.
- Step IV (/?)-6-(4-Benzyloxy phenyl)-l-(tetrahydro pyran-2-yl)-l,5,6,7-tetrahydro-8-oxa- -triaza cyclopenta[Z»]naphthalene.
- Reaction mixture was then heated at 100 °C for 1 hour 30 minutes. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentration under reduced pressure to give viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 30:70) to get (R)-6-(4-benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-l , 5,6,7- tetrahydro- 8 -oxa- 1 ,2,5 -triazacyclopenta[3 ⁇ 4] naphthalene.
- Step V (2- ⁇ 3-[(/?)-6-(4-Benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-6,7-dihydro-iH-8- oxa-l,2,5-triazacyclopenta[Z»]naphthalen-5-yl]-5-fluorophenoxy ⁇ ethyl)-(12-
- Step VI (12-Fluorododecyl)-(2- ⁇ 3-fluoro-5-[(/?)-6-(4-hydroxyphenyl)-l-(tetrahydro pyran-2-yl)-6,7-dihydro-iH-8-oxa-l,2,5-triazacyclopenta[Z»]naphthalen-5-
- Step VII 4-(( ?)-5- ⁇ 3-Fluoro-5-[2-(12-fluorododecylamino)ethoxy]phenyl ⁇ -l,5,6,7- tetrahydro-8-oxa-l,2,5-triazacyclopenta[Z»]naphthalen-6-yl)phenol.
- MCF-7 cells were plated in 96 well plate in the presence of estradiol (1 nM) and incubated overnight. After 24 hours test compound was added at various concentrations and incubated for five days. On the fifth day, cell viability was evaluated using Presto Blue Cell Viability Reagent. Percentage growth inhibition was calculated as follows: 100 - [(O.D. of sample)* 100/ O.D. of vehicle control] wherein O.D. is Optical Density.
Abstract
The present invention provides novel N-aryl containing fused heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/ degraders and process for their preparation.
Description
NOVEL N-ARYL CONTAINING FUSED HETEROCYCLIC COMPOUNDS
RELATED APPLICATION This application claims the benefit of Indian Patent Application no. 3764/MUM/2015 filed on October 03, 2015 which is hereby incorporated by reference.
FIELD OF THE INVENTION The present invention provides novel N-aryl containing fused heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/ degraders and process for their preparation.
BACKGROUND OF THE INVENTION
Endogenous estrogen, 17 ?-estradiol (E2) shows a wide variety of biological activities in the reproductive systems, bone metabolism, and the cardiovascular systems, as well as the central nervous system. The link between estrogen and breast cancer growth and development has been well established.
A number of strategies to inhibit the action of endogenous estrogen in estrogen receptor (ER) positive breast cancer are in practice. These include, selective ER modulators (SERMs) such as tamoxifen, which act as selective tissue-specific antagonist of ER in the breast; selective ER degraders (SERD) such as fulvestrant, which promote ER turnover; and aromatase inhibitors (AI) such as exemestane (steroidal), anastrozole and letrozole (nonsteroidal) which inhibit estrogen biosynthesis and are primarily used for postmenopausal women with ER- positive breast cancer. Unfortunately, many women with breast cancer initially respond well to tamoxifen or AI therapy but develop resistance over a period of time during treatment. In resistant form of breast cancer there is evidence that pro-growth signaling pathways downstream of estrogen receptor still play a significant role. Recently, there has been increasing clinical evidence that following treatment with AIs, resistance develop due to mutations in the ligand-binding domain of ER-a rendering it constitutively active even in the absence of ligand, leading to resistance.
Currently fulvestrant is considered as a first-in-class SERD. Unfortunately, significant pharmaceutical liabilities of fulvestrant (requiring intramuscular injection of large volume) limit its widespread use. Therefore, development of an orally bio-available ER-antagonist especially with ER degrading properties would be beneficial to patients who have developed resistance to currently available therapies targeting ER activity. Many non-steroidal ER antagonists are reported in prior art. For instance WO 2015092634 discloses 1,2,3,4- tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders. Journal of Medicinal Chemistry 2003 (46), 2945-2957 discloses ERa-selective tetrahydroisoquinoline ligands as estrogen receptor modulators. US patent No. 7015219 discloses 3-aryl-hydroxybenzoxazines and 3,4-dihydro-3-aryl-hydroxybenzoxazines as selective estrogen receptor beta modulators. Bioorganic & Medicinal Chemistry, 2006 (14), 3455-3466 discloses hydroxybenzoyl-3,4-dihydroquinoxalin-2(iH)-ones as ligands for estrogen receptors. Bioorganic & Medicinal Chemistry Letters, 2005 (15), 3912-3916 discloses dihydrobenzoxathin as ligands for selective estrogen receptor alpha modulators. US patent number 7138426 discloses pyrrolidinylethoxyphenylbenzoxathins as estrogen receptor modulators.
SUMMARY OF THE INVENTION The present invention provides a compound of Formula I
Formula I and a salt or stereoisomer thereof wherein,
ring Z is a 5 to 10 membered aromatic ring optionally containing 1 or 2 heteroatoms selected from N, O and S;
wherein, m and n are integer independently selected from 1 or 2;
J is -CH- or -N-;
and '{ ' indicates the point of attachment to ring Z;
E is mono- or di-substitution and is selected from hydrogen, halogen, -COOH, -NH2, -NH(Ci_ 3 alkyl), -N(C1-3 alkyl)2, -CN, -C1-3 haloalkyl, -C1-3 alkyl and -OC1-3 alkyl;
B is hydrogen or a Ci_2o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR , -S-, -SO-,-S(0)2-, -CR^CRr, -C≡C-, -NRjCO-, - CONRj-, -NRJCONRJ-, NRjC(0)0-, -OC(0)0- or a group represented by formula N Q
wherein, g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-; wherein, Rj, at each occurrence, is selected from hydrogen, C3_6 cycloalkyl or Ci_6 alkyl;
B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and -C(0)OQ_6 alkyl wherein, R2, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched and cyclic alkyl;
Y is mono or di substitution and is a group selected from -R3, -OR3, halogen, -CN, - NR3COR3, NR3S02R , -OC(0)R3, -OC(0)N(R3)2, -S02C1 alkyl, -N(R3)2 and -OC(0)OR3; wherein R3, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched or cyclic alkyl and Ci_6 linear, branched or cyclic haloalkyl;
L is selected from -0-, -N (d_6 alkyl)-, -N (C3_6 cycloalkyl)-, -N (d_6 haloalkyl)-, -N (C3_6 halocycloalkyl)- and -S-; ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;
D is a group selected from hydrogen, -R4, -OR4, halogen, -CR4=CR4-COOH, -CN, -N(R4)2, - NR4SO2R}, -NR4CHO, -NR4COR4, -OC(0)R4, -OC(0)N(R4)2, -NR4CONR4 and -OC(0)OR4 wherein R^ at each occurrence is hydrogen or Ci-6 linear, branched or cyclic alkyl or
D is a group selected from boronic acid or a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_3 alkyl group wherein the point of attachment to ring X is the boron atom.
The compounds of present invention are modulators of estrogen receptors and can be used for the treatment of diseases which are related to modulation of ER.
GLOSSARY
The term "aromatic ring" or "aryl ring" refers to monocyclic and bicyclic conjugated ring systems containing 4n+2 pi electrons, where n is an integer. The aromatic ring may contain between 6 to 10 carbon atoms unless specified otherwise. The non-limiting examples of aromatic ring or aryl ring are phenyl, naphthyl etc. Wherever specified, the aromatic ring may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur to form heteroaryl ring. Examples of heteroaryl ring include, but not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl.
The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical that includes carbon and hydrogen atoms in the backbone. The alkyl group may have 1 to 20 carbon atoms, both inclusive, unless specified otherwise and is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, w-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl, and 1,1-dimethylethyl (i-butyl). Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be substituted or unsubstituted. The term "cycloalkyl" or "cyclic alkyl" denotes a non-aromatic monocyclic ring of 3 to about 8 carbon atoms, unless specified otherwise. The cycloalkyl ring may be saturated or unsaturated. Monocyclic rings include, but are not limited to cylcopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "halogen", as used herein includes chloro, fluoro, bromo and iodo. The term "haloalkyl" refers to alkyl group substituted with one or more halogen radicals. DESCRIPTION OF THE INVENTION
In one aspect the present invention provides a compound of Formula I
Formula I and a salt or stereoisomer thereof wherein,
ring Z is selected from 5 to 10 membered aromatic ring optionally containing 1 or heteroatoms selected from N, O and S;
wherein, m and n are integer independently selected from 1 or 2;
J is -CH- or -N-; and '{ ' indicates the point of attachment to ring Z;
E is mono- or di-substitution and is selected from hydrogen, halogen, -COOH, -NH2, -NH(Ci_ 3 alkyl), -N(d_3 alkyl)2, -CN, -d_3 haloalkyl, -d_3 alkyl and -Od_3 alkyl;
B is hydrogen or a Ci_2o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR , -S-, -SO-,-S(0)2-, -CR^CRr, -C≡d, -NRjCO-, - CONRj-, -NRJCONRJ-, NRjC(0)0-, -OC(0)0- or a group represented by formula
wherein, g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-;
wherein, Rj, at each occurrence, is hydrogen, C3_6 cycloalkyl or Ci_6 alkyl; B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and -C(0)OCi_6 alkyl wherein, R2, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched and cyclic alkyl;
Y is mono- or di-substitution and is a group selected from -R3, -OR3, halogen, -CN, - NR3COR3, NR3SO2R3, -OC(0)R3, -OC(0)N(R3)2, -SO2Q4 alkyl, -N(R3)2 and -OC(0)OR3; wherein R3, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched or cyclic alkyl and Ci_6 linear, branched or cyclic haloalkyl;
L is selected from -0-, -N (d_6 alkyl)-, -N (C3_6 cycloalkyl)-, -N (d_6 haloalkyl)-, -N (C3_6 halocycloalkyl)- and - or -S-; ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms;
D is a group selected from hydrogen, -R4, -OR4, halogen, -CR4=CR4-COOH, -CN, -N(R4)2, - NR4SO2R*, -NR4CHO, -NR4COR4, -OC(0)R4, -OC(0)N(R4)2, -NR4CONR4 and -OC(0)OR4 wherein R4 at each occurrence is hydrogen or d-6 linear, branched or cyclic alkyl OR
D is a group selected from boronic acid or a 5 or 6 membered ring containing the C-O- Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_3 alkyl group wherein the point of attachment to ring X is the boron atom.
In an embodiment ring Z is a 5 or 6 membered aromatic ring optionally containing lor 2 heteroatoms selected from N, O and S. The examples of ring Z are, but not limited to, phenyl, thiazolyl, imidazolyl, thiophenyl, pyridyl, pyrimidinyl etc. In a preferred embodiment ring Z is phenyl.
In another embodiment, the present invention provides a compound of Formula I wherein, A is selected from a group comprising -0-, -NH-, -S-, -N(Q_3 alkyl)-, -N(C3_6 cycloalkyl)- or bVJ" wherein, m and n are integer independently selected from are 1 or 2; J is -CH- or -N-; and '{ ' indicates the point of attachment of ring Z. Examples of moieties representing the group
In a preferred embodiment, A is -O- or -NH-. In another preferred embodiment A is -0-. When Z is a 5 or 6 membered ring, the substitution A on ring Z may be at 2, 3 or 4 position with respect to the point of attachment of ring Z to the rest of molecule. In a preferred embodiment, Z is phenyl ring and A ia attached at 3-position of the ring.
In another embodiment, the present invention provides a compound of Formula I wherein, E is mono- or di-substitution and is selected from hydrogen, -C1-3 haloalkyl and halogen. The phrase "E is mono- or di-substitution" means that the ring Z can have one or two E groups substituted on it.
In another embodiment, the present invention provides a compound of Formula I wherein, L is -0-.
In another embodiment, the present invention provides a compound of Formula I wherein, B is interrupted by a group
-N Q- wherein, g and h are integer 2 and Q is -N- forming a piperazine ring. In other preffered embodiment the group can be a piperidine ring. In another embodiment the group B can be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and - C(0)OCi_6 alkyl wherein, R2, at each occurrence, is hydrogen or Ci_6 linear, branched or
cyclic alkyl. In a preferred embodiment, group B is substituted with one or more halogen. In another embodiment group B is C3 4 alkyl chain optionally interrupted with groups selected from -NRi-, -S- or -SO-. Ring X is a 5 tolO membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms. Ring X can be aromatic or non-aromatic. In an embodiment ring X is selected from monocyclic ring such as imidazolyl, thiophenyl, indazolyl, phenyl, pyrazinyl pyrazine or piperaznyl. In another embodiment, the present invention provides a compound of Formula I wherein, the
wherein, ']' indicates point of fusion of the group with rest of the molecule. In another referred embodiment ring X is selected from
In another preferred embodiment the ring X is phenyl. Ring X can be substituted with D wherein D is one or more groups selected from hydrogen, -R4, -OR4, halogen, -CR4=CR4- COOH, -CN, N(R4)2, -NR4S02R}, -NR4CHO, -NR^OR^, -OC(0)R4, -OC(0)N(R4)2, - NR4CONR and -OC(0)OR4 wherein R^ at each occurrence is hydrogen or Ci_6 linear, branched or cyclic alkyl. In a preferred embodiment D is selected from -OH, NR4S(¾R4, - NR4CHO, -NR4COR4, -OC(0)R4, -OC(0)N(R4)2, and -OC(0)OR4 or -R4. In another preferred embodiment D is -OH group.
In another embodiment, D is a group selected from boronic acid or a 5 or 6 membered ring containing the C-O-Boron-O-C linkage wherein the ring is optionally substituted with one or more Ci_3 alkyl group wherein the point of attachment to ring X is the boron atom. Following are some representative moieties:
In a preferred embodiment the present invention provides a compound of Formula la
Formula la wherein, B is a Ci-20 linear or branched alkyl chain interrupted with one or more radicals selected from -NRj, -S- or a group represented by a formula -N Q-
V
wherein, g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-; and is optionally further substituted with halogen.
In another embodiment the present invention provides a compound of Formula lb
Formula lb
wherein, D, B and Y are as defined earlier in the specification.
In another embodiment, the compounds of the Formula I can be prepared by coupling a compound of Formula ( 1 ) with the compound of Formula (2) to give a compound of Formula (3), which upon intramolecular cyclization gives compound of Formula (4). Buchwald reaction of Formula (4) with the compound of Formula (5) gives compound of formula (I). The process can be depicted as in Scheme 1.
Scheme 1
Alternatively, compound of the Formula I can be prepared by following the procedure as depicted in Scheme 2. Displacement reaction of compound of Formula (5) with compound of Formula (2a) gives compound of Formula (6). Coupling reaction of compound of Formula (6) with a compound of Formula ( 1) gives adduct of the Formula (7), which upon intramolecular cyclization reaction gives compound of Formula L
Scheme 2
Alternatively, compound of the Formula 1 can also be prepared by following the procedure as depicted in Scheme 3. Displacement reaction of compound of Formula (5) with compound of Formula ( 1 ) gives compound of Formula (8). Coupling reaction of compound of Formula (8)
with a compound of Formula ( 10) gives adduct of Formula (9), which upon intramolecu
Table 1 provides few exemplary compounds of Formula I.
Formula I
85. Ph 3-0 -(CH2)2NH(CH2)10F 5-F O 4-F H0 RS
86. Ph 3-0 5-F O 4-OH R
(CH2)2NH(CH2)20(CH2)20(CH
2)2OCH3
87. Ph 3-0 5-F O 4-OCH2F R
(CH2)2NH(CH2)20(CH2)20(CH
2)2OCH3
88. Ph 3-0 5-F O 4-OCHF2 R
(CH2)2NH(CH2)20(CH2)20(CH
2)2OCH3
89. Pyridi 5-0 -(CH2)2NH(CH2)10F H O 4-OCH2F R ne-3- yi
90. Ph 3-0 -(CH2)2NH(CH2)UCH3 H O 4-OCON(CH3)2 R
1
91. Ph 3-0 -(CH2)2NH(CH2)„CH3 H O 4- R
OCOOC(CH3)3
92. Ph 3-0 -(CH2)2NH(CH2)„CH3 H O 4-OCH3 R
93. Ph 3-0 -(CH2)2NH(CH2)12F 5-F O 4- R
OCOOCH2CH3 H0 ¾
The present invention is further illustrated in detail with reference to the following example. It is desired that the example be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
EXAMPLES
General Method of Preparation
The compounds described herein, including compounds of Formula I can be prepared by reaction schemes depicted in Schemes 1, 2 and 3. Furthermore, in the following examples, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for
example, temperature, duration of the reaction or combinations thereof are envisioned as part of the present invention. The compounds obtained by using the general reaction scheme may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios.
Example 1: Preparation of (/?)-4-r3-(2-dimethylaminoethoxy)phenvn-3-(4- hvdroxyphenyl)-3,4-dihvdro-2H-benzori,41oxazin-7-ol (1)
Step I: (/?)-N-(tert-Butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)-l-(4-
Diisopropylazodicarboxylate (20 mL, 0.102 mol) was added to a stirred mixture of (R)-2- (teri-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (25 g, 0.073 mol), 5-benzyloxy-2- bromophenol (20.3 g, 0.073 mol) and triphenylphosphine (24.8 g, 0.094 mol) in tetrahydrofuran (375 mL) under nitrogen atmosphere. Reaction mixture is stirred for further 4 hours at room temperature. Diisopropylazodicarboxylate (4.3 mL, 0.022 mol) was added and stirring continued for additional 12 hours at room temperature. The mixture was cooled to 0-5 °C, water was added and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate :n-hexane, 8:92) to get (R)-N-(teri-butoxycarbonyl)amino-2-(5-benzyloxy- 2-bromophenoxy)- 1 -(4-benzyloxyphenyl)ethylamine. Step II: (/?)-2-(5-Benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)ethylamine.
