MXPA99008909A - 4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitors - Google Patents

4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitors

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Publication number
MXPA99008909A
MXPA99008909A MXPA/A/1999/008909A MX9908909A MXPA99008909A MX PA99008909 A MXPA99008909 A MX PA99008909A MX 9908909 A MX9908909 A MX 9908909A MX PA99008909 A MXPA99008909 A MX PA99008909A
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Mexico
Prior art keywords
dihydro
quinazolinone
ch2ch2
trifluoromethyl
pyridyl
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MXPA/A/1999/008909A
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Spanish (es)
Inventor
W Corbett Jeffrey
Sung Ko Soo
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Du Pont Pharmaceuticals Company
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Publication of MXPA99008909A publication Critical patent/MXPA99008909A/en

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Abstract

The present invention relates to 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolines of formula (I), or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

Description

3, 4-DIHYDRO-2- (1H) -CUINAZOLINONES 4, 4- DISSTITUTE USEFUL AS INHIBITORS OF THE INVERSE TRANSCRIPTASA OF HIV.
Field of Invention This invention relates generally to 3,4-dihydro-2 (1H) -quinazolinones 4, 4-dibuclides which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic devices comprising the same, methods of use of them to treat a viral infection or as a standard reagent assay, and intermediaries and processes to elaborate it.
Background of the Invention Two different retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunodepressive disorder, acquired immunodeficiency syndrome (AIDS). HIV-positive individuals are initially asymptomatic, but typically develop a complex Ref: 031177 related to AIDS (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression that predisposes them to weakening and fatal terminal opportunistic infections.
The AIDS disorder is the final result of an HIV-1 or HIV-2 virus followed by its complete life cycle. The life cycle of the virus begins with the binding of the virus to itself to the T-4 lymphocyte immune cell of the human host through the binding of a glycoprotein on the surface of the protective coat of the virus with the glycoprotein CD4 in the lymphocyte cell. . Once bound, the virus gets rid of its envelope of glycoprotein, penetrating the membrane of the host cell, and discovering its RNA. The enzyme of the virus, reverse transcriptase, directs the process of transcription of the RNA in the DNA of simple braid. The RNA virus degrades and a second braid of DNA is created. Now double stranded DNA is integrated into the genes of human cells and those genes are used for the production of viruses.
At this point, the RNA polymerase completely transcribes the DNA in the RNA virus. The RNA virus is translated into the gag-poly precursor fusion polyprotein. The polyprotein is then incrusted by the HIV protease enzyme to provide the mature viral proteins. Thus, the HIV protease is responsible for the regularization of a series of incrustation events that begin with the maturation of the virus particles in a virus that is capable of infecting completely.
The typical response of the human immune system, eliminating the invasion of viruses, is put to the test because viruses infect and eliminate the T cells of the immune system. In addition, viral reverse transcriptase, the enzyme used to make a new virus particle, is not very specific, and causes transcription errors that result in a continuous change of glycoproteins on the surface of the virus's protective coat. This lack of specification weakens the effectiveness of the immune system because the antibodies specifically produced against a glycoprotein may be useless against others, thereby reducing the number of antibodies available to deal with viruses. The virus continues to reproduce as the response of the immune system continues to weaken. Eventually, HIV greatly sustains a free domain over the immune system of antibodies, allowing opportunistic infections to occur, and without the administration of anti-virus agents, immunomodulators, or both, death can follow.
These are at least three critical points in the life cycle of the virus that can be identified as possible targets for antiviral drugs: (1) the initial binding of the virus to the T-4 lymphocyte or macrophage site, (2) the transcription of the viral RNA to viral DNA (reverse transcriptase, TI), and (3) the processing of the gag-pol protein by the HIV protease.
The inhibition of the virus is the second critical point, the process of transcription of viral RNA to viral DNA, has provided several of the general therapies used in the treatment of AIDS. This transcription can occur by the virus to reproduce because the genes of the virus are encoded in the RNA and the host cell only reads DNA. By introducing drugs that block reverse transcriptase to complete the formation of viral DNA, replication of HIV-1 can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3 '-azido-3' -deoxy thymidine (AZT), 2 ', 3'-dideoxy cytidine (ddC), 2', 3'-dideoxy thymidinene (d4T), 2 ', 3 '-dideoxinosine (ddl), and 2'-3'-dideoxy-3'-thia-cytidine (3TC) have been shown to be relatively effective in HIV replication defective in the state of reverse transcriptase (TI).
An active area of research is the discovery of non-nucleoside HIV transcriptase inhibitors. As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of HIV infection and the treatment of AIDS. ' U.S. Patent 5,519,021 discloses reverse transcriptase inhibitors which are benzoxazinones of the formula: where X is a halogen, Z can be 0 Patents EP 0.530 and WO 93/04047 disclose inhibitors of HIV reverse transcriptase which are quinazolinones of the formula A: wherein G is a variety of groups, R and R can be H, Z can be O, R2 can be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R may be a variety of groups including sub-alkyl substituted.
WO 95/12583 also describes inhibitors of HIV reverse transcriptase of formula A. In this publication, G is a variety of groups, R3 and R4 can be H, Z can be 0, R2 is substituted alkenyl or substituted alkynyl, and R1 is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S) - (-) - 6-chloro-4-cyclopropyl-3,4-dihydro-4 ((2-pyridi) ethynyl ) -2 - (1H) -quinazolinone.
The synthetic processes for making quinazolinones such as those described above are detailed in the following references: Houpis et al, Te t r. Le t t. 1994, 35 (3 7), 6811-6814; Tucker et al, J. Med. Ch em. 1994, 3 7, 2437-244; and, Huffman et al, J. Org. Ch em. 1995, 60, 1590-1594.
Patent DE 4,320,347 illustrates qui na ol nons of the formula wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this type are not considered to be part of the present invention.
Despite the current success of reverse transcriptase inhibitors, it has been found that patients with HIV can begin to resist a simple inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.
Description of the invention Accordingly, an object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for the treatment of HIV infection, which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a novel method for the treatment of infection, by HIV comprising administering to the host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected from the group consisting of inhibitors of HIV reverse transcriptase and inhibitors of HIV protease.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibitory activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method for inhibiting HIV present in a blood fluid sample comprising treating the blood fluid sample with an effective amount of a compound of the present invention.
It is another object of the present invention to provide a device or container containing at least one of the compounds of the present 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 pharmacist. to inhibit HIV reverse transcriptase, the growth of HIV, or both.
These and other objects, which will be apparent during the following detailed description, will be executed by the inventors discovering that the compounds of formula (I): wherein R1, R2, R3, and R8 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.
Detailed Description of the Preferred Modalities. [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: or a tereoisomer or pharmaceutically acceptable salt thereof, wherein: RJ is alkyl C; substituted with 1-7 halogen; R 'is selected from C? _5 alkyl substituted with 1-2 R, C2_5 alkenyl substituted with 1-2 R "1, and C2-alkynyl substituted with 1 R; R3 in each appearing, is independently selected from alkyl C? _, OH, alkoxy C? _, F, Cl, Br, I, NR5R5a, N02, CN, C (0) R6, NHC (0) R7, and NHC (O) NR5R5a; alternatively, if two R3 are presented and are attached to the adjacent carbons, then these can be combined to form -OCH20-; R4 is selected from C3_5 cycloalkyl substituted with 0-2 of R3, phenyl substituted with 0-5 of R, and a 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 of R3; R5 and R5a are independently selected from H and Ci_3 alkyl; R 'is selected from H, OH alkyl to the coxi R7 is selected from C3_3alkyl and C3_3alkoxy; R8 is selected from H, C3_5 cycloalkyl, and Ci_3 alkyl; Y, n is selected from 0, 1, 2, 3, and 4. [2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein: R is C1-3 alkyl substituted with 1-7 halogen; R2 is selected from C1-5 alkyl substituted with 1 of R4, C2-5 alkenyl substituted with 1 of R4, and C2-5 alkynyl substituted with 1 of R4; R3 in each appearing is independently selected from C C - alkyl, OH, C? _4 alkoxy, F, Cl, Br, I, NR5R5a, N02, CN, C (0) R6, NHC (0) R7, and NHC ( O) NR5R5a; alternatively, if two of R3 are presented and are bonded to the adjacent carbons, then these may be combined to form -0CH20-; R is selected from C3-5 cycloalkyl substituted with 0-2 of R3, phenyl substituted with 0-2 of R3, and a 5-6 member heterocyclic system containing from 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 of R3; R5 and R5a are independently selected from H, CH3 and C2H5.
R (selected from H, OH, CH3, C2H5, OCH3, OC2H5 and NR5R5a, R7 is selected from CH3, C2H5, OCH3, and OC2H5; R8 is selected from H, cyclopropyl, CH3 and C2H5; Y, n is selected from 0, 1, 2, and 3. [3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein: R1 is selected from CF3, and C2F5; R is selected from C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4; R3, in each appearing is independently selected from C1-3 alkyl, OH, C3-alkoxy, F, Cl, Br, I, NR5R5a, N02, CN, C (0) R6, NHC (0) R7, and NHC (O) NR5R5a; alternatively, if two of R3 are presented and are bonded to adjacent carbons, then these can be combined to form -OCH20-; R is selected from C3-5 cycloalkyl substituted with 0-2 of R3, phenyl substituted with 0-2 R3, and a 5-6 member heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0 -1 R3; R and RDa are independently selected from H CH3 ,. and C2H5 R 'is selected from H, OH, CH3'. ? H • OCH3, OC2K5 and NR5R5a; R7 is selected from CH3, C2H5, OCH3, and OC H5; R8 is selected from H, CH and C2H5; Y n is selected from 0, 1, and 2. [4] In still a more preferred embodiment, the present invention provides a novel compound of formula I, wherein: R1 is CF3; R2 is selected from C1-3 alkyl substituted with 1 R4, C2_3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4; R3 in each appearing is independently selected from C1-3alkyl, OH, C1-3.alkoxy, F, Cl, NR5R5a, N02, CN, C (0) R6, NHC (0) R ~, and NHC ( O NR5R5a, alternatively, if two R's are presented and attached to the adjacent carbons, then these can be combined to form -CH20-; R is selected from cyclopropyl substituted with 0-1 R3, phenyl substituted with 0-2 R3, and a 5-6 member heterocyclic system containing from 1-3 heteroatoms selected from 0, N, and S, substituted with 0-1 R3 , 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, -i-soxazolyl, and 2- imidazolyl; R5 and R5a are independently selected from H, CH3 and C2H5; Rb is selected from H, OH, CH3, C2H5, OCH3, OC2H5, And NR5R5a; R is selected from CH3, C2H5, OCH, and OC2H5.
R is selected from H, CH3 and C2H5; Y, n is selected from 1 and 2. [5] In a further preferred embodiment, wherein the compound is of the formula the. [5] In a further preferred embodiment, wherein the compound is of the formula Ib: Ib. [7] In a further preferred embodiment, the compound of formula I is selected from: (+ / -) - β-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quina zol inona; (+ / -) -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- (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, β-difluoro-4-tri-fluororneti 1-3, 4-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone; (+/-) -5,6-difluoro-4-phenylethynyltrifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) - 4-cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone; (+ / -) -6-fluoro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) -6-fluoro-4-phenylethynyl-4-tri-fluoromethyl-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-cyclopropylethynyl-4-tri-fluororne-3-yl-dihydro-2 (1H) -quinazolinone; (+) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) -4-cyclopropylethynyl-5,6-di-fluoro-4-t-rifluoromet-3-yl-dihydro-2 (1H) -quinazolinone; (-) -4-cyclopropylethynyl-5, β-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) -4-E-cyclopropyletenyl-5,6-difluoro-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone; Y, (-) - 6-chloro-4-E-cyclopropyletenyl-4-trifluoromethyl-3, 4-dihydro-2 (1H) -quinazolinone; or a pharmaceutically acceptable salt thereof. [8] In a second embodiment, the present invention provides a novel compound of formula II: II or a tereoisomer or pharmaceutically acceptable salt thereof, wherein: R2 is C = C-R4a; RJ is selected from alkyl C? _, OH, C4-alkoxy, F, .'Cl, Br, I, NR5R5a, N02, CN, C (0) R6, NHC (0) Re, NHC (0) R7, and NHC (0) NR5R5a; Ri 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl R5 and R5a are independently selected from H and C1-3 alkyl, R 'is selected from H, OH, alkyl Ci. coxi C? -4, and NR5R5a; R is selected from C1_3alkyl and C3_3alkoxy; OR R is selected from H, C3_5 cycloalkyl, and C1_3alkyl; Y, n is selected from 0, 1, 2, 3, and 4. [9] In another preferred embodiment, the present invention provides a novel compound of formula II, wherein: R2 is C = C-R4a; RJ is selected from C C4alkyl, OH, C ?4alkoxy, F, Cl, Br, I, NR5R5a, N02, CN, C (0) Rc ', and NHC (0) R7; R, 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl; R and R .5a are independently selected from H CH3 and C2H5 R < is selected from H, OH, CH3, C2H5, 0CH3, OC2H5 and NR5R5a; R7 is selected from CH3, C2H5, OCH3, and OC2H5; R8 is selected from H, cyclopropyl, CH3 and C2Hs; Y n is selected from 0, 1, and 2.
[10] In a further preferred embodiment, wherein the compound is of the formula lialia.
[11] In a further preferred embodiment, wherein the compound is of formula 11b: lib.
[12] In another more preferred embodiment, the compound of formula II is selected from: (+/-) - 6-chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+ / -) -6-chloro-4-ethynylnyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+ / -) - 4-isopropylethynyl-6-methoxy-4-tri fluorome-3, 4-dihydro-2 (1H) -quinazolinone; (+/-) -5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone; (+/-) -5,6-D-fluoro-4-ethylethynyl-4-tri fluoromethyl-3, -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-tri fluorome-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- -tri fluoromethyl-3-dihydro-2 (1H) -quinazolinone; and, (+) - 5, β-difluoro-4-ethynylnyl-4-trifluoromethyl '3,4-dihydro-2 (1H) -quinazolinone; a pharmaceutically acceptable salt thereof In a third embodiment, the present invention provides a novel pharmaceutically effective composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable salt thereof.
In a fourth embodiment, the present invention provides a novel 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 provides a novel method for the treatment of an HIV infection comprising administering, in combination, to a host in need thereof, a therapeutically effective amount of: (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 AZT, 3TC, ddI, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY73497, 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.
Notwithstanding a preferred embodiment, the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, and indinavir.
In yet a further preferred embodiment, the reverse transcriptase inhibitor is AZT.
In yet another preferred preferred embodiment, the protease inhibitor is indinavir.
In a sixth embodiment, the present invention provides a pharmaceutical device useful for the treatment of HIV infection, comprising a therapeutically effective amount of: (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 one or more sterile containers.
In a seventh embodiment, the present invention provides a novel method for inhibiting HIV present in a body fluid sample comprising treating the body fluid sample with an effective amount of a compound of formula I or II.
In an eighth embodiment, the present invention for providing a novel device or container comprises 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 pharmacist to inhibit HIV reverse transcriptase, HIV growth, or both.
Definitions .
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and can be isolated in optically active or racemic forms. The form for preparing optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials is well known in the art. All chiral, diastereomeric, racemic forms and all geometrically isomeric forms of a structure are tried, except the specific stereochemical or isomeric forms are specifically indicated.
The processes of the present invention are contemplated to be practiced on at least one multigram scale, kilogram scale, multikilogram scale, or industrial scale. The multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, however more preferably at least 100 grams or more. The multikilogram scale, as used herein, is projected to mean the scale where more than one kilogram of at least one starting material is used. The industrial scale, as used here, is projected to mean a scale that is other than the laboratory scale and that is sufficient to distribute enough product for both clinical trials or distribution for consumers.
As used herein, "alkyl" is projected to include both straight chain saturated aliphatic hydrocarbon groups having the specific number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is projected to include both groups of straight or branched chain saturated aliphatic hydrocarbons having the specific number of carbon atoms, substituted with 1 or more halogens (for example -CVFW where v = 1 to 3 and w = 1 to ( 2v + l)). Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached together with the oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is projected to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. "Alkenyl" is projected to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain, such as ethenyl, propenyl, and the like. "Alkynyl" is projected to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur at any stable point along the chain, such as ethynyl, propynyl, and the like.
"Halo" or "halogen" as used herein refers to fluoride, chlorine, bromine and iodine. "Counter-ion" is used to represent negatively charged, small species, such as chlorine, bromine, hydroxide, acetate, sulfate and the like.
As used herein, "aryl" or "aromatic residues" is projected to mean an aromatic portion containing the specific number of carbon atoms, such as phenyl or naphthyl. As used herein, "carbocyclic" or "carbocyclic residue" is projected to mean any 3 to 6 membered monocyclic ring, which may be saturated or partially unsaturated. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclopentane, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralino).
As used herein, the term "heterogeneous" or "heterocyclic system" is projected to mean a 5- to 6-membered monocyclic heterocyclic ring that is partially saturated or unsaturated (aromatic), and that consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring can be attached to this pendant group at any heteroatom or carbon atom resulting in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If it is specifically noted, a nitrogen in the heterocyclic may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocyclic is not greater than 1. As used herein, the term "aromatic heterocyclic system" is projected to mean a 5-6 membered monocyclic heterocyclic aromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocyclic is not greater than 1.
Examples of heterocycles include, but are not limited to, 2 -pirrolidonilo, 2H-pyrrolyl, 4-piperidonyl, 6H-1, 2, 5-thiadiazinyl, 2H, 6H- 1, 5, 2 -ditiazinilo, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1, 2, -oxadiazolyl, 1,2,5-oxadiazolyl, 1, 3, 4 -oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl , pteridinyl, piperidonyl, 4 -piperidonilo, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridizinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1, 2, 5 - 1i to adi zini 1 or, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, c, _ thiadiazolyl, 1, 3, 4-thiadiazolyl, thiazolyl, thienyl, t ienotiazolilo, t ienooxa zolil or, thienoimidazolyl, thiophenyl, triazinyl , 1,2,3-triazolyl, 1,2-triazolyl, 1, 2, 5-triazolyl, and 1,3,4-triazolyl. Preferred heterocyclics include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused rings and spiro compounds containing, for example, the above heterocycles.
As used herein, "HIV reverse transcriptase inhibitor" is projected to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (IT) Examples of nucleoside CT inhibitors include, but are not limited to, AZT, ddC, ddl, d4T, and 3TC. Examples of non-nucleoside CT inhibitors include, but are not limited to, delavirdine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine (Boehringer Ingelheim), L-697,661, LY 73497, Ro 18,893 (Roche), loviride (Janssen), trovirdine (Lilly), MKC-442"(Triangle), and HBY 097 (Hoechst).
As used herein, "HIV protease inhibitor" is projected to refer to compounds that inhibit HIV protease. Examples include, but are not limited to, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex / Glaxo Wellcome), nefilnavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include cyclic protease inhibitors described in WO 93/07128, WO 94/19329, WO 94/22840, and PCT Application US No. 96/03426.
As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the familiar compounds are modified to make acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of organic acids or minerals of basic residues such as amines; alkaline or organic salts or acid residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the familiar compounds formed, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloride, hydrobromide, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymethyl, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- toxibenzoic, fumaric, toluensul phonic, methanesulfonic, ethane disulfonic, oxalic, isethonic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the family compound containing a basic or acid portion by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, ether such as non-aqueous medium, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of appropriate salts can be found in Remin gt on 's Pha rma ceu ti cal Sci in ces, 17th edition, Mack Publishing Company, Easton, PA, 1985, page 1418, the description of which is incorporated herein for reference.
The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, appropriate to be used in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication provided with a reasonable benefit / risk range.
"Pro-medicaments" are projected to include any of the co-valently linked carriers that release the family drug in accordance with formula (I) or other formulas or compounds of the present invention in vi when such pro-drugs are administered to a mammalian subject. The pro-medicines of a compound of the present invention, for example of formula (I), are prepared by modifying the functional groups present in the compounds in such a way that the modifications are cut, both in routine or in vivo manipulation, for the family compound. The pro-drugs include compounds of the present invention wherein the hydroxy or amino group is linked to any group which, when the pro-drug is administered to a mammalian subject, cuts to form a free hydroxyl or free amino, respectively. Examples of pro-drugs include, but are not limited to, acetate derivatives, formate and benzoate of functional alcohol and amine groups in the compounds of the present invention, and the like.
"Stable compound" and "stable structure" are mentioned to indicate a compound that is sufficiently robust to survive isolated for a useful degree of purity for a reaction mixture, and formulation into an effective therapeutic agent. Only stable compounds are contemplated by the present invention.
"Substituted" is projected to indicate that one or more hydrogens in the atom indicated in the expression using "substituted" is replaced with a selection of the indicated group (s), with the proviso that the said normal valence is not exceeded, and that the substitution results in a stable compound. When the substituent is a keto group (ie, = 0), then 2 hydrogens are replaced in the atom.
"Therapeutically effective amount" is projected to include an amount of a compound of the present invention or an amount of the combination of rei-indicated compounds effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of the compounds is preferable in a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv.
Enzyme Regul. 22: 27-55 (1984), occurs when the effect (in this case, the inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as an agent simple. In general, a synergistic effect is more clearly demonstrated at sub-optimal concentrations of the compounds. The synergy can be in terms of low cytotoxicity, increased anti-viral effect, or some other beneficial effect of the combination compared with the individual components.
Synthesis The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations immediately after appreciated by those skilled in the art. Preferred methods include, but are not limited to those methods described below. Each of the references cited below are incorporated herein for reference.
IT'S BURNING 1 TMSCl. RlMgX base Scheme 1 illustrates a method of preparing ce to-anilines from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R 1 -substituted ketone. Keto-anions are useful intermediates for the presently claimed compounds.
E SQUEMA 2 Scheme 2 describes another method of preparing keto-anilines, this time from which an aniline is appropriately substituted. After iodination and protection of the amine, a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Deprotection provides cet o-aniline. Additional means of preparing cet o-anilines are known to one of skill in the art, for example, Houpis et al, Te tr. Le t t. 1994, 35 (3 7), 6811-6814, the content of which is incorporated herein by reference.
SCHEME 3 Another method for making 2-tri-fluoroacetylanilines is shown in Scheme 3. After forming the protected aniline, the amide is then reduced and the trifluoromethyl group is added. Oxidation with an oxidant, such as Mn02, provides the useful intermediate.
Using the general method detailed in Scheme 4, one can prepare compounds of the present invention. The keto-aniline 1_, which can be prepared by the methods described in Schemes 1 and 2, is treated with rimethylsilyl isocyanate in dry tetrahydrofuran and the presence of dimethylaminopyridine followed by tetrabutylammonium fluoride to give the hydroxy urea 2_. The 2-hydroxy urea is then dehydrated with a dehydrating agent such as a 4Á molecular sieve in refluxing toluene or xylenes to give ketimine 3_. A substituted acetylenic R2 group is added by treating the ketimide 3_ with a lithium acetylide, which is prepared in a separate vessel by reacting the corresponding acetylene substituted with n-butyllithium in dry tetrahydrofuran, to give the 4,4-disubstituted 3,4-dihydro-2 (1H) -quinazolinone 4_, a compound of formula I the acetylenic bond of the compound 4_ can be reduced, for example, by catalytic hydrogenation, to give the corresponding alkenyl group (not shown) or the saturated compound 5.
Other R groups can also be introduced by directly reacting imine 3_ with an R2Li lithiate or a Grignard R2MgX reagent in the presence or absence of a Lewis acid catalyst, such as BF3 etherate. See also Huffman et al., J. Org. Ch em. 1995, 60, 1590-1594, the contents of which are incorporated herein for reference.
In certain cases, an enantiomer of a compound of Formula I or II may display superior activity compared to the other. When required, the separation of the racemic material can be performed by CLAP using a chiral column as exemplified in Examples 27-34 (Scheme 4) or by a resolution using a resolving agent such as chlophonic chloride as in Thomas J. Tucker, et al. al, J. Med. Ch em. 1994, 3 7, 2437-2444. A chiral compound of Formula I can also be synthesized directly using a chiral catalyst or a chiral ligand, for example, in Mark A. -Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.
Other embodiments of the invention will be apparent in the course of the following descriptions of embodiments of the invention which are given for illustration of the invention and are not intended to limit the same.
E j emplos The abbreviations used in the Examples are defined as follows: "° C" for degrees centigrade, "d" for doublet, "dd" for double of doublets, "eq" for equivalent or equivalents, "g" for gram or grams, " mg "for milligram or milligrams," mL "for milliliter or milliliters," H "for hydrogen or hydrogens," hr "for hour or hours," m "for multiplet," M "for molar," min "for minute or minutes , "MHz" for megahertz, "EM" for mass spectroscopy, "nmr" or "NMR" for magnetic resonance spectroscopy, "t" for triplet, "CCD" thin layer chromatography, "EDAC" for l-hydrochloride (3-dimethylaminopropyl) -3-ethylcarbodiimide, "DIPEA" for diisopropylethylamine, "TBAF" for tetrabutylammonium fluoride, "LAH" for lithium aluminum hydride, and "TEA" for triethylamine.
