EA001991B1 - 4,4-disubstituted -3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitots - Google Patents

Abstract

1. A compound of formula (I): or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R<1> is C1-3-alkyl substituted with 1-7 halogen atoms; R<2> is selected from C1-5-alkyl substituted with 1-2 R<4>, C2-5-alkenyl substituted with 1-2 R<4>, and C2-5-alkynyl substituted with one R<4>; R<3> each is independently selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from C3-5-cycloalkyl substituted with 0-2 R<3>, phenyl substituted with 0-5 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R<3>; R<5> and R<5>a are independently selected from H and C1-3-alkyl; R<6> is selected from H, OH, C1-4-alkyl, C1-4-alkoxy, and NR<5>R<5a>; R<7> is selected from C1-3-alkyl and C1-3-alkoxy; R<8> is selected from H, C3-5-cycloalkyl, and C1-3-alkyl; and, n is selected from 0, 1, 2, 3, and 4. 2. A compound according to Claim 1, wherein: R<1> is C1-3-alkyl substituted with 1-7 halogen; R<2> is selected from C1-5-alkyl substituted with one R<4>, C2-5-alkenyl substituted with one R<4>, and C2-5-alkynyl substituted with one R<4>; R<3> each is independently selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from C3-5-cycloalkyl substituted with 0-2 R<3>, phenyl substituted with 0-2 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R<3>; R<5> and R<5a> are independently selected from H, C3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>; R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, cyclopropyl, CH3 and C2H5; and, n is selected from 0, 1, 2, and 3. 3. A compound according to Claim 2, wherein: R<1> is selected from CF3, and C2F5; R<2> is selected from C1-3-alkyl substituted with one R<4>, C2-3-alkenyl substituted with one R<4>, and C2-3-alkynyl substituted with one R<4>; R<3> each, is independently selected from C1-3-alkyl, OH, C1-3-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from C3-5-cycloalkyl substituted with 0-2 R<3>, phenyl substituted with 0-2 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R<3>; R<5> and R<5a> are independently selected from H, CH3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>; R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, CH3 and C2H5; and, n is selected from 0, 1, and 2. 4. A compound according to Claim 3, wherein: R<1> is CF3; R<2> is selected from C1-3-alkyl substituted with one R<4>, C2-3-alkenyl substituted with one R<4>, and C2-5-alkynyl substituted with one R<4>; R<3> each is independently selected from C1-3-alkyl, OH, C1-3-alkoxy, F, Cl, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; alternatively, if two R<3> substituents are present and are attached to adjacent carbons, then they may combine to form -OCH2O-; R<4> is selected from cyclopropyl substituted with 0-1 R<3>, phenyl substituted with 0-2 R<3>, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R<3>, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl; R<5> and R<5a> are independently selected from H, CH3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>. R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, CH3 and C2H5; and, n is selected from 1 and 2. 5. A compound according to Claim 4, wherein the compound is of formula Ia: 6. A compound according to Claim 4, wherein the compound is of formula Ib: 7. A compound according to Claim 1, wherein the compound is selected from: (+/-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-chloro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-methoxy-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-methoxy-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1)-quinazolinone; (+/-)-6-fluoro-4-(2'-2-pyridyl)ethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-E-4-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and, (-)-6-chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; or a pharmaceutically acceptable salt thereof. 8. A compound according of formula II: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R<2> is C [triple bond] C-R<4a>; R<3> is selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, NHC(O)R<7>, and NHC(O)NR<5>R<5a>; R<4a> is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, and isopentyl; R<5> and R<5a> are independently selected from H and C1-3-alkyl; R<6> is selected from H, OH, C1-4-alkyl, C1-4-alkoxy, and NR<5>R<5a>; R<7> is selected from C1-3-alkyl and C1-3-alkoxy; R<8> is selected from H, C3-5-cycloalkyl, and C1-3-alkyl; and, n is selected from 0, 1, 2, 3, and 4. 9. A compound according to Claim 8, wherein: R<2> is C [triple bond] C-R<4a>; R<3> is selected from C1-4-alkyl, OH, C1-4-alkoxy, F, Cl, Br, I, NR<5>R<5a>, NO2, CN, C(O)R<6>, and NHC(O)R<7>; R<4a> is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, and isopentyl; R<5> and R<5a> are independently selected from H, CH3 and C2H5; R<6> is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR<5>R<5a>; R<7> is selected from CH3, C2H5, OCH3, and OC2H5; R<8> is selected from H, cyclopropyl, CH3 and C2H5; and, n is selected from 0, 1, and 2. 10. A compound according to Claim 9, wherein the compound is of formula IIa: 11. A compound according to Claim 9, wherein the compound is of formula IIb: 12. A compound according to Claim 8, wherein the compound is selected from: (+/-)-6-chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-4-isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-5,6-difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+/-)-6-fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (+)-5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; (-)-5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and, (+)-5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of Claims 1-12 or a pharmaceutically acceptable salt form thereof. 14. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of one of Claims 1-12, or a pharmaceutically acceptable salt form thereof. 15. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound of one of Claims 1-12 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors. 16. A method according to Claim 15, wherein the reverse transcriptase inhibitor is selected from AZT, 3TC, ddI, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L-697 661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-378. 17. A

Description

This invention relates generally to

4,4-disubstituted 3,4-dihydro -2 (1H) -quinazolinones, which are useful as HIV reverse transcriptase inhibitors, pharmaceutical compositions and diagnostic kits containing them, methods for using them to treat a viral infection, or as test standards or reagents and intermediates and methods for their preparation.

BACKGROUND OF THE INVENTION

Two different retroviruses, human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2), are etiologically associated with immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV-seropositive individuals are asymptomatic at first, but AIDS-associated complex (ACS) usually develops and then AIDS. Affected individuals exhibit severe immunosuppression, which predisposes them to weaken and ultimately to fatal infections caused by opportunistic microorganisms.

AIDS is the end result of HIV-1 or HIV-2 after its own complex life cycle. The virion life cycle begins with the attachment of the virion itself to the human T-4 lymphocyte immune cell by binding the glycoprotein on the surface of the virion protective membrane to the SB4 glycoprotein on the lymphocyte. After attachment, the virion drops its glycoprotein membrane, penetrates the membrane of the host cell and exposes its RNA. The virion enzyme, reverse transcriptase, triggers the process of transcribing this RNA into single-stranded DNA. Viral RNA is destroyed and a second strand of DNA is formed. Now double-stranded DNA is integrated into the genes of human cells and these genes are used to reproduce the virus.

At this point, RNA polymerase transcribes integrated DNA into viral RNA. Viral RNA is translated into the fusion polyprotein precursor dad-ροΐ. This polyprotein is then cleaved by the HIV protease enzyme to form mature viral proteins. Thus, HIV protease is responsible for the regulation of the cascade of cleavage events that lead to the maturation of viral particles to a virus that is completely infectious.

The typical response of the human immune system, killing the invading virion, is difficult, as this virus infects and kills the T cells of the immune system. In addition, the reverse transcriptase of the virus, an enzyme used to create a new virion particle, is not very specific and causes transcription errors that lead to continuously changing glycoproteins on the surface of the virus's protective membrane. This loss of specificity reduces the effectiveness of the immune system, since antibodies specifically produced against one glycoprotein can be useless against another, therefore reducing the number of antibodies available to fight this virus. The virus continues to reproduce, while the response of the immune system continues to weaken. In the end, HIV largely dominates the body’s immune system, allowing infections to develop opportunistic microorganisms, and death can occur without the introduction of antiviral agents, immunomodulators, or both.

There are at least three critical points in the life cycle of a virus that have been identified as possible targets for antiviral drugs:

(1) initial attachment of the virion to the site of the T-4 lymphocyte or macrophage, (2) transcription of viral RNA into viral DNA (reverse transcriptase, RT), and (3) protein processing by the dad-ροΐ HIV protease.

Inhibition of the virus at the second critical point, in the process of transcription of viral RNA into viral DNA, has provided a number of modern therapeutic techniques used in the treatment of AIDS. This transcription must occur for reproduction of the virion, since the virion genes are encoded in RNA, and the host cell reads only DNA. By administering drugs that block reverse transcriptase from completing viral DNA production, HIV-1 replication can be stopped.

A number of compounds that inhibit virus replication have been developed for the treatment of AIDS. For example, it has been shown that nucleoside analogues such as 3'-azido-3'-deoxythymidine (ΑΖΤ), 2 ', 3'-dideoxycytidine (66C), 2', 3'-dideoxythymidine (64Τ), 2 ', 3' dedeoxyinosine (661) and 2 ', 3'-dideoxy-3'thiacytidine (ZTS) are relatively effective in stopping HIV replication at the stage of reverse transcriptase (RT).

An active area of research is the detection of non-nucleoside HIV reverse transcriptase inhibitors. As an example, it has been found that certain benzoxazinones and quinazolinones are active in inhibiting HIV reverse transcriptase, preventing or treating HIV infection, and treating AIDS.

In and 8. 5 519 021 describes reverse transcriptase inhibitors that are benzoxazinones of the formula

where X is halogen, Ζ may be 0.

EP 0 530 994 and AO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of formula A

And where O denotes various groups, K ³ and K ⁴ may be H, Ζ may be O, K ² may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle and optionally substituted aryl, and K ¹ may be various groups, including substituted alkyl.

AO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, O denotes various groups, K ³ and K ⁴ may be H, Ζ may be O, K ² is substituted alkenyl or substituted alkynyl, and K ¹ is cycloal- keel, alkynyl, alkenyl or cyano. AO 95/13273 illustrates the asymmetric synthesis of one of the compounds of AO 95/12583, (8) - (-) - 6-chloro-4-cyclopropyl-3,4-dihydro-4 - ((2-pyridyl) ethynyl) -2 (1H) quinazolinone.

Synthesis procedures for the preparation of quinazolinones similar to those described above are described in detail in the following links: Noir! A1, Te1g. LeI 1994, 35 (37), 6811-6814; Tiskeg e! A1., I. Honey. Siesh. 1994, 37, 2437-2444 and Niishap e! A1, I. Ogd. Siesh. 1995, 60, 1590-1594.

ΌΕ 4,320,347 illustrates the quinazolinones of formula k to ³

where K is phenyl, a carbocyclic ring or a heterocyclic ring. Compounds of this type are not considered as part of this invention.

Even with success in developing reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to one inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Thus, one object of the present invention are novel reverse transcriptase inhibitors.

Another object of the present invention is a new method of treating HIV infection, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of this invention or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a new method of treating HIV infection, comprising administering to a host in need of such treatment a therapeutically effective combination of (a) one of the compounds of this invention and (b) one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

Another object of the invention is pharmaceutical compositions with reverse transcriptase inhibiting activity, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the invention or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a method of inhibiting HIV present in a body fluid sample, comprising treating a body fluid sample with an effective amount of a compound of the invention.

Another object of the present invention is a kit or container containing at least one of the compounds of this invention in an amount effective to be used as a standard or reagent in a test or assay to determine the ability of a potential pharmaceutical agent to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent from the following detailed description, were achieved by the discovery by the inventors of the fact that the compounds of formula (I)

I where K ¹ , K ² , K ³ and K ⁸ have the meanings defined below, their stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION [1] Thus, in a first embodiment, this invention relates to a new compound of formula I i ¹ i ²

I or its stereoisomer or pharmaceutically acceptable salt, where

K ¹ is C _1-3 alkyl substituted with 1-7 halogen atoms;

K ^{2 is} selected from C _1-5 alkyl substituted with 1-2 K ⁴ , C2-5 alkenyl substituted with 1-2 K ⁴ , and C2-5 alkynyl substituted with one K ⁴ ;

I ³ each independently selected from C1.4 alkyl, OH, C1-4 alkoxy, E, C1, Br, I, ΝΚ ⁵ Κ ^5α , ΝΟ2, ίΝ, C (O) I ⁶ , M1C (O) I and \ ' NS (O) \ 'I ^:: ;

alternatively, if two H ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OSH ₂ O—;

I ^{4 is} selected from C _3-5 cycloalkyl substituted with 0-2 ³ , phenyl substituted with 0-5 ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N and 8, substituted with 0- 2 i ³ ;

I ⁵ and I ^{5a are} independently selected from H and C _1-3 alkyl;

I ^{6 is} selected from H, OH, C _1-4 alkyl, C _1-4 alkoxy, and NYa ⁵ I ^5a ;

I ^{7 is} selected from C _1-3 alkyl and C _1-3 alkoxy;

I ^{8 is} selected from H, C _3-5 -cycloalkyl and C _1-3 alkyl and n is selected from 0, 1, 2, 3 and 4.

[2] In a preferred embodiment, this invention relates to a new compound of formula I, where

I ¹ is C _1-3 alkyl substituted with 1-7 halogen atoms;

I ^{2 is} selected from C _1-5 alkyl substituted with 1 I ⁴ , C2-5 alkenyl substituted with 1 ⁴ , and C2-5 alkynyl substituted with one ⁴ ;

I ³ each is independently selected from C1-4 alkyl, OH, C1-4 alkoxy, E, C1, Br, I, ΝΒ ^ ⁵³ , ΝΟ2, SI C (O) I ⁶ , ΝΗ ^ Ο ^ ⁷ and \ 'HC ( D) \ ^'YA'YA:;

alternatively, if two H ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OCH 2 O—;

R ^{4 is} selected from C3-5 cycloalkyl substituted with 0-2 R ³ , phenyl substituted with 0-2 R ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N and 8, substituted 0-1 I am ³ ;

I ⁵ and I ^{5a are} independently selected from H and CH ₃ and C2H5;

I ^{6 is} selected from H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ and ΝΚ ^. ⁵ ®;

I ⁷ selected from CH ₃ ; C ₂ H ₅ , OCH ₃ and OS ₂ H ₅ ;

I ^{8 is} selected from H, cyclopropyl, CH ₃ and C ₂ H ₅ and n is selected from 0,1, 2 and 3.

[3] In a more preferred embodiment, the present invention relates to a new compound of formula I, where

I ^{1 is} selected from CE ₃ and C ₂ E ₅ ;

I ^{2 is} selected from C1-3 alkyl substituted with one I ⁴ , C2-3 alkenyl substituted with one I ⁴ , and C2-3 alkynyl substituted with one ⁴ ;

I ³ each independently selected from C1-3 alkyl, OH, C1-3 alkoxy, E, C1, Br, I, NY ⁵ I ^5a , ΝΟ2, SI C (O) I ⁶ , ΝΗ ^ Ο ^ ⁷ and \ 'HC (O) \ 'I ^:: ;

alternatively, if two H ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form -ΟΟΗ ₂ Ο-;

R ^{4 is} selected from C3-5 cycloalkyl substituted with 0-2 R ³ , phenyl substituted with 0-2 R ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, Ν and 8, substituted 0-1 I am ³ ;

I ⁵ and I ^{5a are} independently selected from H, CH ₃ and C2H5;

I ^{6 is} selected from H, OH, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ and Ν ^ Κ ⁵ ®;

I ^{7 is} selected from CH ₃ , C ₂ H ₅ ; OCH ₃ and OS ₂ N ₅ ;

I ^{8 is} selected from H, CH ₃ and C ₂ H _5, and η is selected from 0,1 and 2.

[4] In an even more preferred embodiment, the present invention relates to a new compound of formula I, where

I ¹ is CE3;

I ^{2 is} selected from C 1 _-3 alkyl substituted with one I ⁴ , C2-3 alkenyl substituted with one I ⁴ , and C2-3 alkynyl substituted with one I ⁴ ;

I ³ each independently selected from C1-3 alkyl, OH, C1-3-alkoxy, E, C1, NYa ⁵ I ^5a , ΝΟ2, ΟΝ, C (()) I '. ΝΗ ^ Ο ^ ⁷ and ΝΗ € (Ο) ΝΚ ⁵ Κ ^5ί1 ;

alternatively, if two H ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OCH 2 O—;

I ^{4 is} selected from cyclopropyl substituted with 0-1 I ³ , phenyl substituted with 0-2 I ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, Ν and 8, substituted with 0-1 I ³ , where the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl and 2-imidazolyl;

I ⁵ and I ^{5a are} independently selected from H and CH ₃ and C2H5;

I ⁶ is selected from H, OH, CH _3, C ₂ u, OCH _3, OC ₂ H ₅ and Ν ^ Κ ⁵ ®;

I ⁷ is selected from CH3, C2H5, OCH3, and OC2H5;

I ^{8 is} selected from H, CH3 and C2H5 and n is selected from 1 and 2.

[5] In a further preferred embodiment, the compound has the formula 1a

1a.

[6] In another preferred embodiment, the compound has the formula! B i 'n ²

1b.

[7] In another preferred embodiment, the compound of formula I is selected from the group consisting of (+/-) -6-chloro-4-cyclopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazinone;

(+/-) -6-chloro-4 - (2-pyridyl) ethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) -6-chloro-4-phenylethynyl-4 trifluoromethyl-3,4-dihydro -2 (1H) -quinazino linone;

(+/-) - 4-cyclopropylethynyl-6-methoxy-4 trifluoromethyl-3,4-dihydro -2 (1H) -quinazino linone;

(+/-) - 6-methoxy-4- (2-pyridyl) ethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-methoxy-4-phenylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 4-cyclopropylethynyl-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 5,6-difluoro-4 - (2-pyridyl) ethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 5,6-difluoro-4-phenylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 4-cyclopropylethynyl-6-fluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-fluoro-4- (2-pyridyl) ethynyl-4trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-fluoro-4-phenylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-fluoro-4- (2'-2-pyridyl) ethyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-fluoro-4-phenylethyl-4-trifluoromethyl-

3,4-dihydro -2 (1H) -quinazolinone;

(-) - 6-chloro-4-cyclopropylethinyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+) - 6-chloro-4-cyclopropylethinyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+) - 4-cyclopropylethinyl-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(-) - 4-cyclopropylethynyl-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+) - 4-E-cyclopropylethylene-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone and (-) - 6-chloro-4-E-cyclopropylethylene-4 trifluoromethyl-3,4 -dihydro-2 (1H) -quinazolinone or a pharmaceutically acceptable salt thereof.

[8] In a second embodiment, the invention relates to a new compound of formula II

II or its stereoisomer or pharmaceutically acceptable salt where

B ² is CHC-B ⁴ ;

B ^{3 is} selected from C1-4 alkyl, OH, C! -4-alkoxy, E, C1, Br, I, OH ⁵ B ^5a , 2, CB, C (O) B ⁶ , CNS (O) B ⁷ and YNS (O) YB ⁵ V ^5a ;

^{4a is} selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and isopentyl;

B ⁵ and B ^{5a are} independently selected from H and C _1-3 alkyl;

B ^{6 is} selected from H, OH, C _1-4 alkyl, C _1-4 alkoxy, and HB ⁵ B ^5a ;

B ⁷ selected from C _1-3 alkyl and C _1-3 alkoxy;

B ^{8 is} selected from H, C _3-5 cycloalkyl and C _1-3 alkyl and n is selected from 0, 1, 2, 3 and 4.

[9] In another preferred embodiment, the present invention relates to a new compound of formula II, where

B ² is CHC-B ⁴ ;

B ³ is selected from C1-4 alkyl, OH, C1-4 alkoxy, E, C1, Br, I, YV ^{5 5a,} ΝΟ2, CN, C (O) B ^6, YNS (O) A ^7;

^{4a is} selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and isopentyl;

B ⁵ and B ^{5a are} independently selected from H, CH _3, and C2H5;

⁶ selected from H, OH, CH3, C2H5, OCH3, OC ₂ H ₅ and OH ⁵ B ^5a ;

B ⁷ selected from CH ₃ , C ₂ H ₅ , OCH _3, and OS ₂ H ₅ ;

B ^{8 is} selected from H, cyclopropyl, CH3 and C2H5 and n is selected from 0, 1 and 2.

[10] In another preferred embodiment, the compound has the formula 11a

SRz N ²

On.

[11] In another preferred embodiment, the compound has the formula Pb

11b.

[12] In a further more preferred embodiment, the compound of formula II is selected from the group consisting of (+/-) - 6-chloro-4-isopropylethinyl-4trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-chloro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro -2 (1H) -quinazino linone;

(+/-) - 4-isopropylethynyl-6-methoxy-4 trifluoromethyl-3,4-dihydro -2 (1H) -quinazino linone;

(+/-) - 5,6-difluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 5,6-difluoro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 5,6-difluoro-4-isopentyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-fluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+/-) - 6-fluoro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro -2 (1H) -quinazino linone;

(-) - 5,6-difluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(+) - 5,6-difluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone;

(-) - 5,6-difluoro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro -2 (1H) -quinazino linone and (+) - 5,6-difluoro-4-ethylethynyl-4 trifluoromethyl-3,4 - dihydro -2 (1H) -quinazino linone or a pharmaceutically acceptable salt thereof.

In a third embodiment, the invention relates to a new pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I and II or a pharmaceutically acceptable salt thereof.

In a fourth embodiment, the present invention relates to a new method for treating an HIV infection, comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof.

In a fifth embodiment, the present invention relates to a new method of treating an HIV infection, comprising administering, in combination, to a host in need of such treatment, a therapeutically effective amount:

(a) a compound of formula I or II; and (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is selected from ΑΖΤ, 3TC, 6L, bBC, 64T, delavirdine, derivatives of ΉΒΘ, B [-BC-587. nevirapine, L-697 661, LU 73497, BO 18893, loviride, trovirdine, MKS-442 and ΗΒΥ 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, UH-478, nelfinavira, ΚΝΣ-272, СОР-61906, I1 and ABT-378.

In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from ΑΖΤ and 3TC, and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir and indinavir.

And in an even more preferred embodiment, the reverse transcriptase inhibitor is ΑΖΤ.

In a further preferred embodiment, the protease inhibitor is indinavir.

In a sixth embodiment, the invention relates to a pharmaceutical kit for treating an HIV infection, which comprises a therapeutically effective amount of:

(a) compounds of formula I or II; and (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a seventh embodiment, the present invention relates to a new method for inhibiting HIV present in a body fluid sample, comprising treating this body fluid sample with an effective amount of a compound of formula I or II.

In an eighth embodiment, the present invention relates to a new kit or container containing a compound of formula I or II in an amount effective to be used as a standard or reagent in a test or assay to determine the ability of a potential pharmaceutical agent to inhibit HIV reverse transcriptase, HIV growth, or both , and other.

Definitions

The following terms and expressions used in the description have the indicated meanings. It should be understood that the compounds of this invention contain an asymmetrically substituted carbon atom and can be isolated in optically active or racemic forms. It is well known in the art how to obtain optically active forms, for example, by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of the structure are meant unless a specific stereochemistry or isomeric form is specifically indicated.

It is contemplated that the methods of this invention should be practiced at least on a multi-gram, kilogram, multi-kilogram or industrial scale. A multi-gram scale, as used herein, is preferably a scale in which at least one starting material is present in an amount of 10 or more grams, more preferably at least 50 or more grams, even more preferably in an amount at least 100 or more grams. A multi-kilogram scale, as used herein, means a scale in which more than one kilogram of at least one starting material is used. Industrial scale, as used here, means a scale that is different from the laboratory scale and which is sufficient to produce a product sufficient for either clinical trials or for delivery to consumers.

The term “alkyl” as used herein includes both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, npentyl and sec-pentyl. "Haloalkyl" includes saturated aliphatic hydrocarbon groups, both branched and straight chain, having the indicated number of carbon atoms, substituted with one or more halogen atoms (for example, -C _U P „, where ν = 1-3 and ^ = 1 (2ν + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” means an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, sec-11 butoxy, tert-butoxy, n-pentoxy and sec-pentoxy. “Cycloalkyl” includes saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. “Alkenyl” includes straight or branched hydrocarbon chains with one or more unsaturated carbon-carbon bonds, which can be located at any stable point along the chain, such as ethenyl, propenyl, etc. Alkenyl includes straight or branched hydrocarbon chains with one or more triple carbon-carbon bonds that can be located at any stable point along the chain, such as ethynyl, propynyl, etc.

“Halo” or “halogen,” as used herein, refers to fluoro, chloro, bromo, and iodo. The term “counterion” is used to refer to small, negatively charged molecules such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, the term “aryl” or “aromatic residue” refers to the aromatic part of a molecule containing the indicated number of carbon atoms, such as phenyl or naphthyl. As used herein, the term “carbocycle” or “carbocyclic residue” is intended to mean any stable 35 membered monocyclic ring that may be saturated or partially unsaturated. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5-6 membered monocyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic) and which consists of carbon atoms and 1-3 heteroatoms independently selected from the group consisting of Ν, O and 8. Heteroatoms of nitrogen and sulfur may optionally be oxidized. A heterocyclic ring can be attached to its side group at any heteroatom or carbon atom, which leads to a stable structure. The heterocyclic rings described herein may be substituted at the carbon atom or at the nitrogen atom, if the resulting compound is stable. Unless otherwise indicated, the nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of 8 and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of 8 and O atoms in the heterocycle does not exceed 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5-6 membered monocyclic heterocyclic aromatic ring, which consists of carbon atoms and 1-3 heteroatoms independently selected from the group consisting of Ν, O and 8. Preferably, the total number of atoms 8 and O in the aromatic heterocycle does not exceed 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl , isoxazolyl, morpholinyl, oxadiazolyl,

1.2.3-oxaliazolyl, 1,2,4-oxadiazolyl, 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,

1.2.4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,

1.2.5-triazolyl and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the aforementioned heterocycles.

As used herein, the term “HIV reverse transcriptase inhibitor” is intended to mean both nucleoside and non-nucleoside HIV reverse transcriptase inhibitors (RT). Examples of nucleoside RT inhibitors include, but are not limited to, ΑΖΤ, yC, άάΙ, Q4T, and ZTS. Examples of non-nucleoside RT inhibitors include, but are not limited to, delavirdine (Ryagshaa and Ir_) ip 901528), derivatives of ΤΙΒΟ, ΒΙ-ΒΟ-587, nevirapine (Voyeppdeg 1deche1sh), b-697661, LU 73497, Boe 18893 ( Zapkkep), trovirdin (LShu), ISS-442 (Tpapd1e) and ΗΒΥ 097 (Noesyts).

As used herein, an “HIV protease inhibitor” is intended to refer to compounds that inhibit HIV protease. Examples include, but are not limited to, saquinavir (Voske. Bo31-8959), ritonavir (ABL, ΑΒΤ-538), indinavir (Megsk, MK-639), UX-478 (Uyeh / O1akho Ae11sote), nelfinavir (Adoigop, AO -1343), ΚΝΙ-272, Tsarap Epegdu), СОР-61755 (С1Ьа-Ое1§у), I-140690 (Ріагшааа and ЦрзоЬп) and АВТ-378. Additional examples include cyclic protease inhibitors described in AO 93/07128, AO 94/19329, AO 94/22840 and PCT application No. I8 96/03426.

As used herein, the term “pharmaceutically acceptable salts” refers to derivatives of the described compounds when the starting compound is modified to produce salts thereof with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines; salts with alkalis or organic acids of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts formed from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2-acetoxy fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, etc.

The pharmaceutically acceptable salts of this invention can be synthesized from a parent compound that contains a basic or acidic group by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or free base of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent, or a mixture thereof; non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are usually preferred. Lists of suitable salts can be found in Ket1id1oi '8 Ryattaseibs1 8c1SPSS8. 17111 eb., Mask RiY18ytd Sotrapu, Ea81oi, RA, 1985, p. 1418, the description of which is incorporated herein by reference.

The phrase “pharmaceutically acceptable” is used herein to refer to compounds, materials, compositions and / or dosage forms which, from the point of view of medical practice, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit / risk ratio.

"Prodrugs" include any covalently linked carriers that release the active parent drug of formula (I) or other formulas or compounds of this invention ίη νίνο upon administration of such a prodrug to a mammal subject. Prodrugs of a compound of the present invention, for example, of formula (I), obtain a modification of the functional groups present in this compound so that these modifications are cleaved, either by conventional manipulation or ίη νίνο, to the starting compound. Prodrugs include compounds of the invention in which a hydroxy or amino group is bonded to any group that, when a prodrug is administered to a mammalian subject, cleaves to form a free hydroxy group or free amino group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of functional alcohol groups or amino groups in the compounds of this invention, etc.

The terms “stable compound” and “stable structure” are used for a compound that is sufficiently stable to isolate to an acceptable degree of purity from the reaction mixture and to prepare it as an effective therapeutic agent. Only stable compounds are contemplated by this invention.

The term “substituted” is used to indicate that one or more hydrogens of the atom indicated in the expression using the term “substituted” are replaced by a group selected from these groups, provided that the normal valency of the specified atom is not exceeded and that this substitution leads to stable connection. When the substituent is a keto group (i.e., = 0), 2 hydrogens of this atom are replaced.

The term “therapeutically effective amount” is intended to mean an amount of a compound of the present invention or an amount of a combination of compounds claimed to be effective in inhibiting HIV infection or in treating symptoms of HIV infection in a host. This combination of compounds is preferably a synergistic combination. Synergism, as described, for example, S1oi aib Ta1a1au, Α6ν. Eihute Reshchb. 22: 27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of these compounds when administered separately as single agents. As a rule, the synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergism can be expressed in lower cytotoxicity, increased antiviral effect, or in some other beneficial combination effect compared to the effect of individual components.

Synthesis

The compounds of this invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. The compounds of this invention can be synthesized using the methods described below, together with synthetic methods known in the field of synthetic organic chemistry, or variations thereof, as is understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. Each of the links below is included as a reference.

Scheme 1

TMZS1

K1MdH ’''’

Scheme 1 illustrates a process for preparing ketoanilines from suitably substituted 2-aminobenzoic acid. This acid is converted to its X-methoxy-X-methieamide derivative, which can then be substituted to give a K ¹ -substituted ketone. Ketoanilines are acceptable intermediates for the compounds claimed herein.

Scheme 2

Scheme 2 describes another method for preparing ketoanilines, this time from suitably substituted aniline. After iodination and protection of the amino group, a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Removal of the protective group gives ketoaniline. Additional methods for producing ketoanilines are known to those skilled in the art, for example, NoirN e! A1, Tey. Bay. 1994, 35 (37), 6811-6814, which is incorporated herein by reference.

Scheme 3 ^К ^ ^сoon НССНзЮСНз _r (ОСН _Э ) СНз

TxBr, ΡΙΡΕ * ^E 1 ^ ^{С0Н10СН3)} ^ ethanosis _In e ^K > ^ ^СНО СН ₂ С1 ₂ \ ^ М (Н) Tg ^ Άϊ (Η) Τγ З ^ 3 К ^{3 0}

CPS-agilis, creature »| HuHn, ^E ^ y" ®Rz ^THP ^ = N (H) Tr ^^ N (H) TG

Another method for the preparation of 2-trifluoroacetylanilines is shown in Scheme 3. After the formation of the protected aniline, the amide is reduced and the trifluoromethyl group is attached. Oxidation with an oxidizing agent such as

MnO ₂ provides an acceptable intermediate.