Trifluoroacetic acid (22 mL) was added to a stirred solution of (R)-N-(ieri-butoxycarbonyl)- 2-(5-benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)ethylamine (11 g, 0.018 mol) in dichloromethane (DCM) (55 mL) at 0-5 °C and then stirred at room temperature for 1 hour. Reaction mixture was diluted with DCM, aqueous saturated sodium bicarbonate solution is added to adjust pH ~8. Organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: DCM, 40:60) to get (R)-2-(5-benzyloxy-2-bromophenoxy)-l-(4-benzyloxy phenyl)ethylamine.
Ste III: (/?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine.
Potassium teri-butoxide (2.4 g, 0.021 mol) was added to a stirred mixture of (R)-2-(5- benzyloxy-2-bromophenoxy)-l-(4-benzyloxyphenyl)ethylamine (8.1 g, 0.016 mol), tris (dibenzylideneacetone)dipalladium (0.5 g, 0.0006 mol) and 2,2'-Ws,(diphenylphosphino)l,r- binaphthyl (0.7 g, 0.0011 mol) in toluene (100 mL). Reaction mixture was then heated at 100 C for 3 hours under nitrogen atmosphere, allowed to cool to room temperature and quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulfate. Removal of ethyl acetate under reduced pressure gave residue which was triturated with DCM to get (R)-7-benzyloxy- 3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine.
Step IV: (2-{3-[( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[i,4]oxazine-4- yl]phenoxy}ethyl)dimethylamine
Sodium teri-butoxide (0.07 g, 0.0007 mol) was added to a stirred mixture of (R)-7- benzyloxy-3-(4-benzyloxy phenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.2 g, 0.00047 mol), [2-(3-(iodophenoxy)ethyl]dimethylamine (0.14 g, 0.00047 mol), in dibenzylideneacetone) dipalladium (0.004 g, 0.000047 mol) and tri teri-butylphosphine (0.001 ml, 0.00038 mol, 50 % solution in toluene) in toluene (5 mL). Reaction mixture was then heated at 100 °C for 3 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water is added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol, 95:5) to get (2-{3-[(R)-7-benzyloxy-3-(4-benzyloxyphenyl)-2,3- dihydrobenzo [i, 4] oxazine-4-yl] phenoxy } ethyl)dimethylamine.
Step V: (/?)-4-[3-(2-Dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro- -benzo[i,4]oxazin-7-ol
5 % Palladium on charcoal (0.05 g, 50 % wet) was added to a stirred solution of (2-{3-[(R)-7- benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[i,4]oxazine-4-yl]phenoxy}ethyl) dimethylamine (0.12 g, 0.0002 mol) in a mixture (4 mL) of ethanol and 1,4-dioxane (1 : 1) and then stirred under hydrogen atmosphere at 50-60 °C for 5 hours. Reaction mixture was filtered through celite bed and washed with ethanol. Combined filtrate was concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, DCM:, methanol, 90: 10) to get (R)-4-[3-(2-dimethylaminoethoxy)phenyl]- 3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[i,4]oxazin-7-ol.
Example 2: Preparation of (/Q-3-(4-hvdroxyphenyl)-4-{3-r2-(4-nonylpiperazin-l- yl)ethoxy1phenyl)-3,4-dihvdro-2H-benzori,41oxazin-7-ol (4)
Step I: (/?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-{3-[2-(4-nonylpiperazin-l-yl)ethoxy]
Sodium ieri-butoxide (0.08 g, 0.00083 mol) was added to a stirred mixture of (R)-7- benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.25 g, 0.0006 mol), l-[2-(3-iodophenoxy)ethyl]-4-nonylpiperazine (0.27 g, 0.0006 mol), in dibenzylidene acetone)dipalladium (0.004 g, 0.00006 mol) and tri teri-butylphosphine (O.OOlmL, 0.0005 mol, 50 % solution in toluene) in toluene (5 mL). Reaction mixture was heated at 100 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol, 98:2) to get (R)-7-benzyloxy-3-(4-benzyloxyphenyl)-4-{3-[2-(4- nonylpiperazin- 1 -yl)ethoxy] phenyl } -3 ,4-dihydro-2H-benzo[i, 4] oxazine.
Step II: ( ?)-3-(4-Hydroxyphenyl)-4-{3-[2-(4-nonylpiperazin-l-yl)ethoxy]phenyl}-3,4- ihydro-2H-benzo[i,4]oxazin-7-ol
5 % Palladium on charcoal (0.07 g, 50 % wet) was added to a solution of (R)-7-benzyloxy-3- (4-benzyloxyphenyl)-4- { 3- [2-(4-nonylpiperazin- 1 -yl)ethoxy]phenyl } -3 ,4-dihydro-2H- benzo[i, 4] oxazine (0.2 g, 0.00023 mol) in a mixture (4 mL) of ethanol and 1,4-dioxane (1: 1) and stirred under hydrogen atmosphere at 50-60 °C for 20 hours. Reaction mixture was filtered through celite bed and washed with ethanol. Combined filtrate was concentrated
under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol, 95:5) to get (R)-3-(4-hydroxyphenyl)-4-{3-[2-(4- nonylpiperazin- 1 -yl)ethoxy] phenyl } -3 ,4-dihydro-2H-benzo[i, 4] oxazin-7-ol. Example 3: Preparation of ( ?)-3-(4-hvdroxyphenyl)-4-(3-r9-(4,4,5,5,5-pentafluoro pentylsulfanyl)nonyloxy1phenyl}-3,4-dihvdro-2H-benzori,41oxazin-7-ol (11)
Step I: ( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-(tetrahydropyran-2-yloxy)phenyl]- 3 4-dihydro-2H-benzo[i,4]oxazine
Sodium teri-butoxide (0.16 g, 0.0017 mol) was added to a stirred solution of (R)-7- benzyloxy-3-(4-benzyloxy phenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.5 g, 0.0012 mol), 2- (3-iodophenoxy)tetrahydropyran (0.38 g, 0.0012 mol), bis(dibenzylideneacetone)palladium (0.007 g, 0.00012 mol) and tri teri-butylphosphine (0.002 mL, 0.001 mol) in toluene (5 mL) and heated at 100 °C for 2 hours under nitrogen atmosphere. It was allowed to cool to room temperature, water was added and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-7-benzyloxy-3-(4-benzyloxyphenyl)-4-[3- (tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4]oxazine, which was used for the next step without further purification.
Step II: 3-[( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl] phenol
2N Hydrochloric acid (5 mL) was added to a stirred solution of (R)-7-benzyloxy-3-(4- benzyloxyphenyl)-4-[3-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H-benzo[i,4] oxazine (0.8 g, 0.0013 mol) in tetrahydrofuran (10 mL) at 0-5 °C and then allowed to stir at room temperature for 1 hour. Reaction mixture was made basic (pH~9) with saturated sodium bicarbonate solution, concentrated under reduced pressure, and extracted with ethyl acetate. Combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue which was purified by column chromatography(silica gel 230-400 mesh, ethyl acetate:DCM:n-hexane, 20:20:60) to get 3-[(R)-7-benzyloxy-3-(4-benzyloxy phenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl]phenol.
Step III: ( ?)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-{3-[9-(4,4,5,5,5-pentafluoropentyl
Potassium carbonate (0.1 g, 0.0007 mol) was added to a solution of 3-[(R)-7-benzyloxy-3-(4- benzyloxy phenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl]phenol (0.15 g, 0.00029 mol) in N,N- dimethylformamide (5 mL) at room temperature and stirred for 30 minutes. l-Bromo-9- (4,4,5,5, 5-pentafluoropentylsulfanyl)nonane (0.13 g, 0.0004 mol) was added to the reaction mixture and then heated for 1 hour at 70 °C. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate :n-hexane, 10:90) to get (R)-7-benzyloxy-3-(4-benzyloxyphenyl)- 4-{3-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyloxy]phenyl}-3,4-dihydro-2H- benzo [1,4] oxazine.
Step IV: (/?)-3-(4-Hydroxyphenyl)-4-{3-[9-(4,4,5,5,5-pentafluoropentylsulfanyl) nonyloxy]phenyl}-3,4-dihydro-2H-benzo[i,4]oxazin-7-ol
Boron tribromide (0.36 mL, 0.0038 mol, 1M solution in DCM) was added to a solution of (R)-7-benzyloxy-3-(4-benzyloxyphenyl)-4-{3-[9-(4,4,5,5,5-pentafluoropentylsulfanyl) nonyloxy]phenyl}-3,4-dihydro-2H-benzo[i,4]oxazine (0.14 g, 0.0017 mol) in DCM (5 mL) at -78 °C and stirred for 30 minutes. Reaction mixture was diluted with DCM and made basic (pH~9) with saturated sodium bicarbonate solution. Organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give residue, which was purified by column chromatography (silica gel 230-400 mesh, n- hexane:ethyl acetate:DCM 60:20:20) to get (R)-3-(4-hydroxyphenyl)-4-{3-[9-(4,4,5,5,5- pentafluoropentylsulfanyl)nonyloxy]phenyl}-3,4-dihydro-2H-benzo[i,4]oxazin-7-ol.
Example 4: Preparation of 4 ( ?)-5 3-(2-dodecylaminoethoxy)pheny i-l,5,,6,7- tetrahydro-8-oxa-l,2,5-triaza cvclopentar >1naphthalen-6-yl}phenol
4-{ (R)-5-[3-(2-Dodecylaminoethoxy)phenyl]- 1 ,5,6,7-tetrahydro-8-oxa-l ,2,5-triaza cyclopenta[Z?]naphthalen-6-yl}phenol was prepared by employing Buchwald reaction between (R)-6-(4-benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-l,5,6,7-tetrahydro-8-oxa-l,2,5- triaza cyclopenta[b]naphthalene and dodecyl-[2-(3-iodophenoxy)ethyl]carbamic acid tert- butyl ester as mentioned above in example 2, followed by removal of protective groups.
Example 5: Preparation of 4-(3-fluoro-5-r2-(10-fluorodecylamino)ethoxy1phenyl)-3-(4- fluorophenyl)-3,4-dihydro-2H-benzori,41oxazin-7-ol (85)
A solution of bromine (1.9 mL, 0.036 mol) in chloroform (5 mL) was added to a stirred solution of 4-fluoroacetophenone (5 g, 0.036 mol) in a mixture (40 mL) of chloroform and diethyl ether (1 :1) dropwise at 0-5 °C. Reaction mixture was stirred for 30 min at room temperature and again cooled to 0-5 °C, quenched with 5 % aq. sodium carbonate solution and extracted with ethyl acetate. Combined organic layer was washed with water, brine solution and dried over anh. sodium sulphate. Removal of ethyl acetate under reduced pressure gave 4-fluorophenacyl bromide, which was used for next the next step without further purification.
Anhydrous potassium carbonate (0.74 g, 0.0054 mol) was added to a stirred solution of 5- benzyloxy-2-bromophenol (1 g, 0.036 mol) in acetone (20 mL) at room temperature and stirred for 30 min. 2-Bromo-l-(4-fluorophenyl)ethanone (0.78 g, 0.036 mol) was added to the reaction mixture and stirred at room temperature for 2 hours. Reaction mixture was filtered through sintered funnel and inorganic solid was washed with acetone. Combined filtrate was concentrate at 50 °C under reduced pressure to get crude product, to which, 6 % ethyl acetate in n-hexane was added and stirred for 1 hour. Solid thus obtained was filtered and dried under reduced pressure to give 2-(5-benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethanone.
Ammonium acetate (1.7 g, 0.02 mol) was added to a stirred solution of 2-(5-benzyloxy-2- bromophenoxy)-l-(4-fluorophenyl)ethanone (0.9 g, 0.0021 mol) in methanol (15 mL) at room temperature and stirred for 15 minutes. Sodium cyanoborohydride (0.27 g, 0.0042 mol) was added to reaction mixture and then heated at 65 °C for 4 hours. Reaction mixture was concentrated under reduced pressure, water was added to the residue, made basic (pH~9) with aqueous sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrate under reduced pressure to give crude product. Crude product was treated with 3N hydrochloric acid solution (10 vol) to give clear solution, which was washed with diisopropyl ether (10 vol). Aqueous layer was then basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 2-(5-benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine. zine
rn'5'(dibenzylidineacetone)dipalladium (0.05 g, 0.00005 mol) followed by 2,2'-Ws,(diphenyl phosphino)-l ,l ' -binaphthyl (0.06 g, 0.0001 mol) were added to a stirred solution of 2-(5- benzyloxy-2-bromophenoxy)-l-(4-fluorophenyl)ethylamine (0.4 g, 0.001 mol) in toluene (20 mL) at room temperature. Potassium teri-butoxide (0.16 g, 0.0014 mol) was added to reaction mixture and then heated at 105 °C for 90 min. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gave crude liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate: n-hexane, 10:90) to get 7- benzylozy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo [i,4]oxazine.
Step V: (2-{3-[7-Benzyloxy-3-(4-fluorophenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl]-5- fluoro henoxy)ethyl)-(lO-fluorodecyl)
Palladium acetate (0.007 g, 0.000029 mol) followed by tri-teri-butyl phosphine (0.02 ml, 0.00006 mol, 50 % solution in toluene) were added to a stirred solution of 7-benzyloxy-3-(4- fluorophenyl)-3,4-dihydro-2H-benzo[i,4]oxazine (0.2 g, 0.0006 mol) and [2-(3-bromo-5- fluorophenoxy)ethyl]-(10-fluoro decyl)carbamic acid teri-butyl ester (0.29 g, 0.0006 mol) in toluene (5 ml) at room temperature under nitrogen atmosphere. Sodium teri-butoxide (0.08 g, 0.0008 mol) was added to reaction mixture and heated at 105 °C for one hour. Reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (3x30 mL). Combined organic layer was washed with water followed by brine solution and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gave crude liquid, which was purified by column chromatography (silica gel 230- 400 mesh, ethyl acetate: n-hexane, 10:90) to get (2-{3-[7-benzyloxy-3-(4-fluorophenyl)-2,3- dihydrobenzo[l,4]oxazin-4-yl]-5-fluorophenoxy}ethyl)-(10-fluorodecyl) carbamic acid tert- butyl ester.
Step VI : (10-Fluorodecyl)-(2-{3-fluoro-5-[3-(4-fluorophenyl)-7-hydroxy-2,3-dihydro
5 % Palladium on charcoal (0.06 g, 50 % wet) was added to a stirred solution of (2-{3-[7- benzyloxy-3-(4-fluorophenyl)-2,3-dihydrobenzo[i,4]oxazin-4-yl]-5-fluorophenoxy}ethyl)- (10-fluorodecyl) carbamic acid teri-butyl ester (0.3 g, 0.0004 mol) in mixture (8 mL) of methanol and 1,4-dioxane (1 :1). Ammonium formate (0.25 g, 0.004 mol) was added to reaction mixture and heated at 70 °C for thirty minutes. Reaction mixture was cooled to room
temperature, filtered through celite bed and washed with mixture of methanol and 1,4- dioxane (1 : 1). Combined filtrate was concentrated at 50 °C under reduced pressure. Residue was dissolved in ethyl acetate, washed with water, brine solution and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gave (10-fluorodecyl)-(2- {3-fluoro-5-[3-(4-fluorophenyl)-7-hydroxy-2,3-dihydrobenzo[i,4]oxazin-4-yl]phenoxy} ethyl)carbamic acid teri-butyl ester, which was used for the next step without purification.
Step VII: 4-{3-Fluoro-5-[2-(10-fluorodecylamino)ethoxy]phenyl}-3-(4-fluorophenyl)-3,4-
4M Hydrochloric acid in 1,4-dioxan (1.8 mL) was added to a stirred solution of (10- fluorodecyl)-(2-{3-fluoro-5-[3-(4-fluorophenyl)-7-hydroxy-2,3-dihydrobenzo[i,4]oxazin-4- yl]phenoxy}ethyl)carbamic acid teri-butyl ester (0.35 g, 0.005 mol) in 1,4-dioxan (1 mL) at room temperature and stirred for 30 minutes. Reaction mixture was concentrated under reduced pressure at 45 °C. Residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude thus obtained was purified by column chromatography (silica gel 230-400 mesh, methanol:DCM (3:97) to get 4-{3-fluoro-5-[2-(10-fluorodecylarnino)ethoxy]phenyl}-3-(4-fluorophenyl)-3,4- dihydro-2H-benzo[i, 4] oxazin-7-ol.
Example 6: Preparation of 4-((/ -5-{3-fluoro-5-r2-(12-fluorododecylamino)ethoxy1 phenyl)-l,5,6,7-tetrahvdro-8-oxa-l,2,5-triazacvclopentar >1naphthalen-6-yl)phenol (49)
Step I: 5-Bromo-l
Methane sulfonic acid (0.12 mL, 0.0019 mol) was added to a stirred solution of 5-bromo-iH- indazol-6-ol (2.0 g, 0.0094 mol) and 3,4-dihydro-2H-pyran (4.25 mL, 0.047 mol) in a mixture (40 mL) of DCM and tetrahydrofuran (1 : 1) at room temperature and stirred for 1 hour. Reaction mixture was cooled to 0-5 °C, quenched with saturated sodium bicarbonate solution and extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 45 °C to give crude viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 30:70) to give 5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-ol. Step II: {(/?)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6- yloxy]ethyl}carbamic acid tert-but l ester.
Diisopropylazodicarboxylate (1.0 ml, 0.0048 mol) was added to a stirred mixture of [(R)-l- (4-benzyloxyphenyl)-2-hydroxyethyl]carbamic acid teri-butyl ester (1.18 g, 0.0034 mol), 5- bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-ol (1.0 g, 0.0034 mol) and triphenylphosphine (1.17 g, 0.0044 mol) in a mixture of tetrahydrofuran (4 mL) and toluene (16 mL) under nitrogen atmosphere at room temperature and stirred for 1 hour. Reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 45 °C to get crude viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 15:85) to get the title compound.