Use 1 Preparation of (+ / -) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Cyclopropyl).
Step 1. Synthesis of Il-a from I-a.
To a solution of compound I-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 1 M solution in THF) was added. The thick solution was diluted with additional THF (20 mL) and stirred at room temperature for 0.5 hour. The THF was removed under reduced pressure, the residue was taken up in EtOAc (100 L) and washed sequentially with IN HCl (70 mL), saturated aqueous NaHCO 3 (70 mL), and saturated aqueous NaCl (50 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a light yellow solid. The yellow color was stirred during trituration with hexanes to give the bund (5.09 g, 94%) as a white solid: 1 H NMR (300 Mhz, acetone-d) d 9.06 (br s, 1 H), 7.48 (s, 1 H), 7.40 (br s, 1 H), 7.34 (dd, J = 8.8, 2.6 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 1 H); 19 F NMR (282 MHz, acetone-d) d -86.33, -86.35; IR (KBr Pellet) 1724, 1678, 1398, 1198, 1174 cm "1; MS (Cl) m / e 266 (MH +, 100).
Step 2. Synthesis of Ill-a from Il-a.
A suspension of 11 -a (5.09 g, 19.1 mmol) in toluene (150 mL) containing 4 A molecular sieve (approximately 100 mg) was heated to reflux for 16 hours. The resulting light yellow solution was cooled to room temperature, the precipitated solids were dissolved in acetone and the molecular sieve was removed by vacuum filtration. The filtrate was concentrated under reduced pressure, and triturated with hexanes to give Ill-a (4.25 g, 89%) as a yellow solid: 2 H NMR (300 MHz, acetone-d 6) d 7.86-7.82 (m, 2 H ), 7.61 (d, J = 8.8 Hz, 1 H); NMR MHz, acetone-de) d -67.88.
Step 3. Synthesis of IV-a from Illa A solution of cyclopropylacetylene (13.0 mL of a 30% by weight solution in toluene / THF / hexanes, 59.0 mmol) in anhydrous THF (118 L) was cooled to -78 ° C, treated with n-BuLi (32.8 mL of a 1.6 M solution in hexanes, 52.4 mmoles), warming to 0 ° C in an ice bath, and aging for 0.5 hours. To a solution of Ill-a (3.12 g, 12.6 mmol) in anhydrous THF (66 mL) at -78 ° C was added lithium acetylide for about 10 minutes. To this was added boron trifluoride etherate (0.89 g, 0.80 mL, 6.28 mmol), followed by removal of the ice bath. The reaction was allowed to reach room temperature and stirred at room temperature for 4 hours before quenching with 1 M citric acid (100 mL). The mixture was concentrated under reduced pressure to half its volume, diluting with EtOAc (200 mL), the aqueous phase was stirred and the organic phase was washed sequentially with saturated aqueous NaHCO 3 (100 mL), and saturated aqueous NaCl (100 mL). ). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (3% MeOH / CH ^ Cir) to give a thick yellow oil so that the crystalline IV-a (R4 = cyclopropyl) (3.85 g, 97%) was obtained as a white solid: m.p. 86.6-88 ° C; 1 H NMR (300 MHz, acetone-d 6) d 8.95 (br s, 1 H), 7.51 (br s, 1 H), 7.43 (br s, 1 H), 7.40 (dd, J = 8.8, 2.4 Hz, 1 H ), 7.02 (d, J = 8.8 Hz, 1 H), 1.49-1.41 (m, 1 H), 0.93-0.82 (m, 1 H), 0.77-0.74 (m, 1 H); 19 F NMR (282 MHz, acetone-d 6) d-82.96; IR (KBr Pellet) 1696, 1172 cm "1; MS (Cl) m / e calculated for C14H10CI F3N20: 315.051201, found 315.051626; 315 (MH +, 51), 332 (M + NH4 +, 100); Analysis calculated for C? 4H? 0N2Cl F30 '0.25H20; C, 52.68; H, 3.32; N, 8.78; found: C, 52.61; H, 3.35; N, 8.28.
Example 2 Preparation of (+/-) -6-chloro-4-isopeopylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R4 = isopropyl).
A solution of IZI-a (50 mg, 0.201 mmol) was treated with the lithium acetylide derivative of 3-methyl-1-butynyl (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% EtOAc / hexanes) to provide 26 mg (41%) of the desired product: X H NMR (300 MHz) d 9.08 (br s, 1 H), 7.59 (br s, 1 H), 7.53 (br s, 1 H), 7.40 (dd, J = 8.4, 2.2 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H9, 2.81-2.68 (m, 1 H), 1.20 (dd, J = 6.6 Hz, 6H); 19F NMR (282 MHz, acetone-d6) d -83.05; MS (Cl) m / e calculated for C? 4H? 2ClF3N20: 317.066851, found 317.069433; 317 (MH +, 43), 334 (M + NH 4 +, 100).
Example 3 Preparation of (+/-) -6-chloro-4- (2-pyridyl) ethynyl-4 -tr fluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R4 = 2-pyridyl) A solution of Ill-a (100 mg, 0.402 mmol) was treated with the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.81 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 85 mg (60%) of the desired product: mp 105 ° C dec .; : H NMR (300 MHz, acetone-d6) d 9.14 (br s, 1 H), 8.64-8.61 (m, 1H), 7.89-7.84 (m, 2 H), 7.70-7.66 (m, 2H), 7.48 - 7.43 (m, 2 H), 7.09 (d, J = 8.8 Hz, 1 H); qF NMR (282 MHz, acetone-de) d -82.48; IR (KBr Pellet) 1704, 1430, 1186 cm "1; MS (Cl) m / e calculated for C 16 H 10 ClF 3 N 3 ?: 352.046450, found 352.046956; 352 (MH +, 100); Analysis calculated for C? 6H9ClF3N3O-0.125 H20: C, 54.3; H, 2.56; N, 11.9; found: C, 54.71; H, 3.03; N, 11.3.
Example 4 Preparation of (+/-) -6-chloro-4-ethylenenethynyl-4-trifluoromethyl-3,4-dihydro-2- (1H) -quinazolinone (R 4 = ethyl).
A solution of Ill-a (100 mg, 0.402 mmol) was treated with the lithium acetylide derived from 1-butine (109 mg, 2.01 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 79 mg (65%) of the desired product: aH NMR (300 MH ?, acetone-dβ) d 9.05 (br s, 1 H), 7.54 (br s, 2 H) , 7.41-7.39 (m, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 2.36-2.32 (m, 2 H), 2.18-1.13 (m, 3 H); 15 F NMR (282 MHz, acetone-dg) d-82.99; MS (Cl) m / e calculated for Ci3H10ClF3N2 ?: 303.051201, found 303.051882; 303 (MH +, 55), 320 (M + NH 4 +, 100).
Example 5 Preparation of (+/-) -6-chloro-4-enylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Phenyl) A solution of Ill-a (100 mg, 0.402 mmol) was treated with the lithium acetylide derived from phenyl acetylene (185 mg, 1.81 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 54 mg (38%) of the desired product: XH NMR (300 MHz, acetone-d6) d 9.07 (br s, 1H), 7.74 (br s, 1 H), 7.62- 7.58 (m, 2H), 7.48-7.40 (m, 4H), 7.08 (d, J = 8.4 Hz, 1 H); 19 F NMR (282 MHz, acetone-d 6) d-82.67; IR (KBr pellet) 1696, 1186 cm "1; MS (Cl) m / e calculated for C? 7H ?? ClF3N20: 351.051201, found 351.051704; 351 (MH *, '51), 368 (M + N0H4, 100); Analysis calculated for C? 7H10ClF3N2O- 0.25 H20: c, 57.48; H, 2.98; N, 7.89; found: C, 57.00; H, 3.03; N, 7.48; Example 6 Preparation of (+/-) -4-cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone (R = Cyclopropyl) SAW-? VlII-a Step 1. Synthesis of VI- from V- A solution of Va (0.50 g, 2.28 mmole) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to provide 0.58 g (97%) of the desired product: XH NMR (300 MHz, acetone-de) d 8.81 (br s, 1 H), 7.17 (br s, 1 H), 7.11 (br s, 1 H), 7.00-6.92 (m, 2 H) , 6.83 (s, 1 H), 3.76 (s, 3H); 19 F NMR (282 MHz, acetone-d 6) d -85.99.
Step 2. Synthesis of Vil-a from Vi-a A solution of Vi-a (0.58 g, 2.21 mmol) was heated in refluxing toluene as described in Step 2 of Example 1 to provide 0.50 g (93%) of the desired product: 1 H NMR (300 MHz, acetone-d6 ) d 7.52 (br s, 2 H), 7.27 (s, 1 H), 3.90 (s, 3 H); 19 F NMR (282 MHz, acetone-d 6) d -68.06.
Step 3. Synthesis of Vlll-a from Vil-a.
A solution of Vil-a (100 mg, 0.410 mmol) was treated with the lithium acetylide derived from the cyclopropylacetylene (0.41 mL of a 30% by weight solution in toluene / THF / hexanes, 1.85 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH 2 Cl 2) to provide 103 mg (81%) of the desired product: 1 H NMR (300 MHz, acetone-d 6) d 8.77 (br s, 1 H), 7.29 (br s, 1 H), 7.06 (br s, 1 H), 6.99-6.90 (m, 2 H), 3.77 (s, 3 H), 1.46-1.38 (m, 1 H), 0.91 -0.85 (m, 2 H), 0.79-0.72 (m, 2 H); 19 F NMR (282 MHz, acetone-d 6) d-82.61; MS (Cl) m / e calculated for C15H? 4F3N202: 311.100738, found 311.099970; 311 (MH +, 100).
Example 7 Preparation of (+/-) -4-isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R4 = Isopropyl).
A solution of Vil-a (100 mg, 0.410 mmol) was treated with the lithium acetylide derived 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 resulting crude material was purified by flash chromatography (2.5% MeOH / CH2Cl2) to provide 30 mg (24%) of the desired product: mp. 228-229 ° C; 1 H NMR (300 MHz, acetone-de) d 8.72 (br s, 1H), 7.27 (br s, 1H), 7.00-6.91 (m, 2 H), 3.77 (s, 3H), 2.73-2.67 (m, 1H), 1.20 (dd, J = 7.0, 1.5 Hz, 6H); 19F NRM (282 MHz, acetone-de) d-82.71; (KBr pellet) 1696, 1428, 1190, 1176 cm'1; MS (Cl) m / e calculated for C15H16F3N2? 2: 313.116388, found 313.115871; 313 (MH +, 100), 330 (M + NH 4 *, 15); calculated analysis for C15H? 5 F3N202: C, 57.69; H, • 4.84; N, 8.97; Found: C, 57.74; H, 5.01; N, 8.57.
E j emp lo 8.
Preparation of (+/-) -6-methoxy-4- (2-pyridyl) ethynyl-4-tri-loromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = 2-pyridyl).
A solution of Vi-a (100 mg, 0.410) was treated with the lithium acetylide derived from 2-y-piperazine (0.19 g, 1.85 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material purified by flash chromatography (2.5% MeOH / CH2Cl2) to provide 56 mg (39%) of the desired product: 1 H NMR (300 MHz, acetone-d 6) d 8.81 (br s, 1 H), 8.61 (d, J = 4.8 Hz, 1H), 7.88-7.82 (m, 1H), 7.66 (d, J = 7.7 Hz, 7.61 (br s, 1H), 7.46-7.42 (m, 1 H), 7.23 (br s, 1 H) , 7.06-6.97 (m, 2H), 3.79 (s, 3 H); 19F NRM (282 MHz, acetone-d6) d -82.13; IR (KBr pellet) 1698, 1518, 1464, 1430, 1244, 1208, 1184 cm "1; MS (Cl) m / e calculated for C? 7H? 3F3N302: 348.095987, found 348.095629; 348 (MfT, 100); calculated for C1-7HY2F3 3O2"0.25 C3Hc-0: C, 58.92; H, 3.76; N, 11.61; found: C, 59.38; H, 4.04; N, 11.35.
Example 9 Preparation of (+/-) -6-methoxy-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Phenyl).
A solution of Vil-a (100 mg, 0.410 mmol) was treated with the lithium acetylide derived from phenylaceffylene (0.19 g, 1.85 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material was purified by chromatography Instantaneous (2.5% MeOH / CH2Cl2) to provide 34 mg (24%) of the desired product: mp 206.2-207.7 ° C; X H NMR (300 MHz, acetone-d 6) d 8.85 (br s, 1 H), 7.60-7.57 (m, 3 H), 7.49-7.39 (m, 3 H), 7.21 (br s, 1 H), 7.05 -6.96 (m, 2H), 3.79 (s, 3H); 19 F NMR (282 MHz, acetone-d 6) d-82.32; IR (KBr pellet) 1696, 1516, 1430, 1236, 1204, 1184, 1128 cm "1; MS (Cl) m / e calculated for Ci8H? 4F3N2? 2: 347.100738, found 347.101482; 347 (MH", 100), 364 (M + NHT, 48); calculated for C? 8H13F3N2? 2: C, 62.43; H, 3.78; N, 8.10; found: C, 62.35; H, 3.58; N, 7.83.
Ahem 10 Preparation of (+/-) -4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone (R 4 = Cyclopropyl) Step 1. Synthesis of X-a from IX-a.
A solution of IX-a (6.46 g, 28.7 mmol) was treated with dimethylaminopi ridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to provide 6.74 g (88%) of the desired product: 1 H NRM (300 MHz NMR acetone-d6) d 9.13 (br s, 1 H), 7.45-7.32 (m, 2 H), 718 (br s, 1 H), 6.85-6.80 (m, IH); 19 F NMR (282 MHz, acetone-de) d -86.6 (d, 17.2, 3), -137.52-137.68 (m, 1), - 148.47-148.59 (m, 1).
Step 2. Synthesis of Xl-a from X-a A solution of Xa (6.74 g, 25.1 mmol) was heated in xylene at reflux temperature as described in Step 2 of Example 1, substituting xylene for toluene, to provide 6.3 g (100%) of the desired product: 1 H NMR (300 MHz, acetone-de) d 7.92-7.83 (m, 1H), 7.46-7.44 (m, 1H); 19 F NMR (282 MHz, acetone-d 6) d -70.7 (d, 38.7, 3), -136.72 (s, 1) -146. 7-146.57 (m, 1).
Step 3. Synthesis of Xll-a from Xl-a.
A solution of Xl-a (6.28 g, 25.1 mmol) was treated with the lithium acetylide derived from cyclopropylacetylene (24.9 mL of a 30% by weight solution in toluene / THF / hexanes, 0.113 mol) in accordance with the procedure from Step 3 of Example 1. The resulting crude yellow oil was dissolved in acetone and concentrated under reduced pressure to deliver a yellow solid. Crystallization from acetone gave 5.98 g (75%) of the desired material: m.p. 86.5-88.5 ° C; 2 H NMR (300 MHz, acetone-d 6) d 9.01 (br s, 1 H), 7.46 (br s, 1 H), 7.44-7.35 (m, 1 H), 6.86- 6.81 (m, 1 H), 1.41 -1.37 (m, 1 H), 0.90-0.83 (m, 1 H), 0.74-0.69 (m, 1H); 19 F NMR (282 MHz, acetone-de) d -83.3 (d, J = 12.9, 1), -136.04-136.23 (m, 1), -148.14-148.26 (m, 1); IR (KBr Pellet) 1706, 1516, 1442, 1246, 1214, 1196 cm "1; MS (Cl) m / e calculated for C? 4H? 0F5N2O: 317.071329, found 317.070836; 317 (MH +, 100), 334 (M + NH4 +, 62); Analysis calculated for C? 4H9F5N20: C, 53.17; H, 2.88; N, 8.87; found: C, 53.30; H, 3.16; N, 8.53.
Example 11 Preparation of (+ / -) - 5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Isopropyl).
A solution of Xl-a (7.24 g, 28.9 mmol) was treated with the lithium acetylide derived from 3-methyl-1-butyne (8.87 g, 13.3 mL, 0.130 mol) in accordance with the procedure of Step 3 of Example 1 The resulting crude material was purified by flash chromatography (2.5% MeOH / CH2Cl2) to give a yellow oil. Crystallization from acetone gave 6.77 g (74%) of the desired product: m.p. 79-80 ° C; 2 H NMR (300 MHz, acetone-de) d 9.02 (br s, 1 H), 7.50 (br s, 1 H), 7.44-7.35 (m, 1 H), 6.87-6.82 (m, 1 H), 2.69- 2.65 (m, 1H), 1.17 (d, J = 7.0 Hz, 6H); 19 F NMR (282 MHz, acetone-d 6) d -83.4 (d, J = 12.9, 1), -135.79-135.94 (m, 1), -148.1 -1 8.26 (m, 1); MS (Cl) m / e calculated for C? 4H? 2F5N20: 319.086979, found 319.087376; 319 (MH +, 100), 336 (M + NH 4 +, 76).
Example 12 Preparation of (+/-) -5,6-difluoro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = 2-pyridyl).
A solution of Xl-a (100 mg, 0.400 mmol) was treated with the lithium acetylide derived from 2-ethynylpyridine (0.19 g, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by flash chromatography (4% MeOH / CH2Cl2) to provide 83 mg (59%) of the desired product: mp 219-220 ° C; 1 H NMR (300 MHz, acetone-d 6) d 9.15 (br s, 1 H), 8.61 (d, J = 4.4 Hz, 1 H), 7.88- 7.82 (m, 2 H), 7.63 (dd, J = 7.0, 1.1 Hz, 1H), 7.47-7.42 (m, 2H), 6.94-6.88 (m, 1H); 19 F NMR (282 MHz, acetone-de) d-82.8 (d, J = 12.9, 3), 135.78-135.93 (m, 1), -147.86-1 7.98 (m, 1); IR (KBr pellet) 1712, 1470, 1450, 1430, 1416, 1264, 1238, 1226, 1198, 1186 cm "1; MS (Cl) m / e calculated for C 16 H 9 F 5 N 3 O: 354.066578, found 354.066578; 354 (MH +, 100) .
Example 13 Preparation of (+/-) -5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = 2-ethyl).
A solution of Xl-a (100 mg, 0.400 mmol) was treated with the lithium acetylide derived from 1-butyne (97 mg, 1.80 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material purified by CLAP (2.5% MeOH / CH2Cl2) to provide 69 mg (57%) of the desired product: mp 191-194 ° C; X H NMR (300 MHz, acetone-d 6) d 9.03 (br s, 1 H), 7.50 (br s, 1 H), 7.45-7.35 (m, 1 H), 6.87-6.82 (m, 1 H), 2.34 -2.27 (m, 2H), 1.20-1.15 (m, 3 H); 19 F NMR (282 MHz, acetone-de) d -83.3 (d, J = 12.9, 3), -135.79-135.98 (m, 1), -148.16-148.29 (m, 1); IR (KBr pellet) 1704, 1686, 1518, 1444, 1244, 1210, 1192, 1172 cm "1; MS (Cl) m / e calculated for C? 3H? 0F5N2O: 305.071329, found 305.071146; 305 (MH +, 100) Analysis calculated for C 13 H 9 F 5 N 2 O: C, 51.33; H, 2.98; N, 9.22; found: C, 51.00; H, 2.79; N, 8.99.
Example 14 Preparation of (+/-) -5,6-di luoro-4-enylethynyl-4-trifluoromethyl-3,4-dihydr-2 (1H) -quinazolinone (R 4 = Phenyl).
A solution of Xl-a (100 mg, 0.400 mmol) was treated with the lithium acetylide derived from phenylacetylene (0.18 g, 0.20 mL, 1.80 mmol) according to the procedure of Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 92 mg (65%) of the desired product: 1 H NMR (300 MHz, acetone-d6) d 9.14 (br s, 1 H), 7.80 (br s, 1 H), 7.57-7.54 (m, 2H), 7.49-7.40 (m, 4H), 6.92-6.87 (m, 1H); 1 F NMR (282 MHz, acetone-de) d -83.0 (d, J = 12.9, 3), -136.08-136.27 (m, 1), MS (Cl) m / e calculated for C 17 H 10 F 5 N 2 O: 353.071329, found 353.071716; 353 (MH +, 42), 370 (M + NH 4 +, 100).
Example 15 Preparation of (+/-) -5,6-difluoro-4-isopentyl-4-tri l -ornethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Isopropyl).
Synthesis of XlII-a from Xll-a A solution of XlII-a (R = isopropyl) (26 mg, 82 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon (35 mg) under H2 (1 atmosphere) by 16 hours. The catalyst was removed by vacuum filtration through Celite and the filter cake was washed with EtOAc. The concentrated filtrates were concentrated under reduced pressure to provide 26 mg (100%) of the desired material. No further purification was necessary: XH NMR (300 MHz, acetone-d6) d 8.88 (br s, 1 H), 7.41-7.31 (m, 1H), 6.89-6.81 (m, 2H), 2.55-2.50 (m, 1 H), 1.64-1.45 (m, 2H), 1.06-1.02 (m, 1H), 089 (dd, J = 6.6, 2.2 Hz, 6H); 19 F NMR (282 MHz, acetone-de) d -83.22 (d, J = 12.1, 3), -138.97-139.13 (m, 1), -148.46-148.58 (m, 1); IR (KBr pellet) 1700, 1678, 1518, 1438, 1252, 11.88, 1172 cm "1; MS (Cl) m / e calculated for C? 4H16F5N20: 323.118280, found 323.116703; 323 (MH +, 100), 340 (M + NH4 +, 57).
E 16 Preparation of (+/-) - butyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Ethyl).
A solution of XlII-a (R4 = ethyl) (20 mg, 66 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H2 according to the procedure of Example 15. Purification by CLAP (2.5% MeOH / CH2Cl2) gave 12 mg (56%) of the desired product: 1 H NMR (300 MHz, acetone-d6) d 8.89 (br s, 1 H), 7.41-7.41-7.32 (m, 1 H), 6.86-6.81 (m, 2H), 2.57-2.47 (, 1 H), 1.56-1.15 (m 5H), 0.88 (t, J = 7.3 Hz, 3 H); 19F NMR (282 MHz, acetone-de) d -83.19-83.24 (m, 1), -139.14 (s, 1), -148. 9-148.62 (m, 1); MS (Cl) m / e calculated for C? 3H14F5 2 ?: 309.102629, found 309.103555; 309 (MH *, 100), 326 (M + NH 4 +, 62).
Example 17 Preparation of (+/-) -4-cyclopropylethynyl-6-f luoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R4 = cyclopropyl).
Step 1. Synthesis of XV-a from XI V-a.
A solution of XlII-a (3.07 g, 14.8 mmol) was treated with dimethylaminopyridin and trimethylsilyl isocyanate as described in Step 1 of Example 1 to provide 2.81 g (76%) of the desired product.
Step 2. Synthesis of XVI-a from XV-a.
A solution of XV-a (6.74 g, 25.1 mmol) was heated in toluene at reflux temperature as described in Step 2 of Example 1 to provide 0.73 g (94%) of the desired product.
Step 3. Synthesis of XVII-a from XVI- A solution of XVI-a (100 mg, 0.431 mmol) was treated with the lithium acetylide derived from cyclopropylacetylene (1.43 mL of a 30% by weight solution in toluene / THF / hexanes, 1.94 mmol) in accordance with the procedure from Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH 2 Cl 2) to provide 4 4 mg (34%) of the desired product: 155 ° C; XH NMR (300 MHz, acetone-de) d 8.86 (br 1 H 7.36 1 H 7.30-7; m, 1 H) 7. 22-7.15 (m, 1H), 7.04-6.99 (m, 1 H), 1.47-1.42 (m, 1H), 0.90-0.87 (m, 2H), 0.76-0.75 (m, 2H); 19 F NMR (282 MHz, acetone-d 6) d-82.86, -1234.36- 123.44; MS (Cl) m / e calculated for C? 4HnF4N20: 299.080751, found 299.079976; 299 (MH +, 100).
Example 18 Preparation of (+/-) -6-fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Isopropyl).
A solution of XVI-a (100 mg, 0.431 mmol) was treated with the lithium acetylide derived from 3-methyl-1-butyne (0.13 g, 0.20 L, 1.94 mmol) in accordance with the procedure of Step 3 of Example 1 The resulting crude material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 24 mg (18%) of the desired product: mp. 158 ° C; 1ti NMR (300 MHz, acetone-d6) d 9.07 (br s, 1 H), 7.60 (br s, 1 H), 7.32-7.30 (m, 1 H), 7.24-7.16 (m, 1 H), 7.05- 6.99 (m, 1H), 2.77-2.67 (m, 1 H), 1.20 (dd, J = 7.0, 2.6 Hz, 6H); 19 F NMR (282 MHz acetone-de) d-82.95, -123.41-123.41- 123.49; MS (301) m / e calculated for Ci 4 H 3F 4 N 20 found 301.096235; 301 (MH +, 100).
Example 19 Preparation of (+/-) -6-fluoro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = 2-pyridyl).