Scheme 4

a. N-VIb1 / NSSK ⁴ / TNG

b. BP ₃ 2nd ₂

Using the General method, presented in detail in scheme 4, it is possible to obtain the compounds of this invention. Ketoaniline 1, which can be obtained by the methods described in schemes 1 and 2, is treated with trimethylsilyl isocyanate in dry tetrahydrofuran in the presence of dimethylaminopyridine and then tetrabutylammonium fluoride to give hydroxyurea 2. Then, hydroxyurea 2 is dehydrated with a dehydrating agent such as 4 with molecular sieve refrigerator with toluene or xylenes to obtain ketimine 3. The substituted acetylene group K ^{2 is} added by treating ketimine 3 with lithium acetylenide, which is obtained separately vessel by reaction of the corresponding substituted acetylene with nbutyl lithium in dry tetrahydrofuran to obtain 4,4-disubstituted 3,4-dihydro-2 (1H) quinazolinone 4, a compound of formula I. The acetylene (triple) bond of compound 4 can be reduced, for example, by catalytic hydrogenation , to obtain the corresponding alkenyl group (not shown) or saturated compound 5.

Other K ² groups can also be introduced directly by the reaction of imine 3 with a K L1 lithium or Grignard K MdX reagent in the presence or absence of a Lewis acid as a catalyst, such as a HB ₃ ether. See also Iyshap e! A1, 1. Ogd. Siesh. 1995, 60, 1590-1594, the contents of which are incorporated herein by reference.

In some cases, one enantiomer of a compound of formula I or II may exhibit a predominant activity compared to another. If necessary, separation of the racemic material can be achieved by HPLC using a chiral column, as described in examples 27-34 (Scheme 4), or by separation using a resolving agent, such as camphonic acid chloride, as described in Tyosaz 1. Tiskeg, e! A1, G Meb. Siesh. 1994, 37, 2437-2444. The chiral compound of formula I can also be directly synthesized using a chiral catalyst or a chiral ligand, for example, as described in Magck A. Nee £ tap, e! A1, I. Ogd. Sows. 1995, 60, 1590-1594.

Other features of the invention will become apparent from the following description of specific examples, which are given to illustrate the invention, but are not intended to limit its scope.

Examples

The abbreviations used in the examples are deciphered as follows: “° C” degrees Celsius, “d” doublet, “dd” doublet of doublets, “eq” - equivalent or equivalents, “g” - gram or grams, “mg” - milligrams or milligrams, “ml” is a milliliter or milliliters, “N” is hydrogen or hydrogens, “h” is an hour or hours, “m” is a multiplet, “M” is a molar, “min” is a minute or minutes, “MHz "- megahertz," MB "mass spectroscopy," NMR "or" NMR "-NMR spectroscopy," t "- triplet," TLC "- thin layer chromatography," BOAS "- hydrochloride 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimi and, «ΌΙΡΕΑ» - diisopropylethylamine, "TBAE" tetrabutylammonium fluoride "BAN" - lithium aluminum hydride and "TEA" - triethylamine.

Example 1. Obtaining (+/-) - 6-chloro-4-cyclopropylethinyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (K ⁴ = cyclopropyl)

1-a-a-K ⁴

HI-a ΐν-a

Stage 1. Synthesis of ΙΙ-a from 1-a.

To a solution of compound Ι-a (4.55 g, 20.2 mmol) in anhydrous THF (40 ml) was added dimethylaminopyridine (0.25 g, 2.02 mmol) and trimethylsilyl isocyanate (6.05 g, 7.11 ml, 52.5 mmol). The mixture was stirred at room temperature for approximately 16 hours, then tetrabutylammonium fluoride (21 ml of a 1M solution in THF) was added. The thick suspension was diluted with additional THF (20 ml) and stirred at room temperature for 0.5 h. THF was removed under reduced pressure, the residue was taken up in E! OAc (100 ml) and washed sequentially with 1N. HCl (70 ml), a saturated aqueous solution of HaCO ₃ (70 ml) and saturated aqueous \ aCl (50 ml). The organic phase was dried over MDBO ₄ , filtered and concentrated under reduced pressure to give a light yellow solid. The yellow color was removed by trituration with hexane to give ΙΙ-a (5.09 g, 94%) as a white solid.

^! H-NMR (300 MHz, acetone-b ₆ ) δ 9.06 (br, 1H), 7.48 (s, 1H), 7.40 (br, 1H), 7.34 (dd, 1 = 8, 8,

2.6 Hz, 1H); 6.97 (d, 1 = 8.8 Hz, 1H); ¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ - 86.33, -86.35; IR (KBg granule) 1724, 1678, 1398, 1198, 1174 cm ^-1 ; MB (C1) t / e 266 (MH ⁺ , 100).

Stage 2. Synthesis of ΙΙΙ-a from 11-a.

A suspension of 11-a (5.09 g, 19.1 mmol) in toluene (150 ml) containing 4 A molecular sieves (approximately 100 mg) was refluxed for 16 hours. The resulting clear yellow solution was cooled to room temperature , precipitated solids were dissolved in acetone and molecular sieves were removed by filtration in vacuo. The filtrate was concentrated under reduced pressure and triturated with hexanes to give Sh-a (4.25 g, 89%) as a yellow solid.

'H-NMR (300 MHz, acetone-T) δ 7.86-7.82 (m, 2H), 7.61 (d, 1 = 8.8 Hz, 1H); ¹⁹ G-NMR (282 MHz, acetone-ώ,) δ -67.88.

Stage 3. Synthesis of 1U-a from Sh-a.

A solution of cyclopropylacetylene (13.0 ml of a 30 wt.% Solution in toluene / THF / hexanes, 59.0 mmol) in anhydrous THF (118 ml) was cooled to -78 ° C, treated with n-ViP (32.8 ml 1, A 6 M solution in hexanes, 52.4 mmol) was heated to 0 ° C in an ice bath and kept for 0.5 h. To a solution of Sh-a (3.12 g, 12.6 mmol) in anhydrous THF ( 66 ml) at -70 ° C lithium acetylenide was added over approximately 10 minutes. Then boron trifluoride etherate (0.89 g, 0.80 ml, 6.28 mmol) was added, followed by removal of the cooling bath. The reaction was allowed to reach room temperature and was stirred at room temperature for 4 hours before quenching with 1M citric acid (100 ml). The mixture was concentrated under reduced pressure to 1/2 of the original volume, diluted with E! OAc (200 ml), the aqueous phase was removed and the organic phase was washed successively with saturated aqueous HaHCO ₃ solution (100 ml) and saturated aqueous \ aCl (100 ml). The organic phase was dried over MDBO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (3% MeOH / CH2C12) to give a thick yellow oil, from which crystalline 1U-a (K ⁴ = cyclopropyl) (3.85 g, 97%) was obtained as a white solid. Mp 86.6-88 ° C.

^! H-NMR (300 MHz, acetone-b ₆ ) δ 8.95 (br, 1H), 7.51 (br, 1H), 7.43 (br, 1H), 7.40 (dd, I = 8, 8, 2.4 Hz, 1H), 7.02 (d, 1 = 8.8 Hz, 1H), 1.49-1.41 (m, 1H), 0.93-0.82 (m, 1H ), 0.77-0.74 (m, 1H);

¹⁹ G-NMR (282 MHz, acetone-06) δ -82.96; IR (KBg granule) 1696, 1172 cm ^-1 ;

MB (C1) t / e calculated for

C ₁ 4NuC1p3X2O: 315.051201, found 315.051626;

315 (MH ⁺ , 51), 332 (M + XH4 ⁺ , 100);

Elemental analysis: calculated for

C ₁₄ H ₁₀ X ₂ C1E ₃ O-0.25 H ₂ O: C 52.68; H 3.32; N, 8.78;

Found: C, 52.61; H 3.35; N, 8.28.

Example 2. Obtaining (+/-) - 6-chloro-4-isopropylethinyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = isopropyl).

ΙΙΙ-a solution (50 mg, 0.21 mmol) was treated with lithium acetylenide obtained from 3 methyl-1-butyne (62 mg, 93 ml, 0.905 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by flash chromatography ( 35% EJAe / hexanes) to give 26 mg (41%) of the desired product.

¹ H-NMR (300 MHz, acetone ^) δ 9.08 (br, 1H), 7.59 (br, 1H), 7.53 (br, 1H), 7.40 (dd, 1 = 8, 4, 2.2 Hz, 1H), 7.02 (d, 1 = 8.8 Hz, 1H), 2.81-2.68 (m, 1H), 1.20 (dd, 1 = 6.6 Hz, 6H);

¹⁹ G-NMR (282 MHz, acetone-6) δ -83.05;

M8 (C1) t / e calculated for C ^ H ^ C ^^ O: 317.066851, found 317.069433; 317 (MH ⁺ , 43), 334 (M + ΝΉΛ 100).

Example 3. Obtaining (+/-) - 6-chloro-4- (2pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = 2-pyridyl).

A solution of 111-a (100 mg, 0.402 mmol) was treated with lithium acetylenide obtained from 2 ethynyl pyridine (0.19 g, 1.81 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH ₂ Cl ₂ ) to obtain 85 mg (60%) of the desired product. T. pl. 105 ° C, decomp.

'H-NMR (300 MHz, acetone-b ₆ ) δ 9.14 (br, 1H), 8.64-8.61 (m, 1H), 7.89-7.84 (m, 2H), 7.077 66 (m, 2H), 7.48-7.43 (m, 2H), 7.09 (d, 1 = 8.8 Hz, 1H);

¹⁹ P-NMR (282 MHz, acetone-f) δ -82.48;

IR (KBg granule) 1704, 1430, 1186 cm ^-1 ; M8 (C1) t / e calculated C ₁₆ H ₁₀ C1G ₃ X ₃ O: 352.046450, found 352.046956; 352 (MH ⁺ , 100);

Elemental analysis: calculated for C16H9C1r3X3O-0.125 H ₂ O: C, 54.3; H, 2.56; Ν, 11.9; Found: C, 54.71; H, 3.03, Ν, 11.3.

Example 4. Obtaining (+/-) - 6-chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = ethyl).

A solution of 111-a (100 mg, 0.402 mmol) was treated with lithium acetylenide obtained from 1 butyn (109 mg, 2.01 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH2C12) to obtain 79 mg (65%) of the desired product.

¹ H-NMR (300 MHz, acetone-6) δ 9.05 (br, 1H), 7.54 (br, 2H), 7.41-7.39 (m, 1H), 7.02 (d, 1 = 8.4 Hz, 1H), 2.36-2.32 (m, 2H), 2.18-1.13 (m, 3H);

¹⁹ G-NMR (282 MHz, acetone ₆ ) δ -82.99;

M8 (C1) t / e calculated for С13НюС1Г3 ^ О: 303.051201, found 303.051882; 303 (MH ⁺ , 55), 320 (M -411.) / 100).

Example 5. Obtaining (+/-) - 6-chloro-4-phenylethinyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = phenyl).

ΙΙΙ-a solution (100 mg, 0.402 mmol) was treated with lithium acetylenide obtained from phenylacetylene (185 mg, 1.8 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH ₂ Cl ₂ ) to obtain 54 mg (38%) of the target product.

¹ H-NMR (300 MHz, acetone ₆ ) δ 9.07 (br, 1H), 7.74 (br, 1H), 7.67 (br, 1H), 7.62-7.58 (m , 2H), 7.48-7.40 (m, 4H), 7.08 (d, 1 = 8.4 Hz, 1H);

¹⁹ G-NMR (282 MHz, acetone ₆ ) δ -82.67; IR (KBg granule) 1696, 1186 cm ^-1 ;

M8 (C1) t / e calculated for С1 ₇ Н11С1Г3 ^ О: 351.051201, found 351.051704; 351 (MH ⁺ , 51), 368 (M + Ν ^ ζ 100);

Elemental analysis: calculated for С1 ₇ Н10№С1Г3 ^ О-0.25 Н ₇ О: С, 57.48; H, 2.98; Ν, 7.89; Found: C, 57.00; H, 3.03; Ν, 7.48.

Example 6. Preparation of (+/-) - 4-cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (K ⁴ = cyclopropyl)

Stage 1. Synthesis of νΐ-a from ν-a.

Solution U-a (0.50 g, 2.28 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described for step 1 of Example 1 to obtain 0.58 g (97%) of the expected product;

'H-NMR (300 MHz, acetone-f) δ 8.81 (br, 1H), 7.17 (br, 1H), 7.11 (br, 1H), 7.00-6.92 (m , 2H); 6.83 (s, 1H); 3.76 (s, 3H);

¹⁹ P-NMR (282 MHz, acetone- ^) δ -85.99.

Stage 2. Synthesis of νΐΐ-a from U1-a.

A solution of U1-a (0.58 g, 2.21 mmol) was boiled in toluene under reflux as described for stage 2 of example 1, to obtain 0.50 g (93%) of the desired product:

'H-NMR (300 MHz, acetone ^) δ 7.52 (br, 2H), 7.27 (s, 1H), 3.90 (s, 3H);

¹⁹ P-NMR (282 MHz, acetone- ^) δ -68.08.

Stage 3. Synthesis of νΐΙΙ-a from νΐΐ-a.

The νΐΐ-a solution (100 mg, 0.410 mmol) was treated with lithium acetylenide obtained from cyclopropylacetylene (0.41 ml of a 30 wt.% Solution in a mixture of toluene / THF / hexanes, 1.85 mmol) in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH2C12) to give 103 mg (81%) of the expected product.

¹ H-NMR (300 MHz, acetone-6) δ 8.77 (bs,

1H), 7.29 (br, 1H), 7.06 (br, 1H), 6.99-6.90 (m,

2H), 3.77 (s, 3H), 1.46-1.38 (m, 1H), 0.91-0.85 (m,

2H), 0.79-0.72 (m, 2H);

¹⁹ P-NMR (282 MHz, acetone-6 ₆ ) δ -82.61;

M8 (C1) t / e calculated for С ₁₅ Н ₁₄ Г ₃ X ₂ О ₂ : 311,100738, found 311,099970; 311 (MH ⁺ , 100).

Example 7. Obtaining (+/-) - 4-isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = isopropyl).

The νΐΐ-a solution (100 mg, 0.410 mmol) was treated with lithium acetylenide obtained from 3-methyl-1-butyne (126 mg, 0.19 ml, 1.85 mmol) in accordance with the procedure of step 3 of Example 1. The obtained crude material purified by flash chromatography (2.5% MeOH / CH ₂ Cl ₂ ) to give 30 mg (24%) of the desired product: mp 228-229 ° C;

^! H-NMR (300 MHz, acetone-6 ₆ ) δ 8.72 (br, 1H), 7.27 (br, 1H), 7.10 (br, 1H), 7.00-6.91 (m, 2H), 3.77 (s, 3H), 2.73-2.67 (m, 1H), 1.20 (dd, 1 = 7.0, 1.5 Hz, 6H);

¹⁹ P-NMR (282 MHz, acetone-b6) δ -82.71;

IR (KBg granule) 1696, 1428, 1190, 1176 _cm ^-1 _;

M8 (C1) t / e calculated for ^ ₅ Ηι ₆ Γ ₃ Ν ₂ Θ ₂ : 313.116388, found 313.115871; 313 (MH ⁺ , 100), 330 (Μ + ΝΗ4 ⁺ , 15);

Elemental analysis: calculated for ^ ₅ Η _ί5 Γ ₃ Ν ₂ Θ ₂ : C 57.69; H 4.84; N, 8.97; Found: C, 57.74; H 5.01; N, 8.57.

Example 8. Obtaining (+/-) - 6-methoxy-4- (2pyridyl) ethynyl-4-trifluoromethyl-3, 4-dihydro2 (1H) -quinazolinone (K ⁴ = 2-pyridyl).

The νΐΐ-a solution (100 mg, 0.410 mmol) was treated with lithium acetylenide obtained from 2-ethynylpyridine (0.19 g, 1.85 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by flash chromatography (2 , 5% Meon / CH ₂ Cl ₂ ) to obtain 56 mg (39%) of the target product:

^! H-NMR (300 MHz, acetone-6 ₆ ) δ 8.81 (br, 1H), 8.61 (d, 1 = 4.8 Hz, 1H), 7.88-7.82 (m, 1H) 7.66 (d, 1 = 7.7 Hz, 1H), 7.61 (br, 1H), 7.46-7.42 (m, 1H), 7.23 (br, 1H), 7, 06-6.97 (m, 2H); 3.79 (s, 3H);

¹⁹ G-NMR (282 MHz, acetone ^) δ -82.13;

IR (KBg granule) 1698, 1518, 1464, 1430, 1244, 1208, 1184 cm ^-1 ;

M8 (C1) t / e calculated for ^ ₇ Η ₁₃ Γ ₃ Ν ₃ Ο ₂ : 348.095987, found 348.095629; 348 (MH ⁺ , 100);

Elemental analysis: calculated for C1 ₇ H ₁₂ G ₃ ^ O ₂ -0.25 C ₃ H ₆ O: 58.92; H 3.76; N, 11.61; Found: C, 59.38; H 4.04; N, 11.35.

Example 9. Obtaining (+/-) - 6-methoxy-4 phenylethynyl-4-trifluoromethyl-3, 4-dihydro2 (1H) -quinazolinone (K ⁴ = phenyl).

The νΐΐ-a solution (100 mg, 0.410 mmol) was treated with lithium acetylenide obtained from phenylacetylene (0.19 g, 1.85 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by flash chromatography (2.5% HeΟΗ / СΗ ₂ С1 ₂ ) with the receipt of 34 mg (24%) of the target product. T. pl. 206.2-207.7 ° C.

^! H-NMR (300 MHz, acetone-6 ₆ ) δ 8.85 (br, 1H), 7.60-7.57 (m, 3H), 7.49-7.39 (m, 3H), 7, 21 (br, 1H), 7.05-6.96 (m, 2H), 3.79 (s, 3H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ -82.32; IR (KBg granule) 1696, 1516, 1430, 1236, 1204, 1184, 1128 cm ^-1 ;

M8 (C1) t / e calculated for С ^ and Г ^ О ^ 347,100738, found 347,101482; 347 (MH ⁺ , 100), 364 (Μ ⁺ + NΗ4 ⁺ , 48);

Elemental analysis: calculated for ^ Η ^ Γ ^ Ο ^ C, 62.43; H, 3.78; N, 8.10; Found: C, 62.35; H, 3.58; N, 7.83.

Example 10. Obtaining (+/-) - 4-cyclopropylethinyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (K ⁴ = cyclopropyl).

Stage 1. Synthesis of Xa from I Xa.

A solution of 1X-a (6.46 g, 28.7 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described for step 1 of Example 1 to obtain 6.74 g (88%) of the expected product.

^! H-NMR (300 MHz, acetone-6 ₆ ) δ 9.13 (br, 1H), 7.45-7.32 (m, 2H), 7.18 (br, 1H), 6.85-6, 80 (m, 1H);

¹⁹ P-NMR (282 MHz, acetone ^) δ -86.6 (d, 17.2, 3), -137.52-137.68 (m, 1), -148.47-148.59 (m , one).

Stage 2. Synthesis of Χΐa from Xa.

Solution X-a (6.74 g, 25.1 mmol) was refluxed in xylenes as described for step 2 of Example 1, replacing toluene with xylenes, to give 6.3 g (100%) of the expected product.

Ή-NMR (300 MHz, acetone ^) δ 7.92-7.83 (m, 1H), 7.46-7.44 (m, 1H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ -70.7 (d, 38.7, 3), -136.72 (s, 1), -146.47-146.57 (m, 1 )

Stage 3. Synthesis of Χΐΐ-a from Χΐ-a.

Χΐ-a solution (6.28 g, 25.1 mmol) was treated with lithium acetylenide obtained from cyclopropylacetylene (24.9 ml of a 30 wt.% Solution in a mixture of toluene / THF / hexanes, 0.113 mol), in accordance with the procedure of stage 3 Example 1. The resulting crude yellow oil was dissolved in acetone and concentrated under reduced pressure to give a yellow solid. Crystallization from acetone gave 5.98 g (75%) of the target substance. T. pl. 86.588.5 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.01 (br, 1H), 7.46 (br, 1H), 7.44-7.35 (m, 1H), 6.86-6 81 (m, 1H), 1.41-1.37 (m, 1H), 0.90-0.83 (m, 1H), 0.740.69 (m, 1H);

¹⁹ G-NMR (282 MHz, acetone-be) δ -83.3 (d, 1 = 12.9, 1), -136.04-136.23 (m, 1), -148.14-148, 26 (m, 1);

IR (KBg granule) 1706, 1516, 1442, 1246, 1214, 1196 cm ^-1 ;

M8 (C1) t / e calculated for ί '|. · | Η | ₀ Ε ₅ Ν ₂ Θ: 317.071329, found 317.070836; 317 (MH ⁺ , 100), 334 (Μ + ΝΗ ₄ ⁺ , 62);

Elemental analysis: calculated for SmNE ^ O: C 53.17; H 2.88; N, 8.87; Found: C, 53.30; H 3.16; N, 8.53.

Example 11. Obtaining (+/-) - 5,6-difluoro-4isopropylethinyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = isopropyl).

Solution X1-a (7.24 g, 28.9 mmol) was treated with lithium acetylenide obtained from 3methyl-1-butyne (8.87 g, 13.3 ml, 0.130 mol), in accordance with the procedure of stage 3 of example 1. The resulting crude material was purified by flash chromatography (2.5% MeOH / CH ₂ Cl ₂ ) to give a yellow oil. Crystallization from acetone gave 6.77 g (74%) of the desired product. T. pl. 79-80 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.02 (br, 1H), 7.50 (br, 1H), 7.44-7.35 (m, 1H), 6.87-6 82 (m, 1H), 2.69-2.65 (m, 1H), 1.17 (d, 1 = 7.0 Hz, 6H);

¹⁹ G-NMR (282 MHz, acetone-be) δ -83.4 (d, 1 = 12.9, 1), -135.79-135.94 (m, 1), -148.14-148, 26 (m, 1);

M8 (C1) t / e calculated for ^ ₄ Ηι ₂ Γ ₅ Ν ₂ Ο: 319.086979, found 319.087376; 319 (MH ⁺ , 100), 336 (M + ΝΗ ₄ ⁺ , 76).

Example 12. Obtaining (+/-) - 5,6-difluoro-4 (2-pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (K ⁴ = 2-pyridyl).

X1-a solution (100 mg, 0.40 mmol) was treated with lithium acetylenide obtained from 2 ethynyl pyridine (0.19 g, 1.80 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by flash chromatography (4% MeOH / CH ₂ Cl ₂ ) to obtain 83 mg (59%) of the desired product. T. pl. 219220 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.15 (br, 1H), 8.61 (d, 1 = 4.4 Hz, 1H), 7.88-7.82 (m, 2H ), 7.63 (dd, 1 = 7.0, 1.1 Hz, 1H), 7.47-7.42 (m, 2H), 6.94-6.88 (m, 1H);

¹⁹ G-NMR (282 MHz, acetone-be) δ -82.8 (d, 1 = 12.9, 3), -135.78-135.93 (m, 1), -147.86-147, 98 (m, 1);

IR (KBg granule) 1720, 1470, 1450, 1430, 1416, 1264, 1238, 1226, 1198, 1186 cm ^-1 ;

M8 (C1) t / e calculated for C1 ₆ H ₉ P ₅ No. 0: 354.066578, found 354.067821; 354 (MH ⁺ , 100).

Example 13. Obtaining (+/-) - 5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = 2-ethyl).

Solution X1-a (100 mg, 0.400 mmol) was treated with lithium acetylenide obtained from 1 butyne (97 mg, 1.80 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH ₂ C1 ₂ ) to obtain 69 mg (57%) of the target product. T. pl. 191-194 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.03 (br, 1H), 7.50 (br, 1H), 7.45-7.35 (m, 1H), 6.87-6 82 (m, 1H); 2.34-2.27 (m, 2H); 1, 20-1.15 (m, 3H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ -83.3 (d, 1 = 12.9 3), -135.79-135.98 (m, 1), -148.16-148, 29 (m, 1);

IR (KBg granule) 1704, 1686, 1518, 1444, 1244, 1210, 1192, 1172 cm ^-1 ;

M8 (C1) t / e calculated for C1 ₃ H1 ₀ E ₅ No. 0: 305.071329, found 305.071146; 305 (MH ⁺ , 100);

Elemental analysis: calculated for SnNRb ^ O: C, 51.33; H, 2.98; Ν, 9.22; Found: C, 51.00; H, 2.79; Ν, 8.99.

Example 14. Obtaining (+/-) - 5,6-difluoro-4-phenylethinyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = phenyl).

Solution X1-a (100 mg, 0.400 mmol) was treated with lithium acetylenide obtained from phenylacetylene (0.18 g, 0.20 ml, 1.80 mmol), in accordance with the procedure of stage 3 of example 1. The resulting crude material was purified by HPLC ( 2.5% MeOH / CH ₂ Cl ₂ ) to give 92 mg (65%) of the desired product.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.14 (br, 1H), 7.80 (br, 1H), 7.57-7.54 (m, 2H), 7.49-7 40 (m, 4H); 6.92-6.87 (m, 1H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ -83.0 (d, 1 = 12.9, 3), -136.08-136.27 (m, 1), -147.87-148 , 00 (m, 1);

M8 (C1) t / e calculated for С1 ₇ Н ₁₀ Р ₅ ^ О: 353.071329, found 353.071716; 353 (MH ⁺ , 42), 370 ^ Ν ^ ζ 100).

Example 15. Obtaining (+/-) - 5,6-difluoro-4isopentyl-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = isopropyl).

Synthesis of ΧΙΙΙ-a from X11-a.

A solution of ΧΙΙΙ-a (K ⁴ = isopropyl) (26 mg, 82 mmol) in ethanol (1 ml) and UES (0.5 ml) was treated with 10% Pb on carbon (35 mg) under H ₂ (1 amt) for 16 hours. The catalyst was removed by vacuum filtration through celite and the filter cake was washed with E1OLC. The combined filtrates were concentrated under reduced pressure to obtain 26 mg (100%) of the expected product. Additional cleaning was not required.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 8.88 (bs,

1H), 7.41-7.31 (m, 1H), 6.89-6.81 (m, 2H), 2.552.50 (m, 1H), 1.64-1.45 (m, 2H) 1.06-1.02 (m, 1H),

0.89 (dd, 1 = 6.6, 2.2 Hz, 6H);

¹⁹ P-NMR (282 MHz, acetone-06) δ -83.22 (d, I = 12.1, 3), -138.97-139.13 (m, 1), -148.46-148, 58 (s, 1);

IR (KBg granule) 1700, 1678, 1518, 1438, 1252, 1188, 1172 cm ^-1 ;

M8 (O) t / e calculated for C ₁₄ H ₁₆ P ₅ ^ O: 323.118280, found 323.116703; 323 (MH ⁺ , 100), 340 (Μ + ΝΗ4 ⁺ , 57).

Example 16. Obtaining (+/-) - 4-butyl-5,6difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (B ⁴ = ethyl).

A solution of XIII-a (K ⁴ = ethyl) (200 mg, 66 mmol) in ethanol (1 ml) and ЕУАс (0.5 ml) was treated with 10% Pb on carbon in an atmosphere of Н ₂ in accordance with the procedure of Example 15. Purification of HPLC (2.5% MeOH / CH2C12) gave 12 mg (56%) of the desired product.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 8.89 (br, 1H), 7.41-7.32 (m, 1H), 6.86-6.81 (m, 2H), 2.572 47 (m, 1H), 1.56-1.15 (m, 5H), 0.88 (t, 1 = 7.3 Hz, 3H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ-83.19-83.24 (m, 1), -139.14 (s, 1), -148.49-148.62 (m, 1) ;

M8 (SC t / e calculated for ^ ₃ Η _ί4 Ρ ₅ Ν ₂ Ο: 309.102629, found 309.103555; 309 (MH ⁺ , 100), 326 (Μ + ΝΗ4 ⁺ , 62).

Example 17. Obtaining (+/-) - 4-cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (K ⁴ = cyclopropyl)

Stage 1. Synthesis of XU-a from X ^ -a.

A solution of XIII-a (3.07 g, 14.8 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described for step 1 of Example 1 to obtain 2.81 g (76%) of the expected product.

Stage 2. Synthesis of XUE from XU-a.

A solution of XU-a (6.74 g, 25.1 mmol) was boiled in toluene under reflux, as described for stage 2 of example 1, to obtain 0.73 g (94%) of the target product.

Stage 3. Synthesis of HUP from HUEa.

The XUE solution (100 mg, 0.431 mmol) was treated with lithium acetylenide obtained from cyclopropylacetylene (1.43 ml of a 30 wt.% Solution in a toluene / THF / hexanes mixture, 1.94 mmol) in accordance with the procedure of Step 3 of Example 1. The crude obtained the material was cleaned

HPLC (2.5% MeOH / CH ₂ Cl ₂ ) to give 44 mg (34%) of the desired product. T. pl. 155 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 8.86 (br, 1H), 7.36 (br, 1H), 7.30-7.27 (m, 1H), 7.22-7 15 (m, 1H), 7.04-6.99 (m, 1H), 1.47-1.42 (m, 1H), 0.900.87 (m, 2H), 0.76-0.75 (m, 2H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ -82.86, -123.36-123.44;

M8 (SC t / e calculated for С1 ₄ НЦР ^ ₂ О: 299.080751, found 299.079976; 299 (МН ⁺ , 100).

Example 18. Obtaining (+/-) - 6-fluoro-4isopropylethynyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = isopropyl).

The XUE solution (100 mg, 0.431 mmol) was treated with lithium acetylenide obtained from 3-methyl-1-butyne (0.13 g, 0.20 ml, 1.94 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude the material was purified by HPLC (2.5% MeOH / CH2C12) to give 24 mg (18%) of the desired product. T. pl. 1 58 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.07 (br, 1H), 7.60 (br, 1H), 7.32-7.30 (m, 1H), 7.24-7 , 16 (m, 1H), 7.05-6.99 (m, 1H), 2.77-2.67 (m, 1H), 1.20 (dd, 1 = 7.0, 2.6 Hz) , 6 N);

¹⁹ P-NMR (282 MHz, acetone-06) δ -82.95, -123.41-123.49;

M8 (301) t / e calculated for С1 ₄ Н ₁₃ Рф№ ₂ О: 301.096401, found 301.096235; 301 (MH ⁺ , 100).

Example 19. Obtaining (+/-) - 6-fluoro-4- (2pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = 2-pyridyl).

The XUE solution (100 mg, 0.431 mmol) was treated with lithium acetylenide obtained from 2-ethynylpyridine (0.20 g, 1.94 mmol), in accordance with the procedure of Step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH2C12) to give 65 mg (45%) of the desired product. T. pl. 155 ° C.

¹ H-NMR (300 MHz, acetone-b ₆ ) δ 9.02 (br, 1H), 8.60 (d, 1 = 4.0 Hz, 1H), 7.87-7.78 (m, 2H ), 7.66 (d, 1 = 7.7 Hz, 1H), 7.45-7.41 (m, 2H), 7.267.20 (m, 1H), 7.09-7.05 (m, 1H);

¹⁹ P-NMR (282 MHz, acetone-b ₆ ) δ -82.36, -122.94-123.02;

M8 (SC t / e calculated for С1 ₆ Н ₁₀ Рф№ ₃ О: 336.076000, found 336.074156; 336 (МН ⁺ , 25).

Example 20. Obtaining (+/-) - 6-fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = ethyl).

The XUE solution (100 mg, 0.431 mmol) was treated with lithium acetylenide obtained from 1-butine (0.10 g, 1.94 mmol) in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC (2.5% MeOH / CH2C12) to give 40 mg (33%) of the desired product. T. pl. 190 ° C.