Step III: (/?)-l-(4-Benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6- loxyjethylamine.
4M Hydrochloric acid in 1 ,4-dioxan (7.5 mL) was added to a stirred solution of { (R)-l-(4- benzyloxy phenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-yloxy]ethyl}carbamic
acid teri-butyl ester (1.5 g, 0.0024 mol) in 1 ,4-dioxan (3 mL) at 0-5 °C and stirred for 1 hr. Reaction mixture was basified with saturated sodium bicarbonate solution and extracted with DCM. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get (R)-l-(4-benzyloxyphenyl)-2-[5- bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-yloxy]ethylamine, which was used for the next step without purification.
Step IV: (/?)-6-(4-Benzyloxy phenyl)-l-(tetrahydro pyran-2-yl)-l,5,6,7-tetrahydro-8-oxa- -triaza cyclopenta[Z»]naphthalene.
Potassium teri-butoxide (0.36 g, 0.0032 mol) was added to a stirred solution of (R)-l-(4- benzyloxyphenyl)-2-[5-bromo-l-(tetrahydropyran-2-yl)-iH-indazol-6-yloxy]ethylamine (1.2 g, 0.0023 mol), in'5,(dibenzylideneacetone)dipalladium (0.11 g, 0.00011 mol) and 2,2'- Z?i5'(diphenylphosphino)-l , -binaphthyl (0.14 g, 0.00023 mol) in toluene (25 mL) under nitrogen atmosphere. Reaction mixture was then heated at 100 °C for 1 hour 30 minutes. It was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentration under reduced pressure to give viscous liquid, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 30:70) to get (R)-6-(4-benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-l , 5,6,7- tetrahydro- 8 -oxa- 1 ,2,5 -triazacyclopenta[¾] naphthalene.
Step V: (2-{3-[(/?)-6-(4-Benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-6,7-dihydro-iH-8- oxa-l,2,5-triazacyclopenta[Z»]naphthalen-5-yl]-5-fluorophenoxy}ethyl)-(12-
Sodium teri-butoxide (0.064 g, 0.00066 mol) was added to a stirred mixture of (R)-6-(4- benzyloxyphenyl)- 1 -(tetrahydropyran-2-yl)- 1 ,5,6,7-tetrahydro-8-oxa- 1 ,2,5-triazacyclopenta [b] naphthalene (0.21 g, 0.00047 mol), [2-(3-bromo-5-fluorophenoxy)ethyl]-(12-fluoro dodecyl)carbamic acid teri-butyl ester (0.3 g, 0.00057 mol), palladium acetate (0.005 g, 0.000023 mol) and tri teri-butylphosphine (0.02 mL, 0.000047 mol, 50 % solution in toluene) in toluene (10 mL) under nitrogen atmosphere and then heated at 100 °C for 5 hours. Reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. Combined organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude, which was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 30:70) to get (2-{3-[(R)-6-(4-benzyloxyphenyl)-l-(tetrahydropyran-2-yl)- 6,7-dihydro-iH-8-oxa-l,2,5-triazacyclopenta[¾]naphthalen-5-yl]-5-fluorophenoxy}ethyl)- (12-fluorododecyl)carbamic acid teri-butyl ester. Step VI: (12-Fluorododecyl)-(2-{3-fluoro-5-[(/?)-6-(4-hydroxyphenyl)-l-(tetrahydro pyran-2-yl)-6,7-dihydro-iH-8-oxa-l,2,5-triazacyclopenta[Z»]naphthalen-5-
5 % Palladium on charcoal (0.07 g, 50 % wet) was added to a stirred solution of (2-{3-[(R)- 6-(4-benzyloxyphenyl)-l-(tetrahydropyran-2-yl)-6,7-dihydro-iH-8-oxa-l,2,5-triazacyclo penta[¾]naphthalen-5-yl]-5-fluorophenoxy}emyl)-(12-fluorododecyl)carbamic acid teri-butyl ester (0.17 g, 0.0002 mol) in a mixture (10 mL) of ethanol and 1,4-dioxane (1 : 1) at room temperature and then stirred under hydrogen atmosphere applied through balloon for 45 minutes. Reaction mixture was filtered through celite bed and washed with ethanol. Combined filtrate was concentrated under reduced pressure to get (12-fluorododecyl)-(2-{3- fluoro-5-[(R)-6-(4-hydroxyphenyl)-l-(tetrahydropyran-2-yl)-6,7-dihydro-iH-8-oxa-l,2,5- triazacyclopenta[¾]naphthalen-5-yl]phenoxy}ethyl)carbamic acid teri-butyl ester, which was used for the next step without further purification. Step VII: 4-(( ?)-5-{3-Fluoro-5-[2-(12-fluorododecylamino)ethoxy]phenyl}-l,5,6,7- tetrahydro-8-oxa-l,2,5-triazacyclopenta[Z»]naphthalen-6-yl)phenol.
4M Hydrochloric acid in 1,4-dioxan (1.5 mL) was added to a stirred solution of (12-fluoro dodecyl)-(2- { 3-fluoro-5- [(R)-6-(4-hydroxyphenyl)- 1 -(tetrahydropyran-2-yl)-6,7-dihydro-iH- 8-oxa-l,2,5-triazacyclopenta[¾]naphthalen-5-yl]phenoxy}ethyl)carbamic acid tert-butyl ester (0.15 g, 0.00019 mol) in 1,4-dioxan (1 mL) at room temperature and stirred for 30 minutes. Reaction mixture was heated at 70 °C for 30 minutes and then concentrated under reduced pressure at 45 °C. Residue was basified with saturated sodium bicarbonate solution and extracted with DCM. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude thus obtained was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol: aq. ammonia (94 :4:2) to get 4-((R)-5-{3-fluoro-5-[2-(12-fluorododecylamino)ethoxy]phenyl}- l,5,6,7-tetrahydro-8-oxa-l,2,5-triazacyclopenta[¾]naphthalen-6-yl)phenol.
Some of the representative compounds of Formula I prepared as per the processes described above along with their proton NMR spectroscopy data are provided in Table-2 below.
Table-2
benzo[ , 4] oxazin- 7- ol 6.59-6.61 (m, 3H); 6.64 (d, J=5.2 Hz, IH); 6.67 (d, J=8.5 Hz, IH); 7.1-7.7 (m, 3H); two exchangeable protons.
( ?)-4-[3-(3-Dodecyl (CD3OD): δ 0.8 (t, J=6.6 Hz, 3H); 1.1-1.28 (br s, 18H); 1.40-1.49 (br m, 2H); aminopropoxy)phenyl]-3- 1.86 (quintet, J=6.50 Hz, 2H); 2.55 (t, J=7.4 Hz, 2H); 2.72 (t, J=7.15 Hz, 2H);
(4-hydroxyphenyl)-3,4- 3.83-3.90 (m, 2H); 4.12 (dd, J^IO.8 Hz, J2=2.7 Hz, IH); 4.32 (dd, J^IO.85 dihydro-2//-benzo Hz, J2=3.7 Hz, IH); 4.65 (br s, IH); 6.15-6.20 (m, 2H); 6.46 (dd, 1^8.2 Hz,
[i,4]oxazin-7-ol J2=2.15 Hz, IH); 6.55-6.64 (m,4H); 6.68 (d, J=8.55 Hz, IH); 7.02-7.09 (m,
3H); three exchangeable protons.
4-{(7?>4-[3-(2-Dodecyl (CD3OD): δ 0.81 ( t, J=6.95 Hz, 3H); 1.14-1.33 (br m, 18H); 1.58-1.67 (m, aminoethoxy) phenyl] -7- 2H); 2.93-2.98 (m, 2H); 3.3 ( t, J=4.92 Hz, 2H); 4.08-4.12 (br m, 2H); 4.18 fluoro-3,4-dihydro-2//- (dd, J^IO.9 Hz, J2=2.85 Hz, IH); 4.37 (dd , J^IO.9 Hz, J2=4.15 Hz, IH ); 4,71 benzo[ , 4] oxazin- 3- yl } (t, J = 3.32 Hz, IH); 6.40 (d of t, J1 =8.85 Hz, J2=2.95 Hz, IH); 6.48 (dd, phenol J!=9.62 Hz, J2=2.85 Hz, IH); 6.59(d, J=8.65 Hz, 2H); 6.63 (dd, J1=8.15 Hz ,
J2=2.3 Hz, IH ); 6.70 (t, J = 2.2 Hz, IH); 6.71-6.79 (m, 2H ); 7.03 (d, J=8.5 Hz, 2H); 7.15 (t, J=8.15 Hz, IH); two exchangeable protons.
fi? 4-[3-(2-Dodecyl (CDCI3): δ 0.81 (t, J=7.04Hz, 3H); 1.1-1.28 (br s, 18H); 1.39-1.49 (br m, 2H); aminoethoxy)-5-fluoro 2.55 (t, J=7.4Hz, 2H); 2.85 (t, J=5.0Hz, 2H); 3.90 (t, J=5.0Hz, 2H); 4.13 (dd, phenyl]-3-(4-hydroxy J!=10.88Hz, J2 = 2.72Hz, IH); 4.37 (dd, ^ = 10.88Hz, J2 = 3.0Hz, IH); 4.72 phenyl)-3,4-dihydro-2//- (s,lH); 6.18 (d, J = 2.6Hz, IH); 6.19-6.26 (m, 2H); 6.36 (d, J = 10.8Hz, IH); benzo[ 1 , 4] oxazin- 7- ol 6.42 (s, IH); 6.60 (d, J = 8.52Hz, 2H); 6.81 (d, J = 8.72Hz, IH); 7.05 (d, J =
8.5Hz, 2H); three exchangeable protons.
( ?)-3-(4-Hydroxy (CD3OD): δ 0.78-0.82(m, 3H); 1.12-1.38 (br m, 10H); 1.4-1.5 (m, 2H); 1.5- phenyl)-4-[3-(5- 1.72 (m, 6H); 2.82-2.95 (m, 4H); 3.81 (t, J=5.76Hz, 2H); 4.12 (dd, J!=10.72Hz, octylaminopentyloxy) J2 = 2.72Hz, IH); 4.33 (dd, J1=10.76 Hz, J2=3.68Hz, IH); 4.64 (br s, IH); 6.15- phenyl] -3 ,4-dihydro-2/f- 6.19 (m, IH); 6.45 (d, J=8.2Hz, IH); 6.53 (t, J=2.16Hz, IH); 6.57-6.7 (m, 4H); benzo[ 1 , 4] oxazin- 7- ol 7.05 (d, J=8.28Hz, 4H); three exchangeable protons.
4-[3-(2-Dodecylamino (DMSO-d6): δ 0.86-0.96 (br m, 3H); 1.2-1.4 (br s, 18H); 1.6-1.7 (br s, 2H); 2.9- ethoxy)phenyl]-3-(4- 3.0 (br m, 2H); 3.29-3.35 (br s, 2H); 4.17-4.3 (br m, 3H); 4.6 (d, J = 10.05 Hz, fluorophenyl)3,4-dihydro IH); 5.08 (br s,lH); 6.26-6.3 (br s, IH); 6.34 (d , J = 8.56 Hz, IH); 6.66 (d, J = -2//-benzo [ 1 , 4] oxazin- 7- 7.76 Hz, IH); 6.74 (s, IH); 6.80 (d , J = 8.08 Hz, IH); 6.91 (d, J = 9.68 Hz, ol IH); 7.19 (t, J = 8.48 Hz, 2H); 7.28 (t, J = 8.02 Hz, 2H); 7.45 (t, J = 6.46 Hz,
IH); 8.87 (br s, IH); 9.12 (s, IH ); two exchangeable protons.
4-{( ?>6-Chloro-4-[3-(2- (CD3OD): δ 0.81 (t, J=6.15Hz, 3H), 1.2 (br s, 18H), 1.27 (merged s, 2H), 1.57 dodecyamino ethoxy) (m, 2H), 2.9 (t, J=8Hz, 2H), 4.07 (d, J=4.9Hz, 2H), 4.2 (dd, J!=10.75Hz, phenyl] -3 ,4-dihydro-2/f- J2=2.5Hz, IH), 4.3 (dd, =W.9Hz, J2=4.3Hz, IH), 4.7 (s, IH), 6.53-6.6 (m, benzo[ 1 , 4] oxazin- 3- yl } 4H), 6.76-6.71 (m, 3H), 6.8(d, J=8Hz, IH), 7.0 (d, J=8.5Hz, 2H), 7.2 (t, phenol J=7.95Hz, IH), two exchangeable protons.
( ?)-3-(4-Hydroxy (CDCI3): δ 1.25-1.43 (m, 10H); 1.53-1.63 (m, 2H, merged with H20 of CDC13); phenyl)-4-{3-[9- 1.68-1.75 (m, 2H); 1.84-1.92 (m, 2H); 2.10-2.23 (m, 2H); 2.50(t, J=7.24Hz, (4,4,5,5,5-pentafluoro 2H); 2.59 (t, J=7.0Hz, 2H); 3.85 (t, J=5.46Hz, 2H); 4.28 (d, J=9.64Hz,lH); pentylsulfanyl)nonyloxy] 4.46(d, J=10.68Hz, IH); 4.56(s, IH); 6.28-6.42 (m, IH); 6.55 (d, J=7.8Hz, IH); phenyl } -3 ,4-dihydro-2/f- 6.69 (m, 2H); 6.74(d, 8.4Hz, 2H); 6.92 (d, J=8.6Hz, IH); 7.14 (m, 2H); 7.18(d, benzo[ 1 , 4] oxazin- 7- ol J=8.4Hz, 2H); two exchangeable protons.
( ?)-3-(4-Hydroxy (CDCI3): δ 0.81 (t, J=6.94Hz, 3H); 1.12-1.30 (br m, 10H); 1.40-1.50 (br t, 2H); phenyl)-4-[3-(2- 2.60 (t, J=7.72, 2H); 2.90 (t, J=5.08 Hz, 2H); 3.93(t, J=5.16Hz, 2H); 4.12 (dd, octylamino ethoxy) J^IO.76 Hz, J2=2.72Hz, IH); 4.33 (dd, J!=10.84Hz, J2=3.76 Hz, IH); 4.66 (br phenyl] -3 ,4-dihydro-2/f- s, IH); 6.15-6.20 (m, 2H); 6.50 (dd, J1=8.16 Hz, J2=2.00Hz, IH); 6.57-6.71 benzo[ 1 , 4] oxazin- 7- ol (m, 6H); 7.05 (m, 2H), three exchangeable protons.
Dodecanoic acid-(2-{3- (CDCI3): δ 0.87 (t, J =7.04Hz, 3H); 1.1-1.35 (br s, 16H); 1.5-1.7 (br s, 2H,
[(7? 7-hydroxy-3-(4- merged with H20 of CDC13); 2.18 (t, J=7.8 Hz, 2H); 3.57 (t, J=5.08 Hz, 2H); hydroxyphenyl)-2,3- 3.87-3.91 (m, 2H); 4.28 (dd,
dihydro benzo[i,4] J2=3.68Hz, IH); 4.71 (s, IH); 5.15 (br s, IH); 5.79 (br s, IH); 5.92 (t, J=5.6 Hz, oxazin-4-yl]phenoxy} IH); 6.32 (dd, J!=8.68Hz, J2=2.6Hz, IH); 6.4 (d, J=2.6Hz,lH); 6.53 (dd, ethyl)amide J!=8.2Hz, J2=2.08Hz, IH); 6.61 (br s, IH); 6.73-6.79 (m,3H); 6.86 (d, J=8.7Hz,
IH); 7.12-7.17(m, 3H)
4-{fi? 7-amino-4-[3-(2- (DMSO-d6): δ 0.91 (t, J = 6.78 Hz, 3H); 1.26-1.34 (br s, 18H); 1.6-1.72 (br m, dodecylaminoethoxy)- 2H); 2.9-3.0 (br m, 2H); 3.26-3.36 (br m, 2H); 4.20-4.28 (br m, 2H); 4.32 (dd, phenyl] -3 ,4-dihydro-2/f- Ji = 10.76 Hz, J2 = 2.4 Hz, IH); 4.52 (dd, ^ = 10.8 Hz, J2= 3.08 Hz, IH); 5.0 benzo[ 1 , 4] oxazin- 3- yl } (br s, IH); 6.74 (d, J = 8.56 Hz, 2H); 6.75-6.92 (m , 5H); 6.97 (d, J = 8.68 Hz,
phenol IH); 7.14 (d, J = 8.56 Hz, 2H); 7.33 (t, J = 8.08 Hz, IH); 9.04 (br s, 2H); 9.48 (br s, IH); 10.05 (br s, IH); four exchangeable protons.
( ?)-4-[3-(2-Dodecyl (CD3OD): δ 0.91 (t, J = 6.6 Hz, 3H); 1.2 -1.5 (br s, 18H); 1.66-1.73 (br m, 2H); aminoefhoxy)phenyl]-3- 3.05 (t, J=7.92Hz, 2H); 3.40 (t, J=4.96Hz, 2H); 4.19 (br s, 2H); 4.27 (dd, phenyl-3,4-dihydro-2//- J^IO.92 Hz, J2=2.80 Hz, IH); 4.53 (dd, J1= 10.9 Hz, J2=3.16 Hz, IH); 4.8 (IH, benzo[ 1 , 4] oxazin- 7- ol merged with H20 peak of CD3OD); 6.27-6.3 (br m, IH); 6.31 (d, J=2.72 Hz,
IH); 6.65 (dd, J1=7.92 Hz, J2=2.04Hz, IH); 6.77-6.91 (m, 3H); 7.22 (t, J = 8.12 Hz, 2H); 7.29(t, J =7.04 Hz, 2H); 7.37(d, J = 7.36 Hz, 2H); three exchangeable protons.
