DESC:NOVEL N-ARYL CONTAINING FUSED HETEROCYCLIC COMPOUNDS

FIELD OF 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, 17ß-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(1H)-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

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;

A is selected from a group comprising –O-, -NH-, -S-, -N(C1-3 alkyl)-, -N(C3-6 cycloalkyl)- or
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(C1-3 alkyl), -N(C1-3 alkyl)2, -CN, -C1-3 haloalkyl, -C1-3 alkyl and -OC1-3 alkyl;
B is hydrogen or a C1-20 linear or branched alkyl chain optionally interrupted with one or more radicals selected from –O-, -NR1-, -S-, -SO-,-S(O)2-, -CR1=CR1-, -C=C-, -NR1CO-, -CONR1-, -NR1CONR1-, NR1C(O)O-, -OC(O)O- 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, R1, at each occurrence, is selected from hydrogen, C3-6 cycloalkyl or C1-6 alkyl;

B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and –C(O)OC1-6 alkyl wherein, R2, at each occurrence, is a group selected from hydrogen, C1-6 linear, branched and cyclic alkyl;

Y is mono or di substitution and is a group selected from -R3, -OR3, halogen, -CN, -NR3COR3, NR3SO2R3, -OC(O)R3, -OC(O)N(R3)2, -SO2C1-4 alkyl, -N(R3)2 and –OC(O)OR3; wherein R3, at each occurrence, is a group selected from hydrogen, C1-6 linear, branched or cyclic alkyl and C1-6 linear, branched or cyclic haloalkyl;

L is selected from –O-, -N (C1-6 alkyl)-, -N (C3-6 cycloalkyl)-, -N (C1-6 haloalkyl)-, -N (C3-6 halocycloalkyl)- and -S-;

ring X is a 5 to10 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, -NR4SO2R4, -NR4CHO, -NR4COR4, -OC(O)R4, -OC(O)N(R4)2, -NR4CONR4 and –OC(O)OR4 wherein R4 at each occurrence is hydrogen or C1-6 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 C1-3 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, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-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

and a salt or stereoisomer thereof wherein,
ring Z is selected from 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 –O-, -NH-, -S-, -N(C1-3 alkyl)-, -N(C3-6 cycloalkyl)- or
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(C1-3 alkyl), -N(C1-3 alkyl)2, -CN, -C1-3 haloalkyl, -C1-3 alkyl and -OC1-3 alkyl;

B is hydrogen or a C1-20 linear or branched alkyl chain optionally interrupted with one or more radicals selected from –O-, -NR1-, -S-, -SO-,-S(O)2-, -CR1=CR1-, -C=C-, -NR1CO-, -CONR1-, -NR1CONR1-, NR1C(O)O-, -OC(O)O- 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, R1, at each occurrence, is hydrogen, C3-6 cycloalkyl or C1-6 alkyl;

B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and –C(O)OC1-6 alkyl wherein, R2, at each occurrence, is a group selected from hydrogen, C1-6 linear, branched and cyclic alkyl;
Y is mono- or di-substitution and is a group selected from -R3, -OR3, halogen, -CN, -NR3COR3, NR3SO2R3, -OC(O)R3, -OC(O)N(R3)2, -SO2C1-4 alkyl, -N(R3)2 and –OC(O)OR3; wherein R3, at each occurrence, is a group selected from hydrogen, C1-6 linear, branched or cyclic alkyl and C1-6 linear, branched or cyclic haloalkyl;

L is selected from –O-, -N (C1-6 alkyl)-, -N (C3-6 cycloalkyl)-, -N (C1-6 haloalkyl)-, -N (C3-6 halocycloalkyl)- and - or -S-;

ring X is a 5 to10 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, -NR4SO2R4, -NR4CHO, -NR4COR4, -OC(O)R4, -OC(O)N(R4)2, -NR4CONR4 and –OC(O)OR4 wherein R4 at each occurrence is hydrogen or C1-6 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 C1-3 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 1or 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 -O-, -NH-, -S-, -N(C1-3 alkyl)-, -N(C3-6 cycloalkyl)- or
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
are
In a preferred embodiment, A is –O- or –NH-. In another preferred embodiment A is –O-. 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 –O-.

In another embodiment, the present invention provides a compound of Formula I wherein, B is interrupted by a group

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(O)OC1-6 alkyl wherein, R2, at each occurrence, is hydrogen or C1-6 linear, branched or cyclic alkyl. In a preferred embodiment, group B is substituted with one or more halogen. In another embodiment group B is C3-14 alkyl chain optionally interrupted with groups selected from -NR1-, -S- or -SO-.

Ring X is a 5 to10 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 a bicyclic ring selected from a group of

The bicyclic ring can optionally contain an oxo group (=O) such as

wherein, ‘]’ indicates point of fusion of the group with rest of the molecule. In another preferred embodiment ring X is selected from
, , , , or
wherein ‘]’ indicates points of fusion of the group with rest of the molecule.

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, -NR4SO2R4, -NR4CHO, -NR4COR4, -OC(O)R4, -OC(O)N(R4)2, -NR4CONR4 and –OC(O)OR4 wherein R4 at each occurrence is hydrogen or C1-6 linear, branched or cyclic alkyl. In a preferred embodiment D is selected from –OH, NR4SO2R4, -NR4CHO, -NR4COR4, -OC(O)R4, -OC(O)N(R4)2, and –OC(O)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 C1-3 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 Ia

wherein, B is a C1-20 linear or branched alkyl chain interrupted with one or more radicals selected from –NR1, -S- or a group represented by a formula

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 Ib

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 Scheme1.

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 I.

Scheme 2
Alternatively, compound of the Formula I 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 intramolecular cyclization reaction gives compound of Formula I.

Scheme 3

Table 1 provides few exemplary compounds of Formula I.

Table 1

Compd No. Ring Z A B E L Y
Chirality
1. Ph 3-O -(CH2)2N(Me)2 H O 4-OH
R
2. Ph 4-O -(CH2)2N(Me)2 H O 4-OH
R
3. Ph 3-O -(CH2)2NH(CH2)11CH3 H O 4-OH
R
4. Ph 3-O
H O 4-OH
R
5. Ph 3-O -(CH2)3NH(CH2)11CH3 H O 4-OH
R
6. Ph 3-O -(CH2)2NH(CH2)11CH3 H O 4-OH
R
7. Ph 3-O -(CH2)2NH(CH2)11CH3 5-F O 4-OH
R
8. Ph 3-O -CH2)5NH(CH2)7CH3 H O 4-OH
R
9. Ph 3-O -(CH2)2NH(CH2)11CH3 H O 4-F
RS
10. Ph 3-O -(CH2)2NH(CH2)11CH3 H O 4-OH
R
11. Ph 3-O -(CH2)9S(CH2)3C(F)2CF3 H O 4-OH
R
12. Ph 3-O -(CH2)2NH(CH2)7CH3 H O 4-OH
R
13. Ph
3-O -(CH2)2NHCO(CH2)10CH3 H O 4-OH
R
14. Ph 3-O -(CH2)2NH(CH2)11CH3 H O 4-OH
R
15. Ph
3-O -(CH2)2NH(CH2)11CH3 H O H
R
16. Ph
3-O -(CH2)2NH(CH2)11CH3 H O 4-OCH3
R
17. Ph
3-O -(CH2)2NH(CH2)11CH3 5-CF3 O 4-OH
R
18. Ph
3-O -(CH2)2NH(CH2)11CH3 H O 4-OH
R
19. Ph
3-O -(CH2)2NH(CH2)11CH3 H O 4-OH
R
20. Ph
3-O -(CH2)2NH(CH2)2NH (CH2)7CH3 H O 4-OH
R
21. Ph
3-O -(CH2)2NH(CH2)9CH3 5-F O 4-OH
R
22. Ph
3-O -(CH2)2NH(CH2)13CH3 5-F O 4-OH
R
23. Ph
3-O -(CH2)2NH(CH2)11CH3
H O 4-OH
S
24. Ph
3-O -(CH2)2NHCONH(CH2)8CH3 H O 4-OH
R
25. Ph
4-O -(CH2)2NH(CH2)11CH3
H O 4-OH
R
26. Ph
3-O -(CH2)2NH(CH2)2NH (CH2)7CH3 H O 4-OCH3
R
27. Ph
3-O -(CH2)2NH(CH2)2NH (CH2)7CH3
5-F O 4-OH
R
28. Ph
3-O -(CH2)2NH(CH2)11CH3
5-F O 4-OH
S
29. Ph
3-O -(CH2)2NH(CH2)2NH (CH2)7CH3
5-F O 4-OH
S
30. Ph
3-O -(CH2)2NH(CH2)2NH (CH2)7CH3 5-F O 4-OCH3
R
31. Ph
3-O -(CH2)2NH(CH2)11CH3
5-F O 4-OCH3
RS
32. Ph
3-O -(CH2)2NH(CH2)11CH3
5-F O 4-OCH3
R
33. Ph
3-O -(CH2)2NH(CH2)11CH3
5-F O 4-OH
RS
34. Ph
3-O -(CH2)3NH(CH2)11CH3
5-F O 4-OH
R
35. Ph
3-NH -(CH2)2NH(CH2)11CH3
H O 4-OH
R
36. Ph
3-NH -(CH2)3NH(CH2)11CH3
H O 4-OH
R
37. Ph
3-O -(CH2)3NH(CH2)11CH3
5-F O 4-OH
S
38. Ph
3-O -(CH2)2NH(CH2)11CH3
5-F O 4-OH
R
39. Ph
3-NH -(CH2)3NH(CH2)4NH2
H O 4-OH
R
40. Ph
3-NH -(CH2)3NH(CH2)4N(CH3)2
H O 4-OH
R
41. Ph
3-O -(CH2)2NH(CH2)11CH3
5-F O 4-OCH3
R
42. Ph
3-O -(CH2)2NH(CH2)12F
5-F O 4-OCH3
S
43. Ph
4-O -(CH2)2NH(CH2)12F
5-F O 4-OCH3
R
44. Ph
3-O -(CH2)2NH(CH2)12F
4-F
5-F O 4-OCH3
R
45. Ph
3-O -(CH2)2NH(CH2)12F
5-F O 4-OCH3
R
46. Ph
3-O -(CH2)2N(CH3)(CH2)11CH3
5-F O 4-OH
R
47. Ph
3-O -(CH2)2N(CH3)(CH2)10F
5-F O 4-OH
R
48. Ph
3-O -(CH2)2NH(CH2)10F
5-F O 4-OCH3
R
49. Ph
3-O -(CH2)2NH(CH2)12F
5-F O 4-OH
R
50. Ph
3-O -(CH2)2NH(CH2)10F
4-F
5-F O 4-OCH3
R
51. Ph
3-O -(CH2)2NH(CH2)10F
5-F O 4-OH
R
52. Ph
3-O -(CH2)2NH(CH2)10F
5-F O 4-OCH3
S
53. Ph
3-O -(CH2)2NH(CH2)5NH(CH2)3CF2CF3 5-F O 4-OH
R
54. Ph
3-O -(CH2)2NH(CH2)9CHF2 5-F O 4-OCH3
S
55. Ph
3-NH -(CH2)2NH(CH2)10F
5-F O 4-OH
R
56. Ph
4-O -(CH2)2NH(CH2)10F 5-F O 4-OCH3
R
57. Ph
3-O -(CH2)2NH(CH2)9CHF2 5-F O 4-OCH3
R
58. Ph
3-NH -(CH2)2NH(CH2)10F 5-F O 4-OCH3
R
59. Ph
3-O -(CH2)2NH(CH2)10F 5-F O 4-OCH2F
R
60. Ph
3-O -(CH2)2NH(CH2)12F 5-F O 4-OH
R
61. Ph
3-O -(CH2)2NH(CH2)10F

5-F O 4-OH
S
62. Ph
3-O -(CH2)2NH(CH2)11CH3 5-F O 4-OCH2F
R
63. Ph
3-O -(CH2)2NH(CH2)12F 5-F O 4-OCH2F
R
64. Ph
3-O -(CH2)2NH(CH2)11CHF2 5-F O 4-OCH3
R
65. Ph
3-O -(CH2)2NH(CH2)11CHF2 5-F O 4-OH
R
66. Ph
3-O -(CH2)2NH(CH2)10F 5-F O 4-OH
R
67. Ph
3-O -(CH2)2NH(CH2)10F 5-F O H
R
68. Ph
3-O -(CH2)2NH(CH2)10F 5-F O H
R
69. Ph
4-O -(CH2)2NH(CH2)10F 5-F O 4-OCH2F
R
70. Ph
4-O -(CH2)2NH(CH2)12F 5-F O 4-OH
R
71. Ph
3-O -(CH2)2NH(CH2)8F 5-F O 4-OH
R
72. Ph
3-O
5-F O 4-OH
R
73. Ph
3-O -(CH2)2NH(CH2)10F 5-F O 4-OH
R
74. Ph
4-O -(CH2)2NH(CH2)8F 5-F O 4-OH
R
75. Ph
3-O
5-F O 4-OH
R
76. Ph
3-O
5-F O 4-OCH3
R
77. Ph
4-O
5-F O 4-OH
R
78. Ph
3-O
5-F O 4-OH
R
79. Ph
3-O -(CH2)2NH(CH2)8F 5-F O 4-OCH2F
R
80. Ph
4-O -(CH2)2NH(CH2)8F 5-F O 4-OCH2F
R
81. Ph 3-O -(CH2)2NH(CH2)10F 5-F O 4-OH
R
82. Ph 3-O -(CH2)2NH(CH2)10F 5-F O 4-OCH2F
R
83. Ph 3-O -(CH2)2O(CH2)2O(CH2)2O(CH2)2OCH3 5-F O 4-OH
R
84. Ph 3-O -(CH2)2NH(CH2)10F 5-F O 4-OCHF2
R
85. Ph 3-O -(CH2)2NH(CH2)10F 5-F O 4-F
RS
86. Ph 3-O -(CH2)2NH(CH2)2O(CH2)2O(CH2)2OCH3 5-F O 4-OH
R
87. Ph 3-O -(CH2)2NH(CH2)2O(CH2)2O(CH2)2OCH3 5-F O 4-OCH2F
R
88. Ph 3-O -(CH2)2NH(CH2)2O(CH2)2O(CH2)2OCH3 5-F O 4-OCHF2
R
89. Pyridine-3-yl 5-O -(CH2)2NH(CH2)10F H O 4-OCH2F
R
90. Ph
3-O -(CH2)2NH(CH2)11CH3
H O 4-OCON(CH3)2
R
91. Ph
3-O -(CH2)2NH(CH2)11CH3
H O 4-OCOOC(CH3)3
R
92. Ph
3-O -(CH2)2NH(CH2)11CH3
H O 4-OCH3
R
93. Ph 3-O -(CH2)2NH(CH2)12F 5-F O 4-OCOOCH2CH3
R

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 (R)-4-[3-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (1)

Step I: (R)-N-(tert-Butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine

Diisopropylazodicarboxylate (20 mL, 0.102 mol) was added to a stirred mixture of (R)-2-(tert-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 ºC, 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-(tert-butoxycarbonyl)amino-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine.

