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AU766428B2 - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents
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AU766428B2 - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents

Cyclocarbamate derivatives as progesterone receptor modulators Download PDF

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Publication number
AU766428B2
AU766428B2 AU46886/00A AU4688600A AU766428B2 AU 766428 B2 AU766428 B2 AU 766428B2 AU 46886/00 A AU46886/00 A AU 46886/00A AU 4688600 A AU4688600 A AU 4688600A AU 766428 B2 AU766428 B2 AU 766428B2
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Prior art keywords
substituted
alkyl
oxazin
dihydro
benzo
Prior art date
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AU46886/00A
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AU4688600A (en
Inventor
James P. Edwards
Andrew Fensome
Horace Fletcher Iii
Todd K. Jones
Christopher M Tegley
Eugene A. Terefenko
Jay E. Wrobel
Puwen Zhang
Lin Zhi
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Wyeth LLC
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Wyeth LLC
Ligand Pharmaceuticals Inc
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Priority claimed from US09/552,633 external-priority patent/US6509334B1/en
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Assigned to WYETH reassignment WYETH Alteration of Name(s) in Register under S187 Assignors: LIGAND PHARMACEUTICALS, INC., WYETH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

WO 00/66571 PCT/US00/1 1822 CYCLOCARBAMATE DERIVATIVES AS PROGESTERONE RECEPTOR
MODULATORS
Field of the Invention This invention relates to compounds that antagonists of the progesterone receptor, their preparation and utility.
Background of the Invention Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor estrogen receptor androgen receptor (AR), glucocorticoid receptor and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 Al July 4, 1996).
WO 00/66571 PCT/US00/11822 -2- PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N. Y. Acad. Sci., 761, 224, 1995).
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as antagonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Compounds of the prior art are described by Jones, et al, Patent No.
5,688,810) is the PR antagonist dihydroquinoline 1.
N
Me
S
i Me WO 0066571PCTUSOO/1 1822 WO 00/66571 -3- Jones, et al, described the enol ether 2 Patent No. 5,693,646) as a PR ligand.
Jones, et al, described compound 3 Patent No. 5,696,127) as a PR ligand.
Zhi, et at, described lactones 4, 5 and 6 as PR antagonists Med. Chem., 41, 291,1998).
WO 00/66571 PCT/USOO/11822 o 0 Me Me
N
H Me Zhi, et al, described the ether 7 as a PR antagonist Med. Chem., 41, 291, 1998).
Combs, et al., disclosed the amide 8 as a ligand for the PR Med. Chem., 38, 4880,1995).
Perlman, et. al., described the vitamin D analog 9 as a PR ligand (Tet. Letters, 35,2295, 1994).
WO 00/66571 WO 0066571PCT/USOO/1 1822 Hamann, et al, described the PR antagonist 10 (Ann. NY Acad. Sci., 761, 3 83, 1995).
Chen, et al, described the PR antagonist 11 (Chen, et al, P01-37, 1 6 'l Int.
Cong. Het. Chem., Montana, 1997).
Kurihari, et. al., described the PR ligand 12 (J Antibiotics, 50, 360, 1997).
WO 00/66571PC/SO182 PCTIUSOO/1 1822 -6-
H
3 C OH 3
CH
3
A
0
O
12 Nanr et al. (German Patent, DE 3633861, CA 109:22973) claimed that imidazobenzoxazmnones, e.g. A, as cardotonics; Benzoxazin-2-ones, such as brofoxine being active as an anxiolytic was reported by Hartmann et al. (Proc.
West. PharmacoL Soc. 21, 5l 55 (1978)); More recently, a number of patents (e.g.
Young et al. W095/20389; Christ et al. W098/14436) claimed quinazolin-2-ones and benzoxazin-2-ones such as compound CI and C2 as inhibitors of HIV reverse transcriptase.Me e M Me B r e 0 0 N .10 N N H M H WO 00/66571 PCT/US00/11822 -7- The compounds in the present invention contain a pendent aromatic substituent. The aromatic substituents proved to be critical for the resultant compounds being active as progesterone receptor modulators and have broad structural diversity which may consist of aryl, substituted aryl, heteroaryl or substituted heteroaryl group.
Description of the Invention This invention provides compounds of Formula
R
1
R
2 ,0
R
4 R3
I
wherein: R' and R 2 are independent substituents selected from the group of H, C, to C 6 alkyl, substituted C, to C, alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C, alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C, cycloalkyl, substituted C, to Cs cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or
NRBCOR^;
or R' and R 2 are fused to form: a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring; b) an optionally substituted 3 to 8 membered spirocyclic alkenyl; or c) an optionally substituted 3 to 8 membered heterocyclic ring containing one to three heteroatoms from the group including O, S and N; the spirocyclic rings of b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine, C, to C 6 alkyl, C, to C 6 alkoxy, C, to C 6 thioalkyl, -CF 3 -OH, -CN, NH 2 -NH(CI to C 6 alkyl), or to C 6 alkyl) 2 WO 00/66571 PCT/US00/11822 -8- RA is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
C
3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; RB is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl;
R
3 is H, OH, NH 2 C to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, substituted C, to C 6 alkenyl, alkynyl, or substituted alkynyl, CORC; Rc is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
C
3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl;
R
4 is H, halogen, CN, NO 2 CI to C 6 alkyl, substituted C, to C 6 alkyl, alkynyl, or substituted alkynyl, C, to C, alkoxy, substituted C, to C 6 alkoxy, amino, C, to C 6 aminoalkyl, or substituted C, to C, aminoalkyl;
R
5 is selected from a) or b) a) R 5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is taken from the group including halogen, CN, C, to C 3 alkyl, substituted C, to C 3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 thioalkoxy, substituted C, to C 3 thioalkoxy, amino, C, to C 3 aminoalkyl, substituted C, to C 3 aminoalkyl, NO 2 CI to
C
3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CORD, OCORD, or NRECORD; WO 00/66571 PCT/US00/11822 -9- RD is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
C
3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl;
R
E is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl; Y and Z are independent substituents taken from the group including H, halogen, CN, NO 2 amino, aminoalkyl, C, to C 3 alkoxy, C, to C 3 alkyl, or C, to C 3 thioalkoxy; or b) R 5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, NO 2 amino, and C, to C 3 alkyl, C, to C 3 alkoxy, C, to C 3 aminoalkyl, CORF, or NRGCORF; RF is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
C
3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; RG is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl;
R
6 is H or C, to C 3 alkyl; or pharmaceutically acceptable salt thereof.
Preferred compounds of this invention include those of Formula I R R 2
NO
R
4 R3
I
wherein: R' is H, C, to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C, cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRCORA; WO 00/66571 PCT/US00/1 1822
R
2 is H, C, to C 6 alkyl, substituted C, to C 6 alkyl, C 2 to C 6 alkenyl, substituted C, to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C 3 to C, cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRCORA; or R' and R 2 are fused to form spirocyclic alkyl as a 3 to 8 membered spirocyclic ring, substituted spirocyclic alkyl constructed by fusing R' and R 2 to form a 3 to 8 membered spirocyclic ring, spirocyclic alkenyl constructed by fusing R' and R 2 to form a 3 to 8 membered spirocyclic ring, substituted spirocyclic alkenyl constructed by fusing R' and R 2 to form a 3 to 8 membered spirocyclic ring, spirocyclic alkyl constructed by fusing R' and R 2 to form a 3 to 8 membered spirocyclic ring and containing one to three heteroatoms from the group including O, S and N; substituted spirocyclic alkyl constructed by fusing R' and R 2 to form a 3 to 8 membered spirocyclic ring and containing one to three heteroatoms from the group including O, S and N; the spirocyclic rings made by fusing R' and R 2 being optionally substituted by from 1 to 4 groups selected from fluorine, C, to C 6 alkyl, C, to C, alkoxy, C, to C 6 thioalkyl, -CF 3 -OH, -CN, NH,, -NH(C, to C 6 alkyl), or to C 6 alkyl) 2 RA is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
C
3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; RB is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl;
R
3 is H, OH, NH,, C to C, alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, substituted C, to C 6 alkenyl, alkynyl, or substituted alkynyl, CORC; Rc is H, C, to C 4 alkyl, substituted C, to C 4 alkyl, aryl, substituted aryl, C, to
C
4 alkoxy, substituted C, to C 4 alkoxy, C, to C 4 aminoalkyl, or substituted C, to C4 aminoalkyl;
R
4 is H, halogen, CN, NO 2 C, to C 6 alkyl, substituted C, to C, alkyl, Ci to C 6 alkoxy, substituted C, to C 6 alkoxy, amino, C, to C 6 aminoalkyl, or substituted C, to
C
6 aminoalkyl; WO 00/66571 PCT/US00/1 1822 -11
R
5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: X is taken from the group including halogen, CN, Ci to C 3 alkyl, substituted C, to C 3 alkyl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 thioalkoxy, substituted C, to C 3 thioalkoxy, amino, C, to C 3 aminoalkyl, substituted C, to C 3 aminoalkyl, NO 2 C, to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, CORD, OCORD, or NRECORD; RD is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to
C
3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; RE is H, Ci to C 3 alkyl, or substituted C, to C 3 alkyl; Y and Z are independent substituents taken from the group including H, halogen, CN, NO 2
C
1 to C 3 alkoxy, C, to C 3 alkyl, or C, to C 3 thioalkoxy; or
R
5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, NO 2 amino, and C, to C 3 alkyl, or C, to C 3 alkoxy;
R
6 is H, or C, to C 3 alkyl; or pharmaceutically acceptable salt thereof.
Other preferred compounds are those of Formula I WO 00/66571 PCT/US00/11822 -12-
R
1
R
2
O
R
4 I3
R
I
wherein: R' R 2 and are selected from the group which includes C, to C 3 alkyl, substituted C, to C 3 alkyl, spirocyclic alkyl constructed by fusing R' and R 2 to form a 3 to 6 membered spirocyclic ring;
R
3 is H, OH, NH 2 CI to C 6 alkyl, or substituted C, to C, alkyl, CORC; Rc is H, C, to C 4 alkyl, or C, to C 4 alkoxy;
R
4 is H, halogen, CN, NO 2 CI to C 3 alkyl, substituted C, to C 3 alkyl, C, to C 3 alkoxy, or substituted C, to C 3 alkoxy;
R
5 is a disubstituted benzene ring containing the substituents X, and Y as shown below: x 3' 4',
Y-
X is taken from the group including halogen, CN, C, to C3 alkoxy, C, to C 3 alkyl, NO 2 C, to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, C, to C 3 thioalkoxy; Y is a substituent from the group including H, halogen, CN, NO 2 C, to C 3 alkoxy, C, to C 4 alkyl, CI to C 3 thioalkoxy; or
R
5 is a five membered ring with the structure WO 00/66571 PCT/US00/11822 -13-
X,
-r j u U is O, S, or NR 6
R
6 is H, or C, to C 3 alkyl, or C, to C 4
CO
2 alkyl; X' is from the group including halogen, CN, NO 2 or C, to C 3 alkyl and C, to
C
3 alkoxy, provided that when U is NR 6 then X' is not CN; Y' is from the group including H and C, to C 4 alkyl; or
R
5 is a six membered ring with the structure:
XI
X' is N or CX 2
X
2 is halogen, CN, alkoxy, or NO 2 or pharmaceutically acceptable salt thereof Further preferred compounds are those of Formula I
R
1
R
2
RNO
R
4 3
I
wherein: R' R 2 and are selected from the group which includes CH 3 and spirocyclic alkyl constructed by fusing R' and R 2 to form a 6 membered spirocyclic ring
R
3 is H, OH, NH 2
CH
3 substituted methyl, or CORC; WO 00/66571 PCT/USO0/ 1822 -14- Rc is H, C, to C 3 alkyl, or C, to C 4 alkoxy;
R
4 is H, halogen, NO 2 CN, or C, to C, alkyl;
R
5 is a disubstituted benzene ring containing the substituents X and Y as shown below: x 4-
Y--
X is taken from the group including halogen, CN, methoxy, NO 2 or 2thiazole; Y is H or F; or
R
5 is a five membered ring with the structure:
X'
U is O, S, or NH, X' is halogen, CN, or NO 2 provided that when U is NR 6 X' is not CN; Y'is H or C, to C4 alkyl and pharmaceutically acceptable salts.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
PAWPDOCS\CABMSPEC\7639430 AMENDEDDESCRIPTION.d-I 21/3 The term "alkyl" is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to eight carbon atoms, preferably one to six carbon atoms; "alkenyl" is intended to include both straight- and branched-chain alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms; "alkynyl" group is intended to cover both straight- and branched-chain alkyl group with at least one carbon-carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms.
The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl" refer to alkyl, alkenyl, and alkynyl as just described having from one to three substituents selected from the group including halogen, CN, OH, NO 2 amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term "aryl" is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl.
The term "substituted aryl" refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO 2 amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term "heterocyclic" is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The WO 00/66571 PCT/US00/! 1822 -16heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term "substituted heterocyclic" is used herein to describe the heterocyclic just defined having one to four substituents selected from the group which includes halogen, CN, OH, NO 2 amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or substituted alkyl. The term "aryloxy" is used herein to refer to the OR group, where R is aryl or substituted aryl. The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is alkyl or substituted alkyl. The term "alkylcarboxy" is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. The term "aminoalkyl" refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing one to eight carbon atoms, which may be either same or different and the point of attachment is on the nitrogen atom. The term "halogen" refers to Cl, Br, F, or I.
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo.
WO 00/66571 PCT/USOO/1 1822 -17- This invention includes pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier or excipient.
The invention also includes methods of treatment which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above as antagonists of the progesterone receptor.
The progesterone receptor antagonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors.
Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock.
When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about WO 00/66571 PCT/USOO/11822 -18to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hardfilled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
WO 00/66571 PCT/US00/1 1822 -19- The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
The compounds of this invention can be prepared following the Schemes illustrated below: P:\WPDOCSxCAB\sPECI\7639430 AMENDEDDESCRPTIONdm-12/0/03 20 Scheme 1
F
5 RMgBr, THF, rt, N 2 b CDI, THF, 50 degrees C, N 2 bl ArB(OH) 2 Pd(Ph 3
P)
4 Na 2
CO
3
DME/H
2 0, N 2 ,855 degrees C
R
R RR x 7 OH R3 NH 2 2 2 R N'
R
H
2 3
R
R R Ar R N
H
2 4 R R n-BuLi, THF, B(OMe)3 -78 degrees C to rt, N 2
R
H
2
R
Ar ArBr, Pd(Ph 3
P)
4 Na 2
CO
3 7
DME/H
2 0, 85 degrees C, N 2 2 4 As demonstrated in Scheme 1, the compounds of this invention are generally prepared by employing the suitable coupling reaction as a final step. An appropriately substituted orthoamino benzoic acid or its derivatives such as ethyl ester (X Br, 1, Cl, or a latent coupling precursor such as alkoxy group which can be converted into WO 00/66571 PCT/US00/11822 -21- OTf group suitable in the coupling reaction.) was treated with a suitable organo metallic reagent, e.g. Grignard reagent, in appropriate nonprotic solvents which include but not limited to THF or ether to give ortho-amino carbinol 2 under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature. Ring closure of carbinol 2 to yield benzoxazin-2-ones 3 is commonly effected by a condensing agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 OC. The arylation of benzoxazin-2-ones 3 to yield 4 can be effected by various coupling reactions including Suzuki, Stille reactions. These reactions are commonly performed in the presence of transition metallic catalyst, palladium or nickel complex often with phosphino ligands, Ph 3 P, 1,1'bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane or palladium salt such as palladium acetate. Under this catalytic condition, an appropriately substituted nucleophilic reagent, aryl boronic acid, arylstannane, or aryl zinc compound, is coupled with benzoxazinones 3 to give 4. If a base is needed in the reaction, the commonly used bases include but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, potassium acetate, or cesium fluoride. The most commonly used solvents in these reactions include benzene, DMF, isopropanol, toluene, ethanol, DME, ether, acetone or a mixture of any one of these solvent and water. The coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to the boiling point of the solvent or solvent system or mixture.
Benzoxazinones 3 can be converted into a nucleophile such as boronic acid which can be coupled with an appropriate electrophile, aryl bromide or aryl iodide, to yield 4 employing the coupling reaction condition as described above. The transformation of 3 into 5 can be effected by treating 3 with an organo metallic reagent, n-BuLi, in a nonprotic solvent such as THF or ether followed by quenching the reaction solution with a suitable electrophile such as trimethyl borate, P:\WPDOCS\CAB\SPECI7639430 AMENDEDDESCRIPTION.do-12108/03 22 triisopropyl borate, bishexalkyl tin reagent, or zinc chloride at temperatures ranging from-78 OC to reflux temperature under an inert atmosphere such as argon or nitrogen.
Scheme la Rs R5
R
COOR' X
OH
R"OCOX
IR, NHCOOR" R NH 2 RMgBr, THF, rt, N2 6 1 6
R
KOt-C 4
H
9
THF
3 Scheme Ia illustrates an alternative approach leading to the benzoxazinones 3. Thus, an appropriate aniline 1 is protected with a suitable alkoxy carbonyl protective group including but not limited to allyloxy carbonyl, t-butoxy carbonyl, benzoxy carbonyl, ethoxy carbonyl, or methoxy carbonyl in a suitable solvent such as THF, acetonitrile, with or without presence of a base either as a catalyst or as an acid scavenger. The protected aniline is then treated with a suitable organo metallic reagent such as organo lithium agent or Grignard reagent in the same fashion as to prepare compound 2 to give the carbinol 6. The treatment of 6 with a suitable base such as potassium t-butoxide, n-butyl lithium, potassium hydroxide in an appropriate solvent such as toluene, THF, alcohol under an inert atmosphere such as nitrogen or argon at the temperature ranging from room temperature to the boiling point of the relevant solvent to afford benzoxazinones 3.
-7 WO 00/66571 PCTIUSOO/1 1822 -23- Scheme II describes the procedures to prepare benzoxazinones bearing two different substituents at position-4. The Weinreb amide 8 can be prepared from an appropriately substituted isatoic anhydride 7 when treated with Odimethylhydroxyl-amine hydrochloride salt in a protic solvent such as ethanol, isopropanol at reflux under an inert atmosphere such as argon or nitrogen. Coupling of amide 8 with an aryl electrophile such as aryl boronic acid or arylstannane to give 9 can be effected by employing a typical coupling reaction such as Suzuki, Stille coupling procedure in a similar fashion as described for the preparation of benzoxazinones 4. Treatment of Weinreb amide 9 with organo metallic compounds, alkyllithium, alkynyllithium, aryllithium, or their Grignard counterpart in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78 to room temperature affords amino ketone 10. Conversion of ketone to carbinol 11 can be effected by treatment of 10 with an organo metallic reagent such as alkyl, alkynyl, or aryl Grignard compound in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature. Conversion of ketone 10 to carbinol 11 can also be effected by reduction of ketone group of 10 to the carbinol moiety of 11 using an appropriate reducing reagent such as lithium aluminum hydride, sodium borohydride in a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere in the temperature ranging from 0 °C to the boiling point of the solvent. Ring closure of carbinol 11 to produce the compounds of this invention can be accomplished with condensing agents such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 °C.
P:\WPDOCS\CAB\SPECX7639430 AMENDEDDESCRIPTION.d.l2/8/03 Scheme 11 24 o EtOH, MeNHOMe.HCI, reflux All 0
H
7 ArB(OH) 2 Pd(Ph 3
P)
4 Na 2
CO
3
DME/H
2 0, 85 degrees C, N 2
R
6 Li or R 6 MgX, THF, -78 degrees C tort_ 0-
K-
S.
5 5* 0*
R
7 MgX, -78 degrees C to rt, N 2 S. S
S.
S.
CDI or triphosgene, THF, 0Odegrees Cto 65degrees C Ao
H
F 12 Alternatively, ortho-amino ketone 10 can be prepared by treatment of ortho-amino, benzonitrile 14 with an organo metallic compound such as organo, lithium reagent or Gringard reagent in a suitable solvent such as THF or ether under an inert P:NWPDOCS\CAB\SPECI\763943o AMENDEDDESCRIPIONAdo-tIO83 atmosphere such as argon or nitrogen at temperatures ranging from -78 OC to room temperature as illustrated in Scheme III. Benzonitrile 14 can be readily prepared from an appropriately substituted benzonitrile such as bromobenzonitrile 13 using a suitable coupling reaction such as Stille or Suzuki protocol carried out in a similar fashion as described for the preparation of the Weinreb amide 9.
Scheme III
RS
Br CN R3 NH 2 2 13 ArB(OH)2, Na 2 CO3 Pd(0), DMe/H20,N2 2 14 0 *0 .00.
0 so 0 S 00..
.0 S
S.
S@
*SSSS
R
6 Li or R MgX, 0 degrees C
R
3
NH
2 2 Scheme IV depicts an approach to prepare benzoxazinones with a low perfluoroalkyl substituent at position-4, e.g. R 6 is trifluorormethyl group. An appropriately substituted chloroaniline 15 was protected with a suitable protective reagent such as pivaloyl chloride or di-tert-butyl pyrocarbonate to give protected aniline 16 in a suitable solvent such as acetonitrile, acetone, THF, methylene chloride, or a mixture of solvent such as methylene chloride and water under an inert atmosphere such as argon or nitrogen at temperatures ranging from 0 OC to 70 A suitable base such as sodium carbonate, sodium bicarbonate, or potassium carbonate may be needed when the reaction produces an acid as a side-product such as WO 00/66571 PCT/US00/11822 -26hydrochloride. Treatment of 16 with an appropriate alkyllithium such as nbutyllithium or s-butyllithium followed by reaction with a low perfluorocarboxy derivatives, trifluoroacetyl chloride, 1-(trifluoroacetyl)-imidazole, or ethyl trifluoroacetate in a nonprotic solvent such as ether or THF under an inert atmosphere such as argon or nitrogen at -78 "C to ambient temperature gives the protective orthoamino ketones. Subsequent removal of the protecting group can be effected by reaction of protected amino ketones with a suitable acid such as TFA, 3N aqueous hydrochloride solution in a suitable solvent such as methylene chloride or water at 0 °C to boiling point of the solvent to afford ortho-amino ketone 17. The preparation of 6-chlorobenzoxazinones 19 from 17 can be accomplished in the same fashion as described for the synthesis of benzoxazinone 12 from ketone 10. Coupling of 19 with an aryl group to yield the compounds of this invention, 12 as shown in scheme IV can be effected by a nickel complex catalyzed coupling reaction. The palladium catalysts proved not to be an efficient catalyst in this coupling process. The coupling reaction of 19 with an appropriate aryl boronic acid can be accomplished in the presence of a suitable base such as potassium phosphate and a catalyst of nickel (0 or II) complex, e.g. a nickel complex of dppe, dppf, or triphenylphosphine. The most commonly used solvents in the reaction include dioxane or THF. The coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from ambient temperature to 95 oC.
P:%WPDOCSkCABWSEC\7639430 AMENDEDDESCRPTIONdo-12/08103 -27- Scheme IV
R
(CH3)3CCOCI, Na2C 3 1 CHCI,, H20, rt, N2,1
H
2 16 n-BuLi, THF, -78 degrees C toO0 degrees C
R
6 COX, N2 3N HCI, H20, N2, reflux R7Li or R 7 MgX, THF, -78 degrees C to rt pee.
C C CD1 or triphosgene, THF, 0Odegrres Cto 65 degreesC 0 ArB(OH)2, Ni(dppf)C12, K3P0 4 dioxane, 85 degrees C, N2
R
6
R
7
H
19 2 ArR 6
R
7 N' 0
H
12 2
C.
C
C
p
CCC...
As illustrated in Scheme V, the compounds 6 or 12 can be fuirther derivatized at position-i via numerous approaches leading to a variety of novel cyclocarbamnate derivatives including 1 -alkyl, 1-substituted alkyl, 1 -carbonyl, 1-substituted carbonyl, 1 -carboxy, substituted 1 -carboxy derivatives. For examples, alkyl or substituted alkyl derivatives 20 can be formed by treatment of carbamate 12 or 6 with a suitable base P:XWPDOCSXCAB\SPECI\7639430 AMENDEDDESCRIPTION.d-l2/S/03 -28such as sodium hydride in suitable solvent such as DMF under an inert atmosphere such as argon or nitrogen followed by addition of an appropriate electrophile such as alkyl or substituted alkyl bromide, iodide, or triflate. Such a transformation of 12 or 6 at position-1 can also be effected using biphasic conditions as indicated in scheme V in which alkylation is executed using a biphasic catalyst such as tributylammonium bromide in a suitable solvent such as acetonitrile. Another example of this type of modification includes, but is not limited to, the one depicted in scheme V where heating 12 or 6 with triethyl orthoformate affords 1substituted derivatives of compound 12 or 6.
Scheme V Ar R6 R 7 R3' r RK
R
3 HN 2 12 or 6 (R 6
=R
7 RX, NaH, DMF or RX, K 2 C0 3
CH
3
CN,
Bu 4 NBr or CH(OEt) 3 heat SR 6
R
7 R3 N 2 R g Ar R R 7 R N O 2
R'O
CI
C
*0
C.
C.
C e C RCOX, CH3CN, DMAP
CINH
2 NaH, THF, C
*C
C
ft *r WO 00/66571 PCT/US00/11822 -29- The acylation or carboxylation of the compound 12 or 6 at position-1 to give compound 21 can be readily effected by treatment of 12 or 6 with a suitable acylating or carboxylating reagent such as di-t-butyl dicarbonate in the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen. The amination of position-1 of compound 12 or 6 to give 22 can be accomplished using a suitable aminating reagent such as chloroamine in the presence of a suitable base, such as sodium hydride, in a suitable solvent, such as THF or diethyl ether, following literature procedures (Metlesics et al.
J. Org. Chem. 30, 1311(1965).) EXAMPLE 1 2-(2-Amino-5-bromophenyl)propan-2-ol A solution of 2-amino-5-bromobenzoic acid (10g, 46 mmol) in dry THF (200 mL) was treated at -78 °C under nitrogen with a solution of methylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under nitrogen and then poured into a cold 0.5 N aqueous hydrochloride solution (300 mL). The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of solvent in vacuo, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2) to give 2-(2-amino-5bromophenyl)propan-2-ol as off-white solid (6g, mp 62-63 'H-NMR (CDCl1) 8 7.19 1H, J= 2.3 Hz), 7.12 (dd, 1H, J= 8.4, 2.3 Hz), 6.51 1H, J= 8.4 Hz), 4.70 2H), 1.82 1H), 1.65 6H).
EXAMPLE 2 6-Bromo-4,4-dimethyl-1,4-dihydro-benzo 1,3]oxazin-2-one WO 00/66571 PCTZUSO/11822 To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18g, 78 mmol) in dry THF (150 mL) was added 1,1'-carbonyldiimidazole (15.5g, 94 mmol) under nitrogen. The reaction solution was heated at 50 oC overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with IN aqueous hydrochloride solution (2x40 mL), brine mL), and dried with MgSO 4 After removal of solvent in vacuo, 6-bromo-4,4dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199-200 OC; 'H-NMR (DMSO-d 6 8 10.32 1H, D 2 0 exchangeable), 7.48 1H, J= 2.1 Hz), 7.43 (dd, 1H, J= 8.5,2.1 Hz), 6.84 1H, J= 8.4 Hz), 1.61 6H).
EXAMPLE 3 6-Iodo-4,4-dimethyl-1,4-dihydro-benzo[d] [1,3]oxazin-2-one The product was prepared, from 2-amino-5-iodobenzoic acid following the procedures of Example 1 and 2, as a white solid: mp 196-197 'H-NMR (DMSO- 6 10.30 1H, D 2 0 exchangeable), 7.58 2H), 6.71 1H, J= 8.4 Hz), 1.58 (s, 6H). MS (EI) m/z 326 100%). Anal. Calc. For CoHoINO 2 C, 39.63, H, 3.33, N, 4.62. Found: C, 39.25, H, 3.24, N, 4.49.