(i?)-4-[3-(2-Dodecyl (DMSO-d6): δ 0.91 (t, J = 6.6 Hz, 3H); 1.2-1.4 (br s, 18H); 1.65-1.7 (br m, 2H); aminoefhoxy)phenyl]-3- 2.93-3.1 (br m, 2H); 3.3- 3.40 (br m, peak partially merged with C2D5SOH, (4-mefhoxyphenyl)-3,4- 2H); 3.76 (s, 3H); 4.18-4.25 (m, 3H); 4.57 (dd, J1= 10.9 Hz, J2=2.75 Hz, IH); dihydro-2//-benzo[ 1, 4] 4.99 (s, IH); 6.26 (d, J=2.65 Hz, IH); 6.32 (dd, J!=8.75Hz,J=2.72 Hz, IH); oxazin-7-ol 6.65 (dd, J^IO.35 Hz, J2=2.3Hz, IH); 6.74 (s, IH); 6.80 (d, J=8.1 Hz, IH);
6.85-6.95 (m, 3H); 7.27(t, J=8.2 Hz, IH); 7.32(d, J=8.65 Hz, 2H); 8.73 (br s, 2H); 9.06 (s,lH)
( ?)-4-[3-(2-Dodecyl
aminoethoxy)-5-trifluoro (CDCI3): δ 0.8-0.9 (t, 3H); 1.1-1.4 (br s, 18H); 1.49-1.6 (br s, 2H); 2.66 (br s, mefhylphenyl]-3-(4- 2H); 2.95 (br s, 2H); 3.93 (br s, 2H); 4.21 (d, J=9.2 Hz, IH); 4.42 (d, J=8.44 hydroxyphenyl)-3,4- Hz, IH); 4.69 (br s, IH); 6.2-6.35 (m, 2H); 6.6-6.82 (m, 5H); 6.9-7.0 (m, IH); dihydro-2//-benzo[ 1, 4] 7.0-7.15 (m, 2H); three exchangeable protons.
oxazin-7-ol
JV-[(7? 4-[3-(2-Dodecyl
aminoefhoxy)phenyl]-3- (CD3OD): δ 0.81 ( t, J = 6.3 Hz, 3H) ; 1.15-1.3 ( br s, 18H) ; 1.55-1.65 (br m, (4-hydroxyphenyl)-3,4- 2H) ; 2.95 ( t, J = 7.8 Hz, 2H) ; 3.26-3.33 ( br s, 2H) ; 4.05-4.15 ( br m, 2H); dihydro-2//-benzo[ 1, 4] 4.2-4.3 (m, IH); 4.3-4.42 ( m, IH) ; 4.71 (br s, IH); 6.54-6.9 (m, 7H); 6.95-7.1 oxazin-7-yl] f ormamide (m , 3H); 7.1-7.23 (m, IH); three exchangeable protons.
( ?)-4-[3-(2-Dodecyl (CDCI3): δ 0.87 (t, J=6.44Hz, 3H), 1.23 (br s, 18H), 1.53 (br s, 2H), 2.67 (t, aminoefhoxy)phenyl]-3- (4-hydroxyphenyl)-3,4-
dihydro-2//-benzo[ 1, 4] 6.6 (br m, 3H), 6.7 (d, J=8.48Hz, 2H), 6.76 (d, J=7.8Hz, IH), 7.04 (d, J=8.4Hz, oxazin-8-ol 2H), 7.12 (t, J=8.04Hz, IH), three exchangeable protons.
(i?)-3-(4-Hydroxy (CD3OD): δ 0.81 (t, J = 6.64 Hz, 3H), 1.14-1.30 (br s, 10 H), 1.38 -1.49 (br m, phenyl)-4-{3-[2-(2- 2H), 2.42 (t, J = 6.92 Hz, 2H), 2.54 (t, J =7.20 Hz, 2H), 2.62-2.74 (br s, 3H), octylaminoethylamino) 2.77 -2.89 (m, 2H), 3.86- 3.94 (br s, 2H), 4.12 (d, J = 9.40 Hz, IH), 4.32 (d, J = efhoxy]phenyl}-3,4- 7.84 Hz, IH), 4.65 (S, IH), 6.13-6.20 (m, 2H), 6.44-6.70 (m, 6H), 7.02-7.10 dihydro-2//-benzo[ 1, 4] (m, 3H). three exchangeable protons.
oxazin-7-ol
(i? 4-[3-(2-Decylamino (CDCI3): δ 0.87 (t, J = 7.10 Hz, 3H); 1.18-1.35 (br m, 14 H); 1.5-1.6 (m, 2H); ethoxy)-5-fluoro phenyl]- 2.66 (t, J = 7.5Hz, 2H); 2.9 -3.0 (m, 2H); 3.93 (t, J=5.05 Hz, 2H); 4.23 (dd, ^ 3-(4-hydroxyphenyl)-3,4- = 10.85 Hz, J2 = 2.5 Hz, IH); 4.44 (dd, ^ =10.75 Hz, J2 = 2.6 Hz, IH); 4.7 (s, dihydro-2//-benzo[ 1, 4] IH); 6.2 (d, J =10.3Hz, IH); 6.24 (dd, = 8.8 Hz, J2 = 2.75 Hz, IH); 6.32 (br oxazin-7-ol s, IH); 6.41-6.46 (m, 2H) ; 6.67 (d, J = 8.55 Hz, 2H); 6.84 (d, J= 8.75 Hz, IH);
7.08 (d, J= 8.5 Hz, 2H); three exchangeable protons
( ?)-4-[3-Fluoro-5-(2- (CDCI3): δ 0.87 (t, J = 7.10 Hz, 3H); 1.2-1.35 (br m, 20 H); 1.5-1.6 (m, 2H); tetradecylaminoethoxy) 2.66(t, J = 7.55 Hz, 2H); 2.9-3.0 (m, 2H); 3.92 (t, J= 4.9 Hz, 2H); 4.22 (dd, ^ = phenyl]-3-(4-hydroxy 10.75 Hz, J2 = 2.45 Hz, IH); 4.43 (dd, J1= 10.75 Hz, J2 = 2.20 Hz, IH); 4.69 (s, phenyl)-3,4-dihydro-2//- IH); 6.19 (d, J= 10.35 Hz, IH); 6.22 (dd, ^ = 8.85 Hz, J2 = 2.75 Hz, IH); 6.3- benzo[ 1 , 4] oxazin- 7- ol 6.33( m, IH); 6.41-6.45 (m, 2H); 6.66 (d, J = 8.6 Hz, 2H); 6.82 (d, J=8.75 Hz,
IH); 7.07 (d, J = 8.50Hz, 2H); three exchangeable protons
(5)-4-[3-(2-Dodecyl
aminoefhoxy)phenyl]-3- (DMSO-d6): δ 0.9(s, 3H), 1.3(br s, 18H), 1.43(br s, 2H), 2.85 (s, 2H), 3.96 (s,
(4-hydroxyphenyl)-3,4- 2H), 4.2(d, J=9.68H, IH), 4.5(d, J=8.96Hz, IH), 4.9(s, IH), 6.3(m, 2H), 6.5- dihydro-2//- 6.86 (br m, 3H), 7.17 (t, J=8.04Hz, IH), three exchangeable protons.
benzo[ 1 , 4] oxazin- 7- ol
l-(2-{3-[(7?)-7-Hydroxy- (DMSO-d6): δ 0.91 (t, J = 6.85 Hz, 3H); 1.24-1.35 (br m, 12H); 1.38-1.43 (br 3-(4-hydroxyphenyl)-2,3- m, 2H); 3.01 (q, J = 6.4 Hz, 2H); 3.32-3.38 (br m, 2H); 3.86-3.93 (br m, 2H); dihydrobenzo [1,4] 4.19 ( dd, Ji = 10.95 Hz, J2 = 2.5 Hz, IH); 4.49 (dd, ^ = 11.05 Hz, J2 = 3.05 oxazin-4-yl]phenoxy} Hz, IH ); 4.91 (s,lH); 5.95 (t, J = 5.6 Hz, IH); 6.02 (t, J = 5.65 Hz, IH); 6.25
ethyl)-3-nonyl urea (d, J = 2.65 Ηζ,ΙΗ); 6.30 (dd, = 8.7 Hz, J2 = 2.65 Hz, IH ); 6.6 (dd, = 8.15 Hz, J2 = 2.05 Hz, IH); 6.66 (s, IH); 6.69-6.78 (m, 3H); 6.85 (d, J = 8.8 Hz, IH); 7.15-7.24 (m, 3H ); 8.98 (s, IH ); 9.35 (s,lH); two exchangeable protons.
( ? 4-[4-(2-Dodecyl (CD3OD): δ 0.91 (t, J=7.15 Hz, 3H), 1.22-1.38 (m, 18H), 1.47-1.57 (m, 2H), aminoefhoxy)phenyl]-3- 2.71 (t, J=7.35 Hz, 2H), 3.01 (t, J=5.45 Hz, 2H), 4.05 (t, J=5.45 Hz, 2H), 4.21 (4-hydroxyphenyl)-3,4- (dd, J1=10.8 Hz, J2=2.7 Hz, IH), 4.33 (dd, J1=10.9 Hz, J2=5.35 Hz, IH), 4.7- dihydro-2//-benzo[ 1, 4] 4.73 (m, IH), 6.22 (dd, J1=8.7 Hz, J2=2.6 Hz, IH), 6.29 (d, J=2.7 Hz, IH), 6.41 oxazin-7-ol (d, J=8.6 Hz, IH), 6.69 (d, J=8.55 Hz, 2H), 6.9 (d, J=9.0 Hz, 2H), 7.08 (d,
J=8.85 Hz, 2H), 7.14 (d, J=8.55 Hz, 2H), 8.85 (br s, IH), 9.35 (br s, IH), one exchangeable proton.
(7? 3-(4-Methoxy (DMSO-d6): δ 0.92 (t, J = 6.68 Hz, 3H); 1.29-1.4 (br m, 10H); 1.62-1.72 (m, phenyl)-4-{3-[2-(2- 2H); 2.9- 3.0 (m, 2H); 3.30-3.5 (m, 8H); 3.76(s, 3H); 4.2 (dd, ^ = 11.04 Hz, J2 octylaminoethylamino) = 2.52 Hz, IH); 4.23-4.3 (m, 2H); 4.57 (dd, ^ = 11.08 Hz, J2 = 2.64 Hz, IH); efhoxy]phenyl}-3,4- 5.0(s, IH); 6.26 (d, J = 2.65 Hz, IH); 6.33 (dd, ^ = 8.72 Hz, J2 = 2.64 Hz, IH ); dihydro-2//-benzo[ 1, 4] 6.67 (dd, J[ = 8.12 Hz, J2 =1.78 Hz, IH); 6.76 (s, IH); 6.8 (d, J = 8.08 Hz, IH); oxazine-7-ol 6.91(dd, Ji = 8.72 Hz, J2 =2.32 Hz, 3H); 7.27 (t, J = 8.16 Hz, IH); 7.33 (d, J =
8.64 Hz, 2H); 9.09 (s,lH); 9.33 (s, IH); 9.52 (s, IH); three exchangeable protons.
fi? 4-{3-Fluoro-5-[2-(2- (DMSO-d6): δ 0.9 (t, J=6.4Hz, 3H); 1.28 (br s, 10H); 1.38-1.45 (br m, 2H); octylaminoethylamino) 2.50 (t, J=7.0Hz, 2H); 2.58-2.65 (m, 4H); 2.85 (t, J=5.28 Hz, 2H); 3.97 (t, efhoxy]phenyl}-3-(4- J=5.2Hz, 2H); 4.19 (d, J=8.6 Hz, IH); 4.56 (d, J=9.9Hz, IH); 4.99 (s, IH); 6.25 hydroxyphenyl)-3,4- (d, J=2.56 Hz, IH); 6.33 (dd, J1=8.7 Hz, J2=2.56Hz, IH); 6.4-6.52 (m, 3H); dihydro-2//-benzo[ 1, 4] 6.72 (d, J=8.48 Hz, 2H); 6.96 (d, J=8.76Hz,lH); 7.18 (d, J=8.48Hz, 2H); four oxazin-7-ol exchangeable protons.
(5)-4-[3-(2-Dodecyl (CD3OD): δ 0.80 ( t, J = 6.85 Hz, 3H); 1.1-1.3 ( br m, 18H); 1.38-1.47 (br m, aminoethoxy)-5-fluoro 2H); 2.51 (t, J = 7.27 Hz, 2H); 2.78-2.83 (br t, 2H); 3.84-3.9 (br m, 2H); 4.11 phenyl]-3-(4-hydroxy (d, J = 9.05 Hz, IH); 4.36 (d, J = 8.65 Hz, IH); 4.68-4.72 (br s, IH); 6.16-6.25 phenyl)-3,4-dihydro-2//- (br m, 3H); 6.35 (d, J = 10.70 Hz, IH); 6.41 (s, IH); 6.6 (d, J = 8.15 Hz, 2H ); benzo[i,4]oxazine-7-ol 6.81 (d, J = 8.65 Hz, IH); 7.05 (d, J = 8.15 Hz, 2H); three exchangeable protons.
(5)-4-{3-Fluoro-5-[2-(2- (DMSO-d6): δ 0.9-1.0 (m, 3H); 1.34 (br s, 10 H); 1.47 (br s, 2H); 2.56 (t, octylaminoethylamino) J=6.75 Hz, 2H); 2.58-2.72 (m, 4H); 2.91 (br s, 2H); 4.03 (br s, 2H); 4.26 (d, efhoxy]phenyl}-3-(4- J=9.73 Hz, IH); 4.61 (d, J=10.06Hz,lH); 5.05 (s, IH); 6.31 (s, IH); 6.39 (d, hydroxyphenyl)-3,4- J=8.5 Hz, IH); 6.49 (d, J=10.65 Hz, IH); 6.52-6.58 (m, 2H); 6.78 (d, J=8.13 dihydro-2//-benzo[ 1, 4] Hz, 2H); 7.03 (d, J=8.68 Hz, IH); 7.24 (d, J=8.09 Hz, 2H), four exchangeable oxazin-7-ol protons.
( ?)-4-{3-Fluoro-5-[2-(2- (DMSO-d6): δ 0.92 (t, J=6.9 Hz, 3H), 1.22-1.45 (br m, 10H), 1.62-1.72 (m, octylaminoethylamino) 2H), 2.9-3.0 (m, 2H), 3.3-3.38 (br s, 2H), 3.38-3.45 (br s, 4H), 3.75 (s, 3H), efhoxy]phenyl}-3-(4- 4.21 (d, J=8.9 Hz, IH), 4.29 (br s, 2H), 4.63 (d, J=9.4 Hz, IH), 5.09 (br s, IH), mefhoxyphenyl)-3,4- 6.27 (d, J=2.5 Hz, IH), 6.35 (d, J=8.77 Hz, IH), 6.55-6.62 (m, 3H), 6.92 (d, dihydro-2//-benzo[ 1, 4] J=8.6 Hz, 2H), 7.02 (d, J=8.76 Hz, IH), 7.32 (d, J=8.56 Hz, 2H), 9.1-9.8 (m, oxazin-7-ol 5H).
Dodecyl-(2-{3-fluoro-5- (DMSO-d6): δ 0.90 (t, J = 6.81 Hz, 3H); 1.24-1.36 (br m, 18H); 1.6-1.7 (br m, [6-(4-methoxyphenyl)-6, 2H); 2.9-2.97 (br m, 2H); 3.28-3.34 (br m, 2H); 3.74 (s, 3H); 4.28 (br t, J = 7-dihydro-i#-8-oxa-l, 2, 4.51 Hz, 2H ); 4.40 (dd, ^ = 10.97 Hz, J2 = 2.69 Hz, IH); 4.59 (dd, ^ = 11.05 5-triazacyclopenta[fc] Hz, J2 = 3.35 Hz, IH); 5.13-5.17 (br s, IH); 6.63 (d, J = 10.64 Hz, IH); 6.7 (s, naphthalene-5-yl] IH); 6.74 (d, J = 10.8 Hz, IH); 6.91 (d, J = 8.75 Hz, IH); 6.95 (s, IH); 7.33(d, phenoxy } ethyl)amine J=8.68 Hz, 2H); 7.4 (s, IH ), 7.9 (s, IH); 9.06-9.08 (br m, 2H), two exchangeable protons.
(i?)-4-[3-(2-Dodecyl (DMSO-d6): δ 0.91 (t, J = 6.93 Hz, 3H); 1.28-1.38 (br m, 18H); 1.6-1.7 (br m, aminoethoxy)-5-fluoro 2H); 2.96 (br t, J = 7.99 Hz, 2H); 3.3-3.36 (br m, 2H); 3.76 (s, 3H); 4.21 (dd, ^ phenyl]-3-(4-methoxy = 11.14 Hz, J2 = 2.76 Hz, IH); 4.23-4.29 (br m, 2H); 4.63 (dd , ^ = 11.06 Hz, phenyl)-3,4-dihydro-2//- J2 = 2.37Hz, IH); 5.08 (s, IH); 6.26 (d, J = 2.71 Hz, IH); 6.36 (dd, J1= 8.8 Hz, benzo[ 1 , 4] oxazin- 7- ol J2 = 2.73 Hz, IH); 6.51-6.62 (m, 3H); 6.92 (dd, ^ = 6.82 Hz, J2 = 2.04 Hz, 2H
); 7.01 (d, J = 8.77 Hz, IH); 7.32 (d, J = 7.62 Hz, 2H); 8.82-8.9 (br s, 2H); 9.2 (s, IH); two exchangeable protons.
