EA004512B1 - Cyclocarbamate derivatives as progesterone receptor modulators - Google Patents

Abstract

1. A compound of the formula (I): wherein: R<1> and R<2> are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C1 to C6 alkenyl, C2 to C6 alkynyl, substituted C1 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR<A>, or NR<B>COR<A>; or R<1> and R<2> are fused to form: a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring, containing a carbon skeleton; b) a 3 to 8 membered spirocyclic ring, containing a skeleton with one or more double bonds; c) a 3 to 8 membered spirocyclic ring containing in its skeleton one to three heteroatoms selected from the group of O, S and N; the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkyl, -CF3, -OH, -CN, NH2, -NH (C1 to C6alkyl), or -N (C1 toC6 alkyl)2; R<A> is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 toC3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<B> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R<3> is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 toC6 alkenyl, alkynyl, or substituted alkynyl, COR<C>; R<C> is H, C1 to C3 alkyl, substituted C1 toC3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 toC3 aminoalkyl, or substituted C1 toC3 aminoalkyl; R<4> is H, halogen, CN, NO2, C1 toC6 alkyl, substituted C1 to C6 alkyl, alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; R<5> is selected from a) or b) a) is a substituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is taken from the group including halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 toC3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, SO2NH2 COR<D>, OCOR<D>, or NR<E>COR<D>; R<D> is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 toC3 aminoalkyl; R<E> is H, C1 to C3 alkyl, or substituted C1 toC3 alkyl; Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, amino, aminoalkyl, C1 toC3 alkoxy, C1 to C3 alkyl, or C1 to C3 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, SO2 or NR<6> and containing one or two independent substituents from the group including H, halogen, CN, NO2, amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, SO2NH2, C(N(OH), COR, or NR<G>COR; provided that when R<5> is a 5-membered ring containing in its skeleton two heteroatoms NR<6>, R<1> and R<2> are both not H; provided that when R<5> is a 5-membered ring containing in its skeleton one heteroatom NR<6>, and when R<5> is attached to the second position on said ring, then in the fifth position of said ring there can be no CN substituent; R is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<G> is H, C1 to C3 alkyl, or substituted C1 to C3alkyl; provided that when R<5> is a benzene ring a), substituted by one or two substituents or 5 or 6-membered ring b) containing in its skeleton 1, 2 or 3 heteroatoms, selected from the group of O, S and NR<6> and R<1> is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, R<2> is not alkenyl, 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<1>is not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, provided that when R<5> is a benzene ring a), substituted by one or two substituents or 5 or 6-membered ring b) containing in its skeleton 1, 2 or 3 heteroatoms, selected from the group of O, S and NR<6> and R<1> is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, R<2> is not cycloalkyl, substituted cycloalkyl; or if R<2> is alkyl or substituted alkyl, R<1> is not cycloalkyl, substituted cycloalkyl; R<6> is absent or is H, O, C(O)(C1 to C4 alkoxy) or C1 to C3 alkyl; wherein aryl is selected from the group of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl; heterocyclyl is 5-membered ring, 6-membered ring or a polycyclic ring; wherein 5-membered ring is selected from the group of tetrahydrofuran, pyrrolidinyl, imidazilyl, oxazolyl, izoxazolyl, thienyl, thiophene, pyrrole, thiazole and furyl; 6-membered ring is selected from the group of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, thiamorphilinylsulfoxide; polycyclic ring is selected from indolyl, quinolinyl, benzofuranyl, benzothienyl and izoquinolyl; substituted alkyl, substituted alkenyl and substituted alkynyl contain from 2 to 3 substituents selected from the group of halogen, CN, OH, NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocycle, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkoxy, substituted aminoalkyl and substituted thioalkoxy contain from 2 to 3 substituents selected from the group of alkyl and substituted alkyl; substituted aryl contains from 1 to 4 substituents selected from the group of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted cycloalkyl contains from 1 to 3 substituents selected from the group of halogen, CN, OH, NO2, amino, aryl, heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl contains from 1 to 4 substituents selected from the group of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkyloxy contains from 1 to 3 substituents selected from the group of halogen, CN, OH, NO2, amino, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 having the structure: R<1> and R <2> are independent substituents selected from the group of H, C1 to C6alkyl, substituted C2 to C6alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR<A>, or NR<B>COR<A>; R<1> and R<2> are fused to form a spirocyclic ring selected from a), b) or c): a) a 3 to 8 membered spirocyclic ring, containing a carbon skeleton; b) a 3 to 8 membered spirocyclic ring, containing a skeleton with one or more double bonds; c) a 3 to 8 membered spirocyclic ring containing in its skeleton one to three heteroatoms selected from the group of O, S and N; a), b) or c) rings being optionally substituted by from 1 to 4 substituents selected from fluorine, C1 to C6alkyl, C1 to C6alkoxy, C1 to C6thiaoalkyl, CF3, OH, CN, NH2, NH(C1 to C6alkyl) or N(C1 to C6alkyl)2; R<A> is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, amino, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<B> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R<3> is H, OH, NH2, C1 to C6alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, or substituted alkynyl, or COR<C>; R<C> is selected from H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C4 alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, or substituted C1 to C4 aminoalkyl; R<4> is selected from H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; R<5> is selected from groups a) and b) below: a) is a substituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is selected from the group including halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms, COR<D>, OCOR<D>, or NR<E>COR<D>; R<D> is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<E> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; Y and Z are independent substituents selected from the group of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; b) is a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms in the skeleton selected from the group of O, S, S(O), S(O2) or NR<6> and containing one or two independent substituents from the group of H, halogen, CN, NO2, amino, C1 to C3 alkyl and C1 to C3 alkoxy; provided that when R<5> is a 5-membered ring containing in its skeleton two heteroatoms NR<6>, R<1> and R<2> are both not H; provided that when R<5> i

Description

FIELD OF THE INVENTION

This invention relates to compounds that are antagonists of the progesterone receptor, their preparation and usefulness.

State of the art

Intracellular receptors (1K) form a class of structurally related gene regulators known as ligand-dependent transcription factors (K.M. Euap§, 8c1epse, 240, 889, 1988). The steroid receptor family is a subgroup of the 1K family, including progesterone receptor (PK), estrogen receptor (EC), androgen receptor (AK), glucocorticoid receptor (SC) and mineralocorticoid receptor (MK).

The natural hormone or ligand for the PK receptor is a progesterone steroid, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, can be used in the form of the same ligand. Once the ligand is present in the fluid surrounding the cell, it passes through the membrane through passive diffusion and binds to receptor ΙΚ, forming a receptor / ligand complex. This complex forms a bond with a specific promoter of the cell DNA gene. When interacting with DNA, the complex produces t-RNA and a protein encoded by this gene.

A compound that binds to receptor ΙΚ and mimics the action of a natural hormone is called an agonist here, while a compound that inhibits the action of a hormone is called an antagonist.

PK receptor antagonists can be used in contraception. Moreover, they can be used on their own (i1tapp, e! A1. App. Ν.Υ. Asab. 8st, 261, 248, 1995), in combination with an agonist of the receptor of the Republic of Kazakhstan (Kekkopep, e! A1. Ee111iu apb 8! Ep1yu, 60, 610, 1993) or in combination with a partial EC receptor antagonist such as tamoxifen (AO 96/19997 A1 bi1u 4, 1996).

RK receptor antagonists can also be used to treat hormone-dependent breast cancer (Ηογ ^ ϊ! Ζ, е! А1. Nail. Sapseg, 283, РЬ: В1гкяей§ег, Woog! Op, Mag§§, eb. Uebesk1§) as well as cancer of the uterus and ovaries. RK receptor antagonists can also be used to treat non-malignant chronic diseases such as fibromas (MigRu, e! A1. I. C1t. Epbo. Me! A., 76, 513, 1993) and indometriosis (Ke !! e1, e ! a1. RegShbu apb 8! enShu, 56, 402, 1991).

PK receptor antagonists can also be used for hormone replacement therapy for postmenopausal patients in combination with a partial EC receptor antagonist such as tamoxifen ((8 5719136).

RK receptor antagonists such as mifepristone and onapriston have been shown to be more effective in hormone models, depending on prostate cancer, which may indicate their ability to treat this condition in men (M1sypa, e! A1. App. Ν .Υ. Asab. 8c1., 761, 224, 1995).

The compounds of the present invention act as competitive inhibitors of progesterone binding at the PK receptor, and act as antagonists in functional models of both t νίίτο and t νίνο. These compounds can be used for contraception, as well as for the treatment of cancer of the fibroid, endometriosis, breast, uterus, ovaries and prostate, and postmenopausal hormone replacement therapy.

Compounds known in the art have been described in §§, e! a1. (U.S. Patent No. 5,688,810) are antagonists of the PK receptor and are dihydroquinoline 1.

bope§, e! a1. have described enol 2 ester (US Pat. No. 5,693,646) as a ligand for the PK receptor.

Ί bope§, e! a1. described compound 3 (US patent No. 5696127), as a ligand of the PK receptor.

ΖΙιι, e! a1. described lactones 4, 5 and 6 as an antagonist of the RK receptor (former Meb. C No., 41, 291, 1998).

5 6

ΖΙιι, e! a1. described esters 7 as an antagonist of the RK receptor (former Meb. SNet. 41, 291, 1998).

Hundreds, e! a1. described amide 8 as a ligand for the PK receptor (1. Meb. Sb; 38, 4880, 1995).

Regt1ap, e !. a1. have described an analogue of vitamin Ό 9 as a ligand for the PK receptor (Te !. LeIegm 35, 2295, 1994).

Natapp, e! a1. described a receptor antagonist of PK 10 (App. N. Υ. Asab 8c1., 761, 383, 1995).

Cep, e! a1. described an antagonist of the PK 11 receptor (Cb, e! a1. PO1-37, 16 ^{! b} 1n !. Comp. Not !. Cet., Mop! apa, 1997).

and

Kshtap, e !. a1. described the ligand of the PK 12 receptor (1. Ap! 1by! 1C8, 50, 360, 1997).

Iap; e! a1. (German patent, No. 3633861, CA 109: 22973), patented imidazobenzoxazinones, for example A, as compounds with cardiotonic activity; benzoxazine-2ones, such as brofoxin (B), which turned out to be active as an anolytic, have been described Nag! tapp e! a1. (Proc. Ae + 1. Pbagtaco. 1 8oc. 21, 51-55 (1978)); More recently, a large number of patents (e.d. &apos; e! A1. SH095 / 20389; Cbz! E! A1. SHO98 / 14436) claimed that quinazolin2-ones and benzoxazin-2-ones, such as compounds C1 and C2 are HIV reverse transcriptase inhibitors.

BUT

Description of the invention

The present invention relates to compounds of formula (I)

where K ¹ and K ² are independent substituents selected from the group consisting of H, _C1-C6 alkyl, substituted C1-C ₆ alkyl, C ₂ C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C _{2 to} C ₆ alkynyl substituted C ₂ -C ₆ alkynyl; C ₃ C ₈ cycloalkyl; substituted C ₃ -C ₈ cycloalkyl; aryl; substituted aryl; heterocyclyl; substituted heterocyclyl COK ^A or IR ^B COK ^A ;

or K ¹ and K ^{2 are} condensed to form

a) a 3-8 membered saturated spirocyclic ring having a carbon skeleton; or

b) a 3-8 membered spirocyclic ring having a carbon skeleton with one or more carbon double bonds; or

c) a 3-8 membered heterocyclic ring containing in its skeleton from one to three heteroatoms selected from the group consisting of O, 8 and Ν;

ring a), b) and c) may be optionally substituted by 1 to 4 substituents selected from the group consisting of fluoro, C1C ₆ alkyl, C1C ₆ alkoxy, C ₁ -C ₆ thioalkyl, SR _3, OH, CH ΝΗ ₂ , IN ^ - ^ alkyl) or I (C ₁ -C ₆ alkyl) ₂ ;

K ^{A is} selected from H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C ₁ -C ₃ aminoalkyl;

K ^B represents H, C1-C3 alkyl, or substituted C ₁ -C ₃ alkyl;

K ³ represents H, OH, IN ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C ₆ alkenyl, alkynyl, substituted alkynyl, or COC ^C ;

^C K represents H, C1 to C3 alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl,

_C1-C3 alkoxy, substituted C1 to _C3 alkoxy, C1 to _C3 aminoalkyl, or substituted C ₁ to C ₃ aminoalkyl;

I ⁴ represents H, halogen, CH, ΝΟ ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, alkynyl, substituted alkynyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ aminoalkyl or substituted C ₁ -C ₆ aminoalkyl;

I ⁵ choose from the group including a) and b):

a) a substituted benzene ring containing the substituents X, Υ and Ζ, as shown below:

where X is selected from the group consisting of halogen, CH, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C ₁ -C ₃ alkoxy, substituted C1-C3 alkoxy, C1- C3thioalkoxy, substituted C1C3thioalkoxy, amino, C1-C3 aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, ΝΟ ₂ , C ₁ -C ₃ perfluoroalkyl, 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms in its skeleton, 8Ο ₂ ΝΗ ₂ SOYA®, OSOYA® or YYA ^E SOYA®;

I® represents H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C1 -C3 aminoalkyl;

I ^E represents H, C1-C3 alkyl or substituted C ₁ -C ₃ alkyl;

Υ and Ζ independently are substituents selected from the group consisting of H, halogen, CH, ΝΟ ₂ , amino, C ₁ -C ₃ trifluoromethoxy, aminoalkyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 thioalkoxy; or

B) a 5- or 6-membered ring with 1, 2 or 3 heteroatoms in the ring selected from the group consisting of O, 8, 8Ο, 8Ο ₂ or L6 ⁶ containing one or two independent substituents selected from the group comprising H, halogen, CU, ΝΟ ₂ , amino and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ C ₃ aminoalkyl, 8Ο ₂ NΗ ₂ , C = N (ΟΗ), ΟΌΡ ¹ '' or LN ^ I® ;

with the proviso that when R ⁵ is a 5-membered ring having in its skeleton two hetero atoms L ⁶ , R ¹ and R ^{2 are} both not hydrogen; and provided that when R ⁵ is a 5-membered ring having one heteroatom NL ⁶ in its skeleton, and when R ^{5 is} attached at the second position on the ring, then in the fifth position of the ring there can be no substituent CB;

I® represents H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C1 -C3 aminoalkyl;

I ° represents H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl;

with the proviso that when R ⁵ represents a benzene ring a) substituted with one or two substituents, or a 5- or 6-membered ring b) having in its skeleton 1, 2 or 3 heteroatoms selected from the group consisting of O, 8 and NL ⁶ and R ¹ are alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, R ² cannot be alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; or if I ² is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, I ^{1 is} not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;

with the proviso that when R ⁵ represents a benzene ring a) substituted by one or two substituents, or a 5- or 6-membered ring b) having in its skeleton 1, 2 or 3 heteroatoms selected from the group consisting of O, 8 and HL ⁶ and H ¹ is alkyl or substituted alkyl, H ^{2 is} not cycloalkyl or substituted cycloalkyl; or, if I ² is alkyl or substituted alkyl, I ^{1 is} not cycloalkyl or substituted cycloalkyl;

I ^{6 is} absent or represents H, O, ^ ΟΧ ^^^^^ κ ^) or C ₁ -C ₃ alkyl;

where aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, antryl, tetrahydronaphthyl, phenanthryl;

heterocyclyl is a 5 membered ring, a 6 membered ring or a polycyclic ring; moreover

The 5-membered ring is selected from the group consisting of tetrahydrofuran, pyrrolidinyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiophene, pyrrole, thiazole and furyl;

The 6-membered ring is selected from the group consisting of piperidinyl, piperazinyl, 2oxopiperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide;

the polycyclic ring is selected from the group consisting of indolyl, quinolinyl, benzofuranyl, benzothienyl and isoquinolinyl; substituted alkyl, substituted alkenyl and substituted alkynyl have from one to three substituents selected from the group consisting of halogen, CH, OH, ΝΟ ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl alkylcarboxy, alkylamino and arylthio;

substituted alkoxy, substituted aminoalkyl and substituted thioalkoxy have from one to three substituents selected from the group consisting of alkyl and substituted alkyl;

substituted aryl has from one to four substituents selected from the group consisting of halogen, ΟΝ, OH, ΝΟ ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio;

substituted cycloalkyl has from one to three substituents selected from the group consisting of halogen, ΟΝ, OH, ΝΟ ₂ , amino, aryl, heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio;

substituted heterocyclyl has from one to four substituents selected from the group consisting of halogen, ΟΝ, OH, NO ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy alkylamino and arylthio;

substituted alkyloxy has from one to three substituents selected from the group consisting of halogen, ΟΝ, OH, ΝΟ ₂ , amino, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio;

or their pharmaceutically acceptable salts.

Preferred compounds of the invention include compounds of the formula

where K and K ₂ are independent substituents selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₂ -C ₆ alkyl, C ₂ C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, COA ^A or HC. ^In JUICE ^A ;

or K ¹ and K ^{2 are} condensed to form a ring selected from the group consisting of a), b) and c):

a) a 3-8 membered spirocyclic saturated ring having a carbon skeleton;

b) a 3-8 membered spirocyclic ring having a carbon skeleton with one or more carbon-carbon double bonds; and

c) a 3-8 membered heterocyclic ring containing in its skeleton from one to three heteroatoms selected from the group consisting of O, 8 and Ν;

ring a), b) and c) may be optionally substituted by 1 to 4 substituents selected from the group consisting of fluorine, C1-C6 alkyl, C1C ₆ alkoxy, C ₁ -C ₆ thioalkyl, Cl _3, OH, SH ΝΗ ₂ ΝΙ 1 (C | -C ₆ a.p <il) or ^ C-C ^ lkil ";

K ^{A is} selected from H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl,

C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ C ₃ aminoalkyl or substituted C ₁ C3 aminoalkyl;

K ^B is H, C ₁ -C ₃ alkyl, or substituted C1 to C3 alkyl;

K ³ represents H, OH, ΝΗ ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C ₆ alkenyl, alkynyl, substituted alkynyl, or COC ^C ;

K ^{C is} selected from H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, C ₁ C ₄ aminoalkyl or substituted C ₁ C4 aminoalkyl;

K ^{4 is} selected from H, halogen, ΟΝ, ΝΟ ₂ , C ₁ C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, amino, C ₁ C ₆ aminoalkyl, or substituted C ₁ -C ₆ aminoalkyl;

K ⁵ represents (a) or (b):

a) a substituted benzene ring containing the substituents X, Υ and Ζ, as shown below:

• p where X is selected from the group consisting of halogen, CH, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy, substituted C ₁ -C ₃ thioalkoxy, amino, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, ΝΟ2, C1-C3perfluoroalkyl, 5-membered heterocyclic ring containing from 1 to 3 heteroatoms in its skeleton, RN °, OSOK ° and ХК ^Е СОК °;

K ° represents H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl;

K ^E represents H, C1-C3 alkyl or substituted C ₁ -C ₃ alkyl;

Υ and Ζ independently are substituents selected from the group consisting of H, halogen, Ν Ν, NΟ ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkoxy;

or

b) a 5- or 6-membered ring with 1, 2 or 3 heteroatoms in the skeleton selected from the group consisting of O, 8, 8O, 8O ₂ or LK ⁶ containing one or two independent substituents selected from the group comprising H, halogen, € Ν, NΟ ₂ , amino, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy;

provided that when K ⁵ is a five-membered ring having two heteroatoms ΝΒ ⁶ in its skeleton, K ¹ and K ² are not both hydrogen; and provided that when K ⁵ is a five-membered ring having one heteroatom ΝΒ ⁶ in its skeleton, and when K ^{5 is} attached at the second position on said ring, then there cannot be a SI substituent in the fifth position of said ring;

By ⁶ represents H or _C1-C3 alkyl; or their pharmaceutically acceptable salts.

Other preferred compounds are compounds of the formula

where K ^{1 =} K ² and they are selected from the group consisting of C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, or K ¹ and K ^{2 are} condensed to form a 3-6 membered saturated spirocyclic ring having a carbon skeleton;

K ³ represents H, OH, ΝΗ ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, or SOK ^C :

K ^c is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

K ⁴ represents H, halogen, CH, ΝΟ ₂ , C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; C ₁ -C ₃ alkoxy or substituted C ₁ -C ₃ alkoxy;

K ^{5 is} selected from the group comprising a), b) and c):

a) a substituted benzene ring of the formula below:

where X is selected from the group consisting of halogen, CH C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, ΝΟ ₂ , C ₁ C ₃ perfluoroalkyl, a 5-membered heterocyclic ring containing from 1 to 3 heteroatoms, or C1-C3 thioalkoxy ;

Υ is a substituent selected from the group consisting of H, halogen, ΟΝ, ΝΟ ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, or C ₁ -C ₃ thioalkoxy;

B) a 5-membered ring of the formula

where and represents O, 8 or ΝΚ ⁶ ,

X 'is selected from the group consisting of halogen, SI ΝΟ ₂ , C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy;

Υ selected from the group comprising H and C ₁ -C ₄ alkyl; and

c) 6-membered ring of the formula

X ¹ represents Ν or CX ² ;

X ² represents halogen, SP alkoxy or ΝΟ2;

K ⁶ represents H, C ₁ -C ₃ alkyl or C ₁ -C ₄ OT ^ kil;

or their pharmaceutically acceptable. Another group of preferred compounds are compounds of formula (I), wherein

K ¹ represents H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, CC) K ' or ΝΚΥΟΚΑ

K ^C represents H, C1-C3 alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ^ C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl;

K ⁴ represents H, halogen, ί! Ν, ΝΟ ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ^ C ₆ alkoxy, amino, C ₁ C ₆ aminoalkyl or substituted C ₁ -C ₆ aminoalkyl;

K ⁵ represents a) or b):

a) a substituted benzene ring in which

X is selected from the group consisting of halogen, 6Ν, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy, substituted C 1- C3thioalkoxy, amino C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, ΝΟ2, C1-C3perfluoroalkyl, 5-membered heterocyclic ring containing from 1 to 3 heteroatoms in its skeleton, DCC ^ ΟΕΟΕ ^υ or ΧΚΤΟΚ;

Υ and Ζ independently represent substituents selected from the group consisting of H, halogen, ί! Ν, ΝΟ ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkoxy;

or

b) a 5- or 6-membered ring containing one or two independent substituents selected from the group consisting of H, halogen, ί! Ν, ΝΟ ₂ , amino, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy.

More preferred are compounds of formula (I) in which

K ¹ = K ² and they are selected from the group consisting of C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl; or K ¹ and K ^{2 are} condensed to form a 36 membered spirocyclic saturated ring having a carbon skeleton;

K ³ represents H, OH, ΝΗ2, C1-C6 alkyl, substituted C ₁ -C ₆ alkyl or CΟK ^C ;

K ^c is H, C ₁ -C ₃ alkyl or C1 -C3 -alkoxy;

K ⁴ represents H, halogen, ί! Ν, ΝΟ ₂ , C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; C ₁ -C ₃ alkoxy or substituted C ₁ -C ₃ alkoxy;

K ^{5 is} selected from the group comprising a), b) and c):

a) a substituted benzene ring of the formula below:

where X is selected from the group consisting of halogen, CK, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, ΝΟ ₂ , C _{1 l} .

C ₃ perfluoroalkyl, a 5-membered heterocyclic ring containing from 1 to 3 heteroatoms, or C1-C ₃ thioalkoxy;

Υ is a substituent selected from the group consisting of H, halogen, SI, ΝΟ ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, or C ₁ -C ₃ thioalkoxy;

B) a 5-membered ring of the formula

where and represents O, 3 or ΝΚ ⁶ ,

X 'is selected from the group consisting of halogen, SI, ΝΟ ₂ , C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy;

Υ selected from the group consisting of H and C ₁ -C ₃ alkyl;

I ⁶ represents H or C ₁ -C ₃ alkyl; and

c) 6-membered ring having the structure

where X ¹ represents CX ² ;

X ² represents halogen, SI, C ₁ C3 alkoxy or ΝΟ2;

or their pharmaceutically acceptable salts.

The following group of preferred compounds of the present invention are compounds of formula (I), in which

I ^{1 =} I ² , and they represent CH ₃ or I ¹ and I ^{2 are} condensed to form a 6 membered saturated spirocyclic ring;

I ³ represents H, OH, ΝΗ ₂ , methyl, substituted methyl, or SOYA ^C ;

I ^C represents H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

I ⁴ represents H, halogen, ΝΟ ₂ , SI, C ₁ -C ₃ alkyl;

I ⁵ represents a substituted benzene ring a) of the formula

where X is selected from the group consisting of halogen, SI, methoxy, ΝΟ ₂ or 5 membered heterocyclic ring, wherein said ring is 2-thiazole,

Υ represents H or halogen;

or their pharmaceutically acceptable salts.

Another preferred group are compounds of formula (I) in which

I ¹ = I ² and represents CH ₃ or I ¹ and I ^{2 are} condensed to form a 6-membered spirocyclic saturated ring having a carbon skeleton;

I ³ is H, OH, ΝΗ _2, methyl, substituted methyl or SΟYA ^C;

I ^C represents H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

I ⁴ represents H, halogen, ΝΟ2, SI, C ₁ -C ₃ alkyl;

I ⁵ is a five-membered ring b) having the formula

where and represents O, 3 or ΝΗ,

X 'is selected from the group consisting of halogen, SI, ΝΟ ₂ , provided that when and is ΝΗ, then X' is not SI;

Υ selected from the group consisting of H and C ₁ -C ₃ alkyl;

or their pharmaceutically acceptable salts.

The most preferred compounds are selected from the group consisting of 6- (3-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-methoxyphenyl) -4 , 4-dimethyl-1,4-dihydrobenzo [b] [1,3] -oxazin-2-one, 6- (2-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (4-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-chlorophenyl) -4-methyl -1,4-dihydrobenzo [b] [1,3] oxazin2-one, 6- (3-chlorophenyl) -4-ethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6 - (3-chlorophenyl) -4-phenyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 (4,4-dimethyl-2-oxo-1,4-dihydro-2H- benzo [b] [1,3] oxazin-6-yl) benzonitrile, 4,4-dimethyl-6 (3-ni rophenyl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-bromo-5-fluorophenyl) -4,4-dimethyl 1,4-dihydrobenzo [b] [1,3 ] oxazin-2-one, 3- (4,4dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile, 5- (4 , 4-dimethyl2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) nicotinonitrile, 4- (4,4-dimethyl-2-oxo-1,4dihydro-2H-benzo [b] [1,3] oxazin-6-yl) thiophene 2-carbonitrile, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin- 6-yl) thiophen-2carbonitrile, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-methylthiophene-2 -carbonitrile, 4- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) furan-2carbonite yl, 4,4-diethyl-6- (3-nitrophenyl) -1,4 dihydrobenzo [b] [1,3] -oxazin-2-one, 6- (3-chlorophenyl) -4,4-diethyl-1, 4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-chlorophenyl) spiro [4H-3,1-benzoxazin-4,1'-cyclohexane] -2- (1H) -one, 6- (3-chlorophenyl) spiro [4H-3,1-benzoxazin-4,1'-cyclopentane] -2 (1H) -one, 6- (3-nitrophenyl) spiro [4H-3,1-benzoxazin-4,1 '-cyclohexane] -2 (1H) -one, 4-allyl-6- (3-chlorophenyl) -4-methyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- ( 3-chlorophenyl) -4-methyl4-phenyl-1,4-dihydrobenzo- [b] [1,3] oxazin-2-one, 4-benzyl-6- (3-chlorophenyl) -4-methyl-1,4 -dihydrobenzo [b] [1,3] -oxazin-2-one, 6- (3-chlorophenyl) -413 cyclopropyl-4-methyl-1,4-dihydrobenzo [b] [1,3] ox zin-2-one, 6- (3-chlorophenyl) -4,4-dicyclopropyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3bromo-5-fluorophenyl) -1 , 4,4-trimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-methoxyphenyl) 4-methyl-4-trifluoromethyl-1,4-dihydrobenzo [b] [ 1,3] oxazin-2-one, 6- (3-acetylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3 benzoylphenyl) -4 , 4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4,4-dimethyl-6- [3- (1 H-tetrazol-5-yl) phenyl] - 1, 4-dihydrobenzo [b] [1,3] oxazin-2-one, 4- (4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6 -yl) thiophene-2carbonitrile, 6- (3-bromo-5-fluorophenyl) -4,4dicyclopropyl-1,4-dihydrobenzo- [b] [1,3] oxa in-2-one, 3- (4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile, 6- ( 3-bromo-5-methylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3 bromo-5-trifluoromethoxyphenyl) -4,4- dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazine -6-yl) -5-methylbenzonitrile, 3- (4,4-dimethyl-

2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-trifluoromethoxybenzonitrile, 6- (3,5-difluorophenyl) -4,4-dimethyl-1, 4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3,5-dichlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2 -one, 6 (3,5-bis-trifluoromethylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 - (4,4-dimethyl-2-oxo- 1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-methoxybenzonitrile, 6- (3-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] -oxazin-2-one, 6- (3-chloro-4-fluorophenyl) -4,4-dimethyl-

1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 - (1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2Nbenzo [b] [1,3] oxazine -6-yl) -5-fluorobenzonitrile,

3- fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo-

1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile, phosphoric acid 6- (3-cyano-5-fluorophenyl) -4,4-dimethyl-4H-benzo [b] [ 1,3] oxazin-2-yl diethyl ether, 3- (4,4-dimethyl-2oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) -4-fluorobenzonitrile, 6 - (3-chloro-4-fluorophenyl) -8-fluoro-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-bromophenyl) -4, 4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4,4dimethyl-6- (3-trimethylstannylethynylphenyl) -

1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-ethynylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2- he, 3- [3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenyl] propynnitrile, 6- (3-fluoro- 5-nitrophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6 (3-chloro-5-fluorophenyl) -4,4-dimethyl-1,4 -dihydrobenzo [b] [1,3] oxazin-2-one, 3-chloro-5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile, 6- (3,5-dinitrophenyl) -

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 5- (4,4-dimethyl-2-oxo -1,4-dihydro -2Nbenzo [b] [1,3 ] oxazin-6-yl) isophthalonitrile, 4,4dimethyl-6- (3-thiazol-2-ylphenyl) -1,4-dihydro-benzo [b] [1,3] oxazin-2-one, 6- (3- fluoro-5-methoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-fluoro-5-trifluoromethylphenyl) -

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (5-bromopyridin-3-yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [ 1,3] oxazin-2-one, 6- (5-bromo-1-hydroxypyridin-3-yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-fluorobenzonitrile, 4- (8-fluoro-4.4 -dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) thiophene 2-carbonitrile, 3-fluoro-5- (8-fluoro-4,4-dimethyl-2oxo -1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b ] [1,3] oxazin-6-yl) thiophene-3-carbonitrile, 2- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6- il) thiophene-3 rbonitrile, 6- (1,2,4-thiadiazol-3-yl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6 (3-fluoro -5-thiophen-3-yl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4,4-dimethyl6- (5-nitro-1H-pyrrole- 2-yl) -1,4-dihydrobenzo [b] [1.3] oxazin-2-one, 4,4-dimethyl-6- (1H-pyrrol-2-yl) -1,4-dihydrobenzo [b] [1 , 3] oxazin-2-one, 4,4dimethyl-6- (1-methyl-1H-pyrrol-2-yl) - 1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4, 4-dimethyl-6- (1methyl-5-nitro-H-pyrrol-2-yl) -1,4-dihydrbenzo [b] [1,3] oxazin-2-one, 3 - (1,2-dihydro- 2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) benzonitrile, 3 - (1,2-dihydro-2-oxospiro [4H3,1-benzoxazine-4,1-cyclohexane ] -6-yl) -5-fluorobenzonitrile, 4- (1,2-dihydro-2-oxospiro [4H3,1-benzoxazin-4,1-cyclohexane] -6-yl) -2-thiophenecarbonitrile, 5- (1 , 2-dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -2thiophenecarbonitrile, 5- (1,2-dihydro-2-oxospiro [4H-3,1 - benzoxazine-4,1-cyclohexane] -6yl) -4-methyl-2-thiophenecarbonitrile, 5 - (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-ethylthiophen-2-carbonitrile, 5- (4,4dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) - 4-n-propyl-thiophen-2-carbonitrile, 6- (4-cyano-3-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6 - (4-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenz [b] [1,3] oxazin-2-one, 6- (3,4-difluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- ( 2-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 - (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) phenylacetonitrile, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6- il) furan-2-carbonitrile, 5 (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1.3] oxazin-6-yl) furan-2-carbonitrile, 3- ( 4,4dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-fluorobenzonitrile, 6- (3-cyano-5 fluorophenyl) -4,4- dimethyl-2-oxo-4H-benzo [b] [1.3] oxazine-1-carboxylic acid tert-butyl ether, 6- (2,3-difluorophenyl) -4,4 dimethyl

1.4- dihydrobenzo [b] [1,3] oxazin-2-one, 3- (1-ethyl-

4.4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile, [615 (4,4-dimethyl-2-oxo-1 , 4-dihydro-2H-3,1-benzoxazin-6-yl) pyridin-2-yl] acetonitrile, 3- (4,4dimethyl-2-oxo-1,4-dihydro-2H- [b] [1, 3] oxazin6-yl) -5-fluorophenylacetonitrile, 3- (4,4-dimethyl2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) -4-fluorophenylacetonitrile, 4- (4,4-dimethyl-2oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) -2-fluorophenylacetonitrile, 2- (4,4-dimethyl-2oxo-1,4- dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenylacetonitrile, Y- [4- (4,4-dimethyl-2-oxo-

1.4-dihydro-2H-3,1-benzoxazin-6-yl) -2-fluorophenyl] acetamide; 6- (3-fluoro-4-methoxyphenyl) -

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (6-aminopyridin-3-yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1, 3] oxazin-2-one, 6- (5-diethoxymethylfuran-3-yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4- (4, 4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) furan-2-carbaldehyde, 4,4-dimethyl-6- (3-trimethylsilanylethylene phenyl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 - (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzosulfonamide, 5- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) thiophen-2-sulfonamide and 4- (1,4-dihydro-4,4-dimethyl-2-oxo-2H3,1-benzoxazin-6-yl) furancarboxal egid oxime or a pharmaceutically acceptable salt thereof.