EXAMPLE 4 (1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane M, 2.4 mL, 24 mmol) at -78 OC under nitrogen. After stirring at -78 OC for minutes, a slurry was obtained and treated with triisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowly warmed to ambient temperature and quenched with IN aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added and organic layer was separated, and aqueous layer was extracted with ethyl acetate (3x60 mL). The combined organic layer was washed with brine and WO 00/6657 1'PTUO112 PCT[USOO/1 1822 -31 dried with MgSO 4 The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate :hexane/2: 1) to afford (1 ,4-dihydro- 4,4-dimethyl-2-oxo-2H-3, l-benzoxazin-6-yl)boronic acid as a white solid (1 .4g, mp 249-250 'H-NMR (DMSO-d 6 8 10.21 111, D 2 0 exchangeable), 7.90-7.95 (br s, 211, D 2 0 exchangeable), 7.67 (in, 2H1), 6.79 1H, J 7.8 Hz), 1.61 611); MS (ESI) m/z 222 87%).
EXAMPLE 6-(3-Chlorophenyl)-4,4-dimethyl-1 ,4-dihydrobenzo [dl 11,31 oxazin-2-one (Procedure A) A mixture of 6-bromo-4,4-dimethyl-1 ,4-dihydro-benzo[d] [1 ,3]oxazin-2-one 5.9 mmol), 3-chlorophenyl boronic acid (1.83g, 11.7 minol), tetrakis(triphenylphosphine)-palladium (0.35g, 0.3 mmol), and sodium carbonate (2.48g, 23.4 mmol) in a mixture of DME and water (40 mL/l0 mL) was degassed to remove the oxygen and then heated at 85 'C under a blanket of nitrogen for 3 hours.
The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (50 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x 15 mL). The combined organic layers were washed with brine and dried with MgSO 4 The solvent was removed in vacuc and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/2: 1) to afford 6-(3chlorophenyl)-4,4-dimethyl- 1,4-dihydrobenzo[d] [1 ,3]oxazin-2-one as a yellowish solid (1.4g, mp 158-159 'H-NMR (DMSO-d,) 8 10.31 1H1, D 2 0 exchangeable), 7.75 1H), 7.61 (in, 3H), 7.46 1H, J= 7.9 Hz), 7.39 (dd, 1H1, J 7.0, 1.1 Hz), 6.96 111, J= 8.6 Hz), 1.68 611); Anal. Caic. For C, 6 H,,ClNO 2 -0.l H,O: C, 66.37, H, 4.94, N, 4.84. Found: C, 66.14, H, 4.61, N, 4.71.
EXAMPLE 6 6-(3-Methoxv-phenyl)-4,4-dimethvl-1 ,4-dihydro-benzo I [1,31- WO 00/66571 WO 0066571PCTIUSO0/1 1822 -32oxazin-2-one Prepared according to Procedure A from 6-bromo-4,4-dimnethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-methoxyphenyl boronic acid. Yellow solid: mp 164-16 5 0 'H-NMR (DMSO0-d 6 8 10.3 111), 7.5 6 (in, 2H), 7.3 6 1 H, J =7.8 9 Hz), 7.20 (mn, 211), 6.96 1lH, J =8.8 8 Hz), 6.9 1 (dd, 1lH, J =8.13, 2.3 5 Hz), 3.8 (s, 3H), 1.7 611); MS (ESI) m/z 284 Anal. Caic. For C 17
H
17 N0 3
C,
72.07, H, 6.05, N, 4.94. Found: C, 70.58, H, 5.73, N, 4.67 EXAMPLE 7 6-(2-Chloro-phenyl)-4,4-dimethyl-1 ,4-dihydro-benzo [dI [1,31oxazin-2-one Prepared according to Procedure A from 6-bromo-4,4-dimnethyl-1,4-dihydrobenzo[d] [1 ,3]oxazin-2-one and 2-chlorophenyl boronic acid. White solid: mp 181- 182 MS (ESI) m/z 288 Anal. Calc. For C 1 6
H
14 C1N0 2 C, 66.79, H, 4.90, N, 4.87. Found: C, 66.78, H, 4.82, N, 4.55 EXAMPLE 8 6-(4-Chloro-phenyl)-4,4-dimethyl-l1,4-dihydro-benzo [dI 11,31oxazin-2-one Prepared according to Procedure A from 6-bromo-4,4-dimethyl-1,4-dihydrobenzo[d][1 ,3]oxazin-2-one and 4-chlorophenyl boronic acid. White solid: mp 255- 257 'H-NMR (DMSO-d 6 6 10.3 1lH), 7.7 211, J =8.52 Hz), 7.55 (in, 211), 211, J 8.52 Hz), 6.96 1H1, J 8.52 Hz), 1.7 611); MS (ESI) m/z 288 Anal. Calc. For C 16 11 1 4 C1N0 2 C, 66.79, H, 4.90, N, 4.87. Found: C, 66.34, H, 4.76, N, 4.75 EXAMPLE 9 6-(3-Chloro-phenyl)-4-methyl-1 ,4-dihydro-benzo [dI [1,31oxazin-2-one To a solution of 1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanone (see example 0.15g, 0.61 ninol) in anhydrous methanol was added sodium borohydride (0.07g, WO 00/66571 WO 0066571PCT/US0011 1822 33 1.03 mmol) at room temperature (rt) under nitrogen. After 15 minutes, the reaction mixture was treated with ice-water. Ethyl acetate (30 mL) was then added, the organic layer was separated, and aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (10 mL) and dried over MgSO 4 After removal of solvent, the residue obtained was crystallized from toluene to afford 1-(4-amino-3 '-chloro-biphenyl-3-yl)-ethanol as a white solid (0.0 87g, 58%): 1 H-NMR (DMSO-d) 8 7.5 5 ILH, J =1.4 Hz), 7.50 I1H, J 7.8 Hz), 7.44 IlH, J= 2.1 Hz), 7.39 1H, J= 8.2 Hz), 7.3 1-7.21 (in, 211), 6.68 111, J= 8.1 Hz), 5.25 2H), 5.20 (in, 111), 4.83 (in, 1H), 1.35 311, J= 8.8 Hz); MS (EI) m/z 247 A mixture of l-(4-amnino-3 '-chloro-biphenyl-3-yl)-ethanol (0.03 g, 0. 13 minol) and triphosgene (0.0 1 g, 0.04 minol) in dry THF (3 mL) was stirred under a blanket of nitrogen for 10 minutes. The solvent was removed to give 6-(3-chloro-phenyl)-4methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid (0.031 g, 9 mp 155-156 'H-NMR (DMSO-d 6 8 10.3 1H1), 7.72 (in, 1H), 7.62 (in, 2H), 7.56 (in, 1H1), 7.47 1H, J= 8.00 Hz), 7.39 1H, J= 8.0 Hz), 6.98 1H, J 8.0 Hz), 5.50 1H, J 6.82 Hz), 1.6 3H, J 6.82 Hz); MS (APCI) m/z 274 100%).
EXAMPLE 6-(3-Chloro-phenyl)-4-ethyl-1,4-dihydro-benzo Id] 11,31 oxazin-2-one Prepared according to the procedure of Example 9 from 1 -amino-3 '-chlorobiphenyl-3-yl)-propanol and triphosgene. White solid: mp 146-148 'H-NMR (DMSO-d 6 6 10.3 111), 7.70 (in, 111), 7.60 (in, 311), 7.47 111, J= 8.22 Hz), 7.39 111, J= 8.28 Hz), 6.97 111, J 8.22 Hz), 5.4 1H, J 10.9 Hz), 1.9 (in, 211), 0.97 311, J= 7.68 Hz); MS (ESI) m/lz 286 100%) EXAMPLE 11 6-(3-Chloro-phenyl)-4-phenyl-1,4-dihydro-benzo [1,31oxazin-2-one WO 00/66571 PCV/US00/1 1822 -34- Prepared from 1-(4-amino-3'-chloro-biphenyl-3-yl)-benzyl alcohol and triphosgene according to the procedure of Example 9. Off-white solid: mp 177-178 'H-NMR (DMSO-d.) 8 10.5 1H), 7.68 (dd, 1H, J= 8.7, 1.7 Hz), 7.62 1H, J 1.74 Hz), 7.54-7.5 1H), 7.48-7.34 8H), 7.04 1H, J= 8.7 Hz), 6.6 1H); MS (ESI) m/z 336 EXAMPLE 12 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] 11,3]oxazin-6-yl)-benzonitrile (Procedure B) A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6yl)boronic acid (2.22g, 10 mmol), 3-bromobenzonitrile (2.18g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.6g, 0.52 mmol), and sodium carbonate (2.2g, 21 mmol) in a mixture of DME and water (70 mL/15 mL) was degassed to remove the oxygen and then heated at 85 °C under a blanket of nitrogen for 3 hours.
The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (20 mL). Ethyl acetate (100 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine and dried with MgSO 4 The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/l:1) to give 3-(4,4-dimethyl-2oxo-l,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as an off-white solid (0.7g, mp 236-237 'H-NMR (DMSO-d§) 8 10.34 1H, D 2 0 exchangeable), 8.21 1H), 8.02 1H, J= 8.1 Hz), 7.79 1H, J= 7.7 Hz), 7.60- 7.70 3H), 6.98 1H, J= 8.2 Hz), 1.71 6H); Anal. Calc. For C 17
H,
4
N
2 0 2 -0.1 HzO: C, 72.89, H, 5.11, N, 10.00. Found: C, 72.75, H, 5.05, N, 9.65.
WO 00/66571PCUS I 12 PCT[USOO/I 1822 35 EXAMPLE 13 4,4-Dimetbyl-6-(3-nitrophenyl)-1,4-dihydrobenzo [i1,31 oxazin-2-one Prepared from 6-iodo-4,4-dimnethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Yellowish solid: mp 244- 245 'H-NMR (DMSOA4) 8 10.38 1H, D 2 0 exchangeable), 8.47 111), 8.14- 8.20 (in, 2H), 7.70-7.76 (in, 3H), 7.01 1 H, J 8.1 Hz), 1.68 6H); MIS (El) mlz 100%). Anal. Caic. For Cl 6
H,
4
N
2 C, 64.42, H, 4.73, N, 9.39. Found: C, 63.93, H, 4.91, N, 8.71.
EXAMPLE 14 6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydroenzold] [1,31oxazin-2-one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxazin-6yl)boronic acid and 1,3-dibromo-5-fluorobenzene following Procedure B. White solid: mp 182-183 1 H-NMR (DMSO-d 6 8 10.36 1H, D.,O exchangeable), 7.78 1H), 7.58-7.65 (in, 3H), 7.49 (dd, 1H, J 8.3, 1.8 Hz), 6.96 111, J 8.5 Hz), 1.69 6H); 9 F-NMR (DMSO-d 6 8 -112.46 (in, IF); MIS (CI) m/z 352 (j7M+H]', 350 Anal. Calc. For C 16
H
13 BrFNO 2 C, 54.88, H, 3.74, N, 4.00. Found: C, 54.83, H, 3.82, N, 3.95.
EXAMPLE 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo IdI fluorobenzonitrile A mixture of 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-2Hbenz[d][l,3]oxazin-2-one (1g, 2.8 minol), zinc cyanide (0.2g, 1.7 iniol), and tetrakis(triphenylphosphine)-palladium (0.2g, 0.17 minol) in dry D~ff (20 mL) was degassed to remove oxygen and then was heated at 85 0 C under a blanket of nitrogen for 6.5 hours. The reaction solution was cooled to room temperature and poured onto a cold saturated aqueous amnmoniuin chloride solution (100 inL). The white precipitate appeared and was collected on a filter. The white solid was washed WO 00/66571 WO 00/657 1PCTUSOO/1 1822 -36with the distilled water (3x20 mL) and dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). The solution was applied on a pad of silica gel and eluted with a mixture of ethyl acetate and hexane After evaporation, 3-(4,4-dimethyl- 2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-5-fluorobenzonitrile was obtained as a white solid (0.7g, mp 253-254 'H-NMR (DMSO-d 6 8 10.4 1H, D 2 0 exchangeable), 8.13 1H), 7.92 (in, 1H), 7.82 (mn, 1H), 7.73 (in, 2H), 6.98 1H, J 8.2 Hz), 1.68 6H); 9 F-NMR (DMSO-d 6 8 112.25 (in, 1iF); MS (El) m/z 296 Anal. Calc. For C 17
H,,FN
2 0 2 C, 68.91, H, 4.42, N, 9.45. Found: C, 68.85, H, 4.58, N, 9.14.
EXAMPLE 16 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzotdI [1,3]oxazin-6-y)-nicotinonitrile Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxazin-6-yl) boronic acid and 3-broino-5-cyanopyridine according to Procedure B. Off-white solid: mp 290-291 'H-NMR (DMS0-l 6 8 10.41 1H, D 2 0 exchangeable), 9.21 1H, J= 2.2 Hz), 8.97 1H, J =1.7 Hz), 8.68 1H, J= 2.1 Hz), 7.76 (in, 2H), 7.01 1H, J =8.2 Hz), 1.70 6H); MS (ESI) m/z 278(M-H, Anal. Calc.
For C 16
H
3
N
3 0 2 0.2 H 2 0: C, 67.94, H, 4.77, N, 14.85. Found: C, 68.04, H, 4.70, N, 14.58.
EXAMPLE 17 4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzoldl [1,31 oxazin-6-yl)-thiophene-2carbonitrile Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxazin-6yl)boronic acid and 4-broino-2-thiophenecarbonitrile according to Procedure B.
Yellowish solid: mp 230-231 'C (decomposed); 'H-NM (CDCl 3 8 8.32 1H, D 2 0 exchangeable), 7.8 3 ILH, J 5 Hz), 7.61 IlH, J =1.4 Hz), 7.43 (dd, 1 H, J= 8.2, 1.9 Hz), 7.29 1H, J= 1.8 Hz), 6.85 1H, J= 8.2 Hz), 1.78 6H); MS (El) WO 00/66571.
PCT/US00/11822 -37ni/z 283(M-H, 100%). Anal. Calc. For CsH, 2
N
2 0 2 S-0.2 H20: C, 62.57, H, 4.34, N, 9.73. Found: C, 62.48, H, 4.31, N, 9.64.
EXAMPLE 18 5-Bromo-2-thiophenecarbonitrile A mixture of 5-bromo-2-thiophenecarboxaldehyde (9 6 .0g, 500 mmol), hydroxylamine hydrochloride (111.9g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31g, 215 mmol), copper (II) acetate monohydrate (4.2g, 21 mmol) in acetonitrile (1.4L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (2X30 mL), water (2X30 mL), brine (20 mL), and dried (MgSO 4 The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1L) and allowed to crystallize. The crystal obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the title compound as an off-white solid (31.5g combined, IR (film) cm-' 2200.
'H-NMR (CDC 3 8 7.39-7.38 1H, J= 4. 1 Hz), 7.10 1H, J= 4.0 Hz); MS (EI) m/z 187 98%) 189(M, 100%).
EXAMPLE 19 5-Bromo-4-methyl-2-thiophene carboxaldehyde To a solution of diethylamine (28g, 0.383 mol) in anhydrous THF (400 mL) was added a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol) in hexane. The solution was then stirred at -40 °C under nitrogen for 30 minutes, cooled to -78 OC and treated dropwise with a solution of 2-bromo-3-methylthiophene (45g, 0.254 mol) in anhydrous THF (450 mL). The reaction solution was stirred at -78 °C for 30 minutes WO 00/66571 WO 0066571PCTIUSOO/1 1822 -38and treated with anhydrous DMF (100 mL). The mixture was allowed to warm to ambient temperature and was quenched with 1N aqueous hydrochloride solution (1L).
The product was extracted with ethyl acetate (3x450 m1L). The extracts were washed with water, brine and dried (MgSO 4 After removal of solvent in vacuc, the title compound was obtained as a white solid (46g, A sample of the product was crystallized from hexane: mp 63-65 IR (KBr) 1654 'H-NMR (CDCI 3 8 9.75 1H1), 7.45 1H1), 2.26 311); MS (EL) m/z 204/206 Anal. Caic. For
C
6
H
5 BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.
EXAMPLE 5-Bromo-4-methyl-2-thiophenecarbonitrile Prepared from 5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure of Example 18. White solid: mp 40-42 IR (KBr) 2200 'H-NNM (CDCl 3 8 7.29 1H), 2.21 311). MS (El) m/z 20 1/203 98%/100%); Anal.
Calc. For CAHBrNS: C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00; H, 2.14; N, 6.76.
EXAMPLE 21 5-(4,4-DimethyI-2-oxo-1, 4-dihydro-2H-benzo [d]l 1,31oxazin-6-yl)-thiophene-2carbonitrile Prepared according to Procedure B from 5-bromo-2-thiophenecarbonitrile and (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid. Off-white solid: mp 264-266 'H4S[1'4 (DMSO-d 6 5 10.3 1H), 7.97 1H1, J =7.9 Hz), 7.60-7.66 (in, 3H1). 6.96 1H, J 8.1 Hz), 1.65 611). MS (APCI) m/z 285 302 (M+NH 4 Anal. Calc. For C,,Hl 2
N
2 0 2 S: C, 63.36; H, 4.25; N, 9.85.
Found: C, 63.01; 11, 4.36; N, 9.39.
EXAMPLE 22 WO 00/66571 WO 0066571PCTIUSOO/1 1822 39 4-DimethyI-2-oxo-1, 4-dihydro-2H-benzo [li,31oxazin-6-yl)-4-methylthiophene-2-carbonitrile Prepared according to Procedure B from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H- 3,1 -benzoxazin-6-yl)boronic acid and 5-bromo-4-methyl-2-thiophenecarbonitrile.
Off-white solid: mp 195-200 'H-NMR (DMSO-d 6 8 10.2 111), 8.32 111), 7.4 1-7.44 (in, 2H), 7.01 11H, J =8.8 Hz), 2.28 3H), 1.64 611); MS (AIPCI) m/z 299 Anal. Caic. For C, 6
H,
4
N
2 0 2 S; C, 64.41; H, 4.75; N, 8.89. Found: C, 64.64; H, 4.62; N, 9.39.
EXAMPLE 23 4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-belzoI [1,31oxazin-6-yl)-furan-2carbonitrile Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1 -benzoxazin-6yl)boronic acid and 4-bromo-2-furancarbonitrile according to Procedure B. Off-white solid: mp 255-256 'H-NMR (DMSO-d 6 8 10.32 111, D 2 0 exchangeable), 8.57 1H), 8.15 111), 7.61 111), 7.55 (dd, 1H,J= 8.3, 1.5 Hz), 6.92 LH, J =8.2 Hz), 1.65 611); MS (ESI) m/z 269(M+H, Anal. Caic. For C 15
H
12 NO,: C, 67.16, H, 4.51, N, 10.44. Found: C, 67.14, H, 4.59, N, 10.07.
EXAMPLE 24 4,4-Diethyl-6-(3-nitrophenyl)-1 ,4-dihydrobenzo [dl 11,3] oxazin-2-one Prepared from 4,4-diethyl-6-iodo-1 ,4-dihydrobenzo[d][1 ,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 193-194 'H-NMR (ODCI,) 8 9.19 111, D 2 0 exchangeable), 8.38 1H, J 1.9 Hz), 8.20 (mn, 111), 7.83 (mn, 111), 7.61 111, J=8.0 Hz), 7.50 (dd, 11H, J 2.0 Hz), 7.23 11H, J 1.7 Hz), 6.99 1 H, J =8.3 Hz), 2.09 4H, J =7.4 Hz), 0.96 (t, 611, J 8.3 Hz); MS (El) m/z 325 100%). Anal. Calc. For C, 8
H
18
N
2
O
4 -0.3 1120: C, 65.17,1H, 5.65, N, 8.44. Found: C, 65.3 1, H, 5.60, N, 8. PAWDOMSCABMSPEC\763943O AMENDEDDESCRIPTIONd-1208/03 EXAMPLE 6-(3-Chlorophenvl)-4,4-diethyl-1,4-dihydrobenzo I 11,31 oxazin-2-one Prepared from 4,4-diethyl-6-iodo- 1,4-dihydrobenzo [1 ,3]oxazin-2-one and 3chiorophenyl boronic acid according to Procedure A. White solid: mp 150-15 1 0 C. 'H-NMR (CDCl 3 6 8.52 1H, D 2 0 exchangeable), 7.50 1H), 7.31-7.44 (in, 4H1), 7.16 1H, J Hz), 6.89 1H, J 8.2 Hz), 2.03 (in, 4H), 0.94 6H, J 7.4 Hz); MS (El) in/z 315(M+, Anal. Caic. For C 18
H
18 C1N0 2 C, 68.46, H, 5.75, N, 4.44. Found: C, 68.16, H, 5.8 1, N, 4.3 2.
EXAMPLE 26 1-(2-Amino-5-bromo-phenyl) cyclohexanol Prepared according to the procedure of Examnple 1 from acid and the Grignard reagent prepared from 1 ,5-dibromopentane. A clear oil: 1
H-NMR
(DMSO-d 6 8 7.07 1H, J 2.3 Hz), 7.03 (dd, 1H, J 8.4, 2.4 Hz), 6.55 1H, J 8.6 Hz), 5.49 2H, D 2 0 exchangeable), 5.00 IIH, D 2 0 exchangeable), 2.01 2H, J 1.8 Hz), 1.66-1.77 (in, 2H), 1.44-1.61 (mn, 4H), 1.16-1.34 (mn, 2H). MS (ESI) m/z 270/272 98%/100%).
*00 o0 EXAMPLE 27 6-Bromo-sviroR1H-3, 1 -benzoxazine-4, 1 -cyclohexanel-2(1 H)-one 0000 sees Prepared from 1-(2-amnino-5-bromo-phenyl) cyclohexanol and carbonyl diiinidazole according to the procedure of Example 2. Off-white solid: mp 208-210 'H-NMR (DMS0-cl 6 6 10.26 1H), 7.45 1H, J 2.2 Hz), 7.39 (dcl, 1H, J 8.2, 2.2 Hz), 6.81 (d, :0000o1H, J= 8.3 Hz), 1.90-1.97 (mn, 2H), 1.80-1.85 (in, 5H), 1.25-1.35 (in, 1H); MS (APC1) m/z 296 68%) EXAMPLE 28 000-: Spiro-(4 1 -cyclohexane-1. 4-dihYdro-2-oxo-2H-3. 1-benzoxazin-6-yi) boronic 0 acid pAWPD0CS\CAB\SPECI\763 9 430 AMEDEDDESRIPTON d-1 5 /08/0 3 -41- Prepared according to the procedure of Example 4 from 6-bromo-spiro[4H-3, 1benzoxazine-4, 1'-cyclohexane]-2-(1H)-ofle. Off-white solid: mp 223-225 'H-NMR (DMSO-d 6 5 10.17 1H, D 2 0 exchangeable), 7.92 2H, D 2 0 exchangeable), 7.67 (S, 111), 7.63 (dd, 111, J 8.0, 1.1 Hz), 6.81 1H, J =7.9 Hz), 1.96(s, 111), 1.93 1H), 1.57- 1.88. (in, 7H), 1.24-1.34 (in, 111); MS (ESI) m/z 262 EXAMPLE 29 6-(3-Chlorophevl-spiro 1 -benzoxazine-4, 1 '-cyclohexanel -2-(1H1)-one Prepared according to Procedure A from 6-bromo-spiro[4H-3,l-belzoxazifle-4,l cyclohexane]-2(1H)-ofle and 3-chiorophenyl boronic acid. Off-white solid: mp 165-168 'C.
'H-NMR (DMSO-d 6 6 10.25 1H), 7.74 lH, J= 1.9 Hz), 7.50-7.67 (mn, 3H), 7.42-7.49 (in, 111), 7.35-7.38 (mn 1H), 6.93-6.95 1H, J =4.2 Hz), 1.91-1.98 (in, 4H), 1.64-1.76 (mn, 3H), 1.60 (in, 211), 1.29-1.39 (in, lH); MS (APCI) m/z 328 EXAMPLE 6-Bromo-spiro-14H- 3 1-benzoxazine-4, 1 '-eccopentanel-2-(1H)-one Prepared according to the procedure of Example 26 and 27 from bromobenzoic acid and the Grignard reagent prepared from 1 ,4-dibromobutane. Off-white ::solid: mnp 180-185 'H-NMR (DMSO-d 6 8 10.29 1H, D 2 0 exchangeable), 7.45 1H1, J 2.2 Hz), 7.41 (dd, 111, J= 8.1, 2.1 Hz), 6.82 1H, J= 8.0 Hz), 1.96-2.09 (in, 411), 1.76- 1.87 (in, 4H1); MS (El) m/z 281 (MW, Anal. Calc. For C 12
HI
2 BrNO 2 C 51.08; H, 4.29; N, 4.96. Found: C, 50.53; H, 4.21; N, 4.85 EXAMPLE 31 6-(3-Chlorophenvl)-spiro-14H-3, 1-benzoxazine-4, 1 -cyclopentanel -2(111)-one Prepared from 6-bromo-spiro-14H-3, l-benzoxazine-4, 1'-cyclopentane]-2-(1H)-one and 3chlorophenyl boronic acid according to Procedure A. Off-white solid: WO 00/66571 WO 00/57 1PUSOO/1 1822 -42 mp 140-145 OC. 'H-NMR (DMSO-d 6 5 10.27 ILH), 7.75 1 H, J= 1. 8 Hz), 7.53 7.63 (in, 3H), 7.44 111, J 7.9 Hz), 7.36 (in, 111), 6.95 1H, J 8.6 Hz), 2.09- 2.15 (mn, 411), 1.81-1.89 (mn, 4H1). MS (ESI) m/z 314 Anal. Calc. For
C,
8
H
16 C1N0 2 C, 68.90; H, 5.14; N, 4.46. Found: C,60.94; H, 4.94; N, 3.78.
EXAMPLE 32 6-(3-Nitrophenyl)-spiro[4H-3,1-benzoxazine-4,1 '-cyclohexanl- 2(111)-one Prepared from 6-bromo-spiro[4H-3, 1-benzoxazine-4, 1'-cyclohexane]-2(l1H)one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 245-246 0 C. 'H-NMR (CDC 3 858.39 1H, J= 1.9 Hz), 8.20 (dd, 1H, J= 8.2, 1.4 Hz), 8.11 1H, D 2 0 exchangeable), 7.86 1H; J 8.0 Hz), 7.62 1H, J 8.1 Hz), 7.50 (dd, 1H, J 1.9 Hz), 7.39 111, J 1.8 Hz), 6.93 111, J 8.2 Hz), 2.25 211, J 12.7 Hz), 1.60-1.99 (mn, 711), 1.3 1-1.42 (in, 111); MS (El) m/z 337 100%). Anal. Calc. For C, 9
H,
8
N
2
O
4 -0.35H 2 O: C, 66.21, H, 5.47, N, 8.13.
Found: C, 66.22, H, 5.43, N, 7.86.
EXAMPLE 33 To a mixture of N, O-dimethylhydroxylamine hydrochloride (9.42g, 96 inmol) and triethyl amine (13.5 inL, 96 mmol) in ethanol and water (100 inL/ 10 mL) was added a solution of 5-broinoisatoic anhydride (20g, 74 minol) in ethanol and water (100 mL/10 mL) at ambient temperature under nitrogen. The reaction mixture was heated at reflux. for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with 1N aqueous sodium hydroxide solution (2x 20 mL), brine (30 mL), and dried with MgSO 4 After removal of the solvent, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3 to give 2-ainino-5-broino-N-methoxy-N-methylbenzamide as an off-white solid (13g, mp 80-8 1 0 C; 'H-NMR (CDCl 3 8 7.49 111, J 2.1 Hz), 7.26 WO 00/66571 PCT/US00/11822 -43- (dd, 1H, J= 8.3, 2.0 Hz), 6.59 1H, J= 8.4 Hz), 4.69 (br, 2H), 3.58 3H), 3.34 (s, 3H); Anal. Calc. For CH,,BrN 2 0 2 C, 41.72, H, 4.28, N, 10.81. Found: C, 41.99, H, 4.16, N, 10.82.
EXAMPLE 34 4-Amino-3'-chloro-biphenyl-3-carbonitrile Prepared from 2-amino-5-bromobenzonitrile and 3-chlorophenyl boronic acid according to procedure A. Off-white solid: mp 118-119 'H-NMR (DMSO-d,) 8 7.80 1H, J= 2.3 Hz), 7.65-7.72 2H), 7.57 1H, J= 8.0 Hz), 7.42 1H, J= 7.9 Hz), 7.31 1H), 6.87 1H, J 8.7 Hz), 6.29 (br, 2H); Anal. Calc. For
C
1 3 11CIN 2 C, 68.28, H, 3.97, N, 12.25. Found: C, 67.68, H, 4.06, N, 11.89.