4-{5-[3-(2-Dodecylamino (DMSO-d6): δ 0.74-0.85 (br m, 3H); 1.10-1.13 (br m, 18H); 1.4-1.53 (br m, efhoxy)-5-fluorophenyl]- 2H); 2.6-2.7 (br m, 2H); 2.95-3.0 (br m, 2H); 3.9-4.0 (m, 2H); 4.25-4.4 (m,
l,5,6,7-tetrahydro-8-oxa- 2H); 4.75 (s, merged with H20 peak of CD3OD); 6.36 (d, J = 10.32 Hz, IH); l,2,5-triazacyclopenta[fc] 6.48-6.67 (m, 4H); 6.84-6.86 (br s, lH); 7.05 (d, J = 8.12 Hz, 2H); 7.14 (s, IH ); naphthalene-6-yl } phenol 7.66 (s, IH); three exchangeable protons.
( ?)-4-[3-(3-Dodecyl (CD3OD): δ 0.99 (t, J=6.8 Hz, 3H), 1.30-1.49 (m, 18H), 1.54-1.66 (m, 2H), aminopropoxy)-5-iluoro 2.02 (quint, J1=6.4 Hz, J2=6.7 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.2 phenyl]-3-(4-hydroxy Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 4.31 (dd, Jl=10.9 Hz, J2=2.8 Hz, IH), 4.55 phenyl)-3,4-dihydro-2//- (dd, Jl=11.0 Hz, J2=3.1 Hz, IH) 4.89 (S, IH), 6.34-6.42 (m, 3H), 6.49-6.57 benzo[ 1 , 4] oxazin- 7- ol (m, 2H), 6.78 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.8 Hz, IH), 7.23 (d, J=8.5 Hz, 2H), three exchangeable protons.
( ?)-4-[3-(2-Dodecyl (CD3OD): δ 0.99 (t, J=6.7 Hz, 3H), 1.33-1.45 (m, 18H), 1.55-1.62 (m, 2H), aminoethylamino) 2.67 (t, J=7.45 Hz, 2H), 2.83 (t, J=6.25 Hz, 2H), 3.24 (t, J=6.25 Hz, 2H), 4.28 phenyl]-3-(4-hydroxy (dd, J^IO.8 Hz, J2=2.8 Hz, IH), 4.48 (dd, J^IO.6 Hz, J2=3.85 Hz, IH), 4.79- phenyl)-3,4-dihydro-2//- 4.82 (br m, IH), 6.31-6.37 (m, 2H), 6.4 (d, J=9.25 Hz, IH), 6.5-6.54 (m, 2H), benzo[ 1 , 4] oxazin- 7- ol 6.76 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.45 Hz, IH), 7.09 (t, J=8.2 Hz, IH), 7.23 (d,
J=8.5 Hz, 2H), four exchangeable protons.
( ?)-4-[3-(3-Dodecyl (CD3OD): δ 0.99 (t, J=7.0 Hz, 3H), 1.34-1.44 (m, 18H), 1.57-1.63 (m, 2H), aminopropylamino) 1.83 (quintet, J=7.15 Hz, 2H), 2.68 (t, J=7.65 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), phenyl]-3-(4-hydroxy 3.13 (t, J=6.75 Hz, 2H), 4.28 (dd, J^IO.8 Hz, J2=2.8 Hz, IH), 4.48 (dd, J^IO.7 phenyl)-3,4-dihydro-2//- Hz, J2=3.85 Hz, IH), 4.79 (t, J=3.05 Hz, IH), 6.32-6.35 (m, 2H), 6.4 (dd, benzo[ 1 , 4] oxazin- 7- ol J!=8.95 Hz, J2=1.8 Hz, IH), 6.48-6.53 (m, 2H), 6.76 (d, J=8.55 Hz, 2H), 6.85
(d, J=8.85 Hz, IH), 7.08 (t, J=7.8 Hz, IH), 7.23 (d, J=8.55 Hz, 2H), four exchangeable protons.
(5)-4-[3-(3-Dodecyl (CD3OD): δ 0.99 (t, J=6.8 Hz, 3H), 1.30-1.47 (m, 18H), 1.54-1.65 (m, 2H), aminopropoxy)-5-iluoro 2.02 (quint, J=6.7 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 4.04 phenyl]-3-(4-hydroxy (t, J=6.0 Hz, 2H), 4.30 (dd, Jl=10.9 Hz, J2=2.8 Hz, IH), 4.55 (dd, Jl=11.0 Hz, phenyl)-3,4-dihydro-2//- J2=3.25 Hz, IH) 4.89 (br s, IH), 6.35-6.42 (m, 3H), 6.5-6.57 (m, 2H), 6.78 (d, benzo[ 1 , 4] oxazin- 7- ol J=8.6 Hz, 2H), 6.98 (d, J=8.8 Hz, IH), 7.23 (d, J=8.5 Hz, 2H), three exchangeable protons.
jV-[( ? 4-[3-(2-Dodecyl
(DMSO-d6): δ 0.90 (t, J = 6.74 Hz, 3H); 1.23-1.38 (br s, 18H); 1.59-1.68 (br m, aminoethoxy)-5-iluoro
2H); 2.97 (t, J = 7.8 Hz, 2H); 3.3-3.37 (br m, 2H); 4.2-4.3 (br m, 3H); 4.54- phenyl]-3-(4-hydroxy
4.62 (m, IH); 5.02 (s, IH); 6.54-6.68 (m, 3H); 6.74 (d, J= 8.5 Hz, 2H); 7.04-7.1 phenyl)-3,4-dihydro-2//- (m, 2H); 7.16 (d, J = 9 Hz, 3H); 8.22 (s, IH); 10.1 (s, IH); three exchangeable benzo[ 1 , 4] oxazin- 7- yl]
protons.
formamide
( ?)-4-{3-[3-(4- Amino (CD3OD): δ 1.8-2.0 (m, 4H), 2.2-2.3 (m, 2H), 3.08 (t, J=7.48 Hz, 2H), 3.17 (t, butylamino)propyl J=6.96 Hz, 2H), 3.23 (t, J=7.48 Hz, 2H), 3.54-3.6 (br t, 3H), 4.36 (dd, J^l l.04 amino]phenyl}-3-(4- Hz, J2=2.84 Hz, IH), 4.6 (dd, J^l l.04 Hz, J2=3.16 Hz, IH), 6.39 (d, J=2.6 Hz, hydroxyphenyl)-3,4- IH), 6.43 (dd, 1^8.76 Hz, J2=2.72 Hz, IH), 6.8 (d, J=8.56 Hz, 2H), 7.03 (d, dihydro-2//-benzo[ 1, 4] J=8.68 Hz, IH), 7.19 (d, J=7.84 Hz, IH), 7.27 (d, J=8.52 Hz, 2H), 7.36-7.43 oxazin-7-ol (m, 2H), 7.51-7.56 (m, IH), five exchangeable protons.
( ?)-4-{3-[3-(4-Dimethyl (CD3OD): δ 1.83-1.97 (m, 4H), 2.19-2.28 (m, 2H), 2.97 (s, 6H), 3.16 (t, J=7.35 aminobutylamino)propyl Hz, 2H), 3.21 (t, J=7.45 Hz, 2H), 3.25 (t, J=8.3 Hz, 2H), 3.54 (t, J=8.05 Hz, amino]phenyl}-3-(4- 2H), 4.33 (dd, J^IO.95 Hz, J2=2.55 Hz, IH), 4.57 (dd, J^l l.O Hz, J2=3.05 Hz, hydroxyphenyl)-3,4- IH), 6.36 (d, J=2.6 Hz, IH), 6.4 (dd, 1^8.75 Hz, J2=2.65 Hz, IH), 6.77 (d, dihydro-2//-benzo[ 1, 4] J=8.5 Hz, 2H), 6.99 (d, J=8.85 Hz, IH), 7.14 (d, J=6.95 Hz, IH), 7.24 (d, oxazin-7-ol J=8.55 Hz, 2H), 7.32 (s, IH), 7.36 (d, J=8.25 Hz, IH), 7.5 (t, J=8.0 Hz, IH), one proton merged in CD3OD peak, four exchangeable protons.
Dodecyl-(2-{3-fluoro-5-
[fi? 6-(4-methoxy (DMSO-d6): δ 0.91 (t, J = 6.91 Hz, 3H); 1.25-1.35 (br m, 18 H); 1.6-1.68 (br m, phenyl)-6,7-dihydro-i//- 2H); 2.9-3 (m, 2H); 3.3-3.36 (m, 2H); 3.74 (s, 3H); 4.24-4.29 ( m, 2H) 4.4 (dd,
8-oxa- 1,2,5- Ji =11.06 Hz, J2 = 2.95 Hz, IH); 4.59 (dd, ^ = 11.01 Hz, J2 =3.3 Hz, IH); 5.15 triazacyclopenta[fc] (s, IH); 6.63 (d, J =10.6 Hz, IH); 6.69(s, IH); 6.74(d, J = 10.86 Hz, IH); naphthalene-5-yl] 6.91(d, J = 8.81 Hz, 2H); 7.88 (s,lH); 8.9 (br s, 2H)
phenoxy } ethyl)amine
(5)-4-{3-Fluoro-5-[2-(12- (DMSO-d6): δ 1.23-1.42 (m, 16H), 1.56-1.75 (m, 4H), 2.95 (t, J=8.1 Hz, 2H), iluorododecylamino) 3.27-3.35 (m, 2H), 3.76 (s, 3H), 4.18-4.28 (m, 3H), 4.47 (t of d, J!=47.8, J2= ethoxy]phenyl}-3-(4- 6.1Hz, 2H), 4.64 (dd, J^ll.0, J2= 2.0 Hz, 2H), 5.04-5.10 (br s, IH), 6.26 (d, methoxyphenyl)-3,4- J=2.7 Hz, IH), 6.35 (dd, J^S.S Hz, J2=2.6 Hz, IH), 6.50-6.62 (m, 3H), 6.92 dihydro-2//-benzo[ 1, 4] (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, IH), 7.32 (d, J=8.6 Hz, 2H), 8.32-8.80 (br
oxazin-7-ol s, IH), 9.17 (s, IH).
(i?)-4-{3-Fluoro-4-[2- (DMSO-d6): δ 1.26-1.4 (br m, 18 H); 1.6-1.72 (br m, 2H); 2.96-3.05 (br m, ( 12-fluorododecylamino) 2H); 3.32-3.4 (br m, 2H); 3.75 (s, 3H); 4.22 (dd, J1= 11.0Hz, J2 =2.72 Hz, IH); efhoxy]phenyl}-3-(4- 4.34 (t, J= 4.96 Hz, 2H); 4.41 (t, J = 3.02 Hz, IH); 4.45 (d, J = 4.48 Hz, IH); mefhoxyphenyl)-3,4- 4.53 (t, J = 6.1 Hz, IH ); 4.9 (s,lH); 6.26-6.31 (m, 2H); 6.62 (dd, ^ = 7.44 Hz, dihydro-2//-benzo[ 1, 4] J2= 1.72 Hz, IH); 6.89 (d, J = 8.76 Hz, 2H); 6.96 (d, J = 10.04 Hz, IH); 7.06 oxazin-7-ol (dd, Ji = 13Hz, J2 = 2.52Hz, IH); 7.18 (t, J = 9.3 Hz, IH); 7.3 (d, J = 8.68 Hz,
2H); 9.0-9.1 (br m, 3H). two exchangeable protons.
(R )-4- { 3,4-Difluoro-5- [2- (DMSO-d6): δ 1.23-1.42 (m, 16H), 1.58-1.64 (m, 4H), 2.95 (t, J=7.56 Hz, 2H), ( 12-fluorododecylamino) 3.31 (t, J=4.64 Hz, 2H), 3.7 (s, 3H), 4.16 (dd, J^l l.O Hz, J2=2.52 Hz, IH), efhoxy]phenyl}-3-(4- 4.25-4.35 (br m, 2H), 4.36 (t, J=6.08 Hz, IH), 4.5-4.58 (m, 2H), 4.99 (br s, mefhoxyphenyl)-3,4- IH), 6.22 (d, J=2.64 Hz, IH), 6.26 (dd, J1=8.68 Hz, J2=2.64 Hz, IH), 6.73-6.8 dihydro-2//-benzo[ 1, 4] (m, IH), 6.76 (d, J=8.68 Hz, 2H), 6.85 (d, J=8.76 Hz, 2H), 7.26 (d, J=8.64 Hz, oxazin-7-ol 2H), two exchangeable protons.
fi?)-4-{3-Fluoro-5-[2-(12- (DMSO-d6): δ 1.22-1.43 (m, 16H), 1.58-1.76 (m, 4H), 2.93-3.03 (br s, 2H), fluorododecylamino) 3.30-3.38 (br s, 2H), 3.76 (s, 3H), 4.18-4.30 (m, 3H), 4.48 (t of d, J1 =47.6 Hz, efhoxy]phenyl}-3-(4- J2= 6.1Hz, 2H), 4.63 (d, J=8.8 Hz, IH), 5.05-5.10 (br s, IH), 6.26 (d, J=2.6 Hz, mefhoxyphenyl)-3,4- IH), 6.36 (dd, J1=8.8 Hz, J2=2.7 Hz, IH), 6.50-6.63 (m, 3H), 6.92 (d, J=8.8 Hz, dihydro-2//-benzo[ 1, 4] 2H), 7.00 (d, J=8.8 Hz, IH), 7.32 (d, J=8.6 Hz, 2H), 8.65-8.95 (br s, 2H), 9.19 oxazin-7-ol (s, IH).
(i?)-4-{3-[2-(Dodecyl (CDC13): δ 0.87 (t, J = 6.84 Hz, 3H); 1.2-1.3 (br s, 18H); 1.43-1.53 (br m, 2H); mefhylamino)efhoxy]-5- 2.31 (s, 3H); 2.45 (t, d= 7.9 Hz, 2H); 2.76 (t, J = 5.64 Hz, 2H); 3.94 (t, J = 5.58 fluorophenyl } - 3 - (4- Hz, 2H); 4.23 (dd, ^ = 10.8 Hz, J2 = 2.68 Hz, IH); 4.44 (dd, J1= 10.88 Hz, J2= hydroxyphenyl)-3,4- 3.12 Ηζ,ΙΗ); 4.69 (s, IH); 6.20 (dd, ^ = 10.32 Hz, J2 = 2.08 Hz, IH); 6.27 (dd, dihydro-2//-benzo[ 1, 4] Ji = 8.72 Hz, J2 = 2.76 Hz, IH); 6.32 (d, J = 2.72 Hz, IH); 6.4-6.5 (m, 2H); oxazin-7-ol 6.66 (d, J= 8.6 Hz, 2H); 6.89 (d, J = 8.76 Hz, IH); 7.09 (d, J = 8.44 Hz, 2H).
two exchangeable protons.
(i?)-4-(3-Fluoro-5- { 2-( 10- (CDCI3): δ 1.21-1.31 (br m, 10 H); 1.31-1.41 (br m, 2H); 1.41-1.51 (br m, 2H); fluorodecyl)methyl 1.6-1.75 (m, 2H); 2.31 (s, 3 H); 2.43 (t, J = 7.8 Hz, 2H);2.75 (t, J = 5.72 Hz, amino]efhoxy}phenyl)-3- 2H); 3.90-3.97 (m, 2H); 4.25 (d, J= 8.12 Hz, IH); 4.37 (t, J = 6.18 Hz, IH);
(4-hydroxyphenyl)-3,4- 4.43-4.51 (m, 2H); 4.71 (s, IH); 6.23 (d, J= 10.4 Hz, IH); 6.30 (dd, ^ = 8.72 dihydro-2//-benzo[ 1, 4] Hz, J2 = 2.76 Hz, IH ); 6.34 (d, J = 2.72 Hz, IH); 6.41-6.47 (m, 2H); 6.7 (d, J = oxazine-7-ol 8.6 Hz, 2H ); 6.93 (d, J = 8.72 Hz, IH); 7.12 (d, J = 8.52 Hz, 2H ). two exchangeable protons.
( ?)-4-{3-Fluoro-5-[2-(10- (DMSO-d6): δ 1.26-1.43 (m, 12H), 1.57-1.77 (m, 4H), 2.92 (t, J=7.8 Hz, 2H), fluorodecylamino)ethoxy] 3.26-3.3 (br s, 2H), 3.7 (s, 3H), 4.18-4.28 (m, 3H), 4.36 (t, J=6.12 Hz, IH), phenyl }-3-(4-methoxy 4.48 (t, J=6.12 Hz, IH), 4.57 (dd, J^l l.16 Hz, J2=2.36 Hz, IH), 5.02 (br s, phenyl)-3,4-dihydro-2//- IH), 6.2 (d, J=2.68 Hz, IH), 6.3 (dd, J1=8.76 Hz, J2=2.68 Hz, IH), 6.5-6.62 (m, benzo[ 1 , 4] oxazin- 7- ol 3H), 6.86 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.76 Hz, IH), 7.26 (d, J=8.64 Hz, 2H), two exchangeable protons.
4-((i?)-5-{3-Fluoro-5-[2- (DMSO-d6): δ 1.25-1.34 (br m, 16 H); 1.34-1.48 (br m 4H); 1.6-1.74 (br m, ( 12-fluorododecylamino) 2H); 2.78 (t, J = 5.54 Hz, 2H); 3.93 (t, J = 5.56Hz, 2H); 4.34-4.43 (m, 2H ); efhoxy]phenyl}-l,5,6,7- 4.49-4.5 (m, 2H); 5.06 (s, IH); 6.56 (dd, ^ = 10.84 Hz, J2 = 2.16 Hz, IH); tetr ah ydro-8-oxa- 1,2,5- 6.61-6.67 (br m, 2H); 6.71 (d, J = 8.6 Hz, 2H); 6.94 (s, IH); 7.19 (d, J = 8.56 triazacyclopenta[fc] Hz, 2H); 7.31 (s, IH); 7.85(s, IH); 9.4 (s, IH); 12.63 (s, IH). three naphthalene-6-yl)phenol exchangeable protons.