Step II: (R)-2-(5-Benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine.

Trifluoroacetic acid (22 mL) was added to a stirred solution of (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (11 g, 0.018 mol) in dichloromethane (DCM) (55 mL) at 0-5 ºC 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)-1-(4-benzyloxy phenyl)ethylamine.

Step III: (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine.

Potassium tert-butoxide (2.4 g, 0.021 mol) was added to a stirred mixture of (R)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (8.1 g, 0.016 mol), tris (dibenzylideneacetone)dipalladium (0.5 g, 0.0006 mol) and 2,2’-bis(diphenylphosphino)1,1’-binaphthyl (0.7 g, 0.0011 mol) in toluene (100 mL). Reaction mixture was then heated at 100 ºC 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[1,4]oxazine.

Step IV: (2-{3-[(R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[1,4]oxazine-4-yl]phenoxy}ethyl)dimethylamine

Sodium tert-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[1,4]oxazine (0.2 g, 0.00047 mol), [2-(3-(iodophenoxy)ethyl]dimethylamine (0.14 g, 0.00047 mol), tris(dibenzylideneacetone) dipalladium (0.004 g, 0.000047 mol) and tri tert-butylphosphine (0.001 ml, 0.00038 mol, 50 % solution in toluene) in toluene (5 mL). Reaction mixture was then heated at 100 ºC 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[1,4]oxazine-4-yl]phenoxy}ethyl)dimethylamine.

Step V: (R)-4-[3-(2-Dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]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[1,4]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 ºC 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[1,4]oxazin-7-ol.

Example 2: Preparation of (R)-3-(4-hydroxyphenyl)-4-{3-[2-(4-nonylpiperazin-1-yl)ethoxy]phenyl}-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (4)

Step I: (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-{3-[2-(4-nonylpiperazin-1-yl)ethoxy] phenyl}-3,4-dihydro-2H-benzo[1,4]oxazine

Sodium tert-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[1,4]oxazine (0.25 g, 0.0006 mol), 1-[2-(3-iodophenoxy)ethyl]-4-nonylpiperazine (0.27 g, 0.0006 mol), tris(dibenzylidene acetone)dipalladium (0.004 g, 0.00006 mol) and tri tert-butylphosphine (0.001mL, 0.0005 mol, 50 % solution in toluene) in toluene (5 mL). Reaction mixture was heated at 100 ºC 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[1,4]oxazine.

Step II: (R)-3-(4-Hydroxyphenyl)-4-{3-[2-(4-nonylpiperazin-1-yl)ethoxy]phenyl}-3,4-dihydro-2H-benzo[1,4]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[1,4]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 ºC 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[1,4]oxazin-7-ol.

Example 3: Preparation of (R)-3-(4-hydroxyphenyl)-4-{3-[9-(4,4,5,5,5-pentafluoro pentylsulfanyl)nonyloxy]phenyl}-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (11)

Step I: (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-[3-(tetrahydropyran-2-yloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine

Sodium tert-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[1,4]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 tert-butylphosphine (0.002 mL, 0.001 mol) in toluene (5 mL) and heated at 100 ºC 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[1,4]oxazine, which was used for the next step without further purification.

Step II: 3-[(R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-2,3-dihydrobenzo[1,4]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[1,4] oxazine (0.8 g, 0.0013 mol) in tetrahydrofuran (10 mL) at 0-5 ºC 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[1,4]oxazin-4-yl]phenol.

Step III: (R)-7-Benzyloxy-3-(4-benzyloxyphenyl)-4-{3-[9-(4,4,5,5,5-pentafluoropentyl sulfanyl)nonyloxy]phenyl}-3,4-dihydro-2H-benzo[1,4]oxazine

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[1,4]oxazin-4-yl]phenol (0.15 g, 0.00029 mol) in N,N-dimethylformamide (5 mL) at room temperature and stirred for 30 minutes. 1-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 ºC. 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: (R)-3-(4-Hydroxyphenyl)-4-{3-[9-(4,4,5,5,5-pentafluoropentylsulfanyl) nonyloxy]phenyl}-3,4-dihydro-2H-benzo[1,4]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[1,4]oxazine (0.14 g, 0.0017 mol) in DCM (5 mL) at -78 ºC 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[1,4]oxazin-7-ol.

Example 4: Preparation of 4-{(R)-5-[3-(2-dodecylaminoethoxy)phenyl]-1,5,6,7-tetrahydro-8-oxa-1,2,5-triaza cyclopenta[b]naphthalen-6-yl}phenol

4-{(R)-5-[3-(2-Dodecylaminoethoxy)phenyl]-1,5,6,7-tetrahydro-8-oxa-1,2,5-triaza cyclopenta[b]naphthalen-6-yl}phenol was prepared by employing Buchwald reaction between (R)-6-(4-benzyloxyphenyl)-1-(tetrahydropyran-2-yl)-1,5,6,7-tetrahydro-8-oxa-1,2,5-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-[2-(10-fluorodecylamino)ethoxy]phenyl}-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (85)

Step I : 2-Bromo-1-(4-fluorophenyl)ethanone

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 ºC. Reaction mixture was stirred for 30 min at room temperature and again cooled to 0-5 ºC, 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.

Step II : 2-(5-Benzyloxy-2-bromophenoxy)-1-(4-fluorophenyl)ethanone

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-1-(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 ºC 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)-1-(4-fluorophenyl)ethanone.

Step III : 2-(5-Benzyloxy-2-bromophenoxy)-1-(4-fluorophenyl)ethylamine

Ammonium acetate (1.7 g, 0.02 mol) was added to a stirred solution of 2-(5-benzyloxy-2-bromophenoxy)-1-(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 ºC 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)-1-(4-fluorophenyl)ethylamine.

Step IV : 7-Benzylozy-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[1,4]oxazine

Tris(dibenzylidineacetone)dipalladium (0.05 g, 0.00005 mol) followed by 2,2’-bis(diphenyl phosphino)-1,1’-binaphthyl (0.06 g, 0.0001 mol) were added to a stirred solution of 2-(5-benzyloxy-2-bromophenoxy)-1-(4-fluorophenyl)ethylamine (0.4 g, 0.001 mol) in toluene (20 mL) at room temperature. Potassium tert-butoxide (0.16 g, 0.0014 mol) was added to reaction mixture and then heated at 105 ºC 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 [1,4]oxazine.

Step V: (2-{3-[7-Benzyloxy-3-(4-fluorophenyl)-2,3-dihydrobenzo[1,4]oxazin-4-yl]-5-fluorophenoxy}ethyl)-(10-fluorodecyl) carbamic acid tert-butyl ester

Palladium acetate (0.007 g, 0.000029 mol) followed by tri-tert-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[1,4]oxazine (0.2 g, 0.0006 mol) and [2-(3-bromo-5-fluorophenoxy)ethyl]-(10-fluoro decyl)carbamic acid tert-butyl ester (0.29 g, 0.0006 mol) in toluene (5 ml) at room temperature under nitrogen atmosphere. Sodium tert-butoxide (0.08 g, 0.0008 mol) was added to reaction mixture and heated at 105 ºC 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[1,4]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 benzo[1,4]oxazin-4-yl]phenoxy}ethyl)carbamic acid tert-butyl ester

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[1,4]oxazin-4-yl]-5-fluorophenoxy}ethyl)-(10-fluorodecyl) carbamic acid tert-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 ºC 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 ºC 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[1,4]oxazin-4-yl]phenoxy} ethyl)carbamic acid tert-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-dihydro-2H-benzo[1,4]oxazin-7-ol

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[1,4]oxazin-4-yl]phenoxy}ethyl)carbamic acid tert-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 ºC. 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-fluorodecylamino)ethoxy]phenyl}-3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol.

Example 6: Preparation of 4-((R)-5-{3-fluoro-5-[2-(12-fluorododecylamino)ethoxy] phenyl}-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b]naphthalen-6-yl)phenol (49)

Step I: 5-Bromo-1-(tetrahydropyran-2-yl)-1H-indazol-6-ol

Methane sulfonic acid (0.12 mL, 0.0019 mol) was added to a stirred solution of 5-bromo-1H-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 ºC, 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 ºC 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-1-(tetrahydropyran-2-yl)-1H-indazol-6-ol.

Step II: {(R)-1-(4-Benzyloxyphenyl)-2-[5-bromo-1-(tetrahydropyran-2-yl)-1H-indazol-6-yloxy]ethyl}carbamic acid tert-butyl ester.

Diisopropylazodicarboxylate (1.0 ml, 0.0048 mol) was added to a stirred mixture of [(R)-1-(4-benzyloxyphenyl)-2-hydroxyethyl]carbamic acid tert-butyl ester (1.18 g, 0.0034 mol), 5-bromo-1-(tetrahydropyran-2-yl)-1H-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 ºC 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: (R)-1-(4-Benzyloxyphenyl)-2-[5-bromo-1-(tetrahydropyran-2-yl)-1H-indazol-6-yloxy]ethylamine.

4M Hydrochloric acid in 1,4-dioxan (7.5 mL) was added to a stirred solution of {(R)-1-(4-benzyloxy phenyl)-2-[5-bromo-1-(tetrahydropyran-2-yl)-1H-indazol-6-yloxy]ethyl}carbamic acid tert-butyl ester (1.5 g, 0.0024 mol) in 1,4-dioxan (3 mL) at 0-5 ºC 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)-1-(4-benzyloxyphenyl)-2-[5-bromo-1-(tetrahydropyran-2-yl)-1H-indazol-6-yloxy]ethylamine, which was used for the next step without purification.

Step IV: (R)-6-(4-Benzyloxy phenyl)-1-(tetrahydro pyran-2-yl)-1,5,6,7-tetrahydro-8-oxa-1,2,5-triaza cyclopenta[b]naphthalene.

Potassium tert-butoxide (0.36 g, 0.0032 mol) was added to a stirred solution of (R)-1-(4-benzyloxyphenyl)-2-[5-bromo-1-(tetrahydropyran-2-yl)-1H-indazol-6-yloxy]ethylamine (1.2 g, 0.0023 mol), tris(dibenzylideneacetone)dipalladium (0.11 g, 0.00011 mol) and 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (0.14 g, 0.00023 mol) in toluene (25 mL) under nitrogen atmosphere. Reaction mixture was then heated at 100 ºC 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)-1-(tetrahydropyran-2-yl)-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b]naphthalene.

Step V: (2-{3-[(R)-6-(4-Benzyloxyphenyl)-1-(tetrahydropyran-2-yl)-6,7-dihydro-1H-8-oxa-1,2,5-triazacyclopenta[b]naphthalen-5-yl]-5-fluorophenoxy}ethyl)-(12-fluorododecyl)carbamic acid tert-butyl ester.

Sodium tert-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 tert-butyl ester (0.3 g, 0.00057 mol), palladium acetate (0.005 g, 0.000023 mol) and tri tert-butylphosphine (0.02 mL, 0.000047 mol, 50 % solution in toluene) in toluene (10 mL) under nitrogen atmosphere and then heated at 100 ºC 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)-1-(tetrahydropyran-2-yl)-6,7-dihydro-1H-8-oxa-1,2,5-triazacyclopenta[b]naphthalen-5-yl]-5-fluorophenoxy}ethyl)-(12-fluorododecyl)carbamic acid tert-butyl ester.

Step VI: (12-Fluorododecyl)-(2-{3-fluoro-5-[(R)-6-(4-hydroxyphenyl)-1-(tetrahydro pyran-2-yl)-6,7-dihydro-1H-8-oxa-1,2,5-triazacyclopenta[b]naphthalen-5-yl]phenoxy}ethyl)carbamic acid tert-butyl ester.

5 % Palladium on charcoal (0.07 g, 50 % wet) was added to a stirred solution of (2-{3-[(R)-6-(4-benzyloxyphenyl)-1-(tetrahydropyran-2-yl)-6,7-dihydro-1H-8-oxa-1,2,5-triazacyclo penta[b]naphthalen-5-yl]-5-fluorophenoxy}ethyl)-(12-fluorododecyl)carbamic acid tert-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)-1-(tetrahydropyran-2-yl)-6,7-dihydro-1H-8-oxa-1,2,5-triazacyclopenta[b]naphthalen-5-yl]phenoxy}ethyl)carbamic acid tert-butyl ester, which was used for the next step without further purification.

