4,4-disubstituted-1, 4-dihydro-2H-3, 1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

FIELD OF THE INVENTION

[0001] This invention relates generally to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

[0002] Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

[0003] The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

[0004] At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

[0005] The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

[0006] There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

[0007] Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

[0008] A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxythymidinene (d4T), 2′,3′-dideoxyinosine (ddI), and 2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

[0009] Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describe reverse transcriptase inhibitors which are benzoxazinones of the formula:

[0010] wherein X is a halogen, Z may be O. However, benzoxazinones of this type are specifically excluded from the present invention.

[0011] In U.S. Pat. No. 5,519,021 one compound in particular, (−) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI), shown below,

[0012] has been found to be a potent and specific inhibitor of HIV-1 reverse transcriptase worthy of further study. NNRTI is described in Step D of Example 6 of the disclosure. Rat, monkey, and human microsomes treated with NNRTI, during investigation of the cytochrome P450 metabolism of NNRTI, produced a metabolite which was discovered to also be a potent inhibitor of HIV reverse transcriptase. This metabolite, its stereoisomer, stereoisomeric mixtures, and derivatives thereof are an embodiment of the present invention.

[0013] Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

[0014] Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

[0015] It is another object of the present invention to provide a novel method for treating 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 or prodrug form thereof.

[0016] It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a 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 form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

[0017] It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

[0018] It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

[0019] It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

[0020] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

[0021] wherein A, W, X, Y, Z, R1 and R2 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0022] [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:

[0023] or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

[0024] A is O or S;

[0025] W is N or CR3;

[0026] X is N or CR4;

[0027] Y is N or CR5;

[0028] Z is N or CR6;

[0029] provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

[0030] also, provided that if X is CR4 and R4 is F, Cl, Br, or I, then:

[0031] (a) at least one of W, Y, and Z is other than CH;

[0032] (b) R2 is —OCHR7R8 or —NHCHR7R8;

[0033] (c) if R2 is —C≡C—R8, then R8 is C3-7 cycloalkyl substituted with 1 R9; or

[0034] (d) any combination of (a), (b), and (c);

[0035] R1 is selected from CF3, CF2H, C2F5, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;

[0036] R2 is selected from —QCHR7R8, —QCHR7C≡C—R8, —QCHR7C═C—R8, —Q(CH2)pCHR7R8, —C≡C—R8, —CH═CR7R8, —(CH2)pCHR7R8, —CHR7C≡C—R8, —CHR7CH═CHR8, and CH═CHCHR7R8;

[0037] provided that when R1 is C1-4 alkyl, then R2 is —C≡C—R8;

[0038] R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;

[0039] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0040] alternatively, R3 and R4 together form -—OCH2O—;

[0041] R5 is selected from H, F, Cl, Br, and I;

[0042] alternatively, R4 and R5 together form —OCH2O— or a fused benzo ring;

[0043] R6 is selected from H, OH, C1-3 alkoxy, —CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;

[0044] R7 is selected from H and C1-3 alkyl;

[0045] R7a is selected from H and C1-3 alkyl;

[0046] R7b is C1-3 alkyl;

[0047] R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(—OCH2CH2O—), C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0048] R9 is selected from D, OH, C1-3 alkoxy, C1-3 alkyl, and F;

[0049] R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;

[0050] R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;

[0051] Q is selected from O, S and NH; and,

[0052] p is selected from 0, 1, and 2.

[0053] [2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein: R1 is selected from CF3, CF2H, C2F5, C1-3 alkyl, C3-5 cycloalkyl; and,

[0054] R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(—OCH2CH2O—), C2-6 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10.

[0055] [3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

[0056] R1 is selected from CF3, CF2H, C2F5, C2H5, isopropyl, cyclopropyl;

[0057] R3 is selected from H, F, Cl, Br, I, OCH3, CH3;

[0058] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0059] alternatively, R3 and R4 together form —OCH2O—;

[0060] R5 is selected from H, F;

[0061] R6 is selected from H, OH, OCH3, —CN, F, CF3, CH3, and C(O)NH2;

[0062] R7 is selected from H and CH3;

[0063] R7a is selected from H and CH3;

[0064] R7b is CH3;

[0065] R8 is selected from H, C1-4 alkyl substituted with 0-3 R11, CH(—OCH2CH2O—), C2-4 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10;

[0066] R9 is selected from D, OH, OCH3, CH3, and F;

[0067] R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3; and,

[0068] p is selected from 1 and 2.

[0069] [4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

[0070] A is O;

[0071] R1 is selected from CF3, CF2H, C2F5;

[0072] R2 is selected from —OCHR7R8, —OCH2C≡C—R8, —OCH2C═C—R81 , —OCH2CHR7R8, —C≡C—R8, —CH═CR7R8, —CH2CHR7R8, —CH2C≡C—R8, CHR7CH═CHR8, and CH═CHCHR7R8;

[0073] R3 is selected from H, F, Cl, Br, I;

[0074] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CH═CH2, C≡CH, OCH3, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0075] alternatively, R3 and R4 together form —OCH2O—; and,

[0076] R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2.

[0077] [5] In a further preferred embodiment, the compound of the present invention is selected from:

[0078] (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0079] (−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0080] (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0081] (+/−)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0082] (+/−)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0083] (+/−)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0084] (+/−)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0085] (+/−)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0086] (+/−)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0087] (+/−)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0088] (+/−)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0089] (+/−)-6-Chloro-4-(2-(furan-2-yl)ethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0090] (+/−)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0091] (+/−)-4-(1′-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0092] (+/−)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

[0093] (+/−)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; and

[0094] (+/−)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

[0095] [6] In a second embodiment, the present invention provides a novel compound of formula II:

[0096] or a salt or stereoisomer thereof, wherein:

[0097] A is O or S;

[0098] W is N or CR3;

[0099] X is N or CR4;

[0100] Y is N or CR5;

[0101] Z is N or CR6;

[0102] provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

[0103] R1a is selected from CF3, CF2H, C2F5, CH1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;

[0104] R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;

[0105] R4 is selected from H, F, Cl, Br, I, C13 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0106] alternatively, R3 and R4 together form —OCH2O—;

[0107] R5 is selected from H, F, Cl, Br, and I;

[0108] alternatively, R4 and R5 together form —OCH2O— or a fused benzo ring;

[0109] R6 is selected from H, OH, C1-3 alkoxy, —CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;

[0110] R7 is selected from H and C1-3 alkyl;

[0111] R7a is selected from H and C1-3 alkyl;

[0112] R7b is C1-3 alkyl;

[0113] R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O) CH3;

[0114] R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;

[0115] p is selected from 0, 1, and 2.

[0116] [7] In a another preferred embodiment, the present invention provides a novel compound of formula II, wherein:

[0117] A is O; and,

[0118] R1a is selected from CF3, CF2H, C2F5, C1-3 alkyl, C3-5 cycloalkyl.

[0119] [8] In a more preferred embodiment, the present invention provides a novel compound of formula II, wherein: R1a is selected from CF3, CF2H, C2F5, C2H5, isopropyl, cyclopropyl;

[0120] R3 is selected from H, F, Cl, Br, I, OCH3, CH3;

[0121] R4 is selected from H, F, Cl, Br, I, C13 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C13 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR71 SO2NHR7, NR7SO2R7b, phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0122] alternatively, R3 and R4 together form —OCH2O—;

[0123] R5 is selected from H, F;

[0124] R6 is selected from H, OH, OCH3, —CN, F, CF3, CH3, and C(O)NH2;

[0125] R7 is selected from H and CH3;

[0126] R7a is selected from H and CH3;

[0127] R7b is CH3;

[0128] R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3; and,

[0129] p is selected from 1 and 2.

[0130] [9] In an even more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

[0131] R1a is selected from CF3, CF2H, C2F5;

[0132] R3 is selected from H, F, Cl, Br, I;

[0133] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CH═CH2, C≡CH, OCH3, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0134] alternatively, R3 and R4 together form —OCH2O—; and,

[0135] R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2.