(R )-4- { 3,4-Difluoro-5- [2- (DMSO-d6): δ 1.28-1.43 (br m, 12H), 1.6-1.76 (m, 4H), 3.01 (t, J=7.56 Hz, ( 10-fluorodecylamino) 2H), 3.37 (t, J=4.8 Hz, 2H), 3.76 (s, 3H), 4.22 (dd, J^l l.O Hz, J2=2.6 Hz, IH), efhoxy]phenyl}-3-(4- 4.26-4.36 (m, 2H), 4.42 (t, J=6.12 Hz, IH), 4.5-4.58 (m, 2H), 5.02-5.06 (br m, methoxyphenyl)-3,4- IH), 6.28 (d, J=2.69 Hz, IH), 6.32 (dd, J1=8.7 Hz, J2=2.69 Hz, IH), 6.73-6.8 dihydro-2//-benzo[ 1, 4] (m, IH), 6.82 (d, J=8.68 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.68 Hz, oxazin-7-ol 2H), two exchangeable protons.
4-((i?)-5-{3-Fluoro-5-[2-
(DMSO-d6): δ 1.28-1.48 (br m, 16H); 1.6-1.74 (br m, 2H); 2.84 (t, J = 5.5 Hz, ( 10-fluorodecylamino)
2H ); 3.98 (t, J = 5.48 Hz, 2H); 4.34-4.44 (m, 2H); 4.48-4.57 (m, 2H); 5.05 (s, efhoxy]phenyl}-l,5,6,7- IH); 6.55 (d, J = 10.88 Hz, IH); 6.6-6.68 (m, 2H); 6.71 (d, J = 8.52 Hz, 2H); tetr ah ydro-8-oxa- 1,2,5- 6.94 (s, IH); 7.19 (d, J = 8.44 Hz, 2H); 7.31 (s, IH); 7.85 (s, IH); 9.4 (s, IH); triazacyclopenta[fc]
12.63 (s, IH). three exchangeable protons.
naphthalene-6-yl)phenol
(5)-4-{3-Fluoro-5-[2-(10- (DMSO-d6): δ 1.37-1.43 (m, 12H), 1.58-1.77 (m, 4H), 2.92 (t, J=7.68 Hz, 2H), fluorodec ylamino) 3.28 (t, J=4.32 Hz, 2H), 3.7 (s, 3H), 4.18-4.25 (m, 3H), 4.36 (t, J=6.12 Hz, 1H), ethoxy]phenyl}-3-(4- 4.48 (t, J=6.12 Hz, 1H), 4.57 (dd, J^ll.2 Hz, J2=2.44 Hz, 1H), 4.99-5.03 (br mefhoxyphenyl)-3,4- m, 1H), 6.2 (d, J=2.7 Hz, 1H), 6.3 (dd, 1^8.76 Hz, J2=2.72 Hz, 1H), 6.5-6.62 dihydro-2//-benzo[ 1, 4] (m, 3H), 6.86 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.76 Hz, 1H), 7.25 (d, J=8.6 Hz, oxazin-7-ol 2H), two exchangeable protons.
( ?)-4-(3-Fluoro-5-{2-[5- (DMSO-d6): δ 1.27-1.37 (m, 2H), 1.38-1.48 (m, 4H), 1.61-1.71 (m, 2H), 2.2-
(4,4,5,5,5-pentafluoro 2.37 (m, 2H), 2.45-2.63 (m, merged with DMSO-d6 peak, 6H), 2.84 (t, J=5.48 pentylamino)pentylamino Hz, 2H), 3.98 (t, J=5.52 Hz, 2H), 4.19 (dd, J^l l.12 Hz, J2=2.8 Hz, 1H), 4.55
]ethoxy}phenyl)-3-(4- (dd, J^ll.04 Hz, J2=2.64 Hz, 1H), 5.0 (br s, 1H), 6.25 (d, J=2.68 Hz, 1H), 6.33 hydroxyphenyl)-3,4- (dd, J!=8.76 Hz, J2=2.72 Hz, 1H), 6.42-6.54 (m, 3H), 6.72 (d, J=8.64 Hz, 2H), dihydro-2//-benzo[ 1, 4] 6.96 (d, J=8.76 Hz, 1H), 7.18 (d, J=8.52 Hz, 2H), four exchangeable protons. oxazin-7-ol
(5)-4-{3-[2-(10,10- (DMSO-d6): δ 1.29-1.45 ( br m, 12 H); 1.6-1.7 (m, 2H); 1.75-1.92 (m, 2H); Difluorodecylamino) 2.97(s, 2H); 3.32 (s, 2H); 3.76 (s, 3H); 4.21(dd, ^ = 11.28Hz, J2 = 2.81Hz, ethoxy] -5-fluorophenyl } - 1H); 4.25 (t, J = 4.76 Hz, 2H); 4.64 (dd, ^ = 11.16 Hz, J2 = 2.4 Hz, 1H); 5.08 3 -(4-methoxyphenyl)- 3 , 4- (s, 1H); 6.108 ( t of t; ^ = 56.9 Hz, J2 = 4.48 Hz, 1H); 6.26 (d, J =2.7 Ηζ,ΙΗ); dihydro-2//-benzo[ 1, 4] 6.36 (dd, Ji = 8.8 Hz, J2 = 2.72 Hz, 1H); 6.5-6.62 (m, 3H); 6.92 (d, J =8.8 Hz, oxazin-7-ol 2H); 7.01 (d, J = 8.76 Hz, 1H); 7.31 (d, J = 8.6 Hz, 2H); 8.91 ( s, 2H); 9.19 (s,
1H).
( ?)-4- { 3-Fluoro-5-[2-( 10- (DMSO-d6): δ 1.2-1.48 (m, 14H), 1.67 (d, J=23.9 Hz, 2H), 2.43-2.65 (br m, fluorodecylamino)ethyl merged with solvent peak, 2H), 2.68 (br s, 2H), 3.03 (br s, 2H), 4.16 (d, J=9.65 amino]phenyl}-3-(4- Hz, 1H), 4.42 (br s, 1H), 4.52 (br s, 2H), 4.88 (br s, 1H), 5.9 (s, 1H), 6.02 (dd, hydroxyphenyl)-3,4- J!=20.15 Hz, J2=11.35 Hz, 2H), 6.21 (d, J=14.45 Hz, 1H), 6.32 (d, J=6.9 Hz, dihydro-2//-benzo[ 1, 4] 1H), 6.72 (d, J=6.1 Hz, 2H), 6.92 (d, J=3.85 Hz, 1H), 7.17 (d, J=6.1 Hz, 2H), oxazin-7-ol 9.03 (br s, 1H), 9.37 (br s, 1H) two exchangeable protons.
(R)-4- { 3-Fluoro-4-[2-( 10- (CDC¾): δ 1.2-1.4 (br m, 12H); 1.59-1.72 (m, 2H); 1.8-1.9 (m, 2H); 3.11 (br s, fluorodecylamino)ethoxy] 2H); 3.35 (br s, 2H); 3.73 (s, 3H); 4.20 (dd, ^ = 10.76 Hz, J2 = 2.76 Hz, 1H); phenyl }-3-(4-methoxy 4.29-4.38 (m, 3H); 4.42 (t of d; ^ =47.37 Hz, J2 = 6.16 Hz, 2H); 4.59 (s, 1H); phenyl)-3,4-dihydro-2//- 6.29 (dd, Ji = 8.68 Hz, J2 = 2.4 Hz, 1H); 6.43 (d, J = 2.72 Hz, 1H); 6.62 (d, J = benzo[ 1 , 4] oxazin- 7- ol 8.76 Hz, 1H); 6.77 (d, J = 8.72 Hz, 3H); 6.83 (dd, ^ = 3.88 Hz, J2 = 2.44 Hz,
2H); 7.14 (d, J = 8.64 Hz, 2H); 9.4 (s, 2H); one exchangeable proton
(i?)-4-{3-[2-(10,10- (DMSO-d6): δ 1.2-1.5 (br m, 12H); 1.6-1.74 (m, 2H); 1.74-1.92 (m, 2H); 2.95 Difluorodecylamino) (br s, 2H); 3.32 ( br s, 2H); 3.76 (s, 3H); 4.22 (d, J = 10.8 Hz, 1H); 4.27 (br s, 2 ethoxy] -5-fluorophenyl } - H); 4.63 (d, J = 10.20 Hz, 1H); 5.08 (s, 1H); 6.11 (t, J = 56.66 Hz, 1H); 6.26 (s, 3 -(4-methoxyphenyl)- 3 , 4- 1H); 6.36 (d, J = 8.24 Hz, 1H); 6.56 (t, J = 12.6 Hz, 3H); 6.92 (d, J = 7.84 Hz, dihydro-2//-benzo[ 1, 4] 2H); 7.01 (d, J = 8.44 Hz, 1H); 7.32 (d, J = 7.68 Hz, 2H); 9.09 (br s, 2H); 9.23 oxazin-7-ol (s, 1H)
(i?)-4-{3-Fluoro-5-[2-(10- (DMSO-d6): δ 1.26-1.4 (br m, 12H), 1.54-1.73 (m, 4H), 2.92 (t, J=7.44 Hz, fluorodecylamino)ethyl 2H), 3.07 (t, J=6.2 Hz, 2H), 3.29 (t, J=6.28 Hz, 2H), 3.74 (s, 3H), 4.15 (dd, amino]phenyl}-3-(4- J^ll.12 Hz, J2=2.52 Hz, 1H), 4.4 (t, J=6.08 Hz, 1H), 4.52 (t, J=6.08 Hz, 1H), mefhoxyphenyl)-3,4- 4.56 (dd, J^l l.12 Hz, J2=2.64 Hz, 1H), 4.94 (br s, 1H), 6.07-6.17 (m, 2H), dihydro-2//-benzo[ 1, 4] 6.22 (br s, 1H), 6.23 (d, J=2.72 Hz, 1H), 6.33 (dd, J1=8.76 Hz, J2=2.68 Hz, 1H), oxazin-7-ol 6.89 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.76 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), three exchangeable protons.
(i?)-4-{3-Fluoro-5-[2-(10- (CD3OD): δ 1.27-1.41 (br m, 12H); 1.6-1.74 (m, 4H); 2.94-3.0 (m, 2H); 3.29- fluorodecylamino)ethoxy] 3.37 (m, 2H); 4..21 (d, J = 2.56 Hz, 1H); 4.22-4.28 (m, 2H); 4.48 (t of d, = phenyl }-3-(4-fluoro 47.54 Hz, J2 = 6.11 Hz, 1H); 4,52 (t, J = 6.11 Hz, 1H); 4.67 (dd, ^ = 11.2 Hz, mefhoxyphenyl)-3,4- J2 = 2.2 Hz, 1H); 5.14 (s,lH); 5.88 (d, J = 54.7 Hz, 2H); 6.26 (d, J = 2.68 Hz, dihydro-2//-benzo[ 1, 4] 1H); 6.37 (dd , ^ = 8.8 Hz, J2 = 2.7 Hz, 1H); 6.53-6.58 (m, 2H); 6.6 (d, oxazin-7-ol J=11.22 Hz, 1H); 7.02 (d , J = 8.78 Hz , 1H); 7.1 (d, J = 8.7 Hz, 2H); 7.4 (d, J =
8.64 Hz, 2H); 8.88 (br s, 2H); 9.22 (s, 1H ); two exchangeable protons.
(i?)-4-{3-Fluoro-5-[2-(12- (DMSO-d6): δ 1.22-1.42 (br m, 16H), 1.43-1.53 (m, 2H), 1.6-1.73 (m, 2H), fluorododecylamino) 2.65 (t, J=7.0 Hz, 2H), 2.95 (br t, 2H), 4.03 (t, J=5.0 Hz, 2H), 4.19 (d, J=8.7 ethoxy]phenyl}-3-(4- Hz, 1H), 4.42 (t, J=6.1 Hz, 1H), 4.52 (t, J=6.1 Hz, 1H), 4.56 (d, J=8.9 Hz, 1H), hydroxyphenyl)-3,4- 5.0 (br s, 1H), 6.25 (d, J=2.55 Hz, 1H), 6.34 (dd, J1=8.75 Hz, J2=2.55 Hz, 1H), dihydro-2//-benzo[ 1, 4] 6.43-6.55 (m, 3H), 6.73 (d, J=8.45 Hz, 2H), 6.97 (d, J=8.78 Hz, 1H), 7.18 (d, oxazin-7-ol J=8.45 Hz, 2H), 9.13 (br s, 1H), 9.4 (br s, 1H), one exchangeable proton.
(5)-4-{3-Fluoro-5-[2-(10- (DMSO-d6): δ 1.25-1.42 (br m, 12H), 1.42-1.52 (br m, 2H), 1.5-1.75 (m, 2H), fluorodec ylamino) 2.63 (t, J=7.28 Hz, 2H), 2.94 (t, J=5.52 Hz, 2H), 4.02 (t, J=5.36 Hz, 2H), 4.2 efhoxy]phenyl}-3-(4- (dd, J^l l.08 Hz, J2=2.76 Hz, IH), 4.41 (t, J=6.12 Hz, IH), 4.5-4.6 (m, 2H), hydroxyphenyl)-3,4- 4.99 (br s, IH), 6.26 (d, J=2.68 Hz, IH), 6.34 (dd, 1^8.76 Hz, J2=2.68 Hz, IH), dihydro-2//-benzo[ 1, 4] 6.43-6.53 (m, 3H), 6.72 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.76 Hz, IH), 7.18 (d, oxazin-7-ol J=8.52 Hz, 2H), 9.11 (br s, IH), 9.38 (br s, IH), one exchangeable proton.
(i?)-4-[3-(2-dodecylamino (DMSO-d6): δ 0.91 (t, J = 6.82 Hz, 3H); 1.25-1.4 (br m, 18H); 1.6-1.7 (m, 2H); efhoxy)-5-fluorophenyl]- 2.91-3.02 (m, 2H); 3.3-3.35 (m, 2H); 4.21 (d, J = 2.56 Hz, IH); 4.24 (t, 2.98 3-(4-fluoromethoxy Hz, 2H); 4.66 (d, J = 8.96 Hz, IH); 5.13 (s, IH); 5.87 (d, J = 54.53 Hz, 2H); phenyl)-3,4-dihydro-2//- 6.26 (d, J = 2.68 Hz, IH); 6.37 (dd, ^ = 8.76 Hz, J2 = 2.68 Hz, IH); 6.51-6.63 benzo[i,4] oxazin-7-ol (m , 3H); 7.01 (d, J = 8.76 Hz, IH); 7.103 (d, J = 8.72 Hz, 2H); 7.4 (d, J = 8.6
Hz, 2H); 8.84 (s, 2H); 9.19 (s, IH); two exchangeable protons.
(i?)-4-{3-Fluoro-5-[2-(12- (DMSO-d6): δ 1.26-1.41 (br m, 16H); 1.6-1.75 (m, 4H); 2.92-3.02 (m, 2H); fluorododecylamino) 3.3-3.48 (m, 2H); 4.2-4.28 (m, 3H); 4.48 (t of d, ^ = 41.44 Hz, J2 = 6.21 Hz, efhoxy]phenyl}-3-(4- 2H); 4.67 (d, J = 8.96 Hz, IH); 5.13 (s, IH); 5.88 (d, J = 54.58 Hz, 2H); 6.26 fluoromefhoxyphenyl)- (d, J = 1.84 Hz, IH); 6.37 (dd, ^ = 8.8 Hz, J2 = 2.7 Hz, IH); 6.52-6.64 (m, 3H);
3 ,4-dihydro-2//-benzo 7.02 (d , J = 8.76 Hz , IH); 7.1 (d, J = 8.64 Hz, 2H); 7.4 (d, J = 8.6 Hz, 2H );
[i,4]oxazin-7-ol 8.82 (s, 2H); 9.21 (s, IH ); two exchangeable protons.
( ?)-4-{3-[2-(12,12- (DMSO-d6): δ 1.25-1.47 (m, 16H), 1.58-1.60 (m, 2H), 1.73-1.94 (m, 2H), 2.92- Difluorododecylamino) 3.04 (m, 2H), 3.29-3.37 (m, 2H), 3.76 (s, 3H), 4.14-4.30 (m, 3H), 4.63 (d, ethoxy] -5-fluorophenyl } - J=9.04 Hz, IH), 5.07 (br s, IH), 6.10 (t of t, J1=56.9 Hz, J2=4.6 Hz, IH), 6.26 3 -(4-methoxyphenyl)- 3 , 4- (d, J=2.6 Hz, IH), 6.35 (dd, J1=8.8 Hz, J2=2.5 Hz, IH), 6.47-6.66 (m, 3H), 6.92 dihydro-2//-benzo[ 1, 4] (d, J=8.8 Hz, 2H), 7.00 (d, J=8.7 Hz, IH), 7.31 (d, J=8.6 Hz, 2H), 8.7 (br s, oxazin-7-ol 2H), 9.17 (s, IH).
( ?)-4-{3-[2-(12,12- (DMSO-d6): δ 1.20-1.54 (m, 18H), 1.73-1.93 (m, 2H), 2.60-2.70 (m, 2H), 2.87- Difluorododecylamino) 3.00 (m, 2H), 4.02 (t, J=5.6 Hz, 2H), 4.20 (d, J=8.4 Hz, IH), 4.56 (d, J=8.4 Hz, ethoxy] -5-fluorophenyl } - IH), 5.0 (br s, IH), 6.10 (t of t, J1=56.9 Hz, J2=4.5 Hz, IH), 6.25 (d, J=2.6 Hz, 3-(4-hydroxyphenyl)-3,4- IH), 6.33 (dd, J1=8.8 Hz, J2=2.7 Hz, IH), 6.42-6.55 (m, 3H), 6.73 (d, J=8.5 Hz, dihydro-2//-benzo[ 1, 4] 2H), 6.96 (d, J=8.7 Hz, IH), 7.18 (d, J=8.5 Hz, 2H), 9.11 (S, IH), 9.39 (S, IH), oxazin-7-ol one exchangeable proton.