Step VII: 4-((R)-5-{3-Fluoro-5-[2-(12-fluorododecylamino)ethoxy]phenyl}-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b]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-1H-8-oxa-1,2,5-triazacyclopenta[b]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 ºC for 30 minutes and then concentrated under reduced pressure at 45 ºC. 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}-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b]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
Compd No. Chemical Name 1H-NMR (d, ppm)
1. (R)-4-[3-(2-Dimethyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CDCl3): d 2.32 (s, 6H); 2.69 (t, J= 5.68Hz, 2H); 3.90-4.00 (m, 2H); 4.27 (dd, J1= 10.76 Hz, J2= 2.72Hz, 1H); 4.44 (dd, J1= 10.76Hz, J2= 3.64Hz, 1H); 4.69-4.73 (br t, 1H); 6.29 (dd, J1= 8.76Hz, J2= 2.80Hz, 1H); 6.37 (d, J= 2.76Hz, 1H); 6.54 (dd, J1= 8.12Hz, J2= 2.12 Hz, 1H); 6.64-6.76 (m, 4H); 6.85 (d, J=8.72Hz, 1H), 7.10-7.17 (m, 3H), two exchangeable protons.
2. (R)-4-[4-(2-Dimethyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 2.25 (s, 6H); 2.66 (t, J=5.40Hz, 2H); 3.94 (t, J=5.44Hz, 2H); 4.11(dd, J1=10.76Hz, J2=2.96 Hz, 1H); 4.21 (dd, J1= 10.76 Hz, J2= 5.64Hz, 1H); 4.50 (dd, J1=5.52Hz, J2 =2.88Hz, 1H) 6.09 (dd, J1=8.76 Hz, J2=2.76 Hz, 1H); 6.20 (d, J=2.72 Hz, 1H); 6.31 (d, J=8.76 Hz, 1H); 6.54-6.59 (m, 2H); 6.72-6.76 (m, 2H); 6.91-6.95 (m, 2H); 6.98-7.30 (m, 2H), two exchangeable protons.
3. (R)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CDCl3): d 0.88 (t, J=6.64Hz, 3H); 1.19-1.38 (br m, 18H); 1.49-1.59 (m, 2H); 2.67 (t, J=7.44, 2H); 2.95 (q, J=4.80 Hz, 2H); 3.95 (t, J=4.84Hz, 2H); 4.23 (d, J=8.12 Hz, 1H); 4.41 (dd, J1=10.72Hz, J2=3.36 Hz, 1H); 4.68 (s, 1H); 6.20-6.25 (br dd, 1H); 6.33-6.37 (br d, 1H); 6.50 (d, J=8.08Hz, 1H); 6.62-6.71 (m, 4H); 6.69 (d, J=8.88Hz, 1H); 7.04-7.13 (m, 3H), three exchangeable protons.
4. (R)-3-(4-Hydroxy phenyl)-4-{3-[2-(4-nonyl piperazin-1-yl)ethoxy] phenyl}-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.8 (t, J=7.0 Hz, 3H); 1.19 (br s, 12H); 1.4-1.47 (br s, 2H); 2.33 (t, J=8.0, 2H); 2.37-2.63 (br m, 8H); 2.66 (t, J=5.4 Hz, 2H); 3.92 (br s, 2H); 4.11 (dd, J1=10.85 Hz, J2=2.75 Hz, 1H); 4.31 (dd, J1=10.8 Hz, J2=3.8Hz, 1H); 4.64 (br s, 1H); 6.15-6.2 ( m, 2H); 6.47 (dd, J1=8.2Hz, J2=1.9 Hz, 1H); 6.59-6.61 (m, 3H); 6.64 (d, J=5.2 Hz, 1H); 6.67 (d, J=8.5 Hz, 1H); 7.1-7.7 (m, 3H); two exchangeable protons.
5. (R)-4-[3-(3-Dodecyl aminopropoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo [1,4]oxazin-7-ol (CD3OD): d 0.8 (t, J=6.6 Hz, 3H); 1.1-1.28 (br s, 18H); 1.40-1.49 (br m, 2H); 1.86 (quintet, J=6.50 Hz, 2H); 2.55 (t, J=7.4 Hz, 2H); 2.72 (t, J=7.15 Hz, 2H); 3.83-3.90 (m, 2H); 4.12 (dd, J1=10.8 Hz, J2=2.7 Hz, 1H); 4.32 (dd, J1=10.85 Hz, J2=3.7 Hz, 1H); 4.65 (br s, 1H); 6.15-6.20 (m, 2H); 6.46 (dd, J1=8.2 Hz, J2=2.15 Hz, 1H); 6.55-6.64 (m,4H); 6.68 (d, J=8.55 Hz, 1H); 7.02-7.09 (m, 3H); three exchangeable protons.
6. 4-{(R)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-7-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl} phenol (CD3OD): d 0.81 ( t, J=6.95 Hz, 3H); 1.14-1.33 (br m, 18H); 1.58-1.67 (m, 2H); 2.93-2.98 (m, 2H); 3.3 ( t, J=4.92 Hz, 2H); 4.08-4.12 (br m, 2H); 4.18 (dd, J1=10.9 Hz, J2=2.85 Hz, 1H); 4.37 (dd , J1=10.9 Hz, J2=4.15 Hz, 1H ); 4,71 (t, J = 3.32 Hz, 1H); 6.40 (d of t, J1=8.85 Hz, J2=2.95 Hz, 1H); 6.48 (dd, J1=9.62 Hz, J2=2.85 Hz, 1H); 6.59(d, J=8.65 Hz, 2H); 6.63 (dd, J1=8.15 Hz , J2=2.3 Hz, 1H ); 6.70 (t, J = 2.2 Hz, 1H); 6.71-6.79 (m, 2H ); 7.03 (d, J=8.5 Hz, 2H); 7.15 (t, J=8.15 Hz, 1H); two exchangeable protons.
7. (R)-4-[3-(2-Dodecyl aminoethoxy)-5-fluoro phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CDCl3): d 0.81 (t, J=7.04Hz, 3H); 1.1-1.28 (br s, 18H); 1.39-1.49 (br m, 2H); 2.55 (t, J=7.4Hz, 2H); 2.85 (t, J=5.0Hz, 2H); 3.90 (t, J=5.0Hz, 2H); 4.13 (dd, J1=10.88Hz, J2 = 2.72Hz, 1H); 4.37 (dd, J1 = 10.88Hz, J2 = 3.0Hz, 1H); 4.72 (s,1H); 6.18 (d, J = 2.6Hz, 1H); 6.19-6.26 (m, 2H); 6.36 (d, J = 10.8Hz, 1H); 6.42 (s, 1H); 6.60 (d, J = 8.52Hz, 2H); 6.81 (d, J = 8.72Hz, 1H); 7.05 (d, J = 8.5Hz, 2H); three exchangeable protons.
8. (R)-3-(4-Hydroxy phenyl)-4-[3-(5-octylaminopentyloxy) phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.78-0.82(m, 3H); 1.12-1.38 (br m, 10H); 1.4-1.5 (m, 2H); 1.5-1.72 (m, 6H); 2.82-2.95 (m, 4H); 3.81 (t, J=5.76Hz, 2H); 4.12 (dd, J1=10.72Hz, J2 = 2.72Hz, 1H); 4.33 (dd, J1=10.76 Hz, J2=3.68Hz, 1H); 4.64 (br s, 1H); 6.15-6.19 (m, 1H); 6.45 (d, J=8.2Hz, 1H); 6.53 (t, J=2.16Hz, 1H); 6.57-6.7 (m, 4H); 7.05 (d, J=8.28Hz, 4H); three exchangeable protons.
9. 4-[3-(2-Dodecylamino ethoxy)phenyl]-3-(4-fluorophenyl)3,4-dihydro -2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 0.86-0.96 (br m, 3H); 1.2-1.4 (br s, 18H); 1.6-1.7 (br s, 2H); 2.9-3.0 (br m, 2H); 3.29-3.35 (br s, 2H); 4.17-4.3 (br m, 3H); 4.6 (d, J = 10.05 Hz, 1H); 5.08 (br s,1H); 6.26-6.3 (br s, 1H); 6.34 (d , J = 8.56 Hz, 1H); 6.66 (d, J = 7.76 Hz, 1H); 6.74 (s, 1H); 6.80 (d , J = 8.08 Hz, 1H); 6.91 (d, J = 9.68 Hz, 1H); 7.19 (t, J = 8.48 Hz, 2H); 7.28 (t, J = 8.02 Hz, 2H); 7.45 (t, J = 6.46 Hz, 1H); 8.87 (br s, 1H); 9.12 (s, 1H ); two exchangeable protons.
10. 4-{(R)-6-Chloro-4-[3-(2-dodecyamino ethoxy) phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl} phenol (CD3OD): d 0.81 (t, J=6.15Hz, 3H), 1.2 (br s, 18H), 1.27 (merged s, 2H), 1.57 (m, 2H), 2.9 (t, J=8Hz, 2H), 4.07 (d, J=4.9Hz, 2H), 4.2 (dd, J1=10.75Hz, J2=2.5Hz, 1H), 4.3 (dd, J1=10.9Hz, J2=4.3Hz, 1H), 4.7 (s, 1H), 6.53-6.6 (m, 4H), 6.76-6.71 (m, 3H), 6.8(d, J=8Hz, 1H), 7.0 (d, J=8.5Hz, 2H), 7.2 (t, J=7.95Hz, 1H), two exchangeable protons.
11. (R)-3-(4-Hydroxy phenyl)-4-{3-[9-(4,4,5,5,5-pentafluoro pentylsulfanyl)nonyloxy] phenyl}-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CDCl3): d 1.25-1.43 (m, 10H); 1.53-1.63 (m, 2H, merged with H2O of CDCl3); 1.68-1.75 (m, 2H); 1.84-1.92 (m, 2H); 2.10-2.23 (m, 2H); 2.50(t, J=7.24Hz, 2H); 2.59 (t, J=7.0Hz, 2H); 3.85 (t, J=5.46Hz, 2H); 4.28 (d, J=9.64Hz,1H); 4.46(d, J=10.68Hz, 1H); 4.56(s, 1H); 6.28-6.42 (m, 1H); 6.55 (d, J=7.8Hz, 1H); 6.69 (m, 2H); 6.74(d, 8.4Hz, 2H); 6.92 (d, J=8.6Hz, 1H); 7.14 (m, 2H); 7.18(d, J=8.4Hz, 2H); two exchangeable protons.
12. (R)-3-(4-Hydroxy phenyl)-4-[3-(2-octylamino ethoxy) phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CDCl3): d 0.81 (t, J=6.94Hz, 3H); 1.12-1.30 (br m, 10H); 1.40-1.50 (br t, 2H); 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, J1=10.76 Hz, J2=2.72Hz, 1H); 4.33 (dd, J1=10.84Hz, J2=3.76 Hz, 1H); 4.66 (br s, 1H); 6.15-6.20 (m, 2H); 6.50 (dd, J1=8.16 Hz, J2=2.00Hz, 1H); 6.57-6.71 (m, 6H); 7.05 (m, 2H), three exchangeable protons.
13. Dodecanoic acid-(2-{3-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-2,3-dihydro benzo[1,4] oxazin-4-yl]phenoxy} ethyl)amide (CDCl3): d 0.87 (t, J =7.04Hz, 3H); 1.1-1.35 (br s, 16H); 1.5-1.7 (br s, 2H, merged with H2O of CDCl3); 2.18 (t, J=7.8 Hz, 2H); 3.57 (t, J=5.08 Hz, 2H); 3.87-3.91 (m, 2H); 4.28 (dd, J1=10.8Hz, J2=2.76Hz, 1H); 4.45 (dd, J1=10.76Hz, J2=3.68Hz, 1H); 4.71 (s, 1H); 5.15 (br s, 1H); 5.79 (br s, 1H); 5.92 (t, J=5.6 Hz, 1H); 6.32 (dd, J1=8.68Hz, J2=2.6Hz, 1H); 6.4 (d, J=2.6Hz,1H); 6.53 (dd, J1=8.2Hz, J2=2.08Hz, 1H); 6.61 (br s, 1H); 6.73-6.79 (m,3H); 6.86 (d, J=8.7Hz, 1H); 7.12-7.17(m, 3H)
14. 4-{(R)-7-amino-4-[3-(2-dodecylaminoethoxy)-phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl} phenol (DMSO-d6): d 0.91 (t, J = 6.78 Hz, 3H); 1.26-1.34 (br s, 18H); 1.6-1.72 (br m, 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, J1 = 10.76 Hz, J2 = 2.4 Hz, 1H); 4.52 (dd, J1 = 10.8 Hz, J2= 3.08 Hz, 1H); 5.0 (br s, 1H); 6.74 (d, J = 8.56 Hz, 2H); 6.75-6.92 (m , 5H); 6.97 (d, J = 8.68 Hz, 1H); 7.14 (d, J = 8.56 Hz, 2H); 7.33 (t, J = 8.08 Hz, 1H); 9.04 (br s, 2H); 9.48 (br s, 1H); 10.05 (br s, 1H); four exchangeable protons.
15. (R)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-3-phenyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.91 (t, J = 6.6 Hz, 3H); 1.2 -1.5 (br s, 18H); 1.66-1.73 (br m, 2H); 3.05 (t, J=7.92Hz, 2H); 3.40 (t, J=4.96Hz, 2H); 4.19 (br s, 2H); 4.27 (dd, J1=10.92 Hz, J2=2.80 Hz, 1H); 4.53 (dd, J1= 10.9 Hz, J2=3.16 Hz, 1H); 4.8 (1H, merged with H2O peak of CD3OD); 6.27-6.3 (br m, 1H); 6.31 (d, J=2.72 Hz, 1H); 6.65 (dd, J1=7.92 Hz, J2=2.04Hz, 1H); 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.
16. (R)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 0.91 (t, J = 6.6 Hz, 3H); 1.2-1.4 (br s, 18H); 1.65-1.7 (br m, 2H); 2.93-3.1 (br m, 2H); 3.3- 3.40 (br m, peak partially merged with C2D5SOH, 2H); 3.76 (s, 3H); 4.18-4.25 (m, 3H); 4.57 (dd, J1= 10.9 Hz, J2=2.75 Hz, 1H); 4.99 (s, 1H); 6.26 (d, J=2.65 Hz, 1H); 6.32 (dd, J1=8.75Hz,J=2.72 Hz, 1H); 6.65 (dd, J1=10.35 Hz, J2=2.3Hz, 1H); 6.74 (s, 1H); 6.80 (d, J=8.1 Hz, 1H); 6.85-6.95 (m, 3H); 7.27(t, J=8.2 Hz, 1H); 7.32(d, J=8.65 Hz, 2H); 8.73 (br s, 2H); 9.06 (s,1H)
17. (R)-4-[3-(2-Dodecyl aminoethoxy)-5-trifluoro methylphenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CDCl3): d 0.8-0.9 (t, 3H); 1.1-1.4 (br s, 18H); 1.49-1.6 (br s, 2H); 2.66 (br s, 2H); 2.95 (br s, 2H); 3.93 (br s, 2H); 4.21 (d, J=9.2 Hz, 1H); 4.42 (d, J=8.44 Hz, 1H); 4.69 (br s, 1H); 6.2-6.35 (m, 2H); 6.6-6.82 (m, 5H); 6.9-7.0 (m, 1H); 7.0-7.15 (m, 2H); three exchangeable protons.
18. N-[(R)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-yl]formamide (CD3OD): d 0.81 ( t, J = 6.3 Hz, 3H) ; 1.15-1.3 ( br s, 18H) ; 1.55-1.65 (br m, 2H) ; 2.95 ( t, J = 7.8 Hz, 2H) ; 3.26-3.33 ( br s, 2H) ; 4.05-4.15 ( br m, 2H); 4.2-4.3 (m, 1H); 4.3-4.42 ( m, 1H) ; 4.71 (br s, 1H); 6.54-6.9 (m, 7H); 6.95-7.1 (m , 3H); 7.1-7.23 (m, 1H); three exchangeable protons.
19. (R)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-8-ol (CDCl3): d 0.87 (t, J=6.44Hz, 3H), 1.23 (br s, 18H), 1.53 (br s, 2H), 2.67 (t, J=7.2Hz, 2H), 2.95 (t, J=4.52 Hz, 2H), 3.94 (br m, 2H), 4.33 (dd, J1=10.6Hz, J2=2.6Hz, 1H), 4.44 (dd, J1=10.6Hz, J2=3.96Hz, 1H), 4.7 (s, 1H), 6.4 (m, 2H), 6.6 (br m, 3H), 6.7 (d, J=8.48Hz, 2H), 6.76 (d, J=7.8Hz, 1H), 7.04 (d, J=8.4Hz, 2H), 7.12 (t, J=8.04Hz, 1H), three exchangeable protons.