A solution of XVI-a (100 mg, 0.431 mmol) was treated with the lithium acetylide derived 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 CLAP (2.5% MeOH / CH2Cl2) to provide 65 mg (45%) of the desired product: m.p. 155 ° C; 1 H NMR (300 MHz, acetone-de) d 9.02 (br s, 1 H), 8.60 (d, J = 4.0 Hz, 1 H), 7.87-7.78 (m 2 H), 7.66 (d, J = 7.7 Hz , 1 H), 7.45-7.41 (m, 2 H), 7.26-7.20 (m, 1 H), 7.09-7.05 (m, 1 H); 19 F NMR (282 MHz, acetone-de) d-82.36, -122.94-123.02; MS (Cl) m / e calculated for C? 6H? 0F4N3O: 336.076000, found 336.0741565; 336 (MH +, 25).
Example 20 Preparation of (+/-) -6-fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R4 = Ethyl).
A solution of XVI-a (100 mg, 0.431 mmol) was treated with the lithium acetylide derived from 1-butyne (0.10 g, 1.94 mmol) in accordance with the procedure of Step 3 of Example 1. The resulting crude material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 40 mg (33%) of the desired product: m.p. 190 ° C; H NMR (300 MHz, acetone-de) d 8.86 (br s, 1 H), 7.38 (br s, 1 H), 7.34-7.31 (m, 1 H), 7.22-7.16 (m, 9,001 H), 7.05 -7.00 (m, 1 H), 2.04-2.01 (m, 2H), 1.19-1.14 (m, 3 H); 1 F NMR (282 MHz, acetone-d 6) d -75,392, 123.42-123.50; EM (Cl) m / e calculated for C? 3 HnF4N20: 287.080751 found 287.080740; 287 (MH +, 100).
Example 21 Preparation of (+/-) -6-fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro- (1H) -quinazolinone (R 4 = Phenyl).
A solution of XVI-a (100 mg, 0.431 mmol) was treated with the lithium acetylide derived 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 CLAP (2.5% MeOH / CH2Cl2) to provide 41 mg (28%) of the desired product: mp 107 ° C; X H NMR (300 MHz, acetone-de) d 9.00 (br s, H), 7.69 (br s, 1 H), 7.63-7.59 (m, 2 H), 7.50-7.40 (m, 4 H), 7.27-7.20 ( m, 1 H), 7.10-7.05 (m, 1 H); 19F NMR (282 MHz, acetone-de) d -82.56, 122. 99-123.07; MS (Cl) m / e calculated for C 17 H 11 F N 2 O: 335.080751, found 335.082057; 335 (MH +, 74), 352 (M + NH 4 +, 100).
Example 22 Preparation of (+ / -) - 6-fluoro-4-isopentyl-4-tri luorornethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = Isopropyl).
Synthesis of XVIII-a from XVII-a A solution of XVII-a (R4 = isopropyl) (2.6 mg, 87 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H2 in accordance with the procedure of Example 15 to provide 15 mg (58%) of the desired product. No further purification was necessary: p.f. 179 ° C; a H NMR (300 MHz, acetone-d 6) d 7.02- 6.97 (m, 2 H), 6.80-6.76 (m, 1 H), 2.18-2.09 (m, 2 H), 1.92-1.82 (m, 2 H), 1.52-1.45 (, 1 H), 0.88-0.79 (m, 6H); 19 F NMR (282 MHz, acetone-d 6) d-82.60, -123.72-123.84; MS (Cl) m / e calculated for C 14 H 17 F 4 N 2 O: 305.127707, found 305.126790: 305 (MH +, 100).
Example 23 Preparation of (+/-) -6-fluoro-4- (2'-2-pyridyl) ethyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = 2-pyridyl).
A solution of XVII-a (R4 = 2-pyridyl) (33 mg, 99 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H2 in accordance with the procedure of Example 15 to provide 10 mg (30%) of the desired product. No additional purification is needed: p.f. 88 ° C; 1 H NMR (300 MHz, acetone-de) d 8.35 (d, J = 4. 4 Hz, 1H), 7.63 (dt, J = 7.7, 1.5 Hz, 1H), 7.20-7.13 (m, 3 H), 7.04 -6.98 (m, 1H), 6.83-6.79 (m, 1 H), 2.84-2.78 (m, 1H), 2.68-2.48 (m, 2H), 2.27-2.06 (m, 1H); 19 F NMR (282 MHz, acetone-dg) d-82.58, -123.26-123.34; MS (Cl) m / e calcd for C 16 H 14 F 4 N 3 O: 340.107300, found 340.107719; 340 (MH +, 100).
Example 24 Preparation of (+/-) -4-butyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = ethyl).
A solution of XVII-a (R = ethyl) (2.4 mg, 84 mmol) in ethanol (1 mL) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H2 in accordance with the procedure of Example 15 to provide 24 mg (100%) of the desired product. No further purification was necessary: p.f. 198 ° C; 1 H NMR (300 MHz, acetone-d 6) d 7.03-6.97 (m, 2 H), 6.80-6.76 (m, 1 H), 2.18-2.11 (m, 1 H), 1.90-1.81 (m, 1 H), 1.30-1.19 (m, 3 H), 0.97-0.80 (m, 4 H); 19 F NMR (282 MHz, acetone-d 6) d-82,692, -123.78- 123.86; MS (Cl) m / e calculated for Ci3H15F4N20: 291.112051, finding 291.112227; 291 (MH +, 100).
E j a lo 25.
Preparation of (+/-) -6-fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R4 = phenyl).
A solution of XVII-a (R4 = phenyl) (30 mg, 90 mmol) in ethanol (1 L) and EtOAc (0.5 mL) was treated with 10% Pd on carbon under H2 in accordance with Example 15 to provide 20 mg (67%) of the desired product. No further purification was necessary: p.f. 98 ° C; a H NMR (300 MHz, acetone-de) d 7.18-6.99 (m, 7H), 6.84-6.79 (, 1H), 2.68-2.60 (m 1 H), 2.48-2.12 (m, 3 H); 19F 'NMR (282 MHz, acetone-d6) d -82.67, -123.24-123.32; MS (Cl) m / e calculated for C 17 H 15 F 4 N 20: 339.112051, found 339.11081; 339 (MH +, 100).
Example 26 Preparation of (+/-) -6-fluoro-4-methylpropargyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (R 4 = methyl).
Synthesis of XlX-a from XVI-a.
A solution of 2-butyne (9.4 mg, 1.75 mmol) in anhydrous THF (3.5 ml) was cooled to 0 ° C, treated with n-BuLi (0.97 mL of a 1.6 M solution in hexanes, 1.55 mmol), and It was aged for 0.5 hours. To a solution of XVI-a (90 mg, 0.388 mmol) in anhydrous THF (1.9 mL) at -78 ° C was added lithium anion for 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 hours at room temperature, quenched by addition of 1 M citric acid (10 mL), diluted with EtOAc (50 mL), separated the phases and washed the organic phase sequentially with saturated aqueous NaHCO 3 (20 mL) and saturated aqueous NaCl (20 mL). The resulting material was purified by CLAP (2.5% MeOH / CH2Cl2) to provide 10 mg (9%) of the desired product: p.f. 181 ° C; XH NMR (300 MHz, acetone-de) d 8.91 (br s, 1 H), 7.27 (d, 8 / .4H), 7.18-7.08 (m, 1H), 7.02-6.97 (m.H2), 3.29 (dd, J = 16.8, 2.6 Hz, 1 H), 3.00 (dd, J = 16.8, 2.2 Hz, 1 H), 1.61-1.59 (m, 3 H); 19 F NMR (282 MH ?, acetone-d 6) d -81.86, -123.69-123.70; MS (Cl) m / e calculated for C1 H ??F4N20: 287.080751, found 287.080340; 287 (MH +, 75), 304 (M + NH 4 +, 100).
SCHEME 4: Chiral Resolution Examples 27 and 28 Preparation of (-) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 27) and (+) - 6-chloro-4-cyclopropylethynyl-tri-luomomethyl 3, 4-dihydro-2 (1H) -quinazolinone (Example 28).
Resolution of IV-b, c from IV-a (R4 = Cyclopropyl).
The chiral CLAP using a Quiracel OD column, 3% isopropanol, 5% CH2C12 and 92% hexanes at room temperature with a fluid range of 1.0 mL / minute and detection at 250 nm, gave the separation of IV-b to from IV-c with 99% and 99.4% enantiomeric excess, respectively. IV-b: p.f. 106-109 ° C; [OC-D25 60.34 ° (c = 0.274, MeOH). IV-c: p.f. 105-107 ° C; [a] D25 + 58.33 ° C [c = 0.288, MeOH).
Examples 29 and 30 Preparation of (+) - 4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 29) and (-) - 4-cyclopropylethynyl-5,6-di luoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 30).
Resolution of Xll-b, c from Xll-a (R; Cyclopropyl).
The chiral CLAP using a Quiralpak AD column, 5% water and 95% methanol at room temperature with a flow rate of 0.8 mL / minute and a detection of 250 nm provided the separation of Xll-b from XII-c with enantiomeric excess and 100% and 99%, respectively. XII-b: p.f. 187 ° C; [a] D25 + 1.46 ° (c = 0.274, MeOH). XII-c: p.f. 187.5-1 C; [] ¿B - 1.45 c = 0.278, MeOH).
Examples 31 and 32 Preparation of (-) - 5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 31) and (+) - 5,6-difluoro-4-isopropylethynyl -4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 32).
Resolution of Xll-b, c from Xll-a (R 'Isopropyl).
The chiral CLAP using a Quiralpak AD column, 5% water and 95% methanol at room temperature with a flow rate of 0.5 mL / minute and a detection at 250 nm provided the separation of Xll-b from XII-c with an enantiomeric excess of 100% and 99%, respectively. Xll-b: p.f. 155 ° C; [c d5 -2.14 ° (c = 0.280, MeOH). XII-c: 98 ° C; [] c25 + 4.45 ° (c = 0.292, MeOH).
Examples 33 and 34 Preparation of (-) - 5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 33) and (+) - 5,6-difluoro-4-ethylestynyl -4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 34).
Resolution of Xll-b, c from Xll-a (R4 Ethyl).
The chiral CLAP using an AS column, 20% ethanol and 80% hexanes at room temperature with a flow rate of 1.0 mL / minute and a detection at 250 nm provided the separation of Xll-b from XII-c with an enantiomeric excess of 100% and 99%, respectively. XII-b: p.f. 165-167 ° C. XII-c: p.f. 157-159 ° C.
Examples 35 and 36 Preparation of 5,6-difluoro-4- (2-hydroxyethyl) ethynyl-4-tri-loromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 35) and 5,6-difluoro-4- ( 1-hydroxyethyl) ethynyl-4-trif luoromethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 36).
Compound Ex. 35 CH2CH2OH Ex .. 6 CH (OH) CK3 To a mixture of ketimine (300 mg, 1.20 mm ol) in anhydrous THF (11 mL) at -78 ° C was added sequentially a pre-cooled solution (0 ° C) of lithium acetylide protected by silyl (5.40 mmol) and BF3.0Et2 (0.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 1 M citric acid with EtOAc. The phases were separated, the organic phase was washed with water, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic extracts were dried over MgSO4, filtered and concentrated. The material was purified by regular phase CLAP chromatography (41.4 mm column Rainin Dynamax © using 60 A of silica @ 25 mL / minute): 2.5% MeOH / CH2Cl2 for 24 minutes, increasing to 30% MeOH / CH2Cl2 for 4 minutes, 30% MeOH / CH2Cl2 for 10 minutes, and returning to 2.5% MeOH / CH2Cl2 for 2 minutes. The yield of the protected intermediaries was 47% and 32%, respectively.
Example 35 -intermediary. P.f. 62.9-64 ° C; 1 H NMR (300 MHz, acetone-d 6) d 8.98 (br s, 1 H), 7.41-7.32 (m, 2 H), 6.83-6.78 (m, 1 H), 3.74 (t, J = 6.6 Hz, 2 H), 2.47 (t, J = 6.6 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H); 19F NMR (282 MHz, acetone-d6) d -83.1, 135.16-135.31, -148.09-148.22; MS (Cl) calculated for C? 9H24 F5N202S i: / z 435.152723, found 435.151149; 435 (MH ", 94), 452 (M + NH ^, 100); analysis calculated for C19H23F5N2O YES: C, 52.52; H, 5.35; N, 646; found: C, 52.65; H, 5.29; N, 6.31.
Example 36-intermediary. 1 H NMR (300 MHz, acetone-de) d 8.96 (br s, 1 H), 7.50 (br s, 1 H), 7.37-7.28 (m, 1 H), 6.79- 6.74 (m, 1 H), 4.61 (q, J = 13.2, 6.6Hz, 1H), 1.30 (d J = 6.6 Hz, 3H), 0.78 (s, 9H), 0.01 (s, 6H); 19 F NMR (282 MHz, acetone-de) d -82.88-82.95, -135.20-135.42, 1 8.06-148.23; MS (Cl) calculated for C? 9H24 F5N202 Si: m / z 435.152723, found 435.152927; 435 (MH +, 51, 452 (M + NH4 +, 100); analysis calculated for C19H23F5N202Si; C, 52.52; 5.35; N, 6.46; found C, 52.54; H, 5.34; N, 6.69.
To a solution of the protected intermediate of Example 35 (0.56 mmol) in THF (1.1 mL) was added TBAF (0.62 mL of a 1.0 M solution in THF). The resulting mixture was stirred at room temperature for 1 hour, diluting with EtOAc, washing with IN HCl, saturated aqueous NaHCO 3, and saturated aqueous NaCl. The organic extract was dried over MgSO 4, filtered and concentrated. The material was purified by regular phase CLAP chromatography (41.4 mm using Rainin Dynamax® column of 60 A silica @ 25 mL / minute): 2.5% MeOH / CH2Cl2 for 24 minutes, increasing up to 30% MeOK / CH2Cl2 for 4 minutes, 30 MeOH / CH2Cl2 for 10 minutes, and returning to 2.5% MeOH / CH2Cl2 for 2 minutes. Example 35 was isolated in 82% yield.
Example 35. P.f. 190-192 ° C; 1 H NMR (300 MHz, acetone-de) d 9.05 (br s, 1 H), 7.53 (br s, 1 H), 7.45-7.36 (m, 1 H), 6.88-6.83 (m, 1 H), 4.01-3.98 (m , 1H), 3.68-3.64 (, 2H), 2.50 (t, J = 6.6 Hz 2H 19 F NMR (282 MHz, acetone-d6.3.3, - 132.68-135.88, -148.10-1 8.22; MS (Cl) calculated for C? 3H10F5N2O2: m / z - 321.066244, found 321. 066479; 321 (MH +, 100); analysis calculated for C ^ HgFsN ^: C, 48.76; H, 2.83 N, 8.76; found: C, 49.05; H, 3.23; N, 8.38.
Example 36 was synthesized in a manner analogous to that which delivers the title compound in an 88% yield. P.f. 190-191 ° C; X H NMR (300 MHz, acetone-de) d 9.06 (br s, 1H), 7.56 (br s, 1H), 6.88-6.83 (m, 1H), 4.58-4.57 (m, 2H), 1.39 (d, J = 5.5 Hz, 3H); 19 F NMR (282 MHz, acetone-d¿) d -83-15, -135.40, -135.60, -148.08-148.20; EM (Cl) calculated for Ci3H10F5 2? 2: m / z 321.06624, found 321.066244; 321 (MHT, 58), 338 (M + NH4"100): analysis calculated for C? 3HsF5N2? 2: C, 48.76; H, 2.83; N, 8.76; found: C, 48.84; H, 2.76; N, 8.63 .
Example 37 Preparation of (+) - 4-E-cyclopropylethyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone.
To a solution of Xll-b (200 mg, 0.632 mmol) in anhydrous THF (1.3 mL) at room temperature was added a solution of lithium aluminum hydride (1.3 mL of a 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 10% NaOH (3 mL) and water (3 mL). The mixture was diluted with EtOAc (30 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaCl, dried over MgS? , filtered and concentrated. The title compound was purified by regular phase CLAP (41.4 mm column Rainin Dynamax® using 60A silica): 2.5% MeOH / CH2Cl2 for 24 minutes, increasing up to 30% MeOH / CH2Cl2 for 4 minutes, 30% MeOH / CH2Cl2 for 10 minutes, and returning to 2.5% MeOH / CH2Cl2 for 2 minutes. P.f. 80-83 ° C; ? ti NMR (300 MHz, acetone-d6) d 9.07 (br s, 1H), 7.33 (q, J = 8.8 Hz, 1H), 6.94 (br s, 1H (, 6.84-6.79 (m, 1H), 6.27 (dd, J = 15.6, 7.5 Hz, 1H), 5.67 (dd, J = 15.2, 9.4Hz, 1H), 1.65-1.56 (m, 1H), 0.80-0.71 (m, 2H), 0.50-0.42 (m , 2 H); 19 F NMR (282 MHz, acetone-d 6) d-82.68, -135.05, -148.49; MS (Cl) calculated for Ci 4 H 12 F 5 N 20: m / z 319.086979, found 319.087755; 319 (MH + 100] 20 + 72.77 ° (c = 0.382, MeOH); calculated for C? 4HnF5N20: C, 52.84; H, 3.48; N, 8.80; Found: C, 53.02; H, 3.48; N, 8.61.
Example 38 Preparation of (-) - 6-chloro-4-E-cyclopropyletenyl-4-trifluorornethyl-3,4-di-idro-2 (1H) -quinazolinone.
The title compound was prepared as described by Example 37 (starting from IV-b), except that it was purified using a Quiralcel OD column at 1.5 mL / minute in 0.5% EtOH / 20%. 'CH2Cl2 / 79.5% hexanes. P.f. 87-89 ° C; XH NMR (300 MHz, acetone-de) d 9.08 (br s, 1H), 7.40-7.25 (m, 2H), 7.04-6.90 (m, 2H), 6.28-6.18 (, 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); 1SF NMR (282 MHz, acetone-d6) d -91.67; MS (Cl) calculated for C 14 H 3 ClF 3 N 20: m / z 317.066851, found 317. 065857; 317 (MH +, 100); [a] D20-6.81 ° (c = 0.382, MeOH); calculated analysis for C14H? 2Cl F3N20. 0.27 C3H60: C, 53.52; H, 4.13; N, 8.43; Found C, 53.90; H, 4.07; N, 8.80.