4-(fi? 4-{3-Fluoro-5-[2- (DMSO-d6): δ 1.25-1.45 (br m, 12H), 1.58-1.77 (m, 4H), 2.97 (t, J=7.76 Hz, ( 10-fluorodecylamino) 2H), 3.3-3.38 (br m, 2H), 4.18-4.26 (br m, 2H), 4.28 (dd, J^l l.O Hz, J2=2.28 efhoxy]phenyl}-3,4- Hz, IH), 4.42 (t, J=6.08 Hz, IH), 4.48-4.58 (m, 2H), 5.02 (br s, IH), 6.61-6.71 dihydro-2//-benzo[ 1, 4] (m, 3H), 6.73 (d, J=8.4 Hz, 2H), 6.77-6.89 (m, 3H), 7.07 (d, J=7.68 Hz, IH), oxazin- 3 -yl)phenol 7.15 (d, J=8.44 Hz, 2H), two exchangeable protons.
(i?)-4-{3-Fluoro-5-[2-(10- (DMSO-d6): δ 1.27-1.41 (br m, 12H); 1.6-1.75 (m, 4H); 2.97 (t, J = 7.7 Hz, fluorodecylamino)ethoxy] 2H); 3.3-3.37 (m, 2H); 4.2-4.3 (m, 3H); 4.48 (t of d, ^ = 47.56 Hz, J2 = 6.1 Hz, phenyl }-3-phenyl-3,4- 2H); 4.68 (d, J = 9.4 Hz, IH); 5.16 (s, IH); 6.26 (d, J = 2.6 Hz, IH); 6.37 (dd , dihydro-2//-benzo[ 1, 4] Ji = 8.75 Hz, J2 = 2.5 Hz, IH); 6.5-6.62 (m, 3H); 7.04 (d , J = 8.8 Hz, IH); 7.29 oxazin-7-ol (t, J = 7.1 Hz, IH); 7.34-7.45 (m, 4H); 8.91 (br s, IH); two exchangeable protons.
(10-Fluorodecyl)-{2-[3- (DMSO-d6): δ 1.23-1.43 (m, 12H), 1.53-1.76 (m, 4H), 2.96 (t, J=8.2 Hz, 2H), fluoro-5 - ( f R )- 3 -phenyl- 3.29-3.48 (m, 2H), 4.22 (br s, 2H), 4.33 (d, J=8.5 Hz, IH), 4.47 (t of d, J1=47 2,3-dihydrobenzo[i,4] Hz, J2= 6.1 Hz, 2H), 4.62 (d, J=8.2 Hz, IH), 5.18 (s, IH), 6.61-6.76 (m, 3H), oxazin-4-yl)phenoxy] 6.79-6.93 (m, 3H), 7.14 (d, J=7.0 Hz, IH), 7.26-7.43 (m, 5H), three ethyl} amine exchangeable protons.
(R)-4- { 3-Fluoro-4-[2-( 10- (DMSO-d6): δ 1.28-1.45 (m, 14H); 1.6-1.74 (m, 4H); 3.03 (t, J = 7.64 Hz, 2H); fluorodecylamino)ethoxy] 3.38 (s, 2H); 4.22-4.32 (m, 3H); 4.4-4.5 (m, 2H); 4.52 (t, J = 6.1 Hz, IH); 4.96 phenyl }-3-(4-fluoro (s, IH); 5.87 (d, J = 54.5 Hz, 2H); 6.28-6.33 (m, 2H); 6.64 (t, J = 4.72 Hz, IH); mefhoxyphenyl)-3,4- 6.96 (d, J = 8.4 Hz, IH); 7.06-7.12 (m, 3H); 7.18 (t, J = 9.36, IH); 7.38 (d, J = dihydro-2//-benzo[ 1, 4] 8.64 Hz, 2H); 8.9 (s, IH); two exchangeable protons.
oxazin-7-ol
(R )-4- { 3-Fluoro-4-[2-( 12- (DMSO-de): δ 1.25-1.4 (br m, 16H), 1.4-1.48 (m, 2H), 1.6-1.73 (m, 2H), 2.58 fluorododecylamino) (t, J=7.08 Hz, merged with peak of solvent, 2H), 2.88 (t, J=5.56 Hz, 2H), 4.05 efhoxy]phenyl}-3-(4- (t, J=5.68 Hz, 2H), 4.2 (dd, J1=10.8 Hz, J2=2.56 Hz, IH), 4.33-4.44 (m, 2H), hydroxyphenyl)-3,4- 4.53 (t, J=6.12 Hz, IH), 4.79 (br s, IH), 6.23-6.3 (m, 2H), 6.55 (d, J=8.56 Hz, dihydro-2//-benzo[ 1, 4] IH), 6.7 (d, J=8.56 Hz, 2H), 6.86-6.92 (br m, IH), 6.99 (dd, J1=13.0 Hz, oxazin-7-ol J2=2.44 Hz, IH), 7.11 (t, J=9.3 Hz, IH), 7.15 (d, J=8.52 Hz, 2H), 8.94 (s, IH),
9.37 (s, IH), one exchangeable proton.
71. ( ?)-4-{3-Fluoro-5-[2-(8- (DMSO-d6): δ 1.27-1.42 (br m, 8H); 1.42-1.53 (m, 2H); 1.6-1.75 (m, 2H); fluorooctylamino)ethoxy] 2.63(t, J = 7.16 Hz, 2H); 2.93 (t, J = 5.2 Hz, 2H); 3.45 (s, IH); 4.02 (t, J = 5.4 phenyl }-3-(4-hydroxy Hz, 2H); 4.2 (dd, ^ = 11.16 Hz, J2= 2.68 Hz, IH); 4.41 (t, J = 6.1 Hz, IH); 4.5- phenyl)-3,4-dihydro-2//- 4.6 (m, 2H); 4.99 (s, 1 H ); 6.25 (d, J = 2.68 Hz, IH); 6.34 (dd, ^ =8.76 Hz, J2 benzo[ 1 , 4] oxazin- 7- ol = 2.72 Hz, IH); 6.44-6.53 (m, 3H); 6.73 (d, J = 8.6 Hz, 2H); 6.97 (d, J = 8.76
Hz, IH); 7.18 (d, J = 8.52 Hz, 2H); 9.11 (s, IH); 9.39 (s, IH), three exchangeable protons.
72. ( ?)-4-{3-Fluoro-5-[2-(4- (CD3OD): δ 2.26 (s, 3H), 2.35-2.63 (m, 8H), 2.67 (t, J=5.3 Hz, 2H), 3.93 (t, methylpiperazin- 1 -yl)
J=5.3 Hz, 2H), 4.13 (dd, J^l l.O Hz, J2= 2.7 Hz, IH), 4.37 (dd, J^l l.O Hz, J2= efhoxy]phenyl}-3-(4- 3.3 Hz, IH), 4.71 (br s, IH), 6.16-6.26 (m, 3H), 6.33-6.40 (m, 2H), 6.60 (d, hydroxyphenyl)-3,4- J=8.6 Hz, 2H), 6.80 (d, J=8.7 Hz, IH), 7.06 (d, J=8.4 Hz, 2H), two dihydro-2//-benzo[ 1, 4]
exchangeable protons.
oxazin-7-ol
73. 4-((7?>4-{3-Fluoro5-[2- (DMSO-d6): δ 1.22-1.46 (m, 12H), 1.57-1.78 (m, 4H), 2.91-3.04 (m, 2H), 3.30- ( 10-fluorodecylamino) 3.38 (m, 2H), 3.72 (s, 3H), 4.18-4.30 (m, 3H), 4.48 (t of d, J1=47.5, J2= 6.1Hz, ethoxy] phenyl } -7- 2H), 4.62 (dd, J^ll.O Hz, J2=2.3 Hz, IH), 5.01-5.07 (br s, IH), 6.45 (d, J=2.8 methoxy-3,4-dihydro-2//- Hz, IH), 6.50 (dd, J1=8.9 Hz, J2=2.9 Hz, IH), 6.52-6.66 (m, 3H), 6.74 (d, J=8.6 benzo[ 1 , 4] oxazin- 3- yl) Hz, 2H), 7.08 (d, J=8.8 Hz, IH), 7.12 (d, J=8.5 Hz, 2H), 8.83 (br s, IH), 9.44 phenol (s, IH), one exchangeable proton.
74. ( ?)-4-{3-Fluoro-4-[2-(8- (DMSO-d6): δ 1.3-1.42 (br m, 8H); 1.45-1.55 (m, 2H); 1.6-1.74 (m, 2H); 2.72 fluorooctylamino) (t, J = 7.2 Hz, 2H); 3.03 (t, J = 5.16 Hz, 2H); 4.13 (t, J = 5.4 Hz, 2H); 4.21 (dd, ethoxy]phenyl}-3-(4- Ji = 10.84 Hz, J2= 2.56 Hz, IH); 4.34-4.44 (m, 2H); 4.53 (t, J = 6.1 Hz, 2H); hydroxyphenyl)-3,4- 4.8 (s, IH); 6.24-6.3 (m, 2H); 6.55 (d, J = 8.56 Hz, IH); 6.70 (d, J = 8.56 Hz, dihydro-2//-benzo[ 1, 4] 2H); 6.91 (d, J = 8.80 Hz, IH); 7.01 (dd, ^ = 13.08 Hz, J2 = 2.48 Hz, IH); oxazin-7-ol 7.10-7.18 (m, 3H); 8.95 (s, IH); 9.38 (s, IH), three exchangeable protons.
75. ( ?)-4-{3-[4-(3,3- (CD3OD): δ 0.96 (s, 6H), 1.5 (t, J=7.0Hz, 2H), 2.34 (s, 2H), 2.61 (t, J=7.0Hz, Dimethylpyrrolidin- 1 yl) 2H), 3.3 (s, 2H), 4.14 (dd,
J2 =2.8Hz, IH), 4.38 (dd, but-2ynyloxy]-5-fluoro J2 =3.08Hz, IH), 4.6 (s, 2H), 4.73 (s, IH), 6.19 (d, J=2.68Hz, IH), 6.21-6.28 phenyl }-3-(4-hydroxy (m, 2H) 6.37 (t of d,
IH), 6.48 (s, IH), 6.61 (d, phenyl)-3,4-dihydro-2//- J=8.6Hz, 2H), 6.84 (d, J=8.72Hz, IH), 7.06 (d, J=8.48Hz, 2H), two benzo[ 1 , 4] oxazin- 7- ol exchangeable protons.
76. ( ?)-4-{3-[4-(3, 3- (CD3OD): δ 0.96 (s, 6H), 1.5 (t, J=6.96Hz, 2H), 2.33 (s, 2H), 2.6 (t, J=6.96Hz, Dimethylpyrrolidin- lyl)- but-2ynyloxy]-5-fluoro
phenyl }-3-(4-methoxy
benzo[ 1 , 4] oxazin- 7- ol exchangeable protons.
77. fi?)-4-{4-[4-(3,3- (DMSO-d6): δ 1.08 (s, 6H), 1.61 (t, J=7.0 Hz, 2H), 2.47 (s, 2H), 2.72 (t, J=6.96 Dimethylpyrrolidin- 1-yl)- Hz, 2H), 3.43 (s, 2H), 4.23 (dd, J1 =10.84 Hz, J2=2.8 Hz, IH), 4.37 (dd, but-2-ynyloxy]-3-fluoro J^IO.96 Hz, J2=4.76 Hz, IH), 4.67 (t, J=3.56 Hz, IH), 4.8 (s, 2H), 6.26 (dd, phenyl }-3-(4-hydroxy J!=8.72 Hz, J2=2.68 Hz, IH), 6.31 (d, J=2.64 Hz, IH), 6.61 (d, J=8.72 Hz, IH), phenyl)-3,4-dihydro-2//- 6.71 (d, J=8.56 Hz, 2H) 6.72-6.83 (m, 2H), 7.09 (t, J=9.12 Hz, IH), 7.13 (d, benzo[ 1 , 4] oxazin- 7- ol J=8.44 Hz, 2H), three exchangeable protons.
78. ( ?)-4-{3-Fluoro-5-[2-(3- (DMSO-d6): δ 2.68-2.83 (m, 2H), 3.0-3.1 (m, 2H), 3.3-3.5 (m, merged with fluoromethylazetidin- 1- solvent peak, 2H), 3.84 (t, J=5.48 Hz, 2H), 4.14 (dd, J^l l.08 Hz, J2=2.56 Hz, yl)ethoxy] phenyl }-3-(4- IH), 4.43 (d, J=6.2 Hz, IH), 4.48 (dd, J^l l.08 Hz, J2=8.48 Hz, IH), 4.49 (dd, hydroxyphenyl)-3,4- J!=47.61 Hz, J2=6.2 Hz, 2H), 4.94 (br s, IH), 6.2 (d, J=2.64 Hz, IH), 6.27 (dd, dihydro-2//-benzo[ 1, 4] J!=8.76 Hz, J2=2.64 Hz, IH), 6.4-6.54 (m, 3H), 6.66 (d, J=8.56 Hz, 2H), 6.9 (d, oxazin-7-ol J=8.76 Hz, IH), 7.12 (d, J=8.48 Hz, 2H), 9.04 (s, IH), 9.32 (s, IH).
79. ( ?)-4-{3-Fluoro-5-[2-(8- (DMSO-d6): δ 1.34 (s, 8H), 1.65-1.69 (br m, 4H), 2.94-2.99 (m, 2H), 3.33-3.4 fluorooctylamino)ethoxy] (m, 2H), 4.2-4.25 (m, 3H), 4.42 (t, J=6.08Hz, IH), 4.54 ( t, J=6.08Hz, IH), phenyl }-3-(4-fluoro 4.67 (dd, J^l l.OHz, J2 =2.28Hz, IH), 5.13 (s, IH), 5.8 (s, IH), 5.95 (s, IH), methoxyphenyl)-3, 4- 6.26 (d, J=2.68Hz, IH), 6.37 (dd, J^S.SHz, J2 =2.72Hz, IH), 6.52-6.61 (m, dihydro-2//-benzo[ 1, 4] 3H), 7.02 (d, J=8.76Hz, IH), 7.1 (d, J=8.68Hz, 2H), 7.4(d, J=8.64Hz, 2H), 8.7 oxazin-7-ol (br s, IH), 9.21 (s, IH).
80. ( ?)-4-{3-Fluoro-4-[2-(8- (DMSO-d6): δ 1.35 (s, 8H), 1.67 (br m, 4H), 3.02 (br s, 2H), 3.4 (merged s, fluorooctylamino) 2H), 4.23 (d, J=8.36Hz, IH), 4.32(t, 2H), 4.4- 4.46 (br m, 2H), 4.54 (t,
efhoxyphenyl}-3-(4- J=6.08Hz, IH), 4.96 (s, IH), 5.8(s, IH), 5.93(s, IH), 6.28-6.3(m, 2H), 6.63- fluoromethoxy phenyl)-3, 6.65(m, IH), 6.97(d, J=8.68Hz, IH), 7.06-7. l(m, 3H), 7.2(t, J=9.2Hz, IH), 4-dihydro-2//-benzo[i,4] 7.38(d, J=8.68Hz, 2H), 8.92(br s, IH), 9.03(s, IH).
oxazin-7-ol
81. 4-(( ? 4-{3-Fluoro-5-[2- (DMSO-d6): δ 1.2-1.37 (m, 12H); 1.5-1.65 (m, 4H); 2.95 (t, J = 8.0Hz, 2H); 3.3 ( 10-fluorodecylamino) (t, J = 4.74 Hz, 2H); 4.1 (t, J = 4.94 Hz, 2H); 4.14-4.28 (m, 3H); 4.34-4.44 (m, ethoxy] phenyl } -7- 2H); 5.54 (d, J = 54.94 Hz, 2H); 6.34-6.4 (m, IH); 6.45- 6.55 (m, 4H); 6.60 (d, fluoromefhoxy-3,4- J = 8.56 Hz, 2H); 6.90 (d, J = 9.04 Hz, IH); 7.04 (d, J= 8.48 Hz, 2H), two dihydro-2//-benzo[ 1, 4] exchangeable protons.
oxazin- 3 -yl)phenol
82. (10-Fluorodecyl)-(2-{3- (DMSO-d6): δ 1.2-1.38 (m, 12H); 1.5-1.67 (m, 4H); 2.95 (t, J = 7.98Hz, 2H); fluoro-5-[(i?)-7-fluoro 3.31 (t, J = 4.86 Hz, 2H); 4.11 (t, J = 4.86 Hz, 2H); 4.16-4.28 (m, 3H); 4.37 (t, J methoxy- 3 - (4-fluoro = 6.08 Hz, 2H); 4.47 (d, J1= 11.12 Hz, J2 = 3.08 Hz, IH); 4.87 (s, IH); 5.55 (d, mefhoxyphenyl)-2,3- J = 54.94 Hz, 2H); 5.61 (d, J = 54.54 Hz, 2H); 6.37-6.42 (m, IH); 6.48- 6.55 dihydro benzo[i,4] (m, 4H); 6.90-6.98 (m, 3H); 7.22 (d, J= 8.48 Hz, 2H), one exchangeable oxazin-4-yl]phenoxy} proton.
ethyl)amine
83. fi? 4-[3-Fluoro-5-(2-{2- (D20): δ 3.36 (s, 3H), 3.55-3.59 (m, 2H), 3.62-3.75 (m, 10H), 3.82-3.86 (m,
[2-(2-methoxyethoxy) 2H), 4.1-4.15 (m, 2H), 4.25 (dd, 1^11,04 Hz, J2=2.72 Hz, IH), 4.47 (dd, ethoxy] ethoxy } ethoxy) J^ll.12 Hz, J2=3.4 Hz, IH), 4.9 (s, IH), 6.15 (d, J=2.68 Hz, IH), 6.26 (dd, phenyl]-3-(4-hydroxy Ji=8.8 Hz, J2=2.72 Hz, IH), 6.41 (t of d, J1=10.56 Hz, J2=2.08 Hz, IH), 6.54- phenyl)-3,4-dihydro-2//- 6.65 (m, 4H), 6.9 (d, J=8.76 Hz, IH), 7.11 (d, J=8.56 Hz, 2H), two benzo[ 1 , 4] oxazin- 7- ol exchangeable protons.