20. (R)-3-(4-Hydroxy phenyl)-4-{3-[2-(2-octylaminoethylamino) ethoxy]phenyl}-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 0.81 (t, J = 6.64 Hz, 3H), 1.14-1.30 (br s, 10 H), 1.38 -1.49 (br m, 2H), 2.42 (t, J = 6.92 Hz, 2H), 2.54 (t, J =7.20 Hz, 2H), 2.62-2.74 (br s, 3H), 2.77 -2.89 (m, 2H), 3.86- 3.94 (br s, 2H), 4.12 (d, J = 9.40 Hz, 1H), 4.32 (d, J = 7.84 Hz, 1H), 4.65 (S, 1H), 6.13-6.20 (m, 2H), 6.44-6.70 (m, 6H), 7.02-7.10 (m, 3H). three exchangeable protons.
21. (R)-4-[3-(2-Decylamino ethoxy)-5-fluoro phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CDCl3): d 0.87 (t, J = 7.10 Hz, 3H); 1.18-1.35 (br m, 14 H); 1.5-1.6 (m, 2H); 2.66 (t, J = 7.5Hz, 2H); 2.9 -3.0 (m, 2H); 3.93 (t, J=5.05 Hz, 2H); 4.23 (dd, J1 =10.85 Hz, J2 = 2.5 Hz, 1H); 4.44 (dd, J1 =10.75 Hz, J2 = 2.6 Hz, 1H); 4.7 (s, 1H); 6.2 (d, J =10.3Hz, 1H); 6.24 (dd, J1 = 8.8 Hz, J2 = 2.75 Hz, 1H); 6.32 (br s, 1H); 6.41-6.46 (m, 2H) ; 6.67 (d, J = 8.55 Hz, 2H); 6.84 (d, J= 8.75 Hz, 1H); 7.08 (d, J= 8.5 Hz, 2H); three exchangeable protons
22. (R)-4-[3-Fluoro-5-(2-tetradecylaminoethoxy) phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CDCl3): d 0.87 (t, J = 7.10 Hz, 3H); 1.2-1.35 (br m, 20 H); 1.5-1.6 (m, 2H); 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, J1 = 10.75 Hz, J2 = 2.45 Hz, 1H); 4.43 (dd, J1= 10.75 Hz, J2 = 2.20 Hz, 1H); 4.69 (s, 1H); 6.19 (d, J= 10.35 Hz, 1H); 6.22 (dd, J1 = 8.85 Hz, J2 = 2.75 Hz, 1H); 6.3-6.33( m, 1H); 6.41-6.45 (m, 2H); 6.66 (d, J = 8.6 Hz, 2H); 6.82 (d, J=8.75 Hz, 1H); 7.07 (d, J = 8.50Hz, 2H); three exchangeable protons
23. (S)-4-[3-(2-Dodecyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 0.9(s, 3H), 1.3(br s, 18H), 1.43(br s, 2H), 2.85 (s, 2H), 3.96 (s, 2H), 4.2(d, J=9.68H, 1H), 4.5(d, J=8.96Hz, 1H), 4.9(s, 1H), 6.3(m, 2H), 6.5-6.86 (br m, 3H), 7.17 (t, J=8.04Hz, 1H), three exchangeable protons.
24. 1-(2-{3-[(R)-7-Hydroxy-3-(4-hydroxyphenyl)-2,3-dihydrobenzo[1,4] oxazin-4-yl]phenoxy} ethyl)-3-nonyl urea (DMSO-d6): d 0.91 (t, J = 6.85 Hz, 3H); 1.24-1.35 (br m, 12H); 1.38-1.43 (br m, 2H); 3.01 (q, J = 6.4 Hz, 2H); 3.32-3.38 (br m, 2H); 3.86-3.93 (br m, 2H); 4.19 ( dd, J1 = 10.95 Hz, J2 = 2.5 Hz, 1H); 4.49 (dd, J1 = 11.05 Hz, J2 = 3.05 Hz, 1H ); 4.91 (s,1H); 5.95 (t, J = 5.6 Hz, 1H); 6.02 (t, J = 5.65 Hz, 1H); 6.25 (d, J = 2.65 Hz,1H); 6.30 (dd, J1 = 8.7 Hz, J2 = 2.65 Hz, 1H ); 6.6 (dd, J1 = 8.15 Hz, J2 = 2.05 Hz, 1H); 6.66 (s, 1H); 6.69-6.78 (m, 3H); 6.85 (d, J = 8.8 Hz, 1H); 7.15-7.24 (m, 3H ); 8.98 (s, 1H ); 9.35 (s,1H); two exchangeable protons.
25. (R)-4-[4-(2-Dodecyl aminoethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 0.91 (t, J=7.15 Hz, 3H), 1.22-1.38 (m, 18H), 1.47-1.57 (m, 2H), 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 (dd, J1=10.8 Hz, J2=2.7 Hz, 1H), 4.33 (dd, J1=10.9 Hz, J2=5.35 Hz, 1H), 4.7-4.73 (m, 1H), 6.22 (dd, J1=8.7 Hz, J2=2.6 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.41 (d, J=8.6 Hz, 1H), 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, 1H), 9.35 (br s, 1H), one exchangeable proton.
26. (R)-3-(4-Methoxy phenyl)-4-{3-[2-(2-octylaminoethylamino) ethoxy]phenyl}-3,4-dihydro-2H-benzo[1,4] oxazine-7-ol (DMSO-d6): d 0.92 (t, J = 6.68 Hz, 3H); 1.29-1.4 (br m, 10H); 1.62-1.72 (m, 2H); 2.9- 3.0 (m, 2H); 3.30-3.5 (m, 8H); 3.76(s, 3H); 4.2 (dd, J1 = 11.04 Hz, J2 = 2.52 Hz, 1H); 4.23-4.3 (m, 2H); 4.57 (dd, J1 = 11.08 Hz, J2 = 2.64 Hz, 1H); 5.0(s, 1H); 6.26 (d, J = 2.65 Hz, 1H); 6.33 (dd, J1 = 8.72 Hz, J2 = 2.64 Hz, 1H ); 6.67 (dd, J1 = 8.12 Hz, J2 =1.78 Hz, 1H); 6.76 (s, 1H); 6.8 (d, J = 8.08 Hz, 1H); 6.91(dd, J1 = 8.72 Hz, J2 =2.32 Hz, 3H); 7.27 (t, J = 8.16 Hz, 1H); 7.33 (d, J = 8.64 Hz, 2H); 9.09 (s,1H); 9.33 (s, 1H); 9.52 (s, 1H); three exchangeable protons.
27. (R)-4-{3-Fluoro-5-[2-(2-octylaminoethylamino) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 0.9 (t, J=6.4Hz, 3H); 1.28 (br s, 10H); 1.38-1.45 (br m, 2H); 2.50 (t, J=7.0Hz, 2H); 2.58-2.65 (m, 4H); 2.85 (t, J=5.28 Hz, 2H); 3.97 (t, J=5.2Hz, 2H); 4.19 (d, J=8.6 Hz, 1H); 4.56 (d, J=9.9Hz, 1H); 4.99 (s, 1H); 6.25 (d, J=2.56 Hz, 1H); 6.33 (dd, J1=8.7 Hz, J2=2.56Hz, 1H); 6.4-6.52 (m, 3H); 6.72 (d, J=8.48 Hz, 2H); 6.96 (d, J=8.76Hz,1H); 7.18 (d, J=8.48Hz, 2H); four exchangeable protons.
28. (S)-4-[3-(2-Dodecyl aminoethoxy)-5-fluoro phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-7-ol (CD3OD): d 0.80 ( t, J = 6.85 Hz, 3H); 1.1-1.3 ( br m, 18H); 1.38-1.47 (br m, 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 (d, J = 9.05 Hz, 1H); 4.36 (d, J = 8.65 Hz, 1H); 4.68-4.72 (br s, 1H); 6.16-6.25 (br m, 3H); 6.35 (d, J = 10.70 Hz, 1H); 6.41 (s, 1H); 6.6 (d, J = 8.15 Hz, 2H ); 6.81 (d, J = 8.65 Hz, 1H); 7.05 (d, J = 8.15 Hz, 2H); three exchangeable protons.
29. (S)-4-{3-Fluoro-5-[2-(2-octylaminoethylamino) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 0.9-1.0 (m, 3H); 1.34 (br s, 10 H); 1.47 (br s, 2H); 2.56 (t, J=6.75 Hz, 2H); 2.58-2.72 (m, 4H); 2.91 (br s, 2H); 4.03 (br s, 2H); 4.26 (d, J=9.73 Hz, 1H); 4.61 (d, J=10.06Hz,1H); 5.05 (s, 1H); 6.31 (s, 1H); 6.39 (d, J=8.5 Hz, 1H); 6.49 (d, J=10.65 Hz, 1H); 6.52-6.58 (m, 2H); 6.78 (d, J=8.13 Hz, 2H); 7.03 (d, J=8.68 Hz, 1H); 7.24 (d, J=8.09 Hz, 2H), four exchangeable protons.
30. (R)-4-{3-Fluoro-5-[2-(2-octylaminoethylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 0.92 (t, J=6.9 Hz, 3H), 1.22-1.45 (br m, 10H), 1.62-1.72 (m, 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), 4.21 (d, J=8.9 Hz, 1H), 4.29 (br s, 2H), 4.63 (d, J=9.4 Hz, 1H), 5.09 (br s, 1H), 6.27 (d, J=2.5 Hz, 1H), 6.35 (d, J=8.77 Hz, 1H), 6.55-6.62 (m, 3H), 6.92 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.76 Hz, 1H), 7.32 (d, J=8.56 Hz, 2H), 9.1-9.8 (m, 5H).
31. Dodecyl-(2-{3-fluoro-5-[6-(4-methoxyphenyl)-6, 7-dihydro-1H-8-oxa-1, 2, 5-triazacyclopenta[b] naphthalene-5-yl] phenoxy}ethyl)amine (DMSO-d6): d 0.90 (t, J = 6.81 Hz, 3H); 1.24-1.36 (br m, 18H); 1.6-1.7 (br m, 2H); 2.9-2.97 (br m, 2H); 3.28-3.34 (br m, 2H); 3.74 (s, 3H); 4.28 (br t, J = 4.51 Hz, 2H ); 4.40 (dd, J1 = 10.97 Hz, J2 = 2.69 Hz, 1H); 4.59 (dd, J1 = 11.05 Hz, J2 = 3.35 Hz, 1H); 5.13-5.17 (br s, 1H); 6.63 (d, J = 10.64 Hz, 1H); 6.7 (s, 1H); 6.74 (d, J = 10.8 Hz, 1H); 6.91 (d, J = 8.75 Hz, 1H); 6.95 (s, 1H); 7.33(d, J=8.68 Hz, 2H); 7.4 (s, 1H ), 7.9 (s, 1H); 9.06-9.08 (br m, 2H), two exchangeable protons.
32. (R)-4-[3-(2-Dodecyl aminoethoxy)-5-fluoro phenyl]-3-(4-methoxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 0.91 (t, J = 6.93 Hz, 3H); 1.28-1.38 (br m, 18H); 1.6-1.7 (br m, 2H); 2.96 (br t, J = 7.99 Hz, 2H); 3.3-3.36 (br m, 2H); 3.76 (s, 3H); 4.21 (dd, J1 = 11.14 Hz, J2 = 2.76 Hz, 1H); 4.23-4.29 (br m, 2H); 4.63 (dd , J1 = 11.06 Hz, J2 = 2.37Hz, 1H); 5.08 (s, 1H); 6.26 (d, J = 2.71 Hz, 1H); 6.36 (dd, J1= 8.8 Hz, J2 = 2.73 Hz, 1H); 6.51-6.62 (m, 3H); 6.92 (dd, J1 = 6.82 Hz, J2 = 2.04 Hz, 2H ); 7.01 (d, J = 8.77 Hz, 1H); 7.32 (d, J = 7.62 Hz, 2H); 8.82-8.9 (br s, 2H); 9.2 (s, 1H); two exchangeable protons.
33. 4-{5-[3-(2-Dodecylamino ethoxy)-5-fluorophenyl]-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b] naphthalene-6-yl}phenol (DMSO-d6): d 0.74-0.85 (br m, 3H); 1.10-1.13 (br m, 18H); 1.4-1.53 (br m, 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, 2H); 4.75 (s, merged with H2O peak of CD3OD); 6.36 (d, J = 10.32 Hz, 1H); 6.48-6.67 (m, 4H); 6.84-6.86 (br s,1H); 7.05 (d, J = 8.12 Hz, 2H); 7.14 (s, 1H ); 7.66 (s, 1H); three exchangeable protons.
34. (R)-4-[3-(3-Dodecyl aminopropoxy)-5-fluoro phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.99 (t, J=6.8 Hz, 3H), 1.30-1.49 (m, 18H), 1.54-1.66 (m, 2H), 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 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 4.31 (dd, J1=10.9 Hz, J2=2.8 Hz, 1H), 4.55 (dd, J1=11.0 Hz, J2=3.1 Hz, 1H) 4.89 (S, 1H), 6.34-6.42 (m, 3H), 6.49-6.57 (m, 2H), 6.78 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), three exchangeable protons.
35. (R)-4-[3-(2-Dodecyl aminoethylamino) phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.99 (t, J=6.7 Hz, 3H), 1.33-1.45 (m, 18H), 1.55-1.62 (m, 2H), 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 (dd, J1=10.8 Hz, J2=2.8 Hz, 1H), 4.48 (dd, J1=10.6 Hz, J2=3.85 Hz, 1H), 4.79-4.82 (br m, 1H), 6.31-6.37 (m, 2H), 6.4 (d, J=9.25 Hz, 1H), 6.5-6.54 (m, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.45 Hz, 1H), 7.09 (t, J=8.2 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), four exchangeable protons.
36. (R)-4-[3-(3-Dodecyl aminopropylamino) phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.99 (t, J=7.0 Hz, 3H), 1.34-1.44 (m, 18H), 1.57-1.63 (m, 2H), 1.83 (quintet, J=7.15 Hz, 2H), 2.68 (t, J=7.65 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 3.13 (t, J=6.75 Hz, 2H), 4.28 (dd, J1=10.8 Hz, J2=2.8 Hz, 1H), 4.48 (dd, J1=10.7 Hz, J2=3.85 Hz, 1H), 4.79 (t, J=3.05 Hz, 1H), 6.32-6.35 (m, 2H), 6.4 (dd, J1=8.95 Hz, J2=1.8 Hz, 1H), 6.48-6.53 (m, 2H), 6.76 (d, J=8.55 Hz, 2H), 6.85 (d, J=8.85 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.23 (d, J=8.55 Hz, 2H), four exchangeable protons.
37. (S)-4-[3-(3-Dodecyl aminopropoxy)-5-fluoro phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.99 (t, J=6.8 Hz, 3H), 1.30-1.47 (m, 18H), 1.54-1.65 (m, 2H), 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 (t, J=6.0 Hz, 2H), 4.30 (dd, J1=10.9 Hz, J2=2.8 Hz, 1H), 4.55 (dd, J1=11.0 Hz, J2=3.25 Hz, 1H) 4.89 (br s, 1H), 6.35-6.42 (m, 3H), 6.5-6.57 (m, 2H), 6.78 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), three exchangeable protons.
38. N-[(R)-4-[3-(2-Dodecyl aminoethoxy)-5-fluoro phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl] formamide (DMSO-d6): d 0.90 (t, J = 6.74 Hz, 3H); 1.23-1.38 (br s, 18H); 1.59-1.68 (br m, 2H); 2.97 (t, J = 7.8 Hz, 2H); 3.3-3.37 (br m, 2H); 4.2-4.3 (br m, 3H); 4.54-4.62 (m, 1H); 5.02 (s, 1H); 6.54-6.68 (m, 3H); 6.74 (d, J= 8.5 Hz, 2H); 7.04-7.1 (m, 2H); 7.16 (d, J = 9 Hz, 3H); 8.22 (s, 1H); 10.1 (s, 1H); three exchangeable protons.