¹ H-NMR (300 MHz, acetone-06) δ 8.86 (bs,

1H), 7.38 (br, 1H), 7.34-7.31 (m, 1H), 7.22-7.16 (m, 1H), 7.05-7.00 (m, 1H) 2.04-2.01 (m, 2H); 1.191.14 (m, 3H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -75.392, -123.42-123.50;

M8 (C1) t / e calculated for C1 ₃ НЦЕ ₄ Н ₂ О: 287.080751, found 287.080740; 287 (MH ⁺ , 100).

Example 21. Obtaining (+/-) - 6-fluoro-4-fluorophenylethynyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = phenyl).

The Χνΐ-a solution (100 mg, 0.431 mmol) was treated with lithium acetylenide obtained from phenylacetylene (0.20 g, 0.21 ml, 1.94 mmol), in accordance with the procedure of step 3 of Example 1. The resulting crude material was purified by HPLC ( 2.5% MeOH / CH ₂ Cl ₂ ) to obtain 41 mg (28%) of the target product. T. pl. 107 ° C.

Я-NMR (300 MHz, acetone-b ₆ ) δ 9.00 (br, 1H), 7.69 (br, 1H), 7.63-7.59 (m, 2H), 7.50-7, 40 (m, 4H), 7.27-7.20 (m, 1H), 7.10-7.05 (m, 1H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -82.56, -122.99-123.07;

M8 (C1) t / e calculated for С1 ₇ НЦЕ ₄ Н ₂ О: 335.080751, found 335.082057; 335 (MH ⁺ , 74), 352 (MH + IN ₄ ⁺ , 100).

Example 22. Obtaining (+/-) - 6-fluoro-4isopentyl-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = isopropyl).

Synthesis of ΧνΐΙΙ-a from ΧνΐΙ-a.

A solution of ΧνΐΙ-a (K ⁴ = isopropyl) (26 mg, 87 mmol) in ethanol (1 ml) and ЕУНс (0.5 ml) was treated with 10% P6 on charcoal in an atmosphere of Н ₂ in accordance with the procedure of Example 15 to obtain 15 mg (58%) of the desired product. Additional cleaning was not required.

Mp 179 ° C.

Я-NMR (300 MHz, acetone-b ₆ ) δ 7.02-6.97 (m, 2H), 6.60-6.76 (m, 1H), 2.18-2.09 (m, 2H ), 1.921.82 (m, 2H), 1.52-1.45 (m, 1H), 0.88-0.79 (m, 6H);

¹⁹ E-NMR (282 MHz, acetone-bb) δ -82.60, -123.72-123.84;

M8 (C1) t / e calculated for C1 ₄ H ₁₇ E ₄ N ₂ O: 305.127707, found 305.126790; 305 (MH ⁺ , 100).

Example 23. Obtaining (+/-) - 6-fluoro-4- (2'-2pyridyl) ethyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = 2-pyridyl).

A solution of ΧνΐΙ-a (K ⁴ = 2-pyridyl) (33 mg, 99 mmol) in ethanol (1 ml) and ЕУАс (0.5 ml) was treated with 10% P6 on charcoal in an Н ₂ atmosphere in accordance with the procedure of Example 15 s obtaining 10 mg (30%) of the target product. Additional cleaning was not required. T. pl. 88 ° C.

Я-NMR (300 MHz, acetone-b ₆ ) δ 8.35 (d, I = 4.4 Hz, 1H), 7.63 (dt, I = 7.7, 1.5 Hz, 1H), 7.207 13 (m, 3H), 7.04-6.98 (m, 1H), 6.83-6.79 (m, 1H), 2.84-2.78 (m, 1H), 2.68 -2.48 (m, 2H); 2.27-2.06 (m, 1H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -82.58, -123.26-123.34;

M8 (MF) t / e calculated for C1 ₆ H1 ₄ E ₄ X ₃ O: 340.107300, found 340.107719; 340 (MH ⁺ , 100).

Example 24. Obtaining (+/-) - 4-butyl-6fluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = ethyl).

A solution of ΧνΙΙ-a (K ⁴ = ethyl) (24 mg, 84 mmol) in ethanol (1 ml) and EyAc (0.5 ml) was treated with 10% P6 on charcoal in an atmosphere of H ₂ in accordance with the procedure of example 15 to obtain 24 mg (100%) of the target product. Additional cleaning was not required. T. pl. 198 ° C.

¹ H-NMR (300 MHz, acetone-b6) δ 7.03-6.97 (m, 2H), 6.80-6.76 (m, 1H), 2.18-2.11 (m, 1H ), 1.901.81 (m, 1H), 1.30-1.19 (m, 3H), 0.97-0.80 (m, 4H);

¹⁹ E-NMR (282 MHz, acetone-6 ₆ ) δ -82.692, -123.78-123.86;

M8 (C'CH) t / e calculated for C ^ H ^ E ^ O:

291.112051, found 291.112227; 291 (MH ⁺ , 100).

Example 25. Preparation of (+/-) - 6-fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2 (1H) quinazolinone (K ⁴ = phenyl).

A solution of ΧνΙΙ-a (K ⁴ = phenyl) (30 mg, 90 mmol) in ethanol (1 ml) and EyAc (0.5 ml) was treated with 10% P6 on charcoal in an atmosphere of H ₂ in accordance with the procedure of example 15 to obtain 20 mg (67%) of the target product. Additional cleaning was not required. T. pl. 98 ° C.

¹ H-NMR (300 MHz, acetone-b6) δ 7.18-6.99 (m, 7H), 6.84-6.79 (m, 1H), 2.68-2.60 (m, 1H ), 2,482.12 (m, 3H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -82.67, -123.24-123.32;

M8 (MF) t / e calculated for C ^ H ^ E ^ O:

339.112051, found 339.110781; 339 (MH ⁺ , 100).

Example 26. Preparation of (+/-) - 6-fluoro-4methylpropargyl-4-trifluoromethyl-3,4-dihydro2 (1H) -quinazolinone (K ⁴ = methyl).

Synthesis of X1X-a from ΧνΙ-a.

A solution of 2-butine (94 mg, 1.75 mmol) in anhydrous THF (3.5 ml) was cooled to 0 ° С, treated with НВЦЫ (0.97 ml of a 1.6 M solution in hexanes, 1.55 mmol) and kept within 0.5 hours. To a solution of ΧνΙ-a (90 mg, 0.388 mmol) in anhydrous THF (1.9 ml) at -78 ° С, lithium anion was added over 5 minutes, followed by boron trifluoride etherate (25 ml, 0.194 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After 16 h at room temperature, the reaction was quenched by the addition of 1 M citric acid (10 ml), diluted with ЕУАс (50 ml), the phases were separated, and the organic phase was washed successively with saturated aqueous solution of Н1СО ₃ (20 ml) and saturated aqueous NaCl (20 ml). The resulting material was purified by HPLC (2.5% MeOH / CH ₂ Cl ₂ ) to give 10 mg (9%) of the desired product. Mp 181 ° C.

'H-NMR (300 MHz, acetone-bb) δ 8.91 (br, 1H), 7.27 (d, 8.4 N), 7.18-7.08 (m, 1H), 7.02 -6.97 (m, 2H), 3.29 (dd, 1 = 16.8, 2.6 Hz, 1H), 3.00 (dd, 1 = 16.8, 2.2 Hz, 1H), 1.61-1.59 (m, 3H);

¹⁹ G-NMR (282 MHz, acetone-b ₆ ) δ -81.86, -123.69-123.70;

M8 (C1) t / e calculated for С1 ₃ НЦЕ ₄ Н ₂ О: 287.080751, found 287.080340; 287 (MH ⁺ , 75), 304 (Μ + ΝΗ ₄ ⁺ , 100).

Scheme 4. Chiral separation.

Examples 27 and 28. Preparation of (-) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 27) and (+) 6-chloro-4-cyclopropylethinyl-4-trifluoromethyl3, 4-dihydro-2 (1H) -quinazolinone (Example 28).

Separation 1U-b, c from 1U-a (B ⁴ = cyclopropyl).

Chiral HPLC, using a Syga1ce1 колон column, 3% isopropanol, 5% CH ₂ Cl ₂ hexanes, at ambient temperature with a flow rate of 1.0 ml / min and detection at 250 nm, allowed separation of 1U-L from 1U-s with enantiomeric excesses of 99% and 99.4%, respectively. 1U-b: T. pl. 106-109 ° C; [α] ο ²⁵ −64.34 ° (c = 0.274, MeOH). 1U-s: T. pl. 105 107 ° C; [α] ο ²⁵ + 58.33 ° (c = 0.288, MeOH).

Examples 29 and 30. Obtaining (+) - 4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1 H) -quinazolinone (example

29) and (-) - 4-cyclopropylethynyl-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1 H) -quinazolinone (Example 30).

Separation of X11-b, c from ΧΙΙ-a (B ⁴ = cyclopropyl).

Chiral HPLC, using a Syga1rak ΆΌ column, 5% water and 95% methanol, at ambient temperature with a flow rate of 0.8 ml / min and detection at 250 nm, allowed the separation of ΧΙΙ-L from X11-c with enantiomeric excesses of 100% and 99%, respectively. B: T. pl. 187 ° C; [α] ₀ ²⁵ + 1.46 ° (c = 0.274, MeOH).

С-s: T. pl. 187.5-188.8 ° C; [α] ο ²⁵ -1.45 ° (c = 0.278, MeOH).

Examples 31 and 32. Preparation of (-) - 5,6difluoro-4-isopropylethynyl-4-trifluoromethyl3,4-dihydro-2 (1H) -quinazolinone (Example 31) and (+) - 5,6-difluoro-4-isopropylethinyl -4-trifluoromethyl-3,4-dihydro-2 (1 H) -quinazolinone (Example 32) Separation of CP-b, c from S-a (B ⁴ = isopropyl).

Chiral HPLC, using a Syga1rak колон column, 5% water and 95% methanol, at ambient temperature with a flow rate of 0.5 ml / min and detection at 250 nm, allowed the separation of ΧΙΙ-от from ΧΙΙ-c with enantiomeric excesses of 100% and 99%, respectively.

B: T. pl. 155 ° C; [α] ₀ ²⁵ -2.14 ° (c = 0.280, MeOH). С-s: T. pl. 98 ° C [α] ₀ ²⁵ + 4.45 ° (c = 0.292, MeOH).

Examples 33 and 34. Preparation of (-) - 5,6difluoro-4-ethylethynyl-4-trifluoromethyl-3,4dihydro-2 (1H) -quinazolinone (Example 33) and (+) 5,6-difluoro-4-ethylethinyl- 4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 34).

Separation of ΧΙΙ-ό ^ from ΧΙΙ-a (B ⁴ = ethyl).

Chiral HPLC using a Ά8 column, 20% ethanol and 80% hexanes, at ambient temperature with a flow rate of 1.0 ml / min and detection at 250 nm, allowed the separation of ΧΙΙ-from ΧΙΙ-c with enantiomeric excesses of 100% and 99 %, respectively.

B: T. pl. 165-167 ° C.

С-s: T. pl. 157-159 ° C.

Examples 35 and 36. Preparation of 5,6-difluoro-4 (2-hydroxyethyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 35) and 5,6-difluoro-4- (1-hydroxyethyl) ethinyl-4-trifluoromethyl-3,4-dihydro-2 (1 H) -quinazolinone (example

36).

To a suspension of ketimine (300 mg, 1.20 mmol) in anhydrous THF (11 ml) at -78 ° С, a pre-cooled (0 ° С) solution of silyl-protected lithium acetylenide (5.40 mmol) and ΒΕ3.0Ε12 ( 0.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 1 M citric acid and diluted with EAAc. The phases were separated, the organic phase was washed with water, saturated aqueous solution No. 11CO ₃ and saturated aqueous No. C1. The organic extracts were dried over MgSO ₄ , filtered and concentrated. The material was purified by normal phase HPLC (column 41.4 mm Watt Oupatah® using silica 60 A @ 25 ml / min): 2.5% MeOH / SN2S12 for 24 min, increasing to 30% MeOH / CH ₂ C1 ₂ for 4 minutes, 30% MeOH / CH ₂ Cl ₂ for 10 minutes and a reverse decrease to 2.5% MeOH / CH ₂ Cl ₂ for 2 min. The yield of protected intermediates was 47% and 32%, respectively.

The intermediate product of example 35. T. pl. 62.9-64 ° C;

'H-NMR (300 MHz, acetone-b ₆ ) δ 8.98 (br, 1H), 7.41-7.32 (m, 2H), 6.83-6.78 (m, 1H), 3 74 (t, = 6.6 Hz, 2H), 2.47 (t, 1 = 6, 6 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H);

¹⁹ G-NMR (282 MHz, acetone-b ₆ ) δ -83.17, -135.16-135.31, -148.09-148.22;

M8 (MF) t / e calculated for С1 ₉ Н ₂₄ Е ₅ Н ₂ О ₂ 81: t / ζ 435.152723, found 435.151149; 435 (MH ⁺ , 94), 452 (M + OH ₄ ⁺ , 100);

Anal calculated for C1 ₉ H ₂₃ E ₅ N ₂ O ₂ 81: C, 52.52; H, 5.35; Ν, 6.46;

found; C, 52.65; H, 5.29; Ν, 6.31.

The intermediate product of example 36. ¹ NMR (300 MHz, acetone-b ₆ ) δ 8.96 (br, 1H), 7.50 (br, 1H), 7.37-7.28 (m, 1H), 6, 79-6.74 (m, 1H), 4.61 (q, I = 13.2, 6.6 Hz, 1H), 1.30 (d, I = 6.6 Hz, 3H), 0.78 (s, 9H); 0.01 (s, 6H);

¹⁹ G-NMR (282 MHz, acetone-bb) δ -82.8882.95, -135.20-135.42, -148.06-148.23;

M8 (MF) t / e calculated for С1 ₉ Н ₂₄ Е ₅ Н ₂ О ₂ 81: t / ζ 435.152723, found 435.152927; 435 (MH ⁺ , 51), 452 (M + OH ₄ ⁺ , 100);

Elemental analysis: calculated for C ₁₉ H ₂₃ E ₅ N ₂ O ₂ 81: C, 52.52; H, 5.35; Ν, 6.46; Found: C, 52.54; H, 5.34; Ν, 6.69.

To a solution of the protected intermediate for Example 35 (0.56 mmol) in THF (1.1 ml) was added TBAE (0.62 ml of a 1.0 M solution in THF). The resulting mixture was stirred at room temperature for 1 h, diluted with HU Ac, washed with 1N. HCl, a saturated aqueous solution of NaHCO ₃ and saturated aqueous No. Cl. The organic extract was dried over MgSO ₄ , filtered and concentrated. The material was purified by HPLC with the usual phase (column 41.4 mm Your Eupatam® using silica 60 A @ 25 ml / min): 2.5% MeOH / CH ₂ Cl ₂ for 24 min, an increase of up to 30% MeOH / CH ₂ Cl ₂ for 4 min, 30% MeOH / CH ₂ Cl ₂ for 10 min and the opposite decrease to 2.5% MeOH / CH ₂ Cl for min. The compound of example 35 was isolated with a yield of 82%.

Example 35. T. pl. 190-192 ° C;

'H-NMR (300 MHz, acetone-b ₆ ) δ 9.05 (br, 1H), 7.53 (br, 1H), 7.45-7.36 (m, 1H), 6.88-6 83 (m, 1H), 4.01-3.98 (m, 1H), 3.68-3.64 (m, 2H), 2.50 (t, H = 6.6 Hz, 2H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -83.3, -135.68-135.88, -148.10-148.22;

M8 (MF) calculated for C ^ H ^ E ^ Oy t / ζ 321.066244, found 321.066479; 321 (MH ⁺ , 100);

Elemental analysis: calculated for SVNE ^ Yuu C 48.76; H 2.83; Ν 8.76; Found: C, 49.05; H 3.23; Ν 8.38.

The compound of Example 36 was synthesized in a similar manner to obtain the title compound in 88% yield. T. pl. 190-191 ° C.

'H-NMR (300 MHz, acetone-b ₆ ) δ 9.06 (br, 1H), 7.56 (br, 1H), 7.46-7.37 (m, 1H); 6.88-6.83 (m, 1H), 4.58-4.57 (m, 2H), 1.39 (d, H = 5.5 Hz, 3H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -83.15, -135.40, -135.60, -148.08-148.20;

M8 (MF) calculated for SnNuE ^ Oy t / ζ 321.066244, found 321.065983; 321 (MH ⁺ , 58); 338 (M + IN ₄ ⁺ , 100);

Elemental analysis: calculated for C ^ H ^^ Oy C, 48.76; H, 2.83; Ν, 8.76; Found: C, 48.84; H, 2.76; Ν, 8.63.

Example 37. Preparation of (+) - 4-E-cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone.

To a solution of CP-L (200 mg, 0.632 mmol) in anhydrous THF (1.3 ml) was added a solution of lithium aluminum hydride (1.3 ml of a 1.0 M solution in THF) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 10% NO (3 ml) and water (3 ml). The mixture was diluted with HU Ac (30 ml) and the phases were separated. The organic phase was washed with saturated aqueous solution No. C1, dried over MgSO ₄ , filtered, and concentrated. The title compound was purified by conventional phase HPLC (41.4 mm Watt Eupatach® column using 60 A silica); 2.5% MeOH / SN2S12 for 24 min, increasing to 30% MeOH / CH ₂ C1 ₂ for 4 min, 30% MeOH / CH ₂ C1 ₂ for 10 minutes and back reduction to 2.5% MeOH / SN2S12 for 2 minutes Mp 80-83 ° C.

'H-NMR (300 MHz, acetone-b ₆ ) δ 9.07 (br, 1H), 7.33 (q, H = 8.8 Hz, 1H), 6.94 (br, 1H), 6.846, 79 (m, 1H), 6.27 (dd, H = 15.6, 7.5 Hz, 1H), 5.67 (dd, H = 15.2, 9.4 Hz, 1H), 1.65 -1.56 (m, 1H), 0.800.71 (m, 2H), 0.50-0.42 (m, 2H);

¹⁹ E-NMR (282 MHz, acetone-b ₆ ) δ -82.68, -135.05, -148.49;

M8 (MF) calculated for C ^ H ^ Eb ^ O: t / ζ 319.086979, found 319.087755; 319 (MH ⁺ , 100); | (/. | ² + 72.77 ° (c = 0.382, MeOH);

Elemental analysis: calculated for ScNpE ^ O: C 52.84; H 3.48; Ν 8.80; Found: C, 53.02; H 3.48; Ν 8.61.

Example 38. Obtaining (-) - 6-chloro-4-Cyclopropylethylene-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone.

The title compound was prepared as described in Example 37 (with GU-L as starting material), except that it was purified using a CylAce1 OE column at a flow rate of 1.5 ml / min in a mixture of 0.5% ENL / 20% CH ₂ Cl ₂ / 79.5% hexanes. T. pl. 87-89 ° C.

'H-NMR (300 MHz, acetone-b ₆ ) δ 9.08 (br, 1H), 7.40-7.25 (m, 2H), 7.04-6.90 (m, 2H), 6.286 , 18 (m, 1H), 5.64-5.52 (m, 1H), 1.68-1.55 (m, 1H), 0.83-0.71 (m, 2H), 0.53 -0.41 (m, 2H);

¹⁹ G-NMR (282 MHz, acetone-b ₆ ) δ -81.67;

M8 (C1) calculated for C ₁₄ H1 ₃ C1G ₃ H ₂ O: t / ζ 317.066851, found 317.065857; 317 (MH ⁺ , 100); [α] ο ²⁰ −6.81 ° (c = 0.382, MeOH);

Elemental analysis: calculated for C1 ₄ H ₁₂ C1E ₃ K ₂ O-0.27 C ₃ H ₆ O: C 53.52; H 4.13; N, 8.43; Found: C, 53.90; H 4.07; N, 8.80.

Table 2*

Table 1*

23 6th Sez CH ₂ CH ₂ -2-Pz * read! n 88 340 (MH ⁺ ) 24 6th Sez CH ₂ CH ₂ CH ₂ CHz n 198 291 (MH ⁺ ) 25 6th Sez CH ₂ CH ₂ Pb n 98 339 (MH ⁺ ) 26 6th CE ₃ CH ₂ C ^ C-CH3 n 181 304 (Μ + ΝΗ ₄ ⁺ ) 27 (-) 6-C1 CE ₃ C = C-sous n 106- 109 313 (Μ) 28 (+) 6-C1 CE ₃ C = C-sous n 105- 107 313 (Μ) 29 (+) 5,6-άίΕ Sez C == C-sousRg n 187 315 (M “) DA (-) 5,6-άΐΡ CE ₃ C ^ C-sousPr n 188- 189 315 (Μ) 31 (-) 5,6-άίΕ Sez C ^ C-xPr n 155 317 (m-) 32 (+) 5,6-άίΕ Sez C ^ C-xPr n 98 317 (M “) 33 (-) 5,6-άίΕ CE ₃ C = C-EU n 165- 167 303 (M-) 34 (+} 5,6-άίΡ Sez C == C-EU n 157- 159 303 (Μ) 35 5,6-άΐΕ CE ₃ C = CCH ₂ CH ₂ OH n 190- 192 321 (MH ⁺ ) 36 5,6-άίΓ SRz C ^ C-CH (OH) Me n 190- 191 338 (Μ + ΝΗ ₄ ⁺ ) 37 (+) 5,6-άίΡ Sez C = C-sousPr (E) n 80-83 319 (MH ⁺ ) 38 (-) 6-C1 CE ₃ C = C-sousPr (E) n 87-89 317 (MH ⁺ )

Etc. #. ⁴³ '44

K ³

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1 b-Cx

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1 * Unless otherwise indicated, stereochemistry (+/-),

K ¹ to ² K ⁸ CE ₃ C = CCH ₂ CH ₂ OH N CE ₃ C ^ C-CH (OH) Me N Sez C = C- (2-C1) Pb n CE ₃ C == C- (3-C1) Pb n CE ₃ C®C- (4-C1) Pb n Sez C = C- (2-E) Pb n Sez C = C- (3-P) Pb n Sez ‘ CeS- (4-P) Pb n Sez C = C- (2-OH) Pb n Sez C = C- (3-OH) Pb n CE ₃ C == C- (4-OH) Pb n Sez C = C- (2-OMe) Pb n Sez C ^ C- (3-OMe) Pb n Sez C = C- (4-OMe) Pb n Sez SES- (2-S) Pb n CE ₃ SES- (3-S) Pb n Sez C = C- (4-CY) Pb n Sez C = C- (2-BO ₂ ) Pb n Sez C = C- (3-BO ₂ ) Pb n Sez C = C- (4-ΝΟ ₂ ) Pb n Sez C = C- ( _2-2 ) Pb n CE ₃ Ο0- (3-ΝΗ ₂ ) Ρή n SR ₃ C = C- (4-ΝΗ ₂ ) Pb n SRz C ^ C- (2-KMe ₂ ) Pb n SGZ C = C- (3-IME ₂ ) Pb n SRz C = C- (4THMe ₂ ) Pb n SRz C = C-3-pyridyl n SRz C = C-4-pyridyl n

SGZ C = C-2-. furanyl N Sez C = C-3-lFuranyl N SRz CeS-2- / thienyl N SRz C = C-3-thienyl N Sez CeC-2 - oxazolyl N SRz SnS-2- / thia zolil N Sez C = C-4-Isooxazolyl N Sez Cr = C-2-imidazolyl N SRz C = CCH ₂ CH ₂ OH N SRz C = C-CH (OH) Me n Sez C = C- (2-C1) Pb N SGZ C = C- (3-C1) Pb n Sez. C = C- (4-C1) Pb N Sez C = C- (2-D) Pb n Sez C = C- (3-P) Pb n SRz C = C- (4-P) Pb n SRz C = C- (2-OH) Pb n SRz C = C- (3-OH) Pb n SRz C = C- (4-OH) Pb n SRz C = C- (2-OMe) Pb n SR ₃ C = C- (3-OMe) Pb n Sez C = C- (4-OMe) Pb n CE ₃ C = C- (2-CY) Pb n SRz C = C- (3-CY) Pb n SRz C = C- (4-CH) Pb. n SGZ C = C- {2-ΝΟ ₂ ) Pb n SRz C = C- (3-BO ₂ ) Pb n SRz C = C- (4-2) Pb n SRz C = C- ( _2-2 ) Pb n SRz C = C- (3-MH ₂ ) Pb n SRz C = C- (4-OH ₂ ) Pb n SRz C = C- (2-IME ₂ ) Pb n SRz C = C- (3-She ₂ ) Pb n SGZ C = C- (4-YMe ₂ ) Pb n

63 6-C1 . ^SGS 64 6-C1 Sez 65 6-C1 Sez 66 6-C1 Sez 67 6-C1 Sez 68 6-C1 Sez 69 6-C1 , Sez 70 6-C1 Sez 71 6-C1 Sez 72 6-C1 Sez 73 6-C1 Sez 74 6-C1 Sez 75 6-C1 CE ₃ 76 6-C1 Sez 77 6-C1 SG ₃ 78 6-C1 Sez 79 6-C1 Sez 80 6-C1 CE ₃ 81 6-C1 Sez 82 6-C1 CE ₃ 83 6-C1 Sez 84 6-C1 CE ₃ 85 6-C1 Sez 86 6-C1 Sez 87 6-C1 Sez 88 6-C1 CE ₃ 89 6-C1 Sez 90 6-C1 Sez 91 6-C1 Sez 92 6-C1 Sez 93 6-C1 CE ₃ 94 6-C1 CE ₃ 95 6-C1 Sez 96 6-C1 Sez

C = C-3-pyridylN

C = C-4-PyridylN

C = C-2-Furanyl

C = C-3-furanylN

C = C-2- Thienyln

OS-3- thienyl

C = C-2-.oxazolyl

OS-2- ^ Thaeoliln

C = C-4-isoxazolyl

OS-2- imidazolyln

CH ₂ CH ₂ -sigRgN

CH ₂ CH ₂ CH ₂ CH ₂ ONn

CH ₂ CH ₂ —CH (OH) MeH

CH ₂ CH ₂ -Pn

CH ₂ CH ₂ - (2-C1) RNN

CH ₂ CH ₂ - (3-C1) RNN

CH ₂ CH ₂ - (4-C1) PH

CH ₂ CH ₂ - (2-E) RNN

CH ₂ CH ₂ - (3-E) PHN

CH ₂ CH ₂ - (4-P) PH

CH ₂ CH ₂ - (2-OH) PH

CH ₂ CH ₂ - (3-OH) Rb

CH ₂ CH ₂ - (4-OH) RNN

CH ₂ CH ₂ - (2-OMe) RNN

CH ₂ CH ₂ - (3-OMe) RNN

CH ₂ CH ₂ - (4-OMe) R11H

CH ₂ CH ₂ - (2-SI) RNN

CH ₂ CH ₂ - (3-CY) Rn

CH ₂ CH ₂ - (4-CHY) PHΗ

CH ₂ CH ₂ - (2-ΝΟ ₂ ) PH

CH ₂ CH ₂ - (3-OH ₂ ) RN

CH ₂ CH ₂ - (4-ΝΟ ₂ ) TRN

CH ₂ CH ₂ - (2-ΝΗ ₂ ) TRN

CH ₂ CH ₂ - (3-MH ₂ ) RIN

one hundred

101

102

103

104

105

106

107

108

109

110

111 '112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

Sez CH ₂ CH ₂ - (4-ΝΗ2) pH n CE ₃ CH ₂ CH ₂ - (2 -MMe ₂ ) pH N CE ₃ CH ₂ CH ₂ - (3-YMe ₂ ) pH n Sez CH ₂ CH ₂ - (4-MMe ₂ ) pH n Sez CH ₂ CH ₂ -2 -pyridyl n Sez CH ₂ CH ₂ -3-pyridyl n Sez CH ₂ CH ₂ -4-- 'pyridyl n CE ₃ CH ₂ CH ₂ -2 - hfurani l n Sez CH ₂ CH ₂ -3- furanyl n Sez CH ₂ CH ₂ -4-furanium n Sez CH ₂ CH ₂ -3- 'thienyl n Sez CH ₂ CH ₂ -2- oxazole silt n Sez. CH ₂ CH ₂ -2 - thiazolyl n Sez CH ₂ CH ₂ -4-Igoxazolyl n Sez CH ₂ CH ₂ -2 - imidazolyl n Sez C ^ c SNZ Sez C = C-Pb SNZ Sez C ^ C-2-pyridyl SNZ Sez CaC-Z-l pyridyl SNZ Sez C = C-4 SNZ Sez C = C-2-furanyl SNZ Sez C = C-3- furanyl SNZ Sez C = C-2-thienyl SNZ Sez 0 = 0-3 - thienyl SNZ Sez C = C-sous SNZ Sez C = C-PH SNZ Sez C = C-2-pyridyl SNZ Sez C = C-3-pyridyl SNZ Sez C = C-4-pyridyl SNZ Sez C = C-2-Furanyl SNZ Sez C = C-3-FURanyl SNZ Sez C = C-2-Ti SNZ Sez C = C-3- Thienyl SNZ Sez CH ₂ CH ₂ sigRg CH ₃

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

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158

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161

162

163

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165

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167

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178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-C1

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

6-MeO

CE ₃

CE ₃

CE ₃

CE ₃

CE ₃

CE ₃

CE ₃

SGZ

CE ₃

CE ₃

SGZ

Sez

CE ₃

CE ₃

Sez

Sez

Sez

CE ₃

Sez

CE ₃

Sez

Sez

CE ₃

SGZ

SGZ

CE ₃

Sez

SGZ

CE ₃

SR ₃

Sez

Sez

Sez

Sez

CH ₂ CH ₂ -RN SNZ CH ₂ CH ₂ -2-Pyridyl SNZ CH ₂ CH ₂ -3-pyridyl SNZ CH ₂ CH ₂ -4-yyriDil SNZ CH ₂ CH ₂ -2 - furanium SNZ CH ₂ CH ₂ -3-Furanyl SNZ CH ₂ CH ₂ -2-Thienyl SNZ CH ₂ CH ₂ -3-thienyl SNZ C = C-sous CH ₂ CH C = C-Pb CH ₂ CH C = C-2-pyridyl CH ₂ CH C = C-3-pyria sludge CH ₂ CH ₃ C = C-4-pyridyl CH ₂ CH C = C-2-furanyl CH ₂ CH C = C-3- Furanyl CH ₂ CH C == C_2 ~ thienyl CH ₂ CH C ^ C-3-thienyl CH ₂ CH C = C-sous CH ₂ CH C = C-Pb CH ₂ CH C = C-2-pyridyl sun ₂ sun ₃ C = C-3-pyridyl sun ₂ sun ₃ C = C-4-pyridyl CH ₂ CH ₃ C = C-2-furanyl sun ₂ sun ₃ C = C-3-Furanyl sun ₂ sun ₃ C = C-2-thienyl CH ₂ CH C = C-3-tyyenyl sun ₂ sun ₃ CH ₂ CH ₂ sigRg sun ₂ sun ₃ CH ₂ CH ₂ -PB sun ₂ sun ₃ CH ₂ CH ₂ -2-Pyridyl CH ₂ CH ₃ CH ₂ CH ₂ -3-pyridyl CH ₂ CH ₃ CH ₂ CH ₂ -4-pyridyl CH ₂ CH CH ₂ CH ₂ -2- furanyl CH ₂ CH ₃ CH ₂ CH ₂ -3- Furanyl CH ₂ CH CH ₂ CH ₂ -2- ^ yenyl CH ₂ CH