EXAMPLE 1-(4-Amino-3'-chloro-biphenyl-3-yl)-ethanone A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78g, mmol), 3-chlorophenyl boronic acid (5.63g, 36 mmol), tetrakis(triphenylphosphine)palladium (1.73g, 1.5 mmol), and sodium carbonate (7.63g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and heated at 85 °C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine and dried with MgSO 4 After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-Nmethoxy-N-methylbenzamide as a brown oil (5g, To a solution of this benzamide (5g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at -78 °C under nitrogen.
After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at -78 Ethyl acetate (100 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl WO 00/66571 PCT/US0O/11822 -44acetate (3x20 mL). The combined organic layers were washed (brine) and dried (MgSO 4 After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford 1-(4-amino-3'-chlorobiphenyl-3-yl)-ethanone as a yellow solid (2g, mp 89-90 'H-NMR (CDC1 3 8 7.89 1H, J= 2.0 Hz), 7.51 2H), 7.25-7.40 3H), 6.73 1H, J= 8.6 Hz), 6.38 (br, 2H), 2.65 3H); MS (EI) m/z 268([M+Na] Anal. Calc. For
C,
4
H,
2 C1NO: C, 68.44, H, 4.92, N, 5.70. Found: C, 68.40, H, 4.89, N, 5.61.
EXAMPLE 36 4 -Allyl- 6 -(3-chlorophenyl)-4-methyl-l,4-dihydro-benzo[d [1,3]oxazin-2-one (Procedure C) To a solution of 1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanone (0.2g, 0.82 mmol) in anhydrous THF (10 mL) was added a solution of allylmagnesium bromide in ether (1.0 M, 3 mL, 3 mmol) at 0 oC under nitrogen. The reaction solution was slowly warmed to ambient temperature and stirred under nitrogen for 1 hour. A saturated aqueous ammonium chloride solution (10 mL) was added, followed by addition of ethyl acetate (50 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine and dried with MgSO,. After removal of solvent, the residue was purified by flash chromatography (silica gel, hexane:ethyl acetate/3:1) to afford an amino carbinol intermediate which was used without further purification.
To a solution of above amino carbinol in anhydrous THF was added CDI (0.38g, 2.3 mmol) at ambient temperature under nitrogen. The reaction solution was heated at 55 °C for 12 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, hexane:ethyl acetate/2:1) to yield 4 -allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one as a white solid (130 mg from two steps, mp 128- 129 'H-NMR (CDCI,) 8 8.68 1H, D 2 0 exchangeable), 7.50 1H), 7.44 (dd, 1H, J= 8.2, 1.9 Hz), 7.31-7.40 3H), 7.25 1H, J= 1.6 Hz), 6.92 1H, J= 8.2 WO 00/66571 WO 0066571PCTIUSOO/1 1822 Hz), 5.70-5.85 (nm, 5.17 (in, 2H), 2.76 (in, 2H), 1.79 311); MS (ESI) m/z 314 Anal. Caic. For C 18
H
16 C1N0 2 C, 68.90, H, 5.14, N, 4.46. Found: C, 68.90, H, 5.18, N, 4.43.
EXAMPLE 37 6-(3-Chlorophenyl)-4-methyl-4-propyn-1-yl-1,4-dihydro-benzo [dJ I1,3loxazin-2one Prepared from 1 -(4-amino-3 '-chloro-biphenyl-3 -yl)-ethanone and propynylmagnesium bromide followed by treatment with CDI according to Procedure C.
White solid: mp 184-185 'H-NMR (CDC 3 8 8.18 111, D 2 0 exchangeable), 7.53 11H, J =1.7 Hz), 7.49 1H1), 7.31-7.48 (mn, 4H), 6.92 111, J 8.1 Hz), 2.02 3H), 1.87 3H); MS (ESI) mnk 100%); Anal. Caic. For
C,
8 H,,C1N0 2 C, 69.3 5, H, 4.5 3, N, 4.49. Found: C, 69.19, H, 4.3 7, N, 4.4 1.
EXAMPLE 38 6-(3-Chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzoId]Ii ,31oxazin-2-one Prepared from 1 -(4-amino-3 '-chloro-biphenyl-3-yl)-ethanone (0.2g, 0.82 minol) and ethynylmagnesium bromide followed by treatment with CDI according to procedure C. Off-white solid: mp 185-186 'H-NMR (CDCI 3 8 8.18 1H1, D 2 0 exchangeable), 7.53 1H1, 1.7 Hz), 7.49 1H), 7.3 1-7.48 (in, 411), 6.92 1H, J 8.1 Hz), 2.81 LH), 1.87 311); MIS (ESI) m/z 304 100%); Anal. Caic.
For C 17
H
12 C1N0 2 C, 68.58, H, 4.06, N, 4.7G. Found: C, 68.24, H, 3.94, N, 4.65.
EXAMPLE 39 6-(3-Chlorophenyl)-4-methyl-4-phenyl-1,4-dihydro-benzo I] [1,3]oxazin-2-one Prepared from 1 -(4-ainino-3 '-chloro-biphenyl-3-yl)-ethanone (0.2g, 0.82 minol) and phenylmagnesium bromide followed by treatment with CDI according to Procedure C. White solid: mp 179-180 'Hl-NMR (CDC1 3 8 8.27 111, D 2 0 exchangeable), 7.5 1-7.57 (in, 211), 7.28-7.45 (in, 911), 6.92 1 H, J 8.4 Hz), 2.12 WO 00/66571PCfSO182 PCTIUSOO/I 1822 -46 3H); MIS (ESI) m/z 348 100%); Anal. Caic. For C 2
,H
16 G1N0 2 C, 72. H, 4.6 1, N, 4.00. Found: C, 71.72, H, 4.86, N, 3.9 1.
EXAMPLE 4-Benzyl-6-(3-chloro-phenyl)-4-methyl-1 ,4-dihydro-benzojdI 11,31 oxazin-2-one A mixture of 1 -(4-amino-3'-chloro-biphenyl-3-yl)-1 -benzyl-ethanol (prepared using 1 -(4-amino-3 '-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to Procedure C, 0. 14 g, 0.42 mmol) and triphosgene (0.04 g, 0. 14 mmol) in dry THE (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THE was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chlorophenyl)-4-methyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one (0.045 g, 30%) as an offwhite solid: mp 187-188 'H-NMR (DMSO-d 6 5 10. 1 1 7.70 1LH, J =2.3 Hz), 7.6 1H, J= 8.0 Hz), 7.58-7.53 (in, 2H1), 7.46 1H, J= 8.0 Hz), 7.38 1H, J 8.0 Hz), 7.22-7.17 (in, 3H), 7.06-7.0 (mn, 2H), 6.84 I1H, J 9.14 Hz), 3.24 (d, 1H, J= 14.3 Hz), 3.06 1H, J= 14.3 Hz), 1.68 3H); MIS (ESI) m/z 364 100%); Anal. Calc. For C 22
H
18 C1N0 2 C,72.63; H, 4.99; N, 3.85. Found: C, 71.82; H,5.09; N,3.58.
EXAMPLE 41 6-(3-Chloro-phenyl)-4-cyclopropyl-4-methyl-1,4-dihydro-benzo [1,3J oxazin-2one To a solution of cyclopropylmagnesium bromide in anhydrous THF (prepared using cyclopropyl bromide and magnesium metal, 70 minol) at 52 'C was added under nitrogen 4-amino-3'-chloro-biphenyl-3-carbonitrile (5.2g, 22.7 minol). The reaction mixture was stirred at 52 0 C for 1 hour, cooled to rt, and quenched with 1N aqueous HCl solution (100 mL). Ethyl acetate (100 mL) was added and the aqueous layer was extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine and dried over MgSO 4 The solvent was removed and the residue WO 00/66571 WO 0066571PCTUSO 0/1 1822 -47was purified via silica gel column (hexane:ethyl acetate/20: 1) to give the (4-amino-3 chloro-biphenyl-3-yl)-cyclopropyl-methanone: 'H-NMR (hydrogen chloride salt, DMSO-d 6 5 8.30 1H1, J 2.1 Hz), 7.76 1H, J 1.7 Hz), 7.68-7.63 (in, 211), 7.43 111, J 7.9 Hz), 7.32 (in, 111), 6.88 111, J =8.7 Hz), 4.50 (bs, 311), 3.07 (in, 111), 0.98 (in, 4H); (MS m/z 272/274 To a solution of (4-ainino-3 '-chloro-biphenyl-3-yl)-cyclopropyl-methanone (0.67g, 2.5 minol) in anhydrous THF (10 mL) at -78 'C was added a solution of methylmagnesium. bromide (3.0 M in diethyl ether, 2.5 mL, 7.5 mmol) under nitrogen. The reaction mixture was slowly warmed to if, stirred under nitrogen for 12 hours, and quenched with a saturated aqueous ammonium chloride solution (40 inL).
Ethyl acetate (50 mL) was added, the organic layer was separated, and dried (MgSOj.
After removal of the solvent, the residue was purified via silica gel chromatography (hexane:ethyl acetate/7: 1) to afford 1-(4-amino-3'-chloro-biphenyl-3-yl)-1cyclopropyl-ethanol as yellow oil: MS (El) m/z 287/289 The title compound was prepared from 1-(4-ainino-3'-chloro-biphenyl-3 1 cyclopropyl-ethanol and 1,1 'carbonyldiimidazole according to Procedure C. Offwhite solid: mp 15 8-159 0 C; 'H-NMR (DMSO-d6) 8 10.3 11H), 7.74 111, J 1.71 Hz), 7.67-7.57 (in, 311), 7.47 1H,J= 7.88 Hz), 7.39 1H,J= 8.1 Hz), 6.95 111, J 8.12 Hz), 1.7 311), 1.45 (in, 1H), 0.48 (in, 2H1), 0.28 (in, 211); MS (APCI) m/z 314 100%); Anal. Calc. For C 18 11 16 CIN0 2 C, 6 8.9; H, 5.14; N, 4.46. Found: C, 68.13; H, 5.01; N, 4.36.
EXAMPLE 42 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1-yl-1,4-dihydrobenzoldJ [1,31oxazin-2-one 1 -(4-Ainino-3'-chloro-biphenyl-3-yl)-l1-cyclopropyl-1-propynyl-inethanol was prepared from (4-amino-3 '-chloro-biphenyl-3-yl)-cyclopropyl-methanone and propynylmagnesium bromide according to Example 41.
WO 00/66571PCJS /182 PCTIUSOO/11822 48 A mixture of 1 -(4-amino-3 '-chloro-biphenyl-3-yl)-l1-cyclopropyl-l1-propynylmethanol (0.02 g, 0.064 mmol) and 1,1 '-carbonyldiimidazole (0.0 16 g, 0.096 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the TBff was removed and the residue purified via flash chromatography (silica gel, 40% ethyl acetatelhexane) to give 6-(3-chlorophenyl)-4cyclopropyl-4-prop-1 -ynyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one (0.014 g, 56%) as a light yellow solid: mp 178-179 'H-NM4R (DMSO-d 6 8 10.6 111), 7.68 (in, 2H), 7.64 (bs, 1H), 7.59 1H, J= 7.72 Hz), 7.49 1H, J= 7.82 Hz), 7.42 1H, J 7.95 Hz), 7.02 LH, J 8.0 Hz), 1.86 311), 1.66 (in, 111), 0.82 (in, 1H), 0.66 (mn, 3H); MS (ESI) m/z 336 100%).
EXAMPLE 43 6-(3-Chloro-phenyl)-4,4-dicyclopropyl-1,4-dihydro-benzoldlI [1,31oxazin-2-one (4-Amino-3'-chloro-biphenyl-3-yl)-dicylopropyl-methanol (mp 90-92 MS m/z 314 was prepared from (4-amino-3'-chloro-biphenyl-3-yl)cyclopropyl-methanone and cyclopropylinagnesiumn bromide according to Example 41.
The title compound was prepared according to Example 41 from (4-amino-3chloro-biphenyl-3-yl)-dicylopropyl-methanol and 1,1 '-carbonyldiiinidazole. Yellow solid: mp 198-200 'H-NvlR (DMSO-d 6 5 10.3 1H), 7.72 (bs, lH), 7.67 (bs, LH), 7.62 (mn, 2H), 7.48 1H, J 7.88 Hz), 7.40 1H, J= 8.04 Hz), 6.94 111, J 8.27 Hz), 1.55 (in, 2H), 0.5 (mn, 6H), 0.28 (in, 2H); MS (El) m/z 339 Anal. Calc. For C 20
H,
8 C1N0 2 C, 70.69; H, 5.34 N, 4.12. Found: C, 69.38; H, 5.07; N, 4.02.
EXAMPLE 44 6-(3-Chloro-phenyl)-4,4-dipropyn-1 -yl-l ,4-dihydrobenzo IdI 11,31 oxazin-2-one Following the procedure of Example 41, (4-amino-3'-chloro-biphenyl-3-yl)propynyl-methanone (inp 112-114 MS ESI) m/z 270/272 was WO 00/66571 WO 0066571PCTUSOO/1 1822 -49 treated with propynylmagnesium. bromide to give (4-amino-3'-chloro-biphenyl-3-yl)dipropynyl-methanol which was reacted with 1,1 '-carbonyldiimidazole to afford the title compound. Yellow solid: mp 151 'C (decomposed); 'H-NMR (DMSO-d 6 10.8 7.71 (dd, 1H, J= 8.52, 1.94 Hz), 7.69 (in, 2H), 7.61 1H, J= 7.64 Hz), 7.50 11-, J= 7.85 Hz), 7.43 1H, J1= 7.99 Hz), 7.06 1H1, J= 8.23 Hz), 2.0 (s, 6H); MIS (APC1) m/z 336 EXAMPLE 6-(3-Bromo-5-fluorophenyl)-1 ,4,4-trimethyl-1,4-dihydrobenzo 11,3]oxazin-2one To a solution of 6-(3-bromo-5-fiuorophenyl)-4,4-dimethyl- 1,4dihydrobenzo[d][1,3]oxazin-2-one (0.34g, 0.99 mmol) in dry DMF (10 mL) was added under nitrogen at room temperature sodium hydride (80 mg, 2.0 mmol) in one portion. The mixture was stirred at ambient temperature for 30 minutes, treated with iodomethane (1 mL, excess), and stirred for 2 hours. To the reaction mixture was added a cold saturated ammonium chloride solution (30 mL) and the white precipitate obtained was collected on a filter, washed with the distilled water to afford the title compound as a white solid (0.31g, mp 157-158 'H-NM (DMSO-d 6 6 7.83 LH), 7.76 (dd, 1H, J 8.5, 2.0 Hz), 7.67 (in, 2H), 7.53 (dt, 1H, J 1.9 Hz), 7.18 1H, J 8.5 Hz), 3.33 3H), 1.67 6H); 9 F-NMR (DMSO-d6) 8 1 11.0 1 (in, 11F); MS (APCI) m/z 364 366 100%).
EXAMPLE 46 1-(2-Amino-5-chloro-phenyl)-2,2,2-trifluoro-ethanone To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (6.7g, mmol) in anhydrous THIF (100 mL) under nitrogen at 0 'C was added a solution of n- BuLi (2.5M, 30 mL, 70 mmol) in hexane in a dropwise fashion. After addition, the solution was kept stirring at 0 'C for 40 minutes and treated with a solution of I (trifiuoroacetyl)imidazole (9 m1L, 78 minol) in anhydrous THF (10 mL). The reaction WO 00/66571 PCT/US00/1 1822 mixture was warmed to ambient temperature and kept for 18 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (50 mL) followed by addition of ethyl acetate (100 mL). The organic layer was separated and the solvent was removed in vacuo. The residue obtained was suspended in 3N aqueous hydrochloride solution (50 mL) and heated at reflux overnight. The reaction solution was cooled to room temperature and treated with a cold ammonium hydroxide solution to a pH above 8. The aqueous mixture was extracted with ethyl acetate (3x50 mL) and the organic layers were washed with brine and dried (MgSO 4 After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1) to afford the title compound as a yellow solid (Ig, mp 93-94 'H-NMR (CDC13) 8 7.70 1H), 7.33 (dd, 1H, J= 9.0, 2.3 Hz), 6.70 1H, J= 9.1 Hz), 6.45 (bs, 2H); MS (ESI) m/z 222(M-H, 100%), 224(M-H, 33%).
EXAMPLE 47 6-Chloro-4-methyl-4-trifluoromethyl-l,4-dihydro-benzo[d] [1,3]oxazin-2-one Prepared from 1-(2-amino-5-chloro-phenyl)-2, 2, 2-trifluoro-ethanone by addition of methylmagnesium bromide followed by treatment of the resultant carbinol with 1,1'-carbonyldiimidazole according to the procedure of Example 2. White solid: mp 216-216 OC; 'H-NMR (DMSO-d 6 8 10.91 (bs, 1H, D 2 0 exchangeable), 7.64 (d, 1H, J= 1.6 Hz), 7.49 (dd, 1H, J= 8.6, 2.3 Hz), 6.95 1H, J= 8.6 Hz), 1.91 3H); 9 F-NMR (DMSO-d6) 8 -82.0 1F); MS (EI) m/z 264 100%), 266 Anal. Calc. For CoH 7
CIF
3 NO: C, 45.22, H, 2.66, N, 5.27. Found: C, 45.32, H, 2.77, N, 4.83.
EXAMPLE 48 6-(3-Methoxyphenyl)-4-methyl-4-trifluoromethyl-l,4-dihydrobenzo[d][1,3]oxazin-2-one A mixture of 6-chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.2g, 0.75 mmol), 3-methoxyphenyl boronic acid (0.13g, 0.9 mmol), PAWPDOCS\CARMSPECI\7639430 AMENDEDDESCRIPTIONdo-I12/O03 -51 potassium phosphate (0.23g, 1.1 mmol), and nickel (II) (diphenylphosphino)ferrocenyl dichloride (52 mg, 0.076 mmol) in anhydrous dioxane was subject to a blanket of nitrogen to remove oxygen and heated at 95 OC under nitrogen for 48 hours. Another portion of 3methoxyphenyl boronic acid (0.13g, 0.9 mmol) and nickel (II) (diphenylphosphino)ferrocenyl dichloride (52 mg, 0.076 mmol) was added and the reaction solution was heated at 95 °C under nitrogen for 48 hours. The reaction solution was cooled to room temperature.
Saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layer was washed with brine and dried (MgSO 4 After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/4:1) to afford the title compound as a white solid (50 mg, mp 178- 179 'H-NMR (DMSO-d 6 8 10.85 (bs, 1H, D 2 0 exchangeable), 7.73 2H), 7.38 (t, 1H, J= 7.9 Hz), 7.23 1H, J= 7.7 Hz), 7.19 1H, J= 1.9 Hz), 7.02 1H, J= 8.2 Hz), 6.94 (dd, 1H, J= 8.2, 2.4 Hz), 3.88 3H), 1.98 3H); 9 F-NMR (DMSO-d 6 6 -81.88 (s, 1F); Anal. Calc. For C 17
HI
4
F
3 NO3: C, 60.54, H, 4.18, N, 4.15. Found: C, 60.58, H, 4.44, N, 4.19.
EXAMPLE 49 7-(3-Methoxy-phenyl)-4,4-dimethyl-l,4-dihydro-benzo[dlI1,31-oxazin-2-one A mixture of 7-chloro-4,4'-dimethylbenzoxazin-2-one (0.197 g, 0.93 mmol), 3methoxyphenyl boronic acid (0.21 g, 1.4 mmol), Ni(dppf)C1 2 (0.095 g, 0.14 mmol), and S potassium phosphate (0.59 g, 2.79 mmol) in dioxane (10 mL) was subject to a blanket of nitrogen for 15 minutes at 50 °C and then was heated at 95 oC for 48 hours. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organics were washed twice with aqueous ammonium chloride (30 mL), once with brine mL), and dried over magnesium sulfate. The residue was purified via flash chromatography (silica gel, 40% ethyl acetate/hexane) to give 7-(3-methoxy-phenyl)-4,4-dimethyl-1,4- S dihydro-benzo[d][1,3]oxazin-2-one (0.090 g, 35%) as a *eg o*o* WO 00/66571 WO 0066571PCTIUSOO/I 1822 52 clear oil. The oil was triturated with ether (25 ml) to furnish a white solid: mp 167- 168 'H-NMR (DMSO-d 6 8 10.3 1H), 7.42-7.28 (in, 3H), 7.14 1 H, J= 8.11 Hz), 7.11 (bs, 2H), 6.96 (dd, lH, J= 8.11 Hz), 3.56 3HW, 1.52 6H); MS (El) m/z 283 Anal. Caic. For C 1 7
H,
7 N0 3 C, 72.07, H, 6.05, N, 4.94. Found: C, 71.59, H, 6.08, N, 4.79.
EXAMPLE 6-(3-Acetyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzoldI 11,31 oxazin-2-one 3 -(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)benzonitrile (0.25 g, 0.9 mmol) was dissolved in THE (10 mL) and cooled to 0 To this solution, methylmagnesium bromide (3.0 M in ether, 1.8 mL, 5.4 mmol) was added and the reaction mixture was heated to refiux. under nitrogen. Upon completion of the reaction, the reaction mixture was quenched with 1 N aqueous HCI solution after cooled to rt. The mixture was extracted with ethyl acetate (100 mE), dried over MgSO 4 and concentrated. Purification of the residue obtained via chromatography (silica gel, 50% ethyl acetate! hexane) gave 6-(3-acetyl-phenyl)-4,4-dimethyl-1 ,4dihydro-benzo[d][1,3]oxazin-2-one as a white solid (0.03 1 g, mp 178-179 'C; 1 H-NMIR(CDCl 3 5 8.15 1H, J=1.71 Hz), 8.04 1H), 7.95 (dt, 1H, J =8.85, 1.13 Hz), 7.76 (dt, 1H, J= 7.90, 1.43 Hz), 7.57 LH, J= 7.72 Hz), 7.52 (dd, 1H, J= 8.28, 2.11 Hz), 7.39 1H, J= 1.81 Hz), 6.93 1H, J= 8.19 Hz), 2.69 3H), 1.81 (s, 6H); MS (El) m/z 295 4 EXAMPLE 51 6-(3-Benzoyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzoldI 11,31oxazin-2-one Prepared from 3 -(4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6yl)benzonitrile and phenylmagnesiumn bromide according to the procedure of Example A white solid: mp 156-157 0 C;'H-NMR (DMS0-l 6 5 10.33 1H), 8,0-7.96 (in, WO 00/66571 WO 0066571PCTfUSOO/I 1822 53 2H), 7.80 (in, 2H), 7.73-7.56 (in, 7H), 6.99 1 H, J 8.06 Hz), 1.67 61-1); MS (El) m/z 357 Anal. Caic. For C2H,,N0 3 C, 77.29, H, 5.36, N, 3.92 Found: C, 75.7, H, 5.28, N, 3.86 EXAMEPLE 52 4,4-Dimethyl-6-[3-(lH-tetrazol-5-yl)-phenylj -1,4-dihydrobenzo IdI 11,31 oxazin-2one A mixture of 3 -(4,4-dimethyl-2-oxo-1 ,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6yl)benzonitrile (0.77 g, 2.8 mmol), trimethylsilyl azide (0.68 g, 5.6 mmol), and dibutyl tin oxide (0.071 g, 0.28 mmol) in dioxane (20 mL) was heated at reflux under a blanket of nitrogen. Upon completion of the reaction, the dioxane was removed, the organics taken up in ethyl acetate (100 mL), and washed with NaHCO 3 (100 mL).
The aqueous layer was acidified with 1 N aqueous HCI and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO,, and concentrated.
Crystallization from ether (20 mL) gave 4,4-dimethyl-6-[3-(LH-tetrazol-5-yl)-phenyl]- 1 ,4-dihydrobenzo[d][1,3]-oxazin-2-one as a light yellow solid (0.23 g, mp 238- 240 'H-NMR (DMSO-d 6 6 10.4 1 8.3 (bs, 1 8.02 1 H, J 7.66 Hz), 7.9 lH, J 7.91 Hz), 7.72-7.65 (in, 3H), 7.03 1H, J= 8.75 Hz), 1.70 6m); MS (ESI) m/lz 320 100%); Anal. Caic. For C,,H, 5
N
5 0 2 C, 63.54, H, 4.71, N, 21.79. Found: C, 62.16, H, 4.67, N, 21.3 1.
EXAMPLE 53 4-(4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [dIl 1,31oxazin-6-yl)-thiophene- 2-carbonitrile 4-Dicyclopropyl- 1,4-dihydro-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid was prepared from 2-amino-5-bromobenzoic acid according to Example 1, 2, and 4.
A white solid: mp 240-242 'H-NM (DMSO-d 6 8 10.13 1H), 8.01 2H), 7.85 111), 7.64 1H, J= 7.9 Hz), 6.77 1H, J= 7.9 Hz), 1.38 (in, 2H), 0.52 (in, 2H), 0.39 (in, 4H), 0.22 (in, 2H).
WO 00/66571 WO 0066571PCTUSOO/I 1822 54 The title compound was prepared according to Procedure B from (4,4dicyclopropyl- 1,4-dihydro-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid and 4-bromo- 2-thiophene carbonitrile. A white solid: mp 244-245 'H-NM (DMSO-d 6 10.25 1H), 8.49 1H, J= 0.87 Hz), 8.33 114), 7.74 1H, J= 1.44 Hz), 7.67 (dd, 1H, J 8.28, 1.54 Hz), 6.90 111, J =8.28 Hz), 1.53 (in, 211, 0.59-0.41 (in, 614, 0.31-0.24 (in, 2H); MS (ESI) m/z 335 100%); Anal. Calc. For
C
19
H,
6
N
2 0 2 S: C, 67.84, H, 4.79, N, 8.33. Found: C, 64.92, H, 4.66, N, 7.7 1.
EXAMPLE 54 6-(3-Bromo-5-fluoro-phenyl)-4,4-dicyclopropyl-1,4-dihydrobenzo-[dl 11,31 oxazin- 2-one Prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2oxo-2H-3,l-benzoxazin-6-yl)boronic acid and 1 ,3-dibromo-5-fluorobenzene. A white solid: mp 228-229 'H-NMR (DMSO-d 6 5 10.3 1H), 7.76-7.72 (in, 2H), 7.65 (dd, IIH, J= 8.32, 1.74 Hz), 7.60 1H, J= 10.36 Hz), 7.51 1H, J= 8.3 Hz), 6.93 1H, J 8.31 Hz), 1.63-1.54 (in, 2H), 0.58-0.41 (mn, 6H), 0.30-0.28 (in, 2H); MS (APCI) m/z 402/404 Anal. Caic. For C 20
HI
7 BrFNO 2 C, 58.48, H, 4.17, N, 3.41. Found: C, 58.77, H, 4.23, N, 3.32.
EXAMPLE 4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo IdI 1,3]oxazin-6-yl)-5-fluorobenzonitrile A mixture of 6-(3-broino-5-fluoro-phenyl)-4,4-dicyclopropyl- 1,4-dihydrobenzo-[d][1,3]oxazin-2-one (0.4 g, 1.0 mniol), Zn(CN) 2 (0.71 g, 0.61 inmol), and tetrakis(triphenylphosphine)-palladiuin (0.07 g, 0.06 mmol) in DMF (20 mL) was subject to a blanket of nitrogen for 15 minutes at 50 'C and then was heated at 85 'C for 1 hour. After cooling to room temperature, the reaction mixture was poured into
NII
4 CI (100 mL) and extracted with ethyl acetate (3x50 mL). The organic layers were washed with brine, dried over MgSO 4 and concentrated. The clear oil obtained was P:\WPDOCS\CAEI\SPECI\7639430 AMENDEDDESCRJPITIONd-1208/03 55 triturated with ether (30 ml) to give a white solid. Recrystallization of the solid from ethyl acetate gave 3 -(4,4-dicyclopropyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-5 -fluorobenzonitrile (0.016 g, mp 250-252 0 C; 1 H-NMR (DMSO-d 6 8 10.3 1H), 8.12 (s, lH), 7.97 1H, J 10.54 Hz), 7.81-7.79 (in, 2H), 7.73 (dd, 1H, J 8.3, 1.59 Hz), 6.94 (d, 1H, J 8.34 Hz), 1.59 (in, 2H), 0.58-0.42 (in, 6H), 0.30-0.28 (in, 2H); MS (ESI) m/z 347 100%); Anal. Cale. For C 21
H
17
FN
2 0 2 C, 72.4, H, 4.92, N, 8.04 Found: C, 72.4, H, 4.74, N, 7.61 EXAMPLE 56 6-(3-Bromo-5-methyl-phenyl)-4,4-dimethyl-1 .4-dihydrobenzo-[I [1131 oxazin-2one Prepared from (4,4-dimethyl- 1,4-dihydro-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid and 3,5-dibromotoluene according to Procedure B. White solid: mp 23 1-233 'H-NMR (DMSO-d 6 8 10.4 1H), 7.66 1H), 7.58-7.56 (mn, 2H), 7.50 1H), 7.37 1H), 6.95 1H, J 8.67 Hz), 2.37 3H), 1.67 6H); MS (ESI) m/z 344/346 (EM-Hf-, 100%); Anal. Calc. For C 17
H
16 BrNO 2 C, 58.98, H, 4.66, N, 4.05. Found: C, 58.82, H, 4.62, N, 3.94.
EXAMPLE 57 6-(3-Bromo-5-trifluoromethoxy-Dhenyl)-4,4-dimethyl-1 .4-dihydrobenzo I [1 31oxazin-2-one Prepared from 4-dimethyl- 1,4-dihydro-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid and 1, 3-dibromo-5-trifluoroinethoxybenzene according to Procedure B. White solid: mp 2 14-216 I'H-NMR (DMSO-1 6 8 10.4 1H), 7.99 1H), 7.73 lH), 7.68-7.62 (in, 3H), 6.97 1H, J= 8.0 Hz), 1.68 6H); MS (ESI) m/z 414 (QM 100%); Anal. Calc.