The compounds of the invention may contain an asymmetric carbon atom, and some of the compounds of the invention may contain one or more asymmetric centers, which may lead to the formation of optical isomers and diastereoisomers. Although the stereochemical structure is not shown in Formula I, the present invention includes similar optical isomers and diastereoisomers, as well as racemates and separated enantiomerically pure K. and δ stereoisomers; as well as other mixtures of K and δ stereoisomers and their pharmaceutically acceptable salts.

The term alkyl is used here to mean saturated aliphatic hydrocarbon groups with both linear and branched chains containing from one to eight carbon atoms, preferably from one to six carbon atoms, it is understood that the term alkenyl includes alkyl groups with both linear and branched chain with at least one carbon-carbon double bond containing from two to eight carbon atoms, preferably from one to six carbon atoms, it is understood that alkynyl groups and encompasses both linear and branched chain alkyl groups with at least one carbon-carbon triple bond containing from two to eight carbon atoms, preferably from one to six carbon atoms.

The terms substituted alkyl, substituted alkenyl and substituted alkynyl denote the just described alkyl, alkenyl and alkynyl containing from one to three substituents selected from the group consisting of halogen, ΟΝ, OH, ΝΟ ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents can be attached to any carbon atom in the composition of an alkyl, alkenyl or alkynyl group, provided that upon such addition a chemically stable residue is formed.

The term aryl is used here to mean an aromatic system, which may include one or more aromatic rings, condensed or linked to each other so that at least part of the condensed or connected rings forms a conjugated aromatic system. Aryl groups include, but are not limited to, phenyl, naphthyl, diphenyl, antryl, tetrahydronaphthyl, phenanthryl.

The term substituted aryl means the above-defined aryl containing one to four substituents from the group consisting of halogen, ΟΝ, OH, NO ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio.

The term heterocyclyl is used here to mean a stable 4-7 membered monocyclic or stable polycyclic heterocyclic ring, which may be saturated, partially or completely unsaturated and consists of carbon atoms and from one to four heteroatoms selected from the group consisting of Ν, O, and δ. The Ν and δ atoms can be oxidized. Heterocyclic rings also include any polycyclic rings in which any of the above heterocyclic rings is fused to an aryl ring. A heterocyclic ring may be attached via any heteroatom or carbon atom, provided that the resulting 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 thiomorpholinyl sulphoxide and isoquinolinyl.

The term substituted heterocyclyl is used here to describe heterocyclyls defined above containing one or more substituents selected from the group consisting of halogen, ΟΝ, OH, ΝΟ 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 mean an OK group, where K is alkyl or substituted alkyl. The term aryloxy is used herein to mean an OK group, where K is aryl or substituted aryl. The term alkylcarbonyl is used herein to mean a CSR group. where K represents alkyl or substituted alkyl. The term alkylcarboxy is used herein to mean a COOC group. where K represents alkyl or substituted alkyl. The term aminoalkyl denotes as secondary. and tertiary amines. which include alkyl or substituted alkyl groups. containing from one to eight carbon atoms. which may be the same or different. and their point of attachment is a nitrogen atom. The term halogen means C1, Br, E and 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 of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and in some cases, organic acids such as acetic acid, oxalic acid, succinic acid and maleic acid. Other salts include salts of alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates and other conventional prodrug forms, which upon the introduction of such a form transform ίη νίνο into the active residue.

The present invention encompasses pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier or excipient. The invention also includes a treatment method that comprises administering to the mammal a pharmaceutically effective amount of one or more of the compounds described above as antagonists of the progesterone receptor.

The progesterone receptor antagonists of the invention, used alone or in combination, can be used in methods of contraception and treatment and / or prevention of dysfunctional bleeding, uterine leiomyoma, endometriosis, polycystic ovary syndrome, as well as endometrial carcinomas and adenocarcinomas, ovaries, breasts, colon and prostate, as well as other hormone-dependent tumors. Additional uses of progesterone receptor antagonists include stimulating food absorption.

When the compounds are used for one of the above purposes, they can be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and can be administered orally in the form of tablets, capsules, dispersible powders, granules or suspensions containing, for example, from about 0.05 to 5% of a suspending agent, syrups containing, for example, from about 10 to 50% sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like or parenter flax in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical compositions may contain, for example, from about 25 to about 90% of the active ingredient in combination with a carrier, more often between about 5 and about 60% by weight.

The effective dose used of the active ingredient may vary depending on the particular compound used, route of administration and severity of the patient's condition. However, as a rule, satisfactory results are obtained when the compounds of the invention are administered in a daily dose of from about 0.5 to about 500 mg / kg of the animal’s body weight, preferably the administered dose is divided into two to four doses per day, or the drug is administered in a delayed form selection. For most large mammals, the total daily dose is from 1 to 100 mg, preferably from 2 to 80 mg. Dosage forms for internal use include from 0.5 to 500 mg of the active compound in a uniform mixture with a solid or liquid pharmaceutically acceptable carrier. This mode of administration may be modified to provide an optimal therapeutic effect. For example, several separate doses per day may be administered, or the dose may be proportionally reduced in accordance with the circumstances of the therapeutic situation.

These active compounds can be administered orally as well as intravenously, intramuscularly or subcutaneously. Solid carriers include starch, lactose, calcium hydrogen phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include sterilized water, polyethylene glycols, nonionic surfactants and edible oils such as corn, peanut or sesame oil, in accordance with the nature of the active ingredient and the particular desired form of administration. Advantageously, adjuvants commonly used in the preparation of pharmaceutical compositions, such as flavors, colorants, preservatives and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA, can be included in this formulation.

Preferred pharmaceutical compositions from the point of view of ease of preparation and administration are solid compositions, in particular tablets and capsules with solid and liquid contents. Oral administration of the compounds is preferred.

These active compounds can be administered parenterally or intraperitoneally. Solutions and suspensions of these active compounds in the form of a free base or a pharmaceutically acceptable salt may be prepared in water by mixing with a suitable surfactant such as hydroxypropyl cellulose. Dispersions can also be obtained in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. To store these drugs under ordinary conditions, they contain preservatives that prevent the growth of microorganisms.

Pharmaceutical forms suitable for use as an injection include sterile aqueous solutions or suspensions and sterile powders for the unplanned preparation of sterile injectable solutions or suspensions. In any case, the form must be sterile and fluid to the extent that it can be easily inserted into the syringe. It must be stable under the conditions of production and storage, and must be protected from the contaminating effects of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol (e.g. glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

Compounds according to the invention can be obtained, guided by the schemes depicted below, which introduced the following notation:

d.1. - room temperature;

bsshss5 - degrees;

THP-tetrahydrofuran;

ΌΜΡΆ - dimethylformamide;

gsPih - reflux;

1pr1yu5dsps - triphosgene;

og - or

Scheme I

As shown in Scheme I, the compounds of the invention are generally prepared using a suitable condensation reaction as the final step. A suitably substituted ortho-aminobenzoic acid or derivative thereof, such as ethyl ether (X = Br, I, C1 or a latent condensation precursor, such as an alkoxy group that can be converted to an OT group in the condensation reaction), is treated with a suitable organometallic reagent for example, Grignard reagent, in an appropriate aprotic solvent, which includes, but is not limited to THF or ether to produce ortho-aminocarbinol 2 in an inert atmosphere, such as nitrogen or argon at a temperature of from -78 ° C to room temperature atom. Ring closure in carbinol 2 leading to benzoxazin-2-one 3 usually occurs in the presence of a condensing agent such as carbonyldiimidazole, phosgene, dimethyl carbonate or diethyl carbonate in a suitable aprotic solvent such as THF, in the temperature range from room temperature to 65 ° C. The arylation of benzoxazin-2-ones 3 to give compound 4 can be carried out using a variety of condensation reactions, including Suzuki reactions (8ιιζι.ι1 <ί). Stille (8th-11th). These reactions are usually carried out in the presence of a transition metal catalyst, for example, a palladium or nickel complex often with phosphine ligands, for example, P1 ₃ P, 1,1'-bis (diphenylphosphino) ferrocene, 1,2-bis (diphenylphosphino) ethane or a palladium salt such as palladium acetate. Under the conditions of such catalysis, a suitably substituted nucleophilic reagent, for example, arylboronic acid, arylstannan or an arylzinc compound, is condensed with benzoxazinones 3 to give compound 4. If a base is required for the reaction, then commonly used bases include, but are not limited to sodium bicarbonate sodium carbonate, potassium phosphate, barium carbonate, potassium acetate or cesium fluoride. The most commonly used solvents for these reactions include benzene, DMF, isopropanol, ethanol, ΌΜΕ, ether, acetone, or a mixture of the above solvents with water. The condensation reaction is usually carried out in an inert atmosphere, such as nitrogen or argon, in the temperature range from room temperature to the boiling point of the solvent system or mixture thereof.

Benzoxazinones 3 can be converted to a nucleophile such as boronic acid, which can be condensed with a suitable electrophile, for example, with an aryl bromide or aryl iodide to give compound 4, using the conditions of the condensation reaction described above. The conversion of compound 3 to compound 5 can be accomplished by treating compound 3 with an organometallic reagent, for example n-Cu, in an aprotic solvent such as THF or ether, followed by quenching the reaction solution with a suitable electrophile, such as trimethyl borate, triisopropyl borate, tin bishexalkyl or zinc chloride , in the temperature range from -78 ° C to room temperature, in an inert atmosphere such as nitrogen or argon.

Scheme 1a

Scheme 1a illustrates an alternative approach to the preparation of benzoxazinones 3. Thus, a suitable aniline 1 is protected with an alkoxycarbonyl protecting group including, but not limited to, allyloxycarbonyl, tert-butoxycarbonyl, benzoxycarbonyl, ethoxycarbonyl or methoxycarbonyl, in a suitable solvent such as THF, acetonitrile, the presence or absence of a base as either a catalyst or an acid acceptor. The protected aniline is then treated with a suitable organometallic reagent such as an organolithium agent or Grignard reagent in the same manner as in the preparation of compound 2 to form carbinol 6. Treating compound 6 with a suitable base such as potassium tert-butylate, nbutyl lithium, potassium hydroxide, in a suitable solvent such as toluene, THF, alcohol, in an inert atmosphere such as nitrogen or argon, benzene is obtained in the temperature range from room temperature to the boiling point of the corresponding solvent ksazinony 3.

Scheme II shows the procedure for producing benzoxazinones with two different substituents at position 4. The Vainreba amide (Rzheshb) 8 can be obtained from the correspondingly substituted isatinic anhydride 7 by treating it with a salt such as N-, 0-dimethylhydroxylamine hydrochloride in a protic solvent such as ethanol, isopropanol, when refluxed, in an inert atmosphere such as argon or nitrogen. Amide 8 can be condensed with an aryl electrophile, such as arylboronic acid or arylstannan, to give compound 9, using a conventional condensation reaction, for example, Suzuki or Stille, using a condensation method similar to that described for benzoxazinones 4. In the treatment of amide Vainreba 9 with organometallic compounds, for example, alkyl lithium, alkynyl lithium, arylithium or a Grignard substitute thereof, in an aprotic solvent such as THF or ether, in an inert atmosphere such as argon or nitrogen, at temperatures from -78 ° C to room temperature, an aminoketone 10 is obtained. The conversion of ketone 10 to carbinol 11 can be accomplished by treating compound 10 with an organometallic reagent, such as an alkyl, alkynyl or aryl Grignard compound, in an aprotic solvent such as THF or ether, to inert atmosphere, such as nitrogen or argon, at a temperature of from -78 ° C to room temperature. The conversion of ketone 10 to carbinol 11 can also be accomplished by reducing the keto group in compound 10 to a carbinol residue in compound 11 using a suitable reducing reagent, such as lithium aluminum hydride, sodium borohydride, in a suitable solvent, such as THF, ether or anhydrous alcohol, in an inert atmosphere, in the temperature range from 0 ° C to the boiling point of the solvent. Closing the carbinol ring 11 to produce the compounds of the invention can be accomplished using condensing agents such as carbonyldiimidazole, phosgene, dimethyl carbonate or diethyl carbonate in a suitable aprotic solvent, such as THF, in the temperature range from room temperature to 65 ° C.

Scheme II

aminobenzonitrile 14 with an organometallic reagent, such as an organolithium reagent or Grignard reagent, in a suitable solvent, such as THF or ether, in an inert atmosphere such as nitrogen or argon, in the temperature range from -78 ° C to room temperature, as shown in Scheme III . Benzonitrile 14 can be easily obtained from appropriately substituted benzonitrile, such as bromobenzonitrile 13, using a suitable condensation reaction, for example by the method of Stille or Suzuki, carried out by a method similar to that described for the preparation of Weinreb amide 9.

Scheme III

Scheme IV illustrates an approach to the preparation of benzoxazinones with a lower perfluoroalkyl substituent at position-4, for example, when K. ₆ is a trifluoromethyl group. A suitably substituted chloraniline 15 is protected with a suitable protecting group using, for example, 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 solvents, for example methylene chloride and water, in an inert atmosphere, such as argon or nitrogen, in the temperature range from 0 to 70 ° C. The presence of a suitable base, such as sodium carbonate, sodium bicarbonate or potassium carbonate, may be required when an acid by-product such as hydrochloride is formed during the reaction. Treatment of 16 with appropriate alkyl lithium, such as n-butyl lithium or sec-butyl lithium, followed by reaction with lower perfluorocarboxy derivatives, for example trifluoroacetyl chloride, 1 - (trifluoroacetyl) imidazole or ethyl trifluoroacetate, in an aprotic solvent such as ether or THF, in an inert atmosphere such as argon or nitrogen, at -78 ° C to room temperature, protected ortho-aminoketones are obtained. Subsequent removal of the protective group can be accomplished by reacting substituted aminoketones with a suitable acid, such as ΤΓΆ (trifluoroacetic acid), a 3Ν aqueous hydrochloric acid solution, in a suitable solvent, such as methylene chloride or water, at a temperature from 0 ° C to the boiling point of the solvent, s the preparation of ortho-aminoketone 17. The preparation of 6-chlorobenzoxazinone 19 from compound 17 can be carried out in the same manner as described for the synthesis of benzoxazinone 12 from ketone 10. The condensation of compound 19 with an aryl group yields Compounds 12 can be carried out using a condensation reaction catalyzed by a nickel complex. Palladium catalysts were found to be ineffective for this condensation process. The condensation reaction of compound 19 with the corresponding arylboronic acid can be carried out in the presence of a suitable base, such as potassium phosphate, and a nickel complex (0 or II) as a catalyst, for example a nickel complex with brre, brbr £ or triphenylphosphine. The most commonly used solvents for this reaction include dioxane or THF.

The condensation reaction is usually carried out in an inert atmosphere, such as argon or nitrogen, in the temperature range from room temperature to 95 ° C.

Scheme IV

wherein 1 is toluene; e111apo1 is ethanol;

11еа1 - heating; Bedgeek - degrees; buhape - dioxane

As shown in Scheme V, compounds 6 or 12 can subsequently be converted to the 1-position derivatives through a series of transformations leading to many new cyclocarbamate derivatives, including derivatives such as 1-alkyl, 1-substituted alkyl, 1carbonyl, 1- substituted carbonyl, 1-carboxy; substituted 1-carboxy. For example, alkyl or substituted alkyl derivatives 20 can be formed by treating carbamate 12 or 6 with an appropriate base such as sodium hydride, in a suitable solvent such as DMF, in an inert atmosphere such as argon or nitrogen, followed by the addition of an appropriate electrophile such as alkyl- or substituted alkyl bromide, iodide or triflate. A similar conversion at position 1 of compounds 12 or 6 can also be carried out under two-phase conditions, as shown in Scheme V, when the alkylation is carried out using an interphase catalyst, such as tributylammonium bromide, in a suitable solvent, such as acetonitrile. Other examples of such modifications include, but are not limited to, heating compound 12 or 6 with triethyl orthoformate to give 1 substituted derivatives of compounds 12 or 6.

Scheme V

The acylation or carboxylation of compound 12 or 6 at position 1 to obtain compound 21 can be easily accomplished by treating compound 12 or 6 with a suitable acylating or carboxylating reagent, such as di-tert-butyl dicarbonate, in the presence of a suitable basic catalyst, such as ΌΜΑΡ, in a suitable solvent such as acetonitrile in an inert atmosphere such as argon or nitrogen. Amination of compound 12 or 6 at position 1 to obtain compound 22 can be carried out using a suitable aminating agent, such as chloramine, in the presence of a suitable base, such as sodium hydride, in a suitable solvent, such as THF or diethyl ether, according to the procedure described in literature (Ме11е81С8 е! а1. 1. Оgd. Сет. 30, 1311 (1965)).

The following examples illustrate the preparation of compounds of the present invention.

Example 1. 2- (2-amino-5-bromophenyl) propan-2-ol.

A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF (200 ml) was treated at -78 ° С in a nitrogen atmosphere with a solution of methyl magnesium bromide in ether (3.0 M, 90 ml, 270 mmol). The reaction mixture was slowly warmed to room temperature, stirred for 48 hours under nitrogen, and then poured into an aqueous 0.5 N cooled solution of hydrochloric acid (300 ml). The mixture was neutralized with an aqueous 1Ν sodium hydroxide solution and ethyl acetate (300 ml) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine and dried (MgSO ₄ ). Then the solvent was removed in vacuo, the precipitate was purified by flash chromatography on silica gel (hexane-ethyl acetate / 3: 2) to obtain 2- (2-amino-5-bromophenyl) propan-2-ol as an off-white solid (6 g, 57% ): mp 62-63 ° C; Ή NMR (СОС1 ₃ ) δ 7.19 (d, 1Н, 1 = 2.3 Hz), 7.12 (dd, 1Н, 1 = 8.4, 2.3 Hz), 6.51 (d, 1Н, 1 = 8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).

Example 2. 6-Bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

To a solution of 2- (2-amino-5-bromophenyl) propan-2-ol (18 g, 78 mmol) in dry THF (150 ml) was added 1,1'-carbonyldiimidazole (15.5 g, 94 mmol) in the atmosphere nitrogen. The reaction solution was heated to 50 ° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with an aqueous 1Ν hydrochloric acid solution (2 × 40 ml), brine (20 ml), and dried with MgSO ₄ . The solvent was then removed in vacuo to give 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one as a white solid (20 g, 100%): t. pl. 199-200 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.32 (s, 1H, E ₂ O interchangeable), 7.48 (d, 1H, 1 = 2.1 Hz), 7.43 (dd, 1H, 1 = 8.5, 2.1 Hz), 6.84 (d, 1H, 1 = 8.4 Hz), 1.61 (s, 6H).

Example 3. 6-Iodo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

The product is obtained starting from 2-amino-5-iodobenzoic acid, following the procedures of examples 1 and 2, in the form of a white solid: mp. 196-197 ° C; Ή NMR (DMSO-b ₆ ) δ 10.30 (s, 1H, Ό ₂ Ο interchangeable), 7.58 (m, 2H), 6.71 (d, 1H, 1 = 8.4 Hz), 1, 58 (s, 6H) Μδ (ΕδΙ) m / e 326 (| Μ + Να | '. 100%). Anal calculation for C1 ₀ H ₁₀ JO ₂ : C, 39.63; H, 3.33; Ν, 4.62. Found: C, 39.25; H, 3.24; Ν, 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-dihydrobenzo [b] [1,3] oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 ml) was added a solution of nBiO in hexane (10 M, 2.4 ml, 24 mmol) at -78 ° C in a nitrogen atmosphere. After stirring at -78 ° C for 30 min, a mixture was obtained and treated with triisopropyl borate (6.5 ml, 28 mmol). The reaction solution was slowly warmed to room temperature and quenched with aqueous 1H hydrochloric acid solution (60 ml). Ethyl acetate (100 ml) was added and the organic layer was separated, the aqueous layer was extracted with ethyl acetate (3x60 ml). The combined organic layer was washed with brine and dried Μ§8Ο ₄ . The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate-hexane / 2: 1) to obtain (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6 -yl) boronic acid as a white solid (1.4 g, 81%): mp. 249-250 ° C; ¹ H-NMR (DMSO-b ₆ ) δ 10.21 (s, 1Η, Ό ₂ Ο interchangeable), 7.90-7.95 (broadened with, 2H, Ό ₂ Ο interchangeable), 7.67 (m, 2H), 6.79 (d, 1H, 1 = 7.8 Hz), 1.61 (s, 6H); Μ8 (E81) m / e 222 ([M + H] ⁺ , 87%).

Example 5. 6- (3-Chlorophenyl) -4,4-dimethyl-

1.4- dihydrobenzo [b] [1,3] oxazin-2-one (method

BUT).

A mixture of 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one (1.5 g, 5.9 mmol), 3-chlorophenylboronic acid (1.83 g , 11.7 mmol), tetrakis (triphenylphosphine) palladium (0) (0.35 g, 0.3 mmol) and sodium carbonate (2.48 g, 23.4 mmol) in a mixture of DME and water (40 ml / 10 ml) were degassed to remove oxygen and then heated at 85 ° C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and quenched with a saturated aqueous solution of ammonium chloride (20 ml). Ethyl acetate (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x15 ml). The combined organic layers were washed with brine and dried Μ§8Ο ₄ . The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (hexane-ethyl acetate / 2: 1) to obtain 6- (3chlorophenyl) -4,4-dimethyl-1,4-dihydro-benzo [b] [1,3] nazin-2-one as a yellowish solid (1.4 g, 82%): mp. 158159 ° C; ¹ H-NMR (DMSO-b ₆ ) δ 10.31 (s, 1H, Ό ₂ Ο interchangeable), 7.75 (s, 1Η), 7.61 (m, 3H),

7.46 (t, 1Η, 1 = 7.9 Hz), 7.39 (dd, 1H, 1 = 7.0, 1.1 Hz), 6.96 (d, 1Η, 1 = 8.6 Hz ), 1.68 (s, 6H); Anal calculation for ^^ 0 ^ / 0.1 Η ₂ Ο: C, 66.37; Η, 4.94; S, 4.84. Found: C, 66.14; Η, 4.61; S,

4.71.

Example 6. 6- (3-Methoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Receive according to method a from 6-bromo-

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin2-one and 3-methoxyphenylboronic acid. Yellow solid: mp. 164-165 ° C; ^! H-NMR (DMSO-b ₆ ) δ 10.3 (s, 1H), 7.56 (m, 2H), 7.61 (m, 3H), 7.36 (t, 1H, 1 = 7.89 Hz), 7.20 (m, 2H), 6.96 (d, 1H, 1 = 8.88 Hz), 6.91 (dd, 1H, 1 = 8.13, 2.35 Hz), 3, 8 (s, 3H); 1.7 (s, 6H); Μ8 (E81) m / e 284 ([M + H] ⁺ , 30%). Anal calculation for C ^ Ni ^ s: C, 72.07; Η, 6.05; S, 4.94. Found: C, 70.58; Η, 5.73; S, 4.67.

Example 7. 6- (2-Chlorophenyl) -4,4-dimethyl-

1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Receive according to method a from 6-bromo-

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2one and 2-chlorophenylboronic acid. White solid: mp 181-182 ° C; Μ8 (E81) m / e 288 ([M + H] ⁺ , 70%). Anal calculation for C ₁₆ H ₁ . ₁ SEGO C, 66.79; H, 4.90; S, 4.87. Found: C, 66.78; Η, 4.82; S, 4.5.

Example 8. 6- (4-Chlorophenyl) -4,4-dimethyl-

1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Receive according to method a from 6-bromo-

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2one and 4-chlorophenylboronic acid. White solid: mp 255-257 ° C; ¹ H-NMR (DMTO-sH) δ 10.3 (s, 1H), 7.7 (d, 2H, 1 = 8.52 Hz),

7.55 (m, 2H), 7.5 (d, 2H, 1 = 8.52 Hz), 6.96 (d, 1H, 1 = 8.52 Hz), 1.7 (s, 6H); Μ8 (E81) m / e 288 ([M + H] ⁺ , 70%). Anal calculation for ^ Η ^ ΓΜΟ ^ C, 66.79; Η, 4.90; S, 4.87. Found: C, 66.34; Η, 4.76; S, 4.75.

Example 9. 6- (3-Chlorophenyl) -4-methyl-1,4-dihydro-2H-benzo [b] [1,3] oxazin-2-one.

To a solution of 1- (4-amino-3'-chlorodiphenyl-3yl) ethanone (see Example 35, 0.15 g, 0.61 mmol) in dry methanol (60 ml) was added sodium borohydride at room temperature under a nitrogen atmosphere. After 15 minutes, the reaction mixture was treated with ice water. Ethyl acetate (30 ml) was added, after which the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 20 ml). The combined organic layers were washed with brine (10 ml), dried (Μ§8Ο ₄ ). After removing the solvent, the obtained residue was crystallized from toluene to give 1- (4-amino-3'-chlorodiphenyl-3-yl) ethanol as a white solid (0.087 g, 58%); ¹ H-NMR (DMSO-b ₆ ) δ 7.55 (t, 1H, 1 = 1.4 Hz), 7.50 (d, 1H, 1 = 7.8 Hz), 7.44 (d, 1H , 1 = 2.1 Hz),

7.39 (t, 1H, 1 = 8.2 Hz), 7.31-7.21 (m, 2H), 6.68 (d, 1H, 1 = 8.1 Hz), 5.25 (s , 2H); 5.20 (m, 1H), 4.83 (m, 1H), 1.35 (d, 3H, 1 = 8.8 Hz) Μ8 (E1) m / e 247 (M ⁺ ).

A mixture of the above 1- (4-amino-3′chlorodiphenyl-3-yl) ethanol (0.03 g, 0.13 mmol) and triphosgene (0.01 g, 0.04 mmol) in dry THF (20 ml) stirred at room temperature under nitrogen for 10 minutes The solution was removed to give 6- (3-chlorophenyl) -4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0.031 g, 91%): mp. 155156 ° C; ^! H-NMR (DMSO-b ₆ ) δ 10.3 (s, 1H), 7.72 (m, 2H), 7.62 (m, 1H), 7.56 (m, 1H), 7.47 ( t, 1H, 1 = 8.0 Hz), 7.39 (d, 1H, 1 = 8.0 Hz), 6.98 (d, 1H,

1 = 8.0 Hz), 5.50 (q, 1H, 1 = 6.82 Hz), 1.6 (d, 3H,

1 = 6.82 Hz). Μ8 (APC1) m / e 274 ([M + H] ⁺ , 100%).

Example 10. 6- (3-Chlorophenyl) -4-ethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Receive in accordance with the method according to example 9 from 1- (4-amino-3'-chlorodiphenyl-3-yl) propanol and triphosgene. White solid: mp 146-148 ° C; ¹ H-NMR (DMSO-sR) δ 10.3 (s, 1H), 7.70 (m, 1H), 7.60 (m, 3H), 7.47 (t, 1H, 1 = 8.22 Hz), 7.39 (d, 1H, 1 = 8.28 Hz), 6.97 (d, 1H, 8.22 Hz), 5.4 (t, 1H, 1 = 10.9 Hz), 1 9 (m, 2H); 0.97 (t, 3H, 1 = 7.68 Hz); M8 (Ε8Ι) m / e 286 ([M-H] ^- , 100%).

Example 11. 6- (3-Chlorophenyl) -4-phenyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Obtained from 1- (4-amino-3'-chlorodiphenyl3-yl) benzyl alcohol and triphosgene in accordance with the procedure of example 9. Dirty white solid: so pl. 177-178 ° C; 'NMR (DMSO-bv) δ 10.5 (s, 1H), 7.68 (dd, 1H, 1 = 8.7, 1.7 Hz), 7.62 (t, 1H, 1 = 1.74 Hz), 7.48-7.34 (m, 8H), 7.04 (d, 1H, 1 = 8.7 Hz), 6.6 (s, 1H); M8 (Ε8Ι) m / e 336 ([M + H] ⁺ , 30%).

Example 12. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) benzonitrile (method B).

A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H3,1-benzoxazin-6-yl) boronic acid (2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol), tetrakis (triphenylphosphine) palladium (0) (0.6 g, 0.52 mmol) and sodium carbonate (2.2 g, 21 mmol) in a mixture of OME and water (70 ml / 15 ml) were degassed with oxygen and then heated at 85 ° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and quenched with a saturated aqueous solution of ammonium chloride (20 ml). Ethyl acetate (100 ml) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine and dried over MgSO ₄ . The solvent was removed in vacuo and the precipitate was purified by flash chromatography on silica gel (hexane-ethyl acetate / 1: 1) to obtain 3 - (4,4-dimethyl-2-oxo-1,4-dihydro-2Nbenzo [b] [1, 3] oxazin-6-yl) benzonitrile as an off-white solid (0.7 g, 25%): mp. 236-237 ° C; '1 Ι-NMR (DMSO-be) δ 10.34 (s, 1H, Ό ₂ Ο interchangeable), 8.21 (s, 1H), 8.02 (d, 1H, 1 = 8.1 Hz), 7.79 (d, 1H, 1 = 7.7 Hz), 7.60-7.70 (m, 3H),

6.98 (d, 1H, 1 = 8.2 Hz), 1.71 (s, 6H); Anal calculation for C ₁₇ H ₁₄ N ₂ O ₂ · 0.1 N ₂ O: C, 72.89; H, 5.11; Ν, 10.00. Found: C, 72.75; H, 5.05; Ν, 9.65.

Example 13. 4,4-Dimethyl-6- (3-nitrophenyl) 1,4-dihydro-2H-benzo [b] [1,3] oxazin-2-one.

Prepared from 6-iodo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 3-nitrophenylboronic acid according to method A. Yellowish solid: mp. 244-245 ° C; ^! H-NMR (DMSO-b ₆ ) δ 10.38 (s, 1H), 8.47 (s, 1H),

8.14-8.20 (m, 2H), 7.70-7.76 (m, 3H), 7.01 (d, 1H, 1 = 8.1 Hz), 1.68 (s, 6H) ; M8 (EC m / e 297 ([M-H] ^- , 100%); Anal. Calc. For Ο ₆ Η ₁₄ Ν ₂ Ο ₄ : C, 64.42; H, 4.73; Ν, 9.39 Found: C, 63.93; H, 4.91; Ν,

8.71.

Example 14. 6- (3-Bromo-5-fluorophenyl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from a mixture of (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1,3-dibromo-5-fluorobenzene following Method B. A white solid : t. pl.

182-183 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.36 (s, 1H, E ₂ O interchangeable), 7.78 (s, 1H), 7.58-7.65 (m, 3H), 7.49 ( dd, 1H, 1 = 8.3, 1.8 Hz), 6.96 (d, 1H, 1 = 8.5 Hz), 1.69 (s, 6H); ¹⁹ P-NMR (DMSO-b ₆ ) δ

112.46 (m, 1P); M8 (8Ι) m / e 352 ([M + H] ⁺ , 78%), 350 ([M + H] ⁺ , 75%). Anal calculation for

Ο ₆ Η ₁₃ ΒγΡΝΟ ₂ : C, 54.88; H, 3.74; Ν, 4.00. Found: C, 54.83; H, 3.82; Ν, 3.95.

Example 15. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile.

A mixture of 6- (3-bromo-5-fluorophenyl) -4,4-dimethyl-2H-benzo [b] [1,3] oxazin-2-one (1 g, 2.8 mmol), zinc cyanide (0, 2 g, 1.7 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 g, 0.17 mmol) in dry DMF (20 ml) were degassed to remove oxygen and then heated at 85 ° C in a nitrogen atmosphere in for 6.5 hours. The reaction solution was cooled to room temperature and poured into a saturated aqueous solution of ammonium chloride (100 ml). A white precipitate appeared, which was collected on a filter. The white precipitate was washed with distilled water (3 × 20 ml) and dissolved in a mixture of ethyl acetate (10 ml) and methanol (10 ml). The solution was filtered through a pad of silica gel and eluted with a mixture of ethyl acetate and hexane (1: 1). Then the solvent was removed, 3- (4,4-dimethyl-2oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) -5-fluorobenzonitrile was obtained as a white solid (0.7 g, 84%): mp. 253-254 ° C; ¹ H-NMR (DMSO-b6) δ 10.4 (s, 1H, Ό2Ο interchangeable), 8.13 (s, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7 73 (m, 2H), 6.98 (d, 1H, 1 = 8.2 Hz), 1.68 (s, 6H); ^! NMR (DMSO-b6) δ 112.25 (m, 1P); M8 (EC m / e 296 (M ⁺ , 65%); Anal. Calc. For Ο ₇ Ηι ₃ ΡΝ ₂ Ο ₂ : C, 68.91; H, 4.42; Ν, 9.45. Found: C 68.85; H, 4.58; Ν, 9.14.