SEC CH ₂ CH ₂ -3-thienyl CH ₂ CH ₃

SEC C = CCH ₂ CH ₂ OH

CE ₃ C = C-CH (OH) Me

SGz SzS- (2-C1) RN

SEC C = C- {3-C1) RNN

SG3 C = C- (4-C1) Pb. H ‘CEz C = C- (2-E) PH

SEC C = C- (3-E) RNN

CEz C ^ C- (4-P) Pb.H

CEz C = C- (2-OH) PbH

SEC C = C- (3-OH) pH

SEC C = C- (4-OH) RNN

SEC · s = C- (2-OMe) pH

SGz C = C- (3-OMe) PHN

SEC C = C- (4-OMe) pH

SGz C = C- (2-SI) RNn

SGz C = C- (3-CM) RIN

CE ₃ C = C- (4-SI) pH

Cgz C = C- (2-BO ₂ ) Pb.n

CEC C = C- (3-BO ₂ ) Pb

CE ₃ C = C- (4-NO ₂ ) RNN

CEz C = C- (2-ΝΗ ₂ ) Pb

SG3 C ^ C- (3-IN ₂ ) pH

SEC C = C- (4-ΝΗ ₂ ) pH

CG3 C ^ C- (2-NMe ₂ ) pH

SGz C = C- (3-ΝΜβ ₂ ) pH

CE ₃ C ^ C- (4-MMe ₂ ) pH

SGZ s ^ s-3- yygiridil

Cgz c = C-4- 'pyridylN

SEC s = s_2- furanylN

Ces c = £ _z_ 'furanyl

CEz C = C-2-thienyl

CEz C = C — 3— thienyl H

SEC C ^ C-2- ° xazolyl

199 6-MeO Sez 200 6-MeO Sez 201 6-MeO Sez 202 b-MeO Sez 203 6-MeO CE ₃ 204 6-MeO CE ₃

205 6-MeO * CE ₃

206 6-MeO SG ₃

207 6-MeO SG ₃

208 6-MeO SGZ

209 6-MeO CE ₃

210 6-MeO SG ₃

211 b-MeO CEs

212 b-MeO CE ₃

213 6-MeO SGZ

214 6-MeO CEs

215 b-MeO SGZ

216 b-MeO SG ₃

217 6-MeO CE ₃

218 6-MeO CEs

219 b-MeO sez

220 b-MeO SGZ

221 6-MeO CEs

222 b-MeO SG ₃

223 b-MeO CE ₃

224 6-MeO CEs

225 6-MeO CE ₃

226 6-MeO SGZ

227 6-MeO SGZ

228 6-MeO CEs

229 b-MeO CEs

230 b-MeO SGZ

231 b-MeO SGZ

232 b-MeO SG ₃

233 6-MeO CEs

234 b-MeO CE ₃

235 b-MeO SEZ

236 6-MeO SGZ

237 6-MeO CE ₃

238 b-MeO SGZ

239 6-MeO> SGZ

240 6-MeO CEs

241 b-MeO CEs

242 6-MeO CEs

243 6-MeO SGZ

244 6-MeO SGZ

245 b-MeO CEZ

246 b-MeO CE ₃

247 b-MeO SGZ

248 6-MeO CEs

249 b-MeO CEZ

250 6-MeO CE ₃

251 b-MeO SGZ

252 b-MeO SG ₃

253 6-MeO SGZ

254 b-MeO CE ₃

255 6-MeO SGZ

256 b-MeO SGZ

257 6-MeO CEs

258 6-MeO SG ₃

259 b-MeO CEZ

260 b-MeO CEZ

261 b-MeO SGZ

262 b-MeO SGZ

263 6-MeO SGZ

264 6-MeO SG ₃

265 6-MeO Sez 266 6-MeO CE ₃

C = C-2- thiaEoil

C = C-4-yzoxazolyl

C = C-2-imidazolyl H

C = CCH ₂ CH ₂ ONN

C = C-CH (OH) MeN

С-С- (2-С1) РНН

C = C- (3-C1) Pb

C = C- (4-C1) PbH

C = C- (2-D) PbH

C = C- (3-D) Pb

C = C- (4-D) PbH

C = C- (2-OH) PbH

C = C- (3-OH) Pb

C = C- (4-OH) PH

C = C- (2-ohm) Pb c = c- (3-ohm) Pb

C = C- (4-OMe) PbH

C = C- (2-CY) RH

C = C- (3-CY) Pb

C = C- (4-CH) RH

C = C- (2-ΝΟ ₂ ) PH

C = C- (3-MO ₂ ) Pb

C = C- (4-ΝΟ ₂ ) Pb

C = C- (2-ΝΗ ₂ ) PH

C = C- (3-OH ₂ ) Pb

C = c- (4-OH ₂ ) PH

C = C- (2-IME ₂ ) PH

C = C- (3-YMe ₂ ) PbH

C = C- (4-IME ₂ ) PH

C = C-3-pyridyl

C = C 4 ^_ iiridiln

C = C-2-furanylN

C = C-3- Furanyln

C = C-2-thienyln

C = C-3-thienyl H

C = C-2-oxazolyl H

C = C-2-thiazolyl-n

C = c-4-isoxazoline

C = C-2-. imidazolylN

CH ₂ CH ₂ -sigRgN

CH ₂ CH ₂ CH ₂ CH ₂ ONn

CH ₂ CH ₂ -CH (OH) Men sn ₂ sn ₂ -ryubn

CH ₂ CH ₂ - (2-C1) Pb

CH ₂ CH ₂ - (3-C1) Pb

CH ₂ CH ₂ - (4-C1) PH

CH ₂ CH ₂ - (2-D) PH

CH ₂ CH ₂ - (3-E) Pb

CH ₂ CH ₂ - (4-D) PH

CH ₂ CH ₂ ~ (2-OH) PH

CH ₂ CH ₂ - (3-OH) Pb

CH ₂ CH ₂ - (4-OH) PH

CH ₂ CH ₂ - (2-OMe) PH

CH ₂ CH ₂ - (3-OMe) PH

CH ₂ CH ₂ - (4-OMe) PH

CH ₂ CH ₂ - (2-CH) Pb

CH ₂ CH ₂ - (3-CM) Pb

CH ₂ CH ₂ - (4-CH) RH

CH ₂ CH ₂ - (2-ΝΟ ₂ ) PH

CH ₂ CH ₂ - (3O ₂ ) Pb

CH ₂ CH ₂ - (4-ΝΟ ₂ ) PH

CH ₂ CH ₂ - (2-ΝΗ ₂ ) PH

CH ₂ CH ₂ - {3-W ₂ ) P11n

CH ₂ CH ₂ - (4-ΝΗ ₂ ) PH

CH ₂ CH ₂ - (2-Same ₂ ) PH

CH ₂ CH ₂ - (3-YMe ₂ ) PH

CH ₂ CH ₂ - (4-Same ₂ ) PH

CH ₂ CH ₂ -2-pyridylN

267 b-MeO 268 6-MeO 269 6-MeO 270 b-MeO 271 6-MeO 272 6-MeO 273 6-MeO 274 6-MeO 275 6-MeO 276 6-MeO 277 6-MeO 278 6-MeO 279 6-MeO 280 6-MeO 281 6-MeO 282 6-MeO 283 b-MeO 284 6-MeO 285 6-MeO 286 6-MeO 287 6-MeO 288 6-MeO 289 6-MeO 290 b-MeO 291 6-MeO 292 b-MeO 293 6-MeO 294 b-MeO 295 b-MeO 296 b-MeO 297 6-MeO 298 b-MeO 299 6-MeO 300 6-MeO

CE ₃ CH ₂ CH ₂ -3-pyridyl N Sez CH ₂ CH ₂ -4-Pyridyl n CE ₃ CH ₂ CH ₂ -2 -furanyl n Sez CH ₂ CH ₂ - 3- furanyl n CE ₃ CH ₂ CH ₂ -4-Furanyl n Sez CH ₂ CH ₂ -3-thienyl n SGZ CH ₂ CH ₂ -2 -oxavolyl n Sez CH ₂ CH ₂ -2- thiazolyl n SGZ CH ₂ CH ₂ -4-isoxazolyl n SGZ CH ₂ CH ₂ -2-'imidazolyl n SGZ СеС-сусРг SNZ SGZ C = C-Pb SNZ SGZ C ^ C-2-pyridyl SNZ Sez C = C-3-pyridyl SNZ Sez C == c-4 - pyridyl SNZ Sez C ^ C-2 - furanyl SNZ CE ₃ C == C — 3 - furanyl SNZ Sez C = c-2-thienyl SNZ Sez C = c-s-; thienyl SNZ Sez C = C-sous SNZ Sez C = C-Pb SNZ SGZ C = C-2 -. Pyridyl SNZ Sez C = C-3-pyridyl SNZ SGZ C = C-4-pyridyl SNZ Sez C = C-2-furanyl SNZ Sez C = C-3- Furanyl SNZ SG ₃ C = C-2-thienyl SNZ Sez C = C-3-thienyl SNZ CE ₃ CH ₂ CH ₂ sigRg SNZ CE ₃ CH ₂ CH ₂ -PB SNZ CE ₃ CH ₂ CH ₂ -2- pyridyl SNZ Sez CH ₂ CH ₂ -3-pyridyl SNZ CE ₃ CH ₂ CH ₂ -4-pyridyl SNZ SGZ CH ₂ CH ₂ -2- Furanyl SNZ

301 b-MeO SGZ CH ₂ CH ₂ -3 - Furanyl CH ₃ 302 b-MeO Sez CH ₂ CH ₂ -2-thienyl SNZ 303 b-MeO SGZ CH ₂ CH ₂ -3-thienyl SNZ 304 6-MeO Sez C = C-sous CH ₂ CH ₃ 305 6-MeO SGZ ΟΞΟ-ΡΗ CH ₂ CH 306 6-MeO SGZ c = c-2-pyridyl CH ₂ CH ₃ 3 07 6-MeO . SGZ C = C-3-pyridyl CH ₂ CH 308 b-MeO SGZ SvS-4-: pyridyl CH ₂ CH ₃ 309 6-MeO SGZ C = C-2- ^g furanyl CH ₂ CHZ 310 b-MeO Sez C = C-3-. Furanyl SN2SNZ 311 b-MeO SGZ O = C-2 - ^ thienyl CH ₂ CH ₃ 312 b-MeO SGZ C = c- ₃ - thienyl CH ₂ CH 313 6-MeO SGZ . C = C-sous CH ₂ CH 314 b-MeO SGZ C = C-Pb CH ₂ CH 315 b-MeO SGZ C = C-2-pyridyl CH ₂ CH ₃ 316 b-MeO SGZ C = C-3-7 Pyridyl CH ₂ CH ₃ 317 b-MeO SGZ C ₌ C_4_ pyridyl CH ₂ CH 318 b-MeO SGZ C = C-2- Furanyl CH ₂ CH ₃ 319 b-MeO SGZ C = C — 3 — furanyl CH ₂ CH ₃ 320 6-MeO SGZ C = C-2-thienyl CH ₂ CH ₃ 321 6-MeO SGZ _{c = c} _3_ thienyl CH ₂ CH ₃ 322 b-MeO SGZ CH ₂ CH ₂ sigRg CH ₂ CH ₃ 323 6 meo SGZ CH ₂ CH ₂ -PB CH ₂ CH ₃ 324 6-MeO SGZ CH ₂ CH ₂ -2- YirIDyl CH ₂ CH ₃ 325 b-MeO SGZ CH ₂ CH ₂ -3- 'Pyridyl CH ₂ CH ₃ 326 b-MeO SGZ CH ₂ CH ₂ -4-pyridyl CH ₂ CH ₃ 327 b-MeO SGZ CH ₂ CH ₂ -2- Furandl CH ₂ CH 328 b-MeO SGZ CH ₂ CH ₂ -3- Furanyl CH ₂ CH 329 6-MeO SGZ CH ₂ CH ₂ -2- thienyl CH ₂ CH ₃ 330 b-MeO SGZ CH ₂ CH ₂ -3-thienyl CH ₂ CH ₃ 331 5,6-άχΓ SGZ CsC- (2-C1) Pb n 332 5,6-άχΓ SGZ C = C- (3-C1) Pb N 333 5,6-άίΕ SGZ SvS- (4-C1) Pb n 334 5,6-άχΓ SGZ CrC- (2-G) Pb n

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

84

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

5.6- άίΓ

5.6- άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΓ

5,6-άίΓ

C = C- (3-P) Pb

CEz C ^ C- (4-D) Pb

CEz C = C- (2-OH) PH

CE ₃ C ^ C- (3-OH) Rye

CEz C = C- (4-OH) PbH

CEC C ^ C- (2-OMe) RYA

CEz C = C- (3-OMe) PbH

CEz C = C- (4-OMe) RYA

С? 3 С = С- {2-ΌΝ} Р11Я

SRz C = C- (3-SURYA

CEC C = C- (4-CY) RYA

CP3 0 = c- (2-ΝΟ ₂ ) RYA

CP3 C = C- (3O2 ₂ )

CP3 c = c- (4-ΝΟ ₂ ) PkW

CP3 C = C- (2-ΝΗ ₂ ) RYA

CP3 C = C- (3-OH ₂ )

CP3 C ^ C- (4-YN ₂ ) RYA

SgS- SRH (2-YMe ₂₎ Ph

SRZ C ^ C- (3ME ₂ ) Pb

Срз С = С- (4-НМе ₂ ) РЬ

CP3 C = C-3-pyridyl

SRz OS-4- pyridyl

SRz C = C-2-Furanyl

SRz OS-3- FUVY? ^ILΗ

SRz Ce2-2-thienyl

SRz OS-3- 'thienylN

SRz C = C-2-g-X ^xazolyl I

SRz OS-2-thiazolyl

SRz seS-4-IZ zolilN

SRz OS-2-. imidazolyl

CP3 C = C- {2-C1) PbH

CP ₃ C = C- (3-C1) PbH

CP3 C = C- (4-C1) PbH

CEz C = C- (2-P) PbH

CP3 C = C- (3-E) Pb

CP3 C = C- (4-E) Pb

CP ₃ C = C- (2-OH) Pb

CP3 C = C- (3-OH) PbH

C? S c = c- (4-OH) Pb

CP3 C = C- (2-ohm) PbH

CP3 C = C- (3-OMe) PbH

CP3 C = C- (4-OMe) PbH

CP3 C = C- (2-CU) Pb

CEC C = C- (3-CH) Pb

CP3 C = C- (4-CH) Pb

CP3 C = C- (2-ΝΟ ₂ ) Pb

SRz. C = C- (3-BO ₂ ) Pb

CPz C = C- (4-OO ₂ ) ph

CP3 C = C- (2-OH ₂ ) Pb

CP3 C = C- (3-OH ₂ ) Pb

CP3 C = C- (4-MH ₂ ) Pb

CP3 C = C- (2-MMe ₂ ) PbH

CP3 C = C- (3-MMe ₂ ) PbH

SRH C = C- (4-ΝΜβ ₂₎ Rn

CEz C = C-3-pyridylN

CP3 C = C-4-pyridylN

SRz C = C-2-: furanyl. H

SR ₃ s = C-3 - Furanil

CP3 C = C-2-thienyl H

CP3 C = C-3-thienyl-H

SRz C = C-2-oxazolylz

SRz C = C-2-thiazolylz

CP3 C = C-4-isoxazolyl H

SRz C = C-2-. imidazolylN

SRz CH ₂ CH ₂ -susrgn

SRz CH ₂ CH ₂ CH ₂ CH ₂ ONN

SRz CH ₂ CH ₂ —CH (OH) MeH

SRz CH ₂ CH ₂ -Pn

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5,6-άίΡ SRz CH ₂ CH ₂ - (2-C1) Pb ' N 5,6-άίΡ SRz CH ₂ CH ₂ - (3-C1) Pb N 5,6-άίΡ SRz CH ₂ CH ₂ - (4-C1) Pb N 5,6-άίΡ SRz CH ₂ CH ₂ - (2-E) Pb N 5,6-άίΡ SRz CH ₂ CH ₂ - (3-D) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (4-P) Pb n 5,6-άίΡ . Sez CH ₂ CH ₂ - (2-OH) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (3-OH) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (4-OH) Pb n 5,6-άίΓ SRz CH ₂ CH ₂ - (2-ohm) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (3-OMe) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (4-OMe) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (2-CH) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (3-CH) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (4-CH) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (2-ΝΟ2) Pb n 5,6-άίΓ SRz CH ₂ CH ₂ - (3NO ₂ ) n 5,6-άίΡ SRz CH ₂ CH ₂ - (4-ΝΟ2) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (2 -CH ₂ ) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (3-OH ₂ ) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (4-OH ₂ ) Pb n 5,6-άίΓ SRz CH ₂ CH ₂ - {2-MMe ₂ ) Pb n 5,6-άίΓ SRz CH ₂ CH ₂ - (3-MMe ₂ ) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ - (4TH ₂ ) Pb n 5,6-άίΡ SRz CH ₂ CH ₂ -2- Pyridyl n 5,6-άίΡ SRz CH ₂ CH ₂ -3-pyridyl n 5,6-άίΡ SRz CH ₂ CH ₂ —4-pyridyl n 5,6-άίΡ SRz CH ₂ CH ₂ -2 -furanyl n 5,6-άίΡ SRz CH ₂ CH ₂ -3 furanyl n 5,6-άίΡ SRz CH ₂ CH ₂ -2-'Thienyl Ή 5,6-άίΡ Wed ₃ CH ₂ CH ₂ -3-thienyl n 5,6-άίΡ Sez CH ₂ CH ₂ -2- oxazolyl n 5,6-άίΡ SRz CH ₂ CH ₂ -2- thiazolyl n 5,6-άίΡ SRz CH ₂ CH ₂ -4-isoxazolyl n

437 5,6-άίΡ Sez CH ₂ CH ₂ -2- imideEoOLyl N 438 5,6-άίΓ Sez C = C-sous SNZ 439 5,6-άίΓ Sez C = C-2-pyridyl SNZ 440 5,6-άίΓ Sez C = C-3-pyridyl SNZ 441 5,6-άίΓ SGZ C ^ C-4- Pyridyl- SNZ 442 5,6-άίΓ Sez C == C-2- furanyl SNZ 443 5,6-άίΓ - SGZ C = C-3- furanyl SNZ 444 5,6-άίΓ SGZ SS-2- thienyl SNZ 445 5,6-άίΓ Sez SzS-3-tiyetsil SNZ 446 5,6-άίΓ SGZ C = C-sous SNZ 447 5,6-άίΓ Sez C = C-2-pyriyl SNZ 448 5,6-άίΓ SGZ C = C-3-pyridyl SNZ 449 5,6-άίΓ SGZ _% C = C-4-pyridyl SNZ 450 5,6-άίΓ cg ₃ C = C-2-furanyl SNZ 451 5,6-άίΓ SGZ C = C-3- Furanyl SNZ 452 5,6-άίΓ Sez C = C-2-thienyl SNZ 453 5,6-άίΓ SRz C = C-3-thienyl SNZ 454 5,6-άίΓ SGZ CH ₂ CH ₂ —sigRg SNZ 455 5,6-άίΓ SGZ CH ₂ CH ₂ -PB SNZ 456 5,6-άίΓ SRz CH ₂ CH ₂ -2- ' ^pi R ^idyl SNZ 457 5,6-άίΓ SGZ CH ₂ CH ₂ -3- ^PI R ^OR SNZ 458 5,6-άίΓ Sez CH ₂ CH ₂ -4-pyridyl SNZ 459 5,6-άίΓ cg ₃ CH ₂ CH ₂ -2 - Furanyl SNZ 460 5,6-άίΓ SGZ CH ₂ CH ₂ -3- Furanyl SNZ 461 5,6-άίΓ Sez CH ₂ CH ₂ -2-thienyl SNZ 462 5,6-άίΓ SGZ CH ₂ CH ₂ -3-thienyl SNZ 463 5,6-άίΓ Sez C = C-sous CH ₂ CH 464 5,6-άίΓ SGZ C ^ C-Pb CH ₂ CH 465 5,6-άίΓ Sez SvS-2 - -pyridyl CH ₂ CH 466 5,6-άίΓ SGZ C = C-3-pyridyl CH ₂ CH ₃ 467 5,6-άίΓ Sez C = C-4-pyridyl CH ₂ CH 468 5,6-άίΓ CE ₃ C = C-2-Furanyl CH ₂ CH 469 5,6-άίΓ Sez C = C-3-Furanyl CH ₂ CH ₃ 470 5,6-άίΓ SGZ C = C-2-thienyl CH ₂ CH ₃

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5.6- άχΡ

5.6- άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άχΡ

5.6- άίΡ

5.6- άίΡ

5.6- άίΓ

5.6- άίΡ

5.6- άχΕ

5.6- άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5,6-άίΡ

5.6- άίΡ

5.6- άίΕ

5.6- άίΡ

5.6- άχΡ

5.6- άίΟ1

5.6- άίΟΙ

5.6- άχΟ1

5.6- άίΟΙ

5.6- άίΟ1

5.6- JHS1

5.6- άίΟΙ

5,6-άίΟΙ

5.6- άίΟΙ

5.6- άχΟΙ

5.6- άχΟΙ

5.6- άίοι

5.6- άχΟΙ

5.6- άίοι

5.6- άχΟΙ

5.6- ahs1

5.6- άχΟΙ

5.6- ahS1

5.6- άχΟΙ

5.6- άίΟ1

5.6- άίΟΙ

5.6- άίΟ1

5.6- άίΟ1

5, 6-άχΟ1

5.6- άίΟΙ

5.6- άίΟΙ

5.6- άίΟ1

5.6- άχΟΙ

5,6-άχΟΙ

5.6- άχΟΙ

5.6- άίΟΙ

5.6- άίοι

5.6- άχΟ1

5.6- άίΟ1

5.6- άχΟΙ

5.6- άίΟ1

5.6- άίΟΙ

5.6- άχΟΙ

5.6- άχΟΙ

5.6- άχΟ1

5.6- άχΟΙ

5.6- άχΟΙ

5.6- άίοι

5.6- άίΟ1

5.6- άίοι

5.6- άχΟΙ

5.6- άίοι

5.6- άίοι

5.6- άίΟΙ

SRZ

SRZ

SGZ

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

SRz

C = C-3-thienyl CH ₂ CH ₃ C = C-sous CH ₂ CH ₃ C = C-Pb CH ₂ CH ₃ C = C-2-pyridyl CH ₂ CH C = C-3-. pyridyl CH ₂ CH C = C-4-pyridyl CH ₂ CH ₃ C = C-2-furanyl CH ₂ CH C = C-3-. Furanyl CH ₂ CH C = C-2-thienyl CH ₂ CH C = C-3-thienyl CH ₂ CH CH ₂ CH ₂ sigRg CH ₂ CH CH ₂ CH ₂ -PB CH ₂ CH CH ₂ CH ₂ -2 -pyridyl CH ₂ CH CH ₂ CH ₂ -3-Pyridyl CH ₂ CH CH ₂ CH ₂ -4-pyridyl CH ₂ CH CH ₂ CH ₂ -2-FUR ^ani ^ CH ₂ CH CH ₂ CH ₂ -3 -furanyl CH ₂ CH CH ₂ CH ₂ -2-thienyl CH ₂ CH ₃ CH ₂ CH ₂ -3-thienyl CH ₂ CH

CP3 C = C- (2-C1) Pb

CP3 C3C- (3-C1) Pb

CPz CeC- (4-C1) Pb

SRz C = C- (2-E) PH

CP3 0 = 0- (3-E) Pb

CP3 C = C- (4-P) PbH

CP3 C = C- (2-OH) Pb

CP3 C = C- (3-OH) Pb

CP3 C = C- (4-OH) Pb

CP3 C = C- (2-OMe) Pb

CP3 C = C- (3-OMe) PbH

CP3 C = C- (4-OMe) Pb

CP3 C = C- (2-CU) Pb

SRz C = C- (3-SUR

SRz C = C- (4-SUR

CP3 C = C— ( _2-2 ) Pb

CP3 C = C- (3 -0 ₂ ) Pb

CP3 C = C- (4-OO ₂ ) Pb

CP3 C = C- (2-OH ₂ ) Pb

CP3 C = C- (3-MH ₂ ) Pb

CP3 C = C- (4-OH ₂ ) PbH

CP3 C ^ C- (2-IME ₂ ) PbH

CP3 C = C- (3-MMe ₂ ) PbH

CP3 C = C- (4-IME ₂ ) PbH

SRz C = C-3-DiriDil

CP3 C = C-4-pyridyl

SRz C = C-2-furanylN

CP3 c = c_z-furanylN

CP3 C = C-2- 'thienyl H

CP3 C = C-3-thienyl

SRz szS-2 - oxazolyl

CP3 c = c-2-thiazolylN

CP3 C = C-4-isoxazolyl n CP3 C = C-2-imidazolylN

CP3 C = C- (2-C1) PbH

CP3 C = C- (3-C1) PbH

CP3 C = C- (4-C1) PbH

CP ₃ C = C- (2-P) PH

CP3 C = C- (3-E) Pb

CP3 C = C— (4-E) PbH

CP3 C = C- (2-OH) PbH

SRz C = C- (3-OH) Rn

CP3 C = C- (4-OH) PbH

CP3 C = C- (2-OMe) Pb

CP3 C = C- (3-OMe) PbH

CP3 C = c- (4-OMe) PbH

CP3 C = C- (2-CU) Pb

CP3 C = C- (3-CY) Pb

CP3 C = C- (4-CH) Pb

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5.6- άχΟΙ SRz

5.6- άίΟ1 SRz

5.6- άίΟΙ SRz

5.6- 6.101 SRz

5.6- άχΟΙ SRz

5,6-άχΟΙ SRz

5,6-άχΟΙ ‘SRz

5.6- άχΟΙ SRz

5.6- άίΟ1 SRz

5.6- άχΟΙ SRz

5.6- <1xC1 SRz

5.6- άχΟΙ SRz

5.6- άίοι spp

5.6- άχΟΙ SRz

5,6-άχΟΙ SRz

5,6-άχΟΙ SRz

5.6- άχΟΙ SR ₃

5.6- (1101 SRz

5.6- άχΟΙ SRz

5.6- άίΟΙ SRz

5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ SRz

5,6-άίΟΙ SRz

5,6-άίΟΙ SRz

5.6- άίΟΙ C? S

5.6- άχΟΙ SR ₃

5.6- άίΟΙ SRz

5,6-άίΟΙ SRz

5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ C? S

5,6-άίΟΙ SRz

5.6- άίΟΙ CP ₃

5.6- άίΟ1 SRz

5.6- άίΟΙ CP ₃

5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ CP ₃

5,6-άίΟΙ CP ₃

5,6-άίΟΙ * CP ₃ 5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ SRz

5,6-άίΟΙ SGz

5,6-άίΟΙ CP ₃

5,6-άίΟΙ CP ₃

5,6-άίΟΙ CP ₃

5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ SRz

5, b-άίθΐ CP ₃

5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ C? S

5,6-άίΟΙ SRz

5,6-άίΟΙ CP ₃

5,6-άίΟΙ SRz

5,6-άίΟΙ SRz

5.6- άίΟΙ CP ₃

5.6- άίθΐ CPz

5.6- άχΟΙ SR ₃

5,6-άίΟΙ SGZ 5,6-άίΟΙ Sez 5,6-άίΟΙ SRz 5,6-άίΟΙ Sez 5,6-άχΟ1 CE ₃ 5,6-άίΟΙ Sez

C = C- (2-ΝΟ ₂ ) PH

C = C- (3-ΝΟ ₂ ) Pb

C = C- (4-ΝΟ ₂ ) Pb

C = C- (2-MH ₂ ) PbH

C = C- (3-OH ₂ ) Pb

C = C- (4-ΝΗ ₂ ) Pb

C = C- (2NMe ₂ ) Pb

C = C- (3ME ₂ ) PbH

C = C- (4-LMe ₂ ) PbH

C — C — 3—. pyridyl

0 = 0-4-1 pyridyl

C = C-2- / furanylN * C = C-3- furanyln

C = C-2-thienyl

C = C — 3 - thienyl

C = C-2-oxazolyl

C = C-2-thiazolyl

C = C-4-isoxazolyl

C = C-2-imidazolyl H

CH ₂ CH _{2 -} ssgrn

CH ₂ CH ₂ CH ₂ CH ₂ ONN

CH ₂ CH ₂ —CH (OH) MeH

CH ₂ CH ₂ -Pn

CH ₂ CH ₂ - (2-C1) PH

CH ₂ CH ₂ - (3-C1) Pb

CH ₂ CH ₂ - (4-C1) Pb

CH ₂ CH ₂ - (2-P) PH

CH ₂ CH ₂ - (3-P) Pb

CH ₂ CH ₂ - (4-E) PH

CH ₂ CH ₂ - (2-OH) PH

CH ₂ CH ₂ - (3-OH) Pb

CH ₂ CH ₂ - (4-OH) Pb

CH ₂ CH ₂ - (2-OMe) PH

CH ₂ CH ₂ - (3-OMe) PH

CH ₂ CH ₂ - (4-OMe) PH

CH ₂ CH ₂ - (2-ΟΝ) PH

CH ₂ CH ₂ - (3-CH) RH

CH ₂ CH ₂ - (4-SI) PH

CH ₂ CH ₂ - (2-ΝΟ ₂ ) PH

CH ₂ CH ₂ - (3O ₂ ) Pb

CH ₂ CH ₂ - (4-ΝΟ ₂ ) PH

CH ₂ CH ₂ - (2-ΝΗ ₂₎ PH

CH ₂ CH ₂ - (3-OH ₂ ) Pb

CH ₂ CH ₂ - (4-ΝΗ ₂ ) PbΗ

CH ₂ CH ₂ - (2-IME ₂ ) PH

CH ₂ CH ₂ - (3-KMe ₂ ) PH. CH ₂ CH ₂ - (4HMe ₂ ) PH

CH ₂ CH ₂ -2- pyridylN

CH ₂ CH ₂ -3-pyridyl

CH ₂ CH ₂ -4- pyridyl

CH ₂ CH ₂ -2- furanylN

CH ₂ CH ₂ -3- Furanyln

CH ₂ CH ₂ -2- thienyl

CH ₂ CH ₂ -3-thienylN

CH ₂ CH ₂ -2- · oxazolylN

CH ₂ CH ₂ -2- thiazolyln

CH ₂ CH ₂ -4-isoxazolylz

CH ₂ CH ₂ -2- imidazolylN

Ce2-sousRg SNZ C = C-2-pyridyl SNZ C = c-3-pyridyl SNZ C = c-4-pyridyl SNZ C == C-2- furanyl SNZ ΟξΟ-Z-Furanyl SNZ 0 = 0-2 - thienyl SNZ C = C-3-thienyl. SNZ C = C-sous SNZ C = C-2-pyridyl SNZ