39. (R)-4-{3-[3-(4-Amino butylamino)propyl amino]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 1.8-2.0 (m, 4H), 2.2-2.3 (m, 2H), 3.08 (t, J=7.48 Hz, 2H), 3.17 (t, J=6.96 Hz, 2H), 3.23 (t, J=7.48 Hz, 2H), 3.54-3.6 (br t, 3H), 4.36 (dd, J1=11.04 Hz, J2=2.84 Hz, 1H), 4.6 (dd, J1=11.04 Hz, J2=3.16 Hz, 1H), 6.39 (d, J=2.6 Hz, 1H), 6.43 (dd, J1=8.76 Hz, J2=2.72 Hz, 1H), 6.8 (d, J=8.56 Hz, 2H), 7.03 (d, J=8.68 Hz, 1H), 7.19 (d, J=7.84 Hz, 1H), 7.27 (d, J=8.52 Hz, 2H), 7.36-7.43 (m, 2H), 7.51-7.56 (m, 1H), five exchangeable protons.
40. (R)-4-{3-[3-(4-Dimethyl aminobutylamino)propyl amino]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 1.83-1.97 (m, 4H), 2.19-2.28 (m, 2H), 2.97 (s, 6H), 3.16 (t, J=7.35 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, 2H), 4.33 (dd, J1=10.95 Hz, J2=2.55 Hz, 1H), 4.57 (dd, J1=11.0 Hz, J2=3.05 Hz, 1H), 6.36 (d, J=2.6 Hz, 1H), 6.4 (dd, J1=8.75 Hz, J2=2.65 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.85 Hz, 1H), 7.14 (d, J=6.95 Hz, 1H), 7.24 (d, J=8.55 Hz, 2H), 7.32 (s, 1H), 7.36 (d, J=8.25 Hz, 1H), 7.5 (t, J=8.0 Hz, 1H), one proton merged in CD3OD peak, four exchangeable protons.
41. Dodecyl-(2-{3-fluoro-5-[(R)-6-(4-methoxy phenyl)-6,7-dihydro-1H-8-oxa-1,2,5-triazacyclopenta[b] naphthalene-5-yl] phenoxy}ethyl)amine (DMSO-d6): d 0.91 (t, J = 6.91 Hz, 3H); 1.25-1.35 (br m, 18 H); 1.6-1.68 (br m, 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, J1 =11.06 Hz, J2 = 2.95 Hz, 1H); 4.59 (dd, J1 = 11.01 Hz, J2 =3.3 Hz, 1H); 5.15 (s, 1H); 6.63 (d, J =10.6 Hz, 1H); 6.69(s, 1H); 6.74(d, J = 10.86 Hz, 1H); 6.91(d, J = 8.81 Hz, 2H); 7.88 (s,1H); 8.9 (br s, 2H)
42. (S)-4-{3-Fluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.23-1.42 (m, 16H), 1.56-1.75 (m, 4H), 2.95 (t, J=8.1 Hz, 2H), 3.27-3.35 (m, 2H), 3.76 (s, 3H), 4.18-4.28 (m, 3H), 4.47 (t of d, J1=47.8, J2= 6.1Hz, 2H), 4.64 (dd, J1=11.0, J2= 2.0 Hz, 2H), 5.04-5.10 (br s, 1H), 6.26 (d, J=2.7 Hz, 1H), 6.35 (dd, J1=8.8 Hz, J2=2.6 Hz, 1H), 6.50-6.62 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 8.32-8.80 (br s, 1H), 9.17 (s, 1H).
43. (R)-4–{3-Fluoro-4-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.26-1.4 (br m, 18 H); 1.6-1.72 (br m, 2H); 2.96-3.05 (br m, 2H); 3.32-3.4 (br m, 2H); 3.75 (s, 3H); 4.22 (dd, J1= 11.0Hz, J2 =2.72 Hz, 1H); 4.34 (t, J= 4.96 Hz, 2H); 4.41 (t, J = 3.02 Hz, 1H); 4.45 (d, J = 4.48 Hz, 1H); 4.53 (t, J = 6.1 Hz, 1H ); 4.9 (s,1H); 6.26-6.31 (m, 2H); 6.62 (dd, J1 = 7.44 Hz, J2= 1.72 Hz, 1H); 6.89 (d, J = 8.76 Hz, 2H); 6.96 (d, J = 10.04 Hz, 1H); 7.06 (dd, J1 = 13Hz, J2 = 2.52Hz, 1H); 7.18 (t, J = 9.3 Hz, 1H); 7.3 (d, J = 8.68 Hz, 2H); 9.0-9.1 (br m, 3H). two exchangeable protons.
44. (R)-4-{3,4-Difluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.23-1.42 (m, 16H), 1.58-1.64 (m, 4H), 2.95 (t, J=7.56 Hz, 2H), 3.31 (t, J=4.64 Hz, 2H), 3.7 (s, 3H), 4.16 (dd, J1=11.0 Hz, J2=2.52 Hz, 1H), 4.25-4.35 (br m, 2H), 4.36 (t, J=6.08 Hz, 1H), 4.5-4.58 (m, 2H), 4.99 (br s, 1H), 6.22 (d, J=2.64 Hz, 1H), 6.26 (dd, J1=8.68 Hz, J2=2.64 Hz, 1H), 6.73-6.8 (m, 1H), 6.76 (d, J=8.68 Hz, 2H), 6.85 (d, J=8.76 Hz, 2H), 7.26 (d, J=8.64 Hz, 2H), two exchangeable protons.
45. (R)-4-{3-Fluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.22-1.43 (m, 16H), 1.58-1.76 (m, 4H), 2.93-3.03 (br s, 2H), 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, J2= 6.1Hz, 2H), 4.63 (d, J=8.8 Hz, 1H), 5.05-5.10 (br s, 1H), 6.26 (d, J=2.6 Hz, 1H), 6.36 (dd, J1=8.8 Hz, J2=2.7 Hz, 1H), 6.50-6.63 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 8.65-8.95 (br s, 2H), 9.19 (s, 1H).
46. (R)-4-{3-[2-(Dodecyl methylamino)ethoxy]-5-fluorophenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CDCl3): d 0.87 (t, J = 6.84 Hz, 3H); 1.2-1.3 (br s, 18H); 1.43-1.53 (br m, 2H); 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 Hz, 2H); 4.23 (dd, J1 = 10.8 Hz, J2 = 2.68 Hz, 1H); 4.44 (dd, J1= 10.88 Hz, J2= 3.12 Hz,1H); 4.69 (s, 1H); 6.20 (dd, J1 = 10.32 Hz, J2 = 2.08 Hz, 1H); 6.27 (dd, J1 = 8.72 Hz, J2 = 2.76 Hz, 1H); 6.32 (d, J = 2.72 Hz, 1H); 6.4-6.5 (m, 2H); 6.66 (d, J= 8.6 Hz, 2H); 6.89 (d, J = 8.76 Hz, 1H); 7.09 (d, J = 8.44 Hz, 2H). two exchangeable protons.
47. (R)-4-(3-Fluoro-5-{2-(10-fluorodecyl)methyl amino]ethoxy}phenyl)-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-7-ol (CDCl3): d 1.21-1.31 (br m, 10 H); 1.31-1.41 (br m, 2H); 1.41-1.51 (br m, 2H); 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, 2H); 3.90-3.97 (m, 2H); 4.25 (d, J= 8.12 Hz, 1H); 4.37 (t, J = 6.18 Hz, 1H); 4.43-4.51 (m, 2H); 4.71 (s, 1H); 6.23 (d, J= 10.4 Hz, 1H); 6.30 (dd, J1 = 8.72 Hz, J2 = 2.76 Hz, 1H ); 6.34 (d, J = 2.72 Hz, 1H); 6.41-6.47 (m, 2H); 6.7 (d, J = 8.6 Hz, 2H ); 6.93 (d, J = 8.72 Hz, 1H); 7.12 (d, J = 8.52 Hz, 2H ). two exchangeable protons.
48. (R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino)ethoxy]phenyl}-3-(4-methoxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 1.26-1.43 (m, 12H), 1.57-1.77 (m, 4H), 2.92 (t, J=7.8 Hz, 2H), 3.26-3.3 (br s, 2H), 3.7 (s, 3H), 4.18-4.28 (m, 3H), 4.36 (t, J=6.12 Hz, 1H), 4.48 (t, J=6.12 Hz, 1H), 4.57 (dd, J1=11.16 Hz, J2=2.36 Hz, 1H), 5.02 (br s, 1H), 6.2 (d, J=2.68 Hz, 1H), 6.3 (dd, J1=8.76 Hz, J2=2.68 Hz, 1H), 6.5-6.62 (m, 3H), 6.86 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.76 Hz, 1H), 7.26 (d, J=8.64 Hz, 2H), two exchangeable protons.
49. 4-((R)-5-{3-Fluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b] naphthalene-6-yl)phenol (DMSO-d6): d 1.25-1.34 (br m, 16 H); 1.34-1.48 (br m 4H); 1.6-1.74 (br m, 2H); 2.78 (t, J = 5.54 Hz, 2H); 3.93 (t, J = 5.56Hz, 2H); 4.34-4.43 (m, 2H ); 4.49-4.57 (m, 2H); 5.06 (s, 1H); 6.56 (dd, J1 = 10.84 Hz, J2 = 2.16 Hz, 1H); 6.61-6.67 (br m, 2H); 6.71 (d, J = 8.6 Hz, 2H); 6.94 (s, 1H); 7.19 (d, J = 8.56 Hz, 2H); 7.31 (s, 1H); 7.85(s, 1H); 9.4 (s, 1H); 12.63 (s, 1H). three exchangeable protons.
50. (R)-4-{3,4-Difluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.28-1.43 (br m, 12H), 1.6-1.76 (m, 4H), 3.01 (t, J=7.56 Hz, 2H), 3.37 (t, J=4.8 Hz, 2H), 3.76 (s, 3H), 4.22 (dd, J1=11.0 Hz, J2=2.6 Hz, 1H), 4.26-4.36 (m, 2H), 4.42 (t, J=6.12 Hz, 1H), 4.5-4.58 (m, 2H), 5.02-5.06 (br m, 1H), 6.28 (d, J=2.69 Hz, 1H), 6.32 (dd, J1=8.7 Hz, J2=2.69 Hz, 1H), 6.73-6.8 (m, 1H), 6.82 (d, J=8.68 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.68 Hz, 2H), two exchangeable protons.
51. 4-((R)-5-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-1,5,6,7-tetrahydro-8-oxa-1,2,5-triazacyclopenta[b] naphthalene-6-yl)phenol (DMSO-d6): d 1.28-1.48 (br m, 16H); 1.6-1.74 (br m, 2H); 2.84 (t, J = 5.5 Hz, 2H ); 3.98 (t, J = 5.48 Hz, 2H); 4.34-4.44 (m, 2H); 4.48-4.57 (m, 2H); 5.05 (s, 1H); 6.55 (d, J = 10.88 Hz, 1H); 6.6-6.68 (m, 2H); 6.71 (d, J = 8.52 Hz, 2H); 6.94 (s, 1H); 7.19 (d, J = 8.44 Hz, 2H); 7.31 (s, 1H); 7.85 (s, 1H); 9.4 (s, 1H); 12.63 (s, 1H). three exchangeable protons.
52. (S)-4-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.37-1.43 (m, 12H), 1.58-1.77 (m, 4H), 2.92 (t, J=7.68 Hz, 2H), 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), 4.48 (t, J=6.12 Hz, 1H), 4.57 (dd, J1=11.2 Hz, J2=2.44 Hz, 1H), 4.99-5.03 (br m, 1H), 6.2 (d, J=2.7 Hz, 1H), 6.3 (dd, J1=8.76 Hz, J2=2.72 Hz, 1H), 6.5-6.62 (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, 2H), two exchangeable protons.
53. (R)-4-(3-Fluoro-5-{2-[5-(4,4,5,5,5-pentafluoro pentylamino)pentylamino]ethoxy}phenyl)-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.27-1.37 (m, 2H), 1.38-1.48 (m, 4H), 1.61-1.71 (m, 2H), 2.2-2.37 (m, 2H), 2.45-2.63 (m, merged with DMSO-d6 peak, 6H), 2.84 (t, J=5.48 Hz, 2H), 3.98 (t, J=5.52 Hz, 2H), 4.19 (dd, J1=11.12 Hz, J2=2.8 Hz, 1H), 4.55 (dd, J1=11.04 Hz, J2=2.64 Hz, 1H), 5.0 (br s, 1H), 6.25 (d, J=2.68 Hz, 1H), 6.33 (dd, J1=8.76 Hz, J2=2.72 Hz, 1H), 6.42-6.54 (m, 3H), 6.72 (d, J=8.64 Hz, 2H), 6.96 (d, J=8.76 Hz, 1H), 7.18 (d, J=8.52 Hz, 2H), four exchangeable protons.
54. (S)-4-{3-[2-(10,10-Difluorodecylamino) ethoxy]-5-fluorophenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.29-1.45 ( br m, 12 H); 1.6-1.7 (m, 2H); 1.75-1.92 (m, 2H); 2.97(s, 2H); 3.32 (s, 2H); 3.76 (s, 3H); 4.21(dd, J1 = 11.28Hz, J2 = 2.81Hz, 1H); 4.25 (t, J = 4.76 Hz, 2H); 4.64 (dd, J1 = 11.16 Hz, J2 = 2.4 Hz, 1H); 5.08 (s, 1H); 6.108 ( t of t; J1 = 56.9 Hz, J2 = 4.48 Hz, 1H); 6.26 (d, J =2.7 Hz,1H); 6.36 (dd, J1 = 8.8 Hz, J2 = 2.72 Hz, 1H); 6.5-6.62 (m, 3H); 6.92 (d, J =8.8 Hz, 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).
55. (R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino)ethyl amino]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.2-1.48 (m, 14H), 1.67 (d, J=23.9 Hz, 2H), 2.43-2.65 (br m, merged with solvent peak, 2H), 2.68 (br s, 2H), 3.03 (br s, 2H), 4.16 (d, J=9.65 Hz, 1H), 4.42 (br s, 1H), 4.52 (br s, 2H), 4.88 (br s, 1H), 5.9 (s, 1H), 6.02 (dd, J1=20.15 Hz, J2=11.35 Hz, 2H), 6.21 (d, J=14.45 Hz, 1H), 6.32 (d, J=6.9 Hz, 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), 9.03 (br s, 1H), 9.37 (br s, 1H) two exchangeable protons.
56. (R)-4-{3-Fluoro-4-[2-(10-fluorodecylamino)ethoxy] phenyl}-3-(4-methoxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CDCl3): d 1.2-1.4 (br m, 12H); 1.59-1.72 (m, 2H); 1.8-1.9 (m, 2H); 3.11 (br s, 2H); 3.35 (br s, 2H); 3.73 (s, 3H); 4.20 (dd, J1 = 10.76 Hz, J2 = 2.76 Hz, 1H); 4.29-4.38 (m, 3H); 4.42 (t of d; J1 =47.37 Hz, J2 = 6.16 Hz, 2H); 4.59 (s, 1H); 6.29 (dd, J1 = 8.68 Hz, J2 = 2.4 Hz, 1H); 6.43 (d, J = 2.72 Hz, 1H); 6.62 (d, J = 8.76 Hz, 1H); 6.77 (d, J = 8.72 Hz, 3H); 6.83 (dd, J1 = 3.88 Hz, J2 = 2.44 Hz, 2H); 7.14 (d, J = 8.64 Hz, 2H); 9.4 (s, 2H); one exchangeable proton
57. (R)-4-{3-[2-(10,10-Difluorodecylamino)