Example 16. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) nicotinonitrile.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid, 3-bromocyanopyridine according to method B. Off-white solid: mp. 290291 ° C; '11-NMR (DMSO-b ₆ ) δ 10.41 (s, 1H, Ό ₂ Ο interchangeable), 9.21 (d, 1H, 1 = 2.2 Hz), 8.97 (d, 1H, 1 = 1.7 Hz), 8.68 (t, 1H, 1 = 2.1 Hz), 7.76 (m, 2H), 7.01 (d, 1H, 1 = 8.2 Hz), 1, 71 (s, 6H); M8 (E8C m / e 278 (M-H, 96%). Anal. Calc. For

C1 ₆ H ₁₃ ^ O ₂ · 0.2 H ₂ O: C, 67.94; H, 4.77; Ν, 14.85. Found: C, 68.04; H, 4.70; Ν, 14.58.

Example 17. 4- (4,4-Dimethyl-2-oxo-14-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) thiophene 2-carbonitrile.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid, 4-bromothiophenecarbonitrile according to method B. Yellowish solid: mp. 230-231 ° C (decomposition); ^! H-NMR (DMSO-b ₆ ) δ 8.32 (s, 1H, Ό ₂ Ο interchangeable), 7.83 (d,

1H, 1 = 1.5 Hz), 7.61 (d, 1H, 1 = 1.4 Hz), 7.43 (dd, 1H, 1 = 8.2, 1.9 Hz), 7.29 ( d, 1H, 1 = 1.8 Hz), 6.85 (d, 1H, 1 = 8.2 Hz), 1.78 (s, 6H); MOH (S) m / e 283 (MH, 100%). Anal calculation for S. '| ₅ N | W ₂ O ₂ Z · 0.2 N ₂ O: C, 62.57; H, 4.34; Ν, 9.73. Found: C, 62.48; H, 4.31; Ν, 9.64.

Example 18. 5-Bromo-2-thiophenecarbonitrile.

A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 ml) and ethanol (500 ml) is heated under reflux under nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to an oil. The crude product was triturated twice with ice water and the resulting solid was collected on a filter. A mixture of a portion of the solid product obtained above, copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated at reflux for 3 hours. Then 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 (1 L) and allowed to crystallize. The resulting crystals were collected on a filter and the filtrate was concentrated, and then purified by chromatography (silica gel, chloroform), which afforded the title compound as an off-white solid (31.5 g total, 58%). IR (film) cm ^-1 2200; ¹ H-NMR (SBS _{1 3} -b ₆ ) δ 7.39-7.38 (d, 1H, 1 = 4.1 Hz), 7.10 (d, 1H, 1 = 4.0 Hz); MZ (S) m / e 187 (M '. 98%), 189 (\ P. 100%).

Example 19. 5-Bromo-4-methyl-2-thiophenecarboxaldehyde.

To a solution of diethylamine (28 g, 0.383 mmol) in anhydrous THF (400 ml) was added a solution of n-SiO in hexane (2.5 M, 153 ml, 0.383 mmol). The solution was stirred at −40 ° C. for 30 minutes under nitrogen, cooled to −78 ° C. and treated dropwise with 2-bromo-3-methylthiophene (45 g, 0.254 mmol) in anhydrous THF (450 ml). The reaction solution was stirred at −78 ° C. for 30 minutes and treated with anhydrous DMF (100 ml). The reaction solution was slowly warmed to room temperature and quenched with an aqueous 1Ν hydrochloric acid solution (60 ml). The product is extracted with ethyl acetate (3x450 ml). The extracts were washed with water, brine and dried with MgSO ₄ . The solvent was removed in vacuo to give a white solid (46 g, 88.3%): A sample was crystallized from hexane, mp. 63-65 ° C; IR (KBr) 1654 cm ^-1 . Ή-NMR (DMSO-sR) δ 9.75 (s, 1H), 7.45 (s, 2H), 2.26 (s, 3H); MZ (EZZ m / e 204/206 ([M] ⁺ , 87%). Anal. Calc. For C ₆ H ₅ Br0Z: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.

Example 20. 5-Bromo-4-methyl-2-thiophenecarbonitrile.

Prepared from 5-bromo-4-methyl-2-thiophenecarboxaldehyde using the method of Example 18. White solid: mp. 40-42 ° C; IR (KBr) 2200 cm ^-1 ; ¹ H-NMR (SBS _{1 3} ) δ 7.29 (s, 1H),

2.21 (s, 3H); MZ (EZC m / e 201/203 (M ⁺ , 98% / 100%). Anal. Calc. For WFNR W: C, 35.66; H, 1.99; Ν, 6.93. Found: C , 36.00; H, 2.14; Ν, 6.76.

Example 21. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) thiophene

2-carbonitrile.

Synthesized according to method B using (1,4-dihydro-4,4-dimethyl-2-oxo2H-3,1-benzoxazin-6-yl) boronic acid and 5-bromo-2-thiophenecarbonitrile. The title compound was obtained as a off-white solid: mp. 264-266 ° C; ¹ NMR (DMSO-b6) δ 10.3 (s, 1H), 7.97 (d, 1H, 1 = 7.9 Hz), 7.60-7.66 (m, 3H), 6.96 ( d, 1H, 1 = 8.1 Hz) 1.65 (s, 6H); MZ (LRSZ m / ζ 285 [M + H] ⁺ ; 302 (M + ΝΗν Anal. Calc. For C.'15Н ₁₂ Ж0 ₂ З; С, 63.36; Н, 4.25; Ν, 9.85 Found: C, 63.01; H, 4.36; Ν, 9.39.

Example 22. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-methylthiophene-2-carbonitrile.

Synthesized according to method B using (1,4-dihydro-4,4-dimethyl-2-oxo2H-3,1-benzoxazin-6-yl) boronic acid and 5-bromo-4-methyl-2-thiophenecarbonitrile. The title compound was obtained as an off-white solid: mp. 195,200 ° C; ^! H-NMR (DMSO-b ₆ ) δ 10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01 (d, 1H, 1 = 8.8 Hz),

2.28 (s, 3H); 1.64 (s, 6H); MZ (LRSZ m / ζ 299 [M + H] ⁺ . Anal. Calc. For C ₁₆ H ₁₄ ^ 0 ₂ H; C, 64.41; H, 4.75; Ν, 8.89. Found: C, 64.64; H, 4.62; Ν, 9.39.

Example 23. 4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-furan2-carbonitrile.

Synthesized according to method B using (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 4-bromo-2furancarbonitrile. The title compound was obtained as an off-white solid: mp. 255-256 ° C; ^! H-NMR (DMSO-be) δ 10.32 (s, 1H, E ₂ 0 interchangeably), 8.57 (s, 1H),

8.15 (s, 1H), 7.61 (s, 1H), 7.55 (dd, 1H, 1 = 8.3, 1.5 Hz), 6.92 (d, 1H, 1 = 8, 2 Hz), 1.65 (s, 6H); MOH (EP) m / e 269 [M + H] ⁺ 72%); Anal calculation for

C ₁₅ H ₁₂ ^ O ₃ ; C, 67.16; H, 4.51; Ν, 10.44. Found: C, 67.14; H, 4.59; Ν, 10.07.

Example 24. 4,4-Diethyl-6- (3-nitrophenyl) 1,4-dihydro-2H-3,1-benzo [b] [1,3] oxazin-2-one.

Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 3-nitrophenylboronic acid according to method A. The title compound was obtained as an off-white solid : mp 193-194 ° C; ¹ NNMR (DMSO-b6) δ 9.19 (s, 1H, Ό2Ο interchangeable), 8.38 (t, 1H, 1 = 1.9 Hz), 8.20 (m, 1H), 7.83 (m , 1H), 7.61 (t, 1H, 1 = 8.0 Hz), 7.50 (dd, 1H, 1 = 8.2, 2.0 Hz), 7.23 (d, 1H, 1 = 1.7 Hz), 6.99 (d, 1H, 1 = 8.3 Hz), 2.09 (q, 4H, 1 = 7.4 Hz), 0.96 (t, 6H, 1 = 8, 3 Hz); M8 (ΕΙ) m / e 325 ([M-H] ^- , 100%), Anal. calculation for C18H ₁₈ H ₂ O ₄ 0.3 H ₂ O: C, 65.17; H, 5.65; Ν, 8.44. Found: C, 65.31; H, 5.60; Ν, 8.10.

Example 25. 6- (3-Chlorophenyl) -4,4-diethyl-

1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 3-nitrophenylboronic acid according to method A. White solid: mp. 150-151 ° C; ¹ H-NMR (SES1 ₃ ,) δ 8.52 (s, 1H, Ό ₂ Ο interchangeable),

7.50 (s, 1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, 1 = 1.5 Hz), 6.89 (d, 1H, 1 = 8, 2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, 1 = 7.4, 2.0 Hz), 7.23 (d, 1H, 1 = 1.7 Hz), 6 99 (d, 1H, 1 = 8.3 Hz), 2.09 (q, 4H, 1 = 7.4 Hz), 0.96 (t, 6H, 1 = 7.4 Hz); M8 (ΕΙ) m / e 315 ([M] ⁺ 53%). Anal calculation for C ₁₈ H ₁₈ C1O ₂ : C, 68.46; H, 5.75; Ν,

8.44. Found: C, 68.16; H, 5.81; Ν, 4.32.

Example 26. 1- (2-amino-5-bromophenyl) cyclohexanol.

Obtained from 2-amino-5-bromobenzoic acid and Grignard reagent obtained from

1.5-dibromopentane, according to example 1. Transparent oil: ¹ H-NMR (DMSO-b ₆ ) δ 7.07 (d, 1H, 1 = 2.3 Hz), 7.03 (dd, 1H, 1 = 8, 4, 2.4 Hz), 6.55 (d, 1H, 1 = 8.6 Hz), 5.49 (s, 2H), 5.00 (s, 1H, 1 = 8.3 Hz), 2 01 (d, 2H, 1 = 1.8 Hz), 1.66-1.77 (m, 2H),

1.44-1.61 (m, 4H); 1.16-1.34 (m, 2H); M8 (Ε8Ι) m / e 325 ([M + H] ⁺ , 98% / 100%).

Example 27. 6-Bromo-spiro [4H-3,1-benzo-xazine-4,1'-cyclohexane] -2- (1H) -one.

Obtained from 1- (2-amino-5-bromophenyl) cyclohexanol and carbonyldiimidazole according to the method of example 2. Off-white solid: so pl. 208-210 ° C; 'H NMR (DMSO-b ₆ ) δ

10.26 (s, 1H), 7.45 (d, 1H, 1 = 2.2 Hz), 7.39 (dd, 1H, 1 = 8.2, 2.2 Hz), 6.81 (d , 1H, 1 = 8.3 Hz), 1.90-1.97 (m, 2H), 1.80-1.85 (m, 5H), 1.25-1.35 (m, 1H), M8 (APC1) m / e 296 ([M + H] ⁺ , 68%).

Example 28. Spiro (4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid.

Obtained according to the method of example 4 using 6-bromospiro [4H-3,1-benzoxazine-4,1'-cyclohexane] -2- (1H) -one. Off-white solid: mp. 223-225 ° C. 'H-NMR (DMSO-b ₆ ) δ 10.17 (s, 1H, E ₃ O interchangeable), 7.92 (s, 2H, E ₂ O interchangeable), 7.67 (C, 1H), 7, 63 (dd, 1H, 1 = 8.0, 1.1 Hz), 6.81 (d, 1H, 1 = 7.9 Hz), 1.96 (s, 1H), 1.93 (s, 1H ), 1.57-1.88 (m, 7H), 1.24-1.34 (m, 1H); M8 (Ε8Ι) m / e 262 (M + H) ⁺ .

Example 29. 6- (3-Chlorophenyl) spiro [4H-3,1benzoxazin-4,1'-cyclohexane] -2 (1H) -one.

Prepared from 6-bromospiro [4H-3,1-benzoxazin-4,1'-cyclohexane] -2 (1H) -one and 3-chlorophenylboronic acid according to method A as an off-white solid: mp. 165168 ° C; '11-NMR (DMSO-b ₆ ) δ 10.25 (s, 1H), 7.74 (t, 1H, 1 = 1.9 Hz), 7.50-7.67 (m, 3H), 7 42-7.49 (m, 1H), 7.35-7.38 (m, 1H), 6.93-6.95 (d, 1H, 1 = 4.2), 1.91-1, 98 (m, 4H), 1.64-1.76 (m, 3H), 1.60 (m, 2H),

1.29-1.39 (m, 1H); M8 (APC1) m / e 328 (M ⁺ , 80%).

Example 30. 6-Bromo-spiro [4H-3,1-benzoxazine-4,1'-cyclohexane] -2- (1H) -one.

Receive according to the methods of examples 26 and 27 from 2-amino-5-bromobenzoic acid and Grignard reagent obtained from 1,5dibromobutane. Off-white substance: mp. 180-185 ° C. '11-NMR (DMSO-b ₆ ) δ 10.29 (s, 1H, E ₂ O interchangeable), 7245 (d, 1H, 1 = 2.2 Hz),

7.41 (dd, 1H, 1 = 8.1, 2.1 Hz), 6.82 (d, 1H, 1 = 8.0 Hz), 1.96-2.01 (m, 4H), 1 76-1.87 (m, 4H), M8 (ΕΙ) m / e 281 (M ⁺ , 98%). Anal calculation for

C ^ H ^ B ^ O ^ C, 51.08; H, 4.21; Ν, 4.85. Found: C, 50.53; H, 4.21; Ν, 4.85.

Example 31. 6- (3-Chlorophenyl) spiro [4H-3,1benzoxazin-4,1'-cyclohexane] -2- (1H) -one.

Prepared from 6-bromo-spiro [4H-3,1-benzoxazin-4,1'-cyclohexane] -2- (1H) -one and 3-chlorophenylboronic acid according to method A. Off-white solid: mp. 140-145 ° C; 'H-NMR (DMSO-b ₆ ) δ 10.27 (s, 1H), 7.75 (t, 1H, 1 = 1.8 Hz), 7.53-7.63 (m, 3H), 7 44 (t, 1H, 1 = 7.9 Hz), 7.36 (m, 1H), 6.95 (d, 1H, 1 = 8.6 Hz), 2.09-2.15 (m, 4H), 1.81-1.89 (m, 4H), M8 (Ε8Ι) m / e 314 ([M + H] ⁺ ). Anal calculation for С1 ₈ Н ₁₆ ССО ₂ : С, 68.0; H, 5.14; Ν, 4.46. Found: C, 60.94; H, 4.94; Ν, 3.78.

Example 32. 6- (3-Nitrophenyl) spiro [4H3,1-benzoxazine-4,1'-cyclohexane] -2- (1H) -one.

Prepared from 6-bromospiro [4H-3,1-benzoxazin-4,1'-cyclohexane-2] - (1H) -one and 3-nitrophenylboronic acid according to method A. Off-white solid: mp. 245246 ° C; 'H-NMR (SPS1 ₃ ) δ 8.39 (t, 1H, 1 = 1.9 Hz),

8.20 (dd, 1H, 1 = 8.2, 1.4 Hz), 8.11 (s, 1H, 1) ₃ O, interchangeable), 7.86 (d, 1H, 1 = 8.0 Hz) 7.62 (t, 1H, 1 = 8.1 Th), 7.50 (dd, 1H, 1 = 8.2, 1.9 Hz), 7.39 (d, 1H, 1 = 1.8 Hz), 6.93 (d, 1H, 1 = 8.2 Hz), 2.25 (d, 2H, 1 = 12.7 Hz); 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H) M8 (ΕΙ) m / e 337 ([M-H] ^- , 100%). Anal calculation for 0.35 H ₂ O: C, 66.21; H, 5.47;

Ν, 8.13. Found: C, 66.22; H, 5.43; Ν, 7.86.

Example 33. 2-amino-5-bromo-N-methoxy-Nmethylbenzamide.

To a mixture of ^ O-dimethylhydroxylamine hydrochloride (9.42 g, 96 mmol) and triethylamine (13.5 ml, 96 mmol) in ethanol and water (100 ml / 10 ml), a solution of 5-bromizatonic anhydride (20 g, 74 mmol) ) in ethanol and water (100 ml / 10 ml) at room temperature in a stream of nitrogen. The reaction mass is heated at the boil under reflux for 3 hours. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate (100 ml), washed with 1Ν aqueous sodium hydroxide solution (2x20 ml), brine (30 ml) and dried with MgSO ₄ . Then the solvent was removed35, the precipitate was purified using flash chromatography (silica gel, hexane: ethyl acetate / 3: 2) to obtain 2-amino-5-bromo-Umethoxy-U-methylbenzamide as an off-white substance (13 g, 68%) : mp 80-81 ° C; ¹ H-NMR (SBSl) δ 7.49 (d, 1H, 1 = 2.1 Hz), 7.26 (dd, 1H, 1 = 8.3, 2.0 Hz), 6.59 (d, 1H, 1 = 8.4 Hz), 3.58 (s, 3H), 3.34 (s, 3H); Anal calculation for C ₉ NcBr ₂ O ₂ : C, 41.72; H, 4.28; Ν, 10.81. Found: C, 41.99; H, 4.16; Ν, 10.82.

Example 34. 4-amino-3'-chlorodiphenyl-3carbonitrile.

Obtained from 2-amino-5-bromobenzonitrile and 3-chlorophenylboronic acid according to method A. Off-white solid: mp. 118-119 ° C; ^! H-NMR (DMSO-D ₆ ) δ 7.80 (d, 1H, 1 = 2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, 1 = 8 , 0 Hz), 7.42 (t, 1H, 1 = 7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, 1 = 8.7 Hz), 6.29 ( wide, 2H); Anal calculation for С ₁₃ Н ₉ С1Ы ₂ -0,3Н ₂ О: С, 68.28; H, 3.97; Ν, 12.25. Found: C, 67.68; H, 4.06; Ν, 11.89.

Example 35. 1- (4-amino-3'-chlorodiphenyl-3yl) ethanone.

A mixture of 2-amino-5-bromo-Y-methoxy-Y-methylbenzamide (7.78 g, 30 mmol) of 3-chlorophenylboronic acid (5.63 g, 36 mmol), tetrakis (triphenylphosphine) palladium (0) (17, 6 g, 1.5 mmol) and sodium carbonate (7.63 g, 72 mmol) in a mixture of DME and water (150 ml / 30 ml) were degassed with oxygen removal and heated to 85 ° С in a nitrogen atmosphere for 3 h. 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 the aqueous layer was extracted with ethyl acetate (3 x 40 ml). The combined organic layers were washed with brine and dried with MgSO ₄ . Then the solvent was removed, the precipitate was purified using flash chromatography (silica gel, hexane: ethyl acetate / 1: 1) to obtain 5- (3-chlorophenyl) -Ymethoxy-Y-methylbenzamide as a brown oil (5 g, 57%). To a solution of the obtained benzamide (5 g, 17.2 mmol) in anhydrous TTF was added dropwise methyl lithium in ether (1.4 M, 28.6 ml, 40 ml) at −78 ° C. under a nitrogen atmosphere. After 30 minutes of stirring, the reaction mixture was treated with a saturated aqueous solution of ammonium chloride (50 ml) at -78 ° C. Ethyl acetate (100 ml) was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed (brine) and dried (MgSO ₄ ). After removing the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 2: 1) to obtain 1- (4-amino-3'-chlorodiphenyl-3-yl) ethanone as a yellow solid (2 g, 47 %): mp 8990 ° C; ^! H-NMR (ATP1 ₃ ) δ 7.89 (d, 1H, 1 = 2.0 Hz),

7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, 1 = 8.6 Hz), 6.38 (broad, 2H), 2.65 (s, 3H); M8 (ΕΙ) m / e 268 ([M + Na] ⁺ , 60%), Anal. calculation for

C1 ₄ H ₁₂ C1O: C, 68.44; H, 4.92; Ν, 5.70. Found: C, 68.40; H, 4.89; Ν, 5.61.

Example 36. 4-Allyl-6- (3-chlorophenyl) -4methyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one (process C).

To a solution of 1- (4-amino-3'-chlorodiphenyl-3yl) ethanone (0.2 g, 0.82 mmol) in anhydrous TTF (10 ml) was added a solution of allyl magnesium bromide in ether (1.0 M, 3 ml, 3 mmol) at 0 ° C in a nitrogen atmosphere. The reaction solution was slowly heated and stirred under nitrogen for 1 h. A saturated aqueous solution of ammonium chloride (10 ml) was added and then ethyl acetate (50 ml) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x10 ml). The combined organic layers were washed with brine and dried with MgSO ₄ . After the solvent was removed, the residue was purified using flash chromatography (silica gel, hexane: ethyl acetate / 3: 1), an aminocarbinol intermediate was obtained, which was used in the next step without further purification.

To a solution of the above aminocarbinol intermediate in anhydrous THF was added ί.ΌΙ (0.38 g, 2.3 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 50 ° C for 12 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified using flash chromatography (silica gel, hexane: ethyl acetate / 2: 1) to give 4-allyl-6- (3-chlorophenyl) -4-methyl-1,4-dihydrobenzo [D] [1,3] ] oxazin-2-one as a white solid (130 mg, 52%): mp. 128,129 ° C; ^! H-NMR (SPS1 ₃ ) δ 8.68 (s, 1H, 1st substitution), 7.50 (s, 1H), 7.44 (dd, 1H, 1 = 8.2,

1.9 Hz), 7.31-7.40 (m, 3H), 7.25 (d, 1H, 1 = 1.6 Hz),

6.92 (d, 1H, 1 = 8.2 Hz), 5.70-5.85 (m, 1H), 5.17 (m, 2H), 2.76 (m, 2H), 1.79 (s, 3H); M8 (Ε8Ι) m / e 314 ([M + H] ⁺ , 40%), Anal. calculation for C _{£ 8} H ₁₆ ClO ₂ : C, 68.90; H, 5.14; Ν, 4.46. Found: C, 68.90; H, 5.18; Ν, 4.43.

Example 37. 6- (3-Chlorophenyl) -4-methyl-4propin-1-yl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one.

Prepared from 1- (4-amino-3'-chlorodiphenyl-3yl) ethanone and propynyl magnesium bromide, followed by treatment with CE1 according to method C. White solid: mp. 184-185 ° C; 'H-NMR (SESB,) δ 8.18 (s, 1H, E ₂ O interchangeable), 7.53 (t, 1H 1 = 1.7 Hz), 7.49 (s, 1H), 7.31 -7.40 (m, 4H), 6.92 (d, 1H, 1 = 8.1 Hz), 2.02 (s, 3H), 1.87 (s, 3H); M8 (Ε8Ι) m / e 304 ([M-H] ^- , 100%), Anal. calculation for C _{£ 8} H ₁₄ ClO ₂ : C 69.35; H, 4.53; Ν, 4.49. Found: C, 69.19; H, 4.37; Ν,

4.41.

Example 38. 6- (3-Chlorophenyl) -4-ethynyl-4methyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one.

Obtained from 1- (4-amino-3'-chlorodiphenyl3-yl) ethanone (0.2 g, 0.82 mmol), ethynyl magnesium bromide, followed by treatment ί.ΌΙ according to method C. White solid

so pl. 185-186 ° C; Ή-NMR (SPS1 ₃ ) δ 8.18 (s, 1H, E ₂ O interchangeable), 7.53 (t, 1H, 1 = 1.7 Hz),

7.49 (s, 1H), 7.31-7.40 (m, 4H), 6.92 (d, 1H, 1 = 8.1 Hz), 2.81 (s, 1H), 1.87 (s, 3H); Μ8 (Ε8Ι) m / e 304 ([M-H] ^- , 100%), Anal. calculation for C1 ₇ H _12, SCO ₂ : C, 68.24; H, 4.06; Ν, 4.70. Found: C, 68.24; H, 3.94; Ν, 4.65.

Example 39. 6- (3-Chlorophenyl) -4-methyl-4phenyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Obtained from 1- (4-amino-3'-chlorodiphenyl3-yl) ethanone (0.2 g, 0.82 mmol) ethynyl magnesium bromide, followed by treatment with 0 ° according to method C. White solid: so pl. 179-180 ° C; Ή-NMR (SPS1 ₃ ) δ 8.27 (s, 1H, 1XO interchangeable), 7.51-7.57 (m, 2H), 7.28-7.45 (m, 9H), 7.31- 7.40 (m, 4H), 6.92 (d, 1H, 1 = 8.4 Hz),

2.12 (s, 3H); Μ8 (Ε8Ι) m / e 348 ([M-H] ^- , 100%), Anal. calculation for C ₂ 1H _16, SCO ₂ : C, 72.10; H, 4.61; Ν, 4.00. Found: C, 71.72; H, 4.86; Ν, 3.91.

Example 40. 4-Benzyl-6- (3-chlorophenyl) -4methyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A mixture of 1 - (4-amino-3-chlorodiphenyl-3-yl) -1 benzylethanol (obtained using 1- (4-amino-3'-chlorodiphenyl-3-yl) ethanone and benzyl magnesium bromide according to method C, 0.14 g 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry GHF (10 ml) are stirred in a stream of nitrogen for 10 minutes. Upon completion of the reaction, THF is removed and the residue purified by flash chromatography (silica gel, 35% ethyl acetate / hexane) to give 4-benzyl-6- (3-chlorophenyl) -4-methyl-1,4-dihydrobenzo [b] [1] , 3] oxazin-2-one (0.045 g, 30%) as an off-white solid: mp. 187-188 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.1 (s, 1H),

7.70 (t, 1H, 1 = 2.3 Hz), 7.6 (d, 1H, 1 = 8.0 Hz), 7.58-

7.53 (m, 2H), 7.46 (t, 1H, 1 = 8.0 Hz), 7.38 (d, 1H, 1 = 8.0 Hz), 7.22-7.17 (m , 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, 1 = 9.14 Hz), 3.24 (d, 1H, 1 = 14.3 Hz), 3 06 (d, 1H, 1 = 14.3 Hz); 1.68 (s, 3H); Μ8 (Ε8Ι) m / e 364 ([M + H] ⁺ , 100%); Analysis: Calculated

C ₂₂ H ₁₈ SCO ₂ : C, 72.63; H, 4.99; Ν, 3.85. Found: C, 71.82; H, 5.09; Ν, 3.58.

Example 41. 6- (3-Chlorophenyl) -4-cyclopropyl-4-methyl-1,4-dihydrobenzo [b] [1,3] oxazin-2one.

To a solution of cyclopropylmagnesium bromide in anhydrous THF (obtained using cyclopropyl bromide and magnesium metal, 70 mmol) at 52 ° C, 4-amino-3'-chlorodiphenyl-3-carbonitrile (5.2 g, 22.7 mmol) is added in a stream of nitrogen. The reaction mixture was stirred at 52 ° C for 1 h, cooled to room temperature and quenched with a 1Ν aqueous HC1 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 Μ ^^ φ. The solvent was removed and the residue was purified using a silica gel column (hexane: ethyl acetate / 20: 1) to give (4-amino-3'chlorodiphenyl-3-yl) -cyclopropylmethane: ¹ N

NMR (hydrochloride, DMSO-b ₆ ) δ 8.30 (d, 1H, 1 = 2.1 Hz), 7.76 (t, 1H, 1 = 1.7 Hz), 7.68-7.63 ( m, 2H), 7.43 (t, 1H, 1 = 7.9 Hz), 7.32 (m, 1H), 6.88 (d, 1H, 1 = 8.7 Hz), 4.50 ( broad s, 3H), 3.07 (m, 1H), 0.98 (m, 4H); (Μ8 (+) Ε8Ι) m / e 272/274 (Μ ⁺ ).

To a solution of (4-amino-3'-chlorodiphenyl-3yl) cyclopropylmethanone (0.67 g, 2.5 mmol) in anhydrous THF (10 ml) at -78 ° C, a solution of methyl magnesium bromide (3.0 M in diethyl ether, 2 5 ml, 7.5 mmol) in a stream of nitrogen. The reaction mixture was slowly warmed to room temperature, stirred in a stream of nitrogen for 12 hours, and quenched with a saturated aqueous solution of ammonium chloride (40 ml). Ethyl acetate (50 ml) was added, the organic layers were separated and dried (Μ ^^ φ After removing the solvent, the residue was purified by silica gel chromatography (hexane: ethyl acetate / 7: 1), which afforded 1- (4-amino-3- chlorodiphenyl-3-yl) 1-cyclopropylethanol as a yellow oil: Μ8 (Ε1) m / e 287/289 (M ⁺ ).

The title compound is prepared from 1- (4amino-3-chlorodiphenyl-3-yl) -1-cyclopropylethanol and 1,1'carbonyldiimidazole according to method C. Off-white solid: mp. 158-159 ° C; Ή-NMR (DMSO-be) δ 10.3 (s, 1H),

7.74 (t, 1H, 1 = 1.71 Hz), 7.67-7.57 (m, 3H), 7.47 (t, 1H, 1 = 7.88 Hz), 7.39 (d , 1H, 1 = 8.1 Hz), 6.95 (d, 1H, 1 = 8.12 Hz), 1.7 (s, 3H), 1.45 (m, 1H), 0.48 (m , 2H); 0.28 (m, 2H); Μ8 (APC1) m / e 314 ([M + H] ⁺ , 100%); Analysis. Calculated С1 ₈ Н ₁₆ СШО ₂ : С, 68.9; H, 5.14; Ν, 4.46. Found: C, 68.13; H, 5.01, Ν, 4.36.

Example 42. 6- (3-Chlorophenyl) -4-cyclopropyl-4-propin-1-yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

1- (4-amino-3'-chlorodiphenyl-3-yl) -1-cyclopropyl-1-propynylmethanol is prepared from (4-amino-3'-chlorodiphenyl-3-yl) cyclopropylmethanone and propynyl magnesium bromide according to Example 41.

A mixture of 1 - (4-amino-3'-chlorodiphenyl-3-yl) -1 cyclopropyl-1-propinylmethanol (0.02 g, 0.064 mmol) and 1,1'-carbonyldiimidazole (0.016 g, 0.096 mmol) in dry THF (10 ml) is stirred in a stream of nitrogen for 10 minutes Upon completion of the reaction, THF is removed and the residue purified by flash chromatography (silica gel, 40% ethyl acetate / hexane) to give 6- (3-chlorophenyl) -4-cyclopropyl-4-prop-1-vinyl-1,4-dihydrobenzo [ b] [1,3] oxazin-2-one (0.014 g, 56%) as a light yellow solid: mp. 178-179 ° C; Ή NMR (DMSO-b ₆ ) δ 10.6 (s, 1H), 7.68 (m, 2H), 7.64 (broad s, 1H), 7.59 (d, 1H, 1 = 7.72 Hz ), 7.49 (t, 1H, 1 = 7.82 Hz), 7.42 (d, 1H, 1 = 7.95 Hz), 7.02 (d, 1H, 1 = 8.0 Hz), 1.86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H), Μ8 (Ε8Ι) m / e 336 ([M-H] ^- , 100%).

Example 43. 6- (3-Chlorophenyl) -4,4-dicyclopropyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

(4-amino-3'-chlorodiphenyl-3-yl) dicyclopropylmethanol (mp 90-92 ° С; Μ8 ((+) Ε8Ι) m / e

314 (M + H) ⁺ ), obtained from (4-amino-3′chlorodiphenyl-3-yl) cyclopropylmethanone and cyclopropyl magnesium bromide according to Example 41.

The title compound was prepared according to Example 41 from (4-amino-3′chlorodiphenyl-3-yl) dicyclopropylmethanol and 1,1′-carbonyldiimidazole. Yellow solid: mp. 198-200 ° ^C! H-NMR (DMSO-b ₆ ) δ 10.3 (s, 1H), 7.72 (broad s, 1H), 7.67 (wide s, 1H), 7.62 (m, 2H), 7, 48 (t, 1H, 1 = 7.88 Hz),

7.40 (d, 1H, 1 = 8.04 Hz), 6.94 (d, 1H, 1 = 8.27 Hz),

1.55 (m, 2H), 0.5 (m, 6H), 0.28 (m, 2H); M8 (E1) m / e 339 (M ⁺ , 40%). Analysis. calculated

C ₂₀ H ₁₈ SCO ₂ : C, 70.69; H, 5.34; Ν, 4.12. Found: C, 69.38; H, 5.07; Ν, 4.02.