[0136] [10] In a third embodiment, the present invention provides a novel process for making a compound of formula II:

[0137] or a salt or stereoisomer thereof, comprising:

[0138] (a) contacting a compound of formula III:

[0139] or a suitable salt form thereof, with a carbonyl or thiocarbonyl delivering agent in the presence of a suitable solvent, wherein:

[0140] A is O or S;

[0141] W is N or CR3;

[0142] X is N or CR4;

[0143] Y is N or CR5;

[0144] Z is N or CR6;

[0145] provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

[0146] R1a is selected from CF3, CF2H, C2F5, CH1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;

[0147] R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;

[0148] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C13 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0149] alternatively, R3 and R4 together form —OCH2O—;

[0150] R5 is selected from H, F, Cl, Br, and I;

[0151] alternatively, R4 and R5 together form —OCH2O—or a fused benzo ring;

[0152] R6 is selected from H, OH, C1-3 alkoxy, —CN, F, Cl, Br, I, NO2, CF3, CHO, C13 alkyl, and C(O)NH2;

[0153] R7 is selected from H and C13 alkyl;

[0154] R7a is selected from H and C1-3 alkyl;

[0155] R7b is C1-3 alkyl;

[0156] R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;

[0157] R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;

[0158] Q is selected from O, S and NH; and,

[0159] p is selected from 0, 1, and 2.

[0160] [11] In another preferred embodiment, in formulae II and III,

[0161] A is O;

[0162] R1a is selected from CF3, CF2H, C2F5;

[0163] R3 is selected from H, F, Cl, Br, I;

[0164] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CH═CH2, C≡CH, OCH3, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0165] alternatively, R3 and R4 together form —OCH2O—; and,

[0166] R5 is selected from H, F;

[0167] R6 is selected from H, OH, OCH3, —CN, F, CF3, CH3, and C(O)NH2;

[0168] R7 is selected from H and CH3;

[0169] R7a is selected from H and CH3;

[0170] R7b is CH3;

[0171] R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;

[0172] R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2; and,

[0173] p is selected from 1 and 2.

[0174] [12] In another more preferred embodiment, the carbonyl delivering agent is selected from phosgene, carbonyldiimidazole, chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate.

[0175] [13] In another even more preferred embodiment, the carbonyl delivering agent is phosgene and the solvent is toluene.

[0176] [14] In another more preferred embodiment, in step (a) a base is present and is selected from trimethylamine, triethylamine, and N,N-disopropylethylamine.

[0177] [15] In a fourth embodiment, the present invention provides of process for making a compound of formula Ia:

[0178] or a stereoisomer or pharmaceutically acceptable salt form thereof, comprising:

[0179] (a) contacting a nucleophile, R2b, with a compound of formula II:

[0180] or stereoisomer thereof in a suitable solvent, wherein:

[0181] R2b is selected from R8R7CH—OH, R8R7CH—OM, R8R7CHNH2, R8R7CHNH—M, R8—C≡C—M, R7R8C═CH—M, R8R7CH(CH2)p—M, R8CH═CHC(H)(R7)—M, R8R7CHCH═CH—M;

[0182] M is selected from Na, Li, Mg, Zn, Cu, Pd, Pt, Sn, Al, and B;

[0183] A is O or S;

[0184] W is N or CR3;

[0185] X is N or CR4;

[0186] Y is N or CR5;

[0187] Z is N or CR6;

[0188] provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

[0189] R1a is selected from CF3, CF2H, C2F5, CH1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;

[0190] R2a is selected from —QCHR7R8, —QCHR7C≡C—R8, —QCHR7C═C—R8, —Q (CH2)pCHR7R8, —C≡C—R8, —CH═CR7R8, —(CH2)pCHR7R8, —CHR7C≡C—R8, —CHR7CH═CHR8, and CH═CHCHR7R8;

[0191] R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;

[0192] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0193] alternatively, R3 and R4 together form —OCH2O—;

[0194] R5 is selected from H, F, Cl, Br, and I;

[0195] alternatively, R4 and R5 together form —OCH2O— or a fused benzo ring;

[0196] R6 is selected from H, OH, C1-3 alkoxy, —CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;

[0197] R7 is selected from H and C1-3 alkyl;

[0198] R7a is selected from H and C1-3 alkyl;

[0199] R7b is C1-3 alkyl;

[0200] R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(—OCH2Ch2O—), C2-6 alkenyl, CH3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0201] R9 is selected from D, OH, C1-3 alkoxy, C1-3 alkyl, and F;

[0202] R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;

[0203] R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;

[0204] Q is selected from O, S and NH; and,

[0205] p is selected from 0, 1, and 2.

[0206] [16] In another preferred embodiment, in formulae Ia and II,

[0207] A is O;

[0208] R1a is selected from CF3, CF2H, C2F5;

[0209] R2a is selected from —OCHR7R8, —OCH2C≡C—R8, —OCH2C═C—R8, —OCH2CHR7R8, —C≡C—R8, —CH═CR7R8, —CH2CHR7R8, —CH2C≡C—R8, CHR7CH═CHR8, and CH═CHCHR7R8;

[0210] R3 is selected from H, F, Cl, Br, I;

[0211] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CH═CH2, C≡CH, OCH3, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0212] alternatively, R3 and R4 together form —OCH2O—; and,

[0213] R5 is selected from H, F;

[0214] R6 is selected from H, OH, OCH3, —CN, F, CF3, CH3, and C(O)NH2;

[0215] R7 is selected from H and CH3;

[0216] R7a is selected from H and CH3;

[0217] R7b is CH3;

[0218] R8 is selected from H, CH1-4 alkyl substituted with 0-3 R11, CH(—OCH2CH2O—), C2-4 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10;

[0219] R9 is selected from D, OH, OCH3, CH3, and F;

[0220] R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;

[0221] R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2; and,

[0222] p is selected from 1 and 2.

[0223] [17] In another more preferred embodiment, in step (a), the compound of formula II is added to a solution containing the nucleophile.

[0224] [18] In another more preferred embodiment, in step (a), R2b is R8—C≡C—M; and M is selected from Li, Mg, and Zn.

[0225] [19] In another even more preferred embodiment, in step (a), R8—C≡C—M is formed in situ by addition of a strong base to a solution containing R8—C≡C—H.

[0226] [20] In another further preferred embodiment, in step (a), the strong base is selected from n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium.

[0227] [21] In another further preferred embodiment, the compound of formula Ia is:

[0228] the compound of formula Ia is:

[0229] the nucleophile R2b is lithium cyclopropylacetylide; and, the solvent is THF.

[0230] [22] In a fifth embodiment, the present invention provides a novel method of making a compound of formula IIIb:

[0231] or stereoisomer or salt form thereof, comprising:

[0232] (a) contacting a compound of formula IIIa:

[0233] with R1a-TMS and an anion, wherein:

[0234] the anion is a fluoride or oxyanion and is selected from tetrabutylammonium fluoride, sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate;

[0235] Pg is an amine protecting group;

[0236] W is N or CR3;

[0237] X is N or CR4;

[0238] Y is N or CR5;

[0239] Z is N or CR6;

[0240] provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

[0241] R1a is selected from CF3, CF3CF2, and CF3CF2CF2;

[0242] R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;

[0243] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7a, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R10;

[0244] alternatively, R3 and R4 together form —OCH2O—;

[0245] R5 is selected from H, F, Cl, Br, and I;

[0246] alternatively, R4 and R5 together form —OCH2O— or a fused benzo ring;

[0247] R6 is selected from H, OH, C1-3 alkoxy, —CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;

[0248] R7 is selected from H and C1-3 alkyl;

[0249] R7a is selected from H and C1-3 alkyl;

[0250] R7b is C1-3 alkyl;

[0251] R10 is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I CN, NR7R7a, and C(O)CH3;

[0252] R11 is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;

[0253] p is selected from 0, 1, and 2.