For C 17 Hl 3 BrF 3
NO
3 C, 49.06, H, 3.15, N, 3.37. Found: C, 49.16, H, 3.05, N, 3.30.
WO 00/66571 WO 0066571PCTIUSOO/I 1822 -56- EXAMPLE 58 3-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzoldl I1,3]oxazin-6-yl)-5-methylbenzonitrile Prepared from 6-(3 -bromo-5-methyl-phenyl)-4,4-dimethyl- 1,4-dihydrobenzo- ,3]oxazin-2-one according to the procedure of example 55. White solid: mp 256-258 'H-NMR (DMS0-l 6 8 10.4 IH), 7.99 1H), 7.86 1H), 7.67-7.62 (in, 3H), 6.97 1H, J =8.11 Hz), 2.42 3H), 1.68 6H); MS (APCI) m/z 293 100%); Anal. Caic. For C,,H, 6
N
2 C, 73.96, H, 5.52, N, 9.58. Found: C, 73.26, H, 5.46, N, 9.24.
EXAMPLE 59 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [dl I1,3]oxazin-6-yl)-5trifluoromethoxy-beuzonitrile Prepared from 6-(3-bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl- 1,4dihydrobenzolld]Lj,3]oxazin-2-one according to the procedure of example 55. White solid: mp 227-228 0 C; 'H-NMR (DMSO-d 6 )8610.4 1H), 8.32 1H), 8.09 1H), 7.97 1Hi), 7.75-7.72 (in, 3H), 6.99(d, 1H, J =8.11 Hz), 1.7 6H); MS (APCI) m/z 363 Anal. Calc. For C, 8
H
13
F
3
N
2 0 3 C, 59.67, H, 3.62, N, 7.73.
Found: C, 59.63, H, 3.55, N, 7.58.
EXAMPLE 6-(3,5-difluoro-phenyl)-4,4-dimethyl-1,4-dihydrobelzo-[I I1,3]oxazin-2-one Prepared according to procedure B from (4,4-dimethyl- 1,4-dihydro-2-oxo-2H- 3,l-benzoxazin-6-yl)boronic acid and 1-bromo-3,5-difluorobenzene. A white solid: mp 218-219 0 C; 'H-NMR (DMSO-d 6 8 10.4 1H), 7.67-7.65 (mn, 2H), 7.49 2H, J 7.73 Hz), 7.19 IlH, J =9.29 Hz), 6.96 I1H, J 8.88 Hz), 1.7 6H); MS (APCI) m/lz 290 100%); Anal. Caic. For C 16
H
13
F
2 N0 2 C, 66.43, H, 4.53, N, 4.84. Found: C, 66.01, H, 4.46, N, 4.67.
WO 00/66571 WO 00/657 1PCT/USOO/I 1822 57 EXAMPLE 61 6-(3,5-dichloro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-d [1,3loxazin-2-one Prepared from 6-bromo-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one and 3,5-dichiorophenyl boronic acid according to Procedure A. A white solid: mp 245-246 'H-NMR (DMSO-d 6 5 10.4 1H), 7.77 (in, 2H), 7.67-7.64 (mn, 2H), 7.56 (bs, 1H), 6.96 1lH, J =7.98 Hz), 1.7 6H); MS (El) m/z 321 Anal. Caic. For C 1 6
H
13 C1 2 N0 2 C, 59.32, H, 4.11, N, 4.32. Found: C, 59.13, H, 4.29, N, 4.17.
EXAMPLE 62 6-(3,5-Bis-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzoldI [1,31oxazin- 2-one Prepared from 6-broino-4,4-dimnethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one and bis-trifluoromethyiphenyl boronic acid according to Procedure A. A white solid: mp 25 8-260 'H-NMR (DMSO-d 6 8 10.4 1H), 8.35 2H), 8.05 lH), 7.79- 7.76 (in, 2H), 7.01 1H, J= 8.01 Hz), 1.7 6H); MS (ESI) m/z 390 Anal. Calc. For C,,H 13
F
6 N0 2 C, 55.54, H, 3.37, N, 3.6. Found: C, 55.5, H, 3.54, N, 3.47.
EXAMPLE 63 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo IdI 11,31 beuzonitrile A mixture of (4,4-diinethyl- 1 ,4-dihydro-2-oxo-2H-3, 1 -benzoxazin-6yl)boronic acid (4.2 g, 19.0 nimol), 3-cyano-5-methoxyphenyltriflate (5.1 g, 19.0 mmol), tetrakis(triphenylphosphine)-palladium (1.1 g, 0.95 mmnol), sodium carbonate (4.0 g, 38.0 ninol), and lithium bromide (5 g, 57 inmol) in DME (50 inL) and water (25 mL) was subject to a blanket of nitrogen for 15 minutes at 50 TC and then was heated at 85 TC for 1 hour. The reaction was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layers were washed twice with WO 00/66571 WO 0066571PCTIUSOO/1 1822 58 aqueous ammonium chloride (100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated. Purification via chromatography (silica gel, ethyl acetate! hexane) gave 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2Hbenzo[d][1 ,3]oxazin-6-yl)-5-methoxy-benzonitrile as a white solid (0.69 g, mp 254-255 'H-NMZR (DMSO-d 6 8 10.4 1H), 7.84 IH), 7.67-7.61 (in, 2H1), 7.55 (bs, IH), 7.4 (bs 111) 6.99 1H, J =7.94 Hz), 3.88 3H1), 1.67 6H, MS (El) m/z 308 Anal. Cai~c. For C, 8
H,
6
N
2 0 3 C, 68.13, H, 5.40, N, 8.83. Found: C, 68.03, H, 5.22, N, 8.46.
EXAMPLE 64 6-(3-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzoldI 11,3]oxazin-2-one Prepared from 6-bromo-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one 1-bromo-3-fluorobenzene according to Procedure A. A light yellow solid: mp 181- 182 0 C; 1 H-NMR (DMSO-d 6 8 10.4 1 7.62-7.44 (in, 5H), 7.16 1 H, J =2.22 Hz), 6.97 I1H, J 1.67 6H); MS (El) m/z 271 Anal.
Caic. For Cl 6
H
14 FN0 2 C, 69.91, H, 5.3, N, 5.1. Found: C, 70.0, H, 5.32, N, 4.92.
EXAMPLE 6-(3-Chloro-4-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzoldl 1,3loxazin-2one Prepared from 6-bromo-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one and 1 -bromo-3-chloro-4-fluorobenzene according to Procedure A. White solid: mp 21 1-212 0 C; 1 H-NMR (DMSO-d 6 5 10.4 1H), 7.92 (dd, LH, J =7.13, 2.19 Hz), 7.71-7.66 (mn, ILH), 7.60-7.57 (mn, 2H), 7.49 I1H, J= 8.95 Hz), 6.96 1LH, J =8.01 Hz), 1.67 6H); MS (El) mn/z 305 Anal. Cai~c. For C, 6
H,
3 C1FN0 2 C, 62.86, H, 4.29, N, 4.58. Found: C, 62.52, H, 4.45, N, 4.42.
EXAMPLE 66 WO 00/66571 WO 0066571PCTIUSOO/1 1822 -59- 3-(l-Diethoxymethyl-4,4-dimethyl-2-oxo-1 ,4-dihydro-211-benzo [dJ [1,3Joxazin-6- A mixture of 3-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzo[d] [1 ,3]oxazin- 6y1)-5-fluoro-benzonitrile (0.25 g, 0.84 mmol) and triethylorthoformate (50 mL) was heated at 160 TC for 12 hours. The excess triethylorthoformate was removed in vacuo and purification via chromatography (silica gel, 20% ethyl acetate/hexane) gave 3 diethoxymethyl-4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d][ 1,3]oxazin-6-yl)-5fluoro-benzonitrile (0.116 g, 33%) as a white solid: mp 123-124 0 C; 'H-NMR (DMS0-l 6 5 7.97 1H, J =8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (in, 2H), 7.35-7.32 (mn, 2H), 6.65 1H), 3.88-3.78 (mn, 2H), 3.73-3.61 (in, 2H), 1.77 6H), 1.27 6H, J 7.05 Hz); MS (ESI) m/z 295 100%, lower MW ion consistent with loss of diethyl acetal); Anal. Calc. For C,,H,,FN 2 0 4 C, 66.32, H, 5.82, N, 7.03. Found: C, 65.89, H, 5.92, N, 6.66.
EXAMPLE 67 3-Fluoro-5-(l-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2Hbenzo Id] I1,31oxazin-6-yl)-benzonitrile A solution of 3 ,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1,3 ]oxazin-6- (0.150 g, 0.51 mmol) in DMIF (5 mL) was treated at rt with sodium hydride (0.061 g, 1.53 inmol). The mixture was stirred for 30 minutes and treated with chioromethyl inethylether (0.062 g, 7.7 mnmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3x30 mL), dried over MgSO 4 and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give (1 -iethoxymethyl-4,4-diinethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)benzonitrile as a white solid 11 g, mp 169-171 'H-NMR (DMSO-d 6 8 8.17 (bs, 1H), 8.03 (dt, 1H, J 10.4, 2.13 Hz), 7.85-7.77 (in, 3H), 7.31 1H, J 8.49 Hz), 5.33 2H), 3.35 3H), 1.7 6H); MS (APCD) m/z 341 H' WO 00/66571 WO 0066571PCTUSOO/I 1822 Anal. Caic. For C,,H,,FN 2 0 3 C, 65.32, H, 5.19, N, 8.02. Found: C, 64.92, H, 4.96, N, 7.73.
EXAMPLE 68 Phosphoric acid 6-(3-cyano-5-fluoro-phenyl)-4,4-dimethyl-4Hbeuzoldi I1,3joxazin-2-yI ester diethyl ether To a solution of 3-(4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1,3 ]oxazmn- (0.25 g, 0.84 mmol) in DM1F (5 mL) was added sodium hydride (60% in oil, 0.101 g, 2.53 mmol). After stirred for 30 minutes, the reaction mixture was treated with diethyl chiorophosphate (0.22 mL, 1.52 mmol). Upon completion of the reaction, the reaction solution was quenched with water (25 mL) and the product extracted with ethyl acetate (2x50 mL), dried over MgSO 4 and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give phosphoric acid 6-(3-cyano-5-fluoro-phenyl)-4,4-dimethyl- 4H-benzo[d][1 ,3]oxazin-2-yl ester diethyl. ether as a white solid (0.064 g, mnp 196-198 'H-NMR (DMS0-l 6 8 8.19 (bs, 111), 8.05 I H, J= 10.4 Hz), 7.9-7.8 (in, 3H), 7.51 1H1, J =8.41 Hz), 4.33-4.41 (in, 4H1), 1.76 6H1), 1.27 6H, J 7.05 Hz); MS (APCI) m/z 433 Anal. Calc. For C 2
,H
22
FN
2 0 5 P: C, 58.33, H, 5.13, N, 6.48. Found: C, 58.1,1H, 5.11, N, 6.25.
EXAMPLE 69 3-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzof dI 11,3loxazin-6-yl)-4-fluorobeuzonitrile Prepared from 4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1 -benzoxin-6yl)boronic acid and 5-bromo-2-fluorobenzonitrile according to Procedure B. White solid: mp 229-230 0 C; 1 H-NM~ (DMSO-1 6 5 10.4 111), 8.15 (dd, 1 H, J 7.3 9, 2.12 Hz), 7.95-7.89 (in, 111), 7.59-7.48 (in, 3H1), 6.99 1H, J= 8.1 Hz), 1.7 6H1); MS (APCI) n/z 297 100%); Anal. Caic. For C,,H 13
FN
2 0 2 C, 68.91, H, 4.42, N, 9.45. Found: C, 68.74,1, 4.83, N, 9.10.
WO 00/6657 1PCUS /182 PCTIUSOO/I 1822 -61- EXAMPLE 8-Fluoro-4,4-dimethyl-dihydro-benzold] [1,3loxazin-2-one N-Qtert-Butoxycarbonylamino)-3-fluorobenzoic acid (Takagishi et al. Synlett 4, 360-2 (1992); mp 159-161 was deprotected using trifluoroacetic acid to give oamino benzoic acid which was treated with methylmagnesium bromide to afford oamino dimethyl carbinol. The o-amino dimethyl carbinol (2.23 g, 13.2 mmol) was treated with 1,1 '-carbonyldiimidizole (2.8 g, 17.2 mmol) in THE (20 mL) at 50 0 C for 12 hours. Upon completion of reaction, it was cooled to rt and ethyl acetate (100 mL) added. The organic layer was washed with 10% aqueous HCl solution (2x25 mL), dried over MgSO 4 and concentrated. The residue was purified via chromatography (silica gel, 10% ethyl acetate/hexane) to give 8-fluoro-4,4-dimethyl-dihydrobenzo[d][1,3]oxazin-2-one as a white solid (1.3 g, mp 127-128 0
'H-NMR
(DMSO-d 6 5 10.4 1H), 7.22-7. 12 (in, 2H), 7.07-7.00 (mn, 2H), 1.6 6H); MS (APCI) m/z 196 100%); Anal. Calc. For CXH 1 FN0 2 C, 61.53, H, 5.16, N, 7.18. Found: C, 61.27, H, 5.37, N, 7.02.
EXAMPLE 71 6-(3-Chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzotdI 11,31oxazin-2-one To a solution of 8-fluoro-4,4-dimethyl-dihydro-benzo[d] [1 ,3]oxazin-2-one (0.1 5g, 0.77 inmol) in acetic acid (5 mL) was added dropwise a solution of bromine (0.3 7g, 2.31 mmol) in acetic acid (5 mL) under nitrogen at rt. After stirred for minutes, the mixture was concentrated and the residue obtained was purified by a silica gel column (hexane:ethyl acetate/4: 1) to afford 6-bromo-8-fluoro-4,4-dimethyldihydro-benzo[d][1 ,3]oxazin-2-one as an off-white solid 176g, 84%) which was used in next step without further purification.
A mixture of 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo ld] [1,3 ]oxazin-2one 176 g, 0.64 inmol), 4-fluoro-3-chlorophenyl boronic acid 15 g, 0.84 mmol), WO 00/66571 WO 0066571PCT[USOO/I 1822 62 tetrakis(triphenylphosphine)-palladium (0.04 g, 0.032 mniol), and sodium carbonate (0.20 g, 1.92 mmol) in DME (10 miL) and water (5 mL) was subject to a blanket of nitrogen for 15 minutes at 50 'C and then was heated at 85 'C for 1 hour.
The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (100 niL) and once with brine (100 niL), dried over magnesium sulfate and concentrated.
The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give6-(3-chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl- 1,4-dihydrobenzo[d] oxazin-2-one as a white solid 13 g, nip 246-248 'H-NMR (DMSO-d 6 10.5 1H), 8.00 (dd, 1H, J 7.09, 2.32 Hz), 7.78-7.73 (in, 1H), 7.62 (dd, 1H, J 11.86, 1.77 Hz), 7.7 2H, J 9 Hz), 1.7 6H); MS (APCI) m/lz 324 100%); Anal. Calc. For C ,H,,F 2 N0, 0.5 H 2 0 C, 5 7.76, H, 3.94, N, 4.2 1. Found: C, 57.49, H, 3.69, N, 4.03.
EXAMPLE 72 6-(3-Bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[dJ 1,3J oxazin-2-one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, I -benzoxin-6-yl)boronic acid and 1 ,3-dibromobenzene according to procedure B. A white solid: mp 174-175 0 C; 'H-NMIR (DMSO-d 6 6 10.35 1H), 7.88 (bs, 1 7.68 1LH, J= 7.5 Hz), 7.6- 7.51 (in, 3H), 7.4 1H, J= 7.5 Hz), 6.97 1H, J= 8-:57 Hz), 1.64 6H); MS (El) m/z Anal. Calc. For Cl 6
H
1 4 BrNO 2 C, 57.85, H, 4.25, N, 4.22. Found: C, 57.7, H, 4.36, N, 4.09.
EXAMPLE 73 4,4-Dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1 ,4-dihydrobenzoidj [1,3Joxazin-2-one A mixture of 6-(3 -bromo-phenyl)-4,4-diinethyl- 1,4-dihydrobenzo[d][l ,3]oxazin-2-one (0.8g, 2.4 nimol), trimethylsilylacetylene (1g, 10 nimol), WO 00/66571 PCT/US00/11822 -63tetrakis(triphenylphosphine) palladium (0.17g, 0.24 mmol), and cuprous iodide (0.05g, .28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80 OC for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCI (3x 20 mL) and brine 20 mL). The organic layer was separated and dried (MgSO 4 After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77g, 92%): mp 240-242 'H-NMR (DMSO-d 6 8 10.3 1H), 7.74-7.69 2H), 7.61-7.58 (m, 2H), 7.48-7.40 2H), 6.96 1H, J= 7.98 Hz), 1.67 6H), 0.25 9H); MS (EI) m/z Anal. Calc. For C 21
H
23
NO
2 Si0.2 EtOAc: C, 71.32, H, 6.75, N, 3.82. Found: C, 71.08, H, 6.64, N, 3.82.
EXAMPLE 74 6-(3-Ethynyl-phenyl)-4,4-dimethyl-l,4-dihydro-benzod] 11,3]oxazin-2-one A mixture of 4,4-dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydrobenzo[d][l,3]oxazin-2-one (0.7g, 2 mmol) and potassium carbonate (2g, excess) in anhydrous methanol was stirred at rt under nitrogen for 4 hours. The mixture was treated with ice-water (100 mL) and extracted with ethyl acetate (2x80 mL). The organic layers were washed with brine and dried with MgSO 4 The solvent was removed and the title compound was obtained as a off-white solid (0.4g, mp 171-172 'H-NMR (DMSO-d6) 8 10.3, 1H), 7.78 (bs, 1H), 7.72-7.69 1H), 7.6-7.57 2H), 7.49-7.43 2H), 6.97 1H, J= 7.98 Hz), 4.25 1H), 1.67 (s, 6H); MS (EI) m/z 100%); Anal. Calc. For C,,H,,NO2;0.2 EtOAc: C, 76.56, H, 5.67, N, 4.75. Found: C, 76.34, H, 5.4, N, 4.7.
EXAMPLE 3-[3-(4,4-Dimethyl-2-oxo-l,4-dihydro-2H-benzo[d [1,3]oxazin-6-yl)-phenyllpropynenitrile WO 00/66571 WO 0066571PCTIUSOO/I 1822 -64- To a stirred mixture of DMS0, acetonitrile and water (9 mL/3 mL/O.5 mL) was added at rt under nitrogen cuprous cyanide (0.1 93g, 2.2 mmol), sodium iodide (11 mg, 0.072 mmol), and 6-(3-ethynyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.2 g, 0.72 mmol). Chiorotrimethylsilane was then added to the above mixture in a dropwise manner. After addition, the mixture was heated at 'C for 72 hours. The reaction mixture was then cooled to rt and treated with 0.5 N aqueous HC1 cold solution (50 mL). The precipitate obtained was collected on a filter and washed with water. The solid was purified on a silica gel column (hexane: ethyl acetate/2: 1) to give the title compound as an off-white solid (10 mg, 4.6 mp 212- 213 'H-NMiR (CHCl 3 -d 6 8 7.96 1 7.77 1 7.65 1 H, J =7.8 Hz), 7.60 1H, J= 7.69 Hz), 7.51 1H, J= 7.77 Hz), 7.45 (dd, 1H, J= 8.67, 2.21 Hz), 7.31 1H, J 1.55 Hz), 6.91 1H, J 8.19 Hz), 1.8 6H); MS (El) m/z 302 EXAMPLE 76 6-(3-Fluoro-5-nitro-phenyl)-4,4-dimethyl-1,4-dihydro-benlZOI 11 ,3loxazin-2-one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxin-6-yl)boronic acid and 1-bromo-3-fluoro-5-nitrobenzene according to procedure B. A yellow solid: mp 260-261 'H-NMR (DMSO-d 6 8 10.4 11H), 8.37 (bs, 1H), 8.14-8.05 (in, 2H), 7.77-7.74 (in, 2H1), 7.01 1 H, J 7.94 Hz), 1.7 6H); MS (ESI) m/z 31l5([M 100%); Anal. Calc. For C 16
H
13
FN
2 0 4 C, 60.76, H, 4.14, N, 8.86. Found: C, 60.34, H, 4.2, N, 8.6 1.
EXAMPLE 77 6-(3-Chloro-5-fluoro-phenyl)-4,4-dimethyl-l,4-dihydro-benzoldI 11,3] oxazin-2one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxin-6-yl)boronic acid and 1 -bromo-3-chloro-5 -fluorobenzene according to procedure B. A white solid: mp 193-194 'H-NMR (DMSO-1 6 8 10.4 1H), 7.67-7.64 (in, 3H), 7.61-7.57 WO 00/66571 WO 0066571PCTUSOO/1 1822 65 (in Hf), 7.41-7.37 (mn, 1H), 6.96 1lH, J 8.72 Hz), 1.7 6H); MS (APCI) m/z 306([M 100%); Anal. Caic. For C 1 6
H
13 C1FN0 2 C, 62.86, H, 4.29, N, 4.58.
Found: C, 62.98, H, 4.1, N, 4.6.
EXAMPLE 78 3-Chloro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzoldl I1,3]oxazin-6-yl)benzonitrile Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1 -benzoxin-6-yl)boronic acid and l-bromo-3-chlorobenzonitrile according to procedure B. A white solid: mp 256-257 'H-NMR (DMSO-d 6 6 10.4 1H), 8.22 (bs, 11H), 8.15 (bs, 1H), 7.98 (bs, 1H), 7.74-7.71 (mn, 2H), 6.97 1H1, J1= 8.09 Hz), 1.7 6H); MS (ESI) m/z 311([M 100%); Anal. Caic. For C 1 7
H
1 3 C1N 2 0 2 C, 65.29, H, 4.19, N, 8.96.
Found: C, 65.25, H, 3.92, N, 8.71.
EXAMPLE 79 6-(3,5-Dinitro-phenyl)-4,4-dimethyl-1,4-dihydro-benzold 11,31 oxazin-2-one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1 -benzoxin-6-yl)boronic acid and 1-bromo-3,5-dinitrobenzene according to procedure B. A yellow solid: mp 297-298 )H-NMR (DMSO-d,) 5 10.4 1 H),8.88 2H, J =1.98 Hz), 8.78 (bs, LH), 7.78-7.82 (mn, 2H), 7.04 1H, J 8.23 Hz), 1.7 6H); MS (APCI) m/z 343([M 100%); Anal. Calc. For C 1 6
H
13
N
3 0 6 C, 55.98, H, 3.82, N, 12.24.
Found: C, 55.65, H, 3.7, N, 11.92.
EXAMPLE 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[dI [1,3joxazin-6-yI)isophthalonitrile Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3 1 -benzoxin-6-yl)boronic acid and 5-bromoisophthalonitrile according to procedure B. A white solid: mp 288- 289'"C; 'H-NMR (DMSO-d 6 6 10.4 1H), 8.58 2H), 8.40 1H, J= 0.77 Hz), WO 00/66571 WO 00/657 1PCTIUSOO/1 1822 66 7.80-7.75 (in, 2H), 6.99 1H, J= 8.2 Hz), 1.7 6H1); MS (EI) m/z Anal. Caic. For C, 8
H
13
N
3 Oj 1.65 1120: C, 64.92, H, 4.93, N, 12.62. Found: C, 64.74, H, 4.69, N, 12.32.
EXAMPLE 81 4..4-Dimethyl-6-(3-thiazol-2-yl-phenyl)-1,4-dihydro-benzoldI 11,31oxazin-2-one A mixture of 6-(3 -bromo-phenyl)-4,4-dimethyl- 1,4-dihydrobenzo[d][1,3]oxazin-2-one (0.25g, 0.75 minol), tri-n-butyl-thiazol-2-yl tin (0.5g, 1.3 mmol) in DMF (5 mL) was degassed to remove oxygen and then heated under nitrogen at 90 'C for 3 hours. The reaction mixture was cooled to rt and treated with ice-water (70 mL). Ethyl acetate (100 niL) was added and organic layer was separated, washed with brine, and dried (MgSO 4 After removal of solvent, the residue was purified by a silica gel column (hexane:ethyl acetate/i 1:1) to give the title compound as a white solid (60 mg, mp 223-224 0 C; 'H-NM!R (DMSO-d 6 10.4 1H), 9.13 1H), 8.45 111), 7.94 (bs, 111), 7.67-7.61 (in, 4H), 7.53 1H, J 7.68 Hz), 7.00 11H, J 8.81 Hz), 1.7 6H1); MS (APCI) m/z 3 37([M H+ 100%); Anal. Calc. For C,,H 16
N
2 0 2 S0.25 H 2 0: C, 66.94, H, 4.88, N, 8.22. Found: C, 66.57, H, 4.65, N, 7.92.
EXAMPLE 82 6-(3-Fluoro-5-methoxy-phenyl)-4,4-dimethyl-1.,4-dihydro-benzo IdI 11,31 oxazin-2one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3 ,1 -benzoxin-6-yl)boronic acid and 3-bromo-5-fluoroanisole according to procedure B. A white solid: mp 181- 182 'H-NMR (DMSO-d 6 8 10.4 111), 7.62-7.59 (in, 2H), 7.13-7.06 (in, 211), 6.97-6.94 111, J 8.89 Hz), 6.80 (dt, 111, J 10.95, 2.12 Hz), 3.8 311), 1.7 (s, 611); MS (ESI) m/z 302 100%); Anal. Calc. For C 1 7
H,
6 FN0 3 .0.1 1120: C, 67.36, H, 5.39, N, 4.62. Found: C, 67.11,1H, 5.44, N, 4.48.
WO 00/66571 WO 00/657 1PCTUSOO/1 1822 -67- EXAMPLE 83 6-(3-Fluoro-5-trifluoromethyl-phenyl)-4,4-dimethyl-1,4-dihydrobenzold] [1,31oxazin-2-one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1 -benzoxin-6-yl)boronic acid and 1 -bromo-3-fluoro-5-trifluoromethylbenzene according to procedure B. A white solid: mp 207-208 'H-NMR (DMSO-d 6 5 10.4 LH), 7.94-7.9 (in, 2H1), 7.73-7.7 (mn, 2H), 7.63 1H, J= 8.58 Hz), 6.99 LH, J= 8.68 Hz), 1.7 611); MIS (El) m/z Anal. Caic. For C 17
H
1 3
F
4 N0 2 C, 60.18, H, 3.86, N, 4.13.
Found: C, 59.9, H, 3.99, N, 4.06.