Example 44. 6- (3-Chlorophenyl) -4,4-dipropin-1-yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Following the process of example 41, (4-amino3′-chlorodiphenyl-3-yl) propinylmethanone (mp 112-114 ° C; M8 ((+) EM) m / e 270/272 (M + H) ⁺ ) treated with propynyl magnesium bromide to give (4-amino-3'-chlorodiphenyl-3-yl) dipropinylmethanol, which reacts with 1,1'-carbonyldiimidazole, which affords the title compound. Yellow solid: mp. 151 ° C (decomposition); 'H-NMR (DMSO-b ₆ ) δ 10.8 (s, 1H), 7.71 (dd, 1H, 1 = 8.52, 1.94 Hz), 7.69 (m, 2H), 7 61 (d, 1H, 1 = 7.64 Hz), 7.50 (t, 1H, 1 = 7.85 Hz), 7.43 (d, 1H, 1 = 7.99 Hz), 7.06 (d, 1H, 1 = 8.23 Hz), 2.0 (s, 6H); M8 (ARP) m / e 336 ([M + H] ⁺ , 20%).

Example 45. 6- (3-Bromo-5-fluorophenyl) -1,4,4trimethyl-14-dihydrobenzo [b] [1,3] oxazin-2-one.

To a solution of 6- (3-bromo-5-fluorophenyl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one (0.34 g, 0.99 mmol) in dry DMF (10 ml) was added portionwise in a stream of nitrogen at room temperature, sodium hydride (80 mg, 2.0 mmol). The mixture was stirred at room temperature for 30 minutes, treated with iodomethane (1 ml, excess), and stirred for 2 hours. A cold saturated solution of ammonium chloride (30 ml) was added to the reaction mixture, and a white precipitate was obtained, which was collected on a filter, washed with distilled water, which allows you to get the named compound in the form of a white solid (0.31 g, 87%): so pl. 157-158 ° C; ^! H-NMR (DMSO-b ₆ ) δ 7.83 (s, 1H),

7.76 (dd, 1H, 1 = 8.5, 2.0 Hz), 7.67 (m, 2H), 7.53 (dt, 1H, 1 = 8.3, 1.9 Hz), 7 18 (d, 1H, 1 = 8.5 Hz), 3.33 (s, 3H), 1.67 (s, 6H); ¹⁹ P-NMR (DMSO-b ₆ ) δ -111.01 (m, 1P); M8 (ARP) m / e 364 ([M + H] ⁺ , 96%), 366 ([M + H] ⁺ , 100%).

Example 46. 1- (2-amino-5-chlorophenyl) 2,2,2-trifluoroethanone.

To a solution of No. (4-chlorophenyl) -2,2-dimethylpropanamide (6.7 g, 30 mmol) in anhydrous THF (100 ml) in a stream of nitrogen at 0 ° C was added a solution of n-CuL1 (2.5 M, 30 ml, 70 mmol) in hexane dropwise in portions. After addition, the solution was maintained under stirring at 0 ° C. for 40 minutes and treated with a solution of 1- (trifluoroacetyl) imidazole (9 ml, 78 mmol) in anhydrous THF (10 ml). The reaction mixture was warmed to room temperature and held for 18 hours. A saturated aqueous solution of ammonium chloride (50 ml) was added to the reaction solution, followed by ethyl acetate (100 ml). The organic layer was separated and the solvent was removed in vacuo. The resulting residue was suspended in a 3Ν aqueous hydrochloric acid solution (50 ml) and heated at reflux overnight. The reaction solution was cooled to room temperature and treated with a cold solution of ammonium hydroxide 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 removing the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 4: 1), which afforded the title compound as a yellow solid (1 g, 15%); so pl. 93-94 ° C; ^! NMR (СОС1 ₃ ) δ 7.70 (m, 1Н), 7.33 (dd, 1Н, 1 = 9.0,

2.3 Hz), 6.70 (d, 1H, 1 = 9.1 Hz), 6.45 (broad s, 2H); M8 (EZC m / e 222 (M-H, 100%), 224 (M-H, 33%).

Example 47. 6-Chloro-4-methyl-4-trifluoromethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from 1- (2-amino-5-chlorophenyl) 2,2,2-trifluoroethanone by adding methylmagnesium bromide followed by treatment of the resulting carbinol with 1,1'-carbonyldiimidazole in accordance with Example 2. White solid: mp. 210-216 ° C; 'H-NMR (DMSO ₆ ) δ 10.91 (broad s, 1H, Ό ₂ Ο replaceable),

7.64 (d, 1H, 1 = 1.6 Hz), 7.49 (dd, 1H, 1 = 8.6, 2.3 Hz), 6.95 (d, 1H, 1 = 8.6 Hz ), 1.91 (s, 3H); ¹⁹ P-NMR (DMSO-b6) δ -82.0 (s, 1P); M8 (E1) m / e 264 ([MH] ^- , 100%), 266 ([M-H] ^- , 33%). Analysis. Calculated C ₁₀ H ₇ C1P ₃ TO ₂ : C, 45.22; H, 2.66; Ν, 5.27. Found: C, 45.32; H, 2.77; Ν, 4.83.

Example 48. 6- (3-Methoxyphenyl) -4-methyl4-trifluoromethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A mixture of 6-chloro-4-methyl-4-trifluoromethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one (0.2 g, 0.75 mmol), 3-methoxyphenylboronic acid (0.13 g , 0.9 mmol), potassium phosphate (0.23 g, 1.1 mmol) and nickel (II) (diphenylphosphino) ferrocenyl dichloride (52 mg, 0.076 mmol) in anhydrous dioxane are treated with a stream of nitrogen to remove oxygen and heated at 95 ° C in a stream of nitrogen for 48 hours, then add other portions

3-methoxyphenyl boronic acid (0.13 g, 0.9 mmol) and nickel (II) (diphenylphosphino) ferrocenyl dichloride (52 mg, 0.076 mmol) and the reaction solution are heated at 95 ° C in a stream of nitrogen for 48 hours. The reaction solution is cooled to room temperature. A saturated aqueous solution of ammonium chloride (30 ml) and ethyl acetate (50 ml) were added. The organic layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine and dried (MgO ₄ ). After removing the solvent, the residue was purified by flash chromatography (silica gel, hexane: ethyl acetate / 4: 1), which afforded the title compound as a white solid (50 mg, 20%): mp. 178-179 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.85 (broad s, 1H, B ₂ O, interchangeable), 7.73 (m, 2H), 7.38 (t, 1H, 1 = 7.9 Hz) 7.23 (d, 1H, 1 = 7.7 Hz), 7.19 (d, 1H, 1 = 1.9 Hz), 7.02 (d, 1H, 1 = 8.2 Hz), 6 94 (dd, 1H, 1 = 8.2, 2.4 Hz), 3.88 (s, 3H), 1.98 (s, 3H); ¹⁹ G-NMR (DMSO ₆ ) δ -81.88 (s, 1G); Analysis. Calculated

C, 60.54; H, 4.18; Ν, 4.15. Found: C, 60.58; H, 4.44; Ν, 4.19.

Example 49. 7- (3-Methoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [th] [1,3] oxazin-2-one.

A mixture of 7-chloro-4,4-dimethylbenzoxazin-2one (0.197 g, 0.93 mmol), 3-methoxyphenyl boronic acid (0.21 g, 1.4 mmol), Νΐ (yrp) C1 ₂ (0.095 g, 0.14 mmol) and potassium phosphate (0.59 g, 2.79 mmol) in dioxane (10 ml) are treated with a stream of nitrogen to remove oxygen for 15 min at 50 ° C and then heated at 95 ° C for 48 hours. The reaction mixture was cooled to room temperature and ethyl acetate (100 ml) was added. The organic layers were washed twice with an aqueous solution of ammonium chloride (30 ml), 1 time with brine (30 ml), and dried over magnesium sulfate. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate / hexane) to give 7- (3-methoxyphenyl) -4,4dimethyl-1,4-dihydrobenzo [th] [1,3] oxazin-2-one ( 0.090 g, 35%) as a clear oil. The oil is triturated with ether (25 ml) to give a white solid: mp. 167-168 ° C; Я-NMR (DMSO- _6th ) δ 10.3 (s, 1H), 7.42-7.28 (m, 3H), 7.14 (d, 1H, 1 = 8.11 Hz), 7, 11 (broad s, 2H), 6.96 (dd, 1H, 1 = 8.11 Hz), 3.56 (s, 3H), 1.52 (s, 6H); M8 (E1) m / e 283 ([M + H] ⁺ , 90%); Analysis. Calculated CuNiMOS: C, 72.07; H, 6.05; Ν, 4.94. Found: C, 71.59; H, 6.08; Ν, 4.79.

Example 50. 6- (3-Acetylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [i] [1,3] oxazin-2-one.

3- (4,4-dimethyl-2-oxo-1,4-dihydro-2Nbenzo [a] [1,3] oxazin-6-yl) benzonitrile (0.25 g, 0.9 mmol) is dissolved in THF ( 10 ml) and cooled to 0 ° C. Methyl magnesium bromide (3.0 M in ether, 1.8 ml, 5.4 mmol) was added to this solution, and the reaction mixture was heated to reflux in a stream of nitrogen. Upon completion of the reaction, the reaction mixture was quenched with 1Ν HCl aqueous solution. It was then cooled to room temperature, extracted with ethyl acetate (100 ml), dried over MgSO ₄ and concentrated. Purification of the obtained residue by chromatography (silica gel, 50% ethyl acetate / hexane) gives 6- (3-acetylphenyl) 4,4-dimethyl-1,4-dihydrobenzo [th] [1,3] oxazin-2 it as a white solid substances (0.031 g, 12%): mp 178-179 ° C; Ή-NMR (SBS1 ₃ ) δ 8.15 (t, 1H, 1 = 1.71 Hz), 8.04 (s, 1H), 7.95 (dt, 1H, 1 = 8.85, 1.13 Hz) 7.76 (dt, 1H, 1 = 7.90, 1.43 Hz),

7.57 (t, 1H, 1 = 7.72 Hz), 7.52 (dd, 1H, 1 = 8.28, 2.11 Hz), 7.39 (d, 1H, 1 = 1.81 Hz ), 6.93 (d, 1H, 1 = 8.19 Hz), 2.69 (s, 3H), 1.81 (s, 6H); M8 (E1) m / e 295 ([M + H] ⁺ , 40%).

Example 51. 6- (3-Benzoylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [y] [1,3] oxazin-2-one.

Prepared from 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2Π-benzo [ά] [1,3] oxazin-6-yl) benzonitrile and phenylmagnesium bromide according to Example 50. White solid : mp 156157 ° C; Ή-NMR (DMSO-th ₆ ) δ 10.33 (s, 1H), 8.0-

7.96 (m, 2H), 7.80 (m, 2H), 7.73-7.56 (m, 7H), 6.99 (d, 1H, 1 = 8.06 Hz), 1.67 (s, 6H); M8 (E1) m / e 357 ([M + H] ⁺ , 40%); Analysis. Calculated C ^ H ^ O ^ C, 77.29; H, 5.36; Ν, 3.92. Found: C, 75.7; H, 5.28; Ν, 3.86.

Example 52. 4,4-Dimethyl-6- [3- (Ш-tetrazol-5-yl) phenyl] -1,4-dihydrobenzo [th] [1,3] oxazin-2-one.

A mixture of 3- (4,4-dimethyl-2-oxo-1,4-dihydro2 H-benzo [th] [1,3] oxazin-6-yl) benzonitrile (0.77 g, 2.8 mmol), trimethylsilyl azide (0.68 g, 5.6 mmol), and tin dibutyl oxide (0.071 g, 0.28 mmol) in dioxane (20 ml) are heated under reflux in a stream of nitrogen. Upon completion of the reaction, dioxane is removed, the organics are transferred into ethyl acetate (100 ml) and washed with a solution of No. ₁ HCO ₃ (100 ml). The aqueous layer was acidified with 1Ν aqueous HC1 and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO ₄ and concentrated. Crystallization from ether (20 ml) gives 4,4-dimethyl-6- [3- (1Htetrazol-5-yl) phenyl] -1,4-dihydrobenzo [th] [1,3] oxazin-2-one as a light yellow solid (0.23 g, 26%): mp. 238-240 ° C; Я-NMR (DMSO- _6th ) δ 10.4 (s, 1H), 8.3 (broad s, 1H), 8.02 (d, 1H, 1 = 7.66 Hz), 7.9 (d , 1H, 1 = 7.91 Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, 1 = 8.75 Hz), 1.70 (s, 6H); M8 (E81) m / e 320 ([M-H] ^- , 100%); Analysis. Calculated CuH ^ Oy C, 63.54; H, 4.71; Ν, 21.79. Found: C, 62.16; H, 4.67; Ν, 21.31.

Example 53. 4- (4,4-Dicyclopropyl-2-oxo1,4-dihydro-2H-benzo [y] [1,3] oxazin-6'-yl) thiophene-2-carbonitrile.

(4,4-Dicyclopropyl-1,4-dihydro-2-oxo2 H-3,1-benzoxazin-6-yl) boronic acid is obtained from 2-amino-5-bromobenzoic acid in accordance with examples 1, 2 and 4. White solid: mp 240-242 ° C; Ή-NMR (DMSOO δ 10.13 (s, 1H), 8.01 (s, 2H), 7.85 (s, 1H), 7.64 (d, 1H, 1 = 7.9 Hz), 6 77 (d, 1H, 1 = 7.9 Hz),

1.38 (m, 2H), 0.52 (m, 2H), 0.39 (m, 4H), 0.22 (m, 2H).

The title compound is prepared according to method B from (4,4-dicyclopropyl-1,4-dihydro2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 4-bromo-2-thiophene carbonitrile. White solid: mp 244-245 ° C; ¹ H-NMR (DMSO-ά ..) δ 10.25 (s, 1H), 8.49 (d, 1Η, 1 = 0.87 Hz), 8.33 (s, 1H), 7.74 ( d, 1H, 1 = 1.44 Hz), 7.67 (dd, 1Η, 1 = 8.28, 1.54 Hz), 6.90 (d, 1Η, 1 = 8.28 Hz), 1, 53 (m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H); M8 (Ε8Ι) m / e 335 ([M-H] ^- , 100%); Analysis. Calculated ^ Η ^ Ν ^ δ: C, 67.84; H, 4.79; Ν, 8.33. Found: C, 64.92; H, 4.66; Ν, 7.71.

Example 54. 6- (3-Bromo-5-fluorophenl) -4,4dicyclopropyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from (4,4dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1,3dibromo-5-fluorobenzene. White solid: mp 228-229 ° C; ¹ H-NMR (DMSO-b ₆ ) δ 10.3 (s, 1Η), 7.76-7.72 (m, 2H), 7.65 (dd, 1Η, 1 = 8.32, 1.74 Hz), 7.60 (d, 1Η, 1 = 10.36 Hz), 7.51 (d, 1Η, 1 = 8.3 Hz), 6.93 (d, 1Η, 1 = 8.31 Hz) 1.63-1.54 (m, 2H); 0.58-0.41 (m, 6H); 0.30-0.28 (m, 2H); M8 (APC1) m / e 402/404 ([M-H] ^- , 100%); Analysis. Calculated ^ οΗπΒγΡΝΟ ^ C, 58.48; H, 4.17; Ν, 3.41. Found: C, 58.77; H, 4.23; Ν, 3.32.

Example 55. 3- (4,4-Dicyclopropyl-2-oxo1,4-dihydro-2H-benzo [ά] [1,3] oxazin-6-yl) -5 fluorobenzonitrile.

A mixture of 6- (3-bromo-5-fluorophenyl) -4,4-dicyclopropyl-1,4-dihydrobenzo - [ά] [1,3] oxazin-2one (0.4 g, 1.0 mmol), Ζη ( CK) ₂ (0.71 g, 0.61 mmol), and tetrakis (triphenylphosphine) palladium (0) (0.07 g, 0.06 mmol) in DMF (20 ml) was purged with nitrogen for 15 min at 50 ° C and then heated at 85 ° C for 1 h. After cooling to room temperature, the reaction mixture was poured into ΝΗ · | Ο (100 ml) and extracted with ethyl acetate (3x50 ml). The organic layers are washed with brine, dried over Ο§δΟ ₄ and concentrated. The resulting clear oil was triturated with ether (30 ml) to give a white solid. Recrystallization of a solid from ethyl acetate gave 3- (4,4dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo [ά] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.016 g, 4, 6%): mp 250-252 ° C; ¹ H-NMR (DMSO-b ₆ ) δ

10.3 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H, 1 = 10.54 Hz), 7.81-7.79 (m, 2H), 7.73 (dd, 1H, 1 = 8.3, 1.59 Hz),

6.94 (d, 1H, 1 = 8.34 Hz), 1.59 (m, 2H), 0.58-0.42 (m, 6H), 0.30-0.28 (m, 2H) ; M8 (Ε8Ι) m / e 347 ([M-H] ^- , 100%); Analysis. Calculated C ₂₁ Η ₁ 7pN ₂ Ο ₂ : C, 72.4; H, 4.92; Ν, 8.04. Found: C, 72.4; H, 4.74; Ν, 7.61

Example 56. 6- (3-Bromo-5-methylphenyl) -4,4dimethyl-1,4-dihydrobenzo- [ά] [1,3] oxazin-2-one.

Prepared from (4,4-dimethyl-1,4-dihydro-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3,5-dibromotoluene according to method B. White solid: mp. 231-233 ° C; 'Η NMR (DMSO-a ₆ ) δ 10.4 (s, 1H), 7.66 (s, 1H), 7.58-

7.56 (m, 2H), 7.50 (s, 1H), 7.37 (s, 1H), 6.95 (d, 1H, 1 = 8.67 Hz), 2.37 (s, 3H ), 1.67 (s, 6H); M8 (Ε8Ι) m / e 344/346 ([M-H] ^- , 100%). Analysis. You are numerically ^ Η ^ ι-ΝΟ ^ C, 58.98; H, 4.66; Ν, 4.05. Found: C, 58.82; H, 4.62; Ν, 3.94.

Example 57. 6- (3-Bromo-5-trifluoromethoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [ά] [1,3] oxazin-2-one.

Prepared from (4,4-dimethyl-1,4-dihydro-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1,3-dibromo-5-trifluoromethoxybenzene according to method B. White solid: t .pl. 214-216 ° C; 'Я-NMR (DMSO-b ₆ ) 10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, 1 = 8.0 Hz), 1.68 (s, 6H); M8 (Ε8Ι) m / e 414 ([MH] ^- , 100%); Analysis. Calculated C | -Η | sΒ ^ ΡзNΟз: С, 49.06; H, 3.15; Ν, 3.37. Found: C, 49.16; H, 3.05; Ν, 3.30.

Example 58. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [ά] [1,3] oxazin-6-yl) -5-methylbenzonitrile.

Prepared from 6- (3-bromo-5-methylphenyl) -4,4dimethyl-1,4-dihydrobenzo - [ά] [1,3] oxazin-2-one according to the procedure in Example 55. White solid: mp . 256-258 ° C; ^! H-NMR (DMSO ₆ ) 10.4 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.67-

7.62 (m, 3H), 6.97 (d, 1H, 1 = 8.11 Hz), 2.42 (s, 3H),

1.68 (s, 6H). M8 (APC1) m / e 293 ([M + H] ⁺ , 100%); Analysis. Calculated ^ Η ^^ Ο ^ C, 73.96; H, 5.52; Ν, 9.58. Found: C, 73.26; H, 5.46; Ν, 9.24.

Example 59. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-trifluoromethoxybenzonitrile.

Prepared from 6- (3-bromo-5-trifluoromethoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [ά] [1,3] oxazin-2-one according to Example 55. White solid: mp. 227-228 ° C; 'H-NMR (DMSO-Y6) δ 10.4 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.75- 7.72 (m, 3H), 6.99 (d, 1H, 1 = 8.11 Hz), 1.7 (s, 6H); M8 (APC1) m / e 363 ([M + U ⁺ , 80%); Analysis. Calculated

C ^ P; ^: C, 59.67; H, 3.62; Ν, 7.73. Found: C, 59.63; Η, 3.55; Ν, 7.58.

Example 60. 6- (3,5-Difluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from (4,4dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3,5-difluorobenzene. White solid: mp 218-219 ° C; '11-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H),

7.67-7.65 (m, 2H), 7.49 (d, 2H, 1 = 7.73 Hz), 7.19 (t, 1H, 1 = 9.29 Hz), 6.96 (d, 1H 1 = 8.88 Hz); 1.7 (s, 6H); M8 (APC1) m / e 290 ([M + H] ⁺ , 100%). Analysis. Calculated ^^ βΡ ^ Ο ^ C, 66.43; H, 4.53; Ν, 4.84. Found: C, 66.01; H, 4.46; Ν, 4.67.

Example 61. 6- (3,5-Dichlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [ά] [1,3] oxazin-2-one.

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 3,5-dichlorophenylboronic acid according to method A. White solid: mp. 245-246 ° C; ¹ Η NMR (DMSO-a ₆ ) δ 10.4 (s, 1H), 7.77 (m, 2H),

7.67-7.64 (m, 2H), 7.56 (broad s, 1H), 6.96 (d, 1H, 1 = 7.98 Hz), 1.7 (s, 6H); M8 (Ε1) m / e 321 ([M + H] ⁺ , 40%). Analysis. Calculated

C ₁₆ H ₁₃ Cl ₂ KO ₂ : C, 59.32; H, 4.11; Ν, 4.32. Found: C, 59.13; H, 4.29; Ν, 4.17.

Example 62. 6- (3,5-Bis-trifluoromethyl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and bistrifluoromethylphenylboronic acid according to method A. White solid: mp. 258-260 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H),

8.35 (s, 2H), 8.05 (s, 1H), 7.79-7.76 (m, 2H), 7.01 (d, 1H, 1 = 8.01 Hz), 1.7 (s, 6H); MB (EB1) m / e 390 ([M + H] ⁺ , 20%). Analysis. Calculated

8ι ₈ Η ₁₃ Ρ ₆ ΝΘ ₂ : C, 55.54; H, 3.37; Ν, 3.6. Found: C, 55.5; H, 3.54; Ν, 3.47.

Example 63. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-methoxybenzonitrile.

A mixture of (4,4-dimethyl-1,4-dihydro-2-oxo2H-3,1-benzoxazin-6-yl) boronic acid (4.2 g, 19.0 mmol), 3-cyano-5-methoxyphenyl triflate ( 5.1 g, 19.0 mmol), tetrakis (triphenylphosphine) palladium (0) (1.1 g, 0.95 mmol), sodium carbonate (4.0 g, 38.0 mmol) and lithium bromide (5 g , 57 mmol) in IMO (50 ml) and water (25 ml) was purged with nitrogen for 15 min at 50 ° C and then heated at 85 ° C for 1 h. The reaction was cooled to room temperature and ethyl acetate (100 ml) was added. The organic layers are washed twice with an aqueous solution of ammonium chloride (100 ml) and 1 time with brine (100 ml), dried over magnesium sulfate and concentrated. Purification by chromatography (silica gel, 40% ethyl acetate / hexane) gives 3- (4,4dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5 -methoxybenzonitrile in the form of a white solid (0.69 g, 53%): mp. 254-255 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H),

7.84 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (broad s, 1H), 7.4 (wide s, 1H), 6.99 (d, 1H, 1 = 7.94 Hz),

3.88 (s, 3H); 1.67 (s, 6H); MB (E1) m / e 308 ([M + H] ⁺ , 30%); Analysis. Calculated Οι ₈ Η ₁₆ Ν ₂ Θ ₃ : C, 68.13; H, 5.40; Ν, 8.83. Found: C, 68.03; H, 5.22; Ν, 8.46.

Example 64. 6- (3-Fluorophenyl) -4,4-dimethyl1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 1-bromo-3-fluorobenzene according to method A. Light yellow solid: mp. 181-182 ° C; Ή NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 7.62-7.44 (m, 5H),

7.16 (t, 1H, 1 = 2.22 Hz), 6.97 (d, 1H, 1 = 8.83), 1.67 (s, 6H); MB (E1) m / e 271 ([M + H] ⁺ , 40%); Analysis. Calculated Ο ₁₆ Η ₁₄ ΡΝΘ ₂ : C, 69.91; H, 5.3; Ν, 5.1. Found: C, 70.0; H, 5.32; Ν, 4.92.

Example 65. 6- (3-Chloro-4-fluorophenyl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] o xazin-2-one.

Prepared from 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 1-bromo-3-chloro-4-fluorobenzene according to method A. White solid: mp. 211-212 ° C; Я-NMR (DMSO-sG) δ 10.4 (s, 1H), 7.92 (dd, 1H, 1 = 7.13,

2.19 Hz), 7.71-7.66 (m, 1H), 7.60-7.57 (m, 2H),

7.49 (t, 1H, 1 = 8.95 Hz), 6.96 (d, 1H, 1 = 8.01 Hz),

1.67 (s, 6H); MB (ΕΙ) m / e 305 ([M + H] ⁺ , 20%); Analysis. Calculated Οι ₆ Η ₁₃ Ο1ΡΝΘ ₂ : C, 62.86; H, 4.29; Ν, 4.58. Found: C, 62.52; H, 4.45; Ν, 4.42.

Example 66. 3- (1-Diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile.

A mixture of 3- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) -5 fluorobenzonitrile (0.25 g, 0.84 mmol) and triethyl orthoformate (50 ml) is heated at 160 ° C. for 12 hours. Excess triethyl orthoformate is removed in vacuo and purified by chromatography (silica gel, 20% ethyl acetate / hexane) to give 3 (1-diethoxymethyl-4,4-dimethyl-2-oxo -1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.116 g, 33%) as a white solid: mp. 123-124 ° C; Ή-NMR (DMSO-b ₆ ) δ

7.97 (d, 1H, 1 = 8.68 Hz), 7.66 (broad s, 1H),

7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3, 73-3.61 (m, 2H), 1.77 (s, 6H),

1.27 (t, 6H, 1 = 7.05 Hz); MB (EB1) m / e 295 ([М-Н] ^- , 100%, lower М№ ionic content with loss of diethyl acetal). Analysis. Calculated C ₂₂ H ₂₃ P ^ O ₄ : C, 66.32; H, 5.82; Ν, 7.03. Found: C, 65.89; H, 5.92; Ν, 6.66.

Example 67. 3-Fluoro-5- (1-methoxymethyl-4,4dimethyl-2-oxo -1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile.

Solution 3 - (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.150 g, 0.51 mmol) in DMF (5 ml), it is treated at room temperature with sodium hydride (0.061 g, 1.53 mmol). The mixture was stirred for 30 minutes and treated with chloromethyl methyl ether (0.062 g, 7.7 mmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 ml) and extracted with ethyl acetate (3x30 ml), dried over MDBO ₄ and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate / hexane) to give 3 fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo1,4-dihydro-2H-benzo [b] [1,3] ] oxazin-6-yl) benzonitrile as a white solid (0.11 g, 65%). so pl. 169-171 ° C; Я-NMR (DMSO-sG) δ

8.17 (broad s, 1H), 8.03 (dt, 1H, 1 = 10.4, 2.13 Hz), 7.85-7.77 (m, 3H), 7.31 (d, 1H) , 1 = 8.49 Hz),

5.33 (s, 2H); 3.35 (s, 3H); 1.7 (s, 6H); MB (APC1) m / e 341 ([M + H] ⁺ , 50%); Analysis. Calculated C11 · 1 ^; \ Oh _; : C, 65.32; H, 5.19; Ν, 8.02. Found: C, 64.92; H, 4.96; Ν, 7.73.

Example 68. Phosphoric acid diethyl ester of 6- (3-cyano-5-fluorophenyl) -4,4-dimethyl4H-benzo [b] [1,3] oxazin-2-yl ester.

To a solution of 3- (4,4-dimethyl-2-oxo-1,4dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.25 g, 0.84 mmol ) in DMF (5 ml) add sodium hydride (60% in oil,

0.101 g, 2.53 mmol). After stirring for 30 minutes, the reaction mixture was treated with diethyl chlorophosphate (0.22 ml, 1.52 mmol). Upon completion of the reaction, the reaction solution was quenched with water (25 ml) and the product was extracted with ethyl acetate (2x50 ml), dried over Μ§3Ο ₄ and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate / hexane) to give 6- (3-cyano-5-fluorophenyl) -4,4dimethyl-4H-benzo [b] [1,3] oxazine- phosphoric acid diethyl ester 2-yl ether as a white solid (0.064 g, 18%): mp. 196-198 ° C; Ή-NMR (DMSO-b ₆ ) δ

8.19 (broad s, 1H), 8.05 (d, 1H, 1 = 10.4 Hz), 7.9-7.8 (m, 3H), 7.51 (d, 1Η, 1 = 8 , 41 Hz), 4.33-4.41 (m, 4H), 1.76 (s, 6H), 1.27 (t, 6H, 1 = 7.05 Hz); Μ3 (APC1) m / e 433 ([M + H] ⁺ , 80%); Analysis. Calculated C ₂₁ H ₂₂ RI ₂ O ₅ P: C, 58.33; H, 5.13; And, 6.48. Found: C, 58.1; H, 5.11; And, 6.25.

Example 69. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-fluorobenzonitrile.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 5-bromo-2-fluorobenzonitrile according to method B. White solid: mp . 229230 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.15 (dd, 1H, 1 = 7.39, 2.12 Hz), 7.95-7.89 (m, 1H ), 7.59-

7.48 (m, 3H), 6.99 (d, 1H, 1 = 8.1 Hz), 1.7 (s, 6H); Μ3 (APC1) m / e 297 ([M + H] ⁺ , 100%); Analysis. Calculated ^ ₇ Η ₁₃ ΡΝ ₂ Ο ₂ : C, 68.91; H, 4.42; AND,

9.45. Found: C, 68.74; H, 4.83; And, 9.10.

Example 70. 8-Fluoro-4,4-dimethyldihydrobenzo [b] [1,3] oxazin-2-one.

I- (tert-Butoxycarbonylamino) -3-fluorobenzoic acid (TacadCI s1 a1. acid, which is treated with methylmagnesium bromide, which allows to obtain o-aminodimethylcarbinol. o-amino dimethylcarbinol (2.23 g, 13.2 mmol) was treated with 1,1'-carbonyldiimidazole (2.8 g, 17.2 mmol) in THF (20 ml) at 50 ° C. for 12 hours. Upon completion The reaction was cooled to room temperature and ethyl acetate (100 ml) was added. The organic layer was washed with a 10% aqueous HC1 solution (2x25 ml), dried over Μ§3Ο ₄ and concentrated. The residue was purified by chromatography (silica gel, 10% ethyl acetate / hexane) to give 8-fluoro4,4-dimethyldihydrobenzo [b] [1,3] oxazin-2-one as a white solid (1.3 g, 50% ): mp 127-128 ° C; Я-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 7.22-7.12 (m, 2H), 7.07-7.00 (m, 2H), 1.6 (s 6H); Μ3 (APC1) m / e 196 ([M + H] ⁺ , 100%); Analysis. Calculated ^ οΗιοΡΝΟ ₂ Ή 61.53; Η, 5.16; And, 7.18. Found: C, 61.27; H, 5.37; And, 7.02.

Example 71. 6- (3-Chloro-4-fluorophenyl) -8 fluoro-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

To a solution of 8-fluoro-4,4-dimethyldihydrobenzo [b] [1,3] oxazin-2-one (0.15 g, 0.77 mmol) in acetic acid (5 ml), a bromine solution (0, 37 g, 2.31 mmol) in acetic acid (5 ml) in a stream of nitrogen at room temperature. After stirring for 10 min, the mixture was concentrated and the obtained residue was purified on a silica gel column (hexane: ethyl acetate / 4: 1), which afforded 6-bromo-8-fluoro-4,4-dimethyldihydrobenzo [b] [1,3] oxazine -2-one as an off-white solid (0.176 g, 84%), which is used in the next step without further purification.

A mixture of 6-bromo-8-fluoro-4,4-dimethyldihydrobenzo [b] [1,3] oxazin-2-one (0.176 g, 0.64 mmol),

4-fluoro-3-chlorophenylboronic acid (0.15 g, 0.84 mmol), tetrakis (triphenylphosphine) palladium (0) (0.04 g, 0.032 mmol) and sodium carbonate (0.20 g, 1.92 mmol ) in ΌΜΕ (10 ml) and water (5 ml) was purged with nitrogen for 15 min at 50 ° C and then heated at 85 ° C for 1 h. The reaction mixture was cooled to room temperature and ethyl acetate (100 ml) was added. The organic layer was washed twice with an aqueous solution of ammonium chloride (100 ml) and once with brine (100 ml), dried over magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, 25% ethyl acetate / hexane) to give 6- (3-chloro-4-fluorophenyl) -8 fluoro-4,4-dimethyl-1,4-dihydrobenzo [b] [1, 3] -oxazin-2-one as a white solid (0.13 g, 66%): mp. 246-248 ° C; Ή-NMR (DMSOb ₆ ) δ 10.5 (s, 1H), 8.00 (dd, 1H, 1 = 7.09, 2.32 Hz), 7.78-7.73 (m, 1H), 7.62 (dd, 1H, 1 = 11.86, 1.77 Hz),

7.7 (t, 2H, 1 = 9 Hz), 1.7 (s, 6H); Μ3 (APC1) m / e 324 ([M + H] ⁺ , 100%); Analysis. Calculated ^ ₆ Η ₁₂ Ρ ₂ ΝΟ ₂ · 0.5 4 ₂ Ο: C, 57.76; H, 3.94; And, 4.21. Found: C, 57.49; H, 3.69; And, 4.03.