Unless otherwise indicated, thisguide is (+/-) 29. 6-Cl CF3 C = C-2 -furanyl K 6-Cl CF3 C = C-3 -furanyl K 31 6-Cl CF 3 C = C-2-thienyl 32 6-Cl CF 3 CsC-3-thienyl 33 6-Cl CF 3 c = -2 -oxazolyl? 34 6-Cl CF3 CsC-2-thiazolyl H 6-Cl "CF3? = C-4 isoxazolyl H 36 6-Cl CF3 CsC-2-imidazolyl K 37 6-Cl CF3 C = CCH2CH2OK K 38 6-Cl CF3 C = C-CH (0H) Me H 39 6-Cl CF3 C = C- (2-Cl) Ph H 40 6-Cl CF3 C = C- (3-Cl) Ph H 41 6-Cl CF3 OC- (4-Cl) Ph K 42 6-Cl CF3 C = C- (2-F) Ph K 43 6-Cl CF3 C = C- (3-F) Ph H 44 6-Cl CF3 C = C- (4-F) Ph H 45 6-Cl CF3 C = C- (2-OH) Ph H 46 6-Cl CF3 C = C- (3-0H) Ph H 47 6-Cl CF3 C = C- (4-OH) Ph H 48 6-Cl CF3 C = C- (2-OMe) Ph H 49 6-Cl CF3 C = C- (3-OMe) Ph H 50 6-Cl CF3 C = C- -4-OMe) Ph H 51 6-Cl CF3 C = C- (2-CN) Ph H 52 6-Cl CF3 C = C- (3-C) Ph H 53 6-Cl CF3 C = C- (4-C) Ph H 54 6-Cl CF3 C = C- (2-N02) Ph H 55 6-Cl CF3 C = C- (3-N02) Ph H 56 6-Cl CF3 C = C- (4-N? 2) Ph H 57 6-Cl CF3 C = C- (2-NH2) Ph H 58 6-Cl CF3 C = C- (3-NH2) Ph H 59 6-Cl CF3 C = C- (4-NH2) Ph H 60 6-Cl CF3 C = C-. { 2-NMe2) Ph H 61 6-Cl CF3 C = C- (3 -NMe2) Ph H 62 6-Cl CFT C = C-. { 4 -NMe2) Ph H OJ 6-Cl CF3 C = c-3-pyridyl 64 6-Cl CF3 C = C-4- Pyridyl 65 6-Cl CF3 C = c-2-furanyl H 66 6-Cl CF3 C = c-3furanyl H 67 6-Cl CF3 C = C-2-thienyl p 68 6-Cl CF3 C-C-3-ti enyl O K 69 6-Cl CF3 C = C-2-0? Azolyl H 70 6-Cl CF3 C = C-2-thiazolyl? 71 6-Cl CF3 C = C-4-isoxazolyl H 12 6-Cl CF3 C = C-2-imidazolyl K 73 6-Cl CF3 CH2CH2-cycPr H 74 6-Cl CF3 CH2CK2CH2CK2OK H 75 6-Cl CF3 CH2CK2 -CH (OH) Me H 76 6-Cl CF3 CH CH2-Ph H 77 6-Cl CF3 CH2CK2- (2-Cl) Ph H 7 788 6 6 - CCll CF3 CH2CH2- (3-Cl) Ph H 7 799 6 6 - CCll CF3 CH2CK2- (4-Cl) Ph H 80 6-Cl CF3 CH2CH2- (2-F) Ph H 81 6-Cl CF3 CH2CH2- (3-F) Ph H 8 822 6 6 - CCll CF3 CH2CH2- (4-F) Ph H 8 833 6 6 - CCll CF3 CH2CH2- (2-OH) Ph H 8 B44 6 6 - CCll CF3 CH2CH2-. { 3-OH) Ph H 5 6-Cl CH 2 CH 2 - (4-OH) Ph H 6 6-Cl CF 3 CH 2 CH 2 - (2-OMe) Ph H 7 6-Cl CF 3 CH 2 CH 2 - (3-OMe) Ph H 8 6- Cl CF 3 CH 2 CH 2 - (4-OMe) Ph H 9 6-Cl CF 3 CH 2 CH - (2-CN) Ph H 0 6-Cl CF 3 CH 2 CH 2 - (3-CN) Ph H 1 6-Cl CF 3 CH 2 CH 2 -. { 4-a-) Ph H 2 6-Cl CF 3 CH 2 CH 2 - (2 -N02) Ph H 3 6-Cl CF 3 CH 2 CK 2 - (3 -N02) Ph H 6-Cl CF 3 CH 2 CH 2 - (-N02) Ph H 6 -Cl CF3 CK2CK - (2 -NH2) Ph H 6-Cl CF3 CH2CK2- (3-KH2) Ph H 97. 6-Cl CF3 CH2 H2- (4-H2) Ph H 98 6-Cl CF3 CH2CH2- (2-NMe2) Ph K 99 6-Cl CF3 CH2CH? - (3 -NMe2) Ph K 100 6-Cl CF3 CH2CH2- (4 -NMe2)? H K 101 6-Cl CF3 CH2CH2-2- PIDID1 O " 102 6-Cl CF3 CH2CH2-3- Pyridium 1 D H 103 6-Cl CF3 CK2GÍ2- -PÍridÍlc 'K 104 6-Cl CF3 CH2CH2-2 -furanyl H 105 6-Cl CF3 CH2CH2-3 -f u r a n i 10 H 106 6-Cl CF3? __x "i2? "_í-.2 - 4. - furanyl K 107 6-Cl CF3 CH2CK2-3- thienyl H 108 6-Cl CF3 CH2CK2-2-oxazoyl H 109 6-Cl CF3 CH2CK2-2 -thiazolyl K 110 6-Cl CF3 CH2CH2-4-isoxazoill ° H 111 6-Cl CF3 CH2CK2-2-imidazolyl 0 H 112 6-Cl CF3 C = C-cycPr CH3 113 6-Cl CF3 CeC-Ph CH3 114 6-Cl CF3 C «C-2-pyridium CH3 115 6-Cl CF3 Cec-3-pyridyl CH3 116 6-Cl CF3 CEC-4-pyridyl CH3 117 6-Cl CF3 CsC-2 -furanyl CH3 118 6-Cl CF3 CsC-3- tur a ni CH3 119 6-Cl CF3 CsC-2- thienyl CH3 120 6-Cl CF3 C = C-3-thienyl CH3 121 6-Cl CF3 C = C-cycPr CH3 122 6-Cl CF3 C = C-Ph CH3 123 6-Cl CF3 C = C-2 -Piridyl CH3 124 6-Cl CF3 C = C-3-pyridi lo CH3 125 6-Cl CF3 C = C-4-pyridyl CH3 126 6-Cl CF3 C = C-2- furanyl CH3 127 6-Cl CF3 C = C-3-f uranyl CH3 128 6-Cl CF3 C = C-2-thienyl CH3 129 6-Cl CF3 C = c-3-thienyl CK3 130 6-Cl CF3 CK2CH2- rycPr CH3 131 6-Cl CF3 CK2CK2-Ph CK3 132 6-Cl CF3 CH2CK2 -2 - p i r i d i 1 or CK3 133 6-Cl CF3 CH2CK2-3-plridyl c? 3 134 6-Cl CF3 CH2CH -4- pyridyl CH3 135 6-Cl CF3 CH2CH2-2- furanyl CH3 136 6-Cl CF2 CH2CK2-3- furanyl CH3 137 6-Cl CF3 CH2CH2-2- thienyl c? 3 138 6-Cl CF3 CH2CH2-3- thienyl CH3 139 6-Cl CF3 C = C-cycPr CH2CK3 140 6-Cl CF3 Ce-C-Ph CH2CK3 141 6-Cl CF3 CsC-2-pyridyl or CH2CH3 142 6-Cl CF3 C = c73 -pyridyl CH2CH3 143 6-Cl CF3 C- -4- pir i di lo CH CH 144 6-Cl CF3 C- -2-fUranil CH2CH3 145 6-Cl CF3 CsC-3 -furanyl CH2CH3 146 6-Cl CF3 CsC-2- thienyl CH2CH3 147 6-Cl CF3 CEC-3- ti ^ nyl CH2CK3 148 6-Cl CF3 C = C-cycPr CH2CH3 149 6-Cl CF3 C = C-Ph CH2CH3 150 6-Cl CF3 C = C-2-pyridyl CH2CH3 151 6-Cl CF3 C = C-3-pyridyl CH2CH3 152 6-Cl CF3 C = C-4-pyridyl CH2CH3 153 6-Cl CF3 C = C-2-furanyl CH2CK3 154 6-Cl CF3 C = C-3-furanyl CH2CH3 155 6-Cl CF3 C = C-2-thienyl CH2CH3 156 6-Cl CF3 C = C-3-thienyl CH2CH3 157 6-Cl CF3 CH2CH2-cycPr CH CH3 158 6-Cl CF3. CK2CH2-Ph CH2CH3 159 6-Cl CF3 CH2CK2-2-p i r i d i 10 CH2CH3 160 6-Cl CF3 CH2CK2-3-pyridyl? CH2CH3 161 6-Cl CF3 CH2CH2-4 -p i r i d i 1 or CH CH3 162 6-Cl CF3 CH2CH2-2 - f u r a n f! 0 CH2CH3 163 6-Cl CF3 CH2 K2-3 -f u r a n i 1 or CH2CK3 164 6-Cl CFT CH2CH2-2 -thienyl CH2CH3 165 6-Cl CF3 CH2 c? 2 - 3 - 1 i e n i 1 or c? 2 CK 3 166 6-MeO CF3 C = CCK2CH2OH K 167 6 -MeO CF3 C = C-CH (OH) Me K 168 6 -MeO CF3 C = C- (2-Cl) Ph? 169 6 -MeO CF3 C = C- (3 -CDPh H 170 6 -MeO CF3 C = C- (4-Cl) Ph H 171 6 -MeO CF3 C = C- (2-F) Ph H 172 6 -MeO CF3 C = C- (3-F) Ph H 173 6 -MeO CF3 C = C-. { 4-F) Ph K 174 6 -MeO CF3 C = C- (2 -OH) Ph H 175 6 -MeO CF3 CsC- (3-OH) Ph H 176 6 -MeO CF3 C = C-. { 4 -OH) Ph H 177 6 -MeO CF3 C2C- (2-0Me) Ph K 178 6 -MeO CF3 CsC- (3-OMe) Ph H 179 6 -MeO CF3 CsC- (4-OMe) Ph H 180 6 -MeO CF3 CsC- (2-CN) Ph H 181 6 -MeO CF3 C «C-. { 3-CN) Ph H 182 6 -MeO CF3 OsC- (4-CN) Ph H 183 6 -MeO CF3 CßC- (2-N02) Ph H 184 6 -MeO CF3 0 = C- (3-N02) Ph H 185 6 -MeO CF3 OsC- (4-N02) Ph H 186 6 -MeO CF3 C = C- (2-NH2) Ph H 187 6 -MeO CF3 C = C- (3-NH2) Ph H 188 6 -MeO CF3 C = C- (-NH) Ph H 189 6 -MeO CF3 C = C- (2-NMe2) Ph H 190 6 -MeO CF3 C = C- (3-NMe2) Ph H 191 6 -MeO CF 3 C = C- (4-NMe 2) Ph H 192 6 -MeO CF 3 C = C-3-pyridyl H 193 6 -MeO CF 3 CsC-4-pyridyl H 194 6 -MeO CF3 c = c-2-f uranyl H 195 6 -MeO CF3 C = C-3-f uranyl H 196 6 -MeO CF3 C ^: - 2-thienyl H 197 6 -MeO CF3 CHC-3-thien.il0 H 198 6 -MeO CF3 C = C-2-o? AZolil ° H 199 6 -MeO CF3 C = C-2 -thia zolyl or K 200 6-MeO CF3 CSC-4-isoxazolyl K 201 6 -MeO CF3 C = C-2-imidazolyl? 202 6 -MeO CF3 C = CCH2CH2OH K 203 6 -MeO CF3 C = C-CH (OH) Me K 204 6 -MeO CF3 C = C- (2-Cl) Ph H 205 6 -MeO CF3 C = C- (3-Cl) Ph H 206 6 -MeO CF3 C = C- (4-Cl) Ph H 207 6 -MeO CF3 C = C- (2-F) Ph H 208 6 -MeO CF3 C = C- (3-F) Ph H 209 6 -MeO CF3 C = C- (4-F) Ph H 210 6 -MeO CF3 C = C- (2-OH) Ph H 211 6 -MeO CF3 C = C- (3-OH) Ph H 212 6 -MeO CF3 OC- (4 -OH) Ph H 213 6 -MeO CF3 C = C- (2-OMe) Ph K 214 6 -MeO CF3 C = C- (3-OMe) Ph H 215 6 -MeO CF3 C = C- (4-OMe) Ph H 216 6 -MeO CF3 C = C- (2-CN) Ph H 217 6 -MeO CF3 C = C- (3-CN) Ph H 218 6 -MeO CF3 C = C- (4-CN) Ph H 219 6 -MeO CF3 C = C- (2-N02) Ph H 220 6 -MeO CF3 C = C- (3-N02) Ph H 221 6 -MeO CF3 C = C- (4-N02) Ph H 222 6 -MeO CF3 C = C- (2- H2) Ph H 223 6 -MeO CF3 C = C- (3-NH2) Ph H 224 6 -MeO CF3 C = C- (4- H) Ph H 225 6 -MeO CF3 C = C- (2-NMe2) Ph H 226 6 -MeO CF3 C = C- (3-NMe2) Ph H 227 6 -MeO CF3 C = C- (4-NMe2) Ph H 228 6 -MeO CF3 C = C-3-pyridyl H 229 6 -MeO CF3 C = C-4-pyridyl H 230 6-MeO CF3 C = C-2-furanyl H 231 6 -MeO CF3 C = C-3-furanyl H 232 6 -MeO CF3 C = C-2-thienyl H 234 6-MeO CF3 C = C-2-OXazolyl ° H 235 6-MeO CF3 C = c-2- t i 3 zol i lo u 236 6-MeO CF3 C = c-4-isoxazole? IoH 237 6-MeO CF3 C = C-2-. imidazolyl H 238 6-MeO CF3 CH2CH2-cycPr H 239 6-MeO CF3 CH2CH2CH2CH2OH H 240 6-MeO CF3 CH2 CH2 -CH (OH) e K 241 6-MeO CF3 CH2CH2-Ph H 242 6-MeO CF3 CH2CH2- (2-Cl) Ph H 243 6-MeO CF3 CH2CH2- (3-Cl) Ph H 244 6-MeO CF3 CH2CH2- (4-Cl) Ph H 245 6-MeO CF3 CH2CH2- (2-F) Ph H 246 6-MeO CF3 CH2CH2- (3-F) Ph H 247 6-MeO CF3 CH2CH2- (4-F) Ph H 248 6-MeO CF3 CH2CH2- (2-OH) Ph H 249 6-MeO CF3 CH2CH2- (3-OH) Ph H 250 6-MeO CF3 CH2CH2- (4-OH) Ph H 251 6-MeO CF3 CH2CH2- (2-OMe) Ph H 252 6-MeO CF3 CH2CH2- (3-OMe) Ph H 253 6-MeO CF3 CH2CH2- (4-OMe) Ph H 254 6-MeO CF3 CH2CH2- (2-CN) Ph H 255 6-MeO CF3 CH2CK2- (3-CN) Ph H 256 6-MeO CF3 CH2CH2- (4-C) Ph H 257 6-MeO CF3 CH2CH2- (2-N? 2) Ph H 258 6-MeO CF3 CH CH2- (3-N02) Ph H 259 6-MeO CF3 CH2CH2- (4-N02) Ph H 260 6-MeO CF3 CH2CH2- (2-NH2) Ph H 261 • 6-MeO CF3 CH2CH2- (3-NH2) Ph H 262 6-MeO CF3 CH2CH2- (4-NH2) Ph H 263 6-MeO CF3 CH2CH2- (2 -NMe2) Ph H 264 6-MeO CF3 CH2CH2- (3-NMe2) Ph H 265 6-MeO CF3 CH2CH2- (4-NMe2) Ph H 266 6-MeO CF3 CH2CH2-2- ÍrÍdÍl? H 267 6-MeO CF 3 CH 2 CH 2 - pyridylc > K 268 6 -MeO CF3 CK2CH2- - Diridyl H 269 6 -MeO CF3 CH CK2-2- cu ~ = n i! r K 270 6 -MeO CF3 CH2CK2-3- r? ¡^? D n K 271 6 -MeO CF3 CH2CK2-4- furanyl K 272 6 -MeO CF3 CH2CH2-3-thienyl K 273 6 -MeO CF3 CH2CH2-2- oxazolyl H 274 6 -MeO CF3 CH2CH2-2- the 0l i lO H 275 6 -MeO CF3 CH2CH2- - i 0 a. a • * 0 l i lO H 276 6 -MeO CF3 c? 2CK2-2 - i p i d; azo 1 i fo H 277 6 -MeO CF3 C = C-cycPr CH3 278 6 -MeO CF3 C = C-Ph CH3 279 6 -MeO CF3 c = c-2- iridj lo CH3 280 6 -MeO CF3 C = C-3- Diridyl CH3 281 6 -MeO CF3 CsC-4-pyridyl CH3 282 6 -MeO CF3 CEC-2- furanyl CH3 283 6 -MeO CF3 C ^ - * - furanyl CH3 284 6 -MeO CF3 C = C-2-thienyl CH3 285 6 -MeO CF3 286 tiemlo CH3 6 -MeO CF3 C = C-cycPr CH3 287 6 -MeO CF3 C = C-Ph CH3 88 6 -MeO CF3 ^ - Dxpdilo CH3 89 6 -MeO CF3 C = C-3 - Diridyl CH3 90 6 -MeO CF3 C = C-4 - pyridine CH3 91 6 - MeO CF3 C = C-2-. furanyl CH3 92 6 -MeO CF3 C = C-3 -franyl CH3 93 6 -MeO CF3 C = C-2- thienyl CH3 94 6 -MeO CF3 C = C-3-thienyl CH3 95 6 -MeO CF3 CH2CH2-cycPr CH 3 96 6 -MeO CF 3 CH 2 CH 2-Ph CH 3 97 6 -MeO CF 3 CH 2 CH 2-2- Diridyl CH 3 98 6 -MeO CF 3 CH 2 CH 2 3--. . .,., 9 id piyl CK3 -MeO CF3 CH2CK2-4- pyridyl CK3 0 6 -MeO CF3 CK2CH? - - furanyl CH3 301-6-MeO CF3 CH2CK2-3 -furanyl CK3 302 6-MeO CF3 CH2CK2-2 -thienyl CH3 303 6-MeO CF3 CK2CH2-3 -thienyl C? 3 304 6-MeO CF3 C = C-cvcPr CK2CK3 305 6-MeO CF3 C = C-Ph CK2CK3 306 6-MeO CF3 CsC_2-Pyridylc CH2CK3 307 6-MeO CF3 C = C_3_pyridyl CH2CH3 308 6-MeO CF3 C = C-4-pyridyl CH2CH3 309 6-MeO CF3 csc_2_furanyl CK2CH3 310 6-MeO CF3 CsC-3-f uranyl CH2CH3 311 6-MeO CF3? ? _ == - xr_- «* > - t + .ieni - l io CH2CK3 312 6-MeO CF3 CaC-3-thienyl CH2CH3 313 6-MeO CF3 C = C-cycPr CH2CH3 314 6-MeO CF3 C = C-Ph CH2CH3 315 6-MeO CF3 C = C-2-pyridyl CH2CH3 316 6-MeO CF3 C = C-3-pyridyl CH2CH3 317 6-MeO CF3 C = C-4-pyridyl CH2CH3 318 6-MeO CF3 C = C-2-f uranyl CH2CH3 319 6-MeO CF3 c = c_3_ furanyl CH2CH3 320 6-MeO CF3 C = C-2-thienyl CH2CH3 321 6-MeO CF3 C = c-3-thienyl CH2CH3 322 6-MeO CF3 CK2CH2-cycPr CH2CH3 323 6-MeO CF3 CH2CH2-Ph CH2CH3 324 6-MeO CF3 CH2CK2-2- pyridylCH2CH3 325 6-MeO CF3 CH2CH2-3 - p i r i d i 1 oCH2CH3 326 6-MeO CF3 CH2CH2- • P i r i d i 1 c CH2CH3 327 6-MeO CF3 CH2CH2-2 -f u r a n i 1 or CH2CH3 328 6-MeO CF3 CH2CH2-3-f uranyl CH2CH3 329 6-MeO CF3 CK2CH2-2 -thienyl CH2CH3 330 6-MeO CF3 CH2CK2-3- thienyl CH283 331 5,6-diF CF3 CsC- (2-Cl) Ph H 332 5,6-diF CF3 C = C- (3-Cl) Ph H 333 5,6-diF CF3 CsC- (4-Cl) Ph H 334 5,6-diF CF3 C-? C- (2-F) Ph H 335 5,6-diF CF3 C = C- (3-F) Ph K 336 5, 6-diF CF3 C = C- (4-F) Ph K 337 5,6-diF CF3 C = C- (2-OH) Ph K 338 5,6-diF CF3 CsC- (3 -OH) Ph K 339 5, 6-diF CF3 C = C- (-OH) Ph H 340 5,6-diF CF3 C = C- (2-OMe) Ph H 341 5,6-diF CF3 C = C- (3-OMe) Ph H 342 5,6-diF CF3 C = C- (4-OMe) Ph K 343 5,6-diF CF3 C = C- (2-CN) Ph H 344 5,6-diF CF3 C = C- (3-CN) Ph H 345 5,6-diF CF3 C = C- (4-CN) Ph H 346 5,6-diF CF3 C = C- (2-N02) Ph H 347 5,6-diF CF3 C = C- (3-N02) Ph H 348 5,6-diF CF3 C = C-. { -N02) Ph H 349 5,6-diF CF3 C = C- (2-NH) Ph H 350 5,6-diF CF3 CeC- (3- H2) Ph H 351 5,6-diF CF3 CsC- (4-NH2) Ph H 352 5,6-diF CF3 CßC- (2-NMe2) Ph H 353 5,6-diF CF3 CßC- (3-NMe2) Ph H 354 5,6-diF CF3 CsC- (4- Me) Ph H 355 5,6-diF CF3 C «C-3-pyridyl H 356 5,6-diF CF3 C = C-4-pyridyl H 357 5,6-diF CF3 C = C-2- furanyl H 358 5,6-diF CF3 C = C-3-furanyl H 359 5.6-diF CF3 C = C-2- ^ •. - 360 thienyl H 5,6-diF CF3 CEC-3-thienyl H 361 5,6-diF CF3 O = c-2-oxazolyl H 362 5,6-diF CF3 CsC-2-thiazolyl H 363 5,6-diF CF3 C = C-4-isoxazolyl H 364 5, 6-diF CF3 365 C = c-2-imidazolium H 5, 6-diF CF3 C = C- (2-Cl) Ph H 366 5,6-diF CF3 C = C- (3-Cl) Ph H 367 5,6-diF CF3 OC- (4-Cl) Ph H 368 5,6-diF CF3 C = C- (2-F) Ph 369. 5, 6-diF CF3 C = C- (3-F) Ph K 370 5,6-diF CF3 OC- (4-F) Ph K 371 5,6-diF CF3 C = C- (2-OH) Ph K 372 5,6-diF CF3 C = C- (3-OH) Ph H 373 5,6-diF CF3 C = C- (4-OH) Ph H 374 5,6-diF CF3 C = C- (2-OMe) Ph H 375 5, 6-diF CF3 C = C- (3-OMe) Ph K 376 5.6-diF CF3 C = C-. { 4-OMe) Ph H 377 5,6-diF CF3 C = C- (2-CN) Ph K 378 5,6-diF CF3 C = C- (3-C) Ph H 379 5,6-diF CF3 C = C- (4 -CN) Ph H 380 5,6-diF CF3 C = C- (2-N02) Ph H 381 5,6-diF CF3 C = C- (3-N0) Ph H 382 5,6-diF CF3 C = C- (4-N02) Ph H 383 5,6-diF CF3 C = C- (2-NH2) Ph H 384 5,6-diF CF3 C = C- (3 -MH2) Ph H 385 5,6-diF CF3 C = C- (4-NH2) Ph H 386 5,6-diF CF3 C = C- (2- Me2) Ph H 387 5,6-diF CF3 C = C- (3-Me2) Ph H 388 5,6-diF CF3 C = C- (4- Me2) Ph H 389 5,6-diF CF3 C = C-3-pyridyl H 390 5,6-diF CF3 C = C-4- Pyridyl H 391 5,6-diF CF3 C = C-2-f uranyl H 392 5,6-diF CF3 C = C-3-f uranyl H 393 5,6-diF CF3 C = C-2-thienyl H 394 5,6-diF CF3 C = C-3 -thienyl H 395 5,6-diF CF3 C = C-2-oxazolyl H 396 5,6-diF CF3 C = C-2-thiazolyl H 397 5,6-diF CF3 C = C-4 -isoxazolyl H 398 5,6-diF CF3 C = C-2-imi dazolyl H 399 5,6-diF CF3 CH2CH2-cycPr H 400 5,6-diF CF3 CH2C.