EXAMPLE 84 6-(5-Bromo-pyridin-3-yl)-4,4-dimethyl-1 ,4-dihydro-benzoldl I1,3loxazin-2-one Prepared from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3 ,1 -benzoxin-6-yl)boronic acid and 3,5-dibroinopyridine according to procedure B. A white solid: mp 211-212 'H-NMR (DMSO-d 6 6 10.4 1H), 8.92 lH, J =1.9 Hz), 8.66 1H1, J1 2.09 Hz 8.40 1H, J= 2.02 Hz), 7.72-7.68 (in, 2H), 6.99 1H, J= 8.1 Hz), 1.7 6H); MIS (APCI) ,n/z 333([M 100%), 335([M 100%); Anal. Cai~c. For
C,
5
H
13 BrN 2
O
2 C, 54.07, H, 3.93, N, 8.4 1. Found: C, 54.15, H, 3.89, N, 8.3 1.
EXAMPLE 6-(5-Bromo-l-oxy-pyridin-3-yl)-4,4-dimethyl-1 ,4-dihydro-benzo [dl [1,3joxazin-2one A mixture of 6-(5-broino-pyridin-3-yl)-4,4-diinethyl- 1,4-dihydrobenzo[d][ Il,3]oxazin-2-one (0.34g, 1 mmol), hydrogen peroxide 5 mL) in acetic acid (5 mL) was heated at 60 'C for 3 hours. The reaction mixture was cooled to At and neutralized by addition of a cold saturated sodium bicarbonate solution. The white precipitate obtained was collected on a filter, washed with distilled water and dried to afford the title compound as a white solid 3 5g, 100%): mp 15 7-15 9 H- NMiR (DMSO-d 6 6 10.4 lH), 8.69 1H1), 8.53 lH), 7.99 11H), 7.73-7.69 WO 00/66571 WO 0066571PCTUSOO/I 1822 68 (in, 2H), 6.97 1 H, J= 8.18 Hz), 1.7 6H); MS (APCI) m/z 349([M 100%), 3 5 1([M +I Hj+, 1 Anal. Caic. For C H, 3 BrN 2
O
3 2.5 1120: C, 45.70, H, 4.60, N, 7.11. Found: C, 45.34, H, 4.64, N, 7.
EXAMPLE 86 6-(3-Cyano-5-fluoro-phenyl)-4,4-dimethyl-2-oxo-4H-benzo [dI 11,31 oxazine-lcarboxylic acid tert-butyl ester A mixture of 3 -(4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6- (0.3g, -1 mmol), di-tert-butyl dicarbonate (0.33g, 1.5 mmol), and DMAP (50mg) in anhydrous acetonitrile was stirred at rt under nitrogen for 4 minutes. The reaction mixture was washed with 1N aqueous HC1, brine, dried (MgS04). After removal of solvent, the title compound was obtained as a white solid (0.25g, mp 139-140 'H-NMR (CDC1 3 -d 6 5 7.66-7.63 (in, 211), 7.53-7.48 (in, 2H), 7.38-7.35 (in, 2H), 1.79 611), 1.62 911); MS (AIPCI) m/z 289([M H- 100%); Anal. Caic. For C 22
H
2
,FN
2 0 4 C, 66.66,1H, 5.34, N, 7.07. Found: C, 66.7, H, 5.4 1, N, 7.
EXAMPLE 87 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzoldI [1,31oxazin-6-yI)-2-fluorobeuzonitrile Prepared from (1 ,4-dihydro-4,4-diinethyl-2-oxo-2H-3, 1-benzoxin-6-yl)boronic acid and 1-bromo-2-fluorobenzonitrile according to procedure B. A white solid: mp 255-256 'H-NMR (DMSO-d 6 5 10.4 111), 8.30 (dd, 1H, J 6.15, 2.41 Hz), 8.12-8.07 (in, 111), 7.76-7.58 (in, 3H1), 6.97 1H1, J 8.22 Hz), 1.7 611); MS (APCI) m/z 297 100%); Anal. Calc. For C 17
H,
3
FN
2 0 2 -0-1 H 2 0: C, 68.50, H,4.46, N, 9.40. Found: C, 68.27, H,4.8 1, N, 9. 1.
WO 00/66571PCUSO182 PCTIUSOO/I 1822 69 EXAMPLE 88 4-(8-Fluoro-4,4-dimethyl-2-oxo-1 ,4-dihydro-211-benzo[dl 11,3]oxazin-6-yl)thiophene-2-carbonitrile 8-Fluoro-(l ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxin-6-yl)boronic acid was prepared from 6-bromo-8-Fluoro-4,4-dimethyl-dihydro-benzo[d] [1,3 ]oxazin-2one using the procedure of example 4.
The title compound was prepared from 8-fluoro-(1,4-dihydro-4,4-dimethyl-2oxo-2H-3, 1 -benzoxin-6-yl)boronic acid and 4-bromo-2-cyanothiophene according to procedure B. A white solid: mp 250-251 1 H-NMR (DMSO-d 6 6 10.5 1H), 8.54 1 H, J =1.42 Hz), 8.43 1 H, J 1.3 5 Hz), 7.69 (dd, 1 H,J =11.71, 1.54 Hz), 7.58 (bs, 1H), 1.7 6H); MS (El) m/lz Anal. Calc. For
C
15
H
1
FN
2 0 2 S0.45 H 2 0: C, 58.04, H, 3.86, N, 9.02 Found: C, 58.4, H, 3.89, N, 8.63.
EXAMPLE 89 3-Fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-belzo dI 11 ,31oxazin-6yi)-benzonitrile Prepared from 8-fluoro-(1 ,4-dihydro-4,4-dimnethyl-2-oxo-2H-3, 1-benzoxin-6yl)boronic acid and 5-bromo-3-fluorobenzonitrile according to procedure B. A white solid: mp 256-257 'H-NMR (DMSO-d 6 5 10.5 1H), 8.20 (bs, 1H), 8.06 (dt, 1H, J= 10.48, 2.16 Hz), 7.85-7.82 (in, 1H), 7.77 (dd, 1H, 11.89, 1.81 Hz), 7.63 (s, 1H), 1.7 6H); MS (ES) m/z EXAMPLE 5-(4,4-Dimethyl-2-oxo-l,4-dihydro-2H-belzo~dI 1,3]oxazin-6-yl)-thiophene-3carbonitrile Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H- 3,1 -benzoxin-6-yl)boronic acid and 2-bromo-4-thiophenearbonitrile. An off-white WO 00/66571 WO 00/657 1PCTfUSOO/1 1822 70 solid: mp 255-260 'H-NNM (DMSO-d 6 8 10.3 6 1 8.48(d, 1 H, J 1. 1 Hz),7.88-7.87 1H J= 1.3 Hz), 7.63 1HJ= 1.9 Hz),7.56-7.54 (dd, 1H, J= Hz), 6.93 lH, J= 8.1 Hz),1.64 6H). MS(-ESI) m/z 283 EXAMPLE 91 2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo IdI [1,31oxazin-6-yl)-thiophene-3carbonitrile Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H- 3,1-benzoxin-6-yl)boronic acid and 2-bromo-3-thiophenecarbonitrile. An off-white solid: mp 200-202 'H-NMR (DMSO-d 6 8 10.49 1H),7.75(m, 1H),7.63(d, 1H, J =2.2 Hz), 7.59 (in, 11H), 7.50 (in, 1H), 7.02 1H, J =8.1 Hz), 1.63(s, 6H); MS(- ESI) m/z 283 EXAMPLE 92 6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzoldI [1,31oxazin-2one A mixture of 5-[3-bromo-phenyl]-[1,3,4]oxathiazole-2-one (21.25 g, 82.3 minol), ethylcyano formate (32.5 mL, 329 minol) in o-xylene (500 mL) was heated to 150 'C for 60 hours. After the solvent was removed from the reaction mixture, the product was recrystallized from ethanol to give 3-[3-bromo-phenyl]- [1 ,2,4]thiadiazole-5-carboxylic acid ethyl ester as white crystals (17.5 g, mp 87-90' 0 C; 'H-NMR (CDCI 3 8 8.53 1H, J= 1.76 Hz), 8.28 (dt, LH, J= 5.4, 1.2 Hz), 7.62 (dq, IIH, J= 5.1, 1.0 Hz), 7.36 LH, J= 7.9 Hz), 4.55 2H, J= 7.1 Hz), 1.48 3H1, J 7.1 Hz); MS m/z 313/315. Anal. Calc. For
C
11
H
9 BrN 2
O
2 S: C, 42.19, H, 2.90, N, 8.94. Found: C, 41.8 1, H, 3.0 8, N, 8.7 8.
A mixture of 3-13-bromo-phenyl]-[1 ,2,4]thiadiazole-5.-carboxylic acid ethyl ester (16.8 g, 53.5 mmol), sodium hydroxide (2.4 g, 58.8 minol), distilled water (120 WO 00/66571 WO 0066571PCTUSOO/I 1822 71 mL), and ethanol (20 mL) was heated to 100 'C for 2 hours. The reaction mixture was cooled to room temperature. Concentrated hydrochloric acid (5.1 mL) was added, and the reaction mixture re-heated to 100 'C for 3 hours. The solution was cooled to room temperature and extracted with diethyl ether (3x 150 mL). The combined organic layers were washed with distilled water (3x 100 mL), and dried over MgSO 4 After the solvent was removed, 3-[3-bromo-phenylj-[l ,2,4]thiadiazole was obtained as white needles (12.7 g, mp 69-71 0 C; 'H-NMR (GDC1 3 6 9.89 (s, 111), 8.52 1LH, J =1.8 Hz), 8.28 (dt, 1H, J 1.3 Hz), 7.61 (dq, 1H, J1=4.9, 1.1 Hz), 7.35 1H1, J= 7.9 Hz); MIS m/z 241/243. Anal. Calc. For
CH
5 BrN 2 S: C, 39.85, H, 2.09, N, 11.62. Found: C, 39.82, H, 2.43, N, 11.33.
According to procedure B, (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1 benzoxazin-6-yl)boronic acid was coupled with 3-[3-bromo-phenyl]- [1 ,2,4]thiadiazole to yield 1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl- 1,4-dihydrobenzo[d][l,3]-oxazin-2-one as an off-white solid (0.5 g, mp 214-216 'H- NMR (DMSO-d 6 5 10.40 1H), 10.36 1H), 8.49 1H1), 8.23 1H, J= 7.7 Hz), 7.83 1H, J 7.9 Hz), 7.66 7.61 (in, 3H), 7.02 1H, J 4.4 Hz), 1.70 (s, 6H); MIS m/z 338.
EXAMPLE 93 6-(3-Fluoro-5-thiophen-3-yl-phenyl)-4,4-dimehtyl-1,4-dihydrobeuzoldi fl,3joxazin-2-one Prepared from 6-(3-broino-5-fluoro-phenyl)-4,4-dimethyl- 1,4-dihydrobenzo[d] [1,3]oxazin-2-one and 3-thiophene boronic acid according to procedure B. A brownish-orange solid: mp 200-203 'H-NMR (CDCl 3 6 8.62 11H), 7.53 (q, 1H1, J 1.4 Hz), 7.50 1H, J =1.5 Hz), 7.49 1H, J =2.0 Hz), 7.45 7.40 (in, 1H), 7.35 1H, J= 1.8 Hz), 7.27 7.24 (in, 2 7.15 (dt, 1H, J= 5.8, 2.0 Hz), 6.94 1 H, J 8.2 Hz), 1. 80 6H); MIS [M-HT- m/z 3 52. Anal. Calc. For
C
20
,H,
6
FNO
2 S0.50 H 2 0: C, 66.28, H, 4.73, N, 3.87. Found: C, 66.54, H, 5.03, N, 3.52.
WO 00/66571 PCTUSOO/1 1822 72 EXAMPLE 94 2-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzo [1,31 oxazin-6-yl)-pyrrole-lcarboxylic acid tert-butyl ester A solution of 6-bromo-4,4-dimethyl-1 ,4-dihydro-benzo[d] [1 ,3]oxazin-2-one (0.87 g, 3.4 nimol) and tetrakis(triphenylphosphine)palladium(O) (96 mg, 0.08 mmol) in toluene (40 mL) was stirred under a flow of nitrogen for 25 min. To the solution was added sequentially 1 -t-butoxycarbonylpyrrole-2-boronic acid (1.4 g, 7.0 mmol) in absolute ethanol (10 mL) and potassium carbonate (0.94 g, 7.0 mmol) in water mL). The mixture was heated at 80 'C for 16 h and allowed to cool to rt. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with water (100 mL) and brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuc, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) to give the title compound as an off-white powder (0.7 g, mnp 176 'H NM (CDC1 3 6 1.40 9 1.73 6 6.17 (dd, 1 H, J 3.3 Hz), 6.22 (dd, 1 H, J 3.3 Hz), 6.77 1 H, J 8.1 Hz), 7.13 1 H, J =1.8 Hz), 7.23 (dd, 1 H, J 8.1 Hz), 7.33 (dd, 1 H, J 1.8, 3.3 Hz), 7.69 (bs, 1 MS ESI) m/z 341 Anal. Calcd for C, 9 H22N 2
O
4 C, 66.65; H, 6.48; N, 8.18. Found: C, 65.46; H, 6.51; N, 7.74.
EXAMPLE 2-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzo 11,31 pyrrole-1-carboxylic acid tert-butyl ester To a solution of 2-(4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo [1 ,3]oxazin- 6-yl)-pyrrole-1 -carboxylic acid tert-butyl ester (0.7 g, 2.0 nunol) in acetonitrile mL) and dichloromethane (1 mL) at room temperature was added silver nitrate (0.37 g, 2.1 mmol). After 5 min, acetyl chloride 15 mL, 2.0 mmnol) in acetonitrile (3 mL) P:\WPDOCS\CArnSPECI\7639430 AMENDEDDESCRIPTJONdoc-15/08/03 -73was added and the solution was allowed to stir for 2 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl ether (2 x 50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) to give a yellow oil which crystallized from 5% ethyl acetate/hexane to give the title compound as a bright yellow powder (350 mg, mp 125 'H NMR (CDC13) 8 1.47 9 1.75 6 6.26 1 H, J= 4.2 Hz), 6.87 1 H, J 8.1 Hz), 7.19 1 H, J= 4.2 Hz), 7.34 1 H, J= 2 Hz), 7.4 (dd, 1 H, J= 1.8, 8.1 Hz), 8.17 (bs, 1 MS APCI) m/z 388 [M Anal. Calcd for C 19
H
21
N
3 0 6 C, 58.91; H, 5.46; N, 10.85. Found: C, 58.4; H, 5.55; N, 10.18.
EXAMPLE 96 4,4-Dimethyl-6-(5-nitro-lH-pyrrol-2-vl)-l,4-dihydrobenzo [dl[1,31oxazin-2-one 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo oxazin-6-yl)-5-nitro-pyrrole-1carboxylic acid tert-butyl ester (0.7 g, 1.8 mmol) was placed in a 25 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow. A vigorous flow of nitrogen was maintained as the flask was placed in an S. oil bath and heated to 180 oC After 10 min at this temperature, the flask was removed from the oil bath and allowed to cool to rt. The brown residue was washed into a larger flask with dichloromethane/ethyl acetate and adsorbed onto a small amount of silica gel. Purification by flash column chromatography on silica gel (60% ethyl acetate/hexane) gave the title compound as a brown powder (200 mg, mp 265 oC (dec). 'H NMR (DMSO-d 6 8 1.65 6 6.81 1 H, J= 4.4 Hz), 6.90 1 H, J= 8.6 Hz), 7.25 1 H, J= 4.2 Hz), 7.79 (dd, 1 H, J= 2, 8.3 Hz), 7.91 1 H, J= 2 Hz), 10.37 1 13.17 (bs, 1 MS ESI) m/z 286 Anal. Calcd for C1 4 H13N 3 04: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.25; H, 5.10; N, 12.57.
o *o WO 00/66571 PCT/US00/11822 -74- EXAMPLE 97 4,4-Dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo 1,3]oxazin-2-one 2-(4,4-Dimethyl-2-oxo-l,4-dihydro-2H-benzo oxazin-6-yl)-pyrrole-1carboxylic acid tert-butyl ester (3.5 g, 10 mmol) was placed in a 25 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow. A vigorous flow of nitrogen was maintained as the flask was placed in an oil bath and heated to 180 oC After 10 min at this temperature, the flask was removed from the oil bath and allowed to cool. The brown residue was washed into a larger flask with dichloromethane/ethyl acetate and adsorbed onto a small amount of silica gel. Purification by flash column chromatography on silica gel (60% ethyl acetate/hexane) gave the title compound as a green solid (2 g, mp 202 °C (dec). 'H NMR (CDC1 3 8 1.75 6 6.30 1 6.45 1 6.85 1 H, J= 8.5 Hz), 6.86 1 7.24 1 H, J= 2 Hz), 7.33 (dd, 1 H, J= 2, 8.4 Hz), 8.44 (bs, 1 8.66 1 MS APCI) m/z 243 Anal. Calcd for C 4
H,
4
N
2 0 2 C, 69.41; H, 5.82; N, 11.56. Found: C, 69.20; H, 5.96; N, 11.29.
EXAMPLE 98 4,4-Dimethyl-6-(1-methyl-lH-pyrrol-2-yl)-1,4-dihydro-benzo oxazin-2one To a mixture of 4,4-dimethyl-6-(lH-pyrrol-2-yl)- 1,4-dihydrobenzo[d][1,3]oxazin-2-one (1.5 g, 6.2 mmol) in dimethylformamide (20 mL) at room temperature was added sequentially potassium carbonate (4.28 g, 31 mmol) and a solution of methyl iodide (1.16 mL, 19 mmol) in dimethylformamide (5 mL). After 1 h, the reaction mixture was boiled. The reaction was cooled to room temperature, poured into water (50 mL) and extracted with ethyl ether (2 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on WO 00/66571 PCT/US00/11822 silica gel (40% ethyl acetate/hexane) gave the title compound as an off-white powder g, 31%) mp 230 'H NMR (CDCl 3 8 1.71 6 3.42 3 6.31 (dd, 1 H, J= 2.9, 5.9 Hz), 6.47 1 6.88 1 6.94 1 H, J= 8.6 Hz), 7.26 1 H, J= 2.2 Hz), 7.41 (dd, 1 H, J 2.2, 8.6 Hz), 8.43 (bs, 1 MS ESI) m/z 255 Anal. Calcd for CsH 16
N
2 0 2 C, 70.29; H, 6.29; N, 10.93. Found: C, 68.59; H, 6.16; N, 10.49.
EXAMPLE 99 4,4-Dimethyl-6-(1-methyl-5-nitro-lH-pyrrol-2-yl)-l,4-dihydrobenzo[d] [1,3]oxazin-2-one To a solution of 4,4-dimethyl-6-(1-methyl-lH-pyrrol-2-yl)-1,4-dihydro-benzo oxazin-2-one (0.3 g, 1.2 mmol) in acetonitrile (20 mL) was added silver nitrate (0.21 g, 1.26 mmol). The solution was cooled to -78 °C and treated with a solution of acetyl chloride (0.08 mL, 1.2 mmol) in acetonitrile (1 mL). The reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was poured into water (50 mL) and extracted with ethyl ether (2 x 50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (40% ethyl acetate/hexane) gave the title compound mg, as a yellow solid, mp 180-185 'H NMR (CDCI,) 8 1.75 6 3.45 (s, 3 6.57 (dd, 1 H, J 2.9, 4.3 Hz), 7.04 1 H, J= 8.5 Hz), 7.22 (dd, 1 H, J= 4.3 Hz), 7.36 1 H, J= 2.1 Hz), 7.56 (dd, 1 H, J= 2.1, 8.5 Hz), 9.67 (bs, 1 MS APCI) m/z 302 EXAMPLE 100 5-Bromo-4-ethylthiophene-2-carboxaldehyde Prepared from 2-bromo-3-ethylthiophene in a similar manner to the example 19. 'H-NMR(DMSO-d,) 8 9.82 1H), 7.81 1H), 2.5 2H, J= 7.4 Hz), 1.15 (t, 3H, J= 7.5 Hz).
WO 00/66571 WO 0066571PCTIUSOO/I 1822 76 EXAMPLE 101 5-Bromo-4-ethylthiophene-2 carbonitrile Prepared from 5-bromo-4-ethylthiophene-2-carboxaldehyde using the similar procedure of example 18. IR(KBr) 2221 'HNM(DMSO-d 6 5 7.87 1H), 5 2H, J= 7.3 Hz), 1. 18 3H, J =7.6 Hz). MS (El) m/z 215/217(M').
EXAMPLE 102 5-Bromo-4-n-propylthiophene-2-carboxaldehyde Prepared from 2-bromo-3-n-propylthiophene in a similar manner to the example 19. 'H-NMR(DMSO-d 6 )859.82 1H), 2.6-2.5 (in, 2H), 1.65-1.51 (in, 2H), 3 H,J =4.7 Hz).
EXAMPLE 103 5-Bromo-4-n-propylthiophenecarbonitrile Prepared from 5-bromo-4-n-propylthiiophene-2-carboxaldehyde using the similar procedure of example 18. 'H-NMR(DMSO-d 6 5 7.87 1lH), 2.5 2H, J 5.2 Hz), 1.64-1.5 (in, 2H), 1. 91 3 H, J =5.1 Hz). MS (EI) m/z 229-23 1(M).
EXAMPLE 104 5-Bromo-4-n-butylthiophenecarboxaldehyde Prepared from 2-bromo-3-n-butylthiophene in a similar manner to the example 19. IR(KBr) 1660 cm'f 'H-NMR (DMSO-d 6 8 9.78 IH), 7.85 1H), 2.57-2.53 (in, 2H), 1.57-1.53 (in, 2H), 1.32-1.25 (in, 2H), 0.88 3H, J= 5.2 Hz). MS (El) m/z 246(M').
EXAMPLE 105 5-Bromo-4-n-butylthiophenecarbonitrile WO 00/66571 WO 0066571PCT[USOO/1 1822 77 Prepared from 5-bromo-4-n-butylthiophenecarboxaldehyde using the similar procedure of example 18. 1 H-NMR(DMSO-d 6 8 7.87 1H), 2.58-2.44 (in, 2H), 1.65-1.48 (in, 2H), 1.38-1.23 (m 2H), 0.89 3H, J 5.3 Hz). MS (El) m/z 243 NMr).
EXAMPLE 106 3-(1,2-Dihydro-2-oxospiro[4H-3,1-benzoxazine-4,1-cyclohexanJ-6-yi)-benzonitrile Prepared according to Procedure B from spiro-(4, 1'-cyclohexane- 1,4-dihydro- 2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3-bromobenzonitrile. Tan powder: mp 245-247 'H-NMR(DMSO-d 6 8 10.31 LH), 8.21 11H), 8.02 I H, J= Hz), 7.78 1lH, J 7.7 Hz), 7.68-7.61 (in, 3H), 6.97 11H, J 8.2 Hz), 1.98- 1.96 (in, 4H), 1.75-1.64 (mn, 511), 1.40-1.32 (in, 1H). MS (El) m/z 318[M']. Anal.
Calc. For C 20
HN
2
O
2 -l/2 1120: C 73.38; H, 5.85; N, 8.56. Found: C, 73.86; H, 5.81; N, 8.22.
EXAMPLE 107 2-Dihydro-2-oxospiro[4H-3, 1-benzoxazine-4, 1-cyclohexanj-6-yl)-5fluorobenzonitrile Prepared according to Procedure B from spiro-(4, 1 '-cyclohexane-1 ,4-dihydro- 2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3-bromo-5-fluorobenzonitrile. White powder: mp 250-253 JR (KBr) 2220 'H-NMR (DMSO-d 6 8 10.34 1H1), 8.13 1H1), 8.0 1H1, J 10.6 Hz), 7.80-7.7 (in, 3 6.98-6.95 1H1, J =8.1 Hz), 1.99-1.97 (in, 4H), 1.76-1.65 (in, 611), 1.37-1.33 (in. 1H1). MS (El) m/z 336 Anal.
Calc. For C 2 0
HI
7
FN
2 0 2
H
2 0: C, 67.78; H, 5.40; N, 7.90. Found: C, 67.9; H, 4.93; N, 7.67.
EXAMPLE 108 2-Dihydro-2-oxospiro[4H-3,1-benzoxazine4,1-cyclohexan-6-y)-2thiophenecarbonitrile WO 00/66571 WO 0066571PCTIUSOO/1 1822 78 Prepared according to Procedure B from spiro-(4, 1 '-cyclohexane-1 ,4-dihydro- 2-oxo-2H-3, 1-benzoxazmn-6-yl) boronic acid and 3 -bromo-5-cyanothiophene. White crystals: mp 230-232 IR (KBr) 2200 cm'. 'H-NMR (DMSO-d 6 6 10.29 1H), 8.49 111), 8.33 LH), 7.69-7.63 (mn, 211), 6.93-6.91 1H1, J= 8.2 Hz), 1.99-1.87 (mn, 4H), 1.73-1.64 (in, 511), 1.38-1.31 (in, 1H). MS(+)APCI m/z 325 Anal.
Caic. For C,,H, 6 N0 2 S/4H 2 0: C, 65.73; H, 5.06; N, 8.52. Found: C, 65.55; H, 5.06; N, 8.22.
EXAMPLE 109 2-Dihydro-2-oxospirol4H-3, 1-benzoxazine-4,1-cyclohexanj-6-yl)-2thiophenecarbonitrile Prepared according to Procedure B from spiro-(4, 1 '-cyclohexane-1 ,4-dihydro- 2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 2-bromo-5-cyanothiophene Tan powder: mp 243-245 'H-NMR(DMSO-d 6 8 10.4 1 111), 7.98-7.97 111, J =3.9 Hz), 7.67-7.60 (in, 311), 6.97-6.94 111, J 8.3 Hz), 1.98-1.92 (mn, 411), 1.74-1.64 (in, 511), 1.45-1.21 (in, 111). MS (El) m/z 324 Anal. Caic. For C, 18 Hl 6
N
2 0 2 S 1/2 1120: C, 65.08; H, 5.04; N, 8.18. Found: C, 64.84; H, 5.09; N,8.40.
EXAMPLE 110 2-Dihydro-2-oxospiro[4H-3, 1-benzoxazine-4,1-cyclohexanl-6-yl)-4-methyl-2thiophenecabonitrile Prepared according to Procedure B from spiro-(4, 1 '-cyclohexane-1 ,4-dihydro- 2-oxo-2H-3, 1-benzoxazin-6-yl) boronic acid and 2-bromo-3-methyl-5-cyanothiophene.
White powder: mp 200-203 1 1-NMR (DMSO-d 6 8 10.4 111), 7.85 111), 7.43- 7.40 (in, 211), 7.0 111, J 8.8 Hz), 2.27 (s,3 2.00-1.62 (in, 911), 1.42-1.23 (mn, 111). MS(EI) m/z 338 Anal. Caic. For C 19
H,
8
N
2 0 2 S: C, 67.43; H, 5.36, N, 8.28.
Found: C, 67.12; H, 5.45; N, 8.05.
WO 00/66571 WO 0066571PCTIUSOO/1 1822 79 EXAMPLE 111 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzoldI [1,31oxazin-6-yl)-4-ethylthiophene-2-carbonitrile Prepared according to Procedure B from spiro-(4, 1 '-cyclohexane-1 ,4-dihydro- 2-oxo-2H-3, 1-benzoxazin-6-yl) boronic acid and 2-bromo-3-ethyl-5-cyanothiophene.