Example 72. 6- (3-Bromophenyl) -4,4-dimethyl1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1,3-dibromobenzene according to method B. White solid: mp. 174-175 ° C; Ή NMR (DMSO-b ₆ ) δ 10.35 (s, 1H), 7.88 (broad s, 1H), 7.68 (d, 1H, 1 = 7.5 Hz), 7.6-7.51 (m, 3H), 7.4 (t, 1H, 1 = 7.5 Hz), 6.97 (d, 1H, 1 = 8.57 Hz), 1.64 (s, 6H); Μ3 (Ε1) m / e 331 ([M ⁺ ], 60%), 333 ([M] ⁺ , 60%); Analysis. Calculated Γ'π, Ηι.-ιΒγΝΟχ С, 57.85; H, 4.25; And, 4.22. Found: C, 57.7; H, 4.36; And, 4.09.

Example 73. 4,4-Dimethyl-6- (3-trimethylsilanylethynylphenyl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A mixture of 6- (3-bromophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol ), tetrakis (triphenylphosphine) palladium (0) (0.17 g, 0.24 mmol) and copper (I) iodide (0.05 g, 0.28 mmol) in triethylamine (20 ml) are heated in a stream of nitrogen at 80 ° C for 3 hours. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was taken up in ethyl acetate (50 ml) and washed with a 1Ν aqueous HC1 solution (3 × 20 ml), as well as brine (20 ml). The organic layer was separated and dried (Μ§δΟ ₄ ). After removing the solvent, the residue was purified by silica gel chromatography (hexane: ethyl acetate / 3: 1), which afforded the title compound as a white solid (0.77 g, 92%); so pl. 240-242 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-

7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, 1 = 7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); Μδ (E1) m / e 349 (| Μ '|, 50%); Analysis. Calculated

C ₂ 1H _{2 s} NΟ ₂ δ ^ Ο ₂ · EΐΟAc: C, 71.32; H, 6.75; Ν, 3.82. Found: C, 71.08; H, 6.64; Ν, 3.82.

Example 74. 6- (3-Ethynylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A mixture of 4,4-dimethyl-6- (3-trimethylsilanylethanylphenyl) -1,4-dihydrobenzo [b] [1,3] oxazine 2-one (0.7 g, 2 mmol) and potassium carbonate (2 g, excess) in anhydrous methanol was stirred at room temperature in a stream of nitrogen for 4 hours. The mixture was treated with ice water (100 ml) and extracted with ethyl acetate (2x80 ml). The organic layers are washed with brine and dried over Μ§δΟ ₄ . The solvent was removed and the title compound was obtained as an off-white solid (0.4 g, 72%): mp. 171-172 ° C; Ή NMR (DMSO-b ₆ ) δ 10.3, (s, 1H), 7.78 (broad s, 1H), 7.72-7.69 (m, 1H), 7.6-7.57 (m , 2H), 7.49-7.43 (m, 2H), 6.97 (d, 1H, 1 = 7.98 Hz), 4.25 (s, 1H), 1.67 (s, 6H) ; Μδ (E1) m / e 277 ([M ⁴ ], 100%); Analysis. Calculated С1 ₈ Н15NΟ ₂ · 0.2 ELS: C, 76.56; H, 5.67; Ν, 4.75. Found: C, 76.34; H, 5.4; Ν, 4.7.

Example 75. 3- [3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenyl] propyl nitrile.

To a stirred mixture of DMSO, acetonitrile and water (9 ml / 3 ml / 0.5 ml) at room temperature in a stream of nitrogen add copper cyanide (0.193 g, 2.2 mmol), sodium iodide (11 mg, 0.072 mmol), and 6- (3-ethynylphenyl) -4,4-dimethyl1,4-dihydrobenzo [b] [1,3] oxazin-2-one (0.2 g, 0.72 mmol). Then, chlorotrimethylsilane is added dropwise to the mixture obtained above. After addition, the mixture was heated at 50 ° C for 72 hours. Then the reaction mixture was cooled to room temperature and treated with 0.5Ν aqueous cold HC1 solution (50 ml). The resulting precipitate was collected on a filter and washed with water. The solid was purified on a silica gel column (hexane: ethyl acetate / 2: 1), which afforded the title compound as an off-white solid (10 mg, 4.6%): mp. 212213 ° C; Ή-NMR (SPS1 _3- b ₆ ) δ 7.96 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H, 1 = 7.8 Hz), 7.60 (d , 1H, 1 = 7.69 Hz), 7.51 (d, 1H, 1 = 7.77 Hz), 7.45 (dd, 1H, 1 = 8.67,

2.21 Hz), 7.31 (d, 1H, 1 = 1.55 Hz), 6.91 (d, 1H, 1 = 8.19 Hz), 1.8 (s, 6H); Μδ (E1) m / e 302 ([Μ ⁴ ], 30%).

Example 76. 6- (3-Fluoro-5-nitrophenyl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3-fluoro-5-nitrobenzene according to method B. Yellow solid : mp 260,261 ° C; Я-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.37 (broad s, 1H), 8.14-8.05 (m, 2H), 7.77-7.74 ( m, 2H), 7.01 (d, 1H, 1 = 7.94 Hz), 1.7 (s, 6H); Μδ (E81) m / e 315 ([M-H] ^- , 100%); Analysis. Calculated ^^ πΕΝΉ ^ C, 60.76; H, 4.14; Ν, 8.86. Found: C, 60.34; H, 4.2; Ν, 8.61.

Example 77. 6- (3-Chloro-5-fluorophenyl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3-chloro-5-fluorobenzene according to method B. White solid : mp 193194 ° C; Я-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 7.67-

7.64 (m, 3H), 7.61-7.57 (m, 1H), 7.41-7.37 (m, 1H), 6.96 (d, 1H, 1 = 8.72 Hz) 1.7 (s, 6H); Μδ (APC1) m / e 306 ([M + H] ⁺ , 100%); Analysis. Calculated C1 Ι · _; (Ί1 ^; \ Ό <C, 62.86; H, 4.29; Ν, 4.58. Found: C, 62.98; H, 4.1; Ν, 4.6.

Example 78. 3-Chloro-5- (4,4-dimethyl-2-oxo1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3-chlorobenzonitrile according to method B. White solid: mp . 256,257 ° C; Я-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.22 (broad s, 1H), 8.15 (wide s, 1H), 7.98 (wide s, 1H), 7 74-7.71 (m, 2H), 6.97 (d, 1H, 1 = 8.09 Hz), 1.7 (s, 6H); Μδ (E81) m / e 311 ([M-H] ^- , 100%); Analysis. Calculated CuH ^ NW ^^ C, 65.29; H, 4.19; Ν, 8.96. Found: C, 65.25; H, 3.92; Ν, 8.71.

Example 79. 6- (3,5-Dinitrophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3,5-dinitrobenzene according to method B. Yellow solid: t pl. 297298 ° C; Я-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.88 (d, 2H, 1 = 1.98 Hz), 8.78 (broad s, 1H), 7.78-

7.82 (m, 2H), 7.04 (d, 1H, 1 = 8.23 Hz), 1.7 (s, 6H); Μδ (APC1) m / e 343 ([M-H] ^- , 100%); Analysis. Calculated ^^ βΝβΟ ^ C, 55.98; H, 3.82; Ν, 12.24. Found: C, 55.65; H, 3.7; Ν, 11.92.

Example 80. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) isophthalonitrile.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 5-bromisophthalonitrile according to method B. White solid: mp. 288-289 ° C; Ή NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.58 (s, 2H), 8.40 (d, 1H, 1 = 0.77 Hz), 7.80-7.75 ( m, 2H), 6.99 (d, 1H, 1 = 8.2 Hz), 1.7 (s, 6H); Μδ (E1) m / e 303 ([M ⁴ ], 20%).

Analysis. Calculated S. ' ₁₈ H ₁₃ No. O ₃ -1.65 H ₂ O: C, 64.92; H, 4.93; Ν, 12.62. Found: C, 64.74; H, 4.69; Ν, 12.32.

Example 81. 4,4-Dimethyl-6- (3-thiazol-2-ylphenyl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A mixture of 6- (3-bromophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one (0.25 g, 0.75 mmol), tri-n-butylthiazole-2 α-tin (0.5 g, 1.3 mmol) in DMF (5 ml) is degassed to remove oxygen and then heated in a stream of nitrogen at 90 ° C for 3 hours. The reaction mixture is cooled to room temperature and treated with ice water ( 70 ml). Ethyl acetate (100 ml) was added and the organic layer was separated, washed with brine, and dried (ΜдδΟ ₄ ). After removing the solvent, the residue was purified on a silica gel column (hexane: ethyl acetate / 1: 1), which afforded the title compound as a white solid (60 mg, 23%): mp. 223-224 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (broad s, 1H), 7.67 -7.61 (m, 4H), 7.53 (t, 1H, 1 = 7.68 Hz), 7.00 (d, 1H, 1 = 8.81 Hz), 1.7 (s, 6H) ; Μδ (APC1) m / e 337 ([M + H] ⁺ , 100%); Analysis. Calculated ^ 9 ^^^ - 0.25 Н ₂ О: С, 66.94; H, 4.88; Ν, 8.22. Found: C, 66.57; H, 4.65; Ν, 7.92.

Example 82. 6- (3-Fluoro-5-methoxyphenyl) 4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3-bromo-5-fluoroanisole according to method B. White solid: mp . 181-182 ° C; Ή NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 7.62-7.59 (m, 2H), 7.13-7.06 (m, 2H), 6.97-6.94 (d, 1H, 1 = 8.89 Hz),

6.80 (dt, 1H, 1 = 10.95, 2.12 Hz), 3.8 (s, 3H), 1.7 (s, 6H); Μδ (ΕδΙ) m / e 302 ([M + H] ⁺ , 100%); Analysis. Calculated C ₁₇ H _1b tO ₃ -0.1 H ₂ O: C, 67.36; H, 5.39; Ν, 4.62. Found: C, 67.11; H, 5.44; Ν, 4.48.

Example 83. 6- (3-Fluoro-5-trifluoromethylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3-fluoro-5-trifluoromethylbenzene according to method B. White solid : mp 207-208 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 7.94-7.9 (m, 2H), 7.73-7.7 (m, 2H), 7.63 (d , 1H, 1 = 8.58 Hz), 6.99 (d, 1H, 1 = 8.68 Hz), 1.7 (s, 6H); Μδ (Ε1) m / e 339 ([M ⁺ ], 60%); Analysis. Calculated C1 ₇ H ₁₃ P ^ O ₂ : C, 60.18; H, 3.86; Ν, 4.13. Found: C, 59.9; H, 3.99; Ν, 4.06.

Example 84. 6- (5-Bromopyridin-3-yl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3,5-dibromopyridine according to method B. White solid: mp. 211-212 ° C; Ή NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.92 (d, 1H, 1 = 1.9 Hz), 8.66 (d, 1H, 1 = 2.09 Hz), 8 40 (t, 1H, 1 = 2.02 Hz), 7.72-7.68 (m, 2H), 6.99 (d, 1H, 1 = 8.1 Hz), 1.7 (s, 6H) ; Μδ (APC1) m / e 333 ([M + H] ⁺ , 100%), 335 ([M + H] ⁺ , 100%); Analysis. Calculated C ₁₅ H ₁₃ Br ^ O ₂ : C, 54.07; H, 3.93, Ν, 8.41. Found: C, 54.15; H, 3.89; Ν, 8.31.

Example 85. 6- (5-Bromo-1-hydroxypyridin-3yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A mixture of 6- (5-bromopyridin-3-yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one (0.34 g, 1 mmol), hydrogen peroxide ( 30%, 5 ml), acetic acid (5 ml) is heated at 60 ° C for 3 hours. The reaction mixture is cooled to room temperature and neutralized by adding a cold saturated sodium bicarbonate solution. The resulting white precipitate was collected on a filter, washed with distilled water and dried, which afforded the title compound as a white solid (0.35 g, 100%): mp. 157-159 ° C; Ή-NMR (DMSO-b ₆ ) δ

10.4 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.73-7.69 (m, 2H), 6 97 (d, 1H, 1 = 8.18 Hz); 1.7 (s, 6H); Μδ (APC1) m / e 349 ([M + H] ⁺ , 100%), 351 ([M + H] ⁺ , 100%); Analysis. Calculated C ₁₅ H ₁₃ Bg ^ O ₃ -2.5 H ₂ O: C, 45.70; H, 4.60; Ν, 7.11. Found: C, 45.34; H, 4.64; Ν, 7.

Example 86. 6- (3-Cyano-5-fluorophenyl) -4,4-dimethyl-2-oxo-4Nbenzo [b] [1,3] oxazine-1-carboxylic acid tert-butyl ester.

A mixture of 3- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile (0.3 g, ~ 1 mmol), di-tert-butyl dicarbonate (0.33 g, 1.5 mmol), and ΌΜΑΡ (50 mg) in anhydrous acetonitrile was stirred at room temperature in a stream of nitrogen for 4 minutes. The reaction mixture was washed with 1Ν aqueous HC1 solution, brine, dried (ΜдδΟ ₄ ). After removing the solvent, the title compound was obtained as a white solid (0.25 g, 63%); so pl. 139-140 ° C; Ή-NMR (SPS1 ₃ -b ₆ ) δ 7.66-7.63 (m, 2H), 7.53-7.48 (m, 2H),

7.38-7.35 (m, 2H), 1.79 (s, 6H), 1.62 (s, 9H); Μδ (APC1) m / e 289 ([M-H] ^- , 100%); Analysis. Calculated C ₂₂ H ₂₁ P ^ O ₄ : C, 66.66; H, 5.34; Ν, 7.07. Found: C, 66.7; H, 5.41; Ν, 7.

Example 87. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-fluorobenzonitrile.

Prepared from (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-2-fluorobenzonitrile according to method B. White solid: mp . 255256 ° C; Я-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 8.30 (dd, 1H, 1 = 6.15, 2.41 Hz), 8.12-8.07 (m, 1H ), 7.76-

7.58 (m, 3H), 6.97 (d, 1H, 1 = 8.22 Hz), 1.7 (s, 6H); Μδ (APC1) m / e 297 ([Μ + H] ⁺ , 100%); Analysis. Calculated C1 ₇ H ₁₃ P ^ O ₂ -0.1 H ₂ O: C, 68.50; H, 4.46; Ν, 9.40. Found: C, 68.27; H, 4.81; Ν, 9.1.

Example 88. 4- (8-Fluoro-4,4-dimethyl-2-oxo1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) thiophene-2-carbonitrile.

8-Fluoro- (1,4-dihydro -4,4-dimethyl-2-oxo 2H-3,1-benzoxazin-6-yl) boronic acid is obtained from 6-bromo-8-fluoro-4,4-dimethyldihydrobenzo [ D] [1,3] oxazin-2-one using the methods of example 4.

The title compound is prepared from 8 fluoro - (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 4-bromo-2-cyanothiophene according to method B. White solid: t .pl. 250-251 ° C; 'H-NMR (DMSO-D ₆ ) δ 10.5 (s, 1H), 8.54 (d, 1H, 1 = 1.42 Hz),

8.43 (d, 1H, 1 = 1.35 Hz), 7.69 (dd, 1H, 1 = 11.71,

1.54 Hz), 7.58 (broad s, 1H), 1.7 (s, 6H); M8 (Ε1) m / e 302 ([M ⁺ ], 50%); Analysis. Calculated C ₁₅ H ₁₁ E ₂ O ₂ 8 · 0.45 H ₂ O: C, 58.04; H, 3.86; Ν, 9.02 Found: C, 58.4; H, 3.89; Ν, 8.63.

Example 89. 3-Fluoro-5- (8-fluoro-4,4-dimethyl-

2-oxo-1,4-dihydro-2H-benzo [D] [1,3] oxazin-6yl) benzonitrile.

Prepared from 8-fluoro- (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 5-bromo-3-fluorobenzonitrile according to method B. White solid : mp 256-257 ° C; 'ΙΙ-NMR (DMSO-D ₆ ) δ 10.5 (s, 1H), 8.20 (broad s, 1H), 8.06 (dt, 1H, 1 = 10.48,

2.16 Hz), 7.85-7.82 (m, 1H), 7.77 (dd, 1H, 1 = 11.89,

1.81 Hz), 7.63 (s, 1H), 1.7 (s, 6H); M8 (Ε1) m / e 314 ([M ⁺ ], 60%).

Example 90. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [D] [1,3] oxazin-6-yl) thiophene

3-carbonitrile.

Prepared according to method B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin6-yl) boronic acid and 2-bromo-4-thiophenecarbonitrile. Off-white solid: mp. 255-260 ° C; 'ΙΙ-NMR (DMSO-D ₆ ) δ

10.36 (s, 1H), 8.48 (d, 1H, 1 = 1.1 Hz), 7.88-7.87 (d, 1H, 1 = 1.3 Hz), 7.63 (d , 1H, 1 = 1.9 Hz), 7.56-7.54 (dd, 1H, 1 = 8.0, 2.0 Hz), 6.93 (d, 1H, 1 = 8.1 Hz) ,

1.64 (s, 6H); M8 (-Ε8Ι) m / e 283 (M-H) ^- .

Example 91. 2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [D] [1,3] oxazin-6-yl) thiophene 3-carbonitrile.

Prepared according to method B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 2-bromo-3thiophenecarbonitrile. Off-white solid: mp. 200-202 ° C; 'ΙΙ-NMR (DMSO-D ₆ ) δ

10.49 (s, 1H), 7.75 (m, 1H), 7.63 (d, 1H, 1 = 2.2 Hz),

7.59 (m, 1H), 7.50 (m, 1H), 7.02 (d, 1H, 1 = 8.1 Hz),

1.63 (s, 6H); M8 (-Ε8Ι) m / e 283 (M-H) ^- .

Example 92. 6- (1,2,4-Thiadiazol-3-yl-phenyl) 4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2one.

A mixture of 5- [3-bromophenyl] [1,3,4] oxathiazole-2one (21.25 g, 82.3 mmol), ethyl cyanoformate (32.5 ml, 329 mmol) in o-xylene (500 ml) is heated to 150 ° C. for 60 hours. Then, the solvent was removed from the reaction mixture, the product was recrystallized from ethanol to give 3- [3-bromophenyl] [1,2,4] thiadiazole-5-carboxylic acid ethyl ester as white crystals (17 5 g, 68%): mp 87-90 ° C; 'H-NMR (SBSl) δ 8.53 (t, 1H, 1 = 1.76 Hz), 8.28 (dt, 1H, 1 = 5.4, 1.2 Hz), 7.62 (dq, 1H, 1 = 5.1, 1.0 Hz), 7.36 (t, 1H, 1 = 7.9 Hz), 4.55 (q, 2H, 1 = 7.1 Hz), 1.48 ( t, 3H, 1 = 7.1 Hz); M8 ((+) ΑΡΟ) [M + H] ⁺ , m / e 313/315. Analysis. Calculated ScN9Br ₂ O ₂ 8: C, 42.19; H, 2.90; Ν, 8.94. Found: C, 41.81; H, 3.08; Ν, 8.78.

A mixture of ethyl 3- [3-bromophenyl] [1,2,4] thiadiazole-5-carboxylic acid (16.8 g, 53.5 mmol), sodium hydroxide (2.4 g, 58.8 mmol) distilled water (120 ml) and ethanol (20 ml) are heated to 100 ° C for 2 hours. The reaction mixture is cooled to room temperature, concentrated hydrochloric acid (5.1 ml) is added and the reaction mixture is again heated to 100 ° C for 3 h. The solution was cooled to room temperature and extracted with diethyl ether (3x150 ml). The combined organic layers were washed with distilled water (3x100 ml) and dried over MgO ₄ . Then the solvent was removed to give 3- [3-bromophenyl] [1,2,4] thiadiazole as white needles (12.7 g, 99%): mp. 69-71 ° C; '11-NMR (SBSl), δ 9.89 (s, 1H), 8.52 (t, 1H, 1 = 1.8 Hz),

8.28 (dt, 1H, 1 = 5.2, 1.3 Hz), 7.61 (dq, 1H, 1 = 4.9,

1.1 Hz), 7.35 (t, 1H, 1 = 7.9 Hz); M8 ((+) ΑΡϋΙ) [M + H] ⁺ , m / e 241/243. Analysis. Calculated C ₈ H ₅ VgY ₂ 8: C, 39.85; H, 2.09; Ν, 11.62. Found: C, 39.82; H, 2.43; Ν, 11.33.

According to method B, (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid is condensed with 3- [3-bromophenyl] [1,2,4 ] thiadiazole to give 6- (1,2,4-thiadiazol-3-yl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] -oxazin-2-one as an off white solid (0.5 g, 35%): mp 214-216 ° C; ^! H-NMR (DMSO-D ₆ ) δ 10.40 (s, 1H), 10.36 (s, 1H), 8.49 (s, 1H), 8.23 (d, 1H, 1 = 7.7 Hz), 7.83 (d, 1H, 1 = 7.9 Hz), 7.66-7.61 (m, 3H), 7.02 (t, 1H, 1 = 4.4 Hz), 1, 70 (s, 6H); M8 ((+) ARO) [M + H] ⁺ , m / e 338.

Example 93. 6- (3-Fluoro-5-thiophen-3-yl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one.

Prepared from 6- (3-bromo-5-fluorophenyl) -4,4dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one and 3-thiophenboronic acid according to method B. Brownish-yellow solid : mp 200-203 ° C; 'ΙΙ-NMR (SPS1 ₃ ) δ 8.62 (s, 1H), 7.53 (q, 1H, 1 = 1.4 Hz), 7.50 (d, 1H, 1 = 1.5 Hz), 7.49 (d, 1H, 1 = 2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, 1 = 1.8 Hz), 7.27-7 24 (m, 2H), 7.15 (dt, 1H, 1 = 5.8, 2.0 Hz), 6.94 (d, 1H, 1 = 8.2 Hz), 1.80 (s, 6H); M8 ((-) ΑΡΟ) [M-H] ^- , m / e 352. Analysis. Calculated C ₂₀ H ₁₆ EXO ₂ 8-0.50 H ₂ O: C, 66.28; H, 4.73; Ν, 3.87. Found: C, 66.54; H, 5.03; Ν, 3.52.

Example 94. 2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [D1] [1,3] oxazin-6-yl) pyrrole-1-carboxylic acid tert-butyl ether.

Solution of 6-bromo-4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one (0.87 g, 3.4 mmol) and tetrakis (triphenylphosphine) palladium (0) ( 96 mg, 0.08 mmol) in toluene (40 ml) was stirred in a stream of nitrogen for 25 minutes. To the solution, 1-tert-butoxycarbonylpyrrol-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 (10) were successively added. ml). The mixture was heated at 80 ° C. for 16 hours, after which it was allowed to cool to room temperature. The reaction mixture was poured into an aqueous saturated sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (3x100 ml). The organic layers are combined, washed with water (100 ml) and brine (50 ml) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo, and the residue was purified using flash column chromatography on silica gel (30% ethyl acetate / hexane) to give the title compound as an off-white powder (0.7 g, 62%): mp. 176 ° C. '11 NMR (SPS1 ₃ ) δ 1.40 (s, 9H), 1.73 (s, 6H), 6.17 (dd, 1H, 1 = 1.8, 3.3 Hz), 6.22 ( dd, 1H, 1 = 3.3, 3.3 Hz), 6.77 (d, 1H, 1 = 8.1 Hz), 7.13 (d, 1H, 1 = 1.8 Hz), 7, 23 (dd, 1H, 1 = 1.8, 8.1 Hz), 7.33 (dd, 1H, 1 = 1.8, 3.3 Hz), 7.69 (broad s, 1H). Μ8 (() Ε8Ι) m / e 341 [M-H] ^- . Analysis. Calculated C ₁₉ H ₂₂ ^ O ₄ : C, 66.65; H, 6.48; Ν, 8.18. Found: C, 65.46; H, 6.51; Ν, 7.74.

Example 95. 2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-nitropyrrole-1-carboxylic acid tert-butyl ether .

To a solution of 2- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) pyrrole-1 carboxylic acid tert-butyl ether (0, 7 g, 2.0 mmol) in acetonitrile (25 ml) and dichloromethane (1 ml), silver nitrate (0.37 g, 2.1 mmol) was added at room temperature. After 5 minutes, acetyl chloride (0.15 ml, 2.0 mmol) in acetonitrile (3 ml) was added and the solution was left stirring for 2 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl ether (2x50 ml). The organic layers are 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, resulting in the title compound as a bright yellow powder (350 mg, 45%). so pl. 125 ° C. 'H NMR (COS1 ₃ ) δ 1.47 (s, 9H), 1.75 (s, 6H), 6.26 (d, 1H, 1 = 4.2 Hz), 6.87 (d, 1H, 1 = 8.1 Hz), 7.19 (d, 1H, 1 = 4.2 Hz), 7.34 (d, 1H, 1 = 2 Hz), 7.4 (dd, 1H, 1 = 1, 8, 8.1 Hz), 8.17 (broad s, 1H). Μ8 ((+) ARE) m / e 388 [M + H] ⁺ . Analysis. Calculated for С1дН ₂ Щ ₃ О ₆ : С, 58.91; H, 5.46; Ν, 10.85. Found: C, 58.4; H, 5.55; Ν, 10.18.

Example 96. 4,4-Dimethyl-6- (5-nitro-1H-pyrrol-2-yl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2Nbenzo [b] [1,3] oxazin-6-yl) -5-nitropyrrole-1carboxylic acid tert-butyl ether (0.7 g , 1.8 mmol) is placed in a round-bottomed flask with a volume of 25 ml, closed with a rubber wall and equipped with a nitrogen inlet and a needle that allows you to remove gas. A strong nitrogen flow was maintained while the flask was placed in an oil bath and heated in an oil bath to 180 ° C. After 10 minutes of heating at this temperature, the flask was removed from the oil bath and allowed to cool to room temperature. The brown residue was washed in a large flask with a dichloromethane / ethyl acetate mixture and adsorbed on a small amount of silica gel. Purified by flash column chromatography on silica gel (60% ethyl acetate / hexane) to give (200 mg, 40%) as a brown powder: mp. 265 ° C (decomp.); Ή NMR (DMSO-b6) δ 1.65 (s, 6H),

6.81 (d, 1H, 1 = 4.4 Hz), 6.90 (d, 1H, 1 = 8.6 Hz), 7.25 (d, 1H, 1 = 4.2 Hz), 7, 79 (dd, 1H, 1 = 2, 8.3 Hz), 7.91 ('d', 1H, 1 = 2 Hz), 10.37 (s, 1H), 13.17 (wide s, 1H) ; Μ8 (Ε1) m / e 286 [M-H] ^- . Anal Calc for C1 ₄ H ₁₃ SCHO ₄ : C, 58.53; H, 4.56; Ν, 14.63. Found: C, 58.25; H, 5.10; Ν, 12.57.

Example 97. 4,4-Dimethyl-6- (1H-pyrrol-2yl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

2- (4,4-dimethyl-2-oxo-1,4-dihydro-2Nbenzo [b] [1,3] oxazin-6-yl) pyrrole-1-carboxylic acid tert-butyl ether (3.5 g , 10 mmol) is placed in a round-bottomed flask with a volume of 25 ml, closed with a rubber wall and equipped with a nitrogen inlet and a needle that allows you to remove gas. A strong nitrogen flow was maintained while the flask was placed in an oil bath and heated in an oil bath to 180 ° C. After 10 minutes of heating at this temperature, the flask was removed from the oil bath and allowed to cool to room temperature. The brown residue was washed in a large flask with a dichloromethane / ethyl acetate mixture and adsorbed on a small amount of silica gel. Purification by flash column chromatography on silica gel (60% ethyl acetate / hexane) affords the title compound as a green solid (2 g, 80%): mp. 202 ° C (decomp.); '11 NMR (COC1 ₃ ) δ 1.75 (s, 6H), 6.30 (m, 1H), 6.45 (m, 1H), 6.85 (d, 1H, 1 = 8.5 Hz) 6.86 (m, 1H), 7.24 (d, 1H, 1 = 2 Hz), 7.33 (dd, 1H, 1 = 2, 8.4 Hz), 8.44 (broad s, 1H ), 8.66 (s, 1H); Μ8 ((+) ARC) m / e 243 [M + H] ⁺ . Anal calculation for C1 ₄ H ₁₄ ^ O ₂ : C, 69.41; H, 5.82; Ν, 11.56. Found: C, 69.20; H, 5.96; Ν, 11.29.

Example 98. 4,4-Dimethyl-6- (1-methyl-1Npyrrol-2-yl) -1,4-dihydrobenzo [b] [1,3] oxazin2-one.

To a mixture of 4,4-dimethyl-6- (1H-pyrrol-2-yl) 1,4-dihydrobenzo [b] [1,3] oxazin-2-one (1.5 g, 6.2 mmol) in dimethylformamide (20 ml) at room temperature, potassium carbonate (4.28 g, 31 mmol) and a solution of methyl iodide (1.16 ml, 19 mmol) in dimethylformamide (5 ml) are successively added. After 1 h, the reaction mixture was boiled. Then the reaction was cooled to room temperature, poured into water (50 ml) and the product was extracted with ethyl acetate (2x50 ml). The organic layers were combined, washed with brine (30 ml), dried over MgO ₄ , filtered and concentrated in vacuo. Purified by flash column chromatography on silica gel (40% ethyl acetate / hexane) to give the title compound as an off-white powder (0.5 g, 31%): mp. 230 ° C. ^! H NMR (SBS1 ₃ ) δ 1.71 (s, 6H), 3.42 (s, 3H), 6.31 (dd, 1H, 1 = 2.9, 5.9 Hz), 6.47 (m , 1H),

6.88 (m, 1H), 6.94 (d, 1H, 1 = 8.6 Hz), 7.26 (d, 1H, 1 = 2.2 Hz), 7.41 (dd, 1H, 1 = 2.2, 8.6 Hz), 8.43 (broad s, 1H). M8 ((-) Ε8Ι) m / e 255 [M-H] ^- . Analysis. Calculated C1 ₅ H _{1 &} S ₂ O ₂ : C, 70.29; H, 6.29, Ν, 10.93. Found: C, 68.59; H, 6.16; Ν, 10.49.

Example 99. 4,4-Dimethyl-6- (1-methyl-5-nitro-1H-pyrrol-2-yl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

To a solution of 4,4-dimethyl-6- (1-methyl-1Npyrrol-2-yl) -1,4-dihydrobenzo [b] [1,3] oxazin2-one (0.3 g, 1.2 mmol) in silver nitrate (0.21 g, 1.26 mmol) was added to acetonitrile (20 ml). 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 (2x50 ml). The organic layers are 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) afforded the title compound (5 mg, 1%) as a yellow solid, mp. 180-185 ° C. ¹ H NMR (ΟΌΟΙ ₃ ) δ 1.75 (s, 6H), 3.45 (s, 3 H), 6.57 (dd, 1H, 1 = 2.9, 4.3 Hz), 7.04 (d, 1H, 1 = 8.5 Hz), 7.22 (dd, 1H, 1 = 2.5, 4.3 Hz), 7.36 (d, 1H, 1 = 2.1 Hz), 7 56 (dd, 1H, 1 = 2.1, 8.5 Hz); 9.67 (broad s, 1H). M8 ((+) APC1) m / e 302 [M + H] ⁺ .

Example 100. 5-Bromo-4-ethylthiophene-2-carboxaldehyde.

Obtained from 2-bromo-3-ethylthiophene as in Example 19. ¹ H-NMR (DMSO-b ₆ ) δ 9.82 (s, 1H), 7.81 (s, 1H), 2.5 (q, 2H, 1 = 7.4 Hz), 1.15 (t, 3H, 1 = 7.5 Hz).

Example 101. 5-Bromo-4-ethylthiophene-2 carbonitrile.

Received from 5-bromo-4-ethylthiophene-2 carboxaldehyde using a process analogous to example 18. IR (KBr) 2221 cm ^-1 ; ¹ H-NMR (DMSO-b ₆ ) δ 7.87 (s, 1H), 2.55 (q, 2H, 1 = 7.3 Hz), 1.18 (t, 3H, 1 = 7.6 Hz ) M8 (Ε1) m / e 215/217 (M ⁺ ).

Example 102. 5-Bromo-4-n-propylthiophen-2-carboxaldehyde.

Obtained from 2-bromo-3-n-propylthiophene as in Example 19. 'H-NMR (DMSO-b ₆ ) δ

9.82 (s, 1H), 2.6-2.5 (m, 2H), 1.65-1.51 (m, 2H), 1.0 (t, 3H, 1 = 4.7 Hz) .

Example 103. 5-Bromo-4-n-propylthiophenecarbonitrile.