607 5,6-άίΟΙ SRz C = c-3-. pyridyl SNZ 608 5,6-άίΟΙ 'CP ₃ C = C-4-pyridyl SNZ 609 5,6-άίΟΙ SRz C = C-2 - furanyl SNZ 610 5,6-άίΟΙ SRz C = C-3- Furanyl SNZ 611 5,6-άίΟΙ SRz C = C-2-1thienyl SNZ 612 5,6-άίΟΙ SRz C = C-3-thienyl SNZ 613 5,6-άίΟΙ ₍ SRz CH ₂ CH ₂ sigRg SNZ 614 5,6-άίΟΙ SRz CH ₂ CH ₂ -PB SNZ 615 5,6-άίΟΙ SRz CH2CH2-2- pyridyl SNZ 616 5,6-άίΟΙ SRz CH2CH2-Z- pyridyl SNZ 617 5,6-άίΟΙ SRz CH2CH2-4- pyridyl SNZ 618 5,6-άϊΟ1 SRz CH ₂ CH ₂ -2- furanyl SNZ 619 5,6-άΐΟΙ SRz CH2CH2-Z-Furanyl SNZ 620 5,6-άίΟΙ SRz * CH ₂ CH ₂ -2- thienyl SNZ 621 5,6-άίΟΙ SRz CH2CH2-Z-thienyl SNZ 622 5,6-άίΟ1 SRz C ^ C-sousPr CH ₂ CH ₃ 623 5,6-άίΟΙ SRz C = C-Pb CH ₂ CH ₃ 624 5,6-άίΟΙ SRz C = C-2-pyridyl CH ₂ CH ₃ 625 5,6-άϊΟΙ SRz 0 = 0-3- 'pyridyl CH ₂ CH ₃ 626 5,6-άίΟΙ SRz C = C-4 ~ pyridyl CH ₂ CH ₃ 627 5,6-άίΟ1 SRz C = C-2-furanyl CH ₂ CH ₃ 628 5,6-άίΟΙ SRz C = C-3- furanyl CH ₂ CH ₃ 629 5,6-άίΟΙ SRz C = c-2-thienyl CH ₂ CH ₃ 630 5,6-άίΟΙ SRz C = C_3_thienyl CH ₂ CHZ 631 5,6-άίΟΙ SRz C = C-sous CH ₂ CH ₃ 632 5,6-άίΟΙ SRz C = C-Pb CH ₂ CH ₃ 633 5,6-άίΟΙ SRz C = C-2-pyridyl CH ₂ CH ₃ 634 5,6-άίΟΙ SRz C = C-3-pyridyl CH ₂ CHZ 635 5,6-άίΟΙ SRz C = C-4-pyridyl CH ₂ CH ₃ 636 5,6-άίΟΙ SRz C = C-2- Furanyl CH ₂ CH ₃ 637 5,6-άίΟΙ SRz C = C-3- afuranyl CH ₂ CH ₃ 638 5,6-άίΟΙ SRz C = C-2-thienyl CH ₂ CH ₃ 639 5,6-άίΟΙ SRz C = C-3 - -Phenium CH ₂ CH ₃ 640 5,6-άίΟΙ SRz CH ₂ CH ₂ sigRg CH ₂ CH ₃

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Sez C = C — 3 - Pyridyl n SGZ SzS-4- pyridyl n SGZ SS-2- furanyl n Sez C = C-3-furanyl n SGZ C = C-2-thienyl n SGZ CeS-Z-thienyl n SGZ C = C_2-oxazolyl n Sez C = C-2-thiazolyl n Sez C = C-4-. isoxazolyl n Sez O = C-2-imidazolyl n SGZ C = CCH ₂ CH ₂ OH n SGZ C = C-CH (OH) Me n Sez C = C- (2-C1) Pb n Sez ‘C = C- (3-C1) Pb n Sez C = C- (4-C1) Pb n SGZ C = C- (2-E) Pb n Sez C = C- (3-D) Pb n Sez C = C- (4-D) Pb n Sez C = C- (2-OH) Pb n Sez C = C- (3-OH) Pb n Sez C = C- (4-OH) Pb n Sez C = C- (2-OMe) Pb n Sez C = C- (3-OMe) Pb n Sez C = C- (4-OMe) Pb n Sez C = C- (2-CY) Pb n Sez C = C- (3-CY) Pb n Sez C = C- (4-C1T) Pb n SGZ C = C- ( _2-2 ) Pb n Sez C = C- (3-BO ₂ ) Pb n Sez C = C- (4-ΝΟ ₂ ) Pb n SGZ C = C- ( _2-2 ) Pb n Sez C = C- (3-IN ₂ ) Pb n SGZ C = C- (4-OH ₂ ) Pb n SGZ C = C- (2-YMe ₂ ) Pb n

641 5,6-άίΟ1 . ^Wed z CH ₂ CH ₂ -PB CH ₂ CH ₃ 642 5,6-άίΟΙ SRz CH2CH2-2-: pyridyl CH ₂ CH ₃ 643 5,6-άίΟΙ SGZ CH ₂ CH ₂ -3-pyridyl CH ₂ CH ₃ 644 5,6-άίΟ1 SGZ CH2CH2-4-pyridyl. CH2CH3 645 5, 6-άίΟ1 SGZ CH ₂ CH2-2- furanyl CH ₂ CH ₃ 646 5,6-άίΟΙ SRz CH ₂ CH ₂ -3- Furanyl CH ₂ CH ₃ 647 5,6-άίΟΙ  SRz CH ₂ CH ₂ -2- thienyl CH ₂ CH ₃ 648 5,6-άίΟΙ SGZ CH ₂ CH ₂ -3-thienyl CH ₂ CH ₃ 649 6-Ρ SRZ C = CCH ₂ CH ₂ OH N 650 6-Ρ SGZ C ^ C-CH (OH} Me N 651 6-Ρ SR ₃ C = C- (2-C1) Pb n 652 6-Ρ SGZ C = C- (3-C1) Pb n 653 6-Ρ SGZ , C = C- (4-C1) Pb n 654 6-Γ SGZ C = C- (2-E) Pb n 555 6-Ρ SGZ C = C— (3E) Pb n 656 6-Ρ Sez C = c- (4-P) Pb n 657 6-Ρ SRz C = C- (2-OH) Pb n 658 6-Ρ Sez C = C- (3-OH) Pb n 659 6-Ρ SGZ C = C- (4-OH) Pb n 660 6-Γ SGZ C = C- (2-OMe) Pb n 661 6-Ρ SRz C = C- (3-OMe) Pb n 662 6-Ρ Sez C = C- (4-OMe) Pb n 663 6-Ρ Sez C ^ C- (2-CM) Pb n 664 6-Γ SGZ CO (C-SY) R n 665 6-Ρ SGZ C = C- (4-C) Pb n 666 6-Ρ SGZ C = C- (2-BO ₂ ) Pb n 667 6-Γ SGZ C = C- (3-H0 ₂ ) Pb n 668 6-Γ SGZ C = C- (4-uQ ₂₎ Ph n 669 6-Γ Sez SES- (2-UN ₂ ) Pb n 670 6-Ρ Sez ΟξΟ- (3-ΝΗ ₂ ) Pb n 671 6-Γ Sez C = C- (4 ~ ₂ ) Pb n 672 6-Ρ Sez C ^ C- (2ME ₂ ) Pb n 673 6-Γ Sez C = C- (3-IME ₂ ) Pb n 674 6-Ρ Sez C = C- (4-Mme ₂ ) Pb n

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6-g SGZ C = C- (3-IME ₂ ) Pb N 6 g SGZ C = C- (4THMe ₂ ) Pb n 6-P Sez C = C-3- pyrrhyl n bp Sez C = C-4-pyridyl n b-e SGZ C = C-2- / furanyl n b-e SGZ C = C-3- furanyl n 6-P * SGZ 0 = C_2- thienyl n 6-P Sez C = C-3- -Thienyl n bp SGZ C = C-2-oxazolyl n 6-P Sez C = C-2-thiazolyl n bp Sez C = C-4-isoxazolyl n 6th Sez C = C-2-imidazolyl n 6-P Sez. CH ₂ CH ₂ sigRg n 6-P SGZ CH ₂ CH ₂ CH ₂ CH ₂ OH n 6-g Sez CH ₂ CH ₂ —CH (OH) Me n 6-P Sez CH ₂ CH ₂ - (2-C1) Pb n 6-P Sez CH ₂ CH ₂ - (3-C1) Pb n 6-P SGZ CH ₂ CH ₂ - (4-C1) Pb n 6 g Sez CH ₂ CH ₂ - (2-D) Pb n 6th Sez CH ₂ CH ₂ - (3-E) Pb n 6th CE ₃ CH ₂ CH ₂ - (4-E) Pb n 6-P Sez CH ₂ CH ₂ - (2-OH) Pb n 6-P Sez CH ₂ CH ₂ - (3-OH) Pb n 6-P Sez CH ₂ CH ₂ - (4-OH) Pb n 6-P CE ₃ CH ₂ CH ₂ - (2-OMe) Pb n bp SRz CH ₂ CH ₂ - (3-OMe) Pb n 6th Sez CH ₂ CH ₂ - (4-OMe) Pb n 6th Sez CH ₂ CH ₂ - (2-CH) Pb n 6-P Sez CH ₂ CH ₂ - (3-CH) Pb n 6-P Sez CH ₂ CH ₂ - (4-CH) Pb n b-e Sez CH ₂ CH ₂ - (2NO ₂ ) Pb n 6th Sez CH ₂ CH ₂ - (3O ₂ ) Pb n 6th Sez CH ₂ CH ₂ - (4-MO ₂ ) Pb n 6th SR ₃ CH ₂ CH ₂ - (2-ΝΗ ₂ ) Pb n

743 6-K SR ₃ CH ₂ CH ₂ - (3-ΝΗ2) pH n 744 6-P SGZ CH ₂ CH ₂ - {4-OH ₂ ) pH n 745 6-P SRz CH ₂ CH ₂ - (2-MMe ₂ ) pH n 746 6-P SRz CH ₂ CH ₂ - (3-NMe ₂ ) RI n 747 6-P SRz CH ₂ CH ₂ - (4-MMe ₂ ) pH n 748 6-P SRz CH ₂ CH ₂ -3-pyridyl n 749 6-P ‘SRz CH ₂ CH ₂ -4-pyridyl n 750 6-P SRz CH ₂ CH ₂ -2- furanyl n 751 6-P SRz CH ₂ CH ₂ -3- furanyl n 752 6-P SRz CH ₂ CH ₂ -2-GPIenyl n 753 6-P SRz CH ₂ CH ₂ -3-thienyl n 754 6-P SRz CH ₂ CH ₂ -2-oxazole silt n 755 6-P SRz • CH ₂ CH ₂ -2- Thiazolyl n 756 6-P SRz CH ₂ CH ₂ -4-isoxazolyl n 757 bp SRz CH ₂ CH ₂ -2- imidazolyl n 758 bp SRz C ^ C-sousPr SNZ 759 6-P SRz C = C-1Pg SNZ 760 6-P SRz SnS-Rg SNZ 761 6-P SRz C = C-Vi SNZ 762 6-P SRz Cr = C-1 Vi SNZ 763 6-P SRz C == C-bVi SNZ 764 6-P SRz SGS-E SNZ 765 6-P SRz C ^ C-Me SNZ 766 bp SRz SzS-RI SNZ 767 6-P SRz C = C-2-pyridyl SNZ 768 bp SRz C ^ C-Z-pyridyl SNZ 769 bp SRz SvS-4-; pyridyl SNZ 770 bp SRz C = C-2- Furanyl SNZ 771 bp SRz C = C — 3- Furanyl SNZ 772 6-P SRz CeC-2-thienyl SNZ 773 bp SRz C = c- ₃ - - thienyl SNZ 774 6-P SRz C = C-sous SNZ 775 bp SRz C = C-1Pg SNZ 776 bp SRz C = C-Pr SNZ

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6-P SRz C = C-3-Pyridyl CH ₂ CH 6-P SRz C = C-4-pyridyl, CH ₂ CH 6-P SRz c = c-2-furanyl CH ₂ CH bp SRz C = C-3-furanyl CH ₂ CH 6-P SRz C = C-2- 'thienyl CH ₂ CH 6-P SRz C = C-3-thienyl CH ₂ CH bp ₍ SRz CH ₂ CH ₂ sigRg CH ₂ CH 6-P SRz CH ₂ CH ₂ -RN sun ₂ sun ₃ 6-P SRz CH ₂ CH ₂ -2- pyridyl CH ₂ CH 6-P SRZ CH ₂ CH ₂ -3-pyridyl CH ₂ CH ₃ 6-P SRz CH ₂ CH ₂ -4-pyridyl CH ₂ CH 6-P SRz CH ₂ CH ₂ -2- furanyl CH ₂ CH 6-P SRz CH ₂ CH ₂ -3- Furanyl CH ₂ CH 6-P SRz 'CH ₂ CH ₂ -2- thienyl CH ₂ CH 6-P SRz CH ₂ CH ₂ -3- ι-thienyl CH ₂ CH 5-C1 SRz SS-ssrg n 5-C1 SRz C = CCH ₂ CH ₂ OH n 5-C1 SRz C = C — CH (OH) Me n 5-C1 SRz C = C-PH n 5-C1 SRz C ^ C- (2-C1) pH n 5-C1 SRz CeS- (3-C1) Pb n 5-C1 SRz CeS- (4-C1) Pb n 5-C1 SRz C = C- (2-P) pH n 5-C1 SRz C = C- (3-P) Pb n 5-C1 SRz C = C- (4-P) pH n 5-C1 SRz C = C— (2-OH) pH n 5-C1 SRz C = C- (3-OH) pH n 5-C1 SRz C®C- (4-OH) Pb n 5-C1 SRz C = C- (2-OMe) pH n 5-C1 SRz C = C- (3-OMe) pH n 5-C1 SRz C®C- (4-OMe) pH n 5-C1 SRz C = C- (2-CY) PH n 5-C1 SRz Sn = s- (3-SI) pH n 5-C1 SRZ SzS- (4-SY) PH n

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bp SRz C = C-Vi SNZ bp SRz C = C-1 Vi SNZ bp SRz C = C-HBi SNZ bp SRz C = C-E SNZ 6-P SRz C = c-Me SNZ 6-P SRz C = C-RI SNZ 6-P • SRz C = C-2-pyridyl SNZ 6-P s? s C = c-3-pyridyl SNZ 6-P SRz C = C-4-pyridyl SNZ 6-P SRz C = C-2 - -Furanyl SNZ 6-P SRz C = C-3-furanyl- SNZ 6-P SRz C = C-2-thienyl SNZ 6-P SRz. thienyl SNZ 6-P SRz CH ₂ CH ₂ sigRg SNZ bp SRz CH ₂ CH ₂ -RN SNZ bp SRz CH ₂ CH ₂ -2-'Niridyl SNZ 6-P SRz CH ₂ CH ₂ -3-pyridyl SNZ bp SRz CH ₂ CH ₂ -4-pyridyl SNZ 6-P SRZ CH ₂ CH ₂ -2- FURanyl SNZ 6-P SRz CH ₂ CH ₂ -3 - furanyl SNZ 6-P S? 3 CH ₂ CH ₂ -2- thienyl SNZ 6-P SRz CH ₂ CH ₂ -3 * thienyl SNZ 6-P SRz C ^ C-sousPr CH ₂ CH 6-P SRz C = C-PH CH ₂ CH ₃ 6-P SRz C ^ C-2-pyridyl CH ₂ CH 6-P SRz C = C-3-pyridyl CH2CH3 6-P SRz C ^ C-4-pyridyl CH ₂ CH 6-P SRz _C = C_2-. CH ₂ CH 6-P SRz C = C_3_ furanyl CH ₂ CH 6-P SRz C = C-2-thienyl CH ₂ CH ₃ 6-P SRz C = C_3 _, thienyl CH ₂ CH ₃ 6-P SRz C = C-sous CH ₂ CH 6-P SRz C = C-Pb CH ₂ CH bp SRz C = C-2-pyridyl CH ₂ CH

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5-C1 SRz C = C- (2-ΝΟ ₂ ) PH n 5-C1 SRz C = C- (3-ΝΟ ₂ ) PH n 5-C1 SRz C = C- (4-ΝΟ ₂ ) pH n 5-C1 SRz C = C- (2-ΝΗ ₂ ) PH n 5-C1 SRz C = C- (3-ΝΗ ₂ ) PH n 5-C1 SRz C = C- (4-OH ₂ ) pH n 5-C1 • SRz СеС- (2-НМе ₂ ) LV n 5-C1 SRz C = C- (3ME ₂ ) pH n 5-C1 SRz С = С- (4-НМе ₂ ) PH n 5-C1 SRz C = C-2-pyridyl n 5-C1 SRz C ^ C-2-pyridyl n 5-C1 SRz C = eS-3 - pyridyl n 5-C1 SRz. C = C_4_ pyridyl n 5-C1 SRz C = C-2-furanyl n 5-C1 SRz C ^ C-3-Furanyl n 5-C1 SRz C = C-2-thienyl n 5-C1 SRz C = C — 3 — thienyl n 5-C1 SRz C = C-2-oxazolyl n 5-C1 SRz <2 = c_2- thiazolyl n 5-C1 SRz O = s_4_ isoxazolyl n 5-C1 SRz C = C-2-imidazolyl n 5-C1 SRz C = C-sous n 5-C1 SRz c = sc ₂ sn ₂ he n 5-C1 SRz C = C-CH (OH) Me n 5-C1 SRz C = C-PH n 5-C1 SRz C = C- (2-C1) pH n 5-C1 SRz C = C- (3-C1) pH n 5-C1 SRz C = C- (4-C1) pH n 5-C1 SRz C = C- (2-P) pH n 5-C1 SRz C = C- (3-P) pH n 5-C1 SRz C = C- (4-P) pH n 5-C1 SRz C = C- (2-OH) pH n 5-C1 SRz C = C- (3-OH) pH n 5-C1 SRz C = C- (4-OH) pH n

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C = C- (2-ohm) Pb

C = C- (3-OMe) Pb

C = C- (4-OMe) PbH

C = C- (2-CY) RH

C = C- (3-0Ν) Pb

C = C- (4-CH) Pb

C = C- (2-ΝΟ ₂ ) PH

C = C- (3-BO ₂ ) RIN

C = C- (4-ΝΟ2) RN

C = C- (2-OH ₂ ) Pb

C = C- (3-YN ₂ ) RIN

C = C- (4-ΝΗ ₂ ) Pb

C = C- (2NMe ₂ ) RN

C = C- (3MYe ₂ ) PbH

C = C- (4HMe ₂ ) PbH

C = C-2-pyridyl

C = C-2- ^pi R ^idyl; _C = _C- 3-pyridyl

C = C-4-pyridyl

C = C-2- Furanyl

C = C-3- Furavil

C = C-2-thienyln

C = C-3-thienyl

C ₌ C_2_oxazolyl

C = C-2-gti.azoLiLn

C = C-4-isoxazolyl

C ₌ C_2-imidazolyl

CH ₂ CH ₂ -sigRgN

CH ₂ CH ₂ CH ₂ CH ₂ ONN

CH2CH2-CH (OH) MeN

CH ₂ CH ₂ RN

CH ₂ CH ₂ - (2-C1) RN

CH ₂ CH ₂ - (3-C1) Pb

СН2СН2- (4-С1) РНН

CH2CH2- (2-E) PH

CH ₂ CH ₂ - (3-P) Rb

СН2СН2- (4-Е) РНН

CH ₂ CH ₂ - (2-OH) PH

CH ₂ CH ₂ - (3-OH) Pb

CH2CH2- (4-OH) PH

CH2CH2- (2-OMe) RH

CH ₂ CH ₂ - (3-OMe) РНН

CH ₂ CH ₂ - (4-OMe) RN

CH ₂ CH ₂ - (2-CM) PH

CH ₂ CH ₂ - (3-CM) Pb

CH2CH2- (4-CM) Rb. CH ₂ CH ₂ - (2-ΝΟ ₂ ) RN

CH ₂ CH ₂ - (3-ΝΟ ₂ ) Pb

CH2CH2- (4-ΝΟ2) PHB

CH ₂ CH ₂ - (2-ΝΗ ₂ ) PH

CH ₂ CH ₂ - (3-MH ₂ ) PH

CH ₂ CH ₂ - (4-OH ₂ ) PH

CH ₂ CH ₂ - (2-MMe ₂ ) PH

CH ₂ CH ₂ - (3-IME ₂ ) PH

CH ₂ CH ₂ - (4HMe ₂ ) PH

CH2CH2-2-pyridyln

CH ₂ CH ₂ -3 - pyriddle n CH ₂ CH ₂ ~ 4- pyridyl n CH ₂ CH ₂ -2- furan il n CH ₂ CH ₂ -3- Furanyl n CH ₂ CH ₂ -2-. thienyl n CH ₂ CH ₂ -3-thienyl n CH ₂ CH ₂ -2- oxazolyl n CH ₂ CH ₂ -2- '' thiazolyl n CH ₂ CH ₂ -4- from oxazolyl n CH ₂ CH ₂ -2 - ymidae about l and l n C = C-sous SNZ C = C-Pb SNZ

947 5-C1 CE ₃ C ^ C-2-pyridyl SNZ 948 5-C1 CE ₃ C = c-3-pyridyl SNZ 949 5-C1 Sez Os-4- pyridyl SNZ 950 5-C1 CE ₃ C = C-2-furanyl SNZ 951 5-C1 Sez C = C-3-furanyl SNZ 952 5-C1 Sez C = c-2-thienyl SNZ 953 5-C1 . Sez C ^ C-3-thienyl SNZ 954 5-C1 CE ₃ C = C-sous SNZ 955 5-C1 Sez C = C-Pb SNZ 956 5-C1 Sez C = C-2-pyridyl SNZ 957 5-C1 Sez C — C — 3 — pyridyl SNZ 958 5-C1 Sez C = C-4-pyridyl SNZ 959 5-C1 CE ₃ C = C-2- Furanyl SNZ 960 5-C1 CE ₃ C = C-3- furanyl SNZ 961 5-C1 CE ₃ C = C-2-thienyl SNZ 9 "2 5-C1 CE ₃ C = C — 3-thienyl SNZ 963 5-C1 CE ₃ CH ₂ CH ₂ sigRg SNZ 964 5-C1 CE ₃ CH ₂ CH ₂ -PB SNZ 965 5-C1 Sez CH ₂ CH ₂ -2- pyridyl SNZ 966 5-C1 CE ₃ CH ₂ CH ₂ -3-pyridyl SNZ 967 5-C1 CE ₃ CH ₂ CH ₂ -4-pyridzhl SNZ 968 5-C1 CE ₃ CH ₂ CH ₂ -2-furanyl SNZ 969 5-C1 Sez CH ₂ CH ₂ -3-furanyl SNZ 970 5-C1 Sez CH ₂ CH ₂ -2- clings SNZ 971 5-C1 CE ₃ CH2CH2-Z-thienyl SNZ 972 5-C1 Sez C = C-sous CH ₂ CH ₃ 973 5-C1 CE ₃ C = C-Pb CH ₂ CH ₃ 974 5-C1 Sez C = C-2- Pyridyl CH ₂ CH ₃ 975 5-C1 CE ₃ C = C-3-pyridyl CH ₂ CH ₃ 976 5-C1 CE ₃ OS-4 - pyridyl CH ₂ CH ₃ 977 5-C1 Sez C = C-2-furanyl CH ₂ CH ₃ 978 5-C1 CE ₃ O = C-3-furanyl CH ₂ CH ₃ 979 5-C1 Sez OS-2- thienyl CH ₂ CH ₃ 980 5-C1 Sez C = c ~ z_ thienyl CH ₂ CH ₃

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5-C1 Sez C = C-sous CH ₂ CH ₃ 5-C1 CE ₃ C = C-Pb CH ₂ CH ₃ 5-C1 Sez C = C-2-pyridyl CH ₂ CH ₃ 5-C1 Sez C = C-3-pyridyl CH ₂ CH ₃ 5-C1 CE ₃ C = C-4-pyridyl CH ₂ CH ₃ 5-C1 CE ₃ C = C-2-furanyl CH2CH3 5-C1 * Sez C = C-3-furanyl CH ₂ CH ₃ 5-C1 CE ₃ C = C-2- thienyl CH ₂ CH ₃ 5-C1 CE ₃ C = C-3 - (. Thienyl CH ₂ CH ₃ 5-C1 Sez CH ₂ CH ₂ sigRg CH ₂ CH ₃ 5-C1 CE ₃ CH ₂ CH ₂ -P CH ₂ CH ₃ 5-C1 Sez CH ₂ CH ₂ -2 “pyridyl CH ₂ CH ₃ 5-C1 Sez. CH ₂ CH ₂ -3 - Pyridyl CH ₂ CHZ 5-C1 CE ₃ CH ₂ CH ₂ -4-pyridyl CH ₂ CH ₃ 5-C1 Sez CH ₂ CH ₂ -2 “FURani'L CH ₂ CH ₃ 5-C1 Sez CH ₂ CH ₂ -3- furanyl CH ₂ CH 5-C1 Sez CH ₂ CH ₂ -2 -thienyl CH ₂ CH ₃ 5-C1 Sez CH ₂ CH ₂ -3-thienyl CH ₂ CH ₃ 5th Sez C ^ C-sousPr n 5th Sez C = CCH ₂ CH ₂ OH n 5th CE ₃ C = C-CH (OH) Me n 5th CE ₃ SS-R n 5th CE ₃ C = C- (2-C1) Pb n 5th CE ₃ C = C- (3-C1) Pb n 5th CE ₃ C = C- (4-C1) Pb n 5th CE ₃ C = C- (2-E) Pb n 5th CE ₃ C = C- (3-E) Pb n 5th CE ₃ C = C- (4-E) RI n 5th CE ₃ OS- (2-OH) P n 5th Sez C = C- (3-OH) Pb n 5th CE ₃ & = C- (4-OH) Pb n 5th CE ₃ OS- (2-OMe) Ръ n 5th CE ₃ C = c- (3-OMe) Pb n 5th CE ₃ C = C- (4-OMe) Pb n

1015 5-P SRz

1016 5-P SRz

1017 5-P SRz

1018 5-P SRz

1019 5-P SRz

1020 5-P SRz

1021 5-P · SRz

1022 5-P SRz

1023 5-P SRz

1024 5-P SRz

1025 5-P SRz

1026 5-P SRz

1027 5-P SRz

1028 5-P CP ₃

1029 5-P SRz

1030 5-P SRz

1031 5-P SRz

1032 5-P SRz

1033 5-P CP ₃

1034 5-P SRz

1035 5-P SRz

1036 5-P SRz

1037 5-P CP ₃

1038 5-P SRz

1039 5-P CP ₃

1040 5-P C? S

1041 5-P CP ₃

1042 5-P SRz

1043 5-P C? S

1044 5-P SRz

1045 5-P CP ₃

1046 5-P CP ₃

1047 5-P SRz

1048 5-P SRz

1049 5-P SRz

1050 5-P SRz

1051 5th CP ₃

1052 5-P SRz

1053 5-P CP ₃

1054 5-P SRz

1055 5-P * CP ₃

1056 5-P CP ₃

1057 5-P CP ₃

1058 5-P SRz

1059 5-P SRz

1060 5-P CP ₃

1061 5-P SRz-

1062 5-P C? S. 1063 5-P CPz

1064 5-P CP ₃

1065 5-P SRz

1066 5-P CP ₃

1067 5-P SRz

1068 5-P SRz

1069 5-P CP ₃

1070 5-P CP ₃

1071 5-P SRz

1072 5-P CP ₃

1073 5-P CP ₃

1074 5-P CP ₃

1075 5-P CP ₃

1076 5-P SRz

1077 5-P SRz

1078 5-P CP ₃

1079 5-P SRz

1080 5-P CP ₃

1081 5-P CP ₃

1082 5-P SRz

1083 5-P SRz 1084 5-P SRz 1085 5-P SRz 1086 5-P SRz 1087 5-P SRz 1088 5-P SRz 1089 5-P ‘SRz 1090 5-P SRz 1091 5-P SRz 1092 5-P SRz 1093 5-P SRz 1094 5-P SRZ 1095 5-P SRz 1096 5-P SRz 1097 5-P SRz 1098 5-P SRz 1099 5-P SRz 1100 5-P SRz 1101 5-P SRz 1102 5-P SRz 1103 5-P SRz 1104 5-P SRz 1105 5-P SRz 1106 5-P SRz 1107 5-P SRz 1108 5-P SRz 1109 5-P SRz 1110 5-P SRz 1111 5-P SRz 1112 5-P SRz 1113 5-P SRz 1114 5-P SRZ 1115 5-P SRz 1116 5-P SRz

C = C- (2-SI) Pb

C = C- (3-CY) Pb

C = C- (4-SI) PbH

C = C- (2-OO ₂ ) PH

C = C- (3-ΝΟ ₂₎ Ph

C = C- (4-ΝΟ ₂ ) Pb

C ^ C- (2-OH ₂ ) Pb

C = C- (3-ΝΗ ₂₎ Ph

OS- (4-IN ₂ ) Pb

C ^ C- (2ME ₂ ) Pb

C ^ C- (3ME ₂ ) Pb

C = C- (4HMe ₂ ) PbH

C = C-2-pyridylN

C ^ C-2-pyridyl H

C ^ C-3-lpyridylN

C == c-4-pyridylN

SES-2furanyl

C = C-3- -furanyl H

C = C-2- thienyl H

C ^ C-3-thienyl

C = c-2-yuxazolyl

C = C_2-thiazolyl H _c = 0_4_ isoxazolyl

C = C-2-. Imidazolyl H

C = C-cusPrH

C = CCH ₂ CH ₂ ONN

C = C-CH (0H) MeH

C = C-Pb

C = C- {2-C1) Pb

C = C- (3-C1) Pb

C = C- (4-C1) PbH

C = C- (2-P) PbH

C = C- (3-P) Pb

C = C- (4-P) PbH

C = C- (2-OH) Pb

C = C- (3-OH) RIN

C = C- (4-OH) PH

C = c- (2-OMe) PbH

C = c- (3-OMe) Pb

C = C- (4-OMe) PbH

C = C- (2-CY) RH

С = С- (3-СЫ) РН

C = C- (4-CH) RH

C = C- {2-ΝΟ ₂ ) Pb

C = C- (3-ΝΟ ₂ ) pH

C = C- (4-ΝΟ ₂ ) Pb

C = C- (2-ΝΗ ₂ ) Pbη

C = C- (3-IN ₂ ) Pb

C = C- (4-ΝΗ ₂ ) pbH

C = C- (2NMe ₂ ) Pb

C = C- (3ME ₂ ) PbH

C = C- (4HMe ₂ ) PbH

C = C-2-pyridylN

C = C-2-pyridylN

C = C-3-pyridyl

C = C-4-pyridyl

C = C-2 - ‘furanyl

C = C-3- furanylN

C = C-2 .thienyl H

C = C-3 - thienyln

C = C-2-oxazolyl H

C = C-2-thiazodylN

C = C-4-isoxazolyl H

C = C-2-. ' imidazolylN

CH ₂ CH ₂ -sigRgN

CH ₂ CH ₂ CH ₂ CH ₂ ONN

CH ₂ CH ₂ —CH (OH) MeH

CH ₂ CH ₂ RHN

CH ₂ CH ₂ - (2-C1) Pb

CH ₂ CH ₂ - (3-C1) Pb

CH ₂ CH ₂ - (4-C1) PH

CH ₂ CH ₂ - (2-P) PH

CH ₂ CH ₂ - (3-P) Pb

CH ₂ CH ₂ - (4-P) PH

CH ₂ CH ₂ - (2-OH) PH

CH ₂ CH ₂ - (3-OH) PH

CH ₂ CH ₂ - (4-OH) PH

CH ₂ CH ₂ - (2-OMe) PH

CH ₂ CH ₂ - (3-OMe) PH

CH ₂ CH ₂ - (4-OMe) PH * CH ₂ CH ₂ - (2-ΟΝ) PH

CH ₂ CH ₂ - (3-CH) RH

CH ₂ CH ₂ - (4-CM) PH

CH ₂ CH ₂ - (2-ΝΟ ₂ ) PH

CH ₂ CH ₂ - (3O ₂ ) Pb

CH ₂ CH ₂ - (4O ₂ ) PH

CH ₂ CH ₂ - (2-ΝΗ ₂ ) PH

CH ₂ CH ₂ - (3-OH ₂ ) Pb

CH ₂ CH ₂ - (4-ΝΗ ₂ ) Pb

CH ₂ CH ₂ - (2-MMe ₂ ) PH

CH ₂ CH ₂ - (3-IME ₂ ) PH

CH ₂ CH ₂ - (4-IME ₂ ) PH

CH ₂ CH ₂ -2-pyridylN

CH ₂ CH ₂ -3-pyridylN

CH ₂ CH ₂ —4-pyridyl

CH ₂ CH ₂ -2-furanylN

CH ₂ CH ₂ -3-furanylN

CH ₂ CH ₂ -2- thienylN

CH ₂ CH ₂ -3- “thienylN

CH ₂ CH ₂ -2 -oxazolyl

CH ₂ CH ₂ -2- thiazolylN

CH ₂ CH ₂ -4-.isoxazolyl n

1117 5-P . SRz CH ₂ CH ₂ -2-imidazolyl n 1118 5-P SRz C ^ C-sousPr SNZ 1119 5-P SRz C = C-Pb SNZ 1120 5-P SRz C = C-2-pyridyl SNZ 1121 5-P SRz C ^ C-Z-pyridyl SNZ 1122 5-P SRz C = C-4-pyridyl SNZ 1123 5-P * SRH C = C-2-furanyl SNZ 1124 5-P SRz C = C-3- furanyl SNZ 1125 5-P SRz SzS-2-: thienyl SNZ 1126 5-P SRz C = c- ₃ - thienyl SNZ 1127 5-P SRz C = C-sous SNZ 1128 5-P SRz C = C-Pb SNZ 1129 5-P SRz . C = C-2-pyridyl SNZ Fine art 5-P SRz C = c-3-pyridyl SNZ 1131 5-P SRz C = C-4-pyridyl SNZ 1132 5-P SRz C = C-2-furanyl SNZ 1133 5-P SRz C = C-3- Furanyl SNZ 1134 5-P SRz C = C-2- thienyl SNZ 1135 5-P SRz C = C-3 - „thienyl SNZ 1136 5-P SRz CH ₂ CH ₂ sigRg SNZ 1137 5-P SRz CH ₂ CH ₂ -PB SNZ 1138 5-P SRz CH ₂ CH ₂ -2- pyridyl SNZ 1139 5-P SRz CH ₂ CH ₂ -3-pyridyl SNZ 1140 5-P SRz CH ₂ CH ₂ —4 · “pi ri d and l SNZ 1141 5-P SRz CH ₂ CH ₂ —2- -furanyl SNZ 1142 5-P SRz CH ₂ CH ₂ - 3- furanyl SNZ 1143 5-P SRz CH ₂ CH ₂ -2- thienyl SNZ 1144 5-P SRz CH ₂ CH ₂ -3-thienyl SNZ 1145 5-P SRz C = C-sous CH ₂ CH 1146 5-P SRz C = C-Pb CH ₂ CH ₃ 1147 5-P SRz C = C-2- -pyridyl CH ₂ CH 1148 5-P SRz C = C-3-pyridyl CH ₂ CH 1149 5-P SRz C = c-4 “-pyridyl CH ₂ CH 1150 5-P SRZ C = C-2-furanyl CH ₂ CH