ethoxy]-5-fluorophenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.2-1.5 (br m, 12H); 1.6-1.74 (m, 2H); 1.74-1.92 (m, 2H); 2.95 (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 H); 4.63 (d, J = 10.20 Hz, 1H); 5.08 (s, 1H); 6.11 (t, J = 56.66 Hz, 1H); 6.26 (s, 1H); 6.36 (d, J = 8.24 Hz, 1H); 6.56 (t, J = 12.6 Hz, 3H); 6.92 (d, J = 7.84 Hz, 2H); 7.01 (d, J = 8.44 Hz, 1H); 7.32 (d, J = 7.68 Hz, 2H); 9.09 (br s, 2H); 9.23 (s, 1H)
58. (R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino)ethyl amino]phenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.26-1.4 (br m, 12H), 1.54-1.73 (m, 4H), 2.92 (t, J=7.44 Hz, 2H), 3.07 (t, J=6.2 Hz, 2H), 3.29 (t, J=6.28 Hz, 2H), 3.74 (s, 3H), 4.15 (dd, J1=11.12 Hz, J2=2.52 Hz, 1H), 4.4 (t, J=6.08 Hz, 1H), 4.52 (t, J=6.08 Hz, 1H), 4.56 (dd, J1=11.12 Hz, J2=2.64 Hz, 1H), 4.94 (br s, 1H), 6.07-6.17 (m, 2H), 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), 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.
59. (R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino)ethoxy]phenyl}-3-(4-fluoro methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 1.27-1.41 (br m, 12H); 1.6-1.74 (m, 4H); 2.94-3.0 (m, 2H); 3.29-3.37 (m, 2H); 4..21 (d, J = 2.56 Hz, 1H); 4.22-4.28 (m, 2H); 4.48 (t of d, J1 = 47.54 Hz, J2 = 6.11 Hz, 1H); 4,52 (t, J = 6.11 Hz, 1H); 4.67 (dd, J1 = 11.2 Hz, J2 = 2.2 Hz, 1H); 5.14 (s,1H); 5.88 (d, J = 54.7 Hz, 2H); 6.26 (d, J = 2.68 Hz, 1H); 6.37 (dd , J1 = 8.8 Hz, J2 = 2.7 Hz, 1H); 6.53-6.58 (m, 2H); 6.6 (d, 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.
60. (R)-4-{3-Fluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.22-1.42 (br m, 16H), 1.43-1.53 (m, 2H), 1.6-1.73 (m, 2H), 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 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), 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), 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, J=8.45 Hz, 2H), 9.13 (br s, 1H), 9.4 (br s, 1H), one exchangeable proton.
61. (S)-4-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.25-1.42 (br m, 12H), 1.42-1.52 (br m, 2H), 1.5-1.75 (m, 2H), 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 (dd, J1=11.08 Hz, J2=2.76 Hz, 1H), 4.41 (t, J=6.12 Hz, 1H), 4.5-4.6 (m, 2H), 4.99 (br s, 1H), 6.26 (d, J=2.68 Hz, 1H), 6.34 (dd, J1=8.76 Hz, J2=2.68 Hz, 1H), 6.43-6.53 (m, 3H), 6.72 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.76 Hz, 1H), 7.18 (d, J=8.52 Hz, 2H), 9.11 (br s, 1H), 9.38 (br s, 1H), one exchangeable proton.
62. (R)-4-[3-(2-dodecylamino ethoxy)-5-fluorophenyl]-3-(4-fluoromethoxy phenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 0.91 (t, J = 6.82 Hz, 3H); 1.25-1.4 (br m, 18H); 1.6-1.7 (m, 2H); 2.91-3.02 (m, 2H); 3.3-3.35 (m, 2H); 4.21 (d, J = 2.56 Hz, 1H); 4.24 (t, 2.98 Hz, 2H); 4.66 (d, J = 8.96 Hz, 1H); 5.13 (s, 1H); 5.87 (d, J = 54.53 Hz, 2H); 6.26 (d, J = 2.68 Hz, 1H); 6.37 (dd, J1 = 8.76 Hz, J2 = 2.68 Hz, 1H); 6.51-6.63 (m , 3H); 7.01 (d, J = 8.76 Hz, 1H); 7.103 (d, J = 8.72 Hz, 2H); 7.4 (d, J = 8.6 Hz, 2H); 8.84 (s, 2H); 9.19 (s, 1H); two exchangeable protons.
63. (R)-4-{3-Fluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H-benzo [1,4]oxazin-7-ol (DMSO-d6): d 1.26-1.41 (br m, 16H); 1.6-1.75 (m, 4H); 2.92-3.02 (m, 2H); 3.3-3.48 (m, 2H); 4..2-4.28 (m, 3H); 4.48 (t of d, J1 = 41.44 Hz, J2 = 6.21 Hz, 2H); 4.67 (d, J = 8.96 Hz, 1H); 5.13 (s, 1H); 5.88 (d, J = 54.58 Hz, 2H); 6.26 (d, J = 1.84 Hz, 1H); 6.37 (dd, J1 = 8.8 Hz, J2 = 2.7 Hz, 1H); 6.52-6.64 (m, 3H); 7.02 (d , J = 8.76 Hz , 1H); 7.1 (d, J = 8.64 Hz, 2H); 7.4 (d, J = 8.6 Hz, 2H ); 8.82 (s, 2H); 9.21 (s, 1H ); two exchangeable protons.
64. (R)-4-{3-[2-(12,12-Difluorododecylamino) ethoxy]-5-fluorophenyl}-3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.25-1.47 (m, 16H), 1.58-1.60 (m, 2H), 1.73-1.94 (m, 2H), 2.92-3.04 (m, 2H), 3.29-3.37 (m, 2H), 3.76 (s, 3H), 4.14-4.30 (m, 3H), 4.63 (d, J=9.04 Hz, 1H), 5.07 (br s, 1H), 6.10 (t of t, J1=56.9 Hz, J2=4.6 Hz, 1H), 6.26 (d, J=2.6 Hz, 1H), 6.35 (dd, J1=8.8 Hz, J2=2.5 Hz, 1H), 6.47-6.66 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.6 Hz, 2H), 8.7 (br s, 2H), 9.17 (s, 1H).
65. (R)-4-{3-[2-(12,12-Difluorododecylamino) ethoxy]-5-fluorophenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.20-1.54 (m, 18H), 1.73-1.93 (m, 2H), 2.60-2.70 (m, 2H), 2.87-3.00 (m, 2H), 4.02 (t, J=5.6 Hz, 2H), 4.20 (d, J=8.4 Hz, 1H), 4.56 (d, J=8.4 Hz, 1H), 5.0 (br s, 1H), 6.10 (t of t, J1=56.9 Hz, J2=4.5 Hz, 1H), 6.25 (d, J=2.6 Hz, 1H), 6.33 (dd, J1=8.8 Hz, J2=2.7 Hz, 1H), 6.42-6.55 (m, 3H), 6.73 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.7 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 9.11 (S, 1H), 9.39 (S, 1H), one exchangeable proton.
66. 4-((R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-3,4-dihydro-2H-benzo[1,4] oxazin-3-yl)phenol (DMSO-d6): d 1.25-1.45 (br m, 12H), 1.58-1.77 (m, 4H), 2.97 (t, J=7.76 Hz, 2H), 3.3-3.38 (br m, 2H), 4.18-4.26 (br m, 2H), 4.28 (dd, J1=11.0 Hz, J2=2.28 Hz, 1H), 4.42 (t, J=6.08 Hz, 1H), 4.48-4.58 (m, 2H), 5.02 (br s, 1H), 6.61-6.71 (m, 3H), 6.73 (d, J=8.4 Hz, 2H), 6.77-6.89 (m, 3H), 7.07 (d, J=7.68 Hz, 1H), 7.15 (d, J=8.44 Hz, 2H), two exchangeable protons.
67. (R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino)ethoxy]phenyl}-3-phenyl-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.27-1.41 (br m, 12H); 1.6-1.75 (m, 4H); 2.97 (t, J = 7.7 Hz, 2H); 3.3-3.37 (m, 2H); 4.2-4.3 (m, 3H); 4.48 (t of d, J1 = 47.56 Hz, J2 = 6.1 Hz, 2H); 4.68 (d, J = 9.4 Hz, 1H); 5.16 (s, 1H); 6.26 (d, J = 2.6 Hz, 1H); 6.37 (dd , J1 = 8.75 Hz, J2 = 2.5 Hz, 1H); 6.5-6.62 (m, 3H); 7.04 (d , J = 8.8 Hz, 1H); 7.29 (t, J = 7.1 Hz, 1H); 7.34-7.45 (m, 4H); 8.91 (br s, 1H); two exchangeable protons.
68. (10-Fluorodecyl)-{2-[3-fluoro-5-((R)-3-phenyl-2,3-dihydrobenzo[1,4] oxazin-4-yl)phenoxy] ethyl}amine (DMSO-d6): d 1.23-1.43 (m, 12H), 1.53-1.76 (m, 4H), 2.96 (t, J=8.2 Hz, 2H), 3.29-3.48 (m, 2H), 4.22 (br s, 2H), 4.33 (d, J=8.5 Hz, 1H), 4.47 (t of d, J1=47 Hz, J2= 6.1 Hz, 2H), 4.62 (d, J=8.2 Hz, 1H), 5.18 (s, 1H), 6.61-6.76 (m, 3H), 6.79-6.93 (m, 3H), 7.14 (d, J=7.0 Hz, 1H), 7.26-7.43 (m, 5H), three exchangeable protons.
69. (R)-4-{3-Fluoro-4-[2-(10-fluorodecylamino)ethoxy]phenyl}-3-(4-fluoro methoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.28-1.45 (m, 14H); 1.6-1.74 (m, 4H); 3.03 (t, J = 7.64 Hz, 2H); 3.38 (s, 2H); 4.22-4.32 (m, 3H); 4.4-4.5 (m, 2H); 4.52 (t, J = 6.1 Hz, 1H); 4.96 (s, 1H); 5.87 (d, J = 54.5 Hz, 2H); 6.28-6.33 (m, 2H); 6.64 (t, J = 4.72 Hz, 1H); 6.96 (d, J = 8.4 Hz, 1H); 7.06-7.12 (m, 3H); 7.18 (t, J = 9.36, 1H); 7.38 (d, J = 8.64 Hz, 2H); 8.9 (s, 1H); two exchangeable protons.
70. (R)-4-{3-Fluoro-4-[2-(12-fluorododecylamino) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.25-1.4 (br m, 16H), 1.4-1.48 (m, 2H), 1.6-1.73 (m, 2H), 2.58 (t, J=7.08 Hz, merged with peak of solvent, 2H), 2.88 (t, J=5.56 Hz, 2H), 4.05 (t, J=5.68 Hz, 2H), 4.2 (dd, J1=10.8 Hz, J2=2.56 Hz, 1H), 4.33-4.44 (m, 2H), 4.53 (t, J=6.12 Hz, 1H), 4.79 (br s, 1H), 6.23-6.3 (m, 2H), 6.55 (d, J=8.56 Hz, 1H), 6.7 (d, J=8.56 Hz, 2H), 6.86-6.92 (br m, 1H), 6.99 (dd, J1=13.0 Hz, J2=2.44 Hz, 1H), 7.11 (t, J=9.3 Hz, 1H), 7.15 (d, J=8.52 Hz, 2H), 8.94 (s, 1H), 9.37 (s, 1H), one exchangeable proton.
71. (R)-4-{3-Fluoro-5-[2-(8-fluorooctylamino)ethoxy]phenyl}-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 1.27-1.42 (br m, 8H); 1.42-1.53 (m, 2H); 1.6-1.75 (m, 2H); 2.63(t, J = 7.16 Hz, 2H); 2.93 (t, J = 5.2 Hz, 2H); 3.45 (s, 1H); 4.02 (t, J = 5.4 Hz, 2H); 4.2 (dd, J1 = 11.16 Hz, J2= 2.68 Hz, 1H); 4.41 (t, J = 6.1 Hz, 1H); 4.5-4.6 (m, 2H); 4.99 (s, 1 H ); 6.25 (d, J = 2.68 Hz, 1H); 6.34 (dd, J1 =8.76 Hz, J2 = 2.72 Hz, 1H); 6.44-6.53 (m, 3H); 6.73 (d, J = 8.6 Hz, 2H); 6.97 (d, J = 8.76 Hz, 1H); 7.18 (d, J = 8.52 Hz, 2H); 9.11 (s, 1H); 9.39 (s, 1H), three exchangeable protons.
72. (R)-4-{3-Fluoro-5-[2-(4-methylpiperazin-1-yl) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (CD3OD): d 2.26 (s, 3H), 2.35-2.63 (m, 8H), 2.67 (t, J=5.3 Hz, 2H), 3.93 (t, J=5.3 Hz, 2H), 4.13 (dd, J1=11.0 Hz, J2= 2.7 Hz, 1H), 4.37 (dd, J1=11.0 Hz, J2= 3.3 Hz, 1H), 4.71 (br s, 1H), 6.16-6.26 (m, 3H), 6.33-6.40 (m, 2H), 6.60 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.7 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), two exchangeable protons.
73. 4-((R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-7-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl) phenol (DMSO-d6): d 1.22-1.46 (m, 12H), 1.57-1.78 (m, 4H), 2.91-3.04 (m, 2H), 3.30-3.38 (m, 2H), 3.72 (s, 3H), 4.18-4.30 (m, 3H), 4.48 (t of d, J1=47.5, J2= 6.1Hz, 2H), 4.62 (dd, J1=11.0 Hz, J2=2.3 Hz, 1H), 5.01-5.07 (br s, 1H), 6.45 (d, J=2.8 Hz, 1H), 6.50 (dd, J1=8.9 Hz, J2=2.9 Hz, 1H), 6.52-6.66 (m, 3H), 6.74 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 8.83 (br s, 1H), 9.44 (s, 1H), one exchangeable proton.
74. (R)-4-{3-Fluoro-4-[2-(8-fluorooctylamino) ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.3-1.42 (br m, 8H); 1.45-1.55 (m, 2H); 1.6-1.74 (m, 2H); 2.72 (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, J1 = 10.84 Hz, J2= 2.56 Hz, 1H); 4.34-4.44 (m, 2H); 4.53 (t, J = 6.1 Hz, 2H); 4.8 (s, 1H); 6.24-6.3 (m, 2H); 6.55 (d, J = 8.56 Hz, 1H); 6.70 (d, J = 8.56 Hz, 2H); 6.91 (d, J = 8.80 Hz, 1H); 7.01 (dd, J1 = 13.08 Hz, J2 = 2.48 Hz, 1H); 7.10-7.18 (m, 3H); 8.95 (s, 1H); 9.38 (s, 1H), three exchangeable protons.
75. (R)-4-{3-[4-(3,3-Dimethylpyrrolidin-1yl) but-2ynyloxy]-5-fluoro phenyl}-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.96 (s, 6H), 1.5 (t, J=7.0Hz, 2H), 2.34 (s, 2H), 2.61 (t, J=7.0Hz, 2H), 3.3 (s, 2H), 4.14 (dd, J1=10.88Hz, J2 =2.8Hz, 1H), 4.38 (dd, J1=10.88Hz, J2 =3.08Hz, 1H), 4.6 (s, 2H), 4.73 (s, 1H), 6.19 (d, J=2.68Hz, 1H), 6.21-6.28 (m, 2H) 6.37 (t of d, J1=10.96Hz, J2=1.96Hz, 1H), 6.48 (s, 1H), 6.61 (d, J=8.6Hz, 2H), 6.84 (d, J=8.72Hz, 1H), 7.06 (d, J=8.48Hz, 2H), two exchangeable protons.