-I2CH2CK 0H H 401 5, 6-diF CF3 CH2CH2-CH (OH) Me H 402 5,6-diF CF3 CH2CH2-Ph H 403 5,6-diF CF3 CH2CH2- (2-CI)? H H 404 5, 6-diF CF3 CH2CK2- (3-Cl) Ph H 405 5,6-diF CF3 CH2CH2- (4-Cl) Ph K 406 5, 6-diF CF3 CH2CK2- (2-F) Ph K 407 5,6-diF CF3 CK2CH2- (3-F) Ph H 408 5,6-diF CF 3 CH 2 CH 2 -. { 4-F) Ph J £ 409 5,6-diF CF3 CH2OÍ2- (2-OK) Ph U 410 5,6-diF CF3 CH2CH2- (3-OH) Ph u 411 5,6-diF CF3 CH2CK2- (4-OH) Ph H 412 5, 6-diF CF3 CH2CK2- (2-OMe) Ph H 413 5,6-diF CF3 CH2CH2- (3-OMe) Ph H 414 5, 6-diF CF3 CH2CH2- (4-OMe) Ph H 415 5,6-diF CF3 CH2CH2- (2-CN) Ph H 416 5,6-diF CF3 CH2CH2- (3-CN) Ph H 417 5,6-diF CF3 CH2CH2- (4-CN) Ph H 418 5,6-diF CF3 CH2CK2- (2-N02) Ph H 419 5,6-diF CF3 CH2CH2- (3-N02) Ph H 420 5,6-diF CF3 CH2CH2- (4-N02) Ph H 421 5,6-diF CF3 CH2CH2- (2- H2) Ph H 422 5,6-diF CF3 CH2CK2- (3-NH2) Ph H 423 5,6-diF CF3 CH CH2- (4-NH2) Ph H 424 5,6-diF CF3 CH2CK2- (2-NMe2) Ph H 425 5,6-diF CF3 CH2CH2- (3 -NMe2) Ph H 426 5,6-diF CF3 CH CH2- (4 -NMe2) Ph H 427 5,6-diF CF3 CH CK2-2- Pyridyl H 428 5,6-diF CF3 CH2CH2-3- pyridyl H 429 5,6-diF CF3 CH2CK2-4-Pyridyl H 430 5,6-diF CF3 CH2CH2 -2 -furanyl H 431 5,6-diF CF3 CH2CH2-3-f uranyl H 432 5,6-diF CF3 CH2CH2-2- thienyl H 433 5,6-diF CF3 CH2 H2-thienyl H 434 5,6-diF CF3 CH2CK2 -2 - 0 x to z 01 i 10 H 435 5,6-diF CF3 i CH2CH2-2-tiaz ° l? L? H 436 5,6-diF CF3 C? CK2-4 -isoxazolilc > K 437 5, 6-diF CF3 CH2CH2- K 438 5,6-diF CF3 C = C-cycPr c 3 439 5,6-diF CF3 C = C-2-pyridyl CH3 440 5,6-diF CF3 C = C-3-Pridyl C 3 441 5,6-diF CF3 C = C-4-pyridyl CH3 442 5, 6-diF CF3 C = C-2- furanyl CH 443 5,6-diF CF3 C ^ -3-furanyl n3 444 5,6-diF CF3 C = C-2-thienyl CH3 445 5,6-diF CF3 C = c-3- tiemlo CH3 446 5, 6-diF CF3 C = C-cycPr CH3 447 5,6-diF CF3 C = C-2-thienyl CH3 448 5,6-diF CF3 C = C-3-pyridyl CH3 449 5,6-diF CF3 C = C-4-pI idil? H3 450 5,6-diF CF3 C = C-2-f uranyl CH3 451 5,6-diF CF3 C = C-3-f uranyl CH3 452 5,6-diF CF3 C = C-2-thienyl CH3 453 5,6-diF CF3 C = C-3-thienyl ^ 454 5,6-diF CF3 CH2CH -cycPr CH3 455 5,6-diF CF3 CH2CH2-Ph CH3 456 5,6-diF CF3 CH2CH2-2-pyridyl CH3 457 5,6-diF CF3 CH2CH2-3-Pridyl CH3 458 5,6-diF CF3 CH2CH2-4-pyridyl? CH3 459 5,6-diF CF3 CH2CH2-2-furanyl CH3 460 5,6-diF CF3 CH CH2-3-f uranyl CH3 461 5,6-diF CF3 CH2CH2-2- thienyl CH3 462 5,6-diF CF3 CH2CH2-3-thienyl CH3 463 5,6-diF CF3 C = C-cycPr CH2CH3 464 5,6-diF CF3 O = C-Ph CH2CH3 465 5,6-diF CF3 CsC-2-pyridyl CH CH3 466 5,6-diF CF3 c ^: _ 3_pyridyl CK2CH3 467 5,6-diF CF3 C = c-4- pir i di lo CH2CH3 468 5,6-diF CF3 OeC-2 -furanyl CH2CH3 469 5,6-diF CF3 CsC-3-furanyl CH2CH3 470 5, 6-diF CF3 CsC-2-tÍenii ° CH2CH3 471 5,6-diF CF3 C = C-3-tmemium c? 2c? 3 472 5,6-diF CF3 C = C-cycPr CH CK3 473 5,6-diF CF3 C = C-Ph CK2CH3 474 5,6-diF CF3 C = C-2-pyridylc > CH2CH3 475 5,6-diF CF3 C = C-3 -pipdyl CH2CK3 476 5,6-diF CF3 C = C-4-pyridyl CH2CH3 477 5,6-diF CF3 C = c-2-f ur añil CH2CH3 478 5,6-diF CF3 C = c-3.furanyl CK2CH3 479 5,6-diF CF3 C = C-2-thienyl CH CK3 480 5,6-diF CF3 C = C-3-thienyl CH2CK3 481 5,6-diF CF3 CH2CH2-cycPr CK2CH3 482 5,6-diF CF3 CH CK2-Ph CH2CH3 483 5,6-diF CF3 CH2CK2-2 - p i r i d i 1 or CH2CK3 484 5,6-diF CF3 CH2CH2-3 -pyridyl or CH2CH3 485 5,6-diF CF3 CH CH2-4-pyridylc, CH2CH3 486 5,6-diF CF3 CH2CK2-2-f uranyl CH2CH3 487 5,6-diF CF3 CH2CK2-3 -furanyl CH2CH3 488 5,6-diF CF3 CH2CK2-2 - i e n i 10 CH2CH3 489 5,6-diF CF3 CH2CH2-3-thienyl CH2CH3 490 5,6-diCl CF3 CsC- (2-Cl) Ph H 491 5,6-diCl CF3 C «C- (3-Cl) Ph H 492 5,6-diCl CF3 C = C- (4-Cl) Ph H 493 5,6-diCl - ^ * 3. CeC- (2-F) Ph H 494 5,6-diCl CF3 OsC- (3-F) Ph H 495 5,6-diCl CF3? EC- (4-F) Ph H 496 5,6-diCl CF3 C = C-C2-OH) Ph H 497 5,6-diCl CF3 C = C- (3-OH) Ph H 498 5,6-diCl CF3 C = C- (4-OH) Ph H 499 5,6-diCl CF3 C = C- (2-OMe) Ph H 500 5,6-diCl CF3 C = C-. { 3 -OMe) Ph H 501 5,6-diCl CF3 C = C-. { 4-OMe) Ph H 502 5,6-diCl CF3 CsC- (2-CN) Ph H 503 5,6-d Cl CF3 C = C- (3-CN) Ph H 504 5,6-diCl CF3 C = C- (4-CN) Ph K 505 5,6-diCl CF3 C = C- (2-N02) Ph H 506 5,6-diCl CF3 C = C- (3-N02) Ph K 507 5,6-diCl CF3 C = C-. { 4 -N02) Ph H 508 5,6-diCl CF3 C = C- (2-KH) Ph K 509 5,6-diCl CF3 C = C- (3 -NH2) Ph H 510 5,6-diCl CF3 C = C- (4-NH2) Ph H 511 5,6-diCl CF3 G = C- (2-NMe2) Ph H 512 5,6-diCl CF3 C = C- (3 Me) Ph H 513 5,6-diCl CF3 C = C- (4 -NMe2) Ph H 514 5,6-diCl CF3 C = C-3-pyridyl H 515 5,6-diCl CF3 C = C-4-Pyridyl H 516 5,6-diCl CF3 C = C-2 -furanyl H 517 5,6-diCl CF3 c = -3"furanyl H 518 5,6-diCl CF3 C = c-2-t ienyl H 519 5,6-diCl CF3 CeC-3 - 1 i e n i 1 or H 520 5,6-diCl CF3 CsC-2-oxazolyl H 521 5,6-diCl CF3 CsC-2-thiazolyl H 522 5,6-diCl CF3 O - - isoxazolili 0 H 523 5,6-diCl CF3 CtC-2-imidazolyl H 524 5,6-diCl CF3 C = C- (2-Cl) Ph H 525 5,6-diCl CF3 C = C- (3-Cl) Ph H 526 5,6-diCl CF3 C = C- (4-Cl) Ph H 527 5,6-diCl CF3 OC- (2-F) Ph H 528 5,6-diCl CF3 C = C- (3-F) Ph H 529 5,6-diCl CF3 C = C- (4-F) Ph H 530 5,6-diCl CF3 C = C-. { 2-0H) Ph H 531 5,6-diCl CF3 C = C- (3-OH) Ph H 532 5,6-diCl CF3 C = C- (4-OH) Ph H 533 5,6-diCl CF3 C = C- (2-OMe) Ph H 534 5,6-diCl CF3 C = C- (3-0Me) Ph H 535 5,6-diCl CF3 C = C- (4-OMe) Ph H 536 5,6-diCl CF3 C = C- (2-Gí) Ph H 537 5,6-diCl CF3 C = C- (3-C) Ph H 538 5,6-diCl CF3 c = c - (.: - CN) Ph H 539 5,6-diCl CF3 C = C- (2-N02) Ph H 540 5,6-diCl CF3 C = C- (3-N02) Ph K 541 5,6-diCl CF3 C = C- (4-N02) Ph H 542 5,6-diCl CF3 C = C- (2-NH) Ph H 543 5,6-diCl CF3 C = C- (3-NH2) Ph H 544 5,6-diCl CF3 OC- (4-H2) Ph H 545 5,6-diCl CF3 C = C- (2-NMe2) Ph H 546 5,6-diCl CF3 C = C- (3-NMe2) Ph H 547 5,6-diCl CF3 C = C- (4- Me2) Ph H 548 5,6-diCl CF3 C = C-3-pyridyl H 573 5,6-diCl CF3 CK2 .2 - (- OMe) Ph K 574 5,6-diCl CF3 CH2CK2- (2-CN) Ph H 575 5,6-diCl CF3 CH CH2- (3-CN) Ph H 576 5,6-diCl CF3 CH2CK2- (4-CN) Ph H 577 5,6-diCl CF3 CH2CH2- (2-N02) Ph K 578 5,6-diCl CF3 CH2CK2- (3-N02) Ph H 579 5,6-diCl CF3 CH2CH2- (4-N02) Ph H 580 5,6-diCl CF3 CH2CK2- (2-NH2) Ph H 581 5,6-diCl CF3 CH2 CH2 - (3 -NH2) Ph H 582 5,6-diCl CF3 CH2CH2- (4-NH2) Ph H 583 5,6-diCl CF3 CH2 CH2 - (2 -NMe2) Ph H 584 5,6-diCl CF3 CH CH2 - (3 - Me2) Ph H 585 5,6-diCl CF3 CH2CH2- (4-NMe2) Ph H 586 5,6-diCl CF3 CH CH2-2-Prididyl H 587 5,6-diCl CF3 CH2CH2-3-Pyridyl H 588 5,6-diCl CF3 CH2CH2-4-pyri di lo H 589 5,6-diCl CF3 CH2CH2-2-furanyl H 590 5,6-diCl CF3 CH2CH2-3-furanyl H 591 5,6-diCl CF3 CH2CH2-2-thienyl H 592 5,6-diCl CF3 CH2CH2-3-thienyl H 593 5,6-diCl CF3 CH2CH2-2- oxazolyl H 594 5,6-diCl CF3 CH2CH2-2-thiazole or H 595 5,6-diCl CF3 CH2CH2- -.IS oxazolyl H 596 5,6-diCl CF3 CH2CH2-2-i idazolyl H 597 5,6-diCl CF3 C = C-cycPr CH3 598 5,6-diCl CF3 CsC-2-pyridyl CH3 599 5,6-diCl CF3 C = C-3-pyridyl H3 600 5,6-diCl CF3 C = C-4-pyridyl or ^ 3 601 5,6-diCl CF3 CsC-2-f uranxlo CH3 602 5,6-diCl CF3 C = C-3-f uranyl H3 603 5,6-diCl CF3 C- -2- thienyl CH3 604 5,6-diCl CF3 C = c-3- ienyl CH3 605 5,6-diCl CF3 C = C-cycPr CH3 606 5,6-diCl CF3 C = C-2-pyridyl CK3 607 5,6-diCl CF3 C = C-3- Pir i di i o Cíi3 608 -. 608-5.6-diCl CF3 C = C- pyridyl CH, 609 5,6-diCl CF3 C = c-2-furanüo CK3 610 5,6-diCl CF3 r_r., Furanyl 611 5,6-diCl CF3 C = C-2-thienyl CK3 612 5,6-diCl CF3 c = c_3 -thienyl c? 3 613 5,6-diCl CF3 CK2 Ci-cy c Pr CH3 614 5,6-diCl CF3 CK2CH2-Ph CK3 615 5,6-diCl CF3 CH2CK2-2-pyridyl CH3 616 5,6-diCl CF3 CH2CH2-3 -pyridyl CH3 617 5,6-diCl CF3 CH2CH2-4-pyridyl CH3 618 5,6-diCl CF3 CH2CK2-2-furanyl CH3 619 5, 6-diCl CF3 CH2CK2-3-f uranyl CH3 620 5,6-diCl CF3 CH2CK2-2-thienyl CH3 621 5,6-diCl CF3 CH2CH2-3-thienyl CH3 622 5,6-diCl CF3 CeC-cycPr CH CH3 623 5,6-diCl CF3 CeC-Ph CH2CH3 624 5,6-diCl CF3 CsC-2-piri üo CH2CH3 625 5,6-diCl CF3 C -3-pyridyl CH2CH3 626 5,6-diCl CF3 C ^ -4-pyrid-yl CH2CH3 627 5,6-diCl CF3 sC-2-furanyl CH2CH3 628 5,6-diCl CF3 C = C-3-furanyl CH2CH3 629 5,6-diCl CF3 C = C-2-thienyl CH H3 630 5,6-diCl CF3 ^^ - thienyl CH2CH3 631 5,6-diCl CF3 C = C-cycPr CH2CH3 632 5,6-diCl CF3 C = C-Ph CH2CH3 633 5,6-diCl CF3 C = C-2-pyridylc CH2CH3 634 5,6-diCl CF3 C = C-3-pyridyl or CK2CH3 635 5,6-diCl CF3 C = C-4-pyridyl CH2CH3 636 5,6-diCl CF3 C = c-2-f uranyl CH CH3 637 5,6-diCl CF3 c = C-3-f uranyl CH2CH3 638 5,6-diCl CF3 C = C-2-thienyl Gi2CH3 639 5,6-diCl CF3 C = C ~ 3"thienyl CK2CH3 640 5,6-diCl CF3 CH CH2-cycPr CH, CH, 71 641 5,6-diCl CF3 CH CH2-Ph CH CK3 642 5,6-diCl CF3 CH2CH2-2 -Piridyl CK2CK3 643 5,6-diCl CF3 CH2CK2-3 pyridyl CH2CH3 644 5,6-diCl CF3 CK2CK2- -pyridyl CH2CH3 645 5,6-diCl CF3 CH2CH2-2 -furanyl CH2CK3 646 5,6-diCl CF3 CK2CK2-3 -furanyl CH2CH3 647 5, O-diCl CF3 CH2CK2-2 -thienyl CH2CK3 648 5,6-diCl CF3 CH2CK2-3 -thienyl CH2CH3 649 6-F CF3 C = CCH CH2OH H 650 6-F CF3 C = C-CH (OH) Me H 651 6-F CF3 C = C- (2-Cl) Ph H 652 6-F CF3 C = C- (3-Cl) Ph K 653 6-F CF3 C = C- (4-Cl) Ph H 654 6-F CF3 CsC- (2-F) Ph H 655 6-F CF3 OeC- (3-F) Ph H 656 6-F CF3 CHC- (4-F) Ph H 657 6-F CF3 O = C- (2-0H) Ph H 658 6-F CF3 C? C- (3-OH) Ph H 659 6-F CF3 C «C- (4-OH) Ph H 660 6-F CF3 CsC- (2-OMe) Ph H 661 6-F CF3 CsC- (3-OMe) Ph H 662 6-F CF3 C = C- (4 -OMe) Ph H 663 6-F CF3 C = C- (2-CN) Ph H 664 6-F CF3 C = C- (3-CN) Ph H 665 6-F CF3 C = C- (4-CN) Ph H 666 6-F CF3 C = C- (2-N02) Ph H 667 6-F CF3 C = C- (3-N02) Ph H 668 6-F CF3 C = C- (4-N02) Ph H 669 6-F CF3 C = C- (2-NH2) Ph H 670 6-F CF3 C = € - (3-NH2) Ph H 671 6-F CF3 C = C- (4- H2) Ph H 672 6-F CF3 C = C-. { 2-NMe2) Ph H 673 6-F CF3 C = C- (3-NMe) Ph K 674 6-F CF3? EC- (4-KMe2) Ph H 675 6-F CF3 C = C-3-Pyridyl? 676. 6-F CF3 C = C-4-Prididyl H 677 6-F CF3 (- = ^ - - "furanyl 678 6-F CF3 C = C-3-furanyl H 679 6-F CF3 C- -2-thienyl H 680 6-F CF3 C = C-3-thienyl H 686 6-F CF3 C = C-CH (OH) Me H 687 6-F CF3 C = C- (2-Cl) Ph H 688 6-F CF3 C = C- (3-Cl) Ph H 689 6-F CF3 C = C- (4-Cl) Ph H 690 6-F CF3 OC- (2-F) Ph H 691 6-F CF3 C = C- (3-F) Ph H 692 6-F CF3 C = c- (4-F) Ph H 693 6-F CF3 C = C- (2-OH) Ph H 694 6-F CF3 C = C- (3-OH) Ph H 695 6-F CF3 C = C- (4-OH) Ph H 696 6-F CF3 C = C- (2-OMe) Ph H 697 6-F CF3 C = C- (3-0Me) Ph H 698 6-F CF3 C = C- (4-OMe) Ph H 699 6-F CF3 C = C- (2-CN) Ph H 700 6-F CF3 C = C- (3-CN) Ph H 701 6-F CF3 C = C- (4-CN) Ph H 702 6-F CF3 C = C- (2-N02) Ph H 703 6-F CF3 C = C- (3-N02) Ph H 704 6-F CF3 C = C- (4-N02) Ph H 705 6-F CF3 C = C- (2-NH2) Ph H 706 6-F CF3 C = C- (3-NH2) Ph H 707 6-F CF3 C = C- (4-NH2) Ph H 708 6-F CFi C = C- (2-Me2) Ph H 709 6-F CF3 C = C- < 3-NMe) Ph H 710 6-F CF3 C = C- (4- Me) Ph K 711 6-F CF3 C = C-3-pyridyl H 712 6-F CF3 C = C-4-pyridyl H 713 6-F CF3 C = C-2-f uranyl H 714 6-F CF3 C = c-3-furanyl H 715 6-F CF3 C = C-2-thienyl H 716 6-F CF3 c = c_3_tien? Lo H 717 6-F CF3 C = C-2-oxazyl? H 718 6-F CF3 C = C-2-thiazolyl H 719 6-F CF3 C = C-4-isoxazolyl H 720 6-F CF3 C = C-2-imidazolyl H 721 6-F CF3 CH2CH2-cycPr H 722 6-F CF3 CH2CH2CH2CH2OH H 723 6-F CF3 CH2CH2-CH (OH) Me H 724 6-F CF2 CH2CH2- (2-Cl) Ph H 725 6-F CF3 CH2CK2- (3-Cl) Ph H 726 6-F CF3 CH2CH2- (4-Cl) Ph H 727 6-F CF3 CH2CH2- (2-F) Ph H 728 6-F CF3 CH2CH2- (3-F) Ph H 729 6-F CF3 CH2CH2- (4-F) Ph H 730 6-F CF3 CH2CH2- (2-OH) Ph H 731 6-F CF3 CH CK2- (3-OH) Ph H 732 6-F CF3 CH2CH2- (4-OH) Ph H 733 6-F CF3 CH2CH2- (2-OMe) Ph H 734 6-F CF3 CH2CH2- (3-OMe) Ph H 735 6-F CF3 CH2CH2- (4-OMe) Ph H 736 6-F CF3 CH2CH2- (2-CN) Ph H 737 6-F CF3 CH2CH2- (3-CN) Ph H 738 6-F CF3 CH2CH2- (4-CN) Ph H 739 6-F CF3 CH2C? 2- (2-N02) Ph H 740 6-F CF3 CH2CH2- (3 -N02) Ph H 741 6-F CF3 CH2CH2- (4-N02) Ph H 742 6-F CF3 CH2CK2- (2-NH2) Ph H 743 .. 6-F CF3 CK2CH2 - (3 -KK2) Ph K 744 6-F CF3 CH2 CK2 - (4-NH) Ph H 745 6-F CF3 CH2 CH2 - (2 - Me2) Ph H 746 6-F CF3 CH2CK2- (3-NMe2) Ph K 747 6-F CF3 CH2CH2- (4 -NMe2) Ph H 748 6-F CF3 CH2CH2-3-pÍrÍdílo K 749 6-F CF3 CH2CH2-4-pyridyl H 750 6-F CF3 CH2CH2-2 -furanyl H 751 6-F CF3 CH2CH2r3-furanyl H 752 6-F CF3 CH2CH2-2-thienyl H 753 6-F CF3 CH2CH2-3-thienyl K 754 6-F CF3 CH2CH2-2- oxazolyl H 755 6-F CF3 CH2CH2-2-thiazolyl H 756 6-F CF3 CH2CH2-4-isoxazolylH 757 6-F CF3 CH2CH2-2-imidazolyl? H 758 6-F C v_Fr33 OsC-cycPr CH3 759 6-F C CFF33 CsC-iPr CH3 760 G-F C CFF33 CßC-Pr CH3 761 6-F C CFF33 C «C-Bu CH3 762 6-F C CFF32 OC-iBu CH3 763 6-F C CFF33 C = C-tBu CH3 764 6-F C CFF33 C = C-Et CH 765 6-F C CFF33 C = C-Me CH3 766 6-F C CFF33 c = c-Ph CH3 767 6-F C C CFFF333 CsC-2- Pyridyl CH3 768 6-F C CFF33 CEC-3-Pridine .10 CH3 769 6-F C CFF33 C = C-4-pyridi lo CH3 770 6-F C CFF3. C = C-2- f xu 771 uraani i? ic CH3 6 6 - FP CF3 C = C-3-furanilc CK3 772 6-F CF3 C = C-2-t? Enl? 0 ^ 3 773 6_F CF CF3 C = C-3-thienyl CH3 6_F CF3 C = C-cycPr CH3 775 6-F CF3 C = C-iPr CH3 776 6-F CF3 C = C-Pr CH3 777 6-F CF3 C = C-Bu CH3 778 6-F CF3 C = C-iBu CK3 779 6-F CF3 C = C-tBu CH3 780 6-F CF3 C = C-Et CH3 781 6-F CF3 C = C-Me CH3 782 6-F CF3 C = C-Ph CH3 783 6-F CF3 C = C-2-Pridyl CH3 784 6-F CF3 C = C-3-Pyridyl CH3 785 6-F CF3 C = C-4-Pridyl CH3 786 6-F CF3 C = C-2 -furanyl CIl3 787 6-F CF3 C = C-3-f uranyl CÍ 3 788 6-F CF3 C = C-2-thien? Lo CH_. 789 6-F CF3 C = C-3-tienxlc CH3 790 6-F CF3 CH CH2-cycPr CH3 791 6-F CF3 CH CH2-Ph CH3 792 6-F CF3 CH2CK2-2-Pridyl CH3 793 6-F CF3 CH2CH -3 pyridyl CH3 794 6-F CF3 CH2CH2-4pyridyl CH3 795 6-F CF3 CH2CH2-2 -furanyl CH3 796 6-F CF3 CH2CH -3-furanyl CH3 797 6-F CF3 CH2CH2-2- thienyl CH3 798 6-F CF3 CH2CK2-3-thienyl ^ 799 6-F CF3 Csz-cycPr CH2CH3 800 6-F CF3 CeC-Ph CH2CH3 801 6-F CF3 C = C-2-pyridyl CH2CH3 806 6-F CF3 C = C-2-thienyl CH2CH3 807 6-F CF2 C = C-3 -thienyl CH2CK3 808 6-F CF3 C = C-cycPr CH2CH3 809 6-F CF3 C = C-Ph CH2CK3 810 6-F CF3 C = C-2-pyridyl CH2CH3 845 5-Cl CF3 C = C- (2-N02) Ph K 846 5-Cl CF3 C = C- (3-N02) Ph K 847 5-Cl CF3 C = C- (4 -N02) Ph H 848 5-Cl CF3 C = C- (2-NK2) Ph K 849 5-Cl CF3 C = C-. { 3-NK2) Ph H 850 5-Cl CF3 C = C- (4-NH2) Ph H 851 5-Cl CF3 C = C-. { 2-NMe2) Ph H 852 5-Cl CF3 C = C- (3-NMe2) Ph K 853 5-Cl CF3 C = C- (4-NMe2) Ph H 854 5-Cl CF3 C ^ -2-pyridyl or H 855 5-Cl CF3 C = C-2-pyridyl H 856 5-Cl CF3 C = C-3-p i r i d i 1 or H 857 5-Cl CF3 C = C-4-pyridyl H 858 5-Cl CF3 = -2 - u r a n i 1 or H 859 5-Cl CF3 C = C-3-furanyl H 860 5-Cl CF3 CeC-2-thienyl H 861 5-Cl CF3 C ^ C-3-thienyl H 862 5-Cl CF3 C -2-oxazolyl H 863 5-Cl CF3 CßC-2-thiazolyl H 864 5-Cl CF3 CsC-4- isoxazolyl? H 865 5-Cl CF3 C = C-2-imidazolyl H 866 5-Cl CF3 C = C-cycPr H 867 5-Cl CF3 C = CCH CH20H H 868 5-Cl CF3 C = C-CH (0H) Me H 869 5-Cl CF3 C = C-Ph H 870 5-Cl CF3 C = C- (2-Cl) Ph H 871 5-Cl CF3 C = C- (3-Cl) Ph H 872 5-Cl CF3 C = C- (4-Cl) Ph H 873 5-Cl CF3 C = C- (2-F) Ph H 874 5-Cl CF3 C = C- (3-F) Ph H 875 5-Cl CF3 C = C- (4-F) Ph H 876 5-Cl CF3 C = C- (2-OH) Ph H 877 5-Cl CF3 C = C- (3-0H) Ph H 878 5-Cl CF3 C = C- (4-OH) Ph K 913 5-Cl CF3 CH2CK2- (2-F) Ph K 914 5-Cl CF3 CH2CH2- (3-F) Ph H 915 5-Cl CF3 CH2CH2- (4-F) Ph K 916 5-Cl CF3 CH2CK2- (2-OH) Ph H 917 5-Cl CF2 CH2CH2- (3-OH) Ph H 918 5-Cl CF3 CH CH2- (4-OH) Ph H 919 5-Cl CF3 CH2CH2- (2-OMe) Ph H 920 5-Cl CF3 CH2CH - (3-OMe) Ph H 921 5-Cl CF3 CH2CK2- (4-OMe) Ph H 922 5-Cl CF3 CH2CH2- (2-CN) Ph H 923 5-Cl CF3 CH2CH2- (3-CN) Ph H 924 5-Cl CF3 CH2CH2-. { 4-CN) Ph H 925 5-Cl CF3 CH2CH2 - (2 -K0) Ph H 926 5-Cl CF3 CH CH2- (3-N02) Ph H 927 5-Cl CF3 CH2CH2- (4-N02) Ph H 928 5-Cl CF3 CH2CH2- (2-NH2) Ph H 929 5-Cl CF3 CH2CH2- (3- H2) Ph H 930 5-Cl CF3 CH2CH2- (4- H2) Ph H 931 5-Cl CF3 CH2CH2-. { 2-NMe2) Ph H 932 5-Cl CF3 CH2 CH2 - (3 -NMe2) Ph H 933 5-Cl CF3 CH2CH2- (4-NMe2) Ph H 934 5-Cl CF3 CH2CH2-2-pyridyl H 935 5-Cl CF3 CH2CH2-3-pyridyl H 936 5-Cl CF3 CH2CH2-4-pyridyl H 937 5-Cl CF3 CH2CH2-2-f uranyl or H 938 5-Cl CF3 CH2CH2-3-f ranil H 939 5-Cl CF3 CH2CH2-2-thienyl H 940 5-Cl CF3 CH2CH2-3-thienyl H 941 5-Cl CF3 CH2CH2-2-? Xazolyl H 942 5-Cl CF3 CH2CH2-2- thiazolyl H 943 5-Cl CF3 C CH2CH2-4- isoxazolylH 944 5-Cl CF3 C CH2CH2-2-imidazolyl H 945 5-Cl CF3 C = C-cycPr CH 946 5-Cl CF- > C = C-Ph CH3 981 5-Cl CF3 C = C-cycPr CH2CK3 982 5-Cl CF3 C = C-Ph CH2CK3 983 5-Cl CF3 C = C-2-pyridyl CH2CK3 984 5-Cl CF3 C = C-3-pyridyl CH2CH3 985 5-Cl CF3 C = C-4-pyridyl CH2CH3 986 5-Cl CF3 C = C-2-furanyl CHCH3 987 5-Cl CF3 C = C-3-furanyl CH2CK3 988 5-Cl CF3 C = C-2-thienyl CH2CH3 989 5-Cl CF3 OC-3 - thienyl CH2CH3 990 5-Cl CF3 CH2CH2-cycPr CK2CH3 991 5-Cl CF3 CH2CH2-Ph CH2CH3 992 5-Cl CF3 CH2CK2-2-.pyridyl CK2CH3 993 5-Cl CF3 CH2CK2-3- pyridyl CH2CH3 994 5-Cl CF3 CH2CH2-4- pyridyl CH2CH3 995 5-Cl CF3 CH2CK2-2 - furanyl CH2CH3 996 5-Cl CF3 CH2CH2-3- furanyl CH2CH3 997 5-Cl CF3 CH2CK2-2- thienyl CH2CH3 998 5-Cl CF3 CH2CH2-3-thienyl CH2CH3 999 5-F CF3 OC-cycPr H 1000 5-F CF3 CBCCH2CH2OH H 1001 5-F CF3 C = C-CH (OH) Me H 1002 5-F CF3 C = C-Ph H 1003 5-F CF3 C = C- (2-Cl) Ph H 1004 5-F CF3 C = C- (3-Cl) Ph H 1005 5-F CF3 C = C- (4-Cl) Ph H 1006 5-F CF3 C = C- (2-F) Ph H 1007 5-F CF3 C = C- (3-F) Ph H 1008 5-F CF3 C = C- (4-F) Ph H 1009 5-F CF3 C = C- (2-OH) Ph H 1010 5-F CF3 C = C- (3-OH) Ph H 1011 5-F CF3 C = C- (4-OH) Ph H 1012 5-F CF3 C = C-. { 2-OMe) Ph H 1013 5-F CF3 C = C- (3-OMe.