White crystals: mp 160-162 lH-NMR(DMSO-d 6 8 10.46 111), 7.96 11H), 7.40-7.38 (in, 2H), 7.02-6.99 lH,J= 8.8 Hz), 2.61 2H,J= 7.5 Hz), 1.64 6H), 1.16 3H, J =7.6 Hz). MS APCI m/z [M 313. Anal. Caic. For
C
17
H,
6
N
2
O
2 S. 1/4 H 2 0: C, 64.43; H, 5.25; N, 8.84. Found: C, 64.77; H, 5.23; N, 8.68.
EXAMPLE 112 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo Idi 1,3loxazin-6-yl)-4-n-propylthiophene-2-carbonitrile Prepared according to Procedure B from spiro.-(4, 1 '-cyclohexane-1,4-dihydro- 2-oxo-2H-3,1I-benzoxazin-6-yl) boronic acid and 2-bromo-3-n-propyl-5thiophenecarbonitrile. White crystals: mnp 160-162 IR (KBr) 2220 1
H-
NMR(DMSO-d 6 8 10.47 1H), 7.93 1H), 7.38-7.36 (in, 2H1), 7.01 1H, J 8.7 Hz), 2.59-2.48 (mn, 2H), 1.64-1.5 1 (mn, 2H), 0.85 3H, J 7.3 Hz). MS(-ESI) m/z [M- 325. Anal. Caic. For C 18
H
18
N
2
O
2 S-3/4H 2 O: C, 63.60; H, 5.78, N, 8.24. Found: C, 63.48; H, 5.59; N, 8.04.
EXAMPLE 113 5-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzold [il,31oxazin-6-yl)-4-n-butylthiophene-2-carbonitrile Prepared according to Procedure B from spiro-(4, 1'-cyclohexane-1,4-dihydro- 2-oxo-2H-3, 1 -benzoxazin-6-yl) boronic acid and 2-bromo-3-n-butyl-5thiophenecarbonitrile. White crystals: mp 167-168 0 C. 'H-NMR(DMSO-d 6 8 10.46 (s, 1H), 7.93 LH), 7.38-7.36 (in, 2H), 7.01 1H, J= 8.7 Hz), 2.59 2H, J= 8.1 Hz), 1.63 611), 1.58-1.51 (mn, 2H), 1.48-1.17 (in, 2H), 0.82 3H, J= 7.4 Hz). MS(-ESI) P:XWPDOCS\CAB\SPECI\7639430 AMENDEDDESCRIPTION.d.-I/0/03 80 m/z 339. Anal. Caic. For CjqH 20
N
2 0 2 Sl/4 H 2 0: C, 66.16; H, 5.99; N, 8.12. Found: C, 66.33; H, 5.92; N, 7.85.
EXAMPLE 114 6-(4-Cyano-3-fluorophenyl)-4,4-dimethvl-1 .4-dihydrobenzofdI [1,31oxazin-2-one A solution of 4-cyano-3-fluoro-bromobenzene (0.6 g, 3.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 mL) was stirred under N 2 for 20 minutes. To this mixture was then added (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)borollc acid (1.0 g, 4.5 mmol) and sodium carbonate (1.1 g, 10.6 mmol) in water (5 mL). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (3x50 mL). The combined extracts were washed with water, brine, dried (MgSO 4 and evaporated. The residue was purified by column chromatography (SiO 2 EtOAc:hexane 1:2) to afford the title compound (0.05 g, as an off-white solid. mp: 272 275 'H- NMR (DMS0-cl 6 8 10.4 1H), 8.0 1 H, J= 7.7 Hz), 7.9 (dd, lH, J= 10.3,1.3 Hz), 7.8 (dd, I1H, J= 6.8, 1.4 Hz), 7.7 (in, 2H), 6.9 I H, J 8.9 Hz), 1. 7 6H); MS (El) M+ m/z 296.
EXAMPLE 115 6-(4-Fluoro-phenv1)-4,4-dimethyl-1 ,4-dihydro-benzo [dI [1131oxazin-2-one Prepared according to Procedure B from (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H-3, 1benzoxin-6-yl)boronic acid and 1-bromo-4-fluorobenzene. Off-white crystals: mp 232-23 3 0 C. 'H-NMR(DMSO-d 6 8 10.3 1H), 7.74 (in, 2H), 7.53 (in, 2H), 7.28 (in, 2H1), 6.96 (d, 1H, J= 8.9 Hz), 1.63 6H).
EXAMPLE 116 6-(3,4-Difluoro-phenyl)-4,4-dimethyl-1 ,4-dihydro-benzo [dI [1,31 oxazin-2-one P:\WDOCSCAB\SPECI\7639430 AMENDEDDESCRIP'ION.dC-121O8103 81 Prepared according to Procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1benzoxin-6-yl)boronic acid and 1-bromo-3, 4-difluorobenzene. Off-white crystals: mp 207- 208 0 C. 'H-NMR(DMSO-d 6 6 10.35 1H), 7.79 (in, 1H), 7.40-7.63 (in, 4H), 6.95 1H, J= 8.9 Hz), 1.62 6H).
EXAMPLE 117 6-(2-Fluoro-phenyl)-4,4-dimethyl-1 ,4-dihydro-benzoldI 11,31oxazin-2-one Prepared according to Procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1benzoxin-6-yl)boronic acid and 1 -bromo-2-fluorobenzene. Off-white crystals: mp 164-165 0 C. 'H-NMR(DMSO-d 6 6 10.33 1H), 7.56 (in, 1H), 7.25-7.45 (in, 4H), 6.98 1H, J= 8.7 Hz), 1.64 6H).
EXAMPLE 118 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo I [1 31-oxazin-6y1~phenylacetonitrile Prepared from 3-bromophenylacetonitrile and (1 ,4-dihydro-4,4-dimethyl-2-oxo-2H- ::..3,1-benzoxazin-6-yl)boronic acid. White solid: mp 188-190 'H-NMR (DMSO- d 6 6 10.33 1H), 7.62 (mn, 2H), 7.55 (in, 2H), 7.48 1H, J= 8.00 Hz), 7.33 1H, J= 7.57 Hz), 6.99 1H, J 8.81 Hz), 4.09 2H), 1.67 6H); MS m/z 291(M-H). Anal. Calc. For C1 8 H1 6
N
2
O
2 -0.3 H 2 0: C,72.61, H, 5.62, N, 9.41. Found: C, 73.00, H, 5.43, N, 8.81.
EXAMPLE 119 5-(4,4-Dimethvl-2-oxo-1.,4-dihvdro-2H-benzoldl tl.31oxazin-6-vl)-furan-2carbonitrile V, The title compound was prepared according to the procedure B from cyanofuran (1.0 g, 5.6 inmol) Med. Chem. (1997), 40(23), 3804-3819) and (1,4-dihydro- 4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8 g, 8.18 mmol) WO 00/66571 PCT/US00/11 822 -82as a white solid (0.39 g, 1.45 mmol, mp. 257 260 'H-NMR (DMSO-d 6
C
10.48 1H), 7.73 7.70 3H), 7.19 1 H, J= 3.8 Hz), 6.98 1 H, J= 8.9 Hz), 1.66 6H); MS m/z 269 EXAMPLE 120 3-(4,4-Dimethyl-2-oxo-l,4-dihydro-2H-benzo[d] [1,31oxazin-6-yl)-2-fluorobenzonitrile A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux.
After 16 h, the mixture was evaporated and the residue partitioned between water and Et 2 O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO 4 and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 'H-NMR (CDCl 3 7.90 7.85 1H), 7.71 7.65 (m, 1H), 7.10 (dt, 1H, J= 8.0, 1.0 Hz), 3.94 3H): MS (EI) 232 A solution of the last cited compound (3.077 g, 13.2 mmol) in dry toluene mL) at -78°C under nitrogen was treated with a di-iso-butylaluminum hydride in toluene (1M, 15.7 mL, 15.7 mmol). After 1 h at -78 0 C, the mixture was quenched with aqueous HC1 (3M, 16 mL). The mixture was warmed to RT, partitioned between EtOAc/H20, the aqueous layer was re-extracted with EtOAc, and the combined organic layers were washed with water, dried (MgSO 4 and evaporated to afford 3bromo-2-fluorobenzaldehyde (2.63 g, 12.9 mmol, which was used without further purification: 'H-NMR (CDCl1) 8 10.35 1H), 7.82 2H), 7.18 7.8 Hz).
A mixture of the last cited compound (2.63 g, 12.9 mmol), hydroxylamine hydrochloride (1.0g, 14 mmol) and potassium acetate (1.37 g, 14 mmol) was placed in ethanol/H 2 0 (60 mL, 8:2) and the mixture was heated under reflux. After 30 min. the mixture was cooled, evaporated and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO 4 and evaporated to give 3-bromo- 2-fluorobenzaldoxime which was used without further characterization.
WO 00/66571 PCT/US00/11822 -83- A solution of the last cited compound (0.75 g, 3.43 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.2 g) were stirred in dimethoxy ethane mL) at room temperature under nitrogen. After 15 min., (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,l-benzoxazin-6-yl)boronic acid (1.1 g, 5.0 mmol) and sodium carbonate (1.35 g) in water (10 mL) were added and the mixture heated under reflux.
After 16 the mixture was cooled, partitioned between water and EtOAc, the organic layer was washed with sat. sodium carbonate solution, brine, dried (MgSO4) and evaporated. The residue was then dissolved in acetonitrile (50 mL), treated with copper acetate (0.2 g) and heated under reflux. After 16 h, the mixture was cooled and evaporated. The residue was partitioned between water and EtOAc, the organic layer was then washed with dilute sulfuric acid water, brine, dried (MgSO 4 and evaporated. The residue was then subjected to column chromatography (SiO 2 EtOAc/hexane, gradient elution), and then crystallized from EtOAc-hexane to afford the title compound (0.176 g, 0.59 mmol, 17%) as a white solid: mp. 192-198 oC; 'H- NMR (CDC 3 8 9.15 1H), 7.69 7.58 2H), 7.42 7.31 3H), 6.99 1H, J 8.2 Hz), 1.78 6H); MS 297 [M EXAMPLE 121 PHARMACOLOGY The compounds of this invention were tested in the relevant assay as described below and their potency are in the range of 0.01 nM to 5 p.M in the in vitro assays and 0.001 to 300 mg/kg in the in vivo assays.
Table 1 Potency of the selected cyclocarbamate derivatives as PR antagonists in some in vitro and in vivo models: WO 00/66571 WO 0066571PCTUSOO/1 1822 84
R
2
YZ
3 IIPR CV-1 Decidualization R(2 R(3 IC 50
IC
5 1 (mgfkg) Compound 3-cyano-4fluorophenyl trifluormethylphenyl 3-fluorophenyl 3 ,5-dichlorophenyl 5-cyano-2fluorophenyl 3 -fluoro-5nitrophenyl 4-(2-cyanofuryl) 3-bromo-5fluorophenyl Me Me Me Me 55 80%@1** 54 Me Me Me Me 80%@3 6 7 8 Me Me Me Me Me Me Me Me 68 11.5 50%@ 1 30 11 WO 00/66571 WO 0066571PCTIUSOO/1 1822 9 3-cyano-4- Me Me 13 6.96±0.84 fluorophenyl 5-(2-cyano-4- spirocyclohexyl 2.7 50%@10 methylthiophenyl) 11 5-(2-cyanothio- spirocyclohexyl 12 50%@ phenyl) 12 5-(2-cyanothio- Me Me 19 3.34±0.22 phenyl) 13 3-bromophenyl Me Me 11.5 3 14 3-chloro-5-fluoro- Me Me 22 50%@3 phenyl 3 -cyano-5-fluoro- cyclopropyl cyclopropyl 22 3 phenyl 16 5-(3-bromo- Me Me 26 pyridyl) 17 4-(2-cyanothio- Me Me 12.7 2.3±0.46 phenyl) 18 5-(2-cyano-4- Me Me 5.23 methyithiophenyl) 19 3-cyano-5-fluoro- Me Me 13.8 0.35 phenyl 3-chloro-4-fluoro- Me Me 37 1 phenyl ND, not determined; "*Percentage inhibition at the dose specified A. In-vitro biology The in-vitro biology is determined by competitive Radioligand Binding: using the A-form of the human progesterone receptor with WO 00/66571 PCT/US00/1 1822 -86progesterone as the radioligand; co-transfection assay, which provides functional activity expressed as agonist EC50 and Antagonist IC50 values; a T47D cell proliferation, which is a further functional assay which also provides agonist and antagonist data; and T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agonist and antagonist data.
1. hPR Binding assay This assay is carried out in accordance with: Pathirana, Stein, Berger, Fenical, laniro, T.; Mais, Torres, Glodman, Nonsteroidal human progesterone receptor modulators from the marine alga cymoplia barbata, J. Steroid Biochem. Mol. Biol., 1992,41,733-738.
2. PRE-luciferase assay in CV-1 cells The object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. The materials methods used in the assay are as follows.
a. Medium: The growth medium was as follows: DMEM (BioWhittaker) containing 10% fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows: DMEM (BioWhittaker), phenol red-free, containing 10% charcoalstripped fetal bovine serum (heat-inactivated), 0.1 mM MEM non-essential amino acids, 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax (GIBCO,
BRL).
b. Cell culture, transfection, treatment, and luciferase assay Stock CV-1 cells are maintained in growth medium.
Co-transfection is done using 1.2x107 cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl and BamH1 sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250 ml.
WO 00/66571 PCT/US00/1 1822 -87- Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II.
After electroporation, cells are resuspended in growth medium and plated in 96-well plate at 40,000 cells/well in 200 pl. Following overnight incubation, the medium is changed to experimental medium. Cells are then treated with reference or test compounds in experimental medium. Compounds are tested for antiprogestational activity in the presence of 3 nM progesterone. Twenty-four hr. after treatment, the medium is discarded, cells are washed three times with D-PBS (GIBCO, BRL). Fifty gl of cell lysis buffer (Promega, Madison, WI) is added to each well and the plates are shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity is measured using luciferase reagents from Promega.
c. Analysis of Results: Each treatment consists of at least 4 replicates. Log transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC 5 0 or IC 5 0 values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear response analyses.
d. Reference Compounds: Progesterone and trimegestone are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full doseresponse curves and the EC 5 o or IC 50 values are calculated.
Table 2. Estimated EC50, standard error and 95% confidence intervals (CI) for reference progestins from three individual studies 95% CI Compound Exp. (nM) SE lower upper Progesterone 1 0.616 0.026 0.509 0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637 WO 00/66571 PCT/US00/11822 -88- Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.0094 3 0.0067 0.0003 0.0055 0.0082 Table 3. Estimated ICso, standard error and 95% confident interval (CI) for the antiprogestin, RU486 from three individual studies IC 50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.019 0.042 2 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027 Progestational activity: Compounds that increase PRE-luciferase activity significantly (p<0.05) compared to vehicle control are considered active.
Antiprogestational activity: Compounds that decrease 3 nM progesterone induced PRE-luciferase activity significantly (p<0.05)
EC
50 Concentration of a compound that gives half-maximal increase PREluciferase activity (default-nM) with SE.
IC
50 Concentration of a compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity (default-nM) with SE.
3. T47D cell proliferation assay The objective of this assay is the determination of progestational and antiprogestational potency by using a cell proliferation assay in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured. The materials and methods used in this assay are as follows.
a. Growth medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 10% fetal bovine serum (not heat- WO 00/66571 PCT/US00/11822 -89inactivated), 100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
b. Treatment medium: Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with charcoal stripped fetal bovine serum, 100U/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
c. Cell culture Stock T47 D cells are maintained in growth medium. For BrdU incorporation assay, cells are plated in 96-well plates (Falcon, Becton Dickinson Labware) at 10,000 cells/well in growth medium. After overnight incubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment.
Stock compounds are dissolved in appropriate vehicle (100% ethanol or DMSO), subsequently diluted in treatment medium and added to the cells. Progestin and antiprogestin reference compounds are run in full dose-response curves. The final concentration of vehicle is In control wells, cells receive vehicle only. Antiprogestins are tested in the presence of 0.03 nM trimegestone, the reference progestin agonist. Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) in treatment medium for 4 hr.
d. Cell Proliferation Assay At the end of BrdU labeling, the medium is removed and BrdU incorporation is measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to manufacturer's instructions. Briefly, cells are fixed in an ethanol containing fixative for 30 min, followed by incubation in a blocking buffer for 30 min to reduce background. Peroxidase-labeled anti-BrdU antibody is added to the wells and incubated for 60 min. The cells are rinsed three times with PBS and incubated with 3,3'5,5'-tetramethylbenzidine (TMB) substrate for 10-20 min depending upon the potency of tested compounds. Then 25 tl of 1 M sulfuric acid is WO 00/66571 PCT/US00/11822 added to each well to stop color reaction and optical density is read in a plate reader at 450 nm within 5 min.
e. Analysis of Results: Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. ECso or ICso values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose response analyses in both single dose and dose response studies.
f. Reference Compounds: Trimegestone and medroxyprogesterone acetate (MPA) are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose-response curves and the ECo or ICso values are calculated.
Table 4. Estimated EC50, standard error (CI) for individual studies and 95% confidence intervals Compound Trimegestone
MPA
Exp 1 2 3 ECso (nM) 0.017 0.014 0.019 0.019 0.017
SE
0.003 0.001 0.001 0.001 0.001 95% CI lower upper 0.007 0.040 0.011 0.017 0.016 0.024 0.013 0.011 0.027 0.024 Table 5. Estimated ICso, standard error, and 95% confident interval for the antiprogestin, RU486 ICso 95% CI WO 00/66571 PCTIUSOO/11 822 -91- Compound Exp (nM) SE lower upper RU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.001 0.014 0.022
EC
5 o: Concentration of a compound that gives half-maximal increase in BrdU incorporation with SE; Concentration of a compound that gives half-maximal decrease in 0.1 trimegestone induced BrdU incorporation with SE 4. T47D cell alkaline phosphatase assay The purpose of this assay is to identify progestins or antiprogestins by determining a compound's effect on alkaline phosphatase activity in T47D cells. The materials and methods used in this assay are as follows.
a. Culture medium: DMEM:F12 (GIBCO, BRL) supplemented with 5% charcoal stripped fetal bovine serum (not heat-inactivated), 100U/ml penicillin, 100 gg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
b. Alkaline phosphatase assay buffer: I. 0.1 M Tris-HC1, pH 9.8, containing 0.2% Triton X-100 II. 0.1 M Tris-HC1, pH 9.8 containing 4 mM p-nitrophenyl phosphate (Sigma).
c. Cell Culture and Treatment: Frozen T47D cells were thawed in a 37°C water bath and diluted to 280,000 cells/ml in culture medium. To each well in a 96-well plate (Falcon, Becton Dickinson Labware), 180 gl of diluted cell suspension was added.
Twenty gl of reference or test compounds diluted in the culture medium was then added to each well. When testing for progestin antagonist activity, reference antiprogestins or test compounds were added in the presence of 1 nM progesterone. The cells were incubated at 37°C in a 5% CO2/humidified atmosphere for 24 hr.
d. Alkaline Phosphatase Enzyme Assay: WO 00/66571 PCT/US00/1 1822 -92- At the end of treatment, the medium was removed from the plate and fifty tl of assay buffer I was added to each well. The plates were shaken in a titer plate shaker for 15 min. Then 150 jl of assay buffer II was added to each well. Optical density measurements were taken at 5 min intervals for 30 min at a test wavelength of 405 nM.
e. Analysis of Results: Analysis of dose-response data For reference and test compounds, a dose response curve is generated for dose (X-axis) vs. the rate of enzyme reaction (slope) (Y-axis). Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC 5 s or ICso values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose response analyses in both single dose and dose response studies.
f. Reference Compounds: Progesterone and trimegestone are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC 50 or ICs, values are calculated.
Table 6. Estimated EC50, standard error and 95% confidence intervals (CI) for reference progestins from three independent experiments 95% CI Compound Exp. (nM) SE lower upper Progesterone 1 0.839 0.030 0.706 0.996 2 0.639 0.006 0.611 0.669 3 1.286 0.029 1.158 1.429 Trimegestone 1 0.084 0.002 0.076 0.091 WO 00/66571 PCT/US00/1 1822 -93- 2 0.076 0.001 0.072 0.080 3 0.160 0.004 0.141 0.181 Table 7. Estimated IC50, standard error, and 95% confident interval for the reference antiprogestin RU486 from three independent experiments IC 50 95% CI Compound Exp (nM) SE lower upper RU486 1 0.103 0.002 0.092 0.115 2 0.120 0.001 0.115 0.126 3 0.094 0.007 0.066 0.134 B. In-vivo Biology The primary in-vivo assay is the rat decidualization model which may be used to determine progestational effects of both agonists and antagonists. The secondary in-vivo assay is the rat ovulation inhibition model which is under development and hence the protocol is un-available.
1. Rat decidualization assay The objective of this procedure is used to evaluate the effect ofprogestins and antiprogestins on rat uterine decidualization and compare the relative potencies of various test compounds. The materials and methods used in this assay are as follows.
a. Methods: Test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle). Stock solutions of the test compounds in oil (MazolaTM) are then prepared by heating (-80 oC) the mixture to evaporate ethanol.
Test compounds are subsequently diluted with 100% corn oil or 10% ethanol in corn oil prior to the treatment of animals. No difference in decidual response was found when these two vehicles were compared.
b. Animals (RACUC protocol #5002) WO 00/66571 PCT/US00/1 1822 -94- Ovariectomized mature female Sprague-Dawley rats (-60-day old and 230g) are obtained from Taconic (Taconic Farms, NY) following surgery. Ovariectomy is performed at least 10 days prior to treatment to reduce circulating sex steroids.
Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum.
c. Treatment Rats are weighed and randomly assigned to groups of 4 or before treatment. Test compounds in 0.2 ml vehicle are administered by subcutaneous injection in the nape of the neck or by gavage using 0.5 ml. The animals are treated once daily for seven days. For testing antiprogestins, animals are given the test compounds and a EC50 dose of progesterone (5.6 mg/kg) during the first three days of treatment. Following decidual stimulation, animals continue to receive progesterone until necropsy four days later.
d. Dosing Doses are prepared based upon mg/kg mean group body weight. In all studies, a control group receiving vehicle is included. Determination of dose-response curves is carried out using doses with half log increases 0.1, 0.3, 3.0 e. Decidual induction Approximately 24 hr after the third injection, decidualization is induced in one of the uterine horns by scratching the antimesometrial luminal epithelium with a blunt 21 G needle. The contralateral horn is not scratched and serves as an unstimulated control. Approximately 24 hr following the final treatment, rats are sacrificed by CO2 asphyxiation and body weight measured. Uteri are removed and trimmed of fat. Decidualized (D-hom) and control (C-horn) uterine horns are weighed separately.
f. Analysis of Results: The increase in weight of the decidualized uterine horn is calculated by D-horn/C-hom and logarithmic transformation is used to maximize WO 00/66571 PCT/US00/11822 normality and homogeneity of variance. The Huber M-estimator is used to down weight the outlying transformed observations for both dose-response curve fitting and one-way analysis of variance. JMP software (SAS Institute, Inc.) is used for both oneway ANOVA and non-linear dose-response analyses.
g. Reference Compounds: All progestin reference compounds were run in full doseresponse curves and the EC 5 0 for uterine wet weight were calculated.
Table 8. Estimated ECso, standard error and 95% confidence intervals for individual studies
EC
50 95% CI Compound Exp (mg/kg, SE lower upper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.76 3-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.06 0.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.09 0.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.29 0.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61 WO 00/66571 PCT/US00/11822 -96- Table 9. Estimated average ECs 0 standard error, and 95% confidence intervals for dose-response curves of 3 reference compounds Compound Progesterone 3-Ketodesogestrel Levonorgestrel (mg/kg, s.c.) 5.62 0.10 0.10
SE
0.62 0.02 0.01 lower 4.55 0.07 0.08 95% CI upper 7.00 0.14 0.12 Table 10. Estimated ICso, standard error, and 95% antiprogestin, RU 486 confident interval for the Compound RU 486 ICso Exp. (mg/kg, p.o.) 1 0.21 2 0.14
SE
0.07 0.02 95% CI lower upper 0.05 0.96 0.08 0.27 Concentration: Compound concentration in assay(default-mg/kg body weight) Route of administration: Route the compound is administered to the animals Body weight: Mean total animal body weight (default-kg) D-hor: Wet weight of decidualized uterine horn (default-mg) C-horn: Wet weight of control uterine horn (default-mg) Decidual response: [(D-C)/C]xl00% Progestational activity: Compounds that induce decidualization significantly (p<0.05) compared to vehicle control are considered active Antiprogestational activity: Compounds that decrease EC 5 o progesterone induced decidualization significantly (p<0.05) WO 00/66571 PCT/US00/1 1822 -97- ECso for uterine weight: Concentration of compound that gives half-maximal increase in decidual response (default-mg/kg) ICso for uterine weight: Concentration of compound that gives half-maximal decrease in EC 50 progesterone induced decidual response (default-mg/kg) EXAMPLE 122 6-(3-Methoxyphenyl)spiro 4H-3,1-benzoxazine-4,1-cyclobutanl-2(1H)-one A solution of Boc protected 4-chloroaniline (1.15g, 5 mmol) in anhydrous THF was treated at -78 °C under a blanket of nitrogen with t-butyllithium (7.4 mL, 12.5 mmol). The reaction solution was then slowly warmed to -20 OC, kept stirring for 1.5 hours, and treated with cyclobutanone (lmL, 13.4 mmol). The mixture was warmed to rt and quenched with brine (30 mL) and lN aqueous hydrogen chloride solution (10 mL) was added Ethyl acetate was added and the organic layer was separated and dried (MgSO 4 After removal of the solvent, the residue was purified by flash column chromatography (hexane:ethyl acetate/3:1) to give the alcohol which was used in next step without further purification.
To a solution of above product in ethanol was added potassium hydroxide The reaction mixture was stirred at rt for 18 hours, followed by the addition of brine (20 mL) and a cold IN aqueous hydrogen chloride solution (20 mL). The precipitate was collected on a filter and washed with water to afford 6chlorospiro[4H-3,1-benzoxazine-4,1-cyclobutan]-2(lH)-one as a white solid (0.13g, 12% for two steps): mp 183-184 oC; MS (ESI) m/z 222 [M H].
A mixture of 6-chlorospiro[4H-3,1-benzoxazine-4,1-cyclobutan]-2(1H)-one g, 0.45 mmol), 3-methoxyphenyl boronic acid g, 0.66mmol), bis(diphenylphosphino)ferrocene]dichloronickel (II) (50 mg, 0.073 mmol), potassium phosphate (0.35g, 1.7 mmol) in dioxane (5 mL) was degassed to remove oxygen and then heated at 85 °C under a blanket of nitrogen for 72 hours. The reaction mixture was allowed to cool to rt. Ethyl acetate (30 mL) and brine (20 mL) were added. The organic layer was separated and dried (MgSO 4 After removal of solvent, the WO 00/66571 WO 0066571PCTUSOO/1 1822 -98residue was purified through a column chromatography (hexane:ethyl acetate/3: 1) to yield 6-(3-methoxy-phenyl)spiro[4H-3, 1-benzoxazine-4, 1-cyclobutan]-2(l1H)-one as white solid (18 mg, mp 145-146 'H-NMR (DMSO-d 6 6 8.04 1H), 7.69 1H, J= 1.6 Hz), 7.59 (dd, 1H, J= 8.2, 1.5 Hz), 7.36 1H, J= 7.9 Hz), 7.27 (d, 1H, J= 7.7 Hz), 7.22 1H, J= 2.2 Hz), 6.99 1H, J= 8.2 Hz), 6.92 (dd, 1H, J= 2.4 Hz), 3.83 3H), 2.45-2.62(m, 4H), 1.81-2. 12 (in, MS m/z 296 [M H.
EXAMPLE 123 8-Bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-21-3,1benzoxazin-2-one To a mixture of 6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1 ,4-dihydro-2H- 3, 1-benzoxazin-2-one (0.2g, 0.6 5 minol) and sodium acetate (0.1 g, 1.2 nunol) in acetic acid (5 mL) was added, at rt under nitrogen bromine (0.04 mL, 0.78 minol).
The reaction mixture was stirred for 20 hours and poured into ice water (30 mL).
The precipitate was collected on a filter and washed with water (3x5 mL) to yield 8bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl- 1,4-dihydro-2H-3 ,1 -benzoxazin-2one as off-white solid 18, mp 194-195 0 C; 'H-NMR (DMSO-d 6 )569.77 (s, 1 8.02 (dd, 1 H, J 7.10, 1.81 Hz), 7.92 1LH), 7.77 (in, IlH), 7.66 1LH), 7.47- 7.53 (in, I 1.71 6H). MS (ESI) m/z 3 84, 3 86 [M Hr-.