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5-P SRz C = C-3-furanyl CH ₂ CH ₃ 5th Sez C = C-2-thienyl CH ₂ CH ₃ 5-P SGZ C = C — 3-thienyl CH ₂ CH ₃ 5-P Sez C = C-sous CH ₂ CH ₃ 5th Sez C = C-RI CH ₂ CH ₃ 5th Sez C = C-2-pyridyl CH ₂ CH ₃ 5th * Sez C = C-3-pyridyl CH ₂ CH ₃ 5th Sez C = C-4-pyridyl CH ₂ CH ₃ 5th CE ₃ C = C-2- Furanyl CH ₂ CH ₃ 5th Sez C = C-3- furanyl CH ₂ CH ₃ 5-P CE ₃ C = C-2- 'thienyl CH ₂ CH ₃ 5-P Sez C = C-3 - thienyl CH ₂ CH ₃ 5-P Sez . CH ₂ CH ₂ sigRg CH2CH3 5-P CE ₃ CH ₂ CH ₂ -PB CH ₂ CH ₃ 5-P CE ₃ CH ₂ CH ₂ -2- pyridyl CH ₂ CH ₃ 5-P Sez CH ₂ CH ₂ -3-pyridyl CH ₂ CH ₃ 5-P Sez CH ₂ CH ₂ -4-pyridyl CH ₂ CH ₃ 5-P Sez CH ₂ CH ₂ -2- .. Furanyl CH ₂ CH ₃ 5-P CE ₃ CH ₂ CH ₂ —3 - furanyl CH ₂ CH ₃ 5th Sez CH ₂ CH ₂ -2-thienyl CH ₂ CH ₃ 5th CE ₃ CH ₂ CH ₂ -3-thienyl CH ₂ CH ₃ 5-C1.6-E CE ₃ C = C-sous N 5-C1.6-E Sez C ^ C-Pb n 5-C1.6-E CE ₃ C = C-2-. Pyridyl n 5-S1,6-P SRz C ^ C-3- pyridyl n 5-C1, b-D CE ₃ C = C-4 - pyridyl N 5-S1,6-P CE ₃ C = c-2-furanyl n 5-S1,6-P Sez C = C-3- furanyl N 5-C1.6-P CE ₃ C = C-2-thienyl n 5-C1, br-P CE ₃ g- ^ 2-3.-thienyl n 5-S1,6-P Sez C = C-sous n 5-S1,6-P Sez C = C-Pb n 5-S1,6-P Sez C = C-2 ~ pyridyl n 5-S1,6-P CE ₃ C = C-3-pyridyl n

1219 5-C1.6-E CE ₃ 1220 5-S1,6-P CE ₃ 1221 5-C1, br-P Sez 1222 5-S1,6-P Sez 1223 5-S1,6-P CE ₃ 1224 5-S1,6-P CE ₃ 1225 5-S1,6-P ⁴ sez 1226 5-E, 6-C1 Sez 1227 5-E, 6-C1 CE ₃ 1228 5-E, 6-C1 Sez 1229 5-P, b-C1 Sez 1230 5-E, 6-C1 Sez 1231 5-E, 6-C1 CE ₃ 1232 5-P, 6-C1 Sez 1233 5-E, 6-C1 CE ₃ 1234 5-E, 6-C1 Sez 1235 5-E, 6-C1 Sez 1236 5-E, 6-C1 Sez 1237 5-E, 6-C1 Sez 1238 5-E, 6-C1 Sez 1239 5-E, 6-C1 CE ₃ 1240 5-E, 6-C1 Sez 1241 5-E, 6-C1 Sez 1242 5-P, 6-C1 Sez 1243 5-E, 6-C1 Sez 1244 5-E, 6-C1 Sez 1245 5-E, 6-C1 Sez 1246 5-E, 6-C1 Sez 1247 5-E, 6-C1 Sez 1248 5-P, b-C1 Sez 1249 5-E, 6-C1 Sez 1250 5-P.6-C1 Sez 1251 5-P, 6-C1 Sez 1252 5-E, 6-C1 CE ₃

SN2SN2-2- _P iridium CH2CH2 CH-W-pyridyl CH CH CH ₂ CH ₂ -4-pyridyl SN2SN2-2 .fur _aH-yl CH CH ₂ CH ₂ -3-furanyl SN2SN2-2- thienyl CH CH CH ₂ CH ₂ -3-thienyl _CH3

C = C-sousPrH

C ^ C-Pb n

CeS-2-pyridyl ⁿ CeS-3-pyridyl n C = C-4 pyridyl H C = C-2- 'Furanyl n C = C-3-furanyl ⁿ C = C-2-thienyl H C = C_3-thienyl N

C = C-sousPrH

C = C-Pb H C = C — 2-pyridyl H C = C-3-pyridyl n C = C-4-pyridyl _n C = C-2-furanyl H C = C-3-furanyl n C = C- 2- thienyl n С = С-3- thienyl Н СН ₂ СН ₂ -cuspg Н

CH ₂ CH ₂ -Pb n CH2CH2-2-pyridyl H CH2CH2-Z-pyridyl n CH ₂ CH ₂ -4-pyridyl _n CH ₂ CH ₂ -2 -furanyl H CH ₂ CH ₂ -3-furanyl n CH ₂ CH _{2 n} -2-thienyl CH ₂ CH _{2 n} -3- TDenil

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1218

5-C1.6-P Sez C = C-4-pyridyl n 5-C1.6-E Sez C = C-2 = furanyl n 5-S1,6-P Sez C = C-3-furanyl n 5-S1,6-P Sez C = c-2-thienyl n 5-C1.6-E Sez C = C-3 - thienyl n 5-C1, br-P Sez CH ₂ CH ₂ sigRg n 5-S1,6-P • Ses sn ₂ sn ₂ n 5-C1.6-E Sez CH ₂ CH ₂ -2 -pyridyl n 5-C1.6-E CE ₃ CH ₂ CH ₂ -3 - pyridyl n 5-C1.6-E Sez CH2CH2-4- pyridyl n 5-S1,6-P Sez CH ₂ CH ₂ -2- furanyl n 5-C1.6-E Sez CH2CH2-Z-furanyl n 5-C1.6-E Sez. CH2CH2-2- thienyl n 5-C1.6-E Sez CH ₂ CH ₂ -3-thienyl n 5-S1,6-P Sez C = C-sous SNZ 5-S1,6-P Sez C ^ C-Pb SNZ 5-C1.6-E CE ₃ C = C-2-pyridyl SNZ 5-S1,6-P Sez C == C-3-pyridyl SNZ 5-C1.6-E Sez £ = C_4_ pyridyl SNZ 5-S1,6-P Sez C = C-2-furanyl SNZ 5-S1,6-P Sez C ^ C-Z-Furanyl SNZ 5-C1, br-P Sez C ^ C-2-thienyl SNZ 5-C1.6-E CE ₃ C == C — 3-thienyl SNZ 5-C1.6-E Sez C = C-sous SNZ 5-C1.6-E 'Sez C = C-Pb SNZ 5-C1.6-E Sez C = C-2-pyridyl SNZ 5-S1,6-P CE ₃ C ₌ C_3-pyridyl SNZ 5-C1.6-E CE ₃ C = C-4-pyridyl SNZ 5-S1,6-P CE ₃ C = C-2-furanyl SNZ 5-C1, br-P Sez C = C-3-Furanyl SNZ 5-S1,6-P Sez C = C-2 ^. _thienyl SNZ 5-S1,6-P CE ₃ C = C-3-thienyl SNZ 5-C1.6-E CE ₃ CH ₂ CH ₂ sigRg SNZ 5-S1,6-P CE ₃ sn ₂ sn _2- r. SNZ

1253 5-P, 6-C1 SRz C ^ C-sousPr SNZ 1254 5-P, 6-C1 Sez C ^ C-Pb CH ₃ 1255 5-E, 6-C1 Sez C ^ C-2-pyridyl SNZ 1256 5-P, 6-C1 Sez C = C-3-pyridyl SNZ 1257 5-P, 6-C1 Sez C = C-4-pyridyl SNZ 1258 5-P, 6-C1 CE ₃ C ^ C-2- furanyl CH ₃ 1259 5-P, 6-C1 * Sez C = C-3- furanyl SNZ 1260 5-P, b-C1 SRz C ^ C-2- 'thienyl SNZ 1261 5-P, 6-C1 SRz C = C-3-TYenyl SNZ 1262 5-P, 6-C1 Sez C = C-sous SNZ 1263 5-G, b-C1 CE ₃ C = C-Pb SNZ 1264 5-P, 6-C1 Sez C = C-2- - pyridyl SNZ 1265 5-P, 6-C1 Sez. . C = C-3- 'pyridyl SNZ 1266 5-P, 6-C1 Sez C = C-4- -pyridyl SNZ 1267 5-P, 6-C1 Sez C = C-2-furanyl SNZ 1268 5-P, b-C1 SRz C = C-3-furanyl SNZ 1269 5-P, 6-C1 Sez C = C-2 “Thienyl ' SNZ 1270 5-P, 6-C1 Sez C ₌ C-thienyl SNZ 1271 5-P, 6-C1 Sez CH ₂ CH ₂ sigRg SNZ 1272 5-E, b-C1 Sez CH ₂ CH ₂ -PB SNZ 1273 5-P, 6-C1 Sez CH2CH2-2- pyridyl SNZ 1274 5-P, 6-C1 SRz CH2CH2-Z- 'pyridyl SNZ 1275 5-P, b-C1 Sez CH ₂ CH ₂ -4-pyridyl SNZ 1276 5-P, 6-C1 CE ₃ CH ₂ CH ₂ -2- Furanyl SNZ 1277 5-P, 6-C1 Sez CH ₂ CH ₂ —3 -furanyl SNZ 1278 5-P, 6-C1 Sez CH ₂ CH ₂ -2-. thien.il SNZ 1279 5-P, 6-C1 Sez CH ₂ CH ₂ -3-thienyl SNZ 1280 6-C1.8-E Sez C = C-sous n 1281 6-S1.8-E Sez C = C-Pb n 1282 6-S1.8-P Sez C = C-2 — pyridyl n 1283 6-S1.8-P Sez CeS-3 * “pyridyl n 1284 6-S1.8-E CE ₃ C ^ C-4-pyridyl n 1285 6-S1.8-P Sez C = C-2-furanyl n 1286 6-S1.8-P Sez 0 = C_3_ 'furanyl n

1287

1288

1289

1290

1291

1292

1293

1294

1295

1296

1297

1298

1299

1300

1301

1302

1303

1304

1305

1306

1307

1308

1309

1310

1311

1312

1313

1314

1315

1316

1317

1318

1319

1320

1321

1322

1323

1324

1325

1326

1327

1328

1329

1330

1331

1332

1333

1334

1335

1336

1337

1338

1339

1340

1341

1342

1343

1344

1345

1346

1347

1348

1349

1350

1351

1352

1353

1354

6-S1.8-E

6-S1.8-E 6-S1.8-P 6-S1.8-P 6-S1.8-P 6-S1.8-E 6-S1.8-P 6-S1.8-P 6 -C1.8-E 6-C1.8-R 6-C1.8-R 6-C1.8-R 6-C1.8-R 6-C1.8-R 6-C1.8-R 6- С1.8-Р 6-С1.8-Р 6-С1.8-Е 6-С1.8-Е b-С1.8-Р 6-С1.8-Р 6-С1.8-Р 6-С1 8-P 6-S1.8-P 6-S1.8-P 6-S1.8-E 6-S1.8-P b-S1.8-P 6-S1.8-E 6-S1, 8-E b-S1.8-P 6-S1.8-P 6-S1.8-P b-S1.8-E

6-S1.8-P 6-S1.8-P b-S1.8-P 6-S1.8-E 6-S1.8-E 6-S1.8-P 6-S1.8-P 6 -C1.8-P b-S1.8-P b-S1.8-P 6-S1.8-P b-S1.8-E 6-S1.8-P

6-CH3

6-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6-СНз b-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6-СНз 6- СНз 6-СНз 6-СН ₃ 6-СНз

Sez

Sez

Sez

Sez

C ^ C 2 thienyl

С = С — 3 - thienyl С = С-ссРг С = С-Рй

N n

N n

CPz C = C-2-. Pyridyl H SEz C = C-3-pyridyl n CEz C = C-4-pyridyl _n CEz. C = C-2-. furanyl n CEz C = C-3- furanyl _n CPz C = C-2-thienyl _n CEz C = C-3-thienyl n CE ₃ CH ₂ CH ₂ -cuspg n CPz · CH ₂ CH ₂ -Pb n

SEC CH ₂ CH ₂ -2 ~. pyridylN

SRz CH ₂ CH ₂ -3-pyridyl

SEC CH ₂ CH ₂ -4-pyridyl

SEC CH ₂ CH ₂ -2- Furanyl

SEC CH ₂ CH ₂ -3 · -furanylN

SEC CH ₂ CH ₂ -2-thienyln

CE ₃ CH ₂ CH ₂ -3 - thienyl

Sez

SRz

Sez

Sez

Sez

Sez

Sez

SRz

SRz

Sez

Sez

SRz

SRz

SRz

OS-ssRg SNZ OS Ry SNZ OS-2- pyridyl SNZ OS-3-. Pyridyl SNZ OS-4- pyridyl SNZ OS-2-furanyl SNZ С ^ С-З - furanyl SNZ OS-2- thienyl SNZ C = C_3. thienyl SNZ C = C-sous SNZ C = C-Pb SNZ C = C-2-pyridyl SNZ C = C-3-pyridyl SNZ C = C-4- pyr. Idle SNZ

SEC C = C-2-furanyl CH3

C? S C = C-3- Furanyl CH3

CP3 c = C-2-thienyl CH3

CP3 C = C-3-thienyl _CH3

SR ₃ CH ₂ CH ₂ -sigrg CHz

SRz CH ₂ CH ₂ -Pb CHz

SRz CH ₂ CH ₂ -2- pyridyl CHz

SRz CH ₂ CH ₂ -3-'pyridyl _C H ₃

SRz CH ₂ CH ₂ -4-pyridyl CHz

SEC CH ₂ CH ₂ -2- furanyl CH3

SRz CH ₂ CH ₂ -3- furanyl CHz

SEC CH ₂ CH ₂ —2-thienyl _CH3

Sez. CH ₂ CH ₂ -3-thienyl. SNZ

SRz OS-ssRg Sez OS-RI Cez OS-2- pyridyl Sez C = C — 3 — pyridyl SRz OS-4- 'pyridyl SRz C = c-2-. Furanyl Sez OS-3- Furanyl Sez OS-2- thienyl- SRz OS-3-thienyl SRz C = C-sous Sez C = C-Pb Sez C = C-2-pyridyl Sez C = C-3-pyridyl Sez C = C-4-pyridyl SRz C = C-2-furanyl CE ₃ C = C-3 ~ Furanyl SRz C = C-2-thienyl Sez C = C-3 - thienyl

N

N

N N N N N N N N N N N N N

SEC CH ₂ CH ₂ -sigRg Η

SEC CH ₂ CH ₂ -P11 N

SRz CH ₂ CH ₂ -2- pyridyl H

1355 6-cs SRz CH ₂ CH ₂ -3-pyridyl N 1356 6-cs Sez CH ₂ CH ₂ -4-pyridyl N 1357 6-cs Sez CH ₂ CH ₂ -2- Furanyl n 1358 6-cs Sez CH ₂ CH ₂ -3- furanyl n 1359 6-cs SRz CH ₂ CH ₂ -2- thienyl n 1360 6-cs SRz CH ₂ CH ₂ -3-thienyl n 1361 6-cs • SRz OS-ssRg SNZ 13 62 6-cs Sez OS-R SNZ 1363 6-cs Sez OS-2- pyridyl SNZ 13 64 6-cs SRz 02-3-pyridyl SNZ 1365 6-ss Sez OS-4- pyridyl SNZ 1366 6-cs Sez C = C-2-Furanyl SNZ 1367 6-cs Sez . C = s-3-_FUR ^an . ^silt SNZ 1368 6-cn ₃ Sez OS-2-thienyl SNZ 1369 6-CH ₃ Sez OS-3- Thienyl SNZ 1370 6-cs Sez C = C-sous SNZ 1371 6-cs Sez C = C-Pb SNZ 1372 6-cs Sez C = c-2-pyridyl SNZ 1373 6-cs Sez C = C-3-pyridyl SNZ 1374 6-cn ₃ Sez C = C-4-pyridyl SNZ 1375 6-cn ₃ Sez C = C-2 - furanyl SNZ 1376 6-cs Sez C = C-3- Furanyl SNZ 1377 6-cs Sez C = C-2-thienyl SNZ 1378 6-cs SRz C = C-3-thienyl SNZ 1379 b-SNZ SRz CH ₂ CH ₂ —sigRg SNZ 13 80 6-cs Sez CH ₂ CH ₂ -PB SNZ 1381 6-cs SRz CH ₂ CH ₂ -2- pyridyl SNZ 1382 6-cs SR ₃ CH ₂ CH ₂ -3-pyridyl SNZ 1383 6-cs Sez CH ₂ CH ₂ -4 'pyridyl SNZ 1384 6-CH ₃ SRz CH ₂ CH ₂ -2-furanyl SNZ 1385 6-cs SRz CH ₂ CH ₂ -3-Furanyl SNZ 1386 6-cs SRz CH ₂ CH ₂ -2- thienyl SNZ 1387 6-cs CE ₃ CH ₂ CH ₂ -3-thienyl SNZ 1388 6-SOSNz Sez OS-ssRg N

1389 6-SOSNz 1390 6-SOSNz 1391 6-SOSNz 1392 6-SOSNz 1393 6-SOSNz 1394 6-SOSNz 1395 6-SOSNz 1396 6-SOSNz 1397 6TH ₂ 1398 b-eun ₂ 1399 6TH ₂ 1400 6TH ₂ 1401 6-ΝΗ ₂ 1402 6-ΝΗ ₂ 1403 6-ΝΗ ₂ 1404 6-ΝΗ ₂ 1405 6-ΝΗ ₂ 1406 6-MMe ₂ 1407 6th ME ₂ 1408 6th ME ₂ 1409 6-IME ₂ 1410 6th ME ₂ 1411 6th ME ₂ 1412 6th ME ₂ 1413 b-yme ₂ 1414 6-KMe ₂ 1415 7-C1 1416 7-C1 1417 7-C1 1418 7-C1 1419 7-C1 1420 7-C1 1421 7-C1 1422 7-C1

Sez

Sez

SRz

Sez

Sez

Sez. Sez

Sez

Sez

Sez

Sez

SR ₃

SRz

SRz

SRz

SRz

SRz

Sez

SRz

Sez

CE ₃

SRz

Sez

SRz

Sez

CE ₃

CE ₃

Sez

Sez

SG ₃

Sez

Sez

CE ₃

CE ₃

C ^ C-Pb

OS-2- pyridyl

OS-3-pyridyl

C == C_4-pyridyl

OS-2-furanyl C = C — 3- Furanyl C = c-2-thienyl

OS-3- thienyl

C ^ C-sousPr

OS-P11 C = C-2-pyridyl C ^ C-3-pyridyl OS-4 - pyridyl C = C-2-Furanyl C = C – 3-furanyl OS-2- thienyl OS-3-thienyl

OS-sousRg OS-R

OS-2- pyridyl

Ce2-3- pyridyl

OS-4-pyridyl C = C-2-furanyl

OS-3 - furanyl C = C-2-thienyl C ^ E-3-thienyl.

OS-ssRg

OS-R

OS-2-pyridyl OS-3-pyridyl OS-4-pyridyl OS-2-furan il OS-3 - furanyl OS-2-thienyl

N N N N N N N N N N N N N N N N N N N N N N N N N N N

1423 7-C1 . ^SGZ C = C-3-thienyl 1424 5,6-OCH ₂ O- CE ₃ C = c 1425 5,6-OCH ₂ O- CE ₃ C = CCH ₂ CH ₂ OH 1426 5,6-OCH ₂ O- Sez C = C-CH (OH) Me 1427 5,6-OCH ₂ O- CE ₃ C ^ C-Pb

Η

Η

Η

Η

Η

1428 5,6-0СН ₂ О- СГ ₃

1429 5,6-OCH ₂ O-, SG ₃

1430 5,6-OCH ₂ O-SG ₃

1431 5,6-0СН ₂ О- СГз

1432 5,6-0СН ₂ О- СГ ₃

1433 5.6-0CH ₂ O-CE ₃

1434 5,6-OCH ₂ O-CE ₃

1435 5,6-OCH ₂ O- CE ₃

1436 5,6-OCH ₂ O-SEC

1437 5,6-OCH ₂ O-CE ₃

1438 5,6-OCH ₂ O-CE ₃

1439 5,6-OCH ₂ O- CE ₃

1440 5,6-OCH ₂ O- CE ₃

1441 5.6-0CH ₂ O-CE ₃

1442 5,6-OCH ₂ O-CE ₃

1443 5,6-OCH ₂ O-SG ₃

1444 5,6-OCH ₂ O- CE ₃

1445 5,6-OCH ₂ O- CE ₃

1446 5,6-OCH ₂ O ~ CE ₃

1447 5, b-OCH ₂ O- CE ₃

1448 5,6-OCH ₂ O- CE ₃

1449 5,6-OCH ₂ O- CE ₃

1450 5,6-OCH ₂ O- CE ₃

1451 5,6-OCH ₂ O-SG ₃

1452 5, b-OCH ₂ O-SG ₃

1453 5,6-OCH ₂ O-CE ₃

1454 5,6-OCH ₂ O- CE ₃

1455 5,6-OCH ₂ O-SG ₃

1456 5,6-ОСН ₂ О- СГз

C = C- (2-C1) Pb

C = C- (3-C1) Pb

C = C- (4-C1) Pb

SeS- (2-G) P11

C = C- (3-E) Pb

CeC- (4-E) Pb

C = C- (2-OH) Pb

C = C- (3-OH) Pb

C = C- (4-OH) Pb

CC- (2-OMe) Pb

C = C- (3-OMe) Pb C = C- (4-OMe) Pb

C ^ C- (2-CY) Pb

C = C- (3-CN) Ph C = C- (4-CN) Ph C ^ C- (2-ΝΟ ₂₎ Pb SgS- (3 _uQ-2) Ph C ^ C- (4-uQ ₂₎ Pb C = C- (2-ΝΗ ₂ ) Pb C = C- (3-ΝΗ ₂ ) Pb C = C— (4-CH ₂ ) Pb C = C- (2-IME ₂ ) Pb C ^ C- ( 3-She ₂ ) Pb C = C- (4-Sme ₂ ) Pb

SyaS-2 — pyridyl

C = C-2 - pyridyl CBC-3-pyridyl C = C-4-pyridyl C = C-2-furanyl

N N N nn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

1491 7-C1 CE ₃ C = C-sous n 1492 7-C1 CE ₃ C = C-Pb n 1493 7-C1 CE ₃ C = C-2-pyridyl n 1494 7-C1 CE ₃ C = C-3-pyridyl n 1495 7-C1 Sez C = C-4-pyridyl n 1496 7-C1 CE ₃ C = C-2-furanyl n 1497 7-C1 • Ses C = c-3-furanyl n 1498 7-C1 Sez (2 = (2-2- thienyl n 1499 7-C1 CE ₃ C = C-3-thienyl n 1500 5,6-OCH ₂ O- CE ₃ C = C-sous n 1501 5,6-OCH ₂ O- Sez C = CCH ₂ CH ₂ OH n 1502 5, 6-OCH ₂ O- CE ₃ C = C-CH (OH) Me n 1503 5.6-0CH ₂ O- Sez . C = C-Pb n 1504 5,6-OCH ₂ O- Sez C = C- (2-C1) Pb n 1505 5,6-OCH ₂ O- Sez C = C- (3-C1) Pb n 1506 5,6-OCH ₂ O- Sez C = C- (4-C1) Pb n 1507 5,6-OCH ₂ O- SRz C = C- (2-E) Pb n 1508 5,6-OCH ₂ O- Sez C = C- (3-D) Pb n 1509 5,6-OCH ₂ O- CE ₃ C = C- (4-D) Pb n 1510 5,6-OCH ₂ O- Sez C = C- (2-OH) Pb n 1511 5,6-OCH ₂ O- Sez C = C- (3-OH) Pb n 1512 5,6-OCH ₂ O- Sez C = C- (4-OH) Pb n 1513 5,6-OCH ₂ O- Sez C = C- (2-OMe) Pb n 1514 5,6-OCH ₂ O- SGZ C = C- (3-OMe) Pb n 1515 5,6-OCH ₂ O- Sez C = C- (4-OMe) Pb n 1516 5,6-OCH ₂ O- Sez C = C- (2-CY) Pb n 1517 5,6-OCH ₂ O- SGZ C = C- {3-CY) Pb n 1518 5,6-OCH ₂ O- Sez C = C- (4-CY) Pb n 1519 5,6-OCH ₂ O- Sez C = C- ( _2-2 ) Pb n 1520 5,6-OCH ₂ O- SGZ C = C- (3-BO ₂ ) Pb n 1521 5,6-OCH ₂ O- SGZ C = C- (4-2) Pb n 1522 5,6-OCH ₂ O- SGZ C = C- ( _2-2 ) Pb n 1523 5,6-OCH ₂ O- SGZ C = C- (3-OH ₂ ) Pb n 1524 5,6-OCH ₂ O- SGZ C = C- (4-ΝΗ ₂ ) Pb n

1457 5,6-OCH ₂ O- 1458 5,6-OCH ₂ O- 1459 5,6-OCH ₂ O- 1460 5,6-OCH ₂ O- 1461 5,6-OCH ₂ O- 1462 5,6-OCH ₂ O- 1463 5,6-OCH ₂ O- 1464 6-suns 1465 6-SOSNz 1466 6-suns 1467 6-SOSN ₃ 1468 6-SOSNz 1469 6-SOSNz 1470 6-SOSNz 1471 6-SOSNz 1472 6-SOSNz 1473 6TH ₂ 1474 6th ₂ 1475 6-ΝΗ ₂ 1476 6TH ₂ 1477 6TH ₂ 1478 6TH ₂ 1479 6TH ₂ 1480 6TH ₂ 1481 6TH ₂ 1482 6-IME ₂ 1483 6-IME ₂ 1484 6th ME ₂ 1485 6th ME ₂ 1486 6th ME ₂ 1487 6 ~ IME ₂ 1488 6-ΝΜβ ₂ 1489 6th ME ₂ 1490 6th ME ₂