[0254] [23] In another preferred embodiment, in formulae IIIa and

[0255] the R1a-TMS is trifluoromethyl trimethylsilane;

[0256] the anion is tetrabutylammonium fluoride;

[0257] Pg is trityl;

[0258] R1a is CF3;

[0259] R3 is selected from H, F, Cl, Br, I;

[0260] R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CH═CH2, C≡CH, OCH3, OCF3, —CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0261] alternatively, R3 and R4 together form —OCH2O—; and,

[0262] R5 is selected from H, F;

[0263] R6 is selected from H, OH, OCH3, —CN, F, CF3, CH3, and C(O)NH2;

[0264] R7 is selected from H and CH3;

[0265] R7a is selected from H and OH3;

[0266] R7b is CH3;

[0267] R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;

[0268] R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2; and,

[0269] p is selected from 1 and 2.

[0270] [24] In another more preferred embodiment, the process further comprises:

[0271] (b) contacting a compound of formula IIIb with an oxidizing agent to form compound of formula IIIc:

[0272] [25] In another even more preferred embodiment, the oxidizing agent is MnO2.

[0273] In a fifth embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

[0274] In a sixth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

[0275] In a seventh embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

[0276] (a) a compound of formula I; and,

[0277] (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

[0278] In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.

[0279] In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

[0280] In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

[0281] In a still further preferred ebodiment, the nucleoside reverse transcriptase inhibitor is AZT.

[0282] In another still further preferred embodiment, the protease inhibitor is indinavir.

[0283] In a eighth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

[0284] (a) a compound of formula I; and,

[0285] (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.

[0286] In a ninth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.

[0287] In a tenth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

DEFINITIONS

[0288] 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 may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

[0289] The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. 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, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

[0290] The reactions of the synthetic methods claimed herein may be, as noted herein, carried out in the presence of a suitable base, said suitable base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis. Suitable bases include, but are not intended to be limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammonium carbonate, and ammonium hydroxide. Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexylamine, N,N,N′-triethylenediamine, N,N-dimethyloctylamine; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,4-diazabicyclo[2.2.2]octane (DABCO); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.

[0291] Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,l-trichloroethane, 1,1,2-trichloroethane, 1,1,-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.

[0292] Suitable ether solvents include, but are not intended to be limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.

[0293] Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol.

[0294] Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0295] Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

[0296] As used herein, the term “amine protecting group” (or “N-protected”) refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term “amine protecting group reagent” refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group. Such amine protecting groups include those listed in Greene and Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl (trityl) and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

[0297] Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; N′-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.

[0298] As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified 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 intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl 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 through an 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 intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

[0299] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo and iodo. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

[0300] As used herein, “aryl” or “aromatic residue” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7- membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

[0301] As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 6- membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which 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 may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle 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 one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 6- membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams 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 heterocycle is not more than 1.

[0302] Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0303] As used herein, “HIV reverse transcriptase inhibitor” is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).

[0304] As used herein, “HIV protease inhibitor” is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.

[0305] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0306] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety 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, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0307] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

[0308] “Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.

[0309] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.

[0310] “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

[0311] “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably 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, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

SYNTHESIS

[0312] 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 thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference.

[0313] Scheme 1 illustrates a method of making 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting 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 R1-substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized with phosgene or an equivalent thereof.

[0314] Scheme 2describes a means of obtaining 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 4-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1.

[0315] Because certain benzo-substituents are incompatible with the methods of Schemes 1 and 2, it may be necessary to protect these groups before forming the benzoxazinone. In Scheme 3 there is shown a means of obtaining carbonyl-substituted 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 2 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl2 and HgO or other means well known to those of skill in the art.

[0316] A method for forming 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones, wherein R2 is a vinyl or alkynyl group, is described in Scheme 4. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 1 or 2, an acetylide is added. The product can be deprotected and cyclized to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH4, deprotection by standard means, and cyclization.

[0317] Scheme 5 describes an alternate route to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R2 group can then be added, e.g. via an acetylide, followed by cyclization.

[0318] An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 2. Reduction and reoxidation removes the chloro group leaving the desired intermediate.

[0319] Scheme 7A describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 1, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group.

[0320] Scheme 7B illustrates specific steps of Scheme 7A. Intermediate IIIb (R1a is selected from CF3, CF3CF2, and CF3CF2CF2) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF3CF2TMS, CF3CF2CF2TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about −20° C. to about 50° C., preferably about −10 to about 10° C., more preferably about Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO2, PDC, PCC, K2Cr2O7, CrO3, KMnO4, BaMNO4, Pb(OAc)4, and RuO4. A preferred oxidant is MnO2. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane dichloroethane, or tetrachloroethane, preferably dichloromethane.

[0321] Scheme 8 illustrates a method of forming aza-4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from an appropriately substituted amino-pyridine. Carbonyl addition to the pyridine can be accomplished using a strong base and an appropriate ketone. Addition of base can afford the cyclized product.

[0322] An additional means of making 4-alkynyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones is shown in Scheme 9. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound.

[0323] In addition to the methods of obtaining keto-anilines described in Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 10. This reaction is accomplished by using an anionic nucleophile of the group R1a. See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.

[0324] It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from −20 to +35° C., with temperatures below 0° C. being more preferred and −20° C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent.

[0325] An intermediate in this novel process is the chlorobenzoxazinone (II) which can be synthesized from the corresponding keto-aniline as shown in Scheme 11. The preparation of compounds of formula II works well with either the free base of the keto-aniline or its hydrochloride hydrate, though the free base is preferred due to its inherent reactivity. The carbonylation or thiocarbonylation reagent is selected from the group: phosgene (COCl2), thiophosgene (CSCl2), carbonyldiimidazole (CDI), chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate. Preferably, phosgene is used as the carbonylation reagent.

[0326] About 1, 2, 3, 4, or 5 equivalents of carbonylation or thiocarbonylation reagent are used, preferably from about 1 to about 2.5, even more preferably from about 1 to 2, and still further preferably about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents. With volatile reagents like phosgene more than one equivalent can help the conversion and yield of the reaction but is not necessary to effect transformation.

[0327] Solvents such as toluene may be used. Additional non-reactive solvents, such as ethers (e.g., dimethyl ether and diethyl ether), hydrocarbons (e.g., hexane and cyclohexane) or other aromatic solvents (e.g., benzene, anisole, or quinoline) can also be used. Solvents with boiling points around that of toluene or higher are preferred. Use of such solvents allows heat to be applied to the reaction to promote the cyclization. When the preferred carbonylation reagent, phosgene is use, heat helps drive off the HCl generated and promote the closure reaction. When toluene is used, it is preferred to run the reaction near toluene's boiling point. However, one of ordinary skill in the art would recognize that too high of a temperature may decompose the product. In addition, too low of a temperature may cause an undesirably slow reaction. Reaction progress may be determined by the decoloration of the reaction mixture (indicating consumption of starting material) and confirmation of completeness by proton NMR. The reaction may be catalyzed by the addition of an acid scavenger such as an amine base (e.g., triethylamine or Hunigs base) or an inorganic base (e.g., sodium carbonate or potassium).

[0328] Scheme 12 describes routes to a variety of R2-substituted compounds of formula Ia by reacting a nucleophile (R2b) with a compound of formula II (preferably R1a is CF3). This displacement reaction is quite versatile and a large range of nucleophiles can be used. Preferably the nucleophile is an amine (e.g., R8R7CHNH) or a metallic species selected from R8R7CH—OM, R8R7CH—SM, R8R7CHNH—M, R8—C≡C—M, R7R8C═CH—M, R8R7CH(CH2)p—M, R8CH═CHC(H)(R7)—M, and R8R7CHCH═CH—M. In addition, R8R7CH—OH and its thiol analog, R8R7CH—SH, can be used without formation of their corresponding anions. The metallic moiety, M, is selected from the group Na, Li, Zn, Mg, Cu, Pd, Pt, Sn, Al, and B, preferably Li, Mg, or Zn.