84. ( ?)-3-(4-Difluoro (DMSO-d6): δ 1.28-1.42 (m, 12H); 1.6-1.75 (m, 4H); 2.92-3.02 (m, 2H); 3.3- methoxyphenyl)-4- { 3- 3.37 (m, 2H); 4.2-4.38 (m, 3H); 4.47 (t of d, ^ = 47.57 Hz, J2 = 6.08 Hz, 2H); fluoro-5-[2-(10-fluoro 4.69 (dd, Ji = 11.24 Hz, J2 = 2.04 Hz, IH); 5.18 (s, IH); 6.26 (d, J = 2.68 Hz, decylamino)ethoxy] IH); 6.38 (dd, J1= 8.8 Hz, J2 = 2.72 Hz, IH); 6.52 -6.63 (m, 3H); 7.03 (d, J = phenyl } -3 ,4-dihydro-2/f- 8.8 Hz, IH); 7.18 9 (d, J = 8.68 Hz, 2H); 7.26 (t, J = 74.16 Hz, IH); 7.46 (d, J = benzo[ 1 , 4] oxazin- 7- ol 8.6 Hz, 2H); 8.8 (br s, 2H); 9.24 (s, IH), two exchangeable protons.
85. 4-{ 3-Fluoro-5-[2-(10- (DMSO-d6): δ 1.32 (s, 12H), 1.62-1.69 (br m, 4H), 2.97( s, 2H), 3.33 ( s, 2H), fluorodec ylamino) 4.2- 4.25 (m, 3H), 4.42(t, J=6.12Hz, IH), 4.54 (t, J=6.12Hz, IH), 4.67 (dd, ethoxy]phenyl}-3-(4- J!=11.16Hz, J2=2.12Hz, IH), 5.16(s, IH), 6.27(d, J=2.68Hz, IH), 6.38(dd, fluoro phenyl)-3,4- J!=8.76Hz, J2=2.68Hz, IH), 6.53-6.61 (br m, 3H), 7.01(d, J=8.76Hz, IH), 7.2 dihydro-2//-benzo[ 1, 4] (t, J=8.84Hz, 2H), 7.42-7.46 (m, 2H), 8.89 ( s, IH), 9.22 (s, IH).
oxazin-7-ol
86. ( ?)-4-[3-Fluoro-5-(2-{2- (DMSO-d6): δ 3.18-3.27 (m, 2H), 3.28 (s, 3H), 3.45-3.5 (m, 2H), 3.54-3.65 (m,
[2-(2-methoxyethoxy) 6H), 3.75 (t, J=4.96 Hz, 2H), 4.2 (dd, J1=11.2 Hz, J2=2.8 Hz, IH), 4.25 (t, ethoxy] eth ylamino } J=4.68 Hz, 2H), 4.6 (dd, J^l l.l Hz, J2=2.44 Hz, IH), 5.0 (br s, IH), 6.26 (d, ethoxy)phenyl]-3-(4- J=2.68 Hz, IH), 6.35 (dd, J1=8.76 Hz, J2=2.68 Hz, IH), 6.5-6.61 (m, 3H), 6.74 hydroxyphenyl)-3,4- (d, J=8.6 Hz, 2H), 6.98 (d, J=8.76 Hz, IH), 7.18 (d, J=8.56 Hz, 2H), 8.9 (br s, dihydro-2//-benzo[ 1, 4] 2H), 9.18 (s, IH), 9.44 (s, IH), two protons are merged with solvent peak. oxazin-7-ol
87. fi?)-4-[3-Fluoro-5-(2-{2- (DMSO-d6): δ 3.18-3.24 (br m, 2H), 3.28 (s, 3H), 3.35-3.42 (br m, 2H), 3.44-
[2-(2-methoxyethoxy) 3.5 (m, 2H), 3.53-3.64 (m, 6H), 3.73 (t, J=4.64 Hz, 2H), 4.18-4.28 (m, 3H), ethoxy] eth ylamino } 4.63-4.7 (m, IH), 5.13 (br s, IH), 5.88 (d, J=54.5 Hz, 2H), 6.26 (d, J=2.6 Hz, ethoxy)phenyl]-3-(4- IH), 6.37 (dd, J1=8.8 Hz, J2=2.64 Hz, IH), 6.51-6.63 (m, 3H), 7.02 (d, J=8.76 fluoromefhoxyphenyl)- Hz, IH), 7.1 (d, J=8.68 Hz, 2H), 7.4 (d, J=8.6 Hz, 2H), four exchangeable
3 ,4-dihydro-2//-benzo protons.
[i,4]oxazin-7-ol
88. (7?>3-(4-Difluoro (DMSO-d6): δ 3.19-3.26 (br m, 2H), 3.28 (s, 3H), 3.45-3.5 (m, 2H), 3.53-3.65 methoxyphenyl)-4- [3- (m, 6H), 3.75 (t, J=4.96 Hz, 2H), 4.2-4.3 (m, 3H), 4.69 (dd, J1=11.2 Hz, fluoro-5-(2-{2-[2-(2- J2=2.16 Hz, IH), 5.18 (br s, IH), 6.27 (d, J=2.68 Hz, IH), 6.38 (dd, J1=8.76 Hz, methoxyethoxy)ethoxy] J2=2.68 Hz, IH), 6.53-6.63 (m, 3H), 7.03 (d, J=8.8 Hz, IH), 7.18 (d, J=8.64 eth ylamino } ethoxy)pheny Hz, 2H), 7.25 (t, J=74.2 Hz, IH), 7.46 (d, J=8.6 Hz, 2H), 8.93 (br s, 2H), 9.23 1] -3 ,4-dihydro-2//-benzo (s, IH), two protons are merged with solvent peak.
[i,4]oxazin-7-ol
. ( ?)-4-{5-[2-(10-Fluoro (CD3OD): δ 1.2-1.35 (m, 12H), 1.45-1.64 (m, 4H), 2.68 (t, J=7.56 Hz, 2H), decylamino)ethoxy] 3.02 (t, J=5.12 Hz, 2H), 4.05 (t, J=5.16 Hz, 2H), 4.2 (dd, J^ll.l Hz, J2=2.88 pyridin- 3 - yl } - 3 - (4- Hz, 1H), 4.25 (t, J=6.08 Hz, 1H), 4.37 (t, J=6.12 Hz, 1H), 4.43 (dd, J^l l.2 Hz, fluoromethoxyphenyl)- J2=3.4 Hz, 1H), 4.87 (t, J=2.76 Hz, 1H), 5.6 (d, J=54.5 Hz, 2H), 6.2-6.27 (m, 3 ,4-dihydro-2//-benzo 2H), 6.77 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.6 Hz, 2H), 7.1 (t, J=2.3 Hz, 1H), 7.25 [i,4]oxazin-7-ol (d, J=8.56 Hz, 2H), 7.8 (d, J=2.48 Hz, 1H), 7.92 (d, J=2.16 Hz, 1H), two exchangeable protons.
. Dimethyl carbamic acid (CDCI3): δ 0.87 (t, J=7.04, 3H); 1.12-1.35 (br m, 18H); 1.52-1.7 (br s, 2H); fi? 3-(4-dimethyl 2.90 (t, J=7.84Hz, 2H); 2.98 (s, 6H); 3.06 (d, J=2.20Hz, 6H); 3.16 (br s, 2H); carbamoyloxy phenyl)-4- 4.01 (d, J=4.48 Hz, 2H); 4.27 (dd, J!=1076Hz, J2=2.36Hz, 1H); 4.42 (dd, [3-(2-dodecylamino J^IO.8 Hz, J2=3.4 Hz, 1H); 4.77 (s, 1H); 6.51 (d, J=7.88 Hz, 1H); 6.55 (dd, ethoxy)phenyl] -3 ,4- J!=8.84 Hz, J2=2.64 Hz, 1H); 6.60-6.63 (m,2H); 6.77 (d, J=8.96Hz, 1H); 6.89 dihydro-2//-benzo[ 1, 4] (d, J=8.8 Hz,lH);7.00 (d, J=8.52Hz,2H); 7.10 (t, J=8.08Hz, 1H); 7.25 (d, 2H); oxazin-7-yl ester three exchangeable protons.
. Carbonic acid (i?)-3-(4- (CDCI3): δ 0.87 (t, 3H); 1.15-1.35 (br s, 18 H); 1.5-1.51 (br s, 18 H); 1.51-1.52 rert-butoxycarbonyloxy (br m, 2H); 2.92( t, J = 7.75, 2 H); 3.17 (t, J = 4.45 Hz, 2H); 4.03 (br s, 2H); phenyl)-4-[3-(2-dodecyl 4.27 (dd, Ji = 10.8 Hz, J2= 2.35 Hz, 1H); 4.43 (dd, J1= 10.85 Hz, J2=3.05 Hz, aminoethoxy) phenyl] - 1H); 4.8 (br s, 1H); 6.51 (d, J=8.3 Hz, 1H); 6.61(dd, J1= 9.05 Hz, J2 = 2.7 Hz, 3 ,4-dihydro-2//-benzo 1H); 6.654 (s, 1H); 6.69 (d, J = 2.75 Hz, 1H); 6.76 (d, J=8.05 Hz, 1H); 6.93 (d, [i,4]oxazin-7-yl ester J=8.9 Hz, 1H); 7.06-7.13 (m, 3H); 7.27 (d, J = 8.5 Hz, 2H); three exchangeable rert-butyl ester protons.
. Dodecyl-(2-{3-[(i?)-3-(4- (DMSO-d6): δ 0.91 (t, J = 7.07 Hz, 3H); 1.29 (s, 12H), 1.31 (s, 18 H), 1.51-1.58 methoxyphenyl)-7- (m, 2H), 2.98 (t, J = 7.91 Hz, 2H), 3.35 (t, J = 4.39 Hz, 2H), 3.75 (s, 3H), 4.18-
(4,4,5,5-tetramethyl- 4.24 (m, 2H); 4.31 (dd, ^ = 10.88 Hz, J2 = 2.57 Hz, 1H); 4.46 (dd, ^ = 10.85
[1,3,2] dioxaborolan-2- Hz, J2 = 3.03 Hz, 1H), 5.06 (s, 1H), 6.81 (dd, ^ = 8.29 Hz, J2 = 2.08 Hz, 1H); yl)-2,3-dihydrobenzo 6.86 (t, J = 2 Hz, 1H); 6.87-6.93 (m, 4H); 7.08 (d, J = 1.40 Hz, 1H); 7.15 (dd, ^
[i,4]oxazin-4-yl]
= 8.15 Hz, = 1.41 Hz, 1H); 7.25 (d, J = 8.71 Hz, 2H); 7.35 (t, J = 8.13 Hz, phenoxy } ethyl)amine 1H); three exchangeable protons.
. Carbonic acid ethyl ester- (DMSO-d6): δ 1.22-1.43 (m, 19H), 1.6-1.75 (m, 4H), 2.9-3.03 (m, 2H), 3.28- 4-(( ?>4-{3-lluoro-5-[2- 3.38 (m, 2H, merged with peak of solvent), 4.2-4.34 (m, 5H), 4.42 (t, J=6.12 ( 12-fluorododecylamino) Hz, 1H), 4.53 (t, J=6.24 Hz, 1H), 4.7 (d, J=10.24 Hz, 1H), 5.19 (s, 1H), 6.3 (d, ethoxy] phenyl } -7- J=2.48 Hz, 1H), 6.38 (dd, J1=8.68 Hz, J2=2.36 Hz, 1H), 6.52-6.65 (m, 3H), hydroxy-3,4-dihydro-2//- 7.04 (d, J=8.72 Hz, 1H), 7.23 (d, J=8.56 Hz, 2H), 7.45 (d, J=8.44 Hz, 2H) 8.85 benzo[ 1 , 4] oxazin- 3- yl) (br s, 2H), 9.22 (s, 1H).
phenyl ester
In-vitro cell line assay
MCF-7 Cell Growth Inhibition Assay
MCF-7 cells were plated in 96 well plate in the presence of estradiol (1 nM) and incubated overnight. After 24 hours test compound was added at various concentrations and incubated for five days. On the fifth day, cell viability was evaluated using Presto Blue Cell Viability Reagent. Percentage growth inhibition was calculated as follows: 100 - [(O.D. of sample)* 100/ O.D. of vehicle control] wherein O.D. is Optical Density.
Compounds of Formula I mostly showed growth inhibition more than 50 % at 3 micromolar concentration.
Percentage inhibition at ΙμΜ in MCF-7 for some of the representative compounds is provided in Table-3 below.
Table-3
Claims
1. A compound of Formula I
Formula I
and a salt or stereoisomer thereof wherein,
ring Z is a 5 to 10 membered aromatic ring optionally containing 1 or 2 heteroatoms selected from N, O and S;
wherein, m and n are integer independently selected from 1 or 2;
J is -CH- or -N-; and '{ ' indicates the point of attachment to ring Z;
E is mono- or di-substitution and is selected from hydrogen, halogen, -COOH, -NH2, - NH(d_3 alkyl), -N(d_3 alkyl)2, -CN, -C1-3 haloalkyl, -C1-3 alkyl and -Od_3 alkyl;
B is hydrogen or a Ci_2o linear or branched alkyl chain optionally interrupted with one or more radicals selected from -0-, -NR , -S-, -SO-,-S(0)2-, -CR^CRr, -C≡d, - NRjCO-, -CONRj-, -NRjCONRj-, NRjC(0)0-, -OC(0)0- or a group represented by formula
wherein, g and h are integer independently selected from 1 or 2 and Q is selected from -CH- or -N-;
wherein, Rj, at each occurrence, is selected from hydrogen, C3-6 cycloalkyl or Ci_6 alkyl;
B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and -C(0)OCi_6 alkyl wherein, R2, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched and cyclic alkyl;
Y is mono- or di-substitution and is a group selected from -R3, -OR3, halogen, -CN, - NR3COR3, NR3SO2R3, -OC(0)R3, -OC(0)N(R3)2, and -OC(0)OR3; wherein R3, at each occurrence, is a group selected from hydrogen, Ci_6 linear, branched or cyclic alkyl and Ci_6 linear, branched or cyclic haloalkyl;
L is selected from -0-, -N (d_6 alkyl)-, -N (C3_6 cycloalkyl)-, -N (d_6 haloalkyl)-, -N (C3_6 halocycloalkyl)- and -S-; ring X is a 5 to 10 membered mono- or bi-cyclic ring containing 0 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;
D is a group selected from hydrogen, -R4, -OR4, halogen, -CR4=CR4-COOH, -CN, - N(R4)2, -NR4S02R4, -NR CHO, -NR4COR4, -OC(0)R4, -OC(0)N(R4)2, -NR4CONR4 and -OC(0)OR4 wherein R4 at each occurrence is hydrogen or Ci-6 linear, branched or cyclic alkyl; OR
D is a group selected from boronic acid or a 5 or 6 membered ring containing the C- O-Boron-O-C linkage wherein the ring is optionally substituted with one or more d- 3 alkyl group wherein the point of attachment to ring X is the boron atom.
2. The compound of Formula I of claim 1 , wherein ring Z is phenyl, L is -O- and A is - 0-.
3. The compound of Formula I of claim 1, wherein E is hydrogen, halogen, -C1-3 haloalkyl or -Ci_3 alkyl.
4. The compound of Formula I of claim 1 , wherein B is interrupted by a group
wherein, g and h are 2 and Q is -N-
The compound of Formula I of claim 1 , wherein
ring Z is phenyl;
A is -0-;
E is hydrogen, halogen or -Ci_3 haloalkyl;
Y is -OH and attached at 4-position of the phenyl ring;
L is -0-;
X is a phenyl ring substituted with a group selected from hydrogen, and -OH;
B is a Ci-15 linear or branched alkyl chain interrupted with one or more radicals selected from -NRi and -S-; and B is further substituted with one or more halogen.
The compound of Formula I as in claim 1 , wherein the ring X is selected from a group of
points of fusion of the group with rest of the molecule.
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WO2018138739A1 (en) * | 2017-01-27 | 2018-08-02 | Sun Pharma Advanced Research Company Limited | Novel antiestrogenic heterocyclic compounds |
US10118910B2 (en) | 2015-12-09 | 2018-11-06 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US10208011B2 (en) | 2017-02-10 | 2019-02-19 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
US10703747B2 (en) | 2016-10-24 | 2020-07-07 | The Board of Directors of the University of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
US11364222B2 (en) | 2017-01-06 | 2022-06-21 | G1 Therapeutics, Inc. | Combination therapy for treatment of cancer |
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US10118910B2 (en) | 2015-12-09 | 2018-11-06 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US10377735B2 (en) | 2015-12-09 | 2019-08-13 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US10807964B2 (en) | 2015-12-09 | 2020-10-20 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US11072595B2 (en) | 2015-12-09 | 2021-07-27 | The Board of Trustees of lhe University of Illinois | Benzothiophene-based selective estrogen receptor downregulator compounds |
US11447461B2 (en) | 2015-12-09 | 2022-09-20 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US10703747B2 (en) | 2016-10-24 | 2020-07-07 | The Board of Directors of the University of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
US11364222B2 (en) | 2017-01-06 | 2022-06-21 | G1 Therapeutics, Inc. | Combination therapy for treatment of cancer |
WO2018138739A1 (en) * | 2017-01-27 | 2018-08-02 | Sun Pharma Advanced Research Company Limited | Novel antiestrogenic heterocyclic compounds |
US10208011B2 (en) | 2017-02-10 | 2019-02-19 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
US10633362B2 (en) | 2017-02-10 | 2020-04-28 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
US10981887B2 (en) | 2017-02-10 | 2021-04-20 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
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