76. (R)-4-{3-[4-(3, 3-Dimethylpyrrolidin-1yl)-but-2ynyloxy]-5-fluoro phenyl}-3-(4-methoxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (CD3OD): d 0.96 (s, 6H), 1.5 (t, J=6.96Hz, 2H), 2.33 (s, 2H), 2.6 (t, J=6.96Hz, 2H), 3.39 (s, 2H), 3.66 (s, 3H), 4.15 (dd, J1=10.96Hz, J2=2.88Hz, 1H), 4.4 (dd, J1=10.92Hz, J2 =2.96Hz, 1H), 4.6 (s, 2H), 4.78 (merged s, 1H), 6.18 (d, J=2.68Hz, 1H), 6.21-6.28 (m, 2H), 6.37 (t of d, J=11.0Hz, 1H), 6.48 (s, 1H), 6.75 (d, J=8.68Hz, 2H), 6.85 (d, J=8.76Hz, 1H), 7.17 (d, J=8.64Hz, 2H), one exchangeable protons.
77. (R)-4-{4-[4-(3,3-Dimethylpyrrolidin-1-yl)-but-2-ynyloxy]-3-fluoro phenyl}-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 1.08 (s, 6H), 1.61 (t, J=7.0 Hz, 2H), 2.47 (s, 2H), 2.72 (t, J=6.96 Hz, 2H), 3.43 (s, 2H), 4.23 (dd, J1=10.84 Hz, J2=2.8 Hz, 1H), 4.37 (dd, J1=10.96 Hz, J2=4.76 Hz, 1H), 4.67 (t, J=3.56 Hz, 1H), 4.8 (s, 2H), 6.26 (dd, J1=8.72 Hz, J2=2.68 Hz, 1H), 6.31 (d, J=2.64 Hz, 1H), 6.61 (d, J=8.72 Hz, 1H), 6.71 (d, J=8.56 Hz, 2H) 6.72-6.83 (m, 2H), 7.09 (t, J=9.12 Hz, 1H), 7.13 (d, J=8.44 Hz, 2H), three exchangeable protons.
78. (R)-4-{3-Fluoro-5-[2-(3-fluoromethylazetidin-1-yl)ethoxy]phenyl}-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 2.68-2.83 (m, 2H), 3.0-3.1 (m, 2H), 3.3-3.5 (m, merged with solvent peak, 2H), 3.84 (t, J=5.48 Hz, 2H), 4.14 (dd, J1=11.08 Hz, J2=2.56 Hz, 1H), 4.43 (d, J=6.2 Hz, 1H), 4.48 (dd, J1=11.08 Hz, J2=8.48 Hz, 1H), 4.49 (dd, J1=47.61 Hz, J2=6.2 Hz, 2H), 4.94 (br s, 1H), 6.2 (d, J=2.64 Hz, 1H), 6.27 (dd, J1=8.76 Hz, J2=2.64 Hz, 1H), 6.4-6.54 (m, 3H), 6.66 (d, J=8.56 Hz, 2H), 6.9 (d, J=8.76 Hz, 1H), 7.12 (d, J=8.48 Hz, 2H), 9.04 (s, 1H), 9.32 (s, 1H).
79. (R)-4-{3-Fluoro-5-[2-(8-fluorooctylamino)ethoxy]phenyl}-3-(4-fluoro methoxyphenyl)-3, 4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.34 (s, 8H), 1.65-1.69 (br m, 4H), 2.94-2.99 (m, 2H), 3.33-3.4 (m, 2H), 4.2-4.25 (m, 3H), 4.42 (t, J=6.08Hz, 1H), 4.54 ( t, J=6.08Hz, 1H), 4.67 (dd, J1=11.0Hz, J2 =2.28Hz, 1H), 5.13 (s, 1H), 5.8 (s, 1H), 5.95 (s, 1H), 6.26 (d, J=2.68Hz, 1H), 6.37 (dd, J1=8.8Hz, J2 =2.72Hz, 1H), 6.52-6.61 (m, 3H), 7.02 (d, J=8.76Hz, 1H), 7.1 (d, J=8.68Hz, 2H), 7.4(d, J=8.64Hz, 2H), 8.7 (br s, 1H), 9.21 (s, 1H).
80. (R)-4-{3-Fluoro-4-[2-(8-fluorooctylamino) ethoxyphenyl}-3-(4-fluoromethoxy phenyl)-3, 4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.35 (s, 8H), 1.67 (br m, 4H), 3.02 (br s, 2H), 3.4 (merged s, 2H), 4.23 (d, J=8.36Hz, 1H), 4.32(t, 2H), 4.4- 4.46 (br m, 2H), 4.54 (t, J=6.08Hz, 1H), 4.96 (s, 1H), 5.8(s, 1H), 5.93(s, 1H), 6.28-6.3(m, 2H), 6.63-6.65(m, 1H), 6.97(d, J=8.68Hz, 1H), 7.06-7.1(m, 3H), 7.2(t, J=9.2Hz, 1H), 7.38(d, J=8.68Hz, 2H), 8.92(br s, 1H), 9.03(s, 1H).
81. 4-((R)-4-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-7-fluoromethoxy-3,4-dihydro-2H-benzo[1,4] oxazin-3-yl)phenol (DMSO-d6): d 1.2-1.37 (m, 12H); 1.5-1.65 (m, 4H); 2.95 (t, J = 8.0Hz, 2H); 3.3 (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, 2H); 5.54 (d, J = 54.94 Hz, 2H); 6.34-6.4 (m, 1H); 6.45- 6.55 (m, 4H); 6.60 (d, J = 8.56 Hz, 2H); 6.90 (d, J = 9.04 Hz, 1H); 7.04 (d, J= 8.48 Hz, 2H), two exchangeable protons.
82. (10-Fluorodecyl)-(2-{3-fluoro-5-[(R)-7-fluoro methoxy-3-(4-fluoro methoxyphenyl)-2,3-dihydro benzo[1,4] oxazin-4-yl]phenoxy} ethyl)amine (DMSO-d6): d 1.2-1.38 (m, 12H); 1.5-1.67 (m, 4H); 2.95 (t, J = 7.98Hz, 2H); 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 = 6.08 Hz, 2H); 4.47 (d, J1= 11.12 Hz, J2 = 3.08 Hz, 1H); 4.87 (s, 1H); 5.55 (d, J = 54.94 Hz, 2H); 5.61 (d, J = 54.54 Hz, 2H); 6.37-6.42 (m, 1H); 6.48- 6.55 (m, 4H); 6.90-6.98 (m, 3H); 7.22 (d, J= 8.48 Hz, 2H), one exchangeable proton.
83. (R)-4-[3-Fluoro-5-(2-{2-[2-(2-methoxyethoxy) ethoxy]ethoxy}ethoxy) phenyl]-3-(4-hydroxy phenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (D2O): d 3.36 (s, 3H), 3.55-3.59 (m, 2H), 3.62-3.75 (m, 10H), 3.82-3.86 (m, 2H), 4.1-4.15 (m, 2H), 4.25 (dd, J1=11,04 Hz, J2=2.72 Hz, 1H), 4.47 (dd, J1=11.12 Hz, J2=3.4 Hz, 1H), 4.9 (s, 1H), 6.15 (d, J=2.68 Hz, 1H), 6.26 (dd, J1=8.8 Hz, J2=2.72 Hz, 1H), 6.41 (t of d, J1=10.56 Hz, J2=2.08 Hz, 1H), 6.54-6.65 (m, 4H), 6.9 (d, J=8.76 Hz, 1H), 7.11 (d, J=8.56 Hz, 2H), two exchangeable protons.
84. (R)-3-(4-Difluoro methoxyphenyl)-4-{3-fluoro-5-[2-(10-fluoro decylamino)ethoxy] phenyl}-3,4-dihydro-2H-benzo[1,4]oxazin-7-ol (DMSO-d6): d 1.28-1.42 (m, 12H); 1.6-1.75 (m, 4H); 2.92-3.02 (m, 2H); 3.3-3.37 (m, 2H); 4.2-4.38 (m, 3H); 4.47 (t of d, J1 = 47.57 Hz, J2 = 6.08 Hz, 2H); 4.69 (dd, J1 = 11.24 Hz, J2 = 2.04 Hz, 1H); 5.18 (s, 1H); 6.26 (d, J = 2.68 Hz, 1H); 6.38 (dd, J1= 8.8 Hz, J2 = 2.72 Hz, 1H); 6.52 -6.63 (m, 3H); 7.03 (d, J = 8.8 Hz, 1H); 7.18 9 (d, J = 8.68 Hz, 2H); 7.26 (t, J = 74.16 Hz, 1H); 7.46 (d, J = 8.6 Hz, 2H); 8.8 (br s, 2H); 9.24 (s, 1H), two exchangeable protons.
85. 4-{3-Fluoro-5-[2-(10-fluorodecylamino) ethoxy]phenyl}-3-(4-fluoro phenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 1.32 (s, 12H), 1.62-1.69 (br m, 4H), 2.97( s, 2H), 3.33 ( s, 2H), 4.2- 4.25 (m, 3H), 4.42(t, J=6.12Hz, 1H), 4.54 (t, J=6.12Hz, 1H), 4.67 (dd, J1=11.16Hz, J2=2.12Hz, 1H), 5.16(s, 1H), 6.27(d, J=2.68Hz, 1H), 6.38(dd, J1=8.76Hz, J2=2.68Hz, 1H), 6.53-6.61 (br m, 3H), 7.01(d, J=8.76Hz, 1H), 7.2 (t, J=8.84Hz, 2H), 7.42-7.46 (m, 2H), 8.89 ( s, 1H), 9.22 (s, 1H).
86. (R)-4-[3-Fluoro-5-(2-{2-[2-(2-methoxyethoxy) ethoxy]ethylamino} ethoxy)phenyl]-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazin-7-ol (DMSO-d6): d 3.18-3.27 (m, 2H), 3.28 (s, 3H), 3.45-3.5 (m, 2H), 3.54-3.65 (m, 6H), 3.75 (t, J=4.96 Hz, 2H), 4.2 (dd, J1=11.2 Hz, J2=2.8 Hz, 1H), 4.25 (t, J=4.68 Hz, 2H), 4.6 (dd, J1=11.1 Hz, J2=2.44 Hz, 1H), 5.0 (br s, 1H), 6.26 (d, J=2.68 Hz, 1H), 6.35 (dd, J1=8.76 Hz, J2=2.68 Hz, 1H), 6.5-6.61 (m, 3H), 6.74 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.76 Hz, 1H), 7.18 (d, J=8.56 Hz, 2H), 8.9 (br s, 2H), 9.18 (s, 1H), 9.44 (s, 1H), two protons are merged with solvent peak.
87. (R)-4-[3-Fluoro-5-(2-{2-[2-(2-methoxyethoxy) ethoxy]ethylamino} ethoxy)phenyl]-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H-benzo [1,4]oxazin-7-ol (DMSO-d6): d 3.18-3.24 (br m, 2H), 3.28 (s, 3H), 3.35-3.42 (br m, 2H), 3.44-3.5 (m, 2H), 3.53-3.64 (m, 6H), 3.73 (t, J=4.64 Hz, 2H), 4.18-4.28 (m, 3H), 4.63-4.7 (m, 1H), 5.13 (br s, 1H), 5.88 (d, J=54.5 Hz, 2H), 6.26 (d, J=2.6 Hz, 1H), 6.37 (dd, J1=8.8 Hz, J2=2.64 Hz, 1H), 6.51-6.63 (m, 3H), 7.02 (d, J=8.76 Hz, 1H), 7.1 (d, J=8.68 Hz, 2H), 7.4 (d, J=8.6 Hz, 2H), four exchangeable protons.
88. (R)-3-(4-Difluoro methoxyphenyl)-4-[3-fluoro-5-(2-{2-[2-(2-methoxyethoxy)ethoxy] ethylamino}ethoxy)phenyl]-3,4-dihydro-2H-benzo [1,4]oxazin-7-ol (DMSO-d6): d 3.19-3.26 (br m, 2H), 3.28 (s, 3H), 3.45-3.5 (m, 2H), 3.53-3.65 (m, 6H), 3.75 (t, J=4.96 Hz, 2H), 4.2-4.3 (m, 3H), 4.69 (dd, J1=11.2 Hz, J2=2.16 Hz, 1H), 5.18 (br s, 1H), 6.27 (d, J=2.68 Hz, 1H), 6.38 (dd, J1=8.76 Hz, J2=2.68 Hz, 1H), 6.53-6.63 (m, 3H), 7.03 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.64 Hz, 2H), 7.25 (t, J=74.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 8.93 (br s, 2H), 9.23 (s, 1H), two protons are merged with solvent peak.
89. (R)-4-{5-[2-(10-Fluoro decylamino)ethoxy] pyridin-3-yl}-3-(4-fluoromethoxyphenyl)-3,4-dihydro-2H-benzo [1,4]oxazin-7-ol (CD3OD): d 1.2-1.35 (m, 12H), 1.45-1.64 (m, 4H), 2.68 (t, J=7.56 Hz, 2H), 3.02 (t, J=5.12 Hz, 2H), 4.05 (t, J=5.16 Hz, 2H), 4.2 (dd, J1=11.1 Hz, J2=2.88 Hz, 1H), 4.25 (t, J=6.08 Hz, 1H), 4.37 (t, J=6.12 Hz, 1H), 4.43 (dd, J1=11.2 Hz, 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, 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 (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.
90. Dimethyl carbamic acid (R)-3-(4-dimethyl carbamoyloxy phenyl)-4-[3-(2-dodecylamino ethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4] oxazin-7-yl ester (CDCl3): d 0.87 (t, J=7.04, 3H); 1.12-1.35 (br m, 18H); 1.52-1.7 (br s, 2H); 2.90 (t, J=7.84Hz, 2H); 2.98 (s, 6H); 3.06 (d, J=2.20Hz, 6H); 3.16 (br s, 2H); 4.01 (d, J=4.48 Hz, 2H); 4.27 (dd, J1=10.76Hz, J2=2.36Hz, 1H); 4.42 (dd, J1=10.8 Hz, J2=3.4 Hz, 1H); 4.77 (s, 1H); 6.51 (d, J=7.88 Hz, 1H); 6.55 (dd, J1=8.84 Hz, J2=2.64 Hz, 1H); 6.60-6.63 (m,2H); 6.77 (d, J=8.96Hz, 1H); 6.89 (d, J=8.8 Hz,1H);7.00 (d, J=8.52Hz,2H); 7.10 (t, J=8.08Hz, 1H); 7.25 (d, 2H); three exchangeable protons.
91. Carbonic acid (R)-3-(4-tert-butoxycarbonyloxy phenyl)-4-[3-(2-dodecyl aminoethoxy) phenyl]-3,4-dihydro-2H-benzo [1,4]oxazin-7-yl ester tert-butyl ester (CDCl3): d 0.87 (t, 3H); 1.15-1.35 (br s, 18 H); 1.5-1.51 (br s, 18 H); 1.51-1.52 (br m, 2H); 2.92( t, J = 7.75, 2 H); 3.17 (t, J = 4.45 Hz, 2H); 4.03 (br s, 2H); 4.27 (dd, J1 = 10.8 Hz, J2= 2.35 Hz, 1H); 4.43 (dd, J1= 10.85 Hz, J2=3.05 Hz, 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, 1H); 6.654 (s, 1H); 6.69 (d, J = 2.75 Hz, 1H); 6.76 (d, J=8.05 Hz, 1H); 6.93 (d, J=8.9 Hz, 1H); 7.06-7.13 (m, 3H); 7.27 (d, J = 8.5 Hz, 2H); three exchangeable protons.
92. Dodecyl-(2-{3-[(R)-3-(4-methoxyphenyl)-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydrobenzo [1,4]oxazin-4-yl] phenoxy}ethyl)amine (DMSO-d6): d 0.91 (t, J = 7.07 Hz, 3H); 1.29 (s, 12H), 1.31 (s, 18 H), 1.51-1.58 (m, 2H), 2.98 (t, J = 7.91 Hz, 2H), 3.35 (t, J = 4.39 Hz, 2H), 3.75 (s, 3H), 4.18-4.24 (m, 2H); 4.31 (dd, J1 = 10.88 Hz, J2 = 2.57 Hz, 1H); 4.46 (dd, J1 = 10.85 Hz, J2 = 3.03 Hz, 1H), 5.06 (s, 1H), 6.81 (dd, J1 = 8.29 Hz, J2 = 2.08 Hz, 1H); 6.86 (t, J = 2 Hz, 1H); 6.87-6.93 (m, 4H); 7.08 (d, J = 1.40 Hz, 1H); 7.15 (dd, J1 = 8.15 Hz, J2 = 1.41 Hz, 1H); 7.25 (d, J = 8.71 Hz, 2H); 7.35 (t, J = 8.13 Hz, 1H); three exchangeable protons.
93. Carbonic acid ethyl ester-4-((R)-4-{3-fluoro-5-[2-(12-fluorododecylamino) ethoxy]phenyl}-7-hydroxy-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl) phenyl ester (DMSO-d6): d 1.22-1.43 (m, 19H), 1.6-1.75 (m, 4H), 2.9-3.03 (m, 2H), 3.28-3.38 (m, 2H, merged with peak of solvent), 4.2-4.34 (m, 5H), 4.42 (t, J=6.12 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, J=2.48 Hz, 1H), 6.38 (dd, J1=8.68 Hz, J2=2.36 Hz, 1H), 6.52-6.65 (m, 3H), 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 (br s, 2H), 9.22 (s, 1H).