[0329] If an metallic nucleophile is used, it may be made in situ by methods known to those of skill in the art or formed by methods known to those of skill in the art and then added to a solution. In either case, it is preferred that the compound of formula II is added to a solution containing the nucleophile.

[0330] Preferably, the nucleophile is an acetylide (i.e., R8—C≡C—M) with Li, Mg, or Zn as the counterion. Acetylides are well known in the art. Preferably, R8—C≡C—M is formed in situ by addition of a strong base to a solution containing R8—C≡C—H. Strong bases are well known to those of skill in the art and include, but are not limited to n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium. Preferably, the strong base is n-butyl lithium. The acetylide may also be made in situ by addition of a strong base to a dihalo-olefin (e.g., Br2C═CHR8).

[0331] In the nucleophilic addition reactions the stochiometery is preferably about one equivalent of benzoxazinone to about 1.0 to 2.5 equivalents of nucleophile (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5). More preferable about 1.8 to 2.4 equivalents are used. Even more preferably, 2.1 equivalents of nucleophile are used. It is noted that less than one equivalent may be used, but care must be taken as N—H deprotonation reaction may compete with nucleophilic addition. It is preferable to run the additions from −40 to 0° C., more preferably about −20° C. The solvent used is preferably THF, but any aprotic solvent, such as dimethyl ether, diethyl ether, benzene, or toluene, should be suitable. Non-reaction with the nucleophile, specifically the nucleophilic anion, is the only criterion for exclusion of a solvent.

[0332] An additional example of the utility of the final nucleophilic addition step of the present invention is shown in Scheme 13.

[0333] A preferred example of the present process is shown in Scheme 14.

[0334] In Scheme 14, the preferred temperature of the carbonylation reaction is from about 104 to about 110° C. and the preferred temperature of the acetylide addition is about −20° C.

[0335] One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, both of the following stereochemistries are considered to be a part of the present invention.

[0336] When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940.

[0337] Another method of forming a compound wherein Z is C(OH) involves incubating NNRTI, or a derivative thereof, in microsomes obtained from male rats, male rhesus monkeys or humans, preferably male rats. In addition, it is preferable to orally dose the male rats with NNRTI prior to collection of their livers and microsomal isolation. This procedure will be described in the following Example section.

[0338] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

[0339] Abbreviations used in the Examples are defined as follows: “° C” for degrees Celsius, “d” for doublet, “dd” for doublet 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, “MS” for mass spectroscopy, “nmr” or “NMR” for nuclear magnetic resonance spectroscopy, “t” for triplet, “TLC” for thin layer chromatography, “EDAC” for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “DIPEA” for diisopropylethylamine, “TBAF” for tetrabutylammonium fluoride, “LAH” for lithium aluminium hydride, and “TEA” for triethylamine.

Example 1

[0340]

Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4′-Chloro-2′-methoxy-2,2-dimethylpropionanilide

[0341] A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 ML of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0° C. The mixture was treated with aqueous Na2CO3 until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 then brine. The solution was dried (MgSO4) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH2Cl2 and cooled to 0° C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2 h at 0° C. the mixture was quenched with 0.5 N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1 N HCl, dilute K2CO3, water, and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give 4.68 g (97%) of 4′-chloro-2′-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66-69° C. 1H NMR (300 MHz, CDCl3) δ8.36(d, 1H, J=8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J=8.8, 2.2 Hz); 6.86(d, 1H, J=2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C12H17NO2Cl (M+H)+: 242.0948, found: 242.0943. Analysis calculated for C12H16NO2Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.

Part B: Preparation of 2′-Amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone

[0342] To a stirred, cooled (−20° C.) solution of 12.1 g (50 mmol) of 4′-chloro-2′-methoxy-2,2-dimethylpropionanilide in 150 mL of THF was added 87 mL (115 mmol) of 1.3 M s-BuLi in cyclohexane over 15 min. The dark solution was warmed to 0° C. and stirred for 1.2 h. The solution was re-cooled to −20° C. and treated with 14.3 mL (120 mmol) of ethyl trifluoroacetate over 5 min. The reaction was warmed to 0° C., stirred 15 min., and quenched with saturated aqueous NaHCO3. The mixture was extracted with hexanes and then with ether, and the combined organic extracts were washed sequentially with 0.5 N HCl, water, and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The crude amide was dissolved in 20 mL of 1,2-dimethoxyethane and treated with 100 mL of 6 N aqueous HCl. The mixture was stirred at reflux for 2 h, cooled to 0° C., and brought to pH 9 with K2CO3. The mixture was extracted twice with ether, and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give an oily solid. This crude product was recrystallized from hexanes and a minimal ammount of ethyl acetate to give 7.75 g (61%) of 2′-amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone as yellow needles, mp 124.5-125.50° C. 1H NMR (300 MHz, CDCl3) δ7.32-7.35(m, 1H); 6.87(br. s, 2H); 6.84(d, 1H, J=1.8 Hz); 3.92(s, 3H). High resolution mass spec: calculated for C9H8NO2ClF3 (M+H)+: 254.0196, found: 254.0194. Analysis calculated for C9H7NO2ClF3: C, 42.62; H, 2.78; N, 5.52; Cl, 13.98. Found: C, 42.52; H, 3.04; N, 5.40; Cl, 13.74.

Part C: Preparation of 2′-Amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone

[0343] To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2′-amino-5′-chloro-3′-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH2Cl2 was added 550 mL (550 mmol) of 1 M BBr3 in CH2Cl2 over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction was carefully quenched by dropwise addition of aqueous Na2CO3 until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 30.1 g (100%) of 2′-amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120-122° C. 1H NMR (300 MHz, CDCl3) δ7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C8H6NO2ClF3 (M+H)+: 240.0039, found: 240.0029.

Part D: Preparation of 2′-Amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone

[0344] To a stirred, cooled (0° C.) solution of 29.3 g (122 mmol) of 2′-amino-5′-chloro-3′-hydroxy-2,2,2-trifluoroacetophenone in 280 mL of DMF was added 23.8 g (350 mmol) of imidazole followed by 66 g (250 mmol) of t-butyldimethylsilyl trifluoromethanesulfonate over 10 min. The reaction was stirred 5 h at 0° C. and diluted with 800 mL of 1:1 ether-hexanes. The solution was washed twice with water and once with brine, dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The crude product was rapidly passed through an 800 g plug of silica gel (elution with hexanes followed by 6:1 hexanes-ether) to afford, after evaporation of solvent, 42.5 g (98%) of 2′-amino-5′-chloro-3-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone as a yellow oil. The product solidified after extended evacuation at 0.01 torr to give a yellow solid, mp 45-46.5° C. 1H NMR (300 MHz, CDCl3) δ7.34-7.36(m, 1H); 6.85(d, 1H, J=2.2 Hz); 6.7-6.8(br. s, 2H); 1.03(s, 9H); 0.30(s, 6H). High resolution mass spec: calculated for C14H20NO2ClF3Si (M+H)+: 354.0904, found: 354.0900. Analysis calculated for C14H19NO2ClF3Si: C, 47.52; H, 5.41; N, 3.97; Cl, 10.02. Found: C, 47.71; H, 5.36; N, 3.87; Cl, 10.02.

Part E: Preparation of (+/−)-2-(2-Amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

[0345] To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5 M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to −20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2′-amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1 N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (+/−)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125-126° C. 1H NMR (300 MHz, CDCl3) δ7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C19H26NO2ClF3Si (M+H)+: 420.1373, found: 420.1363.

Part F: Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0346] To a stirred, cooled (−25° C.) solution of 28.8 g(68.6 mmol) (+/−)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 600 mL of toluene was added 36 mL (206 mmol) of N,N-diisopropylethylamine followed by 38.9 mL (75 mmol) of a 1.93 M solution of phosgene in toluene over 20 min. The solution was stirred an additional 20 min. at −25° C. after which time it was warmed to −50° C. and quenched with water. The mixture was washed with 100 mL of 1 N aqueous HCl then brine, dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was dissolved in 200 mL of THF, cooled to 0° C., and treated with 40 mL of 1 M tetra-(n-butyl)ammonium fluoride in THF over 5 min. The solution was diluted with 200 mL of ether and washed sequentially with 1 M aqueous citric acid, water, and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel. Elution with 1:3 ether-hexanes then 1:1 ether-hexanes afforded, after concentration under reduced pressure, 21.4 g (94%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). High resolution mass spec: calculated for C14H10NO3ClF3 (M+H)+: 332.0301, found: 332.0283.