Obtained from 5-bromo-4-n-propylthiophene-2 carboxaldehyde using a process analogous to example 18. ¹ H-NMR (DMSO-b6) δ

7.87 (s, 1H), 2.5 (t, 2H, 1 = 5.2 Hz), 1.64-1.5 (m, 2H), 1.91 (t, 3H, 1 = 5, 1 Hz). M8 (E1) m / e 229-231.

Example 104. 5-Bromo-4-n-butylthiophenecarboxaldehyde.

Obtained from 2-bromo-3-n-butylthiophene in the same manner as in Example 19. IR (KBr) 1660 cm ^-1 . Ή-NMR (DMSO-b ₆ ) δ 9.78 (s, 1H),

7.85 (s, 1H), 2.57-2.53 (m, 2H), 1.57-1.53 (m, 2H), 1.32-1.25 (m, 2H), 0, 88 (t, 3H, 1 = 5.2 Hz). M8 (Ε1) m / e 246 (M ⁺ ).

Example 105. 5-Bromo-4-H-butylthiophenecarbonitrile.

Obtained from 5-bromo-4-n-butylthiophenecarboxaldehyde using a process analogous to example 18. ¹ H-NMR (DMSO-b ₆ ) δ

7.87 (s, 1H), 2.58-2.44 (m, 2H), 1.65-1.48 (m, 2H),

1.38-1.23 (m, 2H), 0.89 (t, 3H, 1 = 5.3 Hz). M8 (Ε1) m / e 243 (M ⁺ ).

Example 106. 3- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) benzonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1benzoxazin-6-yl) boronic acid and 3bromobenzonitrile. Ginger powder: mp 245247 ° C. ¹ H-NMR (DMSO-b6) δ 10.31 (s, 1H), 8.21 (s, 1H), 8.02 (d, 1H, 1 = 8.0 Hz), 7.78 (d, 1H, 1 = 7.7 Hz), 7.68-7.61 (m, 3H), 6.97 (d, 1H, 1 = 8.2 Hz),

1.98-1.96 (m, 4H), 1.75-1.64 (m, 5H), 1.40-1.32 (m, 1H). M8 (Ε1) m / e 318 [M ⁺ ]. Analysis. Calculated C ₂₀ H ₁₈ ^ O ₂ -1/2 H ₂ O: C 73.38; H, 5.85; Ν, 8.56. Found: C, 73.86; H, 5.81, Ν, 8.22.

Example 107. 3- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -5 fluorobenzonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 3-bromo-5-fluorobenzonitrile. White powder: mp 250253 ° C. IR (KBr) 2220 cm ^-1 . ^! H-NMR (DMSO-b ₆ ) δ 10.34 (s, 1H), 8.13 (s, 1H), 8.0 (d, 1H, 1 = 10.6 Hz), 7.80-7, 7 (m, 3H), 6.98-6.95 (d, 1H, 1 = 8.1 Hz),

1.99-1.97 (m, 4H), 1.76-1.65 (m, 6H), 1.37-1.33 (m, 1H). M8 (Ε1) m / e 336 (M ⁺ ). Analysis. Calculated C ₂₀ H ₁₇ E ^ H ₂ O: C, 67.78; H, 5.40; Ν, 7.90. Found: C, 67.9; H, 4.93; Ν, 7.67.

Example 108. 4- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -2thiophenecarbonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1benzoxazin-6-yl) boronic acid and 3-bromo5-cyanothiophene. White crystals: mp 230232 ° C. IR (KBr) 2200 cm ^-1 . ¹ H-NMR (DMSO-b ₆ ) δ 10.29 (s, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 7.69-

7.63 (m, 2H), 6.93-6.91 (d, 1H, 1 = 8.2 Hz), 1.9959

1.87 (m, 4H), 1.73-1.64 (m, 5H), 1.38-1.31 (m, 1H). M8 (+) ARS. CH m / e 325 (M + H) ⁺ . Analysis. Calculated C ₁₈ H ₁₆ ^ O ₂ 8-1 / 4H ₂ O: C, 65.73; H, 5.06; Ν, 8.52. Found: C, 65.55; H, 5.06; Ν, 8.22.

Example 109. 5- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -2thiophenecarbonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1 benzoxazin-6-yl) boronic acid and 2-bromo-5-cyanothiophene red powder: so pl. 243245 ° C. ^! H-NMR (DMSO-b ₆ ) δ 10.41 (s, 1H), 7.98-

7.97 (d, 1H, 1 = 3.9 Hz), 7.67-7.60 (m, 3H), 6.97-

6.94 (d, 1H, 1 = 8.3 Hz), 1.98-1.92 (m, 4H), 1.74-

1.64 (m, 5H); 1.45-1.21 (m, 1H). M8 (E1) m / e 324 (M ⁺ ). Analysis. Calculated C1 ₈ H _{1 &} S ₂ O ₂ 8 · 1/2 H ₂ O: C, 65.08; H, 5.04; Ν, 8.18. Found: C, 64.84; H, 5.09; Ν, 8.40.

Example 110. 5- (1,2-Dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) -4methyl-2-thiophenecarbonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-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 ° C. ^! H-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H),

7.85 (s, 1H), 7.43-7.40 (m, 2H), 7.0 (d, 1H, 1 = 8.8 Hz), 2.27 (s, 3H), 2.00 -1.62 (m, 9H); 1.42-1.23 (m, 1H). M8 (E0 m / e 338 (M ⁺ ). Analysis. Calculated C ₁₉ H ₁₈ ^ O ₂ 8: C, 67.43; H, 5.36; Ν, 8.28. Found: C, 67.12; H, 5.45; Ν, 8.05.

Example 111. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-ethylthiophen-2-carbonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1 benzoxazin-6-yl) boronic acid and 2-bromo-3-ethyl-5-cyanothiophene. White crystals; so pl. 160-162 ° C. 'ίί-NMR (DMSO-b ₆ ) δ 10.46 (s, 1H), 7.96 (s, 1H), 7.40-7.38 (m, 2H), 7.02-6.99 ( d, 1H, 1 = 8.8 Hz), 2.61 (q, 2H, 1 = 7.5 Hz), 1.64 (s, 6H),

1.16 (t, 3H, 1 = 7.6 Hz). M8 (+) ARSCH m / e [M + H] ⁺ 313. Analysis. Calculated C1 ₇ H _{1 &} S ₂ O ₂ 8 · 1/4 H ₂ O: C, 64.43; H, 5.25; Ν, 8.84. Found: C, 64.77; H, 5.23; Ν, 8.68.

Example 112. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-n-propylthiophen-2-carbonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1 benzoxazin-6-yl) boronic acid and 2-bromo-3-n-propyl-5-thiophenecarbonitrile. White crystals: mp 160-162 ° C. IR (KBr) 2220 cm ^-1 . '11 NMR (DMSO-b ₆ ) δ 10.47 (s, 1H), 7.93 (s, 1H),

7.38-7.36 (m, 2H), 7.01 (d, 1H, 1 = 8.7 Hz), 2.59-

2.48 (m, 2H), 1.64-1.51 (m, 2H), 0.85 (t, 3H, 1 = 7.3 Hz). M8 (-E8P m / e [M-H] ^- 325. Analysis. Calculated C ₁₈ H ₁₈ ^ O ₂ 8 · 3/4 H ₂ O: C, 63.60; H, 5.78; Ν, 8, 24. Found: C, 63.48; H, 5.59; Ν, 8.04.

Example 113. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-n-butylthiophen-2-carbonitrile.

Prepared according to method B from spiro (4,1'-cyclohexan-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 2-bromo-3-n-butyl-5-thiophenecarbonitrile. White crystals: mp 167-168 ° C. ^! H-NMR (DMSO-b ₆ ) δ

10.46 (s, 1H), 7.93 (s, 1H), 7.38-7.36 (m, 2H), 7.01 (d, 1H, 1 = 8.7 Hz), 2.59 (t, 2H, 1 = 8.1 Hz), 1.63 (s, 6H), 1.58-1.51 (m, 2H), 1.48-1.17 (m, 2H), 0, 82 (t, 3H, 1 = 7.4 Hz). M8 (-E8T) m / e [M-H] ^- , 339. Analysis. Calculated C1 ₉ H ₂₀ ^ O ₂ 8-1 / 4 H ₂ O: C, 66.16; H, 5.99; Ν, 8.12. Found: C, 66.33; H, 5.92; Ν, 7.85.

Example 114. 6- (4-Cyano-3-fluoro) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

A solution of 4-cyano-3-fluorobromobenzene (0.6 g, 3.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 g) in ethylene glycol dimethyl ether (20 ml) was stirred for 20 min in an atmosphere of Ν2. To this mixture are then added (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid (1.0 g, 4.5 mmol) and sodium carbonate (1 1 g, 10.6 mmol) in water (5 ml). The solution was refluxed for 18 hours and then cooled to room temperature, poured into 2Ν No. 1OH and extracted with EyAc (3x50 ml). The combined extracts were washed with water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (81O ₂ , E1OAc: hexane = 1: 2), which afforded the title compound (0.05 g, 6%) as an off-white solid, mp: 272-275 ° FROM; ¹ H-NMR (DMSO-b6) δ 10.4 (s, 1H), 8.0 (t, 1 H, 1 = 1.1 Hz), 7.9 (dd, 1H, 1 = 10.3, 1.3 Hz), 7.8 (dd, 1H, 1 = 6.8, 1.4 Hz), 7.7 (m, 2H), 6.9 (d, 1H, 1 = 8.9 Hz) 1.7 (s, 6H); M8 (E1) M ⁺ , m / e 296.

Example 115. 6- (4-Fluoro-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-4-fluorobenzene. Off-white crystals: mp. 232-233 ° C. ^! H-NMR (DMSO-b ₆ ) δ 10.3 (s, 1H),

7.74 (m, 2H), 7.53 (m, 2H), 7.28 (m, 2H), 6.96 (d, 1H, 1 = 8.9 Hz), 1.63 (s, 6H) )

Example 116. 6- (3,4-Difluorophenyl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-3,4-difluorobenzene. Off-white crystals: mp. 207-208 ° C. Ίί-NMR (DMSO-b ₆ ) δ 10.35 (s, 1H),

7.79 (m, 1H), 7.40-7.63 (m, 4H), 6.95 (d, 1H, 1 = 8.9 Hz), 1.62 (s, 6H).

Example 117. 6- (2-Fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 1-bromo-2 fluorobenzene. Off-white crystals: mp. 164-165 ° C. Ή-NMR (DMSO-b ₆ ) δ 10.33 (s, 1H),

7.56 (m, 1H), 7.25-7.45 (m, 4H), 6.98 (d, 1H, 1 = 8.7 Hz), 1.64 (s, 6H).

Example 118. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenylacetonitrile.

Prepared from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-6yl) boronic acid. White solid: mp 188-190 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, 1 = 8.00 Hz), 7.33 (d, 1H, 1 = 7.57 Hz), 6.99 (d, 1H, 1 = 8.81 Hz), 4.09 (s, 2H), 1.67 (s, 6H); MZ m / e 291 (M-H). Analysis. Calculated C1 ₈ H1 ^ ₂ 0 ₂ -0.3 H ₂ O: C, 72.61; H, 5.62; Ν, 9.41. Found: C, 73.00; H, 5.43; Ν, 8.81.

Example 119. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) furan-2carbonitrile.

The title compound is prepared according to method B from 2-bromo-5-cyanofuran (1.0 g, 5.6 mmol) (1. Meb. Siesz. (1997), 40 (23), 38043819) and (1,4-dihydro -4,4-dimethyl-2-oxo-2H-3,1benzoxazin-6-yl) boronic acid (1.8 g, 8.18 mmol) as a white solid (0.39 g,

1.45 mmol, 17%): mp 257-260 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.48 (s, 1H), 7.73-7.70 (m, 3H),

7.19 (d, 1H, 1 = 3.8 Hz), 6.98 (d, 1H, 1 = 8.9 Hz), 1.66 (s, 6H); MZ ((+) - ARP) m / e = 269 (M + H) ⁺ .

Example 120. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-fluorobenzonitrile.

A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 ml) in a stream of nitrogen is treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated at the boil under reflux. After 16 h, the mixture was evaporated and the residue was partitioned between water and E1 ₂ 0. The organic layer was washed with saturated aqueous sodium bicarbonate, water, brine, dried (MgSO ₄ ) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): Ή-NMR (SBS _{1 3} ) δ 7.90-7.85 (m, 1H), 7.71-

7.65 (m, 1H), 7.10 (dt, 1H, 1 = 8.0, 1.0 Hz), 3.94 (s, 3H): MOH (E1) 232 (M ⁺ ).

A solution of the obtained compound (3.077 g, 13.2 mmol) in dry toluene (80 ml) at -78 ° C in a stream of nitrogen is treated with diisobutylaluminum hydride in toluene (1M, 15.7 ml, 15.7 mmol). After 1 h at −78 ° C., the mixture was quenched with an aqueous HC1 solution (3M, 16 ml). Then the mixture was warmed to room temperature, partitioned between E10Ac / H ₂ 0, the aqueous layer was again extracted with EOAc, and the combined organic layers were washed with water, dried (MgSO ₄ ) and evaporated, which afforded 3-bromo-2-fluorobenzaldehyde (2 ? 63 g, 12.9 mmol, 98%), which is used without further purification: Ή-NMR (SBS1 ₃ ) δ 10.35 (s, 1H),

7.82 (m, 2H); 7.18 (t, 7.8 Hz).

A mixture of the latter compound (2.63 g, 12.9 mmol), hydroxylamine hydrochloride (1.0 g, 14 mmol) and potassium acetate (1.37 g, 14 mmol) was placed in ethanol / H ₂ O (60 ml, 8: 2) and heated at the boil under reflux. After 30 minutes, the mixture was cooled, evaporated and partitioned between ESAc 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 purification.

A solution of the latter compound (0.75 g, 3.43 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 g) was stirred under a stream of nitrogen at room temperature in dimethoxyethane. After 15 min (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid (1.1 g, 50 mmol) and potassium carbonate (1.35 g) in water (10 ml) is heated at the boil under reflux. After 16 hours, the mixture was cooled, partitioned between water and ЕУАс, the organic layer was washed with water (100 ml) and brine (50 ml) and dried over magnesium sulfate and evaporated. The residue was partitioned between water and EJAc, the organic layer was then washed with dilute sulfuric acid (1Ν), water, brine, dried (MgSO ₄ ) and evaporated. The residue was purified by flash column chromatography on silica gel (30% ethyl acetate / hexane) and then crystallized from EHA hexane to give the title compound as a white solid (0.176 g, 0.59 mmol 17%). so pl. 192-198 ° C. Ή NMR (SBS _{1 3} ) δ 9.15 (s, 1H), 7.69-7.58 (m, 2H), 7.42-7.31 (m, 3H), 6.99 (d, 1H, 1 = 8.2 Hz), 1.78 (s, 6H). MZ ((+) EZC m / e 297 [M + H] ⁺ .

Example 121. Pharmacology.

The compounds of this invention were subjected to appropriate studies as described below, and their activity was in the range from 0.01 nM to 5 μM in the ίη νίΐτο assay and from 0.001 to 300 mg / kg in the ίη νίνο assay.

Table 1

The activity of the selected derivatives of cyclocarbamates as antagonistic agents in some models ίη νίΐτο and ίη νίνο

I about Co- units K.2 I ₃ ЬРЯ | SU-1 Decidualization TC50, nM U50, mg / kg one 3-cyano-4 fluorophenyl Me Me 55 80% @ 1 ** 2 3-fluoro-5 trifluorome- tilphenyl Me Me 54 50% @ 1

3 3-fluorophenyl Μе Μе 6 80% @ 3 4 3,5-dichlorophenyl Μе Μе 134 60% @ 1 5 5-cyano-2 fluorophenyl Μе Μе 68 60% @ 1 6 3-fluoro-5nitrophenyl Μе Μе 11.5 50% @ 1 7 4- (2-cyano furil) Μе Μе thirty 75% @ 3 8 3-bromo-5fluorophenyl Μе Μе eleven 50% @ 3 nine 3-cyano-4 fluorophenyl Μе Μе thirteen 6.96 ± 0684 10 5- (2-cyano- 4-methylthiophenyl) Spirocycle logexil 2.7 50% @ 10 eleven 5- (2-cyanothiophenyl) Spirocyclohexyl 12 50% @ 10 12 5- (2-cyanothiophenyl) Μе Μе nineteen 3.34 ± 0.22 thirteen 3-Bromophenyl Μе Μе 11.5 3 14 3-chloro-5fluorophenyl Me Μе 22 50% @ 3 fifteen 3-cyano-5fluorophenyl Cycle cut 22 3 sixteen 5- (3-Bromopyridyl) Μе Μе 26 50% @ 3 17 4- (2-cyanothiophenyl) Μе Μе 12.7 2.3 ± 0.46 eighteen 5- (2-cyano- 4-methylthiophenyl) Μе Μе 5.23 1,5 nineteen 3-cyano-5fluorophenyl Me Μе 13.8 0.35 twenty 3-chloro-4 fluorophenyl Μе Μе 37 one

SHO, not defined; ** Percentage inhibition at a certain dose

A. Biological activity ίη νίίΓΟ.

The biological activity of ίη νίΐτο was determined using: (1) a study of competitive binding to a radioactive ligand using the A-form of the human progesterone receptor and progesterone as a radioactive ligand; (2) studies using co-transfection, the result of which are data on functional activity expressed using EC50 values for agonists and 1C ₅₀ for antagonists; (3) studies of Τ47Ό cell proliferation, which is also a source of data on the functional activity of agonists and antagonists; and (4) studies involving alkaline phosphatase Τ47Ό cells, which also provides functional data on agonists and antagonists.

1. The study of binding to EPYA.

This study is carried out in accordance with: Rabngapa, S .; 81e1p, Y.V .; Vegdeg, Τ.8 .; Yeshesa 1, V .; 1ashto, T .; Μηίδ, I.E ,; Toggek, A .; S1obtap, ΜΈ., Опоп8181егоего11111 Еититапап ргодгодгодЮесЮгггггггггггг т т т т т т т т Иг Иг Иг Иг т Игее т т т т т т т т т т т т т т т т т т т т тап тапапапап а а а а а а1 сут сут сут сут 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 81 81 81 81 81 81 81 81 81 81 81 81 81 81 81 81 81 81 81. Μο1. Vu1, 1992, 41, 733-738.

2. Study using pYaeluciferase in SU-1 cells.

The aim of this study is to determine the presence of gestagenic or antigestagenic activity in the compounds based on their effect on the reporter activity of PNE-luciferase in SU-1 cells co-transfected with plasmids of human RS and RSE-luciferase. The following materials and methods were used in the study.

a. Wednesday.

The following growth medium was used: ΟΜΞΜ (B | o ^ И Iakeg) containing 10% (v / v) germinal bovine serum (heat-inactivated), 0.1 mM ΜΉΜ non-essential amino acids, 100 Units / ml penicillin, 100 mg / ml streptomycin, and 2 mM S1iίaΜax (C [V SJ, VYa). The following experimental medium was used: ΌΜΉΜ (Vu ^ Yyakeg) free of phenol red, containing 10% (v / v) purified from coal (heat-inactivated) germinal bovine serum, 0.1 mM ΜΉΜ amino acids, which are not essential , 100 Units / ml of penicillin, 100 mg / ml of streptomycin, and 2 mM C1iΐaΜax (CIVSCX ON).

b. Cell cultivation, transfection, processing and research involving luciferase.

The original SU-1 cells were stored in growth medium. Joint transfection was performed using 1.2 × 10 ⁷ cells, 5 mg of the plasmid ρΒΒΜ with the EPYa-B gene cloned at the sites 8рЕ1 and ВАТН1, 10 mg of the plasmid рСЬ3 with two inserts of the РЯЕ above the luciferase sequence and 50 mg of the calf thymus DNA treated with ultrasound as DNA carrier in 250 ml. Electroporation was carried out at 260 V and 1000 mF in Vyutab Sepa Ricket II. After electroporation, the cells were resuspended in growth medium and plated on 96-well plates at 40,000 cells / well in 200 μl. After incubation overnight, the medium was replaced with experimental. Then the cells were treated with comparative or test compounds in an experimental medium. Compounds were tested for antigestagenic activity in the presence of 3 nM progesterone. 24 hours after treatment, the medium was removed, the cells were washed 3 times with I-PB8 (Ό ^ ΟΟ, ON). 50 μl of cell lysis buffer (Rgoteda, Yabkop, XVI) was added to each well and the plates were shaken for 15 min on a plate shaker (Lbnn 1nPrice, 1ps.). Luciferase activity was measured using special reagents from the company Rgoteda.

from. Analysis of the results.

Each treatment consisted of at least 4 repetitions of the experiment. Log-transformed data was used to analyze variance and non-linear dose response curves corresponding to the activity of both agonists and antagonists. Huber's weighting (Nieuh teschbpd) was used to smooth out the effect of sharply distinguished values. EC values of ₅₀ or Ιί. ' _{50 was} calculated based on reconverted values. The 4MR software (8A8 ISL, IS) was used for one-way analysis of variance and analysis of non-linear effects.

b. Comparative Compounds.

Progesterone and trimegestone served as comparative progestins, and KI486 served as comparative antiprogestin. For all comparative compounds, complete dose response curves were constructed and EC50 or GS50 values were calculated.

Table 2 Approximate values of EC50, standard errors (8E) and 95% confidence intervals (O) of comparative progestins for three separate experiments

Connection The ex P. EU ₅ 0 95% CT nM 8E Lower value Upper value Progesterone one 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 Trimegeston one 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 Approximate values of TS ₅ o, standard errors (8E) and 95% confidence intervals (O) of KI486 antiprogestin for three separate experiments

Connection Exp. Ι6’50 95% C nM 8E Lower value Upper value KI486 one 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

Gestagenic activity: Compounds that significantly (p <0.05) increase the activity of PKE-luciferase compared to the control substance are considered active.

Antigestagenic activity: Compounds that significantly (p <0.05) reduce the activity of PKE-luciferase induced by 3 nM progesterone.

EC ₅₀ : The concentration of the compound at which the activity of PKE-luciferase increases by half from the maximum value (default - nM), with 8E.

TC ₅₀ : The concentration of the compound at which the activity of PKE-luciferase induced by 3 nM progesterone is reduced by half the maximum value (default is nM), from 8E.

3. The study of the proliferation of Τ47Ό cells.

The aim of this study is to determine the presence of gestagenic or antigestagenic activity in compounds by studying the effect of Τ47Ό cells on proliferation. The magnitude of the effect of compounds on DNA synthesis in Τ47Ό cells was measured. The following materials and methods were used in the study.

a. Growing medium.

IMEM: P12 (1: 1) (SIWSS). ON), supplemented with 10% (v / v) fetal bovine serum (not heat-inactivated), 100

Units / ml of penicillin, 100 mg / ml of streptomycin, and 2 mM C1i! AMax (6Ό (Ό. ON).

b. The medium for processing.

Minimum Required Medium (MEM) (# 51200-038 ВВ. BBB) free of phenol red, supplemented with 0.5% coal-free bovine serum purified with 100 Units / ml penicillin, 200 mg / ml streptomycin, and 2 mM C1i ! aMax (ΟΙΒΓΌ, ON).

c. The cultivation of cells.

The original T47 Ό cells were stored in the growth medium. To investigate the incorporation of HBi, cells were plated on 96-well plates (Pa1cop, Weight! Op Oyuknop BaMage) at 10,000 cells / well in the growth medium. After overnight incubation, the medium was replaced with treatment medium and the cells were cultured for another 24 hours before treatment. The starting compounds were dissolved in a suitable solvent (100% ethanol or 50% ethanol / 50% DMSO), and subsequently diluted with the treatment medium and added to the cells. For progestin and antiprogestin comparative compounds, complete dose response curves were constructed. The final solvent concentration was 0.1%. In control wells, only solvent was added to the cells. Antiprogestins were tested in the presence of 0.03 nM Trimegestone, a comparative progestin agonist. 24 hours after the treatment, the medium was removed and the cells were labeled with 10 mM Brb (Agatein Lye 8c1epse, Ar1td! Op NeschieK Eb) in the treatment medium for 4 hours.

b. The study of cell proliferation.

At the end of the HBi labeling, the medium was removed and the inclusion of HBi was measured using an E8AA kit for cell proliferation (# No. 250, ATEG5Lat 8be1se) in accordance with the manufacturer's instructions. Briefly, cells were fixed using a fixative containing ethanol for 30 minutes, followed by incubation in blocking buffer for 30 minutes to reduce background. A peroxidase-labeled anti-HBi antibody was added to the wells and incubated for 60 minutes. Cells were washed three times with PB8 and incubated with a 3.3'5.5'-tetramethylbenzidine (TMB) substrate for 10-20 minutes depending on the activity of the test compounds. Then, 25 μl of 1 M sulfuric acid was added to each well to stop the color reaction, and the optical density was measured using a plate reader at 450 nm for 5 minutes.

e. Analysis of the results.

The data converted by square root extraction was used to analyze the variance and non-linear dose-response curves corresponding to the activity of both agonists and antagonists. Huber weighting was used to smooth out the effect of sharply distinguished values. Values 5С5 ₀ or Ш, calculated on the basis of repeatedly converted values. The DMR software (8А8 РШШИЕ, Мс.) Was used for one-way analysis of variance and analysis of non-linear dose-effect curves for both a single dose and a dose-effect relationship.

£. Comparative Compounds.

Trimegestone and medroxyprogesterone acetate (MPA) served as comparative progestins, and VI486 served as comparative antiprogestin. For all comparative compounds, complete dose response curves were constructed and EC ₅₀ or GS50 values were calculated.

Table 4 Approximate values of ΕС5 ₀ , standard errors (8Ε) and 95% confidence intervals (C.CH) for individual experiments

Connection Exp. Ε№ 95% a nM 8Ε Lower value Upper value Trime geston one 0.017 0.003 0.007 0,040 2 0.014 0.001 0.011 0.017 3 0.019 0.001 0.016 0.024 MPA one 0.019 0.001 0.013 0,027 2 0.017 0.001 0.011 0.024

Table 5

Approximate values are ^ ₅₀ , standard errors (8Ε) and 95% confidence intervals (S.CH). antiprogestin KI486

Connection Exp. ΡΝ 95% s nM 8Ε Lower value Upper value No. 486 one 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 ₅₀ : The concentration of the compound, at which the inclusion of HBr increases by half from the maximum value, from 8 °; Κ ₅₀ : The concentration of the compound at which the inclusion of Brb induced by 0.1 trimegestone decreases by half the maximum value, from 8 Ε.

4. A study involving alkaline phosphatase Τ47Ό cells.

The aim of this study is to identify progestins and antiprogestins by determining the effect of compounds on alkaline phosphatase activity in Τ47Ό cells. The following materials and methods were used in the study.

a. Cultivation medium: ΌΜΕΜ: Ρ12 (1: 1) (SSSO, ON), supplemented with 5% (vol./about.) Purified bovine germ whey (not heat-inactivated), 100 U / ml penicillin, 100 mg / ml streptomycin and 2 mM C1i! aMax (SIWSO. ON).

b. The buffer for the study of alkaline phosphatase activity.

Ι. 0.1 M TPK-HC1, pH 9.8, containing 0.2% Three! Op X-100.

ΙΙ. 0.1 M TPK-HC1, pH 9.8, containing 4 mM p-nitrophenyl phosphate (81 dt).

c. Cultivation and processing of cells.

Frozen T47L cells were thawed at 37 ° C in a water bath and diluted to 280,000 cells / ml with culture medium. 180 μl of a diluted cell suspension was added to each well of a 96-well plate (Pa1cop, Weight! Op Oyktkop ba ^^ ae). Then, twenty μl of comparative or test compounds were added to each well. When examining the activity of progestin antagonists, comparative antiprogestins or test compounds were added in the presence of 1 nM progesterone. Cells were incubated at 37 ° C in a humid atmosphere with 5% CO ₂ for 24 hours.

b. The study of the enzymatic activity of alkaline phosphatase.

At the end of the treatment, the medium from the plate was removed and fifty μl of research buffer Ι was added to each well. The plates were shaken for 15 minutes on a plate shaker. Then 150 μl of research buffer ΙΙ was added to each well. The optical density was measured with an interval of 5 min for 30 min at a control wavelength of 405 nm.

e. Analysis of the results. Dose effect data analysis.

For comparative and tested compounds, dose-response curves were constructed based on the dose-dependent (X axis) rate of the enzymatic reaction (tilt angle) (ос axis). The data converted by square root extraction was used to analyze the variance and non-linear dose-response curves corresponding to the activity of both agonists and antagonists. Huber weighting was used to smooth out the effect of sharply distinguished values. EC values of ₅₀ or Ιί. ' _{50 was} calculated based on reconverted values. The DMR software (8A8 and Shche, Rchs.) Was used for one-way analysis of variance and analysis of non-linear dose-response curves for both a single dose and a dose-effect relationship.

£. Comparative Compounds.

Progesterone and trimegestone served as comparative progestins, and KL486 served as comparative antiprogestin. For all comparative compounds, complete dose-response curves were constructed and EC50 or 1C50 values were calculated.

Table 6 Approximate values of EC ₅₀ , standard errors (BE) and 95% confidence intervals (C1) of comparative progestins for three separate experiments

Connection Exp. EC50 95% C1 nM BE Lower value Upper value Progesterone one 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 Trimegeston one 0,084 0.002 0,076 0,091 2 0,076 0.001 0,072 0,080 3 0.160 0.004 0.141 0.181

Table 7 Approximate values of 1C ₅₀ , standard errors (CU) and 95% confidence intervals (C1) of comparative antiprogestin KP486 for three independent experiments

Connection Exp. 1C50 95% C1 nM BE Lower value Upper value KP486 one 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. Biological activity ίη νίνο.

The primary study of ίη νίνο is a model for stimulating the excretion of a falling membrane in rats and can be used to determine gestagenic effects of both agonists and antagonists. The исследованиеη νίνο secondary study is a rat ovulation suppression model; it is under development and therefore its protocol is not available.

1. The study of the allocation of dropping shell in rats. The aim of this study is to evaluate the effect of progestins and antiprogestins on the excretion of the falling uterine membrane in rats, and to compare the relative activity of various test compounds. The following materials and methods were used in the study.

a. Methods

Test compounds were dissolved in 100% ethanol and mixed with corn oil (solvent). Then, stock solutions of the test compounds in oil (MaζοΗ ™) were prepared by heating this mixture (~ 80 ° C) to evaporate ethanol. Subsequently, before treatment, the test compounds were diluted with 100% corn oil or 10% ethanol in corn oil. When comparing these two solvents, there was no difference in the effect of precipitating shell release.

b. Animals (CASIS protocol # 5002).

Mature female Brgadie OaMeu rats with ovaries removed (~ 60 days of age and weighing 230 g) were obtained from (Ταοοπίο Eagtk, ΝΥ) after surgery. Ovarian removal was performed at least 10 days prior to treatment to reduce the circulation of sex steroid hormones. The animals were kept in a 12 hour light / dark cycle and were given standard rat food and water as needed.

from. Treatment.

Rats were weighed before treatment and randomly divided into groups of 4 or 5 animals. Test compounds were administered in 0.2 ml of solvent by subcutaneous injection into the back of the neck or in 0.5 ml using a probe. The treatment of animals was carried out 1 time daily for 7 days. In the case of a progestin test, animals received test compounds and a dose of EC ₅₀ progesterone (5.6 mg / kg) during the first 3 days of treatment. After stimulating the release of the decaying shell, the animals continued to receive progesterone until the autopsy, which was carried out 4 days later.

b. Dosage.

Doses were selected based on mg / kg of the average body weight in the group. All experiments included a control group that received the solvent. To plot the dose-response curves, a hemogarithmic dose increase (for example, 0.1, 0.3, 1.0, 3.0 mg / kg) was used.

e. Induction of precipitating shell release.

Approximately 24 hours after the third injection, precipitation was induced in one of the fallopian tubes by scratching the antimesometrial cavity epithelium with a blunt 21 O needle. The opposite tube was not touched and was used as an unstimulated control. Approximately 24 hours after the final treatment, the rats were euthanized by strangulation of CO2 and their bodies were weighed. The uterus was removed and purified from fat. The fallopian tubes with the separated falling-out shell (Ό-tube) and control tubes (C-tube) were weighed separately.

E Analysis of the results.

The increase in the weight of the fallopian tube with the released falling-off shell was calculated by the Ό-tube / C-tube ratio and the logarithmic transformation was used to optimize the normality and homogeneity of the dispersion. We used NiMeM-eqbtaYy to smooth the effect of the observed sharply distinguished transformed values for constructing dose-response curves and a one-way analysis of variance. The 1MR software (BAB 1p5111p1e. 1ps.) Was used for one-sided ΑΝΟνΑ and analysis of non-linear dose-response curves.

e. Comparative Compounds.

For all comparative progestin compounds, complete dose response curves were constructed and EC ₅₀ values were calculated for the wet weight of the uterus.