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 1µM in MCF-7 for some of the representative compounds is provided in Table-3 below.

Table-3
Compd. No. % Inhibition at 1µM in MCF-7 Compd. No. % Inhibition at 1µM in MCF-7
2 30.9 27 38.2
3 57.0 30 71.2
4 55.2 32 64.1
5 76.0 36 76.3
8 57.1 72 66.7
14 57.4 75 52.5
15 59.0 76 45.1
19 22.9 77 46.2
20 76.9 78 63.3

,CLAIMS:1. A compound of 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;

A is selected from a group comprising –O-, -NH-, -S-, -N(C1-3alkyl)-, -N(C3-6 cycloalkyl)- or
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(C1-3 alkyl), -N(C1-3 alkyl)2, -CN, -C1-3 haloalkyl, -C1-3 alkyl and -OC1-3 alkyl;

B is hydrogen or a C1-20 linear or branched alkyl chain optionally interrupted with one or more radicals selected from –O-, -NR1-, -S-, -SO-,-S(O)2-, -CR1=CR1-, -C=C-, -NR1CO-, -CONR1-, -NR1CONR1-, NR1C(O)O-, -OC(O)O- 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, R1, at each occurrence, is selected from hydrogen, C3-6 cycloalkyl or C1-6 alkyl;

B can optionally be further substituted with one or more groups selected from halogen, -OR2, -N(R2)2 and –C(O)OC1-6 alkyl wherein, R2, at each occurrence, is a group selected from hydrogen, C1-6 linear, branched and cyclic alkyl;

Y is mono- or di-substitution and is a group selected from -R3, -OR3, halogen, -CN, -NR3COR3, NR3SO2R3, -OC(O)R3, -OC(O)N(R3)2, and –OC(O)OR3; wherein R3, at each occurrence, is a group selected from hydrogen, C1-6 linear, branched or cyclic alkyl and C1-6 linear, branched or cyclic haloalkyl;

L is selected from –O-, -N (C1-6 alkyl)-, -N (C3-6 cycloalkyl)-, -N (C1-6 haloalkyl)-, -N (C3-6 halocycloalkyl)- and -S-;

ring X is a 5 to10 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, -NR4SO2R4, -NR4CHO, -NR4COR4, -OC(O)R4, -OC(O)N(R4)2, -NR4CONR4 and –OC(O)OR4 wherein R4 at each occurrence is hydrogen or C1-6 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 C1-3 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 –O-.

3. The compound of Formula I of claim 1, wherein E is hydrogen, halogen, -C1-3 haloalkyl or -C1-3 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-.

5. The compound of Formula I of claim 1, wherein
ring Z is phenyl;
A is –O-;
E is hydrogen, halogen or -C1-3 haloalkyl;
Y is –OH and attached at 4-position of the phenyl ring;
L is –O-;
X is a phenyl ring substituted with a group selected from hydrogen, and -OH;
B is a C1-15 linear or branched alkyl chain interrupted with one or more radicals selected from –NR1 and -S-; and B is further substituted with one or more halogen.

6. The compound of Formula I as in claim 1, wherein the ring X is selected from a group of
, , , , or wherein ‘]’ indicates points of fusion of the group with rest of the molecule.