Example 2

[0347]

Preparation of (−)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0348] Chromatography of 22 g of racemic 6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (I) on a Chiralpak AD-7.5 cm I.D.×30 gm column using 20% methanol-80% carbon dioxide as the mobile phase at a flow rate of 120 mL/min. gave two fractions. The faster-eluting fraction was concentrated and recrystallized from hexanes and a minimal amount of ethyl acetate to afford 5 g of the title compound as a white solid, mp 170-172° C. 1H NMR (300 MHz, CDCl3) δ8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). [α]Nad (25° C.)=−32°, c=0.28. Analysis calculated for C14H9NO3ClF3: C, 50.70; H, 2.75; N, 4.22; Cl, 10.69. Found: C, 50.74; H, 2.86; N, 4.26; Cl, 10.77.

Example 3

Preparation of (−) 6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one by Rat Hepatic Microsomal Fractions

[0349] Incubation of (−) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI) with hepatic microsomes from rats previously treated with NNRTI and cofactors required to support cytochromes P450 oxidative metabolism resulted in the formation of one major metabolite separable from NNRTI by reverse phase high performance liquid chromatography (HPLC). Incubations were conducted for 2 hours at 37° C. in a physiological buffer. After precipitating the protein with acetonitrile, the supernatants were dried under nitrogen and reconstituted in a mixture of 55:45 (v/v) acetonitrile:0.01% aqueous formic acid (pH 3.5) and injected onto the HPLC system. The column effluent was monitored at 247 nm. The single peak observed to elute at approximately 4 minutes was collected and combined from multiple injections. Final purification was accomplished using the same HPLC system and a linear gradient developed over 15 minutes starting with solvent A (50:50 (v/v) methanol:0.01% aquesous formic acid, pH 3.5) and increasing the proportion of solvent B (80:20 v/v methanol:0.01% aqueous formic acid pH 3.5), then holding solvent B constant for 5 minutes before re-equilibration with solvent A. The single, sharp peak eluting at approximately 16.5 minutes was collected and dried under vacuum.

[0350] The purified metabolite described above was dissolved in 0.2 mL of methanol-d4 and placed in a 3 mm NMR tube. The proton NMR spectrum was acquired using a 30 degree pulse, a 4 second acquisition time and a 2 second relaxation delay during which the residual water signal was suppressed by selective irradiation. The spectrum was referenced to solvent at 3.30 ppm.

Example 4

[0351]

Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4′-Chloro-2′-fluoro-2,2-dimethylpropionanilide

[0352] To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO3 and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5-71° C. 1H NMR (300 MHz, CDCl3) δ8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). 19F NMR (282 MHz, CDCl3) δ−129.8. High resolution mass spec: calculated for C11H14NOClF(M+H)+: 230.0748, found: 230.0760.

Part B: Preparation of 2′-(Trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone

[0353] To a stirred, cooled (−50° C.) solution of 0.92 g (4.0 mmol) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide in 10 mL of THF was added 2.5 mL (4.2 mmol) of 1.7 M t-BuLi in pentane over 5 min. The solution was stirred for 5 min. and treated with 1.0 mL (8.4 mmol) of ethyl trifluoroacetate over 2 min. The reaction was warmed to ambient temperature, stirred 15 min., and quenched with 1N aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed sequentially with water then brine. The solution was dried(MgSO4) and concentrated under reduced pressure to give an oil. The crude amide was chromatographed on silica gel (elution with 3:1 hexanes-ether followed by 1:1 hexanes-ether) to give 570 mg (43%) of 2′-(trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone as an off-white solid. 1H NMR(300 MHz, CDCl3) δ8.68(s, 1H); 7.45-7.47(m, 1H) ; 7.08(dd, 1H, J=9.5, 2.6 Hz); 1.3(s, 9H). High resolution mass spec: calculated for C13H13NO2ClF4(M+H)+: 326.0571, found: 326.0579.

Part C: Preparation of 2′-Amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone

[0354] A stirred solution of 0.35 g (1.07 mmol) of 2′-(trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K2CO3. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give 240 mg (92%) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. 1H NMR (300 MHz, CDCl3) δ7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C8H4NOClF4(M+): 240.9918, found: 240.9914. 19F NMR (282 MHz, CDCl3) δ−132.7(s, 1F), −70.6(s, 3F).

Part D: Preparation of (+/−)-2-Amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

[0355] To a stirred, cooled (0° C.) solution of 2.0 mL (7.0 mmol) of 3.5 M cyclopropylacetylene in toluene was added 2 mL of THF followed by 2.8 mL (7.0 mmol) of 2.5 M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at 0° C., warmed to RT, and stirred a further 20 min. The reaction was cooled to 0° C. and treated with a solution of 300 mg (1.24 mmol) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of THF over 2 min. The solution was stirred an additional 10 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 0.5 N citric acid. The mixture was extracted with ether, and the organic extract was washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 185 mg (49%) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol as an off-white solid, mp 131-135° C. 1H NMR (300 MHz, CDCl3) δ7.34-7.36(m, 1H); 7.04(dd, 1H, J=10.4, 2.4 Hz); 4.58(br. s, 2H); 3.82(br. s, 1H); 1.35-1.44(m, 1H); 0.80-0.99(m, 4H). 19F NMR (282 MHz, CDCl3) δ−131.5(s, 1F), −80.5(s, 3F). High resolution mass spec: calculated for C13H11NOClF4(M+H)+: 308.0470, found: 308.0465.

Part E: Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0356] To a stirred, cooled (−25° C.) solution of 144 mg (0.47 mmol) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL (1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperatue and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine. The solution was dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). 19F NMR (282 MHz, CDCl3) δ−132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C14H9NO2ClF4(M+H)+: 334.0258, found: 334.0244.

Example 5

Preparation of (+/−)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Amino-5-methylbenzoyl N-methoxy-methylamide

[0357] To a solution of 2-amino-5-methylbenzoic acid (7.6 g, 50.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (12.5 g, 60.4 mmol) in acetonitrile (80 mL) were added triethylamine (15.8 mL, 60.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g, 55.3 mmol) and the mixture was stirred at room temperature for 5 hours. At the end of the stirring, methylene chloride (200 mL) was added and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow syrupy residue. It was purified by column chromatography on silica gel with elution by 15:85 ethyl acetate-hexane to give pure 2-amino-5-methylbenzoyl N-methoxy-methylamide.

Part B: Preparation of 2-Amino-5-methylphenylisopropylketone

[0358] To a solution of 2-amino-5-methylbenzoyl N-methoxy-methylamide (472.6 mg, 2.4 mmol) in dry THF (3 mL) at −20° C. were added diisopropylethylamine (0.84 mL, 4.8 mmol) and chlorotrimethylsilane (0.61 mL, 4.8 mmol) dropwise and the mixture was stirred for 1 hour at −20˜5° C. It was then cooled to −20° C. again and was added 2M-isopropyl magnesium chloride in THF (4.8 mL, 9.6 mmol) dropwise. The mixture was stirred for 1.5 hours at −20˜10° C. After cooling to 0° C. was added saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with 1N-HCl, water, saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. It was evaporated in vacuo to give an oily residue. Column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane affored pure 2-amino-5-methylphenylisopropylketone (201 mg) as an oil.