Table 8 Approximate values of EC50, standard errors (8E) and 95% confidence intervals (C1) for individual experiments

Connection Exp. EU ₅ 0 95% C1 mg / kg subcutaneously 8E Lower value Upper value Pro- steron one 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.76 3- Ketodesogestrel one 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 one 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 one 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

Table 8 Approximate average values of EC50, standard errors and 95% confidence intervals (C1) dose-response curves for the three comparative compounds

Connection EU ₅ 0 95% C1 mg / kg subcutaneously 8E Lower value Upper value Progesterone 5.62 0.62 4,55 7.00 3-Ketodesogestrel 0.10 0.02 0,07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12

Table 9

Approximate values of 1C ₅₀ , standard errors and 95% confidence intervals (C1) for antiprogestin KI 486

Connection Exp. 1C50 95% C1 mg / kg orally 8E Lower value Upper value KB486 one 0.21 0,07 0.05 0.96 2 0.14 0.02 0.08 0.27

Concentration: The concentration of the compound in the study (default is mg / kg body weight)

Method of administration: the method by which the compound is administered to animals

Body Weight: Average total animal body weight (kg by default)

B-tube: wet weight of the fallopian tube with a falling out shell (default - mg)

C-tube: wet weight of the control fallopian tube (default is mg)

The effect of the allocation of the falling away shell: [(B-C) / C] x100%

Gestagenic activity: compounds that significantly (p <0.05) induce the release of a falling membrane compared to a control solvent are considered active

Antigestagenic activity: compounds that significantly (p <0.05) reduce the EC50 of progesterone-induced excretion

EC50 for uterine weight: the concentration of the compound at which the release effect of the falling membrane increases by half the maximum value (default is mg / kg)

1С ₅₀ for uterine weight: the concentration of the compound at which the effect of the precipitation of the precipitating membrane induced by progesterone is reduced by half the maximum value of the EC50 (default is mg / kg).

Example 122. 6- (3-Methoxyphenyl) spiro [4H-3,1-benzoxazine-4,1-cyclobutane] -2 (III) -one.

A solution of Boc-protected 4-chloraniline (1.15 g, 5 mmol) in anhydrous THF was treated at -78 ° C in a stream of nitrogen with butyl lithium (7.4 ml, 12.5 mmol). The reaction solution was slowly heated to -20 ° C and maintained with stirring for 1.5 hours, and then treated with cyclobutanone (1 ml, 13.4 mmol). The mixture was warmed to room temperature and quenched with brine (30 ml), and then a 1 водорода aqueous solution of hydrogen chloride (10 ml) was added. Ethyl acetate was then added and the organic layer was separated and dried (MgO ₄ ). After removing the solvent, the residue was purified by flash column chromatography (hexane: ethyl acetate / 3: 1) to give an alcohol, which was used in the next step without further purification.

Potassium hydroxide (2 g) was added to a solution of the product obtained above in ethanol. The reaction mixture was stirred at room temperature for 18 hours, then brine (20 ml) and a cold aqueous 1Ν hydrogen chloride solution (20 ml) were added. The precipitate was collected on a filter and washed with water, which afforded 6chlorspiro [4H-3,1-benzoxazine-4,1-cyclobutane] 2 (1H) -one as a white solid (0.13 g, 12% from two stages) : mp 183-184 ° C; M8 (E81) m / e 222 [M-H] ^- .

A mixture of 6-chlorospiro [4H-3,1-benzoxazine4,1-cyclobutane] -2 (1H) -one (0.1 g, 0.45 mmol), 3methoxyphenylboronic acid (0.1 g, 0.66 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloronickel (II) (50 mg, 0.073 mmol), potassium phosphate (0.35 g, 1.7 mmol) in dioxane (5 ml) are degassed to remove oxygen and then heated at 85 ° C in a stream of nitrogen for 72 hours. The reaction mixture was allowed to cool to room temperature. Ethyl acetate (30 ml) and brine (20 ml) were added. The organic layer was separated and dried (Md ₈ O ₄ ). After removing the solvent, the residue was purified by passing through a chromatographic column (hexane: ethyl acetate / 3: 1) to obtain 6- (3-methoxyphenyl) spiro [4H-3,1 benzoxazine-4,1-cyclobutane] -2 (1H) -one as a white solid (18 mg, 14%): mp. 145-146 ° C; Ή-NMR (DMSO-b ₆ ) δ 8.04 (s, 1H),

7.69 (d, 1H, 1 = 1.6 Hz), 7.59 (dd, 1H, 1 = 8.2, 1.5 Hz), 7.36 (d, 1H, 1 = 7.9 Hz ), 7.27 (d, 1H, 1 = 7.7 Hz),

7.22 (d, 1H, 1 = 2.2 Hz), 6.99 (d, 1H, 1 = 8.2 Hz), 6.92 (dd, 1H, 1 = 8.0, 2.4 Hz ), 3.83 (s, 3H), 2.45-2.62 (m, 4H), 1.81-2.12 (m, 2H); Μδ ((+) APC1) m / e 296 [M + H] ⁺ .

Example 123. 8-Bromo-6- (3-chloro-4-nitrophenyl) -4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a mixture of 6- (3-chloro-4-fluorophenyl) -4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.2 g, 0.65 mmol) and acetate sodium (0.1 g, 1.2 mmol) in acetic acid (5 ml) is added at room temperature in a stream of nitrogen bromine (0.04 ml, 0.78 mmol). 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 obtain 8-bromo-6- (3chloro-4-fluorophenyl) -4,4-dimethyl-1,4-dihydro2H-3,1-benzoxazin-2-one as an off-white solid (0.18 g, 72%); so pl. 194195 ° C; Я-NMR (DMSO-b ₆ ) δ 9.77 (s, 1H), 8.02 (dd, 1H, 1 = 7.10, 1.81 Hz), 7.92 (s, 1H), 7, 77 (m, 1H), 7.66 (s, 1H), 7.47-7.53 (m, 1H), 1.71 (s, 6H). Μδ (E81) m / e 384, 386 [M-H] ^- .

Example 124. 3- (8-Bromo-4,4-dimethyl-2oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -5 fluorobenzonitrile.

Prepared according to the above process from 3- (4,4-dimethyl-2-oxo-1,4-dihydro2H-3,1-benzoxazin-6-yl) -5-fluorobenzonitrile (0.5 g, 1.7 mmol) as an off-white solid (0.48 g, 75%): mp. 216-217 ° C; Я-NMR (DMSO-b6) δ 9.78 (s, 1H), 8.18 (t, 1H, 1 = 1.6Hz), 8.02-8.08 (m, 2H), 7.81 ( m, 1H), 7.75 (d, 1H, 1 = 1.8 Hz), 1.66 (s, 6H). Μδ (E81) m / e 373, 375 [M-H] ^- .

Example 125. 5- (8-Bromo-4,4-dimethyl-2oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2 fluorobenzonitrile.

Received according to the above process from 5- (4,4-dimethyl-2-oxo-1,4-dihydro2H-3,1-benzoxazin-6-yl) -2-fluorobenzonitrile (0.2 g, 0.67 mmol) as an off-white solid (0.18 g, 72%); so pl. 235-236 ° C; Ή NMR (DMSO-b ₆ ) δ 9.78 (s, 1H), 8.38 (dd, 1H, 1 = 6.1, 2.4 Hz), 8.14-8.20 (m, 1H), 7.98 (d, 1H,

1 = 1.9 Hz), 7.71 (d, 1H, 1 = 1.8 Hz), 7.62 (t, 1H,

1 = 9.1 Hz), 1.69 (s, 6H). Μδ (E81) m / e 373, 375 [MH] ^- .

Example 126. 6- (3-Bromophenyl) -1,4,4trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of 6- (3-bromophenyl) -4,4-dimethyl1,4-dihydro-2H-3,1-benzoxazin-2-one (1 g, 3.0 mmol) in anhydrous DMF was added at room temperature in a stream of nitrogen Sodium hydride (60% in mineral oil, 0.24 g, 6.0 mmol). After stirring for 20 minutes, the reaction solution was treated with iodine with methane and stirred for 1.5 hours. The mixture was poured into a saturated aqueous solution of ammonium sulfate (40 ml) and ethyl acetate (40 ml) was added. The organic layer was separated, dried and evaporated to give 6- (3bromophenyl) -1,4,4-trimethyl-1,4-dihydro-2H-3,1benzoxazin-2-one as an off-white solid (0.75 g , 72%); so pl. 142-143 ° C; Ή NMR (DMSO-b ₆ ) δ 7.93 (s, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.55 (d, 1H, 1 = 8.0 Hz) 7.42 (t 1H, 1 = 7.7 Hz), 7.18 (d, 1H, 1 = 8.4 Hz), 3.35 (s, 3H), 1.67 (s, 6H). Μδ (E81) m / e 368, 370 [Μ + Να] ⁺ .

Example 127. 6- (3-Fluorophenyl) -4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

4-amino-3'-fluoro [1,1'-diphenyl] -3-carbonitrile is prepared from 3-fluorophenylboronic acid and 2-amino-5-bromobenzonitrile according to method A. Solution of 4-amino-3'-fluoro [1, 1′-diphenyl] -3-carbonitrile (6.65 g, 31.3 mmol) in anhydrous THF (100 ml) was treated dropwise at room temperature with a stream of nitrogen methyl magnesium bromide (3.0 M in ether, 21 ml, 63 mmol). After addition, the reaction mixture is heated at a low boil for 1.5 h, cooled to room temperature and treated with a 3Ν aqueous solution of hydrogen chloride (30 ml). The mixture is heated at the boil under reflux for 3 hours, cooled to room temperature and adjusted to pH 5-6 by adding a saturated aqueous solution of sodium carbonate. Ethyl acetate (100 ml) was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x50 ml). The combined organic layers were dried (Μ§δΟ ₄ ) and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 3: 1), which afforded 1 (4-amino-3 '-fluoro [1,1'-diphenyl] -3-yl) ethanone (3.1 g , 43%). so pl. 156-157 ° C.

A solution of 1 - (4-amino-3'-fluoro [1,1'-diphenyl] 3-yl) ethanone (3 g, 13 mmol) in anhydrous methanol (60 ml) is treated at room temperature in a stream of nitrogen with sodium borohydride in portions. After addition, the reaction mixture was stirred for 4 hours, treated with saturated aqueous ammonium sulfate (50 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (Μ§δΟ ₄ ) and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 3: 1) to obtain 1- (4-amino-3'-fluoro [1,1'-diphenyl] -3-yl) ethanol as a white solid (2 g, 67%): mp 136-137 ° C.

A mixture of the above alcohol (0.2 g, 0.87 mmol) and triphosgene in anhydrous THF (20 ml) was stirred at room temperature in a stream of nitrogen. After 15 minutes, the mixture was treated with saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (40 ml). The organic layer was separated, dried (Μ§δΟ ₄ ) and evaporated to give 6- (3-fluorophenyl) -4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid (0 18 g, 81%): mp 160-161 ° C; Я-NMR (DMSO-b ₆ ) δ 10.31 (s, 1H), 7.62 (dd, 1H, 1 = 8.2, 1.9 Hz), 7.57 (s, 1H), 7, 44-7.53 (m, 3H), 7.13-7.20 (m 1H), 6.97 (d, 1H, 1 = 8.2 Hz), 5.57 (q, 1Η, 1 = 6 6 Hz), 1.63 (d, 3H, 1 = 6.6 Hz). Μ3 (Ε3Ι) m / e 256 [M-H] ^- .

Example 128. 3- (4,4-Dimethyl-8-methoxy-2oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -5 fluorobenzonitrile.

To a solution of 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) in anhydrous THF (100 ml) was added methylmagnesium bromide (3.0 M in THF, 50 ml, 150 mmol) at room temperature in a stream of nitrogen. The reaction mixture was heated at 50 ° C for 18 h, cooled to room temperature and treated with a saturated aqueous solution of ammonium chloride (50 ml). Ethyl acetate (100 ml) was added and the organic layer was separated, dried (Μ§3Ο ₄ ) and evaporated. The residue was dissolved in anhydrous THF (100 ml) and treated at room temperature under nitrogen with 1,1'-carbonyldiimidazole (5.4 g, 33 mmol). After 24 hours, the mixture was quenched with 1A aqueous hydrogen chloride (30 ml). Ethyl acetate (100 ml) was added, the organic layer was separated, dried (Μ§3Ο ₄ ) and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate / 3: 1), which afforded 8-methoxy-4,4-dimethyl-1,4-dihydro2H-3,1-benzoxazin-2-one as a white solid (3.5 g, 56%): Μ3 (E31) m / e 208 [M + H] ⁺ .

To a mixture of 8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.1 g, 10.1 mmol), sodium acetate (1.5 g, 18 mmol) in acetic acid (30 ml) add bromine (0.62 ml, 12 mmol) at room temperature. After 30 minutes, the solution was treated with a concentrated solution of ammonium hydroxide (50 ml). The precipitate was collected on a filter and washed with water (3x20 ml) to obtain 6-bromo-8-methoxy4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2one (2.7 g, 93%) in as an off-white solid: Μ3 (Ε3Ι) m / e 286, 288 [M + U ⁺ .

A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis (pinacolato) dibor (1, 6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol) and [1,1'bis (diphenylphosphino) ferrocene] palladium (II) chloride (1: 1 complex with methylene chloride, 0, 5 g, 0.6 mmol) in DMF (30 ml) was purged with a stream of nitrogen to remove oxygen and then heated at 85 ° C in a stream of nitrogen for 18 hours. The reaction mixture was allowed to cool to room temperature, then it was treated with 3-bromo-5- fluorobenzonitrile (1.2 g, 6 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (1: 1 complex with chlorine methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 ml). The resulting solution was heated at 85 ° C for 3 hours in a stream of nitrogen, cooled to room temperature, and treated with brine (50 ml). Ethyl acetate (100 ml) was added, the organic layer was separated, dried (Μ§3Ο ₄ ) and evaporated. The residue was purified by flash column chromatography on silica gel (THF: hexane / 2: 3) to obtain 3 (4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H3,1-benzoxazine-6 -yl) -5-fluorobenzonitrile as a white solid (0.6 g, 33%). so pl. 252-253 ° C; Я-NMR (DMSO-b ₆ ) δ 9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, 1 = 10.6 Hz), 7.82 (m, 1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). Μ3 (Ε3 ^ m / e 325 [M-Η] ^- .

Example 129. 3- (4,4-Dimethyl-8-hydroxy-2oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -5 fluorobenzonitrile.

Mixture of 3 - (4,4-dimethyl-8-methoxy-2-oxo1,4-dihydro-2H-3,1-benzoxazin-6-yl) -5 fluorobenzonitrile (0.1 g, 0.31 mmol), lithium iodide (0.3 g, 2.24 mmol) in 2,4,6-collidine is heated at the boil under reflux in a stream of nitrogen for 5 hours. The solvent is removed in vacuo and the residue is taken up in a mixture of brine (10 ml) and ethyl acetate (30 ml ) The organic layer was separated, dried (Μ§3Ο ₄ ) and evaporated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate / 1: 1), which afforded the title compound as white plates (0.03 mg, 31%): mp. 197-198 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.16 (s, 1H),

9.55 (s, 1H), 8.01 (s, 1H), 7.79-7.87 (m, 2H), 7.20 (s, 1H), 7.08 (d, 1H, 1 = 1.0 Hz), 1.65 (s, 6H). Μ3 (Ε3 ^ m / e 311 [M-H] ^- .

Example 130. 6- (2,3-Difluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from (1,4 dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and 2,3-difluorobenzyl triflate. Yellow solid: mp. 166-167 ° C; Ή-NMR (DMSO-b ₆ ) δ 10.4 (s, 1H), 7.5-7.2 (m, 5H), 7.0 (m, 1H), 1.7 (s, 6H); Μ3 (Ε1) m / e 289 ([M + H] ⁺ ). Analysis. Calculated ^ ΗηΡ ^ Ο ^ C, 66.43; H, 4.53; And, 4.84. Found: C, 66.15; H, 4.37; And, 4.64.

Example 131. 3- (1-Ethyl-4,4-dimethyl-2oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) -5-fluorobenzonitrile.

Prepared according to the procedure of Example 125 from 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2Nbenzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile. White solid: mp 154-155 ° C; Ή NMR (DMSO-b ₆ ) δ 8.17 (s, 1H), 8.03 (d, 1H, 1 = 10.5 Hz), 7.84-7.77 (m, 3H), 7.27 ( d, 1H, 1 = 8.54 Hz), 3.97 (q, 2H, 1 = 6.89 Hz), 1.67 (s, 6H), 1.21 (t, 3H, 1 = 6.95 Hz); Μ3 (Ε1) m / e 324 ([M + H] ⁺ ). Analysis. Calculated C1dH ₁₇ RI ₂ O ₂ : C, 70.36; H, 5.28; And, 8.64. Found: C, 70.33; H, 5.51; And, 8.48.

Example 132. 6- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) pyridin-2ylacetonitrile.

Prepared according to method B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid and (6-bromo-2 pyridyl) acetonitrile (1. Ογ§. SN. 1988, 53, 786-790). Off-white solid, mp 210-212.5 ° C. ^! H NMR (DMSO-th ₆ ) δ 1.68 (s, 6H),

4.27 (s, 2H), 7.00 (d, 1H, 1 = 8.3 Hz), 7.34 (d, 1H, 1 = 7.1 Hz), 7.89-7.96 (m , 2H), 8.00-8.05 (m, 2H), 10.42 (s, 1Η). M8 (Ε8Ι) [M-U ^- = 292. Analysis. Calculated C ₁₇ H ₁₅ K ₃ O ₂ : C, 69.61; H, 5.15; Ν, 14.33. Found: C, 68.49; H, 5.19; Ν, 13.74.

Example 133. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [y] [1,3] oxazin-6-yl) -5-fluorophenylacetonitrile.

To a solution of 3-bromo-5-fluorobenzaldehyde (22.25 g, 0.11 moles) in methanol was added Να добавляют at room temperature. ₄ , (2.07 g, 0.055 moles), stirred at room temperature for 2 hours. The reaction was quenched with H ₂ O and concentrated. The residue was diluted with diethyl ether, washed with 1Ν Ν, brine, dried over Mg ^ concentrated. 3-Bromo-5-fluorobenzyl alcohol was collected as a colorless oil (14.6 g, 65%). ¹ Η NMR (DMSO-a ₆ ) δ 4.50 (m, 2H), 5.44 (t, 3H, 1 = 5.93 Hz), 7.16 (dd, 1H, 1 = 1.09, 8 , 79 Hz), 7.36 (s, 1H), 7.38 (dd, 1H, 1 = 2.99, 6.15 Hz); Analysis. Calculated With ₇ H ₆ Vg ₂ PO: 41.01; H, 2.95. Found: C, 41.30; H, 3.01.

To a solution of 3-bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 moles) in CH2C12 (15 ml) was added 12.4 ml of 1.0 M Rvg ₃ (3.33 g, 0.0123 moles) in CH ₂ C1 ₂ , stirred for 3 hours, diluted with ether (100 ml), washed with water (50 ml, 3X), dried over MgO ₄ , concentrated and purified by column chromatography using 1: 9 ethyl acetate / hexane as the eluent solvent system. Receive 3brom-5-fluorobenzylbromide in the form of a white crystalline material, so pl. 41-43 ° C. ¹ H NMR (DMSO-ά ..) δ 4.69 (s, 2H), 7.52 (d, 1H, 1 = 1.76 Hz),

7.54 (d, 1H, 1 = 1.91 Hz); 7.56 (s, 1H); M8 (Ε1): M ⁺ . m / e 266; Analysis. Calculated С-Η ₅ В ^ 2р: С, 31.38; H, 1.88. Found: C, 31.75; H, 1.78.

To a solution of 3-bromo-5-fluorobenzyl bromide (3.2 g, 0.0112 moles) in 1,4-dioxane (20 ml) is added a solution of ί <ί.'Ν (0.82 g, 0.013 moles) in H ₂ О (5 ml) and ЕУН (5 ml), heated at the boil under reflux for 2 h, extracted with ether, washed with brine, dried over Μд8Ο ₄ , concentrated. Column chromatography using hexane / ethyl acetate (19: 1) affords 3-bromo-5-fluorophenylacetonitrile as a colorless oil ^:! Η NMR (DMSO-a ₆ ) δ 4.15 (s, 2H), 7.29 (d, 1H, 1 = 9.37 Hz), 7.47 (s, 1H), 7.55 (d, 1H, 1 = 8.45 Hz); M8 (Ε1) M + m / e 213; Analysis. Calculated C ₈ H ₅ BrHP No. C, 44.89; H, 2.35; Ν, 6.54. Found: C, 44.88; H, 2.32; Ν, 6.46.

The title compound is prepared according to method B from 3-bromo-5-fluorophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. The resulting white solid was recrystallized from ethanol / ether: mp. 218-220 ° C. ¹ Η NMR (DMSO-Y6) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98 (d, 1H, 1 = 8.92 Hz), 7.18 (d, 1H , 1 = 9.26), 7.52-7.62 (m, 3H), 10.37 (s, 1H); M8 (Ε1) (M-Η) ^- , m / e 309. Analysis. Calculated for ^ Η ^ Ρ ^ Ο ^ C, 69.67; H, 4.87; Ν, 9.03. Found: C, 69.78; H, 4.97; Ν, 8.36.

Example 134. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [y] [1,3] oxazin-6-yl) -4-fluorophenylacetonitrile.

To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mol) in CC1 ₄ (150 ml) was added ΝΒ8 (14.2 g, 0.080 mol). The resulting reaction solution is heated at the boil under reflux for 2 hours until all of the starting material has reacted. CCl _{4 was} removed under reduced pressure and the residue was diluted when dissolved in ether, washed with brine (3X), after which it was dried over Mg ^^ concentrated. Chromatography / hexane affords 5-bromo-2-fluorobenzyl bromide. The product is immediately used in the next step.

5-Bromo-2-fluorobenzyl bromide (8.0 g, 0.03 moles) was dissolved in 1,4-dioxane (60 ml) and added to a solution of Ι <ί.'Ν (2.04 g, 0.031 moles) in N ₂ O (20 ml) and ethanol (20 ml). The resulting mixture was heated at the boil under reflux for 5 hours. After cooling to room temperature, the product was extracted with ether (200 ml), washed with brine, dried over MgSO ₄ , concentrated. Crystallized from ether / hexane to give 5-bromo-2-fluorophenylacetonitrile as a white crystalline material (5.6 g, 88%): mp. 55-58 ° C; ¹ H NMR (DMSO-Y6) δ 4.07 (s, 2H), 7.29 (t, 1H, 1 = 9.23 Hz), 7.60-7.69 (m, 2H); M8 (Ε1) M ⁺ , m / e 213. Analysis. Calculated CLE ^ RK C, 44.89; H, 2.35; Ν, 6.54. Found: C, 44.90; H, 2.24; Ν, 6.43.

The title compound is prepared from 5-bromo-2-fluorophenylacetonitrile and (1,4-dihydro4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6yl) boronic acid. White solid; so pl. 184-187 ° C; Ή NMR (DMSO-th ₆ ) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98 (d, 1H, 1 = 8.92 Hz), 7.36 (t, 1H , 1 = 9.13 Hz), 7.54 (d, 2H, 1 = 7.91 Hz), 7.67-7.75 (m, 2H), 10.37 (s, 1H); M8 (Ε1) (M-H) ^- , m / e 309; Analysis. Calculated: ^ Η ^ ΡΝ ^^ C, 69.67; H, 4.87; Ν, 9.03. Found: C, 68.71; H, 4.80; Ν, 8.54.

Example 135. 4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [y] [1,3] oxazin-6-yl) -2-fluorophenylacetonitrile.

Prepared according to method B from 4-bromo-2-fluorophenylacetonitrile (T. A1e551 A.N.R. and 8 Ra) en) Νο: 4895862) and (1,4-dihydro-4,4-dimethyl2-oxo-2H-3,1 -benzoxazin-6-yl) boronic acid. Gray solid; so pl. 253-256 ° C; ¹ H NMR (DMSO-a6) δ 10.35 (s, 1H), 7.67 -7.49 (m, 5H), 6.97 (d, 1Η, 1 = 8.6 Hz), 4.09 (s, 2H); 1.67 (s, 6H); M8 [M-Η] ^- , m / e 309. Analysis. Calculated C18Η ₁ 5N ₂ ΡΟ ₂ · 0.15H ₂ Ο: C, 69.07; H, 4.93; Ν, 8.95. Found: C, 69.27; H, 5.05; Ν, 8.50.

Example 136. 2- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenylacetonitrile.

Prepared according to method B from 2 bromophenylacetonitrile and (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. White solid; t. pl. 176-179 ° C; Я-NMR (DMSO-b ₆ ) δ 10.31 (s, 1H), 7.53 (m, 1H), 7.48 (m, 2H), 7.22-7.32 (m, 3H), 6.98 (d, 1H, 1 = 8.0 Hz), 3.90 (s, 2H), 1.64 (s, 6H). Μ8 (+) ARO [M + H] ⁺ , m / e = 293. Analysis. Calculated C1 ₈ H _{1 &} S ₂ O ₂ : C, 73.95; H, 5.52; Ν, 9.58. Found: C, 73.51; H, 5.70; Ν, 9.39.

Example 137. No. [4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2-fluorophenyl] acetamide.

Prepared according to method B from 4'-bromo2'-fluoroacetanilide and (1,4-dihydro-4,4-dimethyl2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. Off-white solid; so pl. 245-247 ° C. Ή-NMR (DMSO-b ₆ ) δ 10.3 (s, 1H),

9.79 (s, 1H), 7.95 (t, 1H, 1 = 8.4 Hz), 7.56-7.63 (m, 3H), 7.47 (dd, 1H, 1 = 1, 64, 8.47 Hz), 6.95 (d, 1H; 1 = 8.9 Hz), 2.1 (s, 3H), 1.67 (s, 6H); Μ8 + ARC [Μ + H] ⁴ m / e 329. Analysis. Calculated C1 ₈ H ₁₇ ^ PO ₃ : C, 65.85; H, 5.22; Ν, 8.53. Found: C, 65.46; H, 5.24; Ν, 8.12.

Example 138. 6- (3-Fluoro-4-methoxyphenyl) 4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from 4-bromo-2-fluoroanisole and (1,4-dihydro-4,4-dimethyl-2-oxo2H-3,1-benzoxazin-6-yl) boronic acid. White solid: mp 210-211C; Ή NMR (DMSO-b ₆ ) δ 10.27 (s, 1H), 7.52-7.60 (m, 3H), 7.45 (d, 1H, 1 = 8.6 Hz), 7.22 ( t, 1H; 1 = 8.9 Hz),

6.94 (d, 1H, 1 = 8.8 Hz), 3.87 (s, 3H), 1.66 (s, 6H). Μ8 [M-H] ^- , m / e = 300. Analysis. Calculated C ₁₇ H _1b EXO ₃ : C, 67.76; H, 5.35; Ν, 4.65. Found: C, 67.88; H, 5.39; Ν, 4.70.

Example 139. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenylacetonitrile.

Prepared according to method B from 3-bromophenylacetonitrile and (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-6-yl) boronic acid. White solid: mp 188-190 ° C. Ή NMR (DMSO-b ₆ ) δ 10.33 (s, 1H), 7.62 (m, 2H),

7.55 (m, 2H), 7.48 (d, 1H, 1 = 8.00 Hz), 7.33 (d, 1H, 1 = 7.57 Hz), 6.99 (d, 1H, 1 = 8.81 Hz), 4.09 (s, 2H), 1.67 (s, 6H); Μ8 m / e 291 (M-H). Analysis. Calculated for C1 ₈ H _{1 &} S ₂ O ₂ —H ₂ O: C, 72.61; H, 5.62; Ν,

9.41. Found: C, 73.00; H, 5.43; Ν, 8.81.

Example 140. 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzenesulfonamide.

Prepared according to method B from 3-bromobenzenesulfonamide and (1,4-dihydro-4,4dimethyl-2-oxo-2H-3,1-6-yl) boronic acid. White solid: mp 242-244 ° C (decomp.) Я-NMR (DMSO-b ₆ ) δ 10.28 (s, broad

1H), 8.07 (s, 1H), 7.9 (d, 1H, 1 = 7.80 Hz), 7.78 (d, 1H, 1 = 7.86 Hz), 7.64 (t, 1H, 1 = 7.79 Hz), 7.59 (m, 2H), 7.42 (s, broad 2H), 7.02 (d, 1H, 1 = 8.86 Hz), 1.68 (s 6H); Μ8 m / e 331 (M + H). Analysis. Calculated C ₁₆ H _{1 &} S ₂ O ₄ 8: C, 57.82; H, 4.85; Ν,

8.43. Found: C, 57.49; H, 5.08; Ν, 8.05.

Example 141. 5- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) thiophen2-sulfonamide.

Prepared according to method B from 5bromothiophen-2-sulfonamide and (1,4-dihydro-

4.4-dimethyl-2-oxo-2H-3,1-6-yl) boronic acid. White solid: mp 258-260 ° C, Ή-NMR (DMSO-b ₆ ) δ 10.41 (s, 1H), 7.71 (s, 2H),

7.58 (m, 2H), 7.52 (d, 1H, 1 = 3.9 Hz), 7.48 (d, 1H, 1 = 8.16 Hz), 6.95 (d, 1H, 1 = 8.16), 1.66 (s, 6H); Μ8 m / e 337 (M-H). Analysis. Calculated C ₁₄ H ₁₄ ^ O ₄ 8 ₂ : C, 49.69; H, 4.17; Ν, 8.28. Found: C, 49.90; H, 4.28; Ν, 8.12.

Example 142. 6- (6-Aminopyridin-3-yl) -4,4dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from 2-amino5-bromopyridine and (1,4-dihydro-4,4-dimethyl-2oxo-2H-3,1-6-yl) boronic acid. White crystals, mp 257-259 ° C. ¹ H-NMR (DMSO-b ₆ ) δ 10.20 (s, 1H), 8.22 (d, 1H, 1 = 2.38 Hz), 7.69, 7.66 (dd, 1H, 1 = 2.5, 2.5 Hz), 7.42 (m, 2H), 6.89 (d, 1H, 1 = 8.8 Hz), 6.49 (d, 1H, 1 = 8.64 Hz) 6.02 (s, 2H); 1.64 (s, 6H); Μ8 m / e 269 M +. Analysis. Calculated: C ₁₅ H ₁₅ K ₃ O ₂ -17 H ₂ O: C, 66.15; H, 5.68; Ν,

15.43. Found: C, 66.10; H, 5.81; Ν, 15.02.

Example 143. 6- (5-Diethoxymethylfuran-3yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one.

Prepared according to method B from 4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazine-6-boronic acid and 3-bromo-5-diethoxymethylfuran. Brown resin: 'NMR (DMSO-b ₆ ) δ 10.2 (s, 1H), 8.12 (s, 1H), 7.54-

7.49 (m, 2H), 6.93-6.88 (m, 2H), 5.56 (s, 1H), 3.60-

3.38 (m, 4H), 1.67 (s, 6H), 1.2-1.14 (m, 6H). Μ8 (Ε8Ι) m / e 344 [M-H] ^- . Analysis. Calculated for C ₁₉ H ₂ ^ O ₅ -1/2 H ₂ O: C, 64.39; H, 6.77; Ν, 3.95. Found: C, 64.90; H, 6.79; Ν, 3.78.

Example 144. 4- (4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) furan-2carbaldehyde.

Solution 6- (5-diethoxymethylfuran-3-yl) -

4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2one (1.1 g, 3 mmol) was stirred in THF (20 ml) and 2Ν HCl (2 ml) for 1 h. The crystalline product was filtered and dried (0.52 g, 69%), mp. 262263 ° C; Ή NMR (DMSO-b ₆ ) δ 10.3 (s, 1H), 9.65 (s, 1H), 8.59 (s, 1H), 8.04 (s, 1H), 7.65-7 64 (d, 1H, 1 = 1.5 Hz), 7.61-7.60 (d, 1H, 1 = 1.8 Hz), 7.59-7.58 (d, 1H, 1 = 1 8 Hz), 6.94-6.91 (d, 1H, 1 = 8.2 Hz), 1.65 (s, 6H). Μ8 (Ε8Τ) m / e 270 [M-H] ^- .

Example 145. 4- (1,4-Dihydro-4,4-dimethyl2-oxo-2H-3,1-benzoxazin-6-yl) -2-furancarboxaldehyde oxime.

A mixture of 4- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) furan-2carbaldehyde (2.7 g, 10 mmol), hydroxylamine hydrochloride (0.75 g, 10.6 mmol) and sodium acetate (0.87 g, 10.6 mmol) are heated at reflux in 80% ethanol (25 ml) for 2 hours. The title compound is crystallized from the cooled reaction mixture in the form of red crystals (1.5 g, 52.4%): so pl. 236-238 ° C. Ή NMR (DMSO-b ₆ ) δ 11.97 (s, 1H), 10.26 (s, 1H),

8.2 (s, 1H), 7.63 (s, 1H), 7.56-7.52 (m, 3H), 6.91-

6.88 (d, 1H, 1 = 8.1 Hz), 1.66 (s, 6H). MB EB1 m / e 285 [M-H] ^- . Analysis. Calculated Οι ₅ Ηι ₄ Ν ₂ 0 ₄ : C, 62.93; H, 4.93; Ν, 9.79. Found: C, 62.77; H, 5.00; Ν, 9.79.