SGZ

CE ₃

CE ₃

CE ₃

SGZ

Sez

Sez

Sez

Sez

CE ₃

CE ₃

Sez

CE ₃

SG ₃

Sez

SGZ

Sez

Sez

CE ₃

Sez

Sez

CE ₃

SG ₃

SG ₃

SG ₃

SGZ

SR ₃

Sez

CE ₃

Sez

CE ₃

Sez

Sez

SGZ

C == C ^- 3 - furanyl

C = C-2-thienyl H (2 = (2_3_ thienyl H

SzS-2-oxazolyl

C = C-2-thiazolyl

C = C-4 - isoxazolyl H

C = C ~ 2- imidazolylN

C = C-cusPrH

C = C-PbH

C = C-2-pyridylN

C = C-3-pyridylN

C = C-4-pyridyl

C = C-2-. FURanyl

C = C-3- furanylN

C = C-2 - thienyln

C = C-3-thienyln

C = C-cusPrH

C = C-Pb

C = C-2-pyridylN

C = C-3-pyridylN

C = C-4-pyridylN

C = C-2- Furanyln

C = C-3-furanylN

C = C-2-thienyl H

C = C-3-thienyln

C = C-cusPrH

C = C-PbH

C = C-2- ^t pyridylN

C = C-3-pyri'dylN

C = C-4 - pyridyl

C = C-2-furanyl

C = C-3- furanyl

C = C-2-thienyl H

C = C-3-thienyl H

1525 5,6-OCH ₂ O-. CE ₃ C = C- (2-MMe ₂ ) Pb n 1526 5,6-OCH ₂ O- SGZ C = C- (3ME ₂ ) Pb n 1527 5,6-OCH ₂ O- Sez C = C- (4THMe ₂ ) Pb n 1528 5,6-OCH ₂ O- SGZ C = G-7- ' pyridyl n 1529 5,6-OCH ₂ O-. SGZ C = C-2-pyridyl n 1530 5,6-OCH ₂ O- Sez C = C-3-pyridyl n 1531 5,6-OCH ₂ O- ¹ ‘Sez C-C-4-pyridyl n 1532 5,6-OCH ₂ O- CE ₃ C = C-2-furanyl n 1533 5,6-OCH ₂ O- SG ₃ C = C-3-furanyl n 1534 5,6-OCH ₂ O- SGZ C = C-2-thienyl n 1535 5,6-OCH ₂ O- SGS C = C-3-thienyl n 1536 5,6-OCH ₂ O- Sez C = C-2-oxazolyl n 1537 5,6-OCH ₂ O- SRz. C = C-2-thiazolyl n 1538 5,6-OCH ₂ O- Sez C = C-4-isoxazolyl n 1539 5.6-0CH ₂ O- Sez C = c-2-imidazolyl n 1540 5,6-OCH ₂ O- Sez CH ₂ CH ₂ sigRg n 1541 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ CH ₂ CH ₂ OH n 1542 5,6-OCH ₂ O- SG ₃ CH ₂ CH ₂ —CH (OH) Me n 1543 5,6-OCH ₂ O- Sez CH ₂ CH ₂ Pb n 1544 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ - (2-C1) Pb n 1545 5.6-0CH ₂ O- CE ₃ CH ₂ CH ₂ - (3-C1) Pb n 1546 5, b-0CH ₂ O- SG ₃ CH ₂ CH ₂ - (4-C1) Pb n 1547 5,6-OCH ₂ O- Sez CH ₂ CH ₂ - (2-E) Pb n 1548 5.6-0CH ₂ O- Sez CH ₂ CH ₂ - (3-D) Pb n 1549 5,6-OCH ₂ O- Sez CH ₂ CH ₂ - (4-E) Pb n 1550 5.6-0CH ₂ O- SG ₃ CH ₂ CH ₂ - (2-OH) Pb n 1551 5.6-0CH ₂ O- Sez CH ₂ CH ₂ - (3-OH) Pb n 1552 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ - (4-OH) Pb n 1553 5.6-0CH ₂ O- Sez CH ₂ CH ₂ - (2-OMe) Pb n 1554 5,6-OCH ₂ O- Sez CH ₂ CH ₂ - (3-OMe) Pb n 1555 5,6-OCH ₂ O- Sez CH ₂ CH ₂ - (4-OMe) Pb n 1556 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ - (2-CH) Pb n 1557 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ - (3-CH) Pb n 1558 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ - (4-CH) Pb n

1559 5,6-OCH ₂ O-

1560 5.6-0CH ₂ O-

1561 5,6-OCH ₂ O-

1562 5,6-OCH ₂ O-

1563 5,6-OCH ₂ O-

1564 5,6-OCH ₂ O-

1565 5,6-OCH ₂ O-

1566 5,6-OCH ₂ O-

1567 5,6-OCH ₂ O-

1568 5,6-OCH ₂ O-

1569 5,6-OCH ₂ O-

1570 5,6-OCH ₂ O-

1571 5, 6-OCH ₂ O-

1572 5,6-OCH ₂ O-

1573 5, b-OCH ₂ O-

1574 5,6-OCH ₂ O-

1575 5,6-OCH ₂ O-

1576 5,6-OCH ₂ O-

1577 5,6-OCH ₂ O-

1578 5,6-OCH ₂ O-

1579 5.6-0CH ₂ O-

1580 5,6-OCH ₂ O-

1581 5,6-OCH ₂ O-

1582 5,6-OCH ₂ O “

1583 5,6-OCH ₂ O-

1584 5,6-OCH ₂ O-

1585 5.6-0CH ₂ O-

1586 5,6-OCH ₂ O-

1587 5,6-OCH ₂ O-

1588 5,6-OCH ₂ O-

1589 5, b-OCH ₂ O-

1590 5,6-OCH3-

1591 5,6-OCH ₂ O-

1592 5,6-OCH ₂ O-

1593 5,6-OCH ₂ O-

1594 5,6-OCH ₂ O-

1595 5,6-OCH ₂ O-

1596 5, b-OCH ₂ O-

1597 5,6-OCH ₂ O-

1598 5,6-OCH ₂ O-

1599 5,6-OCH ₂ O-

1600 5,6-OCH ₂ O ~

1601 5,6-OCH ₂ O-

1602 5,6-OCH ₂ O-

1603 5,6-OCH ₂ O-

1604 5,6-OCH ₂ O-

1605 5,6-OCH ₂ O-

1606 5,6-OCH ₂ O-

1607 5,6-OCH ₂ O-

1608 5,6-OCH ₂ O-

1609 5,6-OCH ₂ O-

1610 5,6-OCH ₂ O-

1611 5,6-OCH ₂ O-

1612 5,6-OCH ₂ O-

1613 5, b-OCH ₂ O-

1614 5,6-OCH ₂ O-

1615 5.6—0CH ₂ O-

1616 5.6-0CH ₂ O-

1617 5,6-OCH ₂ O-

1618 5.6-0CH ₂ O-

1619 5,6-OCH ₂ O-

1620 5,6-OCH ₂ O-

1621 5,6-OCH ₂ O-

1622 5,6-OCH ₂ O-

1623 5, b-OCH ₂ O-

1624 5.6-0CH ₂ O-

1625 5.6-0CH ₂ O-

1626 5,6-OCH ₂ O-

Sez CH ₂ CH ₂ - (2NO ₂ ) Pb N CE ₃ CH ₂ CH ₂ - (3O ₂ ) Pb n CE ₃ CH ₂ CH ₂ - (4-ΝΟ ₂ ) Pb n Sez CH ₂ CH ₂ - (2-ΝΗ ₂ ) Pb n Sez CH ₂ CH ₂ - (3-OH ₂ ) Pb n CE ₃ CH ₂ CH ₂ - {4-Y ₂ ) Pb n CE ₃ CH ₂ CH ₂ - (2-YMe ₂ ) Pb n CE ₃ CH ₂ CH ₂ - (3-She ₂ ) Pb n SRz CH ₂ CH ₂ - (4-YMe ₂ ) Pb n Sez CH ₂ CH ₂ -2- pyridyl n CE ₃ CH ₂ CH ₂ -3-pyridyl n Sez CH ₂ CH ₂ -4- -pyridyl n CE ₃ • CH ₂ CH ₂ -2- furanyl n CE ₃ CH ₂ CH ₂ -3- Furanyl n Sez CH ₂ CH ₂ -2- thienyl n Sez CH ₂ CH ₂ -3-thienyl n CE ₃ CH ₂ CH ₂ -2- oxazolyl n Sez CH ₂ CH ₂ -2- thiazolyl n

SG ₃ CH ₂ CH ₂ —4-isoxazolyl _n

SEC CH ₂ CH ₂ -2- imidazolyl H

SRz

SGZ

SGZ

SGZ SGZ

Sez

Sez

CE ₃

Sez

CE ₃

CE ₃

Sez

CE ₃

CE ₃

Pops-susrg C ^ C-Pb SNZ SNZ SO-2 _ pyridyl SNZ C ^ s-Z _ pyridyl SNZ C = C-4- - pyridyl SNZ SOS-2 .'furanil SNZ C = C-3 . furanyl SNZ C = C-2- _ thienyl SNZ C = C-3- _ thienyl sun ₃ C = C- -SusRg SNZ c = Cb SNZ C = C-2- pyridyl SNZ C = C-3 pyridyl SNZ C = C-4 pyridyl SNZ

SEC C = C-2-furanyl CH ₃

SEC C = C-3- furanyl CH3

SEC C = C-2- Dienyl _CH3

CEz C = C-3-thienyl _CH3

SEC CH ₂ CH ₂ -sucrg CHs

SEC CH ₂ CH ₂ -PB CH

SEC CH ₂ CH ₂ -2- _pi ridyl CH

SEC CH ₂ CH ₂ -3 — pyridyl CH3

SG ₃ CH ₂ CH ₂ -4-pyridyl CH ₃

SEC CH ₂ CH ₂ —2 — furanyl CH ₃

SEC CH ₂ CH ₂ -3-furanyl CH3

CP ₃ CH ₂ CH ₂ -2- thienyl CH ₃

CP ₃ * CH ₂ CH ₂ -3-thienyl CH ₃

SR ₃

CE ₃

Sez

Sez

Sez

Sez

CE ₃

SR ₃

SG ₃

CE ₃

SG ₃

CE ₃

Sez

Sez

CE ₃

CE ₃

Sez

Sez

Sez

CE ₃

Sez

C ^ C-sousPr CH ₂ CH ₃ C = C-Pb CH ₂ CH ₃ C ^ C-2-pyridyl CH ₂ CH CeC-3- pyridyl CH ₂ CH C = C-4 - pyridyl CH ₂ CH ₃ C = C — 2-. Furanyl CH ₂ CH ₃ C = s-3 - Furanyl CH ₂ CH SOC-2- thienyl CH ₂ CH ₃ C = c-3-thienyl CH2CH3 C = C-sous CH ₂ CH ₃ C = C-Pb CH ₂ CH C = C-2-pyridyl CH ₂ CH ₃ C = C-3-pyridyl CH ₂ CH ₃ C = C-4-- pyridyl CH ₂ CH C ₌ C-2- Furanyl CH ₂ CHZ C = C-3- -furanyl CH ₂ CH C = C-2 - thienyl CH ₂ CH _{3 <} 2 = c-3 ^{t Thienyl} CH ₂ CH ₃ CH ₂ CH ₂ sigRg CH ₂ CH ₃ CH ₂ CH ₂ -PB CH ₂ CH ₃ ; H ₂ CH ₂ -2-'pyridyl CH ₂ CH ₃

1627 5, b-OCH ₂ O- Sez CH ₂ CH ₂ -3-pyridyl sun ₂ sun ₃ 1628 5,6-OCH ₂ O- Sez CH ₂ CH ₂ -4-pyridyl CH ₂ CH ₃ 1629 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ -2- 'furanyl CH ₂ CH ₃ 1630 5,6-OCH ₂ O- SRz CH ₂ CH ₂ -3- furanyl CH ₂ CH ₃ 1631 5,6-OCH ₂ O- CE ₃ CH ₂ CH ₂ —2-thienyl CH ₂ CH ₃ 1632 5,6-OCH ₂ O- . CE ₃ CH ₂ CH ₂ -3-thienyl CH ₂ CH

* Unless otherwise indicated, stereochemistry (+/-).

Table 3 *

Etc·" - K ³ to ¹ to ² Ηθ one 6-C1 SGZ ‘ SES-Rg n 2 6-C1 SGZ C ~ C ~ Vi n 3 6-C1 Sez C ^ C-tvi n four 6-C1 Sez C ^ C-bVi n 5 6-C1 SRz C ^ C-Me n 6 6-C1 Sez CH2CH ₂ CH ₂ CH ₂ CHz n 7 6-C1 SRz CH ₂ CH ₂ CH {CH 3) 2 n 8 6-C1 Sez CH2CH2CH2CH3 n 9 6-C1 Sez CH ₂ CH ₂ CH n 10 6-C1 Sez CH ₂ CH ₂ -BVi n eleven 6-C1 Sez sn ₂ s = s-sn ₃ n 12 6-C1 Sez CH ₂ SyS-CH ₂ CHZ n 13 6-C1 Sez C = C-1Pg SNZ fourteen 6-C1 Sez C = C-Pr SNZ fifteen 6-C1 Sez C = C-Vi SNZ 16 6-C1 Sez C = C-1 Vi SNZ 17 6-C1 SRz CGC-bVi SNZ eighteen 6-C1 SRz C = C-EU SNZ 19 6-C1 Sez C ^ C-Me SNZ twenty 6-C1 Sez CH ₂ C ^ C-CH ₃ SNZ 21 6-C1 Sez CH ₂ C ^ C-CH ₂ CH ₃ SNZ 22 6-C1 Sez CH ₂ CH ₂ CH (CHz) ₂ SNZ 23 6-C1 Sez СН2СН2СН2СНЗ SNZ 24 6-C1 Sez CH ₂ CH ₂ CH SNZ 25 6-C1 Sez sn ₂ sn ₂ -evi SNZ 26 6-C1 Sez C == C-1Pg CH ₂ CH ₃ 27 6-C1 SRz C ^ C-Pr CH ₂ CH ₃ 28 6-C1 SRz C ^ C-Vi CH ₂ CH

29th 6-C1 Sez thirty 6-C1 CE ₃ 31 6-C1 CE ₃ 32 6-C1 CE ₃ 33 6-C1 SGZ 34 6-C1 CE ₃ 35 6-C1 Sez 36 6-C1 CE ₃ 37 6-C1 CE ₃ 38 6-C1 CE ₃ 39 6-MeO CE ₃ 40 6-MeO Sez 41 6-MeO CE ₃ 42 6-MeO SRz 43 6-MeO CE ₃ 44 6-MeO Sez 45 6-MeO Sez 46 6-MeO CE ₃ 47 6-MeO Sez 48 6-MeO CE ₃ 49 6-MeO CE ₃ fifty 6-MeO CE ₃ 51 6-MeO Sez 52 6-MeO SGZ 53 6-MeO Sez 54 6-MeO SGZ 55 6-MeO SGZ 56 6-MeO SGZ 57 6-MeO SGZ 58 6-MeO SGZ 59 6-MeO SGZ 60 6-MeO Sez 61 6-MeO SGZ 62 6-MeO SGZ

C = C-1 Vi CH ₂ CH ₃ SGS-SVi sun ₂ sun ₃ SVS-EU sun ₂ sun ₃ Ses Me sun ₂ sun ₃ CH ₂ CaS-CH ₃ sun ₂ sun ₃ CH ₂ C = C-CH ₂ CH ₃ sun ₂ sun ₃ CH ₂ CH ₂ CH (CHz) 2 sun ₂ sun ₃ CH ₂ CH ₂ CH ₂ CHz sun ₂ sun ₃ CH ₂ CH ₂ CH ₃ CH ₂ CH ₃ CH ₂ CH ₂ -Bi sun ₂ sun ₃ C = C — Pr n C ^ C-Vi n ’SGS-1Vi n C ^ C-bVi n C = C-E n C == C-Me n CH ₂ C ^ C-CH ₃ n CH ₂ C = C-CH ₂ CH ₃ n CH ₂ CH ₂ CH ₂ CH ₂ CHz n CH ₂ CH ₂ CH (CHz) 2 n CH ₂ CH ₂ CH ₂ CHz n CH ₂ CH ₂ CH n CH ₂ CH ₂ -BVi n CH ₂ C ^ C-CH ₃ n CH ₂ C ^ C-CH ₂ CH ₃ n SGS-xRg sun ₃ OS-Rg SNZ C ^ C-Vi SNZ C = C-1 Vi SNZ C = C-bBu CH ₃ SHS-E sun ₃ Ses Me SNZ CH ₂ O = C-CH ₃ SNZ CH ₂ C = C-CH ₂ CH ₃ SNZ

97 5,6-άίΕ CE ₃ 98 5,6-άίΕ CE ₃ 99 5,6-άίΕ CE ₃ one hundred 5,6-άίΕ SGZ 101 5,6-άίΕ CE ₃ 102 5,6-άίΕ SG ₃ 103 5,6-άίΕ SGZ 104 5,6-άίΕ CE ₃ 105 5,6-άίΕ cg ₃ 106 5,6-άίΕ CE ₃ 107 5,6-άίΕ Sez 108 5,6-άίΕ CE ₃ 109 5,6-άίΕ CE ₃ 110 5,6-άίΕ CE ₃ 111 5,6-άίΓ Sez 112 5,6-άίΕ SGZ 113 5,6-άίΕ CE ₃ 114 5,6-άίΕ CE ₃ 115 5,6-άίΕ CE ₃ 116 5,6-άίΕ SGZ 117 6-Ε CE ₃ 118 6-Ε CE ₃ 119 6-Ε Sez 120 6-Γ CE ₃ 121 6-Ε Sez 122 6-Ε cg ₃ 123 6-Ε Sez 124 6-Ε CE ₃ 125 6-Ε Sez 126 6-Γ cg ₃ 127 6-Ε Sez 128 6-Ε cg ₃ 129 6-Ε SG ₃ 130 6-Ε Sez

Cec-pb SNZ sn ₂ s = s-sn ₃ CH ₃ sn ₂ s = s-sn ₂ sn ₃ SNZ CH ₂ CH ₂ CH (CHz) 2 CH ₃ CH ₂ CH ₂ CH ₂ CH ₃ SNZ CH ₂ CH ₂ CH SNZ CH ₂ CH ₂ -BVi SNZ C = C-1Pg CH ₂ CH ₃ C = C-Pr CH ₂ CH ₃ SS Wi sun ₂ sun ₃ C ^ C-xVi CH ₂ CH C ^ C-bVi CH ₂ CH ₃ .C ^ C-E sun ₂ sun ₃ SS-Me sun ₂ sun ₃ CH ₂ C = C-CH ₃ sun ₂ sun ₃ CH ₂ C = C-CH ₂ CH ₃ CH ₂ CH CH ₂ CH ₂ CH (CH ₃ ) ₂ CH ₂ CH ₃ CH ₂ CH ₂ CH ₂ CH ₃ CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ CH ₂ CH ₃ CH ₂ CH ₂ -BVi CH ₂ CH ₃ C = C-Pr n C ^ C-Vi n C == C-1 Vi n SES-bVi n SS-Me n CH ₂ C = C-CH ₂ CH ₃ n CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ n CH ₂ CH ₂ CH ₃ n CH ₂ CH ₂ -BVi n C ^ C-xPr sun ₃ C = C-Pr sun ₃ C ^ C-Vi sun ₃ SGS-hVi CH ₃ C = C-bBu sun ₃

63 6-MeO SGZ CH ₂ CH ₂ CH (CHz) ₂ SNZ 64 6-MeO SGZ CH ₂ CH ₂ CH ₂ CH ₃ SNZ 65 6-MeO SGZ CH ₂ CH ₂ CH SNZ 66 6-MeO SGZ CH ₂ CH ₂ -Svi CH ₃ 67 6-MeO Sez C = C-1Pg CH ₂ CH ₃ 68 6-MeO SGZ C = C-Pr CH ₂ CH ₃ 69 6-MeO CE ^ C ^ C-Vi CH ₂ CH 70 6-MeO Sez C == C-1 Vi CH ₂ CH ₃ 71 6-MeO CE ₃ SES-bVi CH ₂ CH ₃ 72 6-MeO Sez C = C — E CH ₂ CH ₃ 73 6-MeO SGZ C = C-Me CH ₂ CH ₃ 74 6-MeO Sez CH ₂ C = C-CH ₃ CH ₂ CH ₃ 75 6-MeO Sez СН ₂ С = С-СН ₂ СНз CH ₂ CH ₃ 76 6-MeO CE ₃ CH ₂ CH ₂ CH (CHz) 2 CH ₂ CH ₃ 77 6-MeO CE ₃ CH ₂ CH ₂ CH ₂ CHz CH ₂ CH ₃ 78 6-MeO SGZ CH ₂ CH ₂ CH ₃ CH ₂ CH ₃ 79 6-MeO Sez CH ₂ CH ₂ -BVi CH ₂ CH ₃ 80 5,6-άίΕ Sez C = C-Pr n 81 5,6-άίΓ SGZ C = C-Vi n 82 5,6-άίΓ Sez C = C-1 Vi N 83 5,6-άίΕ SGZ SS-bVi n 84 5,6-άίΓ CE ₃ C = C-Me n 85 5,6-άίΕ Sez CH ₂ C ^ C-CH ₃ n 86 5,6-άίΕ CE ₃ CH ₂ C = C-CH ₂ CH ₃ n 87 5,6-άίΕ SGZ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ n 88 5,6-άίΕ CE ₃ CH ₂ CH ₂ CH ₃ n 89 5,6-άίΕ CE ₃ CH ₂ CH ₂ -BVi n 90 5,6-άίΓ CE ₃ C = C-1Pg SNZ 91 5,6-άίΕ Sez C = C-Pr SNZ 92 5,6-άίΕ Sez C = C-Vi SNZ 93 5,6-άίΓ Sez C = C-1 Vi SNZ 94 5,6-άίΕ CE ₃ CGC-bVi SNZ 95 5,6-άίΓ CE ₃ C = C ~ E SNZ 96 5,6-άίΕ Sez C = C-Me SNZ

131 6-g CE ₃ 132 bg Sez 133 6th CE ₃ 134 6-g SGZ 135 6th SGZ 136 b-e CE ₃ 137 6-g CE ₃ ' 138 b-e Sez 139 b-e Sez 140 b-e CE ₃ 141 b-e SG ₃ 142 6th Sez 143 b-e Sez 144 b-e Sez .145 6th CE ₃ 146 b-e CE ₃ 147 6th Sez 148 bg Sez 149 6-g SGZ 150 6th SGZ 151 6th CE ₃ 152 5-C1 Sez 153 5-C1 Sez 154 5-C1 cg ₃ 155 5-C1 CE ₃ 156 5-C1 CE ₃ 157 5-C1 Sez 158 5-C1 Sez 159 5-C1 CE ₃ 160 5-C1 Sez 161 5-C1 CE ₃ 162 5-C1 Sez 163 5-C1 CE ₃ 164 5-C1 SGZ

C = C-E SNZ C = C-Me SNZ CH ₂ C = C-CH ₃ SNZ sn ₂ s = s-sn ₂ sn ₃ SNZ CH ₂ CH ₂ CH (CH ₃ ) ₂ SNZ CH ₂ CH ₂ CH ₂ CH ₃ SNZ CH ₂ CH ₂ CH ₃ SNZ CH ₂ CH ₂ -BVi SNZ C = C-1Pg sun ₂ sun ₃ C = C-Pr CH ₂ CH C = C-Vi CH ₂ CH ₃ C ^ C-1 Vi CH ₂ CH ₃ • C = C-bVi CH ₂ CH C = C-E CH ₂ CH C = C-Me CH ₂ CH ₃ CH ₂ C = s-CH ₃ CH ₂ CH ₃ CH ₂ C = C-CH ₂ CH ₃ CH ₂ CH ₃ CH ₂ CH ₂ CH (CH ₃ ) ₂ CH ₂ CH CH ₂ CH ₂ CH ₂ CH ₃ CH ₂ CH CH ₂ CH ₂ CH CH ₂ CH ₃ CH ₂ CH ₂ -BVi CH ₂ CH ₃

C = C-1Pg

C ^ C-Pr

C = C-ViΗ

C ^ C-xVi

C = C-bBu

SvS-Εύ

C = C-Me

CH ₂ C = C-CH ₃ n

CH ₂ C = C-CH ₂ CH ₃ n

CH ₂ CH ₂ CH ₂ CH ₂ CH

CH ₂ CH ₂ CH (CH ₃ ) ₂ n sn ₂ sn ₂ sn ₂ sn ₃ n

CH ₂ CH ₂ CH

165

166

167

168

169

170

171

172 '173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

5-C1 Sez CH ₂ CH ₂ -EVi 5-C1 Sez OS-1RG 5-C1 Sez OS-Rg 5-C1 Sez Os vi 5-C1 Sez OS-1Vi 5-C1 CE ₃ OS-EVi 5-C1 Ces ’ OS-EE 5-C1 Sez OS Me 5-C1 Sez CH ₂ OS-CH ₃ 5-C1 CE ₃ CH ₂ OS-CH ₂ CH ₃ 5-C1 CE ₃ CH ₂ CH ₂ CH (CH ₃ ) ₂ 5-C1 Sez CH ₂ CH ₂ CH ₂ CHz 5-C1 Sez CH ₂ CH ₂ CH 5-C1 Sez CH ₂ CH ₂ -EVi 5-C1 Sez OS-xRg 5-C1 Sez OS-Rg 5-C1 CE ₃ Os vi 5-C1 CE ₃ C ^ C-1 Vi 5-C1 Sez SGS-EVi 5-C1 CE ₃ OS-EE 5-C1 Sez C = C-Me 5-C1 Sez CH ₂ OS-CH ₃ 5-C1 Sez CH ₂ C = C-CH ₂ CH ₃ 5-C1 Sez CH ₂ CH ₂ CH (CH ₃ ) ₂ 5-C1 Sez CH ₂ CH ₂ CH ₂ CHz 5-C1 CE ₃ sn ₂ sn ₂ sn ₃ 5-C1 Sez sn ₂ sn ₂ -gui 5th Sez C = C-1Pg 5th Sez OS-Rg 5th Sez Os vi 5-P Sez OSV 5-P SR ₃ OS-EVi 5th Sez OS-EE 5-P Sez OS Me

199 5th Sez 200 5th Sez 201 5th Sez 202 5th CE ₃ 203 5th Sez 204 5th CE ₃ 205 5-P Sez 206 5th CE ₃ 207 5th Sez 208 5th Sez 209 5-P CE ₃ 210 5th Sez 211 5th Sez 212 5th Sez 213 5-P Sez 214 5th Sez 215 5th Sez 216 5th Sez 217 5th Sez 218 5th Sez 219 5th Sez 220 5th CE ₃ 221 5th Sez 222 5-P CE ₃ 223 5th Sez 224 5th Sez 225 5th Sez 226 5th Sez 227 5-g CE ₃ 228 5-P Sez 229 5-P Sez 230 5th SRz 231 5-P Sez 232 5-C1.6-E Sez

CH ₂ OS-CH ₃

CH ₂ C = C — CH ₂ CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ CH (CHz) 2

CH ₂ CH ₂ CH ₂ CH ₃

CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ -Zi

OS-1RG

OS-Rg

OS-Vi С ^ С-хВи OS-EVi. С = С-ЕЕ OS-Me sn ₂ os-sn ₃ CH ₂ OS-СН ₂ СН ₃ СН ₂ СН ₂ СН (СНз) ₂ СН ₂ СН ₂ СН ₂ СН ₃ СН ₂ СН ₂ СН ₃ СН ₂ СН ₂ - BVi OS-yrg C ^ C-Prr OS-Vi C = C-1Bi OS-EVi OS-EE-Me CH ₂ C = C-CH ₃ CH ₂ C = C-CH ₂ CHs sn ₂ sn ₂ sn {SN ) 2 sn ₂ sn ₂ sn ₂ sn ₃ CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ -BVi OS-1Pg

N

CHS sn ₃

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

СНз sn ₂ sn ₃ СН ₂ СНз СН ₂ СНз СН ₂ СН ₃ СН ₂ СНз СН ₂ СНз СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СНз СН ₂ СНз СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СН ₃

N N N N N N N N N N N

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СН ₃ СН ₂ СНз СН ₂ СН ₃ СН ₂ СНз СН ₂ СНЗ СН ₂ СНз СН ₂ СНз n

233 5-C1, b-R CE ₃

234 5-C1, br-CP ₃

235 5-C1.6-P CP ₃

236 5-C1.6-R C? S

237 5-C1.6-P SEz

238 5-C1.6-E C? 3

239 5-C1.6-R SEC *

240 5-C1.6-E CEz

241 5-C1.6-E CEz

242 5-C1.6-E CEs

243 5-C1.6-E CE ₃

244 5-C1.6-P SEz

245 5-C1.6-P SEz

246 5-C1.6-P SEz

247 5-C1.6-E CEz

248 5-C1.6-R SEz

249 5-C1.6-E CEs

250 5-C1.6-P CE ₃

251 5-C1.6-P SEz

252 5-C1.6-P SEz

253 5-C1.6-E CEz

254 5-C1.6-P SEz

255 5-C1.6-E CEz

256 5-C1.6-E CEz

257 5-C1.6-E CEs

258 6-C1.8-E CE ₃

259 6-C1.8-EEC

260 6-C1.8-P SEz

261 6-C1.8-EEC

262 b-S1.8-E CEz

263 6-C1.8-EEC

264 6-C1.8-E CE ₃

265 6 ~ C1.8-E SEC

266 6-C1.8-E CE ₃

267 6-C1.8-EEC.

268 6-C1.8-EEC

269 6-C1.8-E CEz

270 6-C1.8-EEC

271 b-S1.8-E CEz

272 6-C1.8-E CEz

273 6-C1.8-E CEz ‘

274 6-C1.8-E CEz

275 6-C1.8-E CEz

276 6-C1.8-E CEz

277 b-S1.8-E CEz

278 6-C1.8-E CEz

279 6-C1.8-E CEz

280 6-C1.8-E CEz

281 6-C1.8-EEC

282 b-S1.8-G SEz

283 b-C1.8-E CE ₃

284 6-CHs SEZ

285 6-CH ₃ SEZ

286 6-CHs SEZ

287 6-CH3 CE ₃

288 6-CHs SEZ

289 6-CH3 SG ₃

290 6-CHs SEZ

291 6-CH3 CE ₃

292 6-CH3 SEZ

293 6-CH3 SEZ

294 6-CHs SEZ

295 6-CH3 CE ₃

296 6-CH3 CP ₃

297 6-CH ₃ SEZ

298 6-CHs SEZ

299 6-CHs SEZ

300 6-CH3 CE ₃

OS-Rg

Os vi

OS-1Vi

OS-EVi

OS-EE CrS-Me CH ₂ OS-CH ₃ CH ₂ C ^ C-CH ₂ CH ₃ CH ₂ CH ₂ CH (CH ₃ ) ₂ CH ₂ CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ -1: Vi '0C-1Pr OS-Pr OS-Vi С = С-1Vi С ^ С-ЛВи OS-ЕЕ OS-Me СН ₂ ОС-СН ₃ СН ₂ С = С-СН ₂ СН ₃ СН2СН2СН (СНз) 2 CH ₂ CH ₂ CH ₂ CHs CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ -EVi

C = C-1Pg

OS-Rg

C = C-Vi

OS-1Vi

OS-EVi OS-EE S == S-Me

CH ₂ OS-CH ₃

CH ₂ OS-CH ₂ CH ₃

CH2CH2CH (CH3) 2

СН ₂ СН ₂ СН ₂ СНз СН ₂ СН ₂ СНз СН ₂ СН ₂ - Ви С = С-1Рг ОС-Рг ОС-Ви С = С-1Ви ОС-ЕВи ОС – ЕЕ OS-Me СН ₂ С = С- CH ₃

CH ₂ C = C-CH ₂ CH ₃

CH2CH2CH (CH3) 2

CH ₂ CH ₂ CH ₂ CHz CH ₂ CH ₂ CHz CH ₂ CH ₂ -EVi С ^ С-1Рг С = С-РГ OS-Ви OS-1Ви OS-ЕВи С = С-ЕЕ С = С-Ме СН ₂ С = C-SNZ

CH ₂ C = C-CH ₂ CH ₃

CH ₂ CH ₂ CH (CH ₃ ) ₂

CH ₂ CH ₂ CH ₂ CHz CH ₂ CH ₂ CHz CH ₂ CH ₂ -EVi OS-1RG OS-Rg OS-Vi OS-1Vi n

n n

n n

n n

n n

n n

n

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

SNZ

N

N

N n n n n n n n n n Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh Nh

SNZ SNZ SNZ SNZ

301 6-cs Sez CEC-bVi SNZ 302 6-cs SGZ SES-EB SNZ 303 6-cs Sez C = C-Me SNZ 304 6-cs Sez CH ₂ C = C-CH 3 SNZ 305 6-cs CE ₃ CH ₂ C ^ C-CH ₂ CH ₃ SNZ 306 6-cs SRz CH ₂ CH ₂ CH (CH ₃ ) ₂ SNZ 307 6-cs SGZ ‘ CH ₂ CH ₂ CH ₂ CHz SNZ 308 6-cs SGZ CH ₂ CH ₂ CH SNZ 309 6-cs SRz CH ₂ CH ₂ -GVi SNZ 310 6-SOSNz CE ₃ SES-xRg n 311 6-SOSNz Sez C = C-Pr n 312 6-SOSNz Sez Sns-vi n 313 6-SOSNz Sez .С = С-1Ви n 314 6-SOSNz Sez C ^ C-GVi n 315 6-suns CE ₃ Sez-eb n 3-6 6-SOSNz CE ₃ C = C-Me n 317 6-ΝΗ2 CE ₃ C = C-1Pg n 318 6-ΝΗ ₂ SRz C = C-Pr n 319 6-ΝΗ ₂ cg ₃ C = C-Vi n 320 6-ΝΗ ₂ SRz SzS-xVi n 321 6TH ₂ Sez C = C-bVi n 322 6TH ₂ Sez C ^ 3-EG n 323 6TH ₂ SGZ C ^ C-Me n 324 6-IME ₂ CE ₃ C = C-1Pg n 325 6th ME ₂ CE ₃ C = C-Pr n 326 6th ME ₂ SR ₃ C = C-Vi n 327 6-ΝΜε ₂ SR ₃ C = C-1 Vi n 328 6-ΝΜε ₂ SRz SVS-IVi n 329 6-IME ₂ SRz C = C-EG n 330 6th ₂ SRz C = C-Me n 331 7-C1 SRz OS-xRg n 332 7-C1 SRz C = C-Pr n 333 7-C1 SRz SGS-Wi n 334 7-C1 SRz C ^ C-xVi n

^{335 7} ' ^{C1 Wed} 3 s ^ s-evi n

336 7-C1 CE ₃ s ^ C-Εϋ n

337 7-C1 CE ₃ C = C-Me H * Unless otherwise indicated, stereochemistry (+/-).