Part C: Preparation of 2-Amino-5-methyl-α-cyclopropylethynyl-α-isopropyl-benzyl alcohol

[0359] To a solution of cyclopropylacetylene (105 mg, 1.59 mmol) in THF (3 mL) at −20° C. was added 1.6M-nBuLi in hexane (0.96 mL, 1.54 mmol) dropwise and the mixture was stirred at the same temperature for 0.5 hours. Then a solution of 2-amino-5-methylphenylisopropylketone (94.5 mg, 0.53 mmol) in THF (3 mL) was added and the mixtire was stirred for 5 hours at −20˜20° C. The reaction was quenched with saturated NH4Cl and the product was extraxted with ethyl acetate. After washing with brine, the extract was dried over anhydrous sodium sulfate and evaporated to give the crude amino-alcohol as an oil.

Part D: Preparation of 4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0360] To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at −20° C. were added diisopropylethylamine (0.29 mL, 1.89 mmol) and 0.31 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at −20˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na2SO4 and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) provided pure titled compound (38 mg).

Example 6

[0361] Preparation of (+/−)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Iodo-4-methylaniline

[0362] To a stirred solution of p-toluidine (5 g, 46.7 mmol) in methylene chloride (25 mL) was added a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (75 mL) Then was added iodine (11.26 g, 44.33 mmol) in small portions and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with saturated NaHSO3 and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over Na2SO4, and evaporated in vacuo to give a crude 2-iodo-4-methylaniline.

Part B: Preparation of Trimethylacetyl 2-iodo-4-methylanilide

[0363] To a stirred mixture of 2-iodo-4-methylaniline (46.7 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride dropwise over a period of 15 minutes and the mixture was stirred vigorously for 45 minutes at room temperature. The product was extracted with chloroform, washed with water and dried over Na2SO4. Evaporation of the solvent in vacuo affored the pivaloyl amide as a solid. It was recrystallized from ethyl acetate and hexane.

Part C: Preparation of Trimethylacetyl 4-methyl-2-trifluoroacetylanilide

[0364] To a stirred solution of trimethylacetyl 2-iodo-4-methylanilide (10.7 g, 33.75 mmol) in 50 mL of dry THF at −78° C. was added 1.6M-nBuLi in hexane (48.5 mL, 77.6 mmol) dropwise and the mixture was stirred for an hour at the same temperature. Then ethyl trifluoroacetate (9.6 mL, 81 mmol) was added dropwise and the mixture was stirred for 0.5 hours at −78° C. At the end of the stirring saturated NH4Cl solution was added and the mixture was warmed up to room temperature. The product was extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g, 13% yield) and trimethylacetyl 4-methylanilide (major product).

Part D: Preparation of 4-Methyl-2-trifluoroacetylaniline

[0365] To a solution of trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g) in 10 mL of dimethoxyethane was added 6N-HCl (5 mL) and the mixture was refluxed for 2.5 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO3. The product was extracted with ethyl acetate, washed with brine, and dried over Na2SO4. Evaporation of the solvent provided the aniline as a yellow solid in near quantitative yield.

Part E: Preparation of 2-Amino-5-methyl-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

[0366] To stirred solution of 3-methyl-1-butyne (0.26 mL, 2.59 mmol) in 5 mL of dry THF at −20° C. was added 1.6M-nBuLi in hexane (1.4 mL, 2.24 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 1 hour with stirring. It was the cooled back to −20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for an hour at −20˜0° C. was added saturated NH4Cl (−5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na2SO4. The solvents were evaporated off to give crude amino-alcohol as a yellow solid residue.

Part F: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0367] To a solution of the crude amino-alcohol (0.74 mmol) in dry toluene (7.5 mL) at −20° C. were added diisopropylethylamine (0.39 mL, 2.22 mmol) and 0.42 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at −20˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na2SO4 and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) and recrystallization (EtOAc and hexane) provided pure titled compound (61 mg, 28% yield for 2 steps) as white crystals, mp 198-199° C.

Example 7

Preparation of (+/−)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4-Amino-3-iodo-acetophenone

[0368] To a solution of 4-aminoacetophenone (5 g, 37 mmol) in 15 mL of CH2Cl2 and 75 mL of water was added sodium bicarbonate (3.73 g, 44.4 mmol) followed by iodine (8.92 g, 35.1 mmol), and the mixture was stirred for 5 hours at room temperature. The reaction was quenched by portionwise addition of sodium bisulfite until the iodine color disappeared. The product was extracted with CH2Cl2, washed with water, dried over Na2SO4. Evaporation of the solvent gave crude 4-amino-3-iodo-acetophenone as solid (7.92 g).

Part B: Preparation of Trimethylacetyl 2-iodo-4-acetylanilide

[0369] To a stirred mixture of 4-amino-3-iodo-acetophenone (7.92 g, 30.3 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride (7.8 mL, 63.7 mmol) dropwise over a period of 15 minutes and the mixture was stirred vigorously for 16 hours at room temperature. The product was extracted with chloroform, washed with water and dried over Na2SO4. Evaporation of the solvent in vacuo affored the pivaloyl amide as a brown oil. It was column chromatographed (silica gel, 1:9 EtOAc-hexane) to afford pure trimethylacetyl 2-iodo-4-acetylanilide (5.83 g) as white crystals.

Part C: Preparation of Trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide

[0370] To a stirred solution of trimethylacetyl 2-iodo-4-acetylanilide (2.9 g, 8.45 mmol) and 1,3-propanedithiol in 25 mL of THF at 0° C. was added borontrifluorate etherate (0.63 mL, 5.1 mmol) and the mixture was stirred for 16 hours at room temperature. Then was added second portion of borontrifluorate etherate (0.63 mL, 5.1 mmol) and it was continued to stir for 44 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water saturated NaHCO3 and brine, dried over MgSO4 and evaporated to a clear oil. It was column chromatographed (silica gel, 5:95 EtOAc-hexane) to give pure thioaketal as a foamy solid (2.85 g).

Part D: Preparation of Trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide

[0371] To a stirred solution of trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide (2.29 g, 5.26 mmol) in 20 mL of dry THF at −78° C. was added 1.6M-nBuLi in hexane (6.7 mL, 10.7 mmol) dropwise and the mixture was stirred for 45 minutes at the same temperature. Then ethyl trifluoroacetate (12.6 mL, 105.2 mmol) was added dropwise and the mixture was gradually warmed up to room temperature over a period of 3 hours. At the end of the stirring saturated NH4Cl solution was added, and the product was extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) and trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)anilide (1.33 g).

Part E: Preparation of 4-(2-Methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline

[0372] To a solution of trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) in 10 mL of methanol was added 6N-HCl (2 mL) and the mixture was refluxed for 4 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO3. The product was extracted with ethyl acetate, washed with brine, and dried over Na2SO4. Evaporation of the solvent provided the desired 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline as a bright yellow solid.

Part F: Preparation of 2-Amino-5-(2-methyl-1,3-dithian-2-yl)-a-cyclopropylethynyl-a-trifluoromethyl-benzyl alcohol

[0373] To stirred solution of cyclopropylacetylene (122 mg, 1.9 mmol) in 5 mL of dry THF at −20° C. was added 1.6M-nBuLi in hexane (0.99 mL, 1.59 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 45 minutes with stirring. It was the cooled back to −20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for 1.5 hours at −20-0° C. was added saturated NH4Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na2SO4. The solvents were evaporated off to give crude amino-alcohol as a bright yellow solid residue.

Part G: Preparation of 4-cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0374] To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at −20° C. were added diisopropylethylamine (0.28 mL, 1.59 mol) and 0.3 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1.5 hours at −20˜0° C. and for 5 minutes at room temperature. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na2SO4 and evaporated in vacuo to give an oily residue. It was purified by preparative TLC on a silica gel plate (3:7 EtOAc-hexane) to give pure titled compound (77 mg).