EXAMPLE 124 3-(8-Bromo-4,4-dimethyl-2-oxo-1 ,4-dihydro-2H-3,1-benzoxazin-6-yl)-5fluorobeuzonitrile Prepared according to the above procedure from 3-(4,4-dimethyl-2-oxo- 1,4dihydro-2H-3, 1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.5g, 1.7 inmol) as an offwhite solid (0.48g, mp 216-217 'H-NNvI (DMSO-d 6 6 9.78 1H), 8.18 WO 00/66571 WO 0066571PCTUSOO/1 1822 -99- 1H, J= 1.6 Hz), 8.02-8.08 (in, 2H), 7.81 (in, 1H), 7.75 IIH, J= 1.8 Hz), 1.66 6H). MS (ESI) m/z 373, 375 [M EXAMPLE 125 5-(8-Bromo-4,4-dimethyl-2-oxo-1 ,4-dihydro-211-341-benzoxazin-6-yl)-2fluorobeuzonitrile Prepared according to the above procedure from 5-(4,4-dimethyl-2-oxo-1,4dihydro-2H-3, 1 -benzoxazin-6-yl)-2-fluorobenzonitrile (0.2g, 0.67 inmol) as an offwhite solid (0.18g, mp 235-236 'H-NMR (DMSO-d 6 8 9.78 111), 8.38 (dcl, 1H,J= 6.1, 2.4 Hz), 8.14-8.20 (in, 1H), 7.98 lH, J= 1.9 Hz), 7.71 1H, J =1.8 Hz), 7.62 111,J= 9.1 Hz), 1.69 6H). MS (ESI) m/z 373, 375 [M EXAMPLE 126 6-(3-Bromophenyl)-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one To a solution of 6-(3-bromophenyl)-4,4-diniethyl- 1,4-dihydro-2H-3, 1benzoxazin-2-one (1 g, 3.0 innol) in anhydrous DMff was added, at rt under a blanket of nitrogen, sodium hydride (60% in mineral oil, 0.24g, 6.0 inmol). After stirring for minutes, the reaction solution was treated with iodoinethane and stirred for hours. The mixture was poured into a saturated aqueous amnmoniumn sulfate solution (40 mL) and ethyl acetate (40 inL) was added. The organic layer was separated, dried (MgSO 4 and evaporated to yield 6-(3-bromophenyl)-l ,4,4-trimethyl- 1,4dihyclro-2H-3,1-benzoxazin-2-one as off-white solid (0.75g, mp 142-143 'C; 'H-NNM (DMSO-d 6 6 7.93 LH), 7.71 (mn, 1H), 7.65 1H), 7.55 LH, J Hz), 7.42 (t LH,J= 7.7 Hz), 7.18 1H,J 8.4 Hz), 3.35 3H), 1.67 6H). MS (ESI) ,n/z 368, 370 [M Na]+.
EXAMPLE 127 6-(3-Fluorophenyl)4-methyl-1,4-dihdro-2H-3,1-bezoxazi-2-ofle WO 00/66571 PCT/USOO/11822 -100- 4-Amino-3'-fluoro[l, '-biphenyl]-3-carbonitrile was prepared from 3fluorophenyl boronic acid and 2-amino-5-bromobenzonitrile according to procedure A. A solution of 4-amino-3'-fluoro[1,1'-biphenyl]-3-carbonitrile (6.65g, 31.3 mmol) in anhydrous THF (100 mL) was treated drop wise at rt under nitrogen with methylmagnesium bromide (3.0 M in ether, 21 mL, 63 mmol). After addition, the reaction mixture was heated at gentle reflux for 1.5 hours, cooled to rt, and treated with 3N aqueous hydrogen chloride solution (30 mL). The mixture was heated at reflux for 3 hours, cooled to ambient temperature, and adjusted to pH 5-6 by addition of a saturated aqueous sodium carbonate solution. Ethyl acetate (100 mL) was added, organic layer was separated and aqueous layer was extracted with ethyl acetate (3x50 mL). The combined organic layers were dried (MgSO 4 and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1) to afford 1-(4-amino-3'-fluoro[1,1'-biphenyl]-3-yl)ethanone (3.1g, mp 156-157°C.
A solution of 1-(4-amino-3'-fluoro[1,1'-biphenyl]-3-yl)ethanone (3g, 13 mmol) in anhydrous methanol (60 mL) was treated at rt under nitrogen with sodium borohydride in a portion wise manner. After addition, the reaction mixture was stirred for 4 hours, treated with a saturated aqueous ammonium sulfate solution mL) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO 4 and evaporated. The residue was purified on a silica gel column chromatography (hexane:ethyl acetate/3:1) to yield 1-(4-amino-3'-fluoro[ 1,1 '-biphenyl]-3-yl)ethanol as a white solid (2g, mp 136-137 °C.
A mixture of above alcohol (0.2g, 0.87 mmol) and triphosgene in anhydrous THF (20 mL) was stirred at rt under nitrogen. After 15 minutes, the mixture was treated with a saturated aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (40 mL). The organic layer was separated, dried (MgSO 4 and evaporated to give 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0.18g, mp 160-161 'H-NMR (DMSO-d 6 8 10.31 1H), 7.62 (dd, WO 00/66571 PCT/US00/1 1822 101 1H, J= 8.2, 1.9 Hz), 7.57 1H), 7.44-7.53 3H), 7.13-7.20 (m 1H), 6.97 1H, J= 8.2 Hz), 5.57 1H, J= 6.6 Hz), 1.63 3H, J= 6.6 Hz). MS (ESI) m/z 256 [M EXAMPLE 128 3-(4,4-Dimethyl-8-methoxy-2-oxo-l,4-dihydro-2H-3,1-benzoxazin-6-yl)-5fluorobenzonitrile To a solution of 2-amino-3-methoxybenzoic acid (5g, 30 mmol) in anhydrous THF (100 mL) was added at ambient temperature under a blanket of nitrogen methylmagnesium bromide (3.0 M in THF, 50 mL, 150 mmol). The reaction mixture was heated at 50 oC for 18 hours, cooled to rt, and treated with a saturated aqueous ammonium chloride solution (50 mL). Ethyl acetate (100 mL) was added and organic layer was separated, dried (MgSO4), and evaporated. The residue was dissolved in anhydrous THF (100 mL) and treated at ambient temperature under nitrogen with 1,1 '-carbonyldiimidazole (5.4g, 33 mmol). After 24 hours, the mixture was quenched with IN aqueous hydrogen chloride solution (30 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO 4 and evaporated.
The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1) to afford 8-methoxy-4,4-dimethyl- 1,4-dihydro-2H-3,1 -benzoxazin-2-one as white solid (3.5g, MS (ESI) m/z 208 [M To a mixture of 8-methoxy-4,4-dimethyl- 1,4-dihydro-2H-3,1-benzoxazin-2one (2.1g, 10.1 mmol), sodium acetate (1.5g, 18 mmol) in acetic acid (30 mL) was added bromine (0.62 mL, 12 mmol) at ambient temperature. After 30 minutes, the solution was treated with a concentrated ammonium hydroxide solution (50 mL).
The precipitate was collected on a filter and washed with water (3x20 mL) to yield 6bromo-8-methoxy-4,4-dimethyl-l,4-dihydro-2H-3,1-benzoxazin-2-one (2.7g, 93%) as off-white solid: MS (ESI) m/z 286, 288 [M WO 00/66571 PCT/US00/11822 -102- A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1benzoxazin-2-one (1.6g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5g, 15.3 mmol), and bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85 °C under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), bis(diphenylphosphino)- ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5g, 0.6 mmol), and sodium carbonate (2g, 19 mmol) in water mL). The resulted solution was heated at 85 °C for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO 4 and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3- (4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3, 1 fluorobenzonitrile as a white solid (0.6g, mp 252-253 'H-NMR (DMSOd 6 8 9.76 1H), 8.21 1H), 8.07 1H, J= 10.6 Hz), 7.82 7.39 (s 1H), 7.36 1H), 3.93 3H), 1.66 6H). MS (ESI) m/z 325 [M EXAMPLE 129 3-(4,4-Dimethyl-8-hydroxy-2-oxo-l,4-dihydro-2H-3,1-benzoxazin-6-yl)-5fluorobenzonitrile A mixture of 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1- (0.1g, 0.31 mmol), Lithium iodide (0.3g, 2.24 mmol) in 2,4,6-collidine was heated at reflux under nitrogen for 5 hours. The solvent was removed in vacuo and the residue was taken in a mixture of brine (10 mL) and ethyl acetate (30 mL). The organic layer was separated, dried (MgSO4), and evaporated. The resultant residue was purified on a silica gel column chromatography (hexane:ethyl acetate/l: 1) to give the title compound as white plates WO 00/66571 WO 0066571PCT/USOO/I 1822 103 (0.03mg, 3 mp 197-198 'H-NMR (DMSO-d 6 8 10.16 1H), 9.55 1H), 8.01 1H), 7.79-7.87 (in, 2H), 7.20 7.08 1H, J 1.0 Hz), 1.65 6H).
MS (ESI) m/z 311 [M EXAMPLE 130 6-(2,3-Difluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo I] 11,31 oxazin-2-one Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H- 3,1-benzoxazin-6-yl)boronic acid and 2,3-difluorobenzyltriflate. A yellow solid: mp 166-167 0 C; 'H-NMR (DMSO-d 6 8 10.4 1H), 7.5-7.2 (in, 5H), 7.0 (in, 1H), 1.7 6H); MS (El) in/z 289 Anal. Calc. For C, 6
H
13
F
2 N0 2 C, 66.43, H, 3, N, 4.84. Found: C, 66.15, H, 4.3 7, N, 4.64.
EXAMPLE 131 3-(l-EthyIl4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzodI I1,31oxazin-6-yl)-5fluoro-beuzonitrile Prepared according to the procedure for example 125 from 3-(4,4-dimethyl-2oxo- 1,4-dihydro-2H-benzo[d][ 1,3 ]oxazin-6-yl)-5-fluoro-benzonitrile. A white solid: mp 154-155 0 C; 'H-NMR (DMSO-d 6 6 8.17 1H), 8.03 1H, J 10.5 Hz), 7.84- 7.77 (in, 3H1), 7.27 1H, J 8.54 Hz), 3.97 2H, J 6.89 Hz), 1.67 6H) 1.21 3H, J 6.95 Hz); MS (El) mlz 324 +I Anal. Calc. For C, 9 H,.,FN,0 2
C,
70.36, H, 5.28, N, 8.64. Found: C, 70.33, H, 5.51, N, 8.48.
EXAMPLE 132 t6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridil-2vii acetonitrile Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H- 3,1-benzoxazin-6-yl)boronic acid and (6-bromo-2-pyridyl)acetonitrile Org. Chem.
1988, 53, 786-790). An off-white solid, mp 210-212.5 'H NMR (DMSO-d 6 Q 1.68 6 4.27 2 7.00 1 H, J 8.3 Hz), 7.34 1 H, J =7.1 Hz), P:\WPDOCS\CAB\SPECI\7639430 AMENDEDDESCRIPTIONAMo-2O8/O3 104 7.89 7.96 (in, 2 8.00 8.05 (in, 2 10.42 1 MIS (ESI) 292. Anal.
calcd. for C1 7 H1 5
N
3 0 2 C, 69.61; H, 5.15; N, 14.33. Found: C, 68.49; H, 5.19; N, 13.74.
EXAMPLE 133 3-(4,4-Dimethl-2-oxo-1.,4-dihydro-2H-benzo[dl 11,31-oxazin-6-vl)-5-fluorophenylacetonitrile To a solution of 3-bromo-5-fluorobenzaldehyde(22.25g, 0. 11 mole) in methanol at rt was added NaBH 4 ,(2.07g, 0.055 mole) stirred at rt for 2 hr. The reaction was quenched with
H
2 0, and concentrated. The residue was diluted with diethyl ether, washed with 1 N HCl, brine, dried over MgSO 4 concentrated. 3-Bromo-5-fluorobenzyl alcohol as a colorless oil was collected (14.6 g, 'H NMR (DMS0-l 6 64.50 2H), 5.44(t, 3H, J=5.93 Hz), 7.16 (dcl, 1H, J= 1.09, 8.79Hz), 7.36( s, 1H), 7.38 (dd, 11H,J= 2.99, 6.15Hz); Anal. Caic. For
C
7
H
6 Br 2 FO: C, 41.01, H, 2.95 Found: C, 41.30, H, 3.01.
To a solution of 3-Bromo-5-fluorobenzyl alcohol (2.3g, 0.011 mole) in CH 2 Cl 2 was added 12.4mL of 1.OM PBr 3 (3.33g, 0.0123 mole) in CH 2 Cl 2 stirred for 3 hr, diluted with ether (lOOinL), washed with H 2 0 (50m1,3X), dried over MgSO 4 concentrated.
Purified by column chromatography using 1:9 ethyl acetate/hexane as an eluant solvent system. 3-Bromo-5-fluorobenzyl bromide as a white crystalline material was obtained, mp ::41-43-C. 'H NMR (DMS0-l 6 6 4.69 s, 2H), 7.52( d, 1H, J =1.76Hz) 7.54(d, 1H, J =1.91 Hz), 7.56( s, 1H); MIS( El): m/z 266 Anal. Caic. For C 7
H
5 Br 2 F: C, 31.38, H, 1.88.
Found: C, 31.75, H, 1.78.
To a solution of 3-broino-5-fluorobenzyl bromide (3.2g, 0.0112 mole) in 1,4-dioxane (2OmL) was added a solution of KCN (0.82g, 0.013 mole) in H 2 0 (5mL) and EtOH refluxed for 2 hours. Extracted with ether, washed with brine, dried over MgSO 4 concentrated. Column chromatography using hexane/ethyl acetate fluorophenylacetonitrile obtained was a colorless oil: 'H NMR P\WPDOCS\CASPEC1\7639430 AMENDEDDESCRIPTIONdc-12108/03 105 (DMSO-d 6 d 4.15 2H), 7.29( d, 1H, J= 9.37 Hz), 7.47(s, 1H), 7.55( d, 1H, J= 8.45Hz); MS( EI) M m/z 213 Anal. Calc. For C 8
H
5 BrFN: C, 44.89, H, 2.35, N,6.54. Found: C, 44.88, H, 2.32, N, 6.46.
The title compound was prepared according to the procedure B from fluorophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1 -benzoxazin-6yl)boronic acid. A white solid was obtained and recrystallized from ethanol/ether: mp 218- 220. 'H NMR (DMSO-d 6 6 1.67 s, 6H), 4.11( s, 2H 6.98(d, 1H, J= 8.92Hz), 7.18( d, 1H, J= 9.26), 7.52-7.62( m, 3H), 10.37( s, 1H); MS( EI) m/z 309; Anal. Calcd. For
C
18
H
15
FN
2 0 2 C, 69.67, H, 4.87, N, 9.03. Found: C, 69.78, H, 4.97, N, 8.36.
EXAMPLE 134 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[dl11,31-oxazin-6-vl)-4-fluorophenylacetonitrile To a solution of 5-bromo-2-fluorotoluene (15g, 0.079 mole) in CC14 (150mL) was added NBS (14.2g, 0.080 mole). The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr. CCl 4 was removed under reduced pressure and the residue was diluted dissolved in ether, washed with brine (3X), dried over MgSO 4 concentrated. Chromatographed/hexane yielded 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below.
5-Bromo-2-fluorobenzyl bromide (8.0g, 0.03 mole) was dissolved in 1,4-Dioxane (60mL) and added to a solution of KCN (2.04g, 0.031 mole) in H 2 0 20mL) and ethanol The resulting mixture was heated under reflux for 5 h. After cooling to rt, the product was extracted with ether 200mL), washed with brine, dried over MgSO 4 concentrated. Crystallized from ether/hexane to give 5-bromo-2-fluorophenylacetonitrile as a white crystalline material (5.6g, mp 55-58 0 C; 'H NMR (DMSO-d 6 5 4.07 s, 2H), 7.29( t, 1H,J= 9.23Hz), 7.60-7.69( m, P:\WPDOCS\CAfl\SPECI\7639430 AM.ENDEDDESCRIPTIONd.-2/08/03 106 2H); MS( EL) m/z 213 Anal. Caic. For C 8
H
5 Br 2 FN: C, 44.89, H, 2.35, N, 6.54. Found: C, 44.90, H, 2.24, N, 6.43.
The title compound was prepared from 5-Bromo-2-fluorophenylacetonitrile and 1,4dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxaxin-6-yl)boronic acid. White solid; mp 184-187 0 C 'H NMR (DMSO-d 6 a 1.67 s, 6H), 4.11( s, 2H), 6.98(d, 1H, J= 8.92Hz), 7.36(t, 1H, J 9.13 Hz) 7.54 d, 2H, J= 7.91 Hz), 7.67-7.75( m, 2H), 10.37( s, 1H); MS( El) m/z 309; Anal. Calc. For C1 8 H1 5
FN
2 0 2 C, 69.67, H, 4.87, N, 9.03. Found: C, 68.71, H, 4.80, N, 8.54.
EXAMPLE 135 4-(4,4-Dimethvl-2-oxo-1,4-dihydro-211-benzoldl 1.31 oxazin-6-yl)-2fluoronhenylacetonitrile Prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (T.
Alessi A.H.P. US Patent No: 4895862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1benzoxazin-6-yl)boronic acid. A grey solid; mp 253-2560 C 'HNMR(DMSO-d6) a 10.35 (s,1H) 7.67 -7.49(m,5H), 6.97(d,1H;J=8.6Hz) 4.09 (s,2H) 1.67(s, 6H); MS [M-Hf- m/z 309.
Anal. Calc. For C1 8
HI
5
N
2 F0 2 0.15H20: C,69.07, H, 4.93, N, 8.95. Found C,69.27, H 5.05, N, 8.50 EXAMPLE 136 24.4-Dimethyl 2- oo14dhdo2-ez~]13-xzn6 Prepared according to procedure B from 2- bromophenylacetonitrile and 4dihydro-4,4-dimethyl-2-oxo- 2H-3,1-benzoxazin-6-yl)boronic acid. White solid mp 176- 179'C; 'H-NMR (DMSO-d6), 6 10.31 1H), 7.53 (in, 1H), 7.48(m,2H), 7.22-7.32(m,3H), 6.98(d,1H; J=8.0 Hz), 3.90(s,2H), 1.64(s,6H). MS (+)APCI m/z =293. Anal. Calc.
For C 18
H,
6
N
2 0 2 C, 73.95, H, 5.52, N, 9.58. Found: C,73.51, H, 5.70, N, 9.39.
PVPDOSCAB\SPECX7639430 AMENDEDDESCRPTIONdo-12=S/3 107 EXAMPLE 137 N-14-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluoro-phenvllacetamide Prepared according to procedure B from 4'-bromo-2'-fluoroacetanilide and (1,4dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off white solid mp 245- 247 0 C. 'H-NMR (DMSO-d6) 510.3 9.79 lH), 7.95 (t,1H;J=8.4 Hz), 7.56- 7.63(m,3H), 7.47(dd,1H J= 1.64, 8.47Hz), 6.95(d,1H; J=8.9 Hz), 2.1(s, 3H), 1.67(s,6H); MS +APCI m/z 329. Anal. Caic. For C 18
HI
7
N
2 F0 3 C, 65.85, H, 5.22, N, 8.53. Found: C,65.46, H,5.24, N,8.12.
EXAMPLE 138 6-(3-Fluoro-4-methoxv-nhenyl)4.,4-dimethv1-1,4-dihydro-benzoI [1,31oxazin-2one Prepared according to procedure B from 4-bromo-2-fluoroanisole and 4-dihydro- 4,4-dimethyl-2-oxo- 2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 210-21 1'C 'H1- NMR (DMSO-d6), 5 10.27(s,lH), 7.52-7.60 7.45(d,1H, J=8.6 Hz), 7.22 1H; J=8.9 Hz), 6.94(d,1H, J=8.8 Hz), 3.87(s,3H), 1.66(s, 6H). MS [M-H]fm/z 300.
EE DAnal. Calc. For C1 7
HI
6 FN0 3 C, 67.76, H, 5.35, N, 4.65. Found: C,67.88, H,5.39, N, 4.70.
EXAMPLE 139 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzoldl I1,31-oxazin-6v1)Dhenylacetonitrile Prepared according to the procedure B from 3-bromophenylacetonitrile and (1,4dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid. White solid: mp 188- *:190 0 C. 1H-NMiR (DMSO-d6) 8 10.33(s, 1H), 7.62(m, 2H), 7.55 (in, 2H), 7.48 1H J=8.00 Hz), 7.33 1H, J=7.57Hz), 6.99 (d,lH, J=8.81 Hz) 4.09 2H), 1.67 6H); MS m/z Anal. Calc.For C1 8
H
16
N
2 0 2 )2.0.3 H20: C,72.61, H, 5.62, N, 9.41. Found: C, 73.00, H,5.43, N, 8.81.
PA\WPDOCS\CAB\SPEC\7639430 AMENDEDDESCRIPTION8-1208/03 108 EXAMPLE 140 3-(4,4-Dimethyl-2-oxo-1,4-dihvdro-2H-benzoldI 11,31-oxazin-6-vl) benzenesulfonamide Prepared according to procedure B from 3-bromobenzenesulfonamide and (1,4dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 242- 244'C (dec) 'H-NMR (DMSO-d6) 5 10.28(s, broad 1H), 8.07(s,1H), 7.9(d, 1H, J=7.80 Hz), 7.78 1H J=7.86Hz), 7.64 1H, J=7.79 Hz), 7,59 (in, 2H 7.42(s, broad 2H), 7.02(d, 1H, J 8.86Hz), 1.68(s, 6H); MS in/z 331I(M+H). Anal. Calc.For C 16
HI
6
N
2 0 4 C,57.82, H, 4.85, N, 8.43. Found: C, 57.49, H,5.08, N, 8.05.
EXAMPLE 141 5-(4,4-Dimethyl-2-oxo-1 ,4-dihydro-2H-benzo dIl [131-oxazin-6-vl)-thionihene-2sulfonamide Prepared according to procedure B from 5-bromothiophene-2-sulphonamide and (1,4dihydro-4,4-dimethyl-2-oxo-2H-3, 1-benzoxazin-6-yl)boronic acid. White solid: mp 258- 260-C, 'H-NMR (DMSO-d6) 5 1.41(s,1H), 7.71(s,2H), 7.58(m,2H), 7.52(d, 1H, J=3.9Hz), 7.48(d, 1H J=8.l6Hz), 6.95(d, 1H J=8.16), 1.66(s,6H); MS in/z 337(M-H). Anal. Caic. For
C
14
H
14
N
2
O
4
S
2 C,49.69, H, 4.17, N, 8.28. Found: C, 49.90, H, 4.28, N, 8.12.
EXAMPLE 142 6-(6-Amino-pyridin-3-vl)-4,4-dimethyl-1 ,4-dihydro-benzo I [1131 oxazine-2-one Prepared according to procedure B from 2-amino-5-bromopyridine and (1,4-dihydro-., 4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White crystals, mp, 257-259'C. 'H- NMR (DMSO-d6) 8 10.20 8.22 (d,1H, J=2.38 Hz) 7.69,7.66 (dd, 1H, J=2.5, 2.5 Hz), 7.42 6.89 (d,1H, J=8.8Hz), 6.49(d,1H, J=8.64Hz), 6.02 1.64 MS m/z 269 Anal. Calcd. For C 15
H
15
N
3 0 2 .17 H20: C, 66.15, H, 5.68, N, 15.43. Found: C, H, 5.8 1, N, 15.02.
WO 00/66571 WO 0066571PCTUSOO/1 1822 -109- EXAMPLE 143 6-(5-Diethoxymethyl-furan-3-yl) -4,4 -dimethyl 1,4 dihydro benzoldi 1 1.3 1 oxazin-2-one Prepared according to procedure B from 4,4-dimethyl 2 oxo 4 dihydro, 2 H benzo, 1,3 oxazine boronic acid and 3-bromo-5-diethoxymeyhyl furan.
A brown gum: 'H NMR (DMSO-d, 8 10.2 1LH), 8.12(s, 1 7.54-7.49 (in, 2H), 6.93-6.88(mi, 2H1), 5.56(s, 1H), 3.60-3.38(m, 4H), 1.67(s 1.2-1.14 (mn, 6H). .MS (ESI) rn/z 344 Anal. Calcd. For C, 9 H23NO, 5 1f2 H 2 0: C, 64.39; H, 6.77; N, 3.95. Found C, 64.90; H, 6.79; N, 3.78.
EXAMPLE 144 4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzoldI 11,31 oxazin-6-yl)-furan-2carbaldehyde A solution of 6-(5-diethoxymethyl-furan-3-yl)-4,4-dimnethyl- 1,4-dihydrobenzo[d] oxazin-2-one, (1.1g, 3 mmol) was stirred in THF (20 niL) and 2N HC1 (2 mL) for 1 hour. The crystalline product was filtered and dried (0.52 g, mp 262-263 'H NMR DMS0-cl 6 10.3 1H 9.65 s, 1H 8.59 s, 1H 8.04 1H), 7.65-7.64 1H, J 1.5 Hz),7.61-7.60 1H, J 1.8 Hz), 7.59-7.58 (d, 1H, J 1.8 Hz), 6.94-6.91 1H, J 8.2 Hz), 1.65 6H). .MS (ESI) m/z 270 [M- EXAMPLE 145 4-(1,4-Dihydro-4,4-dimethyl-2-oxo-211-3,1-benzoxazin-6-yl)-2furancarboxaldehyde oxime A mixture of 4-(4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1,3 ]oxazin-6yl)-fiiran-2-carbaldehyde (2.7 g, 1 mmol), hydroxylamine hydrochloride (0.75 G, 10.6 mmol) and sodium acetate 0.87 g, 10.6 inmol) was heated at reflux in 80% ethanol mL for 2 hours. The title compound crystallized from the cooled reaction mixture as tan crystals (1.5g, mp 236-238 0 C. 'H NMR (DMSO-d 6 5 11l.97(s, -110- 1H), 10.26 111), 8.2 114), 7.63 1H), 7.56-7.52 (in, 311), 6.91-6.88 I H, J=8.1 Hz), 1.66 6H). MS ESI m/z 285 [M-HI. Anal. Calcd. For C,,H,,N 2
C,
62.93; H, 4.93; N, 9.79. Found C, 62.77; H, 5.00; N, 9.79.
All publications cited in this specification are incorporated herein by reference herein. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are 10 intended to fall within the scope of the appended claims.
:0:110Throughout this specification and the claims which follow, unless the context se requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as an acknowledgment or any form of suggestion that, that prior art forms part of the common general knowledge in Australia.