}. Ph H 1014 5-F CF3 C = C- (4 -OMe) Ph H 1015 5-F CF3 C = C- (2-CN) Ph H 1016 5-F CF3 C = C- (3-CN) Ph K 1017 5-F CF3 C = C- (4-CN) Ph H 1018 5-F CF3 C = C- (2-N02) Phii 1019 5-F CF3 C = C- (3-N02) Ph K 1020 5-F CF3 C = C- (4-N02) Ph H 1021 5-F CF3 C = C- (2- H2) Ph H 1022 5-F CF3 C = C- (3 -NH2) Ph H 1023 5-F CF3 C = C- (4-NK2) Ph H 1024 5-F CF3 C = C- (2-NMe2) Ph H 1025 5-F CF3 C = C- (3- Me2) Ph H 1026 5-F CF3 C = C- (4-NMe) Ph H 1027 5-F CF3 C = C-2-pyridyl H 1028 5-F CF3 C = C-2-pyridyl H 1029 5-F CF3 C = C-3-pyri H 1030 5-F CF3 Cs - -pyridyl H 1031 5-F CF3 CsC-2 -furanyl H 1032 5-F CF3 C «C-3-f uranyl H 1033 5-F CF3 CEC-2-thienyl H 1034 5-F CF3 CsC-3-thienyl H 1035 5-F CF3 CsC-2-oxazolyl H 1036 5-F CF3 CeC-2-txazolyl H 1037 5-F CF3 C = c-4-isoxazolyl. D H 1038 5-F CF3 C = c-2-imidazole H 1039 5-F CF3 C = C-cycPr H 1040 5-F CF3 C = CCH2CH2OH H 1041 5-F CF3 C = C-CH (OH) Me H 1042 5-F CF3 C = C-Ph H 1043 5-F CF3 C = C- (2-Cl) Ph H 1044 5-F CF3 C = C- (3-Cl) Ph H 1045 5-F CF3 C = C- (4-Cl) Ph H 1046 5-F CF3 C = C- (2-F) Ph H 1047 5-F CF3 C = C- (3-F) Ph H 104e 5-F CF3 C = C- (4-F) Ph H 1049 5-F CF3 C = C- (2-OH) Ph K 1050 5-F CF3 C = C- (3-OH) Ph K 1051 5-F CF3 C = C- (4-OH) Ph K 1052 5-F CF3 C = C- (2-OMe) Ph H 1053 5-F CF3 C = C- (3-OMe) Ph K 1054 5-F CF3 C = C- (4-OMe) Ph K 1055 5-F CF2 C = C- (2-C) Ph H 1056 5-F CF3 C = C- (3-C) Ph H 1057 5-F CF3 C = C- (4-CN) Ph H 1058 5-F CF3 C = C- (2-N0) Ph H 1059 5-F CF3 C = C- (3-N02) Ph H 1060 5-F CF3 C = C- (4-N02) Ph H 1061 5-F CF3 C = C- (2- K) Ph H 1062 5-F CF3 C = C- (3-NH2) Ph H 1063 5-F CF3 C = C- (4-NH) Ph H 1064 5-F CF3 OC- (2-NMe2) Ph H 1065 5-F CF3 C = C- (3-NMe2) Ph H 1066 5-F CF3 C = C- (4- Me2) Ph H 1067 5-F CF3 C = C-2-pyridyl H 1068 5-F CF3 C = C-2-pyridyl H 1069 5-F CF3 C = C-3-pyridyl H 1070 5-F CF3 C = C-4-pyridyl H 1071 5-F CF3 C = C-2- furanyl H 1072 5-F CF3 C = C-3-: furanyl H 1073 5-F CF3 C = C-2-thienyl H 1074 5-F CF3 C = C-3-thienyl H 1075 5-F CF3 C = C-2-Oxazolyl H 1076 5-F CF3 C = C-2-thiazolyl H 1077 5-F CF3 C = C-4- isoxazolyl H 1078 5-F CF3 C = C-2-imidazolyl H 1079 5-F CF3 CH2CH2- ycPr H 1080 5-F CF3 CH2CH2CH2CH2OH H 1081 5-F CF3 CH2CH2-CH (OH) Me H 1082 5-F CF3 CHCH2Ph H 1083 5-F CF3 CH2CH2- (2-Ci) Ph K 1084 5-F CF3 CH2CH2- (3-Cl) Ph H 1085 5-F CF3 CK2CK2- (4-Cl) Ph H 1086 5-F CF3 CHCK2- (2-F) Ph H 1087 5-F CF3 CH2CH2- (3-F) Ph n 1088 5-F CF3 CH2CH2- (4-F) Ph K 1089 5-F CF3 CH2CK2- (2-0H) Ph K 1090 5-F CF3 CH2CH2- (3-OH) Ph K 1091 5-F CF3 CK2CH2- (4-OH) Ph H 1092 5-F CF3 CH2CH- (2-OMe) Ph H 1093 5-F CF3 CH2CK2- (3 -OMe) Ph H 1094 5-F CF3 CH2CH2- (4-OMe) Ph H 1095 5-F CF3 CH2CK2- (2-CN) Ph K 1096 5-F CF3 CH2CK2- (3-CN) Ph H 1097 5-F CF3 CH2CK2- (4-CN) Ph H 1098 5-F CF3 CH2CK2- (2-N02) Ph H 1099 5-F CF3 CH2CK2- (3-N? 2) Ph H 1100 5-F CF3 CH2CH2- (4-N02) Ph H 1101 5-F CF3 CHCH2- (2-NH2) Ph H 1102 5-F CF3 CH2CH2- (3-NH2) Ph H 1103 5-F CF3 CH2CK2- (4- H2) Ph H 1104 5-F CF2 CH2CK2- (2-NMe2) Ph H 1105 5-F CF3 CH2CH2- (3 -NMe2) Ph H 1106 5-F CF3 CH2CH2- (4- Me2) Ph H 1107 5-F CF3 CH2CH2-2-pyridyl H 1108 5-F CF3 CH2CH2-3-pyridyl H 1109 5-F CF3 CH2CH2-4-pyridyl H 1110 5-F CF3 CH2CH2-2- furanyl H 1111 5-F CF3 CH2CH2-3-furanyl H 1112 5-F CF3 CH2CH2-2-thienyl H 1113 5-F CF3 CH2CH2-3-thienyl H 1114 5-F CF3 CH2CH2-2- oxazolflo H 1115 5-F CF3 (CH2CK2-2- .thiazolyl H 1116 5-F CFT rCH2CH2- -isoxazolyl H 1117 5-F CF3 CH2CH2-2- imidazolyl K 1118 5-F CF3 C = C-cycPr H3 1119 5-F CF3 C = C-Ph CK3 1120 5-F CF3 C = C-2-pyridyl c? 3 1121 5-F CF3 C = C-3-pyridyl CH3 1122 5-F CF3 C = C-4-pyridyl CH3 1123 5-F CF3 C = C-2-: furanyl CH3 1124 5-F CF3 C = C-3-.furanyl CH3 1125 5-F CF3 C = C-2-thienyl CH3 1126 5-F CF3 C = C-3-thienyl CH3 1127 5-F CF3 C = C-cycPr CH3 1128 5-F CF3 C = C-Ph CK3 1129 5-F CF3 C = C-2- -pyridyl CK3 1130 5-F CF3 C = C-3 -. "Pyridyl CH3 1131 5-F CF3 C = C-4-pyridyl CH3 1132 5-F CF3 C = C-2- furanyl CH3 1133 5-F CF3 C = C-3-furanyl CH3 1134 5-F CF2 C = C-2-1 ienyl CH3 1135 5-F CF3 C = C-3-tthienyl CH3 1136 5-F CF3 CH2CH2-cycPr CH3 1137 5-F CF3 CH2CH2-Ph CH3 1138 5-F CF3 CH2CH2-2-pyridyl CH3 1139 5-F CF3 CH2CK2-3-pyridyl CH3 1140 5-F CF3 CH2CH2- -'pyridyl CH3 1141 5-F CF3 CH2CH2-2-furani? O CH3 1142 5-F CF3 CH2CH2-3-f ranny CH3 1143 5-F CF3 CH2CH2-2-thienyl CH3 1144 5-F CF3 CH2CH2-3- thienyl CH3 1145 5-F CF3 C = C-cycPr CH2CH3 1146 5-F CF3 OC-Ph CH2CH3 1147 5-F CF3 CEC-2-pyridyl CH2CH3 1148 5-F CF3 CsC-3-.pyridyl CH2CH3 1149 5-F CF3 C = C-4-pyridyl CH2CH3 1150 5-F CF3 C = C-2- furanyl CH2CH3 CN rH ro ro ro ro ro r ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro ro Ul Ul Ul U Ul Ui Ul Ui Ul Ul U Ul U? Ul Ui U, Ui Ui U Ul U U U U U, U U U U U U U U U U U U U U U U U U U U U? ? u U U U U U U U U U U C U U U U Ul Ul Ul ul Ul Ul Ul Ul Ul Ul Ul Ul Ul Ui Ui Ui u. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Ul Ul Ul Un Uln Ul Ul ul Ul Ul l ui tn m tn l tH C r ^ ^ i ^ r ^ 8 si Or you rN ^ tn to r ^? if O rH r ^ O x- \ CN ro "» u? n?? u3 to to D io o to t? o? or ~ r ^ r ^ r ^ r ^ r ^ r ^ r-r??? CO CO CO CO CO 1-l rH rH rl H r I H H r H H H H r H r H H r H r H r H H r H H r H r H H r r r H H r H H H H H H H H H H H H H H r r r r r r H r H H H H r r r HH rH HH rl H l 1185 5-Cl, 6-F CF3 C = C-4-.pyridyl H 1186 5-Cl, 6-F CF3 C = C-2- 'furanyl H 1187 5-Cl, 6-F CF3 C = C-3: furanyl K 1188 5-Cl, 6-F CF3 C = C-2-thienyl K 1189 5-Cl, 6-F CF3 C = C-3-thienyl? 1190 5-Cl, 6-F CF3 CH2CK-cycPr K 1191 5-Cl, 6-F CF3 CH2CK2-Ph H 1192 5-Cl, 6-F CF3 CH2CH2-2- pyridyl K 1193 5-Cl, 6-F CF3 CH2CH2-3-pyridyl H 1194 5-Cl, 6-F CF3 CH2CH2-4-pyridyl H 1195 5-Cl, 6-F CF3 CH2CH2-2-furanyl H 1196 5-Cl, 6-F CF3 CH2CH2-3- furanyl H 1197 5-Cl, 6-F CF3 CH2CK2-2- thienyl H 1198 5-Cl, 6-F CF3 CH2CK2-3- 'thienyl H 1199 5-Cl, 6-F CF3 CsC-cycPr CH3 1200 5-Cl, 6-F CF3 OeC-Ph CH3 1201 5-Cl, 6-F CF3 C ^ C-2-pyridyl CH3 1202 5-Cl, 6-F CF3 CsC-3-pyridyl CH3 1203 5-Cl, 6-F CF3 Cs-C-4-pyridyl CH3 1204 5-Cl, 6-F CF3 CsC-2- furanyl CH3 1205 5-Cl, 6-F CF3 C = C-3-furanyl CH3 1206 5-Cl, 6-F CF3 C = C-2-thienyl C 3 1207 5-Cl, 6-F CF3 C «C-3-thienyl CH3 1208 5-Cl, 6-F CF3 C = C-cycPr CH3 1209 5-Cl, 6-F CF3 C = C-Ph CH3 1210 5-Cl, 6-F CF3 C = C-2- 'pyridyl CH3 1211 5-Cl, 6-F CF3 C = C-3-pyridyl CH3 1212 5-Cl, 6-F CF3 C = C-4-pyridyl CH3 1213 5-Cl, 6-F CF3 C = C-2-. furanyl CH3 1214 5-Cl, 6-F CF3 C = C-3-furanyl CH3 1215 5-Cl, 6-F CF3 C = C-2-thienyl CH3 1216 5-Cl, 6-F CF2 C = C-3-thienyl CH3 1217 5-Cl, 6-F CF3 CH2CH2-c and Pr CH3 1218 5-Cl, 6-F CF3 CH2CH-Ph CH3 1219 5-Cl, 6-F CF3 CH2CH2-2- pyridyl CK3 1220 5-Cl, 6-F CF3 CH CH2-3-.pindyl CK3 1221 5-Cl, 6-F CF3 CH2CK2-4- pyridyl CH3 1222 5-Cl, 6-F CF3 CH2 C? ' 2-:: furanyl CH3 1223 5-Cl, 6-F CF3 CHCH2-3- furanyl CH3 1224 5-Cl, 6-F CF3 CH2CH2-2- thienyl CK3 1225 5-Cl, 6-F CF3 CH2CK2-3- thienyl CH3 1226 5-F, 6-Cl CF3 C = C-cycPr H 1227 5-F, 6-Cl CF3 CsC-Ph K 1228 5-F, 6-Cl CF3 C = C-2-pyridyl H 1229 5-F, 6-Cl CF3 C = C-3-pyridyl H 1230 5-F, 6-Cl CF3 C = C-4-pyridyl K 1231 5-F, 6-Cl CF3 C = C-2-furanyl H 1232 5-F, 6-Cl CF3 C = C-3-furanyl H 1233 5-F, 6-Cl CF3 C = C-2-thienyl H 1234 5-F, 6-Cl CF3 CsC-3-thienyl H 1235 5-F, 6-Cl CF3 C = C-cycPr H 1236 5-F, 6-Cl CF3 C = C-Ph H 1237 5-F, 6-Cl CF3 C = C-2-pyridyl H 1238 5-F, 6-Cl CF3 C = C-3-pyridyl H 1239 5-F, 6-Cl CF3 C = c-4-pyridyl H 1240 5-F, 6-Cl CF3 C = C-2- furanyl H 1241 5-F, 6-Cl CF3 C = C-3-furanyl H 1242 5-F, 6-Cl CF3 C = C-2-thienyl H 1243 5-F, 6-Cl CF3 C = C-3-thienyl H 1244 5-F, 6-Cl CF3 CH2CH2-cycPr H 1245 5-F, 6-Cl CF3 CH2CH2-Ph H 1246 5-F, 6-Cl CF3 CH2CH2- - iridyl H 1247 5-F, 6-Cl CF3 CH2CK -3-: pyridyl H 1248 5-F, 6-Cl CF3 CH2CH2-4-pyridyl H 1249 5-F, 6-Cl CF3 CH2CH2-2 furanyl H 1250 5-F, 6-Cl CF3 CH2CH2-3- -furanyl H 1251 5-F, 6-Cl CF3 CH2CH-2-thienyl H 1252 5-F, 6-Cl CF 3 CH 2 CH 2 3 -thienyl H 1253 5-F, 6-Cl CF 3 C = C-cycPr c 3 1254 5-F, 6-Cl CF3 C = C-Ph c? 3 1255 5-F, 6-Cl CF3 c = C-2-pyridine CH3 1256 5-F, 6-Cl CF3 C = C-3-pyridyl c? 3 1257 5-F, 6-Cl CF3 C = C-4-pyridyl CH3 1258 5-F, 6-Cl CF3 C = C-2- furanyl c? 3 1259 5-F, 6-Cl CF 3 C = C-3-furanyl c 3 1260 5-F, 6-Cl CF3 C = C-2-thienyl CH3 1261 5-F, 6-Cl CF3 C = C-3-thienyl CH3 1262 5-F, 6-Cl CF3 C = C-cycPr CH3 1263 5-F, 6-Cl CF3 C = C-Ph CH3 1264 5-F, 6-Cl CF3 C = C-2-pyridyl CH3 1265 5-F, 6-Cl CF3 C = C-3-pyridyl CH3 1266 5-F, 6-Cl CF3 C = C-4-pyridyl CH3 1267 5-F, 6-Cl CF3 C = C-2- furanyl CH3 1268 5-F, 6-Cl CF3 C = C-3-furanyl CH3 1269 5-F, 6-Cl CF3 C = C-2-thienylb CH3 1270 5-F, 6-Cl CF3 C = C-3-thienyl CH3 1271 5-F, 6-Cl CF3 CH2CH -cycPr CH3 1272 5-F, 6-Cl CF3 CH2CH2-Ph CH3 1273 5-F, 6-Cl CF3 CH2CH2-2-pitidyl CH3 1274 5-F, 6-Cl CF3 CH2CK2-3-pyridyl CH3 1275 5-F.6-Cl CF3 CH2CK2- -pyridyl CH3 1276 5-F, 6-Cl CF3 CH2 H2-2-furanyl CH3 1277 5-F, 6-Cl CF3 CH2CH2-3-furanyl CH3 1278 5-F, 6-Cl CF3 CH2 H2-2-thienyl CH3 1279 5-F, 6-Cl CF3 CH2CH2-3-thienyl CH3 1280 6-C1.8-F CF3 C = C-cycPr H 1281 6-C1.8-F CF3 C = C-Ph H 1282 6-Cl, 8-F CF3 C = C-2- p ± ridyl H 1283 6-C1.8-F CF3 C-C-3-pyridyl H 1284 6-C1.8-F CF3 C = C-4-pyridyl H 1285 6-C1.8-F CF3 C = C-2 - furani? 0 H 1286 6-C1.8-F CF3 C = C-3-furanyl H H H H M H H H H H H H H H M H H H l- > H H H H M J LO Lo Lo OJ OJ U > The OJ OJ Ul OJ l LO J OJ 00 LO LO LO Ul Ul (JL L? Lp L? Lp? X_. Ta. »Rf rfa» * > e * í- * - OJ LO to to tt? C to l to o to co -o cn L? ** OJ to O «5 CO in Ul ip» LO to n ^ n'il n ^ n ^ ohi q ^ nrj ohl ol oí n n n n n nj ni T i n rij oj oi o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o r o 33 33 33 33 X 33 33 33 33 33 33 33 33 33 3: 3 33 3: 3: 1355 6-CH3 CF CH2CH2-3-pyridyl K 1356 '6-CK3 CF3 CH CH - -pyridyl? 1357 6-CK3 CF3 CH2CH2-2- furanyl K 1358 6-CH3 CF3 CH2CK2-3- furanyl H 1359 6-CH3 CF3 CH2CH2-2-thienyl K 1360 6-CK3 CF3 CH2CH2-3-thienyl K 1361 6-CH3 CF3 C = C-cycPr CH3 1362 6-CH3 CF3 C = C-Ph CH3 1363 6-CK3 CF3 c = c-2-pyridyl CH3 1364 6-CK3 CF3 c = c-3-pyridyl CH 1365 6-CK3 CF3 c = c-4-pyridyl CH3 1366 6-CK3 CF3 a = c-2- furanyl CH3 1367 6-CK3 CF3 c = c-3-furanlío CH3 1368 6-CK3 CF3 C? C-2- ienyl CH3 1369 6-CK3 CF3? Sc-3- thienyl CH3 1370 6-CK3 CF3 C = C-cycPr CH3 1371 6-CH3 CF3 C = C-Ph CH3 1372 6-CH3 CF3 c = c-2-.pyridyl CH3 1373 6-CH3 CF3 c = c-3-pyridyl CH3 1374 6-CH3 CF3 C = c-4-pyridyl CH3 1375 6-CH3 CF3 c = c-2- furanyl CH3 1376 6-CH3 CF3 c = c-3-furanyl CH3 1377 6-CH3 CF3 C = C-2- thienyl CH3 1378 6-CH3 CF3 c = c-3-thienyl CH3 1379 6-CH3 CF3 CH2CH2-cycPr CH3 1380 6-CH3 CF3 CH2CH2-Ph CH3 1381 6-CK3 CF3 CH2CH2-2- pyridyl CH3 1382 6-CK3 CF3 CH2CH2-3-pyridyl CH3 1383 6-CK3 CF3 CH2CH2-4- pyridyl CH3 1384 6-CK3 CF3 CH2CH2-2- furanyl CH3 1385 6-CH3 CF3 CH2Ch'2-3-furanyl CH3 1386 6-CH3 CF3 CH2CH2-2- ienyl CH3 1387 6-CH3 CF3 CH2CH2-3- thienyl CH3 1388 6-COCK3 CF3! -cycPr H 1389. 6-COCH;, CF3 C = C-Ph H 1390 6-COCK3 CF3 c = c-2-pyridyl K 1391 6-COCK3 CF3 c = c-3 pyridium V 1392 6-COCH3 CF3 c = e-4-pyridyl K 1393 6-COCK3 CF3 c = c-2-furanyl K 1394 6-COCK3 CF3 c = c-3-furanyl H 1395 6-COCK3 CF3 c = c-2-thienyl H 1396 6-COCH3 CF3 c = c-3-thienyl H 1397 6- H CF3 C = C-cycPr H 1398 6-NK2 CF3 C = C-Ph H 1399 6-NH2 CF3 c = c-2-pyrocarphyl H 1400 6-NH2 CF3 c = c-3-pyridyl H 1401 6-NH2 CF3 c = c-4-pyridyl H 1402 6-NH2 CF3 c = c-2-furanyl H 1403 6- H2 CF3 cs-c-3-furanyl H 1408 6-NMe2 CF3 Cßc-2-pyridyl H 1409 6- Me2 CF3? -3-pyridyl H 1410 6-MMT2 CF3 csc-4-pyridyl H 1411 6- Me2 CF3 CsC-2-furanyl H 1412 6-NMT2 CF3 c = c-3-furanyl "or H 1413 6-NMe2 CF3 c = c-2-thienyl H 1414 6-NMT2 CF3 or = c-3-thienyl H 1415 7-Cl CF3 C = € -cycPr H 1416 7-Cl CF3 CeC-Ph H 1417 7-Cl CF3 c = c-2-pyri: say H 1418 7-Cl CF3 c = c-3-pyridyl H 1419 7-Cl CF3 CHC-4-pyridyl H 1420 7-Cl CF3 C € -2-furañilo H 1421 7-Cl CF3 C? C-3-furanyl H 1422 7-Cl CF3 c = c-2-thienyl H 1423 7-Cl CF3 c = c-3-thienyl? 1424 5,6-OCK20-CF3 C = C-cycPr ** 1425 5,6-OCH20-CF3 C = CCHCH2OK H 1426 5,6-OCH20-CF3 C = C-CH (OH) Me H 1427 5,6-OCH20-CF3 C = C-Ph? 1428 5,6-OCH20-CF3 C = C- (2-Cl) Ph H 1429 5.6-OCH20-CF3 C = C- (3-Cl) Ph? 1430 5,6-OCH20-CF3 C = C- (4-Cl) Ph H 1431 5.6-0CH2O- CF3 CsC- (2-F) Ph? 1432 5,6-OCH20-CF3 C = C- (3-F) Ph K 1433 5,6-OCH20-CF3 C = C- (4-F) Ph K 1434 5,6-OCH20-CF3 C = C- (2-OH) Ph H 1435 5,6-OCH20-CF3 C = C- (3-OH) Ph H 1436 5.6-0CH2O- CF3 C = C- (4-OH) Ph H 1437 5.6-OCH20-CF3 CeC-. { 2-OMe) Ph H 1438 5,6-OCH20-CF3 CsC- (3-OMe) Ph H 1439 5,6-OCH20-CF3 CßC- (4-OMe) Ph H 1440 5.6-0CH2O- CF3 C «C- (2-CN) Ph H 1441 5.6-0CH2O- CF3 Cßc- (3-CN) Ph H 1442 5,6-OCH20-CF3 CsC- (4-CN) Ph H 1443 5,6-OCH20-CF3 CsC- (2-N02) Ph H 1444 5.6-OCH20-CF3 C = C- (3-N02) Ph H 1445 5,6-OCH0- CF3 C = C- (4-N0) Ph H 1446 5,6-OCH20-CF3 C = C- (2-NH2) Ph H 1447 5.6-OCH20-CF3 C = C- (3-NH2) Ph H 1448 5,6-OCH2C-CF3 C = C- (4- H2) Ph H 1449 5,6-OCH20-CF3 OsC- (2-NMe2) Ph H 1450 5,6-OCH0-CF3 GsC- (3-NMe2) Ph H 1451 5,6-OCH20-CF2 CsC- (4-NMe2) Ph H 1452 5,6-OCH20-CF3 csz-2-pyridyl H 1453 5,6-OCH20-CF3? SC-2-pyridyl H 1454 5, 6-OCH0-CF3 c = c-3-pyridyl H 1455 5,6-OCH20-CF3 os-4-pyridyl K 1456 5,6-OCH20-CF3 csc-2- furanyl? 