Part H: Preparation of 6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0375] To a stirred solution of 4-cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (64 mg, 0.154 mmol) in 5 mL of methanol and 0.5 mL of water were added mercuric chloride (92 mg, 0.339 mmol) and mercuric oxide (50 mg, 0.23 mmol), and the mixture was refluxed for 2 hours. After cooling it was filtered through Celite and rinsed with EtOAc. The filtrate was washed with water and brine, dried over MgSO4, and evaporated to give an oily residue. Column chromatography (silica gel, 2:8 EtOAc-hexane) afforded pure 6-6cetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Example 8

Preparation of (+/−)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol

[0376] To a solution of 3-methyl-1-butyne (0.73 g, 10.7 mmol) in dry THF (5 mL) at −20° C. was added 1.6M-nBuLi in hexane dropwise and the mixture was stirred for 15 minutes at the same temperature. Then a solution of 2,3-diflupro-6-triphenylmethylamino-α,α,α-trifluoroacetophenone (1 g, 2.14 mmol) in 5 mL of THF was added dropwise at −20° C. After stirring for 10 minutes, the cooling bath was removed and it was allowed to warm up to room temperature. The mixture was stirred for 45 minutes and was poured into saturated NH4Cl. The product was extracted with ether, washed with saturated NaHCO3 and brine and dried over MgSO4. Evaporation of solvent gave an oily residue, which was crystallized from methanol, ether and hexane mixture to provide pure product (0.432 g, 37.6%).

Part B: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol

[0377] To a solution of 2,3-difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol (0.431 g, 0.8 mmol) in 5 mL of dry THF was added 1M-lithium aluminumhydride in THF (2.41 mL, 2.41 mmol) at room temperature and the mixture was stirred for 1 hour. The reaction was quenched with several drops of saturated NH4Cl and was added about 20 mL of ether. After stirring for 10 minutes it was washed with saturated NaHCO3 and dried over MgSO4. Evaporation of the solvent gave the desired trans-olefinic compound in near quantitative yield.

Part C: Preparation of 6-Amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-(-trifluoromethyl-benzyl alcohol

[0378] A solution of the crude product of step 2 (0.8 mmol) and 1.33 mL of c-HCl in methanol (5 mL) was stirred for 1 hour at room temperature and basified with saturated NaHCO3. It was extracted with ether and washed with brine. After drying over MgSO4, the solvent was evaporated off to give an oily residue. It was crystallized from hexane to give pure 6-amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol (0.184 g, 78%).

Part D: Preparation of 5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifloromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0379] To a solution of the crude amino-alcohol (0.13 g, 0.44 mmol) in dry toluene (5 mL) at 0° C. were added diisopropylethylamine (0.23 mL, 1.32 mmol) and 0.24 mL of 2M-phosgene in toluene (0.48 mmol) dropwise and the mixture was stirred for 5 minutes at 0° C. and for 30 minutes at room temperature. After addition of saturated NH4Cl (5 mL) it was extracted with ether and the organic layer was washed with brine. It was dried over MgSO4 and evaporated in vacuo to give an oily residue. It was purified by column chromatography on Silica gel (1:9 ether-hexane) to give pure titled compound (0.051 g, 36%).

Example 9

Preparation of (+/−)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of N-trimethylacetyl-3,4-difluoroanilide

[0380] To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° C. was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl and extracted with methylene chloride (3×100 mL) and the combined organic extracts were dried over anhydrous NaSO4 and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92% yield).

Part B: Preparation of N-Trimethylacetyl 5,6-difluoro-2-trifluoroacetylanilide

[0381] To a solution of N-trimethylacetyl-3,4-difluoroanilide (4.0 g, 14.6 mmol) in THF (60 mL) at −78° C. was added dropwise 1.6M nBuLi in hexane (22 mL, 35 mmol) and the resulting reaction mixture was allowed to stir at −78° C. for 1 h. The Ethyl trifluoroacetate (4 mL, 33.6 mmol) is added to the reaction mixture and the resulting solution was allowed to stir with warming to room temperature (ice bath removed after the addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH4Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part C: Preparation of 5,6-Difluoro-2-trifluoroacetylaniline

[0382] To a solution of the orange oil in DME (15 mL) was added 6N HCl (75 mL) and the resulting mixture was allowed to reflux for 2 h. The reaction mixture was cooled, made basic with solid Na2CO3 and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO2, 20% EtOAc-hexanes eluant) provided 2110 mg of 5,6-Difluoro-2-trifluoroacetylaniline as a yellow solid (3285 mg theoretical, 64% yield).

Part D: Preparation of 2-Amino-5,6-difluoror-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

[0383] To a solution of 3-methyl-1-butyne (0.36 mL, 3.56 mmol) in THF (6 mL) at 0° C. was added 1.6M nBuLi in hexane (2.2 mL, 3.56 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5,6-Difluoro-2-trifluoroacetylaniline (200 mg, 0.89 mmol) in THF (6 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH4Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part E: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0384] To a solution of amino-alcohol (crude product, 1.21 mmol) in toluene (4 mL) at 0° C. was added N,N-diisopropylethylamine (0.54 mL, 3.12 mmol) followed by a solution of 1.93M phosgene in toluene (0.6 mL, 1.16 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO2, 20% EtOAc-hexanes eluant) provided 45 mg of the title compound (284 mg theoretical, 16% yield).

Example 10

Preparation of 2-Trifluoroacetylaniline

Part A: Preparation of 2-Amino-α-trifluoromethyl-benzyl alcohol

[0385] To a solution of amino ketone (155 mg, 0.7 mmol) in methanol (2 mL) at room temperature was added Pd(OH)2 (20 mg) and hydrogenated (H2/balloon) for 2 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The solids were triturated with ether (20 mL) and dried in vacuo to give 117 mg of 2-Amino-α-trifluoromethyl-benzyl alcohol as a pale yellow solid. (134 mg theoretical, 87% yield).

Part B: Preparation of 2-Trifluoroacetylaniline

[0386] To a slurry of amino alcohol (520 mg, 2.72 mmol) in methylene chloride (5 mL) at room temperature was added MnO2 (10×wt, 5 g) and the resulting reaction mixture was allowed to stir at room temperature for 0.75 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give an orange oil which is used without further purification due to instability of compound.

Example 11

Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

Part A: Preparation of 2-Amino-6-fluorobenzoyl N-methoxy-methylamide

[0387] To a solution of 2-amino-6-fluorobenzoic acid (5 g, 32.26 mmol) in AcCN (100 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (3.8 g, 38.71 mmol), EDAC (7.4 g, 38.71 mmol) followed by triethylamine (5.38 mL, 38.71 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was poured onto saturated NaHCO3 and extracted with EtOAc (3×100 mL). The combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 25% EtOAc-hexanes eluant) provided 4.29 g of the desired compound (5.87 g theoretical, 73% yield).

Part B: Preparation of 2-Triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide

[0388] To a solution of 2-amino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 2.14 mmol) in methylene chloride (10 mL) at room temperature was added N,N′-diisopropylamine (1.2 mL, 6.4 mmol) followed by triphenylmethyl bromide (830 mg, 2.57 mmol) and the resulting reaction mixture is allowed to stir at room temperature for 0.5 h. The reaction mixture was poured onto water and extracted with methylene chloride (3×50 mL) and the combined organic extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 10% EtOAc-hexanes) provided 832 mg of the desired compound (942 mg theoretical, 88% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluorobenzaldehyde

[0389] To a solution of 2-triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 0.68 mmol) in THF (4 mL) at −78° C. was added lithium aluminum hydride (30 mg, 0.82 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (dry ice bath removed after addition of reagent) for 1 h. The reaction mixture was quenched with 20% KHSO4 and extracted with EtOAc (3×100 mL) and the combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 5% EtOAc-hexanes) provided 182 mg of the title compound (260 mg theoretical, 70% yield).

Part D: Preparation of 2-Amino-6-fluoro-α-trifluoromethyl-benzyl alcohol

[0390] To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).