Claims (6)

1. A compound of the formula: R 1 R 2 R O R 4 13 RR I wherein: R' and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A and NRBCORA; or R' and R 2 are fused to form: a) a carbon-based 3 to 8 membered saturated spirocyclic ring; b) a carbon-based 3 to 8 membered spirocyclic ring having one or more carbon- carbon double bonds; or c) a 3 to 8 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N; the rings of b) and c) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, Ci to C 6 thioalkyl, CF3, OH, CN, NH 2 NH(C 1 to C 6 alkyl), and N(CI to C 6 alkyl) 2 R A is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl; RB is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl; i P:\WPDOCSCABSPECI\7639430 AMENDEDCLAIMS.dM-2I08/03 -112- R 3 is H, OH, NH 2 C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, or CORC; R c is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl; R 4 is H, halogen, CN, NO 2 C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, alkynyl, substituted alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, amino, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl; R 5 is selected from the group consisting of a) and b): a) a substituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is selected from the group consisting of halogen, CN, C 1 to C 3 alkyl, substituted SCI to C 3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 C 1 to C 3 perfluoroalkyl, 5 or 6 membered S" heterocyclic ring containing in its backbone 1 to 3 heteroatoms, CORD, OCOR D and NRECORD; RD is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, CI to C 3 aminoalkyl, or substituted CI to C 3 aminoalkyl; R E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl; Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 amino, aminoalkyl, C 1 to C 3 alkoxy, Ci to C 3 alkyl, and C 1 to C 3 thioalkoxy; or b) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and containing one or two independent P-\WPDOCS\CAB\SPECI7639430 AMENDEDCLAMS.d-1210803 -113- substituents selected from the group consisting of H, halogen, CN, NO 2 amino, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F and NRGCOR; with the proviso that when R 5 is the five membered ring having in its backbone two NR 6 heteroatoms, R' and R 2 are not both H; and with the proviso that when R 5 is a five-membered ring having in its backbone one NR 6 heteroatom, and wherein R 5 is attached at the two position on said ring, there is no CN substituent in the five position on said ring; RF is H, Ci to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted C 1 to C 3 alkoxy, CI to C 3 aminoalkyl, or substituted CI to C 3 aminoalkyl; R G is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl; with the proviso that when R 5 is the benzene ring a) substituted with one or two substituents or the 5 or 6 membered ring b) having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR 6 and R' is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, R 2 is not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; or if R 2 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, R' is not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; with the proviso that when R 5 is the benzene ring a) substituted with one or two substituents or the 5 or 6 membered ring b) having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR 6 and R' is alkyl or substituted alkyl, R 2 is not cycloalkyl or substituted cycloalkyl; or if R 2 is alkyl or substituted alkyl, R 1 is not cycloalkyl or substituted cycloalkyl; R 6 is H or CI to C 3 alkyl; or pharmaceutically acceptable salt thereof. A compound of the structure:
2. A compound of the structure: PAWPDOCS\CAMhSPECA7639430 AMENDEDCLAIMS.d-1210/03 -114- R 1 R 2 /-YNO NO R 4 R I wherein: R' and R 2 are independent substituents selected from the group consisting of H, C 1 to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to Cg cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A and NRBCORA or R 1 and R 2 are fused to form a ring selected from the group consisting of and c): a) a carbon-based 3 to 8 membered saturated spirocyclic ring; b) a carbon-based 3 to 8 membered spirocyclic ring having one or more S carbon-carbon double bonds; c) a 3 to 8 membered heterocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of 0, S and N; the rings of and c) being optionally substituted by from 1 to 4 **o groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 OH, CN, NH 2 NH(CI to C 6 alkyl), and N(CI to C 6 alkyl) 2 R A is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, CI to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl; RB is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl; R 3 is H, OH, NH 2 CI to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, or CORC; Rc is H, Ci to C 4 alkyl, substituted C 1 to C 4 alkyl, aryl, substituted aryl, C 1 to C 4 alkoxy, substituted CI to C 4 alkoxy, C, to C 4 aminoalkyl, or substituted Ci to C 4 aminoalkyl; P:\WPDOCS\CAB\SPECI\7639430 AMENDEDCLMMS.dmc-12108/03
115- R 4 is H, halogen, CN, NO 2 C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, amino, C 1 to C 6 aminoalkyl, or substituted CI to C 6 aminoalkyl; R 5 is or (ii): a substituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is selected from the group consisting of halogen, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, CORD, OCOR D and NRECORD; RD is H, CI to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, S C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted Ci to C 3 *0@ aminoalkyl; RE is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl; Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or (ii) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and containing one or two independent 4 substituents selected from the group consisting of H, halogen, CN, NO 2 amino, C 1 to C 3 alkyl, and Ci to C 3 alkoxy; with the proviso that when R 5 is the five membered ring having in its backbone two NR 6 heteroatoms, R' and R 2 are not both H; and P:\WPDOCSCAB\SPECI\7639430 AMENDEDCLAIMS.doc-12J08/03
116- with the proviso that when R 5 is a five-membered ring having in its backbone one NR 6 heteroatom, and wherein R 5 is attached at the two position on said ring, there is no CN substituent in the five position on said ring; R 6 is H, or C 1 to C 3 alkyl; with the proviso that when R 5 is the benzene ring a) substituted with one or two substituents or the 5 or 6 membered ring b) having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR 6 and R' is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, R 2 is not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; or if R 2 is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, R' is not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; with the proviso that when R 5 is the benzene ring a) substituted with one or two substituents or the 5 or 6 membered ring b) having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR 6 and R' is alkyl or substituted alkyl, R 2 is not cycloalkyl or substituted cycloalkyl; or if R 2 is alkyl or substituted alkyl, R' is not cycloalkyl or substituted cycloalkyl; or pharmaceutically acceptable salt thereof. 3. A compound of the formula: R1 R 2 RR4 w..Rr R3 wherein: •1 whrein P:\WPDOCS\CAB\SPECI\7639430 AMENDEDCLAJMSd-12/08/03
117- R' R 2 and are selected from the group consisting of C 1 to C 3 alkyl and substituted C 1 to C 3 alkyl, or R' and R2 are fused to form a carbon-based 3 to 6 membered saturated spirocyclic ring; R 3 is H, OH, N11 2 CI to C 6 alkyl, substituted C, to C 6 alkyl, or CORc; Rc is H, C 1 to C 4 alkyl, or C, to C 4 alkoxy; Wi is H, halogen, CN, NO 2 C 1 to C 3 alkyl, substituted C, to C 3 alkyl, C 1 to C 3 atkoxy, or substituted C, to C 3 alkoxy; R 5 is selected from the group consisting of b) and c): a) a substituted benzene ring of the formrula shown below: x 3, Y_ b7 wherein: X is halogen, CN, C, to C 3 alkoxy, C, to C 3 alkyl, NO 2 C 1 I to C 3 0 0 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, or CI to C 3 thioalkoxy; 000. 6:00 Y is H, halogen, CN, NO 2 CI to C 3 alkoxy, C 1 to C 4 alkyl, or C 1 to C 3 thioalkoxy; b) a five membered ring of the structure: S. C *see *0 *0e P:\WPDOCS\CAB\SPEC7639430 AMENDEDCLAIMS.doc 12108/03 -118- X' is selected from the group consisting of halogen, CN, NO 2 C 1 to C 3 alkyl, and C 1 to C 3 alkoxy; Y' is selected from the group consisting of H and C 1 to C 4 alkyl; and c) a six membered ring of the structure: wherein: X' is N or CX2 X 2 is halogen, CN, alkoxy, or NO 2 R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl; or pharmaceutically acceptable salt thereof. 4. The compound according to any of claims 1 to 2, wherein: R' is H, Ci to C 6 alkyl, substituted CI to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A or NRBCORA; Rc is H, Ci to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl; R 4 is H, halogen, CN, NO 2 C 1 to C 6 alkyl, substituted Ci to C 6 alkyl, CI to C 6 alkoxy, substituted C 1 to C 6 alkoxy, amino, C 1 to C 6 aminoalkyl, or substituted CI to C 6 aminoalkyl; R 5 is a) or b): a) the substituted benzene ring, wherein: X is selected from the group consisting of halogen, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C, to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, C 1 to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl, P:\WPDOCS\CABSPECI\7639430 AMENDEDCLAIMS.do-120803
119- NO 2 C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, CORD, OCORD, and NRECORD; Y and Z are independent substituents selected from the group consisting of H, halogen, CN, NO 2 C 1 to C 3 alkoxy, Ci to C 3 alkyl, and CI to C 3 thioalkoxy; or b) the five or six membered ring, wherein said one or two independent substituents are selected from the group consisting of H, halogen, CN, NO 2 amino, C 1 to C 3 alkyl, and CI to C 3 alkoxy. The compound according to any of claims 1 to 4, wherein: R' R 2 and are selected from the group consisting of C 1 to C 3 alkyl and substituted Ci to C 3 alkyl, or R' and R 2 are fused to form the carbon-based 3 to 6 membered saturated spirocyclic ring; R 3 is H, OH, NH 2 C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or CORC; RC is H, C 1 to C 3 alkyl, or C 1 to C 3 alkoxy; R 4 is H, halogen, CN, NO 2 C 1 to C 3 alkyl, substituted Ci to C 3 alkyl, C 1 to C 3 alkoxy, or substituted C 1 to C 3 alkoxy; R 5 is selected from the group consisting of b) and c): a) the substituted benzene ring of the formula shown below: x 3' Y- wherein: X is halogen, CN, C 1 to C 3 alkoxy, C, to C 3 alkyl, NO 2 C 1 to C 3 P:\WPDOCS\CAB'.SPECI\763943o AMENDEDCLAIMS.do-IOS103 -120- perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, or CI to C 3 thioalkoxy; and Y is H, halogen, CN, NO 2 C 1 to C 3 alkoxy, C 1 to C 3 alkyl, or Ci to C 3 thioalkoxy; b) the five membered ring of the structure: wherein: U is O, S, or NR6; X' is selected from the group consisting of halogen, CN, NO 2 C 1 to C 3 alkyl, and Ci to C 3 alkoxy; Y' is selected from the group consisting of H and C 1 to C 3 alkyl; R 6 is H or C 1 to C 3 alkyl; and c) the six membered ring of the structure: X oeo• go o ego. wherein: X' is CX2; X 2 is halogen, CN, C 1 to C 3 alkoxy, or NO 2 or pharmaceutically acceptable salt thereof. 6. The compound according to any of claims 1 to 4, wherein: NN. P:\WPDOCS\CAB\SPECI\7639430 AMENDEDCLAIMSdo-I2108/03 -121- R 1 R 2 and are CH 3 or R 1 and R 2 are fused to form the carbon-based 6 membered saturated spirocyclic ring; R 3 is H, OH, NH 2 C 1 alkyl, substituted C 1 alkyl, or CORC; Rc is H, C 1 to C 3 alkyl, or C 1 to C 3 alkoxy; R 4 is H, halogen, NO 2 CN, or C 1 to C 3 alkyl; R 5 is the substituted benzene ring a) of the formula: x 3' 4- Y_ 5.>7 wherein: X is selected from the group consisting of halogen, CN, C 1 alkoxy, NO 2 or the heterocyclic ring, wherein said heterocyclic ring is 2-thiazole; Y is H or halogen. S 7. The compound according to any of claims 1 to 4, wherein: R' R 2 and are CH3 or R' and R 2 are fused to form the carbon-based 6 membered saturated spirocyclic ring; R 3 is H, OH, NH 2 C 1 alkyl, substituted C 1 alkyl, or CORC; Rc is H, C 1 to C 3 alkyl, or Ci to C 3 alkoxy R 4 is H, halogen, NO 2 CN, or C 1 to C 3 alkyl; R 5 is the five membered ring b) having the structure: *S S*wherein: o P:\WPDOCS\CAB\SPECI\7639430 AMENDEDCLAIMSdo.I12O8/03 122 U isO0, S, or NH; X' is halogen, CN, or NO 2 provided that when U is NH, then X' is not CN; Y' is H or C I to C 3 alkyl or a pharmaceutically acceptable salt thereof. 8. The compound according to any of claims 1 to 4, wherein R 5 is selected from the group consisting of: N NC NC- :S and 9. A compound selected from the group consisting of 6-(3-Chlorophenyl)-4,4- dimethyl- 1,4-dihydrobenzo[d] [1 ,3]oxazin-2-one, 6-(3-Methoxy-phenyl)-4,4-dimethyl- 1,4- dihydro-benzo[d] [1 ,3]-oxazin-2-one, 6-(2-Chloro-phenyl)-4,4-dimethyl- 1,4-dihydro- benzo[d] oxazin-2-one, 6-(4-Chloro-phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] :oxazin-2-one, 6-(3-Chloro'-phenyl)-4-methyl- 1,4-dihydro-benzo [1 ,3]oxazin-2-one, 6-(3- *Chloro-phenyl)-4-ethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-phenyl- 1 ,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H- :::benzo[d] oxazin-6-yl)-benzonitrile, 4,4-Dimethyl-6-(3 -nitrophenyl)- 1,4- dihydrobenzo[d] [1 ,3]oxazin-2-one, 6-(3-Bromo-5 -fluorophenyl)-4,4-dimethyl- 1,4- P:%WPDOCS\CAB\SPECI\7639430 AMENDEDCLAIMS.d.-2/8O3 123 dihydrobenzo[d] oxazin-2-one, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin- 5-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] oxazin-6-yl)- nicotinonitrile, 4-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-thiophene-2- carbonitrile, 5-(4,4-Dimethyl-2-oxo- 1, 4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-thiophene-2- carbonitrile, 5-(4,4-Dimethyl-2-oxo- 1, 4-dihydro-2H-benzo [1 ,3]oxazin-6-yl)-4-methyl- thiophene-2-carbonitrile, 4-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1,3 ]oxazin-6-yl)- fuiran-2-carbonitrile, 4,4-Diethyl-6-(3-nitrophenyl)- 1,4-dihydrobenzo[d] [1 ,3]oxazin-2-one, 6-(3- Chlorophenyl)-4,4-diethyl- 1,4-dihydrobenzo[d] [1 ,3]oxazin-2-one, 6-(3-Chlorophenyl)-spiro[4H- 3, 1 -benzoxazine-4, 1' -cyclohexane] -2-(l1H)-one, 6-(3-Chlorophenyl)-spiro-[4H-3, 1- benzoxazine-4, 1' -cyclopentane]-2( 1H)-one, 6-(3-Nitrophenyl)-spiro[4H-3, 1-benzoxazine-4, 1'- cyclohexan]-2( 1H)-one, 4-Allyl-6-(3 -chlorophenyl)-4-methyl- 1,4-dihydro-benzo[d] [1,3 ]oxazin- 2-one, 6-(3 -Chlorophenyl)-4-methyl-4-phenyl- 1,4-dihydro-benzo[d] oxazin-2-one, 4- Benzyl-6-(3-chloro-phenyl)-4-methyl- 1,4-dihydro-benzo[d] oxazin-2-one, 6-(3-Chloro- phenyl)-4-cyclopropyl-4-methyl- 1,4-dihydro-benzo[d] oxazin-2-one, 6-(3-Chloro-phenyl)- 4,4-dicyclopropyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(3-Bromo-5-fluorophenyl)- 1,4,4- trimethyl- 1,4-dihydrobenzo[d] [1 ,3]oxazin-2-one, 6-(3-Methoxyphenyl)-4-methyl-4- .trifluoromethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(3-Acetyl-phenyl)-4,4-dimethyl- 1,4- dihydro-benzo[d] oxazin-2-one, 6-(3-Benzoyl-phenyl)-4,4-dimethyl- 1,4-dihydro- benzo[d] -oxazin-2-one, 4,4-Dimethyl-6-[3-(l1H-tetrazol-5-yl)-phenyl]- 1,4- dihydrobenzo[d] [1 ,3]oxazin-2-one, 4-(4,4-Dicyclopropyl-2-oxo- 1,4-dihydro-2H- benzo[d] oxazin-6-yl)-thiophene-2-carbonitrile, 6-(3-Bromo-5-fluoro-phenyl)-4,4- dicyclopropyl- 1,4-dihydrobenzo-[d] [1,3 ]oxazin-2-one, 3-(4,4-Dicyclopropyl-2-oxo- 1,4-dihydro- :2H-benzo[d] [1 ,3]oxazin-6-yl)-5-fluoro-benzonitrile, 6-(3-Bromo-5-methyl-phenyl)-4,4- I: dimethyl- 1,4-dihydrobenzo-[d] [1 ,3]oxazin-2-one, 6-(3 -Bromo-5-trifluoromethoxy-phenyl)-4,4- *dimethyl- 1,4-dihydrobenzo[d] -oxazin-2-one, 3 -(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H- benzo[d] [1 ,3]oxazin-6-yl)-5 -methyl-benzonitrile, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H- :benzo[d] [1 ,3]oxazin-6-yl)-5-trifluoromethoxy-benzonitrile, 6-(3 ,5-difluoro-phenyl)-4,4- P:\WPDOCS\CABSPECI\7639430 AMENDEDCLAIMS.de-12/09103 -124- dimethyl- 1,4-dihydrobenzo-[d] [1 ,3]oxazin-2-one, 6-(3 ,5-dichloro-phenyl)-4,4-dimethyl- 1,4- dihydrobenzo-[d] [1 ,3]oxazin-2-one, 6-(3 ,5-Bis-trifluoromethyl-phenyl)-4,4-dimethyl- 1,4- dihydrobenzo [1 ,3]oxazin-2-one, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1,3 ]oxazin- -methoxy-benzonitrile, 6-(3 -Fluoro-phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] oxazin-2-one, 6-(3 -Chloro-4-fluoro-phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2- one, 3-(l1-Diethoxymethyl-4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-5- fluoro-benzonitrile, 3-Fluoro-5-( 1-methoxymethyl-4,4-dimethyl-2-oxo- 1,4-dihydro-2H- benzo[d] [1 ,3]oxazin-6-yl)-benzonitrile, Phosphoric acid 6-(3 -cyano-5-fluoro-phenyl)-4,4- dimethyl-4H-benzo[d] [1 ,3]oxazin-2-yl ester diethyl ether, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro- 2H-benzo[d] oxazin-6-yl)-4-fluoro-benzonitrile, 6-(3-Chloro-4-fluoro-phenyl)-8-fluoro-4,4- dimethyl- 1,4-dihydrobenzo[d] -oxazin-2-one, 6-(3-Bromo-phenyl)-4,4-dimethyl- 1,4- dihydro-benzo[d] -oxazin-2-one, 4,4-Dimethyl-6-(3 -trimethylsilanylethynyl-phenyl)- 1,4- dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(3-Ethynyl-phenyl)-4,4-dimethyl- 1,4-dihydro- benzo[d] -oxazin-2-one, 3-[3 -(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6- yl)-phenyl] -propynenitrile, 6-(3-Fluoro-5 -nitro-phenyl)-4,4-dimethyl- 1,4-dihydro- *benzo[d] oxazin-2-one, 6-(3-Chloro-5-fluoro-phenyl)-4,4-dimethyl- 1,4-dihydro- benzo[d] [1 ,3]oxazin-2-one, 3-Chloro-5-(4,4-dimethyl-2-oxo- 1,4-dihydro-2H- benzo[d] [1 ,3]oxazin-6-yl)-benzonitrile, 6-(3 ,5-Dinitro-phenyl)-4,4-dimethyl- 1,4-dihydro- benzo[d] [1 ,3]oxazin-2-one, 5-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo oxazin-6-yl)- isophthalonitrile, 4,4-Dimethyl-6-(3-thiazol-2-yl-phenyl)- 1,4-dihydro-benzo[d] oxazin-2- one, 6-(3 -Fluoro-5-methoxy-phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(3- Fluoro-5-trifluoromethyl-phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] oxazin-2-one, ~:Bromo-pyridin-3 -yl)-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(5 -Bromo-l-1y :pyridin-3 -yl)-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 5-(4,4-Dimethyl-2-oxo- 1,4- .::dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-2-fluoro-benzonitrile, 4-(8-Fluoro-4,4-dimethyl-2-oxo- 1 ,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-thiophene-2-carbonitrile, 3-Fluoro-5-(8-fluoro-4,4- *:dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-benzonitrile, 5-(4,4-Dimethyl-2-oxo- P:\WPDOCS\CA]3\SPECI\7639430 AMENDEDCLAIMS.dc-12/08/03 125 1 ,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-thiophene-3-carbonitrile, 2-(4,4-Dimethyl-2-oxo- 1,4- dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-thiophene-3 -carbonitrile, 1,2,4-thiadiazol-3-yl- phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 6-(3 -Fluoro-5-thiophen-3-yl- phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] [1 ,3]oxazin-2-one, 4,4-Dimethyl-6-(5 -nitro- 1 H- pyrrol-2-yl)- 1,4-dihydrobenzo [1 ,3]oxazin-2-one, 4,4-Dimethyl-6-( 1H-pyrrol-2-yl)- 1,4- dihydro-benzo[d] -oxazin-2-one, 4,4-Dimethyl-6-( 1-methyl-i H-pyrrol-2-yl)-l1,4-dihydro- benzo[d] [1 ,3]oxazin-2-one, 4,4-Dimethyl-6-( 1 -methyl-5 -nitro- 1 H-pyrrol-2-yl)- 1 ,4-dihydro- benzo[d] [1 ,3]oxazin-2-one, 3 ,2-Dihydro-2-oxospiro [4H-3, 1-benzoxazine-4, 1-cyclohexan] -6- yl)-benzonitrile, 3 ,2-Dihydro-2-oxospiro[4H-3, 1-benzoxazine-4, 1-cyclohexan] -6-yl)-5 fluorobenzonitrile, 1,2-Dihydro-2-oxospiro[4H-3, 1-benzoxazine-4, 1-cyclohexan]-6-yl)-2- thiophenecarbonitrile, 5 ,2-Dihydro-2-oxospiro[4H-3, 1-benzoxazine-4, 1-cyclohexan] -6-yl)-2- thiophenecarbonitrile, 5 ,2-Dihydro-2-oxospiro[4H-3, 1-benzoxazine-4, 1-cyclohexan] -6-yl)-4- methyl-2-thiophenecarbonitrile, 5 -(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6- yl)-4-ethyl-thiophene-2-carbonitrile, 5-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H- benzo[d] [1 ,3]oxazin-6-yl)-4-n-propyl-thiophene-2-carbonitrile, 6-(4-Cyano-3-fluoro-phenyl)- 4,4-dimethyl- 1,4-dihydrobenzo[d] oxazin-2-one, 6-(4-Fluoro-phenyl)-4,4-dimethyl- 1,4- .dihydro-benzo[d] -oxazin-2-one, 6-(3 ,4-Difluoro-phenyl)-4,4-dimethyl- 1,4-dihydro- benzo[d] [1 ,3]oxazin-2-one, 6-(2-Fluoro-phenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d] oxazin-2-one, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]-oxazin-6- yl)phenylacetonitrile, 5-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-furan-2- carbonitrile, 3-(4,4-Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-2-fluoro- benzonitrile, and 6-(3-Cyano-5-fluoro-phenyl)-4,4-dimethyl-2-oxo-4H-benzo[d] [1 ,3]oxazine- 1- ~:carboxylic acid tert-butyl ester, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 3, which is 2-(4,4-Dimethyl-2-oxo-1,4- dihydro-2H-benzo[d] [1,3]oxazin-6-yl)-pyrrole- 1-carboxylic acid tert-butyl ester, 2-(4,4- :Dimethyl-2-oxo- 1,4-dihydro-2H-benzo[d] [1 ,3]oxazin-6-yl)-5-nitro-pyrrole-l1-carboxylic acid P:\WPDOCS\CA\SPEC1X7639430 AMENDEDCLAIMSdo-2IO8IO3 -126- tert-butyl ester, 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] 1,3]oxazin-6-yl)-4-n-butyl- thiophene-2-carbonitrile, or a pharmaceutically acceptable salt thereof. 11. The compound according to any of claims 1 to 3, wherein R 5 is selected from the group consisting of 3-chloro-4-fluoro-phenyl, 3,5-dichloro-phenyl, 3-cyano-4-fluoro-phenyl, 3,4- difluoro-phenyl, 3-cyano-5-chloro-phenyl, 3-trifluoromethyl-5-fluoro-phenyl, 2-fluoro-3-cyano- phenyl, 2-fluoro-phenyl, 3,4-dichloro-phenyl, 3-fluoro-4-chloro-phenyl, 3-bromo-4-fluoro- phenyl, 3-chloro-4-bromo-phenyl, and 12. The compound according to any of claims 1 to 3, wherein R 5 is 4-cyano-3- furanyl. 13. A pharmaceutical composition comprising a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 14. A method of inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof. A method of treating hormone-dependent neoplastic disease in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof. 16. The method according to Claim 15 wherein the hormone-dependent neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, S P:\WPDOCS\CAR\SPECI\7639430 AMENDEDCLAIMS.doc-12108/03 -127- benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, and meningioma. 17. A method of synchronizing estrus in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof. 18. A method of inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of 6-(3-Chlorophenyl)-4-methyl-4-propyn- l-yl-1,4-dihydro- benzo[d][1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro- benzo[d][1,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1-yl-1,4-dihydro- benzo[d][1,3]oxazin-2-one, and 6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4- dihydrobenzo[d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt thereof. 19. A method of treating hormone-dependent neoplastic disease in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of 6-(3-Chlorophenyl)-4-methyl-4- propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4-ethynyl-4-methyl- 1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1-yl-1,4- dihydro-benzo[d][1,3]oxazin-2-one, and 6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4- dihydrobenzo[d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt thereof. The method according to Claim 19 wherein the hormone-dependent neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, Sbenign prostatic hypertrophy, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, and meningioma. P:\WPDOCS\CAB\SPEC\7639430 AMENDEDCLAIMS~do.I1281/03 -128- 21. A method of synchronizing estrus in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of 6-(3-Chlorophenyl)-4-methyl-4-propyn-l-yl-l,4-dihydro- benzo[d] [1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro- benzo[d] [1,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1-yl-1,4-dihydro- benzo[d][1,3]oxazin-2-one, and 6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4- dihydrobenzo[d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt thereof. 22. Use of the compound according to any of claims 1 to 12, or said acceptable salt, in preparing a medicament for administration to a mammalian subject. 23. Use of the compound according to any of claims 1 to 12, or said acceptable salt, in preparing a medicament for administration to a mammalian subject, wherein an effective S amount of said compound induces contraception in said mammalian subject. 24. Use of the compound according to any of claims 1 to 12, or said acceptable salt, in preparing a medicament for administration to a mammalian subject, wherein said compound treats hormone-dependent neoplastic disease in said mammalian subject. The use according to claim 24, wherein said hormone-dependent neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, and meningioma. P:\WPDOCSCAB\SPECI\7639430 AMENDEDCLAIMS.do-I12/0/03 -129- 26. Use of the compound according to any of claims 1 to 12, or said acceptable salt, in preparing a medicament for administration to a mammalian subject, wherein said compound synchronizes estrus in said mammalian subject. 27. Use of a compound selected from the group consisting of 6-(3-Chlorophenyl)-4- methyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4-ethynyl-4- methyl-i ,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn- 1- yl-l ,4-dihydro-benzo[d][1,3]oxazin-2-one, and 6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4- dihydrobenzo[d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt, in preparing a medicament for administration to a mammalian subject, wherein an effective amount of said compound induces contraception in said mammalian subject. 28. Use of a compound selected from the group consisting of 6-(3-Chlorophenyl)-4- methyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4-ethynyl-4- methyl-i ,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn-1- yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, and 6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4- dihydrobenzo[d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt thereof, in preparing a medicament for administration to a mammalian subject, wherein said compound treats hormone- dependent neoplastic disease in said mammalian subject. 29. The use according to Claim 28, wherein the hormone-dependent neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, Sbreast, colon, prostate, pituitary, and meningioma. Use of a compound selected from the group consisting of 6-(3-Chlorophenyl)-4- methyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4-ethynyl-4- :methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chloro-phenyl)-4-cyclopropyl-4-propyn- 1- PAWPDOCS\CASPEC7639430 AMENDEDCLAIMS.doc-12/0803 -130- yl-1,4-dihydro-benzo[d][ 1,3]oxazin-2-one, and 6-(3-Chloro-phenyl)-4,4-dipropyn-1-yl-1,4- dihydrobenzo[d][1,3]oxazin-2-one, or a pharmaceutically acceptable salt, in preparing a medicament for administration to a mammalian subject, wherein said compound synchronizes estrus in said mammalian subject. 31. Compounds of formula 1, methods for their preparation, compositions containing same, methods of treatment involving same and/or uses thereof substantially as herein described with reference to the Examples. 32. Use of the compound according to any of claims 1 to 12, or said acceptable salt, in preparing a medicament for administration to a mammalian subject for hormone replacement therapy. DATED this 12 t h day of August 2003. WYETH AND LIGAND PHARMACEUTICALS, INC. By Their Patent Attorneys DAVIES COLLISON CAVE o S
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CA2562160C (en) * 2004-04-27 2013-05-28 Wyeth Cyanopyrrole containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0510235A1 (en) * 1991-04-26 1992-10-28 Dong-A Pharm. Co., Ltd. Novel benzoxazine or benzothiazine derivatives and process for the preparation of the same
WO1996019458A2 (en) * 1994-12-22 1996-06-27 Ligand Pharmaceuticals Incorporated Steroid receptor modulator compounds and methods
WO1998014436A1 (en) * 1996-10-02 1998-04-09 Dupont Pharmaceuticals Company 4,4-disubstituted-1,4-dihydro-2h-3,1-benzoxazin-2-ones useful as hiv reverse transcriptase inhibitors and intermediates and processes for making the same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995020389A1 (en) * 1994-01-28 1995-08-03 Merck & Co., Inc. Benzoxazinones as inhibitors of hiv reverse transcriptase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0510235A1 (en) * 1991-04-26 1992-10-28 Dong-A Pharm. Co., Ltd. Novel benzoxazine or benzothiazine derivatives and process for the preparation of the same
WO1996019458A2 (en) * 1994-12-22 1996-06-27 Ligand Pharmaceuticals Incorporated Steroid receptor modulator compounds and methods
WO1998014436A1 (en) * 1996-10-02 1998-04-09 Dupont Pharmaceuticals Company 4,4-disubstituted-1,4-dihydro-2h-3,1-benzoxazin-2-ones useful as hiv reverse transcriptase inhibitors and intermediates and processes for making the same

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