1457 5, 6-OCH20-CF3 c = c-3-furanyl or 1458 5.6-0CH20- CF3 c = c-2-thienyl H 1459 5, 6-0CH20-CF3 c = c-3-thienyl H 1460 5.6-0CH20-CF3 c = c-2-oxazolyl K 1461 5, 6-0CH20-CF3 c = c-2-thiazole ilo K 1462 5,6-OCH20-CF3 c = c-4-isoxazolyl K 1463 5,6-OCH20-CF3 H c = c-2-imidazolyl 1464 6-COCH3 CF3 C = C-cycPr K 1465 6-COCH3 CF3 C = C-Ph H 1466 6-COCH3 CF3 c = c-2- pyridjlo u 1467 6-COCH3 CF3 c = c-3-pyridyl H 1468 6-COCH3 CF3 c = c-4-pyridyl H 1469 6-COCH3 CF3 c = c-2- furanyl 1470 6-COCH3 CF3 c = c-3-furanyl H 1471 6-COCH3 CF3 c = c-2-thienyl H 1472 6-COCH3 CF3 c = c-3-thienyl H 1473 6-NK2 CF3 C = C-cycPr H 1474 6-NH2 CF3 C = C-Ph H 1475 6-NH2 CF3 C = C-2-: pyridjlo H 1476 6-NH2 CF3 C = c-3- ^ iridyl H 1477 6-NH2 CF3 C = c-4-pyridyl H 1478 6-NH2 CF3 c = c-2- furanyl H 1479 6-NH2 CF3 c = c-3-furanyl H 1480 6-NH2 CF3 c = c-2-thienyl H 1481 6- H2 CF3 c = C-3-thienyl H 1482 6-MMß2 CF3 C = C-cycPr H 1483 6-NMe2 CF3 C = C-Ph H 1484 6-NMe2 CF3 c = c-2-pyridyl H 1485 6-NM? 2 CF3 C = C-3-pyridyl? H 1486 6-NMT2 CF3 C = c-4-pyridyl H 1487 6-NMe2 CF3 c = C-2- furanyl H 1488 6-NMß2 CF3 c = c-3-furanyl H 1489 6-NMe2 CF3 c = c-2-thienyl H 1490 6- MT2 CF3 c = c-3-thienyl H 1491. 7-Cl CF3 C = C-cycPr H 1492 7-Cl CF3 C = C-Ph K 1493 7-Cl CF3 c = c-2-pyridyl K 1494 7-Cl CF3 c = c-3-pyridyl K 1495 7-Cl CF3 c = c-4-pyridyl K 1497 7-Cl CF3 c = c-3-furanyl K 1498 7-Cl CF3 c = c-2-thienyl H 1499 7-Cl CF3 c = c-3-thienyl H 1500 5,6-OCH20- CF3 C = C-cycPr H 1501 5, 6-OCH20-CF3 C = CCK2CH20H H 1502 5, 6-OCH0-CF3 C = C-CH (OH) Me H 1503 5,6-OCH20-CF3 C = C-Ph H 1504 5.6-0CH20- CF3 C = C- (2-Cl) Ph H 1505 5.6-0CH20- CF3 C = C-. { 3-Cl) Ph H 1506 5.6-0CH20- CF3 C = C- (4-Cl) Ph H 1507 5.6-0CH20- CF3 C = C- (2-F) Ph H 1508 5,6-0CH0- CF3 OC- (3-F) Ph H 1509 5.6-0CH20- CF3 C = C- (4-F) Ph H 1510 5.6-0CH20- CF3 C = C- (2-OH) Ph H 1511 5, 6-0CH20- CF3 C = C- (3-OH) Ph H 1512 5.6-0CH20- CF3 C = C- (4-OH) Ph H 1513 5.6-0CH20- CF3 C = C- (2-0Me) Ph H 1514 5.6-0CH20- CF3 C = C- (3-0Me) Ph H 1515 5,6-0CH0- CF3 C = C- (4-OMe) Ph H 1516 5.6-0CH20- CF3 C = C- (2-C) Ph H 1517 5, 6-0CH20- CF3 C = C- (3-C) Ph H 1518 5.6-0CH20- CF3 C = C- (4-C) Ph H 1519 -. 1519 - 5,6-0CH20- CF3 C = C- (2-N02) Ph H 1520 5,6-OCH20-CF3 C = C- (3-N02) Ph H 1521 5,6-OCH20-CF3 C = C- (4-N02) Ph H 1522 5.6-OCH20-CF3 C = C- (2-I> JH2) Ph H 1523 5.6-0CH20- CF3 C = C- (3- H2) Ph H 1524 5.6-0CK20- CF3 C = C- (4-NH2) Ph H 1525- 5,6-OCH20-CF3 C = C- (2- Me2) Ph H 1526 5,6-OCH0-CF3 C = C- (3-NMe2) Ph H 1527 5, 6-OCH20-CF3 C = C- (4-NMe2) Ph H 1528 5,6-OCH20-CF3 c = c-2-pyridyl H 1529 5, 6-OCH20-CF3 c = c-2-pyridyl H 1530 5.6-OCH20-CF3 C = c-3-pyridyl H 1531 5, 6-OCH20-CF3 c = c-4-pyridyl H 1532 5, 6-OCH20-CF3 c = c-2-: furanyl H 1533 5, 6-0CH2O-CF3 c = c-3-furanyl H 1534 5, 6-OCH2O-CF3 c = c-2-thienyl H 1535 5,6-OCH20-CF3 c = c-3-thienyl H 1536 5, 6-OCH20-CF3 c = c-2-oxazolyl H 1537 5,6-OCH20-CF3 c = c-2-thiazophil H 1538 5, 6-OCH 0-CF3 c = c-4-isoxazolyl H 1539 5, 6-OCH2O-CF3 c = c-2-imidazolyl H 1540 5.6-0CH2O- CF3 CH2CH2-cycPr H 1541 5,6-OCH20-CF3 CH2CH2CH2CH2OH H 1542 5,6-OCH20-CF3 CH2CH2-CH (OH) Me H 1543 5,6-OCH20-CF3 CH2CH2Ph H 1544 5.6-0CH2O- CF3 CH2CH2- (2-Cl) Ph H 1545 5,6-OCH20-CF3 CH2CH2- (3-Cl) Ph H 1546 S, 6-OCH20-CF3 CHCH2- (4-Cl) Ph H 1547 5,6-OCH0- CF3 CH2CH2- (2-F) Ph H 1548 5,6-OCH20-CF3 CH2CH2- (3-F) Ph H 1549 5,6-OCH20-CF3 CH2CH2- (4-F) Ph H 1550 5,6-OCH20-CF3 CH2CH2- (2-OH) Ph H 1551 5,6-OCH20-CF3 CH2CH2- (3-OH) Ph H 1552 5,6-OCH20-CF3 CH2CH2- (4-OH) Ph H 1553 5,6-OCH20-CF3 CH2CH2- (2-OMe) Ph H 1554 5,6-OCH2? - CF3 CH2CH2- (3-OMe) Ph H 1555 5,6-OCH20-CF3 CH2CH2- (4-OMe) Ph H 1556 5,6-OCH20-CF3 CH2CH2- (2-C) Ph H 1557 5,6-OCH20-CF3 CK2CH2- (3-C) Ph H 1558 5.6-0CH2O- CF3 CK2CK2- (4-CN) Ph H M H H H H H H r-1 r- 'H H H H H H H H H H H H H L? L? L? L? L? L? L? L? L? Lp L? L? L? 1/1? L? L? L? L? L? L? L? L? L? ? ? L? Lp L? L? Ul L? L? p LO co oo co 00 oo co co co 03 oo • o -o in C? ? yes or > in C? C? yes? t o LO oo • o n Lp OJ to o 00 -o C? L? l to o vo co -o L? LO NJ r-1 o. to o hi o'tj oj ohi o ol o o o o o o o o o o o o o o o o o o o o o o o o o o o o n o o n o o n o o o o o o o o o o o r r \ 1 \ * n ^ ^ "1 H1 'liirí oh oí nrrj ohí ohl nrrJ l o'Tl h] h) hl to ui to u > u > u > to? o what? OJ S 3 S S 0 S S S S S S S S 33 33 K 33 33 33 33 33 33 33 33 33 33 33 33 33 33 3: 3; 3: 1593 5,6-OCH20-CF3 c = c-2-furanyl CH3 1594 5,6-OCH20-CF3 c = c-3-furanyl c? 3 1595 5,6-OCH 20 -FC 3 c = c-2-thienyl c 3 1596 5.6-OCH20-CF3 c = c-3-thienyl c? 3 1597 5,6-OCH20-CF3 CH2CH2-cycPr CH3 1598 5,6-OCH20-CF3 CH2CH2-Ph CH3 1599 5,6-OCH20-CF3 CH2CH2-2- pyridyl c? 3 1600 5,6-OCH20- CF3 CH2CH2-3- pyridium lo CH3 1601 5,6-OCH20- CF3 CH2CK2-4- pjrid.ilo CH3 1602 5,6-OCH20-CF3 CH2CK2-2- furanyl CH3 1603 5,6-OCH20-CF3 CH2CH2-3-furanyl CH3 1604 5.6-OCH20-CF3 CH2CH2-2- thienylu. CH3 1605 5,6-OCH20- CF3 CH2CH2-3- thienyl CH3 1606 5,6-OCH20-CF3 OC-cycPr CHCH3 1607 5,6-OCH20-CF3 C = C-Ph CH2CH3 1608 5,6-OCH0-CF3 C? C-2-pyridyl CH2CH3 1609 5,6-OCH20-CF3 Cßc-3-pyridyl CH2CH3 1610 5,6-OCH20- CF3 Cßc-4-pyridyl CH2CH3 1611 5,6-OCH20-CF3 or @ -2-furanyl CH2CH3 1612 '5,6-OCH20-CF3 asc-3-furanyl CH2CH3 1613 5,6-OCH0-CF3 c * c-2-thienyl CH2CH3 1614 5,6-OCH 0-CF3 c = c-3-thienyl CH 2 CH 3 1615 5,6-OCH20-CF3 C = C-cycPr CH2CH3 1616 5, 6-OCH2O- CF C = C-Ph CH2CH3 1617 5,6-OCH0-CF3 c = c-2-pyridyl CH2CH3 1618 5.6-0CH20- CF3 C = C-3-pyridyl CH2CH3 1619 5,6-0CH20- CF3 CH2CH3 1620 5,6-0CH0- CF3 c = c-2- furanyl CHCH3 1621 5.6-0CH20- CF3 c = c-3-furanyl CH2CH3 1622 5.6-0CH20- CF3 c = c-2-thienyl CHCH3 1623 5,6-OCH2? - CF3 c = c-3-thienyl CH2CH3 1624 5,6-OCK20- CF3 CH2CH2- ycPr CH2CH3 1625 5,6-OCK20-CF3 CKCH2-Ph CH2CH3 1626 5,6-OCH20-CF3 CH2CH2-2- pyridyl CH2CH3 1627. 5, 6-OCH20-CF3 CK2CH2-3 -pÍ rÍd Í l o CK2CK3 1628 5,6-OCH20-CF3 CK2CH2-4-PÍrÍdÍ lo CK2CK3 1629 5.6-OCH2O-CF3 c? 2c? 2-2-furani 10 CE2CE2 1630 5 (6-OCH2O-CF3 c? 2c? 2-3-.furani lo CH2CK3 1631 5,6-OCK20-CF3 CH2CH2-2-thienyl CH2CK3 1632 5,6-OCH0-CF3 CH2CH2-3-thieni CK2CH3 Unless otherwise indicated, stereochemistry is (+/-).
Ex. # P.3 R- R2 R8 1 6-Cl CF3 C = C-Pr H 2 6-Cl CF3 C = C-Bu H 3 6-Cl CF3 O = C-iBu H 4 6-Cl CF3 CsKT-tBu H 6-Cl CF3 C = C-Me H 6 6-Cl CF3 CH2CK2CH2CH2CH3 H 7 6-Cl CF3 CH2CH2CH. { CH3) H 8 6-Cl CF3 CH2CH2CH2CH3 H 9 6-Cl CF3 CH2CH CH3 H 6-Cl CF3 CH CH2-tBu H 11 6-Cl CF3 CH CesC-CH3 H 12 6-Cl CF3 CH2C «C-CH2CH3 H 13 6-Cl CF3 C? C-iPr CH3 14 6-Cl CF3 CsC-Pr CH3 6-Cl CF3 CsC-Bu CH3 16 6-Cl CF3 CsC-iBu CH3 17 6-Cl CF3 CssC-tBu CH3 18 6-Cl CF3 Cec-Et CH3 19 6-Cl CF3 OsC-Me CH3 6-Cl CF3 CH2C = C-CH3 CH3 21 6-Cl CF3 CH2C = C-CH2CH3 CH3 22 6-Cl CF 3 CH 2 CH 2 CH (CH 3) 2 CH 3 3 6-Cl CF 3 CH 2 CH 2 CH 2 CH 3 CH 3 4 6-Cl CF 3 CH 2 CH 2 CH 3 CH 3 5-Cl CF 3 CH 2 CH 2 - Bu CH 3 6 6-Cl CF 3 CsC-iPr CH 2 CH 3 7 6-Cl CF 3 CsC- Pr CH 2 CH 3 8 6-Cl CF 3 CsC-Bu CH 2 CH 3 CCHH 22CCFH 3)) 22 CH 2 CH 3 63 6 -MeO CF 3 CK 2 CH 2 CH (CH 3) 2 c 3 64 6 -MeO CF3 CH2CH CK2CH3 CK3 65 6 -MeO CF3 CH2CH2CK3 CH3 66 6 -MeO CF3 CH2CK2-tBu CK3 67 6 -MeO CF3 C = C-iPr CH2CE3 68 6 -MeO CF3 C = C-Pr CH2CH3 69 6 -MeO CF3 C = C-Bu CH2CH3 70 6 -MeO CF3 G = C-iBu CH2CH3 71 6 -MeO CF3 C = C-tBu CH2CK3 72 6 -MeO CF3 C = C-Et CH2CK3 73 6 -MeO CF3 C = C-Me CH2CH3 74 6 -MeO CF3 CH C = C-CH3 CH2CK3 75 6 -MeO CF3 CH2C = C-CH2CH3 CH2CH3 76 6 -MeO CF3 CH2CH2CH (CH3) 2 CH2CK3 77 6 -MeO CF3 CH2CH2CH2CH3 CH2CH3 78 6 -MeO CF3 CH2CH2CH3 CH2CH3 79 6 -MeO CF3 CH2CH2-tBu CH2CH3 80 5,6-diF CF3 OC-Pr H 82 5,6-diF CF3 C «C-iBu H 83 5,6-diF CF3 OsC-tBu H 84 5,6-diF CF3 C = C-Me H 85 5.6-diF CF3 CH2C = C-CH3 H 86 5.6-diF CF3 CH2CsC-CH2CH3 H 87 5,6-diF CF3 CH2CH2CH2CH2CH3 H 88 5,6-diF CF3 CH2CK2? Í3 H 89 5,6-diF CF3 CH2CH2-tBu H 90 5,6-diF CF3 C = C-iPr CH3 91 5, 6-diF CF3 C = C-Pr CH3 92 5,6-diF CF3 Cs = C-Bu CH3 93 5,6-diF CF3 CeC-iBu CH3 94 5,6-diF CF3 C = C-tBu CH3 95 5,6-diF CF3 OeC-? T CH3 96 5,6-diF CF3 OsC-Me CH 3 H H μo H H H H H H H H | _ > μj μi H H H M to LO Ul tO to t o t t t T o o o o o s o o o o o o o o o o o o o o o o o o o o o o o o o L? i J t O to 00 C? Lp Ul tO O LO CD cn L? C- Ul t O to co -o L? L? W L? L? L? I L? L? L? an L? L? L? L? L? L? C? C? C? C? C? C? C? C? C? C? C? n C? C? C? s > C? P, o. P- P. p. Pi Pi I "- o. I P. - tJ H- o. I Pi Pi P. r &g - H- r-» 1 11 1J 'I »1 hl • I' ll 11" 3 • 1 11 1J hl "1 oj nhí ol oh oh ohl oí ohí oí ní oí ohl ol oi olí olíí ohl ohl ohí ohí ol oí ohi o ol oh o ol oí ohí oitl oi noh) n 1) 131 6-F CF3 C = C-Et CH3 132 6-F C? 3 CsC-Me CH3 133 6-F CF3 CH C = C-CH3 CH3 134 6-F CF3 CH2CsC-CH2CH3 c? 3 135 6-F CF3 CH2CH2CH (CK3) 2 CK3 136 6-F CF3 CH2CH2CK2CH3 CH3 137 6-F CF3 CH2CH2CH3 CH3 138 6-F CF3 CH2CK-tBu CH3 139 6-F CF3 C = C-iPr CH2CK3 140 6-F CF3 C = -Pr CH2CE3 141 6-F CF3 CsC-Bu CH2CK3 142 6-F CF3 CEC-ÍBU CH2CK3 143 6-F CF3 C = C-tBu CH2CH3 144 6-F CF3 CsC-Et CH2CK3 145 6-F CF3 CsC-Me CH2CH3 146 6-F CF3 CH2CsC-CH3 CH2CH3 147 6-F CF3 CH2CßC-CH2CH3 CH2CH3 148 6-F CF3 CH2CH2CH (CH3) 2 CHCK3 149 6-F CF3 CH2CH2CH2CH3 CH2CH3 150 6-F CF3 CH2CHCH3 CH2CH3 151 6-F CF3 CH2CH2-tBu CH2CH3 152 5-Cl CF3 C = C-iPr H 153 5-Cl CF3 CeC-Pr H 154 5-Cl CF3 C = C-Bu H 155 5-Cl CF3 C = C-iBu H 156 5-Cl CF3 C = C-tBu H 157 5-Cl CF3 C = C-Et H 158 5-Cl CF3 C = C-Me H 159 5-Cl CF3 CH2C = C-CH3 H 160 5-Cl CF3 CH2CsC-CH2CH3 H 161 5-Cl CF3 CHCH2CH2CH2CH3 H 162 5-Cl CF3 CH2CH2CH (CH3) 2 H 163 5-Cl CF3 CH2CH2CH2CH3 H 164 5-Cl CF3 CH2CK2CH3 H 165 5-Cl CF3 CH CH2-tBu K 199 - 5-F CF3 CH2C = C-CH3 H 200 5-F CF3 CH2C = C-CH CH3 H 201 5-F CF3 CK2 CH2 CH2 CH2 CH3 H 202 5-F CF3 CK2CH2CH (CH3) 2 H 203 5-F CF3 CH CH2CH2CH3 H 204 5-F CF3 CH2CH2CH3 H 205 5-F CF3 CH2CK2-tBu H 206 5-F CF3 C = C-iPr CH3 207 5-F CF3 C = C-Pr CH3 208 5-F CF3 C = C-Bu CH3 209 5-F CF3 C = C-iBu CH3 210 5-F CF3 C = C-tBu CH3 211 5-F CF3 C = C-Et CH3 212 5-F CF3 CeC-Me CH3 213 5-F CF3 CH2CEC-CH3 CH3 214 5-F CF3 CH2CeC-CH2CH3 CH3 215 5-F CF3 CH2CH2CH (CH3) 2 CH3 216 5-F CF3 CH2CH2CH2CH3 CH3 217 5-F CF3 CH2CH2CH3 CH3 218 5-F CF3 H2CH2- Bu CH3 219 5-F CF3 C * C-iPr CH2CH3 220 5-F CF3 CsC-Pr CH2CH3 221 5-F CF3 C = C-Bu CH2CH3 222 5-F CF3 CsC-iBu CH2CH3 223 5-F CF3 CEC-tBu CH2CH3 224 5-F CF3 CsC-Et CH2CH3 225 5-F CF3 C = C-Me CH2CH3 226 5-F CF3 CH2CsC-CH3 CH2CH3 227 5-F CF3 CH2C = C-CH2CH3 CH2CH3 228 5-F CF3 CH2CH2CH (CH3) 2 CH2CK3 229 5-F CF3 CH2CH2CH2CH3 CH CH3 230 5-F CF3 CH2CH2CH3 CH2CH3 231 5-F CF3 CH2CH2-tBu CH2CH3 232 5-Cl. 6-F CF3 C = C-iPr H 233 5-Cl, 6-F CF3 C = C- Pr w 234 5-Cl, 6-F CF3 C = C-Bu H 235 5-Cl, 6-F CF3 C = C-iBu K 236 5-Cl, 6-F CF3 C = C-tBu H 237 5-Cl, 6-F CF3 CsC-Et H 238 5-Cl, 6-F CF3 C = C-Me H 239 5-Cl, 6-F CF3 CH2C = C-CH3 H 240 5-Cl, 6-F CF3 CK2CsC-CK2CH3 H 241 5-Cl, 6-F CF 3 CH 2 CH 2 CH (CH 3) 2 H. 242 5-Cl, 6-F CF3 CH2CH2CH2CH3 H 243 5-Cl, 6-F CF3 CH2CH CK3 H 244 5-Cl, 6-F CF3 CH2CH2-tBu H 245 5-Cl, 6-F CF3 C = C-iPr CH3 246 5-Cl, 6-F CF3 CsC-Pr CH3 248 5-Cl, 6-F CF3 C C-ÍBU CH3 249 5-Cl, 6-F CF3 CeC-tBu CH3 260 6-C1.8-F CF3 c = c-Bu H 261 6-Cl, 8-F CF3 cse-iBu H 262 6-Cl, 8-F CF3 CsC-tBu H 263 6-C1.8-F CF3 CßC-Et H 264 6-C1.8-F CF3 CsC-Me H 265 6-C1.8-F C v_Fr3. CH2C = C-CH3 H 266 6-Cl, 8-F CF3 CH2C = C-CH CH3 H 10 Ul Ul t-J t u? LO? 00 W LO LO Ul Ul OJ OJ UJ OJ 00 LO J LO Ul J Ul UI Ul w 0J J LO Ul Ulto to (J Ul to M t M tO to t t--> MHHHHH ooooooooo it Ul) H o to O ^ J 01 L? * - J to LO ~ J C? Lp • Ul to H O LO co -J < ? Lp l. u > t M C? C? C? C? Ol (? 01 C? C? C? C? C? C? -o -J ~ J • J 1 1 1 1 1 1 1 C? C? C? Cr?? C? 1 1 1 1 1 1 1 C? C? C? C? C? C? C? C? C? 1 1 I I I 1 i i 1 O O O O O N n 1 1 1 1 1 1 I 1 1 1 n o o o § § Y o O O O t-i CD CD CD Ü Ü CD t n 8 o O n f) o 8 8 n a n a y a a m a t t M t m CD o t t a t a a? ao to t 8 or > tl or hj or hj n itl n hl o »tl p hj o hl nl ol n hl o»?) oí ol o hj n h) o hl o h] o hl ol n > ?) or h or h] or hl nil or h) or h) or h) or h) or hl or i? or hj or h) or h | Uf UJ UJ Lo ? 8 8? 88 ?? 88? 88 ?? 88? s? | g? s? i? i? »E» x * HI 35 m x x ¡3. K m SE m n Í? ? m TX tX x x ¡x e w m ^. O O Q O O O O O a a a a a a a a a 335 7 -Cl CF3 C = C-tBt K 336 7-Cl CF3 C = C-? T H 337 7 -Cl CF3 C = C-Me H * Unless otherwise indicated, stereochemistry is (+/-).
Utility The compounds of this invention possess inhibitory activity of the reverse transcriptase, in particular, inhibitory efficacy of HIV. The compounds of formula (I) possess inhibitory activity of HIV reverse transcriptase and are therefore useful as antiviral agents for the treatment of HIV infection and associated disorders. The compounds of formula (I) have inhibitory activity of HIV reverse transcriptase and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral or infectious growth is demonstrated in standard viral or infectious growth assays, for example, using the assay described below.
The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or waiting to be exposed to HIV. Thus, the compounds of the present invention can be used to inhibit HIV. present in a body fluid sample (eg, a serum or semen sample) that contains or is likely to contain or be exposed to HIV.
The compounds provided by this invention are also useful as reference or standard compounds for use in tests or assays to determine the ability of an agent to inhibit viral clonal replication and / or HIV reverse transcriptase, for example in a program of pharmaceutical resources. Thus, the compounds of the present invention can be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention can be provided in a commercial device or container for use as such a reference or standard compound.
Since the compounds of the present invention exhibit a specific action for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, the inhibition of reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention may be indicative of the presence of HIV reverse transcriptase and HIV virus.
As used herein, "μg" means microgram, "mg" means milligram, "g" means gram, "μL" means microliter, "mL" means milliliter, "L" means liter, "nM" means nanomolar, "μM" means micromolar, "mM" means millimolar, "M" means molar and "nm" means nanometer. "Sigma" is shown for the Sigma-Aldrich Corp. of San Luis, MO.
HIV RNA assay.
Transcriptionists RNA in vi tro and plasmids DNA.