All cited publications cited herein are incorporated by reference. Since the invention has been disclosed with reference in part to the preferred embodiment, it should be understood that modifications can be made without departing from the scope of the invention. These modifications are within the scope of the claimed claims.

Claims (22)

CLAIM 1. The compound of the formula I wherein I ¹ and I ² are independent substituents selected from the group consisting of H, _C1-C6 alkyl, substituted C1-C ₆ alkyl, C ₂ C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl or soy ^A DICE ^In SOYBEAN ^A; or I ¹ and I ^{2 are} condensed to form a) a 3-8 membered saturated spirocyclic ring having a carbon skeleton; or b) a 3-8 membered spirocyclic ring having a carbon skeleton with one or more carbon double bonds; or c) a 3-8 membered heterocyclic ring containing in its skeleton from one to three heteroatoms selected from the group including O, B and Ν; rings a), b) and c) may be optionally substituted with 1 to 4 substituents selected from the group including fluorine, C ₁ -C ₆ alkyl, C ₁ C ₆ alkoxy, C ₁ -C ₆ thioalkyl, CP ₃ , OH, SL, ΝΗ ₂ , KSCHS ^ Sbalkyl) or MS | -C ₆ alkyl) ₂ ; I ^{A is} selected from H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C 1 -C 3 alkoxy, substituted C 1 -C 3 alkoxy, C 1 -C ₃ aminoalkyl or substituted C 1 -C ₃ aminoalkyl; I ^B is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; I ³ is H, OH, ΝΗ2, C1-C6 alkyl, substituted C1-C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C ₆ alkenyl, alkynyl, substituted alkynyl, or ^soybean; I ^C is H, C 1 -C ₃ alkyl, substituted C 1 -C ₃ alkyl, aryl, substituted aryl, C 1 -C ₃ alkoxy, substituted C 1 -C ₃ alkoxy, C 1 -C ₃ aminoalkyl, or substituted C 1 -C ₃ amino alkyl; I ⁴ is H, halogen, ΟΝ, Ν0 _{2, C1-C6} alkyl, substituted _C1-C6 alkyl, alkynyl, substituted alkynyl, _C1-C6 alkoxy substituted C1-C6alkoxy, amino, C1-S6aminoalkil or substituted C ₁ -C ₆ aminoalkyl; I ^{5 is} selected from the group consisting of a) and b): a) a substituted benzene ring containing the substituents X, Υ, and показано, as shown below, wherein X is selected from the group comprising halogen, CH C1-C ₃ alkyl, substituted C1-C ₃ alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 1 -C ₃ alkoxy, substituted C 1 -C ₃ alkoxy, C 1 -C ₃ thioalkoxy, substituted C ₁ C ₃ thioalkoxy, amino, C 1 -C ₃ amino alkyl, substituted C 1 -C ₃ aminoalkyl, Ν0 ₂ , C 1 -C ₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms NΗ BO _{2 2,} SOYBEAN ^B OSOYA ^B or ^E FL SOYBEAN ^{B; I} is H, C1C ₃ alkyl substituted C1C ₃ alkyl, aryl, substituted aryl, C1C ₃ alkoxy, substituted alkoxy C1C _3, C1C ₃ aminoalkyl, or substituted S1S3aminoalkil; I ^E is H, C 1 -C 3 alkyl or substituted C 1 -C 3 alkyl; Υ Ζ and represent substituents independently selected from the group consisting of H, halogen, SR, NO _2, amino, _C1-C3 trifluoromethoxy, aminoalkyl, C1 -C3 -alkoxy, C1 -C3 alkyl, _C1-C3 thioalkoxy; or B) a 5 or 6 membered ring with 1, 2 or 3 heteroatoms in the ring selected from the group consisting of O, B, BO, BO ₂ or F ⁶ , containing one or two independent substituents selected from the group including H, halogen, SP N ₂ , amino and C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, C ₁ C ₃ aminoalkyl, BO ₂ NΗ ₂ , C = N (OΗ), SOY ^E or J ° SOY ^E ; provided that when I ⁵ is a five-membered ring that has in its skeleton two heteroatoms N ⁶ , I ¹ and I ² both are not hydrogen; and provided that when I ⁵ is a five-membered ring having one heteroatom ΝΚ ⁶ in its skeleton, and when I ^{5 is} attached at the second position on the specified ring, then there cannot be a substituent ΟΝ in the fifth position of the specified ring; I ^p is H, _C1-C3 alkyl, substituted C1 to _C3 alkyl, aryl, substituted aryl, C1 to _C3 alkoxy, substituted C1 to _C3 alkoxy, C / C ₃ aminoalkyl, or substituted C1 to _C3 aminoalkyl; I ° is H, C 1 -C ₃ alkyl or substituted C 1 -C 3 alkyl; provided that when I ⁵ is a benzene ring a), substituted by one or two substituents, or a 5- or 6-membered ring b) having in its skeleton 1, 2 or 3 heteroatoms selected from the group including O, δ and ΝΚ ⁶ , and I ¹ is alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, I ² cannot be alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; or if I ² is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, I ^{1 is} not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; provided that when I ⁵ is a benzene ring a), substituted by one or two substituents, or a 5- or 6-membered ring b) having in its skeleton 1, 2 or 3 heteroatoms selected from the group consisting of O, δ is both NY ⁶ and I ¹ is alkyl or substituted alkyl, I ^{2 is} not cycloalkyl or substituted cycloalkyl; or, if I ² is alkyl or substituted alkyl, I ^{1 is} not cycloalkyl or substituted cycloalkyl; I ⁶ is absent or is H, O, C (O) (C1-C ₄ alkoxy) or _C1-C3 alkyl; where aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl; heterocyclyl is a 5-membered ring, 6-membered ring, or polycyclic ring; wherein the 5-membered ring is selected from the group consisting of tetrahydrofuran, pyrrolidinyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiophene, pyrrole, thiazole, and furyl; The 6-membered ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulphoxide; the polycyclic ring is selected from the group consisting of indolyl, quinolinyl, benzofuranyl, benzothienyl, and isoquinolinyl; substituted alkyl, substituted alkenyl and substituted alkynyl have from one to three substituents selected from the group consisting of halogen, 0Ν, OH, NΟ ₂ , amino, aryl, hetero cyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkoxy, substituted aminoalkyl, and substituted thioalkoxy have from one to three substituents selected from the group consisting of alkyl and substituted alkyl; substituted aryl has one to four substituents selected from the group consisting of halogen,, OH, NΟ ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted cycloalkyl has from one to three substituents selected from the group consisting of halogen,, OH, NΟ ₂ , amino, aryl, heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl has from one to four substituents selected from the group consisting of halogen,, OH, NΟ ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy alkylamino and arylthio; substituted alkyloxy has from one to three substituents selected from the group consisting of halogen,, OH, NΟ ₂ , amino, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; or its pharmaceutically acceptable salt. 2. A compound of formula where R ¹ and H ² are independent substituents selected from the group consisting of H, C1-C ₆ alkyl, substituted C ₂ -C ₆ alkyl, C ₂ C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, SOYBEAN ^A or ^B nI SΟYA ^Α; or I ¹ and I ^{2 are} condensed to form a ring selected from the group consisting of a), b) and c): a) a 3-8 membered spirocyclic saturated ring having a carbon skeleton; b) a 3-8 membered spirocyclic ring having a carbon skeleton with one or more carbon-carbon double bonds; and C) a 3-8 membered heterocyclic ring containing in its skeleton from one to three heteroatoms selected from the group consisting of O, 8 and Ν; rings a), b) and c) may be optionally substituted with 1 to 4 substituents selected from the group including fluorine, C1-C6 alkyl, C1 C ₆ alkoxy, C ₁ -C ₆ thioalkyl, CE ₃ , OH, CH XH ₂ , HH (C ₁ -C ₆ alkyl) or K (C ₁ -C ₆ alkyl) ₂ ; K ^{A is} selected from H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, or substituted C ₁ -C ₃ aminoalkyl; K ^B is H, C 1 -C 3 alkyl or substituted C 1 -C 3 alkyl; K ³ is H, OH, XH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C ₆ alkenyl, alkynyl, substituted alkynyl or JUICE ^C ; K ^{C is} selected from H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy, C ₁ -C ₄ aminoalkyl, or substituted C ₁ -C ₄ aminoalkyl; K ^{4 is} selected from H, halogen, SL, KO ₂ , C ₁ C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ aminoalkyl, or substituted C ₁ - C ₆ aminoalkyl; K ⁵ is (a) or (b): a) substituted benzene ring containing the substituents X, Υ and Ζ, as shown below Where X is selected from the group consisting of halogen, SL, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ thioalkoxy, substituted C ₁ -C ₃ thioalkoxy, amino, C ₁ -C ₃ amino alkyl, substituted C ₁ -C ₃ aminoalkyl, XO ₂ , C ₁ -C ₃ perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms in its skeleton, JUICE ¹ ". OCOK ^with and ZhAOK ¹ '; K ^c represents H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl or substituted C ₁ -C ₃ aminoalkyl; K ^E is H, C ₁ -C ₃ alkyl or substituted C ₁ -C ₃ alkyl; And Ζ independently represent substituents selected from the group consisting of H, halogen, CL, XO ^ C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ thioalkoxy; or b) a 5 or 6 membered ring with 1, 2 or 3 heteroatoms in the skeleton selected from the group consisting of O, 8, 8O, 8O ₂ or ΝΒ ⁶ , containing one or two independent substituents selected from the group including H, halogen, CN, NΟ ₂ , amino, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; with the proviso that when K ⁵ is a five-membered ring having two heteroatoms ΝΗ ⁶ in its skeleton, K ¹ and K ² are not both hydrogen; and provided that when K ⁵ is a five-membered ring having one heteroatom ΝΒ ⁶ in its skeleton, and when K ^{5 is} attached at the second position on the specified ring, then there cannot be a SL substitute in the fifth position of the specified ring; K ⁶ is H or C ₁ -C ₃ alkyl; with the proviso that when K ⁵ is a benzene ring a), substituted by one or two substituents, or a 5- or 6-membered ring b) having in its skeleton 1, 2 or 3 heteroatoms selected from the group including O, 8 and ΝΒ ⁶ , and K ¹ is alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, K ² cannot be alkyl, substituted by alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; or, if K ² is alkenyl, substituted by alkenyl, alkynyl or substituted alkynyl, K ^{1 is} not alkyl, substituted by alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; with the proviso that when K ⁵ is a benzene ring a), substituted by one or two substituents, or a 5- or 6-membered ring b), having in its skeleton 1, 2 or 3 heteroatoms selected from the group consisting of O , 8 and ΝΒ ⁶ , and K ¹ is alkyl or substituted alkyl, K ^{2 is} not cycloalkyl or substituted cycloalkyl; or, if K ² is alkyl or substituted alkyl, K ^{1 is} not cycloalkyl or substituted cycloalkyl; where aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl; heterocyclyl is a 5-membered ring, 6-membered ring, or polycyclic ring; where The 5-membered ring is selected from the group consisting of tetrahydrofuran, pyrrolidinyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiophene, pyrrole, thiazole and furyl; The 6-membered ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulphoxide; the polycyclic ring is selected from the group consisting of indolyl, quinolinyl, benzofuranyl, benzothienyl, and isoquinolinyl; substituted alkyl, substituted alkenyl and substituted alkynyl have from one to three substituents selected from the group consisting of halogen, SP, OH, NΟ ₂ , amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkoxy, substituted aminoalkyl, and substituted thioalkoxy have from one to three substituents selected from the group consisting of alkyl and substituted alkyl; substituted aryl has from one to four substituents selected from the group consisting of halogen, CH OH, Ν0 ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted cycloalkyl has from one to three substituents selected from the group consisting of halogen, CK, OH, Ν0 ₂ , amino, aryl, heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl has from one to four substituents selected from the group consisting of halogen, CK, OH, Ν0 ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy alkylamino and arylthio; substituted alkyloxy has from one to three substituents selected from the group consisting of halogen,, OH, Ν0 ₂ , amino, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; or its pharmaceutically acceptable salt. 3. The compound of the formula I where K ^{1 =} K ² and they are selected from the group including C 1 -C ₃ alkyl, substituted C _g C ₃ alkyl, or K ¹ and K ^{2 are} condensed to form a 3-6 membered saturated spirocyclic ring having a carbon skeleton; K ³ is H, OH, Ν11 ₂ . C ₁ C ₆ alkyl, substituted C 1 -C ₆ alkyl or ^C 0 ^C : K ^C is H, C _g C ₄ alkyl or C 1 -C ₄ alkoxy; K ⁴ is H, halogen, CI Ν0 ₂ , C 1 -C ₃ alkyl or substituted C _g C ₃ alkyl; C _D C ₃ alkoxy or substituted C 1 -C ₃ alkoxy; K ^{5 is} selected from the group consisting of a), b) and c): a) a substituted benzene ring of the formula below, where X is selected from the group consisting of halogen,, C1-C3 alkoxy, C1-C3 alkyl, Ν02, C1C3 perfluoroalkyl, 5-membered heterocyclic ring containing from 1 to 3 heteroatoms, or C1-C3 thioalkoxy; Is a substituent selected from the group consisting of H, halogen,, 0 ₂ , C1-C ₃ alkoxy, C _g C ₄ alkyl or C ₁ C ₃ thioalkoxy; B) the 5-membered ring of the formula where is O, 8 or ΝΒ ⁶ , X 'is selected from the group consisting of halogen,, Ν0 ₂ , C1-C ₃ alkyl, and C _g C ₃ alkoxy; 'Is selected from the group consisting of H and C 1 -C ₄ alkyl; and c) 6-membered ring of the formula X 'represents Ν or CX ² ; X ² is halogen, ϋΝ, alkoxy or NO ₂ ; K ⁶ is H, C _g C ₃ alkyl or C 1 -C 4 C ₁₀ alkyl; where aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl; heterocyclyl is a 5-membered ring, 6-membered ring, or polycyclic ring; where The 5-membered ring is selected from the group consisting of tetrahydrofuran, pyrrolidinyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiophene, pyrrole, thiazole and furyl; The 6-membered ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulphoxide; the polycyclic ring is selected from the group consisting of indolyl, quinolinyl, benzofuranyl, benzothienyl, and isoquinolinyl; substituted alkyl having from one to three substituents selected from the group consisting of halogen, CH OH, Ν0 _2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio; substituted alkoxy, substituted aminoalkyl, and substituted thioalkoxy have from one to three substituents selected from the group consisting of alkyl and substituted alkyl; substituted aryl has from one to four substituents selected from the group consisting of halogen, SI OH, NΟ ₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted cycloalkyl has from one to three substituents selected from the group consisting of halogen, SI OH, NΟ ₂ , amino, aryl, heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl has from one to four substituents selected from the group consisting of halogen, SI OH, N ₂ , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkyloxy has from one to three substituents selected from the group consisting of halogen, SI OH, NΟ ₂ , amino, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; or its pharmaceutically acceptable salt. 4. The compound according to any one of claims 1 and 2, in which K ¹ is H, C ¹ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, JUA ^A or XE'SON ''; ^C K represents H, C1 to _C3 alkyl, substituted C1 to _C3 alkyl, aryl, substituted aryl, C1 to _C3 alkoxy, substituted C1 to _C3 alkoxy, C1 to _C3 aminoalkyl, or substituted C ₁ to C ₃ aminoalkyl ; K ⁴ represents H, halogen, SR NΟ _{2, C1-C6} alkyl, substituted _C1-C6 alkyl, _C1-C6 alkoxy substituted _C1-C6 alkoxy, amino, C _{1 to} C ₆ aminoalkyl, or substituted C1 C ₆ aminoalkyl; K ⁵ is a) or b): a) substituted benzene ring, in which X is selected from the group consisting of halogen, C ₁ -C ₃ alkyl, substituted C 1 -C ₃ alkyl, C 1 -C ₃ alkoxy, substituted C 1 -C ₃ alkoxy, C 1 -C ₃ thioalkoxy, substituted C 1 -C ₃ thioalkoxy, amino C 1 -C ₃ aminoalkyl, substituted C1 to _C3 aminoalkyl, NΟ _{2, C1-C3} perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 hetero atoms in its skeleton ^with CSB, sedges ^with or HN'SON; And Ζ independently represent substituents selected from the group consisting of H, halogen, SI N ₂ , C1-C ₃ alkoxy, C1-C ₃ alkyl or C ₁ -C ₃ thioalkoxy; or B) a 5 or 6 membered ring containing one or two independent substituents selected from the group consisting of H, halogen, CI NΟ ₂ , amino, C 1 -C ₃ alkyl and C 1 -C ₃ alkoxy. 5. The compound according to any one of claims 1 to 4, in which K ¹ = K ² and they are selected from the group comprising C 1 -C ₃ alkyl, substituted C 1 -C ₃ alkyl; or K ¹ and K ^{2 are} condensed to form a 36-membered spirocyclic saturated ring having a carbon skeleton; K ³ is H, OH, ΝΉ _2, C1C ₆ alkyl, substituted C ₁ -C ₆ alkyl or ^C CSB; K ^C is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; K ⁴ is H, halogen, CI NΟ ₂ , C 1 -C ₃ alkyl or substituted C 1 -C ₃ alkyl; C ₁ C ₃ alkoxy or substituted C ₁ -C 3 alkoxy; K ^{5 is} selected from the group consisting of a), b) and c): a) a substituted benzene ring of the formula below, where X is selected from the group including halogen, SI C1-C ₃ alkoxy, C1-C ₃ alkyl, NΟ ₂ , C1-C ₃ perfluoroalkyl, 5-membered heterocyclic ring containing from 1 to 3 heteroatoms, or C1-C3 thioalkoxy; Υ is a substituent selected from the group consisting of H, halogen, CI NΟ ₂ , C 1 -C ₃ alkoxy, C 1 -C ₃ alkyl or C 1 -C ₃ thioalkoxy; B) the 5-membered ring of the formula where it is O, 8 or ΝΕ ⁶ . X 'is selected from the group consisting of halogen, CK, NΟ ₂ , C 1 -C ₃ alkyl and C 1 -C ₃ alkoxy; 'Is selected from the group consisting of H and C 1 -C ₃ alkyl; K ⁶ is H or C 1 -C ₃ alkyl; and c) a 6-membered ring having the structure where X ¹ is CX ² ; X ² is halogen, CH C1-C ₃ alkoxy, or NΟ ₂ ; or its pharmaceutically acceptable salt. 6. The compound according to any one of claims 1 to 4, in which K ¹ = K ² and they are CH 3 or K ¹ and K ^{2 are} condensed to form a 6-membered saturated spirocyclic ring; K ³ is H, OH, CH ₂ , methyl, substituted methyl or JUOC ^C ; K ^C is H, C 1 -C ₃ alkyl or C 1 -C ₃ alkoxy; K ⁴ is H, halogen, L ₂ , CU, C 1 -C ₃ alkyl; K ⁵ is a substituted benzene ring of a) of the formula: wherein X is selected from the group consisting of halogen, CHU, methoxy, NO ₂ or a 5-membered heterocyclic ring, where said ring is 2-thiazole, is H or halogen. 7. The compound according to any one of claims 1 to 4, in which K ^! = K ² and represents CH ₃ or K ¹ and K ^{2 are} condensed to form a 6-membered spirocyclic saturated ring having a carbon skeleton; K ³ is H, OH, CH ₂ , methyl, substituted methyl or JUOC ^C ; K ^C is H, C 1 -C ₃ alkyl or C 1 -C ₃ alkoxy; K ⁴ is H, halogen, CH 2, CY, C 1 -C ₃ alkyl; K ⁵ is a five-membered ring b), having the formula where is O, 8 or NH, X ′ is selected from the group consisting of halogen, CH, NO ₂ , provided that when is HH, then X ′ is not CH; 'Is selected from the group consisting of H and C 1 -C ₃ alkyl; or its pharmaceutically acceptable salt. 8. The compound according to any one of claims 1 to 5, in which K ^{5 is} selected from the group including CH 9. The compound according to claim 1, which is selected from the group comprising 6- (3-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6 (3 -methoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (2-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [D ] [1,3] oxazin-2-one, 6 (4-chlorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3-chlorophenyl ) -4-methyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3-chlorophenyl) -4-ethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2on, 6- (3-chlorophenyl) -4-phenyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 3- (4,4-dimethyl-2-oxo-1, 4dihydro-2H-benzo [D] [1,3] oxazin-6-yl) benzonitrile, 4,4-dimethyl-6- (3-nitro-phenyl) -1,4- igidrobenzo [D] [1,3] oxazin-2-one, 6- (3-bromo-5fluorophenyl) -4,4-dimethyl-1,4-dihydro-benzo [D] [1.3] oxazin-2-one, 3 - (4,4-dimethyl-2-oxo-1,4-di-hydro-2H-benzo [D] [1,3] oxazin-6-yl) -5-fluorobenzonitrile, 5- (4,4- dimethyl-2-oxo-1,4-dihydro2H-benzo [D] [1,3] oxazin-6-yl) nicotino-nitrile, 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 [D] [1,3] oxazin-6-yl) -4 -methylthiophene-2-carbonitrile, 4- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [D] [1,3] oxazin-6-yl) furan-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-benzoxazin-4,1'-cyclohexane] -2 (1H) -one, 6- ( 3-chlorophenyl) spiro [4H-3,1-benzoxazin-4,1'-cyclopentane] -2 (1H) -one, 6- (3-nitrophenyl) spiro [4H-3,1-benzoxazin-4,1 ' -cyclohexane] -2 (1H) -one, 4-allyl-6- (3-chlorophenyl) -4-methyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3 chlorophenyl) -4-methyl-4-phenyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 4-benzyl-6- (3-chlorophenyl) 4-methyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3-chlorophenyl) -4-cyclopropyl-4-methyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one , 6- (3-chlorophenyl) -4,4-dicyclopropyl-1,4-dihydrobenzo [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-dihydrobenzo [D ] [1,3] oxazin-2on, 6- (3-acetylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3-benzoylphenyl) - 4.4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2on, 4,4-dimethyl-6- [3- (1H-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] [1.3] oxazin-6-yl ) thiophene-2-carbonitrile, 6- (3 - bromo-5-fluorophenyl) -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-fluorobenzonitrile, 6- (3-bromo-5-methylphenyl) -4,4 -dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3-bromo-5-trifluoromethoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1 , 3] oxazin-2-one, 3- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [D] [1,3] oxazin-6-yl) -5-methylbenzonitrile, 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [D] [1,3] oxazin-6-yl) -5-trifluorometo ibenzonitrile, 6- (3,5-difluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3] oxazin-2-one, 6- (3,5-dichlorophenyl) -4,4-dimethyl -1,4-dihydrobenzo [D] [1.3] oxazin-2-one, 6- (3,5-bis-trifluoromethylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [D] [1,3 ] oxa93 zin-2-one, 3- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] Coxazin-6-yl) -5-methoxybenzonitrile, 6- ( 3-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-chloro-4-fluorophenyl) -4,4-dimethyl-1, 4-dihydrobenzo [b] [1,3] oxazin-2-one, 3- (1-diethoxymethyl-4,4-dimethyl-2oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazine -6il) -5-fluorobenzo-nitrile, 3-fluoro-5- (1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2 -Benzo [b] [1,3] oxazin-6-yl) benzonitrile, phosphoric acid 6- (3-cyan-5-fluorophenyl) -4,4-dimethyl4H-benzo [b] [1,3] oxazin-2 -yl diethyl ether, 3- (4,4-dimethyl-2-o-x-1,4-dihydro-2H-benzo [b] [1.3] Koxazin-6-yl) -4-fluorobenzonitrile, 6- (3-chloro -4-fluorophenyl) -8-fluoro-4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-bromophenyl) -4,4-dimethyl-1 , 4-dihydrobenzo [b] [1,3] oxazin-2-one, 4,4-dimethyl-6- (3-trimethylstannyl ethynylphenyl) -1,4-dihydrobenzo [b] [1,3] oxazin-2on, 6 - (3-ethynylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 - [3 - (4,4-dimethyl-2oxo-1,4- dihydro-2H-benzo [b] [1,3] Coxazin-6-yl) phenyl] propynonitrile, 6- (3-ft 5-p-nitrοfenil) - 4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] 3-xoxazin-2-οκ, 6- (3-chloro-5-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [ 1,3] oxazin-2-one, 3-chloro-5- (4,4 dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile, 6- (3,5-dinitrophenyl) - 4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2on, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3 ] oxazin-6-yl) isophthalonitrile, 4,4-dimethyl-6- (3-thiazol-2-ylphenyl) -1,4-dihydrobenzo [b] [1.3] oxazin-2-one, 6- (3-fluoro -5-methoxyphenyl) - 4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2on, 6- (3-fluoro-5-trifluoromethylphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [ 1,3] oxazin-2-one, 6- (5bromopyridin-3 -yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] Toxazin-2-one, 6- (5 - bromo-1-hydroxypyridin-3 -yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 5- (4,4-dimethyl-2-x-xo-1 , 4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-fluorobenzonitrile, 4- (8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro- 2H-benzo [b] [1,3] -oxazin-6-yl) thiophene-2carbonitrile, 3-fluoro-5- (8-fluoro-4,4-dimethyl-2oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) benzonitrile, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6- il) thiophene-3-carb onitrile, 2- (4,4-dimethyl-2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) thiophene-3-carbonitrile, 6- (1,2,4 -thiadiazol-3-yl-phenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6 (3-fluoro-5-thiophen-3-yl-phenyl -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4,4-dimethyl-6- (5-nitro-1H-pyrrol-2-yl) -1,4-dihydro-benzo [b] [1,3] oxazin-2-one, 4,4-dimethyl-6- (1H-pyrrol-2-yl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4 , 4dimethyl-6- (1-methyl-1H-pyrrol-2-yl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 4,4-dimethyl-6- (1methyl-5 -nitro-H-pyrrol-2-yl) -1,4-dihydrbenzo [b] [1,3] oxazin-2-one, 3 - (1,2-dihydro-2-oxospiro [4H-3,1 - benzoxazin-4,1-cyclohexane] -6-yl) benz onitrile, 3- (1,2-dihydro-2-oxospiro [4H3,1-benzoxazin-4,1 -cyclohexane] -6-yl) -5-fluorobenzonitrile, 4- (1,2-dihydro-2-oxospiro [ 4H3,1-benzoxazin-4,1-cyclohexane] -6-yl) -2-thiophenecarbonitrile, 5- (1,2-dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] - 6-yl) -2-thiophene carbonitrile, 5- (1,2-dihydro-2-oxospiro [4H-3,1-benzoxazin-4,1-cyclohexane] -6-yl) 4-methyl-2-thiophene carbonitrile, 5- ( 4,4-dimethyl2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6yl) -4-ethylthiophene-2-carbonitrile, 5- (4,4-dimethyl-2-x) -1,4-dihydro-2H-benzo [b] [1,3] Koksazin-6-yl) -4-n-napyltyo phen-2-carbonitrile, 6 (4-cyano-3-fluorophenyl) -4,4 dimethyl-1,4-dihydro benzo [b] [1,3] oxazin-2-one, 6- (4-fluorophenyl) - 4.4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3,4-difluorophenyl) -4,4-dimethyl-1,4-dihydro-benzo [b] [1, 3] Koksazin-2-Or, 6- (2-fluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 - (4,4-dimethyl- 2-oxo-1,4-dihydro2H-benzo [b] [1,3] oxazin-6-yl) phenylaceto nitrile, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] Coxazin-6-yl) furan-2-carbonitrile, 5 (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1.3] oxazin-6 -yl) furan-2-carbonitrile, 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] ο ^ sazin-6-yl) -2-fluorobenzonitrile, 6- (3-cyano-5fluorophenyl) -4,4-dimethyl-2-oxo-4H-benzo [b] [1.3] oxazin-1-carboxylic acid tert-butyl New ester, 6- (2,3-difluorophenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3 (1-ethyl-4,4-dimethyl- 2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -5-fluorobenzonitrile, [6 (4,4-dimethyl-2-oxo-1,4-dihydro -2H-3,1-benzoxazin-6-yl) pyridin-2-yl] acetonitrile, 3- (4,4 dimethyl-2-oxo-1,4-dihydro-2H- [b] [1,3] oxazin6- yl) -5-fluorophenylacetonitrile, 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -4-fluorophenylacetonitrile, 4- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) -2-fluorophenylacetonitrile, 2- (4,4-dimethyl-2- oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) phenylacetonitrile, N - [4 - (4,4-dimethyl2-oxo -1,4-dihydro-2H-3,1 -benzoxazin-6-yl) -2fluorophenyl] acetamide, 6- (3-fluoro-4-methoxyphenyl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (6-aminopyridin-3-yl) -4,4-dimethyl- 1.4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (5-diethoxymethyl-furan-3-yl) -4,4-dimethyl-1,4-dihydrobenzo [b] [1, 3] oxazin-2-one, 4- (4,4-dimethyl2-oxo-1,4-dihydro-2H-benzo [b] [1,3] scxazin-6yl) furan-2-carbaldehyde, 4,4- dimethyl-6- (3-trimethylsilyl ethylethylphenyl) -1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 3- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [ b] [1,3] oxazin-6-yl) benzosulfonamide, 5- (4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl ) thiophene-2-sulfonamide and 4- (1,4-dihydro-4,4-dimethyl-2-oxo2H-3,1-benzoxazin-6-yl) furancarboxaldehyde oxime, or its pharmaceutically acceptable salt. 10. The compound according to claim 3, which is selected from the group consisting of 2- (4,4-dimethyl-2-oxo95 1,4-dihydro-2H-benzo [b] [1,3] oxazin-6-yl) pyrrole-1-carboxylic acid tert-butyl ester, 2- (4,4-dimethyl-2-oxo-1,4 -dihydro-2Nbenzo [b] [1,3] oxazin-6-yl) -5-nitropyrrole-1-carboxylic acid tert-butyl ester, 5 (4,4-dimethyl-2-oxo-1,4-dihydro-2H- benzo [b] [1,3] oxazin-6-yl) -4-n-butylthiophene-2-carbonitrile or its pharmaceutically acceptable salt. 11. The compound according to any one of claims 1 to 3, in which K ^{5 is} selected from the group comprising 3 chloro-4-fluorophenyl, 3,5-dichlorophenyl, 3-cyano-4 fluorophenyl, 3,4-difluorophenyl, 3-cyano-5 -chlorophenyl, 3-trifluoromethyl-5-fluorophenyl, 2-fluoro-3-cyanophenyl, 2-fluorophenyl, 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-bromo-4-fluorophenyl, 3-chloro-4-bromophenyl, and 3.5 -dibromophenyl. 12. The compound according to any one of claims 1 to 3, where K ⁵ is 4-cyano-3-furanyl. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 14. A method of contraception in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 15. A method of treating hormone-dependent neoplasms in mammals, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 16. The method of claim 15, wherein the hormone-dependent neoplasms in mammals are selected from the group including uterine leiomyoma, endometriosis, benign prostatic hypertrophy, and endometrial carcinoma and adenocarcinoma, ovaries, breast, colon and prostate, pituitary and meningioma. 17. A method for synchronizing estrus in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 18. A method of contraception in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound selected from the group including 6- (3-chlorophenyl) -4-methyl-4-propyn-1-yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-chlorophenyl) -4-ethynyl-4-methyl-1,4-dihydrobenzo [b] [1,3] oxazin-2on, 6- ( 3-chlorophenyl) -4-cyclopropyl-4-propyn-1yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 6- (3 chlorophenyl) -4,4-dipropin-1-yl- 1,4-dihydrobenzo [b] [1,3] oxazin-2-one, or its pharmaceutically acceptable salt. 19. A method of treating hormone-dependent neoplasms in mammals, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound selected from the group comprising 6- (3-chlorophenyl) -4-methyl-4-propyne-1yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3 chlorophenyl) -4-ethynyl-4-methyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-Chlorophenyl) -4-cyclopropyl-4-propyn-1-yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 6- (3-chlorophenyl) -4,4-dipropine -1yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, or its pharmaceutically acceptable salt. 20. The method according to claim 19, in which hormone-dependent neoplasms include uterine leiomyoma, endometriosis, benign prostatic hypertrophy, as well as endometrial carcinoma and adenocarcinoma of the endometrium, ovary, breast, colon and prostate, pituitary and meningioma. 21. A method for synchronizing estrus in mammals, comprising administering to a mammal in need a pharmaceutically effective amount of a compound selected from the group 6- (3-chlorophenyl) -4-methyl-4 propin-1 -yl-1,4-dihydrobenzo [b] [1,3] oxazin-2on, 6- (3-chlorophenyl) -4-ethynyl-4-methyl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one, 6- (3-chlorophenyl ) -4-cyclopropyl-4-propyn-1-yl-1,4-dihydrobenzo [b] [1,3] oxazin-2-one and 6- (3-chlorophenyl) 4,4-dipropin-1 -yl- 1,4-dihydrobenzo [b] [1,3] oxazin-2-one, or its pharmaceutically acceptable salt. 22. A method of hormone replacement therapy of a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.