Utility

The compounds of the present invention have reverse transcriptase inhibitory activity, in particular HIV inhibitory activity. The compounds of formula (I) have inhibitory activity against HIV reverse transcriptase and, therefore, are useful as antiviral agents for treating HIV infection and related diseases. The compounds of formula (I) have HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of this invention to inhibit the growth or infectivity of viruses is demonstrated in a standard test for the growth or infectivity of viruses, for example, using the test described below.

The compounds of formula (I) of the present invention are also useful for inhibiting HIV in an ex νινο sample containing HIV or suspected to be HIV-infected. Thus, the compounds of this invention can be used to inhibit HIV present in a body fluid sample (for example, a serum or sperm sample) that contains or is suspected to contain HIV or is exposed to HIV.

The compounds of this invention are also useful as standard or reference compounds for use in tests or assays to determine the ability of an agent to inhibit viral clone replication and / or HIV reverse transcriptase, for example, in a pharmaceutical research program. Thus, the compounds of this invention can be used as a control or comparative compound in such tests and as a control quality standard. The compounds of this invention may be provided in a commercial kit or container for use as such a standard or comparative compound.

Since the compounds of this invention are specific for HIV reverse transcriptase, the compounds of this invention can also be used as diagnostic reagents in diagnostic studies to detect HIV reverse transcriptase. Thus, inhibition of reverse transcriptase activity in a test (such as the tests described herein) by a compound of this invention will indicate the presence of HIV reverse transcriptase and HIV virus.

As used herein, the designation “μg” means micrograms, “mg” means milligram, “g” means gram, “μl” means microliter, “ml” means milliliter, “l” means liter, “nM” means nanomolar, “μM” means micromolar, “mm” stands for millimolar, “M” stands for molar, and “nm” stands for nanometer. “81dta” means 8idta-A1dpsI Comp., Lox, Mo.

HIV RNA Analysis

DNA plasmids and RNA transcriptase t νΐΐΓο.

The rIAB 72 plasmid containing the sequences of both dad and po1 BH10 (bp 1131816), cloned into 19B, was obtained according to Epskop-Ushapep! a1. ΑΙΌ8 Vezeagsk apd Nitap 1 <e1go \ z1T18e8 1989, 5, 577. This plasmid was linearized with WatH1 before generating m \ Ago RNA transcripts using the Xorgoe Oet1 zuzetet II (Rgoted) kit with T7 RNA polymerase. The synthesized RNA was purified by treatment with RNase-free DNase (Rgoted), extraction with a phenol-chloroform mixture and ethanol precipitation. RNA transcripts were dissolved in water and stored at -70 ° C. RNA concentration was determined based on A ₂₆₀ .

Probes

The biotinylated capture probes were purified by HPLC after synthesis on an Arrneb Vyuzuyep DNA synthesizer (Ez! Sju, SA) by adding biotin to the 5'-terminal side of the oligonucleotide using the biotin-phospharamidite reagent Sociζζ, Te !. B11. 1989, 30, 6287. The biotinylated capture probe dad (5'-biotin-STA6STSSC T6STT6SSSATASTA-3 ') was complementary to nucleotides 889-918 HXB2, and the biotinylated capture probe po1 (5'-biotinSSSTATCATTTTT66-23) HXB2. Alkaline phosphatase-conjugated oligonucleotides used as reporter probes were prepared by Bupdepe (Bap O1edo, CA). The reporter probe ro1 (5'STSTSTSTASTTTSATAAAAASSTS-3 ') was complementary to nucleotides 2403-2425 HXB2. The dad reporter probe (5'-SSSASTATTTS TSTASASSSTTST-3 ') was complementary to nucleotides 950-973 NHB2. All nucleotide positions correspond to the provisions of the SepWapC Separate Betznepse Eaa Wapk Databank, which is provided to the Separates Sotriet Sgoir Bes | Iepse Apa1u818 Boyt at Raskade (Eeeuete ShsShs Aabz Vezeatsy 1984, 12, 387). Reporter probes were prepared as initial 0.5 μM solutions in 2 x BBS (0.3 M IaCl, 0.03 M sodium citrate), 0.05 M Tris, pH 8.8, 1 mg / ml BSA.

Biotinylated capture probes were prepared as 100 μM stock solutions in water.

Streptavidin Coated Tablets

Streptavidin-coated tablets were obtained from Ei Rop! Vyupesipodod Buz! Et8 (Vozgop, MA).

Stock solutions of cells and viruses

MT-2 and MT-4 cells were stored in ΒРМI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg / ml gentamicin, all from C1bco. HIV-1 RF was propagated in MT-4 cells in the same medium. Stock virus solutions were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at -70 ° C. Infectious titers of the initial HIV-1 (RF) were 1-3 x 10 ⁷ PFU (plaque forming units) / ml according to the analysis of plaque formation on MT-2 cells (see below). Each aliquot of the viral stock solution used for infection was thawed only once.

To evaluate the antiviral efficacy, the cells that were to be infected were subcultured one day before infection. On the day of infection, the cells were resuspended at 5 × 10 ⁵ cells / ml in ΒРМI 1640, 5% FCS for volumetric infection or at 2 × 10 ⁶ cells / ml in Dulbecco's modified Eagle medium with 5% FCS for infection in microtiter plates. The virus was added and cultivation was continued for 3 days at 37 ° C.

HIV RNA Analysis

Cell lysates or purified RNA in

M or 5 M SEI was mixed with 5 M SEI and a capture probe to a final concentration of 3 M guanidinium isothiocyanate and a final concentration of 30 nM biotin oligonucleotide. Hybridization was carried out in sealed 96-well plates with a ϋ-shaped bottom for tissue culture (Νιπκ Is Soz! At) for 16-20 at 37 ° C. RNA hybridization reactions were diluted three times with deionized water to a final concentration of 1 M guanidinium isocyanate and aliquots (150 μl) were transferred to streptavidin-coated wells in microtiter plates. The binding of the capture probe and the hybrid capture probe RNA with immobilized streptavidin was allowed to occur for 2 hours at room temperature, after which the plates were washed 6 times with wash buffer for EIBA I Rop tablets! (phosphate buffered saline, 0.05% Tween 20). The second hybridization of the reporter probe with the immobilized complex of the capture probe and hybridized RNA targets was carried out in a washed streptavidin-coated well by adding 120 μl of a hybridization cocktail (mixture) containing 4 x BBS, 0.66% Triton X-100, b, 66% deionized formamide, 1 mg / ml BSA and 5 nM reporter probe. After hybridization for one hour at 37 ° C, the plate was washed again 6 times. Immobilized alkaline phosphatase activity was determined by adding 100 .mu.l of 0.2 mM 4metilumbelliferilfosfata (MIVR, CHV Bs1epyys) in buffer δ (2,5 M diethanolamine pH 8.9 (CHV Bshepyys), 10 mM MdS1 _2, 5 mM zinc acetate dihydrate and 5 mM Ν-hydroxyethylethylenediamine triacetic acid). The plates were incubated at 37 ° C. Fluorescence at 450 nm was measured using a microplate fluorometer (Iupa! Esk) with excitation at 365 nm.

Evaluation of the compound using a microplate in relation to HIV-1-identified MT-2 cells

The compounds to be evaluated were dissolved in DMSO and diluted in culture medium to a concentration twice as high as the concentration to be tested and a maximum concentration of DMSO of 2%. Further threefold serial dilutions of the compound in the culture medium were carried out directly in microtiter plates with a ϋ-shaped bottom (Mts). After dilution of the compounds, MT-2 cells (50 μl) were added to a final concentration of 5 x

10 ⁵ cells / ml (1 x 10 ⁵ cells per well). Cells were incubated with compounds for 30 min at 37 ° C in a CO ₂ thermostat. To assess antiviral activity, a suitable dilution of the original HIV-1 virus solution (RF) was added to the culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μl. Eight wells per plate were left uninfected by adding 50 μl of medium instead of virus, while eight wells were infected in the absence of any antiviral compound. To evaluate the toxicity of the compound, parallel plates were cultured without virus infection.

After 3 days of cultivation at 37 ° C in a humidified chamber inside the CO ₂ thermostat, the entire medium, except 25 kml of medium / well, was removed from the HIV-infected plates. Thirty-seven μl of 5 M ΘΕΌ containing a biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M ΘΕΌ and 30 nM of the capture probe. Hybridization of the capture probe in HIV RNA in the cell lysate was carried out in the same well of the microplate used for culturing the virus by sealing the tablet with a tablet sealant (Co!! Ag) and incubating for 16-20 hours in an incubator at 37 ° C. Then, distilled water was added to each well to dilute the hybridization reaction three times and 150 μl of this diluted mixture was transferred to a streptavidin-coated microtiter plate. The amount of HIV RNA was determined as described above. A standard curve obtained by adding known amounts of RNA 72 ΐη νίΐτο RNA transcript to wells containing lysed uninfected cells was plotted for each microtiter plate to determine the amount of viral RNA produced during infection.

To standardize the viral inoculum used to evaluate the compounds for antiviral activity, virus dilutions were selected that yielded Ι ^ ₀ (the concentration of the compound necessary to reduce HIV RNA levels by 90%) for dideoxycytidine (bBC) 0.2 μg / ml . Values of ΙΟ _{90 of} other antiviral compounds, both more and less active than ddC, were reproducible using several initial HIV-1 (RF) solutions during this procedure. This virus concentration corresponded to ~ 3 x 10 ⁵ PFU (measured by plaque assay on MT-2 cells) per test well and usually yielded approximately 75% of the maximum level of viral RNA achieved with any viral inoculum. For HIV RNA analysis, ΙΟ ₉₀ values were determined based on the percentage reduction in the net signal (signal from samples of infected cells minus the signal from samples of uninfected cells) in the RNA analysis, relative to the net signal from infected, untreated cells in the same culture plate (average of eight holes). The representativeness (impartiality) of performing individual infectivity tests and RNA tests was evaluated according to three criteria. Virus infection was required to result in an RNA test signal equal to or greater than the signal generated from 2 ng of the rEAB 72 ίη νίΐτο RNA transcript. 1C ₉₀ for bbs. defined in each test should be between 0.1 and 0.3 μg / ml. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in the case of non-inhibited infection. A compound was considered active if it was found to be ΙΟ ₉₀ less than 20 μM.

In tests for antiviral activity, all manipulations in microtiter plates, after the initial addition of a 2-concentrated solution of the compound to one row of wells, were performed using Regct E1teg / Ce! And 8 PropoE !! e.

Protein Binding and Mutant Resistance

To characterize the ΝΝ ^ аналогов analogues on their potential for clinical efficacy, we studied the effect of plasma proteins on antiviral activity and measured the antiviral activity against wild-type HIV species and mutant species that have amino acid substitutions at the known ΝΝ ^ Π binding site. There are two rationales for this testing strategy.

1. Many drugs bind strongly to plasma proteins. Although the binding affinity for most drugs for the main components of human plasma, namely human serum albumin (NBA) or alpha-1-acid glycoprotein (AAO) is low, these basic components are present in high concentrations in the blood. Only a free or unbound drug is suitable for crossing the membrane of an infected cell to interact with a target site (i.e., HIV-1 reverse transcriptase, HIV HIV1 transcriptase). Thus, the effect of the added NBA + AAO on antiviral activity in tissue culture more closely reflects the effectiveness of a particular compound in a clinical setting. The concentration of the compound required for 90% inhibition of virus replication, measured by the sensitive viral RNA-based method, is designated as 1C ₉₀ . Then, an increase in one or another number of times of the average HS _{90 was} calculated for the tested compounds in the presence or upon addition of levels of H8A and LAS, which reflect the concentrations of ίη νίνο (45 mg / ml H8A, mg / ml AAS). The lower this increase by a number of times, the more this compound will be suitable for interaction with the target site.

2. The combination of a high rate of virus replication in an infected individual and weak specificity of viral RT (reverse transcriptase) leads to the formation of pseudo-species or mixtures of HIV species in an infected individual. These species will include most wild-type species, but also mutant variants of HIV, and the proportion of each mutant will reflect its relative relevance and replication rate. Since mutant variants, including mutants with changes in the amino acid sequence of viral reverse transcriptase, seem to pre-exist in the pseudo-species of an infected individual, the overall activity observed in the clinical setting will reflect the ability of the drug to inhibit not only wild-type HIV-1, but also mutant options. Thus, mutants of HIV-1 have been constructed, with a known genetic background, carrying amino acid substitutions at positions that are thought to be involved in ΝΝΚΤΊ binding, and the ability of test compounds to inhibit the replication of these mutant viruses has been measured. The concentration of the compound required for 90% inhibition of virus replication, measured by the sensitive viral RNA-based method, is designated as 1C ₉₀ . It is desirable to have a compound that has high activity against a wide variety of mutants.

Dose and formulation

The antiviral compounds of this invention can be administered for the treatment of viral infections by any method that provides contact of the active agent with the site of action of this agent, i.e. viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means suitable for use in combination with pharmaceutical agents, either as individual therapeutic agents or in a combination of therapeutic agents. They may be administered separately, but are preferably administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

The dose administered will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of a particular agent and its form and route of administration; age, health and weight of the recipient; the nature and extent of the symptoms; type of concomitant therapy; frequency of administration and desired effect. It can be expected that the daily dose of the active ingredient will be ~ 0.001-1000 milligrams per kg of body weight, with the preferred dose being ~ 0.1 - ~ 30 mg / kg.

Dosage forms of the compositions suitable for administration contain from about 1 mg to about 100 mg of the active ingredient per unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of ~ 0.595% by weight based on the total weight of the composition. The active ingredient can be administered orally in the form of solid dosage forms, such as capsules, tablets and powders, or as liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally in the form of sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Such diluents can be used to prepare compressed tablets. Both tablets and capsules can be formulated as sustained release products to provide continuous release of the drug over the course of hours. Compressed tablets may be coated with sugar or a film to mask an unpleasant taste and protect the tablets from the atmosphere, or have an enteric coating for selective destruction in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and taste and odor enhancing agents to improve patient perception.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar and glycol solutions, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering agents. Antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, individually or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Kesh1pd1op'8 Ryattaseijs1 8c1epse§, § Sirga, a standard reference guide in this area.

Capsules

A large number of standard capsules can be prepared by filling in standard two-part solid 71 latin capsules, each containing 100 mg of the powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

A mixture of the active ingredient in edible oil, such as soybean oil, cottonseed oil, or olive oil, can be prepared and introduced using a feed piston pump into gelatin to form soft gelatin capsules containing 100 mg of active ingredient. Then these capsules should be washed and dried.

Pills

A large number of tablets can be prepared using conventional methods, so that a standard dosage unit contains 100 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Suitable coatings may be applied to improve palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that every 5 ml contains 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, I. 8. P., and 0.025 mg of vanillin.

Injection solutions

A parenteral composition suitable for administration by injection can be prepared by mixing 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is sterilized using conventional methods.

Combination of components (a) and (b)

Each component of the therapeutic agent of the present invention may independently be in any dosage form, such as those described above, and may also be administered in various ways, as described above. It should be understood that in the following description, component (b) refers to one or more of the agents described previously. So, if components (a) and (b) are to be treated equally or independently, each agent of component (b) can also be treated equally or independently.

Components (a) and (b) of the present invention can be prepared together in a single dosage unit (i.e., combined together in one capsule, tablet, powder or liquid, etc.) as a combined product. When component (a) and component (b) are not prepared together in the same dosage unit, component (a) can be administered simultaneously with component (b) or in any order; for example, component (a) of this invention may be introduced first, followed by component (b), or they may be introduced in reverse order. If component (b) contains more than one agent, for example, one RT inhibitor and one protease inhibitor, these agents can be administered together or in any sequence. If they are not administered at the same time, it is preferred that the administration of component (a) and component (b) take place at intervals of less than one hour. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound or the like, as used herein, means compounds that can be administered orally. Although it is preferable to administer component (a) and component (b) in the same way (i.e., for example, administering both orally) or in the same dosage form, if desired, they can each be independently administered in different ways (i.e., for example, one component of this combination product may be administered orally and the other component may be administered intravenously) or in different dosage forms.

As it should be understood by a practitioner with qualifications in this field, the dose of combination therapy of this invention may depend on various factors, such as the pharmacodynamic characteristics of a particular agent and its form and route of administration, age, state of health and weight of the recipient, nature and degree of symptoms, type of concomitant treatment, frequency of administration and desired effect, as described above.

The exact dose of components (a) and (b) of the present invention will be readily determined by a practitioner with qualifications in this field based on this description. As a general guideline, usually a daily dose may be approximately 100 ml - approximately 1.5 g of each component. If component b) represents more than one compound, then usually the daily dose may be from ~ 100 ml to ~ 1.5 g of each agent of component (b). As a general guideline, with the combined administration of the compounds of component (a) and component (b), the dose of each component can be reduced by approximately 70-80% relative to the usual dose of the component when it is administered separately as a single agent for treating HIV infection, in connection with synergistic effect of this combination.

The combined products of this invention can be prepared so that although these active ingredients are combined in a single dosage unit, physical contact between them is minimized. To minimize contact, for example, when the product is orally administered, one active ingredient may have an enteric coating. By coating one of the active ingredients with an enteric coating, not only can the contact between the combined active ingredients be minimized, but also the release of one of these components in the gastrointestinal tract can be controlled in such a way that one of these components is not released in the stomach, but is significantly released in the intestine . Another embodiment of this invention, in which oral administration is desired, is provided for a combination product in which one of the active ingredients is coated with a sustained release material that allows sustained release through the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. In addition, the sustained release component may be further coated with an enteric coating so that release of this component occurs only in the intestine. If one approach involves preparing a combination product in which one component is coated with a polymer for sustained and / or enteric release, and the other component is also coated with a polymer, such as low viscosity hydroxypropyl methylcellulose, or other suitable materials known in the art, to further separate active components. The polymer coating serves to form an additional barrier to interaction with another component. In each composition in which contact between components (a) and (b) is prevented by means of a coating or some other material, contact can also be prevented between the individual agents of component (b).

Dosage forms of the combined products of this invention in which one active ingredient is enteric coated can be prepared in the form of tablets so that the enteric coated component and the other active ingredient are mixed together and then compressed into a tablet, or such that coated with an enteric coating the component is compressed into one layer of the tablet, and the other active component is compressed into an additional layer. Optionally, to further separate these two layers, one or more placebo layers may be present, so that the placebo layer is between the active ingredient layers. In addition, the dosage forms of the present invention may be in the form of capsules in which one active ingredient is compressed into a tablet or in the form of a variety of microtablets, particles, granules or resistant forms, which are then enteric coated. Then, these enteric-coated microtablets, particles, granules or resistant forms are placed in a capsule or compressed into a capsule together with granulation of another active ingredient.

These, as well as other ways to minimize contact between the components of the combined products of this invention, whether they are administered in the same dosage form or in separate forms, but at the same time or in the same way, will be obvious to specialists in this field on the basis of this descriptions.

Also included within the scope of this invention are pharmaceutical kits useful for treating HIV infection, which contain a therapeutically effective amount of a pharmaceutical composition comprising the compounds of component (a) and one or more compounds of component (b) in one or more sterile containers. Sterilization of the container may be carried out using a conventional sterilization technique well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. Sterile material containers may contain individual containers or one or more multi-part containers, if desired. Component (a) and component (b) can be separated, or physically combined into a single dosage form or unit, as described above. Such kits may additionally contain, if desired, one or more different generally accepted pharmaceutical components of the kit, such as, for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art . Instructions may also be included in the kit, either in the form of inserts or in the form of labels indicating the quantities of the components to be introduced, guidelines for use and / or directions for mixing the components.

Obviously, in the light of the above description, numerous modifications and variations are possible. Thus, it should be understood that, within the scope of the appended claims, the invention may be practiced in a manner other than specifically described herein.

Claims (18)

CLAIM 1. The compound of formula (I) in ¹ in ² I or a stereoisomer thereof, or a pharmaceutically acceptable salt, wherein K ¹ is C _1-3 alkyl substituted with 1-7 halogen atoms; K ^{2 is} selected from C1-5 alkyl substituted with 1-2 K ⁴ , C2-5 alkenyl substituted with 1-2 K ⁴ , and C _2-5 alkynyl substituted with one K ⁴ ; K ³ each is independently selected from C _1-4 alkyl, OH, C _1-4 alkoxy, P, C1, Br, I, ΝΕ ⁵ ^ ³ , ΧΟ-, ΟΝ, C (O) K ⁶ , MUOA and ^ C (O) MK ⁵ K ^5a ; alternatively, if two K ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OCH 2 O—; K ^{4 is} selected from C3-5 cycloalkyl substituted with 0-2 K ³ , phenyl substituted with 0-5 K ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, Ν and 8, substituted 0-2 K ³ ; K ⁵ and K ^{5a are} independently selected from H and C _1-3 alkyl; K ^{6 is} selected from H, OH, C _1-4 alkyl, C _1-4 alkoxy, and NK ⁵ K ^5a ; K ^{7 is} selected from C _1-3 alkyl and C _1-3 alkoxy; K ^{8 is} selected from H, C _3-5 cycloalkyl and C _1-3 alkyl and n is selected from 0.1, 2, 3 and 4. 2. The compound according to claim 1, in which K ¹ is C _1-3 alkyl substituted with 1-7 halogen atoms; K ^{2 is} selected from C _1-5 alkyl substituted with one K ⁴ , C2-5 alkenyl substituted with one K ⁴ , and C2-5 alkynyl substituted with one K ⁴ ; K ³ each is independently selected from C _1-4 alkyl, OH, C _1-4 alkoxy, P, C1, Br, I, MK ⁵ K ^5a , ΧΟ-, CM, C (O) K ⁶ , XI 1C (O ) K and XI 1C (O) x R ^{5 K:;} alternatively, if two K ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OCH 2 O—; K ^{4 is} selected from C3-5 cycloalkyl substituted with 0-2 K ³ , phenyl substituted with 0-2 K ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, Ν and 8, substituted 0-1 K ³ ; K ⁵ and K ^{5a are} independently selected from H and C ₃ and C ₂ H ₅ ; K ^{6 is} selected from H, OH, CH3, C2H5, OCH3, OS ₂ H ₅ and XK'K ⁵ :; K ^{7 is} selected from CH ₃ , C ₂ H ₅ , OCH _3, and OS ₂ H ₅ ; K ^{8 is} selected from H, cyclopropyl, CH ₃ and C2H5; and n is selected from 0,1, 2 and 3. 3. The compound according to claim 2, in which K ^{1 is} selected from CP3 and C2P5; K ^{2 is} selected from C _1-3 alkyl substituted with one K ⁴ , C2-3 alkenyl substituted with one K ⁴ , and C2-3 alkynyl substituted with one K ⁴ ; K ^{3 is} each independently selected from C _1-3 alkyl, OH, C _1-3 alkoxy, P, C1, Br, I, MK ⁵ K ^5a , ΧΟ-, εΝ, C (O) K ⁶ , X'HN ( O) K and HNS (O) HCK ⁵ :; alternatively, if two K ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OCH 2 O—; K ^{4 is} selected from C3-5 cycloalkyl substituted with 0-2 K ³ , phenyl substituted with 0-2 K ³ and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, Ν and 8, substituted 0-1 K ³ ; K ⁵ and K ^{5a are} independently selected from H, CH _3, and C2H5; K ^{6 is} selected from H, OH, CH3, C2H5, OCH3, OS ₂ H ₅ and XK'K ⁵ :; K ^{7 is} selected from CH ₃ , C ₂ H ₅ , OCH _3, and OS ₂ H ₅ ; K ^{8 is} selected from H, CH ₃ and C ₂ H _5, and η is selected from 0,1 and 2. 4. The compound according to claim 3, in which K ¹ is CP3; K ^{2 is} selected from C _1-3 alkyl substituted with one K ⁴ , C2-3 alkenyl substituted with one K ⁴ , and C2-5 alkynyl substituted with one K ⁴ ; K ^{3 is} each independently selected from C1-3 alkyl, OH, C1-3 alkoxy, P, C1, MK. ⁵ K ^5a, NΟ2, CN, C (O) K ^6, H'NS (O) R and MNF (G ^ K ⁵ K ^5a; alternatively, if two K ³ substituents are present and they are attached to adjacent carbon atoms, then they can combine to form —OCH 2 O—; K ^{4 is} selected from cyclopropyl substituted with 0-1 K ³ , phenyl substituted with 0-2 K ³ , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, Ν and 8, substituted with 0-1 K ³ , where the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl and 2-imidazolyl; K ⁵ and K ^{5a are} independently selected from H, CH _3, and C2H5; K ^{6 is} selected from H, OH, CH3, C2H5, OCH3, OS ₂ H ₅ and XK'K ⁵ :; K ^{7 is} selected from CH ₃ , C ₂ H ₅ , OCH _3, and OS ₂ H ₅ ; K ^{8 is} selected from H, CH 3 and C ² H ⁵ and n is selected from 1 and 2. 5. The compound according to claim 4, having the formula 1a ’H l < A® 1a. 6. The compound according to claim 4, having the formula F 7. The compound according to claim 1, selected from (+/-) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-chloro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-chloro-4-phenylethinyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 4-cyclopropylethynyl-6-methoxy-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-methoxy-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-methoxy-4-phenylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 4-cyclopropylethynyl-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4- (2-pyridyl) ethynyl-4trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4-phenylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 4-cyclopropylethynyl-6-fluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-fluoro-4- (2-pyridyl) ethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-fluoro-4-phenylethinyl-4 trifluoromethyl-3,4-dihydro-2 (1) -quinazolinone; (+/-) - 6-fluoro-4- (2'-2-pyridyl) ethyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-fluoro-4-phenylethyl-4-trifluoromethyl3,4-dihydro-2 (1H) -quinazolinone; (-) - 6-chloro-4-cyclopropylethinyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) - 6-chloro-4-cyclopropylethinyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) - 4-cyclopropylethinyl-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (-) - 4-cyclopropylethinyl-5,6-difluoro-4trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) - E-4-cyclopropylethylene-5,6-difluoro-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; and (-) - 6-chloro-4-E-cyclopropylethenyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone, or a pharmaceutically acceptable salt thereof. 8. The compound of formula II II or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein K ² is C = ^{CK 4a} ; K ³ is selected from C1 _-4 alkyl, OH, C1 _-4 -alkoxy, E, C1, Br, I, \ Ί \ Ί \ ':. ΝΟ2, MF C (O) K ⁶ , ΝΗ ^ Ε ⁷ and ΝΗ ^ ΝΕ ⁵ ^; K ^{4a is} selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and isopentyl; K ⁵ and K ^{5a are} independently selected from H and C _1-3 alkyl; K ⁶ is selected from H, OH, C1 _-4 alkyl, _C1-4 alkoxy and KK ⁵ K ^5a; K ⁷ is selected from C1 _-3 alkyl, and C1 _-3 alkoxy; K ^{8 is} selected from H, C _3-5 cycloalkyl and C _1-3 alkyl and n is selected from 0, 1, 2, 3 and 4. 9. The compound of claim 8, in which K ² denotes C C-KU K ³ is selected from C1 _-4 alkyl, OH, C1 _-4 -alkoxy, E, C1, Br, I, K IR ^{5 5a,} ΝΟ2, MF C (O) K ^6, Ν№ (θχ ^7; K ^{4a is} selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and isopentyl; K ⁵ and K ^{5a are} independently selected from H, CH _3, and C2H5; K ^{6 is} selected from H, OH, CH3, C2H5, OCH3, OC ₂ H ₅ and MK ⁵ ^; K ^{7 is} selected from CH3, C2H5, OCH3, and OCH2H5; K ^{8 is} selected from H, cyclopropyl, CH3 and C2H5 and n is selected from 0, 1 and 2. 10. The compound according to claim 9, having the formula 11a SR ₃ a ² Pa 11. The compound according to claim 9, having the formula & pi. 12. The compound of claim 8, selected from (+/-) - 6-chloro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-chloro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 4-isopropylethynyl-6-methoxy-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4-isopropylethynyl-4tifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4-isopentyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-fluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 6-fluoro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (-) - 5,6-difluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) - 5,6-difluoro-4-isopropylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (-) - 5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; and (+) - 5,6-difluoro-4-ethylethynyl-4 trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone, or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof. 14. A method of treating an HIV infection, comprising administering to a host in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof. 15. A method of treating HIV infection, comprising administering in combination to a host in need thereof, a therapeutically effective amount of (a) a compound according to any one of claims 1-12 or its stereoisomeric forms, mixtures of stereoisomeric forms or its pharmaceutically acceptable salts, and (b) according to at least one compound selected from the group comprising HIV reverse transcriptase inhibitors and HIV protease inhibitors. 16. The method according to clause 15, in which the reverse transcriptase inhibitor is selected from A2T, 3TC, bbC bbC, b4T, delavirdine, derivatives of TCO, BBBC-587, nevirapine, b-697 661, b 73497, BO 18,893, loviride, trovirdine, MKS-442 and NVU 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, UH-478, nelfinavir, ΚΝΡ272, SSR-61755, I-140690 and AVT-378. 17. The method according to clause 16, in which the reverse transcriptase inhibitor is selected from A2T and ZTS, and the protease inhibitor is selected from saquinavir, nelfinavir, ritonavir and indinavir. 18. A pharmaceutical kit for treating an HIV infection that contains a therapeutically effective amount of (a) a compound according to any one of claims 1-12 or its stereoisomeric forms, mixtures of stereoisomeric forms or its pharmaceutically acceptable salts and (b) at least one compound, selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.