Plasmid pDAB 72 containing both the gag and pol sequences of BH10 (bp 113-1816) cloned in PTZ 19R was prepared according to Erickson-Vii tañen et al. AIDS Res ea rch and Huma n Re trovi rus is 1989, 5, 577. The plasmid was linearized with bam Hl before the generation of RNA transcripts in vi t ro using the system II Riboprobe Gemini device (Promega) with T7 RNA polymerase . The synthesized RNA was purified by treatment with DNase-free RNase (Promega), extraction of phenol-chloroform, and ethanol precipitation. The RNA transcripts were dissolved in water, and stored at -70 ° C. The concentration of RNA was determined from A260 • Probes The biotinylated capture probes were purified by CLAP after synthesis in an Application Biosystems DNA synthesizer (Foster City, CA) by adding biotin from the 5 'end of the oligonucleotide, using Cocuzza's biotin-phosphoramidite ta, Te t. Le t t. 1989, 30, 6287. The biotinylated capture probe (5 -biotin-CTAGCTCCCTGCTTGCCCATACTA 3 ') complements nucleotides 889-912 of HXB2 and the biotinylated capture probe pol (5'-biot in-CCTATCATTTTTGGTTTCCAT 3') complemented nucleotides 2374-2395 of HXB2. Conjugated alkaline phosphatase oligonucleotides used as report probes were prepared by Syngene (San Diego, CA.). The pol reporter (5 'CTGTCTTACTTTGATAAAACCTC 3') was complemented to nucleotides 2403-2425 of HXB2. The gag report probe (5 'CCCAGTATTTGTCTACAGCCTTCT 3') was complemented to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Computer Group Sequence Analysis Software Package (Devereau Nu cli i Aci ds Res ea rch 1984, 1 2, 387). Reporting probes were prepared as 0.5 M stored in 2 x SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg / mL BSA. Biotinylated capture probes were prepared as 100 μM stored in water.
Streptavidin-coated plates: Streptavidin-coated plates were obtained from Du Pont Biotechnology Systems (Boston, MA).
Storage of cells and viruses The MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% calf fetus serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 nM L-glutamine and 50 μg / mL of gentamicin, all from Gibco. HIV-1 RF spread in MT-4 cells in the same medium. Batches of .virus were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at -70 ° C. The titers of HIV-1 (RF) infections stored were 1-3 x 10 ~ 7 PFU (plaque forming units) / mL measured as plaque assays in MT-2 cells (see below). Each aliquot of stored viruses used for infection was thawed only once.
To evaluate antiviral efficacy, the cells that were infected were subcultured one day before infection. On the day of infection, the cells were re-suspended at 5 x 10 5 cells / ml in RPMI 1640, 5% FCS for infection volumes or at 2 x 106 / ml in a Dulbecco's modified Eagles medium with 5% FCS for infection in plaques my croti t uladas. The viruses were added and the culture was continued for 3 days at 37 ° C.
HIV RNA assays The dissolved or purified RNA cells in 3 M or 5 M GED were mixed with 5 M GED and the capture probe at a final concentration of isothiocyanate guanidine 3 M and at a final oligonucleotide concentration of 30 nM. Hybridization was carried out in a sealed U-bottom tissue 96 culture plate (Nunc or Costar) for 16-20 hours at 37 ° C. The hybridization reactions of the RNA were diluted in three steps with deionized water to a final concentration of isocyanate guanidine of 1 M and the aliquots (150 μL) were transferred to streptavidin-coated microtitre plates. The ligation of the capture probe and the hybrid capture-RNA probe to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after the plates were washed 6 times with DuPont ELISA plate buffer (washing solution). phosphate buffered saline (PBS), 0.05% among 20). A second hybridization of test probe to the immobilized complex of the capture probe and to the hybridized RNA target was carried out in the washed streptavidin coated by adding 120 μl of a hybridization mixture containing 4 x SSC, 0.66% Triton x 100, 6.66 % of deionized formamide, 1 mg / mL of BSA and 5 nM of report probe. After annealing for one hour at 37 ° C, the plate was again washed 6 times. The activity of the immobilized alkaline phosphatase was detected by the addition of 100 μL of 0.2 nM of 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer solution d (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl2, 5 M dehydrated zinc acetate and 5 mM N-hydroxyethyl ethylene diamine triacetic acid). The plates were incubated at 37 ° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) excising at 365 nM.
Evaluation of the compound based on the microplate in MT-2 cells infected with HIV-1: The compounds to be evaluated were dissolved in DMSO and diluted in a de-culture medium twice for the highest concentration to be tested and a maximum DMSO concentration of 2%. Three additional dilutions of the compounds were run in a culture medium directly on the microtitre plates of U background (? Unc). After the dilution was complete, the MT-2 cells (50 μL) were added to a final concentration of 5 x 105 per mL (1 x 105 each). The cells were incubated with compounds for 30 minutes at 37 ° C in C02 incubator. To evaluate the antiviral potency, an appropriate dilution of HIV-1 (RF) virus storage (50 μL) was added to the cell-containing cultures and dilutions of the test compounds. The final volume of each of them was 200 μL. Each of the plates was laterally disinfected with 50 μL of the medium added to the virus site, while each was infected in the absence of any antiviral compound. For the evaluation of the compound's toxicity, parellels were cultured without virus infection.
After 3 days of culture at 37 ° C in a humid chamber inside a C02 incubator, all but 25 μL of the medium / well were removed from the HIV infected plates. Thirty-seven μL of 5 M GED containing the biotinylated capture probe were added to the established cells and the remaining medium in each at a final concentration of 3 M GED and a 30 nM capture probe. The hybridization of the capture probe for an HIV RNA in the cell used was carried out in the same microplate that was used to culture the virus by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hours in an incubator at 37 ° C. Distilled water was then added to each to dilute the hybridization reaction three times and 150 μL of this diluted mixture was transferred to a mi-tilled plate coated with streptavidin. HIV RNA was quantified as described above. A standard curve, prepared by adding known amounts of RNA transcriptor in vi tro pDAB 72 to each containing disinfected cells used, was conducted on each of the microtitre plates in order to determine the amount of RNA virus made during the infection.
In order to standardize the inoculation of viruses used in the evaluation of the compounds for antiviral activity, the dilutions of the viruses were selected to result in an IC90 value (concentration of compound required to reduce the level of VOH RNA by 90%). dideoxicit idina (ddC) of 0.2 μg / mL. The values of ICg0 of other antiviral compounds, both more or less potent than the ddC, were reproduced using various assortments of HIV-1 (RF) where this procedure was followed. This concentration of virus corresponds to ~ 3 x 10 5 PFU (measured by assay plate in MT-2 cells) per assay and typically yielding approximately 75% of the maximum level of maximum viral RNA made in any virus inoculation. For the HIV RNA assay, the ICgo values were determined from the percentage reduction of the signal taken (signal from the infected cell samples minus the signal from the disinfected cell samples) in the RNA assay relative to the signal taken from the untreated cells, infected in the same culture plate (average of each of them). The valid execution of the individual infection and the RNA assay tests were judged according to three criteria. This was required so that the results shown of virus infection in an RNA test signal were equal to or greater than the signal generated from the RNA 2 ng transcriptase of pDAB 72 in vi tro. The IC90 for ddC, determined in each test run, showed between 0.1 and 0.3 μg / mL. Finally, the plate level of the viral RNA produced by an effective reverse transcriptase inhibitor showed less than 10% of the level performed in an uninhibited infection. A compound is considered active if its ICgo is found to be less than 20 μM.
For the antiviral potency tests, all manipulations on my crotified plates, followed by the initial addition of a 2x concentrated compound solution to a single row of wells, was performed using a ProPette Perkin Elmer / Cetus.
Protein Link and Mutant Resistance.
In order to characterize the NNRTI analogs for each effective clinical potential, the effect of plasma proteins on antiviral potency and measurements of antiviral potency against the non-cultured type and mutant variants of HIV carrying amino acid changes at the site of known link for the NNRTIs were examined. The rationality of this test strategy is two parts: 1. Many drugs are linked exivamente to plasma proteins. Through the binding affinity for many drugs for most components of human plasma, nominally, human albumin serum (HSA) of alpha-l-glycoprotein acid (AAG), is lower, this majority of components occurs in a high concentration in the blood. Only the free or unbound drug is available to cross the membrane of the infected cell by interaction with the target site (this is, HIV-1 reverse transcriptase, HIV-1 TI). Therefore, the effect of adding the HSA + AAG on the antiviral potency in the tissue culture more closely reflects the potency of the given compound in the clinical sample. The concentration of compound required to 90% inhibit virus replication is measured in a detection method based on the sensitive viral RNA designating IC90. The doubled increase in the apparent IC9o for the test compounds in the presence of aggregated levels of HSA and AAG reflecting the in vi vo concentrations (45 mg / ml HSA, 1 mg / ml AAG) are then calculated. The lower the doubled increase, the greater the compound available to interact with the target site. 2. The combination of the high range of virus replication in the infected individual and the poor fidelity of viral TI results in the production of quasi-species or mixtures of HIV species in the infected individual. These species may include a majority of species of non-cultivated type, but also mutant variants of HIV and the proportion of a given mutant may reflect their relative fitness and range of replication. Since several mutants include mutants that change in the amino acid sequence of the viral TI linking pre-existing species in the infected individual, the overall potential observed in the clinical sample will reflect the ability of a drug to inhibit not only HIV-1 type not cultivated, but also mutant variants. It has been constructed in this manner, in a known genetic background, mutant variants of HIV-1, which carry amino acid substitutions at the positions through which an NNRTI link is involved, and the ability of the test compounds has been measured. to inhibit the replication of these mutant viruses. The concentration of the compound required to inhibit virus replication by 90% is measured in a detection method based on sensitive viral RNA designating the ICgo. It is desirable to have a compound that has a high activity against a variety of mutants.
Two i s L r or uia ci on The antiviral compounds of this invention can be administered as a treatment for antiviral infections by any means that produces contact of the active agent with the agents of the site of action, i.e. viral reverse transcriptase, in the body of a mammal. These can be administered by any of the conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination of therapeutic agents. These may be administered alone, but preferably administered with a selected pharmaceutical carrier at the bases of the chosen route of administration and standard pharmaceutical practice.
The dose administered will, of course, be variable depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; and the desired effect. A daily dose of active ingredient may be expected to be from about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being from about 0.1 to about 30 mg / kg.
The dosage forms of the compositions suitable for administration contain from about 1 mg to about 100 mg of the active ingredient per unit. In antiserum pharmaceutical compositions, the active ingredient may ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient may be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. They can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and carrier powders, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Such tablets and capsules can be made as sustained release products to provide a continuous release of the drug over a period of oras.- The compressed tablets can be coated with sugar or coated with a film to mask any unpleasant taste and protect the tablet from the atmosphere, or enterically coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavors to increase patient acceptance.
In general, aqueous solutions, of suitable oil, salines, of aqueous dextrose (glucose), and related to sugar and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, stabilizing agents are suitable, and if necessary, buffering substances. Antioxidant agents such as sodium bisulfide, sodium sulfide, or ascorbic acid, either alone 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 Remingt on 's Pharma ceu ti cal Sciences, s upra, a standard reference text in this field.
The pharmaceutical dosage forms useful for the administration of the compounds of this invention can be illustrated as follows: Capsules A large number of capsule units can be prepared by hard gelatin capsules of two standard-sense pieces each with 100 mg of the active ingredient powder, 150 mg of lactose, 50 mg of cellulose, and 6 mg of stearic magnesium.
Gelatin capsules Sua e A mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump in gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. . The capsules can then be washed and dried.
Tablets A large number of tablets can be prepared by conventional procedure so that the unit dose is 100 mg of the active ingredient, 0.2 mg of colloidal silica dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase the flavor or delay absorption.
Suspension An aqueous suspension can be prepared for oral administration so that each 5 L contains 25 mg of the finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, USP, and 0.025 mg of vanilla.
Injectable A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is sterilized by commonly used techniques.
Combination of components (a) and (b).
Each component of the therapeutic agent of this invention can independently be in any dosage form, as described above, and can also be administered in various ways, as described above. In the following description of component (b) it will be understood that one or more agents are represented as previously described. Thus, if components (a) and (b) are to treat the same or independently, each agent of component (b) may also treat the same or independently.
The components (a) and (b) of the present invention can be formulated together, in a single unit dose (that is, combined together in a capsule, tablet, powder, or liquid, etc.) as a combined product. When component (a) and (b) are not formulated together in a single unit dose, component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or these may be administered in reverse order. If component (b) contains more than one agent, for example, a TI inhibitor and a protease inhibitor, these agents can be administered together in any order. When they are not administered at the same time., preferably the administration of component (a) and (b) occurs in less than about one hour of separation. Preferably, the route of administration of component (a) and 8B9 is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, mean compounds that can be administered orally. However it is preferred that component (a) and component (b) are both administered by the same route (which is, for example, both orally) or dosage forms, if desired, these can each be administered by different routes (which is, for example, one component of the combination product can be administered orally, and the other component can be administered intravenously) or dosage forms.
It will be appreciated, by a skilled medical practitioner in the art, that the dose of the combination therapy of the invention may vary depending on various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, age, health and recipient's weight, the nature and extent of symptoms, the type of concurrent treatment, the frequency of treatment, and the desired effect, as described above.
The appropriate dose of components (a) and (b) of the present invention may be readily ascertained by a medical practitioner skilled in the art, based on the present disclosure. As a general guide, typically the daily dose may be around 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one component, then typically a daily dose may be from about 100 milligrams to about 1.5 grams of each agent of component (b). As a general guide, when the compounds of component (a) and component (b) are administered in combination, the dose amount of each component may be reduced by about 70-80% relative to the usual dose of the component when it is used. administer only as a simple agent for the treatment of HIV infection, in view of the synergistic effect of the combination.
The combination of products of this invention can be formulated such that, although the active ingredients are combined in a single unit dose, physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, an active ingredient can be enterically coated. To cover one of the active ingredients enterically, this is possible not only to minimize contact between the combined active ingredients, but also, this is possible to control the release of one of these components in the gastrointestinal tract such that one of these components are not released in the stomach but in turn is released in the intestines. Another embodiment of this invention where oral administration is desired to provide for a combination product of the active ingredients is covered with a sustained release material that effect a sustained release totally in the gastrointestinal tract and also serves to minimize physical contact between the ingredients combined assets. In addition, the sustained release component can additionally be enteric coated in such a way that the release of this component occurs only in the intestine. Still in another approach it may involve the formulation of a combination product in which one of the components is coated with an enteric and / or sustained release polymer, and the other component is also coated with a polymer such as a low grade polymer. viscosity of hydropropyl methylcellulose or other suitable materials known in the art, in order to further separate the active components. The polymer shell serves to form an additional barrier for interaction with the other component. In each formulation where contact is prevented between components (a) and (b) 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 combination products of the present invention wherein an active ingredient is enteric coated may be in tablet form such that the enteric coated component and the other active ingredient are mixed together and then compressed into a tablet or such that the enteric coated component is compressed into a tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more layers of placebo may be presented in such a way that the placebo layer is between the layers of the active ingredients. further, the dosage forms of the present invention may be in the form of capsules wherein an active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-hazardous, which are then enteric coated. These microtablets, particles, granules or non-dangerous enteric coated are then placed in a capsule or compressed in one capsule along with a granulation of the other active ingredient.
This is as well as other ways of minimizing contact between the components of the combination products of the present invention, if they are administered in a single dose form or are administered in separate forms but at the same time or concurrently in the same manner, they may be quickly appreciated by those skilled in the art, based on this description.
Pharmaceutical devices useful for the treatment of an HIV infection, comprising a therapeutically effective amount of a pharmaceutical composition, comprise a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, they are also within the scope of the present invention. Sterilization of the container can be carried out using a conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) can be in the same sterile container or in separate sterile containers. Sterile containers of materials may comprise separate containers, or one or more large containers, as desired. The component (a) and the component (b), can be separated, or physically combined in a single or unit dose form as described above. Such devices may additionally, if desired, include one or more of several conventional pharmaceutical device components, such as, for example, one or more pharmaceutically acceptable carriers, additional means for mixing the components, etc., which will be readily apparent to those skilled in the art. in the technique. The instructions, either as inserts or labels, indications of quantities of the components to be administered, guides for administration, and / or guides for mixing the components, may also be included in the device.
Obviously, numerous variations and modifications of the present invention are possible in the light of the prior art. It will be understood therefore that within the scope of the appended claims, the invention may be practiced contrary to what is specifically described herein.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention

Claims (18)

Claims
1. A compound of formula (I) or a tereosisomer or pharmaceutically acceptable salt thereof, characterized in that R1 is C3 alkyl substituted with 1-7 halogen; R2 is selected from C1-5 alkyl substituted with 1-2 R4, C2-5 alkenyl substituted with 1-2 R4, and C5 alkynyl substituted with 1 R4; R3 in each appearing, is independently selected from C1-4alkyl, OH, C4-4alkoxy, F, Cl, Br, I, NR5R5'a, N02, CN, C (0) R6, NHC (0) R7, and NHC (O) NR5R5a; alternatively, if two Rs are presented and are bonded to the adjacent carbons, then these can be combined to form -OCH20-; R is selected from C3_5 cycloalkyl substituted with 0-2 of R3, phenyl substituted with 0-5 of R3, and a 5-6 member heterocyclic system containing from 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 of R3; R5 and R5a are independently selected from H and Ci_3 alkyl; R is selected from H, OH, C? _4 alkyl, alkoxy C1-4, and RN5R5a; R7 is selected from C3_3alkyl and C1-3alkoxy; R is selected from H, C3_5 cycloalkyl, and C1-3 alkyl; Y, n is selected from 0, 1, 2, 3, and 4.
2. The compound according to claim 1, characterized in that R1 is C1-3 alkyl substituted with 1-7 halogen; R2 is selected from C1-5 alkyl substituted with 1 R4, C2-5 alkenyl substituted with 1 R4, and C2_5 alkynyl substituted with 1 R4; R3 in each production, is independently selected from alkyl C? _, OH, C? _4 alkoxy, F, Cl, Br, I, NR5R5a, N02, CN, C (0) R? NHC (0) R ', and NHC (0 NR5R5a, alternatively, if two Rs are presented and joined to the adjacent carbons, then these may be combined to form -0CH20-; R is selected from C3-5 cycloalkyl substituted with 0-2 of R3, phenyl substituted with 0-2 of R, and a 5-6 member heterocyclic system containing from 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 of R3; R5 and R5a are independently selected from H CH3 and C2H5; R s e s the e ction of H, OH, CH3, C2H5, OCH3, OC2H5, and RN5R5 a; R is selected from CH3, C2H5, OCH3 and OC; H5; R8 is selected from H, cyclopropyl, CH3 and C2H5; Y, n is selected from 0, 1, 2, and 3.
3. The compound according to claim 2, characterized in that R1 is selected from CF3, and C2F5; R is selected from C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R, and C2_3 alkynyl substituted with 1 R4; R in each production, is independently selected from C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, Br, I, NR5R5a, N02, CN, C (0) R6, NHC (0) R7, and NHC ( O) NR5R5a; alternatively, if two of R are presented and joined to adjacent carbons, then these can be combined to form -OCH20-; R4 is selected from C3-5 cycloalkyl substituted with 0-2 of R3, phenyl substituted with 0-2 R3, and a 5-6 member heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0 -1 R3; R and R, 5a are independently selected from H, CH 3, and C Hs; R6 is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a, R is selected from CH3, C2H5, OCH3, and OC2H5; R8 is selected from H, CH3 and C2H5; Y n is selected from 0, 1, and 2.
4. The compound according to claim 3, characterized in that R1 is CF3; R ~ is selected from C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R "*, and C2-3 alkynyl substituted with 1 R4; R3 in each production is independently selected from C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, NR5R5a, N02, CN, C (0) R6, NHC (0) R7, and NHC (0) NR5R5a; alternatively, if two R's are presented and attached to the adjacent carbons, then these can be combined to form -CH20-; R is selected from cyclopropyl substituted with 0-1 R3, phenyl substituted with 0-2 R3, and a 5-6 member heterocyclic system containing from 1-3 heteroatoms selected from 0, N, and S, substituted with 0-1 R3 , 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 -i-soxazolyl , and 2-imidazolyl; R5 and Rsa are independently selected from H, CH3 and C2H5; R6 is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; R7 is selected from CH3, C2H5, OCH3, and OC2H5; R8 is selected from H, CH3 and C2H5; Y, n is selected from 1 and 2.
5. The compound according to claim 4, characterized in that the compound is of the formula la:
6. The compound according to claim 4, characterized in that the compound is of the formula: Ib.
7. The compound according to claim 1, characterized in that the compound is selected from: (+/-) -6-chloro-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) -6-chloro -.- (2-pyridyl) ethynyl-4-tri fluorome-3, 4-dihydro-2 (1H) -quinazolinone; (+ / -) - 6-chloro-4-phenylethynyl-4-tri fluorome-3, 4-dihydro-2 (1H) -quinazolinone; (+ / -) -4-cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3, -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; (+/-) - -cyclopropyl-ethynyl-5,6-di-fluoro-4-trifluoromethyl-3-dihydro-2 (1H) -quinazolinone; (+/-) - 5,6-difluoro-4- (2-pyridyl) ethynyl-4-trifluoromethyl-3, -dihydro-2 (1H) -quinazolinone; (+/-) -5,6-difluoro-4-phenylethynyl-4-tri fluorometyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) -4-cyclopropylethynyl-6-fluoro-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-trif luoromethyl-3,4-dihydr-2 (1H) -quinazolinone; (+/-) - 6-fluoro-4- (2'-2-pyridyl) ethyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+ / -) -6-fluoro-4-phenylethyl-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (-) - 6-chloro-4-cyclopropyl ethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3, -dihydro-2 (lH) -quinazolinone; (+) - 4-cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (-) -4-cyclopropylethynyl-5,6-di-fluoro-4-rifluoromethyl-3, -dihydro-2 (1H) -quinazolinone; (+) -4-E-cyclopropyletenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; Y, (-) - 6-chloro-4-E-cyclopropyletenyl-4-trifluoromethyl-3, 4-dihydro-2 (1H) -quinazolinone; or a pharmaceutically acceptable salt thereof
The compound according to formula II II or a tereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R is selected from C C _4 OH alkyl, C? _4 alkoxy, F, Cl, Br, I, NR5R5a, N02, CN, C (0) R6, NHC (0) R6, NHC (0) R7, and NHC (O) NR5R5a; R, 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl R5 and R5a are independently selected from H and C3_3 alkyl; R is selected from H, OH, C? _4 alkyl, C? -4 alkoxy, and NR5R5a; R is selected from C3-3 alkyl and C1-3 alkoxy; R is selected from H, C3_5 cycloalkyl, and C ?_3 alkyl; Y, n is selected from 0, 1, 2, 3, and 4.
9. The compound according to claim 8, characterized in that R is C = C-R 4a R is selected from C C _ OH alkyl to C 1-4 r coxi F, Cl, Br, I, NR5R5a, N02, CN, C (0) R6, and NHC (O) R7; R, 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl; R5 and R5a are independently selected from H, CH3 and C2H5; R & is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; R is selected from CH3, C2H5, OCH3, and OC2H5; Rfc is selected from H, cyclopropyl, CH 3 and C 2 H; Y n is selected from 0, 1 and
10. The compound according to claim 9, characterized in that the compound is of the formula lia: lia
11. The compound according to claim 9, characterized in that the compound is of formula Ilb: Ilb.
12. The compound according to claim 8, characterized in that the compound is selected from: (+/-) -6-chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) -6-chloro-4-ethynylnyl-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-ethynylnyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+/-) -5,6-difluoro-4-isopentyl-4 -tri fluorometyl-3-dihydro-2 (1H) -quinazolinone; (+/-) -6-fluoro-4-isopropylethynyl-4-trifluoromethyl '3,4-dihydro-2 (1H) -quinazolinone; (+/-) -6-fluoro-4-ethylethynyl-4-trifluoromethyl-3, dihydro-2 (1H) -quinazolinone; (-) -5,6-difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (+) - 5, β-difluoro-4-isopropylethynyl-4-tri-fluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; (-) -5,6-difluoro-4-ethynylnyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; Y, (+) - 5,6-difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2 (1H) -quinazolinone; a pharmaceutically acceptable salt thereof
13. A pharmaceutical composition, characterized in that it comprises: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of the rei indications 1-12 or a pharmaceutically acceptable salt thereof.
14. A method for the treatment of an HIV infection, characterized in that it comprises: administering to the host in need of treatment a therapeutically effective amount of a compound of one of claims 1-12, or a pharmaceutically acceptable salt thereof.
15. A method for the treatment of an HIV infection comprising 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 shapes * is tereoisomeric, or pharmaceutically acceptable salts thereof; and (b) at least one compound selected from the group consisting of inhibitors of trans crypts to HIV reverse and inhibitors of HIV protease.
16. The method according to claim 15, characterized in that the reverse transcriptase inhibitor is selected from AZT, 3TC, ddl, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapina, 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. The method according to claim 16, characterized in that the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, nelfinavir, ritonavir, and indinavir.
18. A pharmaceutical device useful for the treatment of HIV infection, characterized in that it comprises 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, in one or more sterile containers.
MXPA/A/1999/008909A 1997-04-09 1999-09-28 4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitors MXPA99008909A (en)

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US838540 1997-04-09
US071322 1998-01-14

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MXPA99008909A true MXPA99008909A (en) 2000-01-01

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