Part E: Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

[0391] To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO2, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Example 12

Preparation of (+/−)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 5-(t-Butoxycarbonylamino)-2-chloropyridine

[0392] To a stirred solution of 2.83 g (22.0 mmol) of 5-amino-2-chloropyridine in 20 mL of anhydrous THF was added 44.0 mL(44.0 mmol) of a 1.0M solution of NaHMDS in toluene over 5 min. The dark solution was stirred 15 min. and 4.36 g (20 mmol) of di-t-butyldicarbonate in 5 mL of THF was introduced over 2 min. The thick mixture was stirred an additional 1 h and poured into 0.5N aq. HCl. The solution was extracted with ethyl acetate, and the organic extract was washed with saturated aq. NaHCO3, water, and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel(gradient elution with 3:1 hexanes-ether then ether) to give, after evaporation of solvents, 3.81 g (83%) of 5-(t-butoxycarbonylamino)-2-chloropyridine as a white solid, mp 122-123° C. 1H NMR (300 MHz, CDCl3) δ8.23(d, 1H, J=2 Hz); 7.98(br. d, 1H, J=8 Hz); 7.25(d, 1H, J=8 Hz); 6.58(s, 1H); 1.52(s, 9H).

Part B: Preparation of 2-(5-(t-Butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

[0393] To a stirred, cooled (−50° C.) solution of 643 mg (2.8 mmol) of 5-(t-butoxycarbonylamino)-2-chloropyridine in 8 mL of anhydrous THF was added 4.7 mL(7.0 mmol) of t-BuLi in pentane over 3 min. The solution was stirred an additional 35 min. at −50° C. after which time 1 mL(large excess) of 4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-one. The solution was stirred an additional 20 min., warming to ambient temperature. The reaction was poured into 10% aq. citric acid, and the mixture was extracted with 1:1 ether-ethyl acetate. The organic extract was washed with saturated aq. NaHCO3, then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel(gradient elution with 6:1 then 3:1 hexanes-ethyl acetate) afforded, after removal of solvent, 620 mg (56%) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an amorphous solid. Mass spec.(NH3—CI): 391((M+H)+, 100%); 291((M+H-t-Boc)+, 49%). 1H NMR(300 MHz, CDCl3) δ9.08(br. s, 1H); 8.19(br. s, 1H); 7.59(s, 1H); 150 (s, 9H); 1.37-1.43(m, 1H); 0.81-0.97(m, 4H).

Part C: Preparation of 4-Cyclopropylethynyl-6-chloro-4 trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0394] To a stirred solution of 230 mg (0.59 mmol) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 6 mL of anhydrous toluene was added 0.92 mL of a 2.5M solution of n-BuLi in hexanes. The solution was brought to reflux and stirred 10 min. after which time an additional 0.10 mL of n-BuLi was added. The solution was stirred an additional 20 min. at reflux and cooled to ambient temperature. The reaction was poured into 10% aq. citric acid and extracted with ether. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel(elution with 3:1 hexanes-ethyl acetate) afforded 25 mg (13%) of 4-cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one as an amorphous solid. Mass spec.(NH3—CI): 334((M+NH4)+, 100%); 317((M+H)+, 100%); 273((M+H—CO2)+, 21%). 1H NMR(300 MHz, CDCl3) δ9.62(br. s, 1H); 8.17(s, 1H); 7.44(s, 1H); 1.36-1.44(m, 1H); 0.82-0.99(m, 4H).

Example 13

Preparation of (+/−)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4-Chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0395] To a stirred, gently refluxing solution of 7.0 g (31.9 mmol) of 2-amino-5-methoxy-(1′,1′,l′-trifluoro)acetophenone in 27 mL of anhydrous toluene was added 24.8 mL(47.9 mmol) of a 1.93M solution of phosgene in toluene over 2 min.(Note: A dry ice-acetone cold finger is used to condense phosgene during this reaction.). The solution is warmed at reflux for 2 h, cooled, and charged with 15 mL of hexanes. Upon stirring overnight at ambient temperature a precipitate formed which was filtered, washed with hexanes, and briefly air-dried to give 5.06 g (60%) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid mp 112-114° C. 1H NMR(300 MHz, CDCl3) δ9.05(br. s, 1H); 7.07(br. s, 1H); 7.02(dd, 1H, J=8, 2 Hz); 6.90(d, 1H, J=8 Hz); 3.83(s, 3H).

Part B: Preparation of 6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0396] To a solution of 0.15 mL of 2-methoxyethanol in 5 mL of anhydrous THF at ambient temperature was added 20 mg of 100% sodium hydride. After 20 min, 100 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone was added, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous ammonium chloride and was extracted with ethyl acetate. The organic extracts were washed with brine, dried and evaporated. The crude product was purified by preparative TLC on silica gel (elution with ethyl acetate/hexanes 1:1) to afford a material which was crystallized from ethyl acetate-hexanes to afford 81 mg (71%) of the title compound.

Example 14

Preparation of (+/−)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0397] To a solution of 230 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone in 20 mL of dry ether was added 0.250 mL of n-propylamine. After stirring 30 min at ambient temperature, the solution was partitioned between ether and water, and the organic layer was washed with brine, dried, and evaporated. The crude product was purified by column chromatography on silica gel (elution with ethyl acetate-hexanes 1:3) to afford after crystallization from hexanes 24 mg (9.7%) of the title compound.

Example 15

Preparation of (+/−)-6-Chloro-4-[2-(furan-2-yl)ethynyl]-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0398] To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at −20° was added dropwise 31.0 mL of 1.6 M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to −50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to −35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.

Example 16

Preparation of (+/−)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0399] To a stirred, cooled(−78° C.) solution of 0.5 g (excess) of 1-butyne in 3 mL of anhydrous THF was added 1.6 mL (4.0 mmol) of a 2.5M solution of n-BuLi in hexanes over 3 min. The solution was stirred 5 min. and charged with 266 mg (l.00 mmol) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a single portion. The solution was warmed to −10° C. over 20 min., whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO3 then brine. The solution was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexanes to afford 144 mg (48%) of 4-(1-butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 161-162° C. 1H NMR(300 MHz, CDCl3) δ8.81(br. s, 1H); 7.07(d, 1H, J=2 Hz); 6.94(dd, 1H, J=9, 2 Hz); 6.81(d, 1H, J=8 Hz); 3.82(s, 3H); 2.34(q, 2H, J=7 Hz); 1.22(t, 3H, J=7 Hz).

Example 17

Preparation of (+/−)-4-(1-hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0400]

Part A: Preparation of Methyl 1-hydroxy-1-cyclopropanecarboxylate

[0401] 1-Hydroxy-1-cyclopropanecarboxylic acid (587 mg, 5.75 mmol) was dissolved in methanol (20 mL) under nitrogen. Thionyl chloride (4 drops) were added and the reaction was stirred overnight at room temperature. Triethylamine was then added until the reaction was alkaline as judged by moistened pH paper. The solvent was then removed on the rotary evaporator.

Part B: Preparation of Methyl 1-triisopropylsilylhydroxy-1-cyclopropanecarboxylate

[0402] The residue was then dissolved in dry methylene chloride (20 mL) under a nitrogen atmosphere. Dry 2,6-lutidine (distilled from calcium hydride, 1.0 mL, 8.62 mmol) was added and the reaction cooled to 0° C. Triisopropylsilyl trifluoromethanesulfonate (2.3 mL, 8.62 mmol) was then added dropwise and stirring continued for 1 hour. The reaction was then poured into 1 N HCl and extracted with hexanes. The organic layer was washed successively with water and brine, then dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (silica) using 19:1 hexanes/ethyl acetate. This provided the silyl methyl ester in 87% yield for two steps (1.35 g)

Part C: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanemethanol

[0403] The silyl methyl ester (1.05 g, 3.86 mmol) was dissolved in hexane (12 mL) under nitrogen. The reaction was cooled in a dry ice/acetone bath and a solution of diisobutylaluminum hydride (1.5 M in toluene, 6.4 mL, 9.64 mmol) was introduced dropwise. Stirring was continued for 2 hours when the reaction was quenched by the addition of methanol (12 mL) The reaction was warmed to room temperature and poured into a saturated aqueous solution of sodium potassium tartrate. The clarified solution was extracted with ether and the organic layer washed with water and brine. After drying over magnesium sulfate, the product was isolated by filtration and evaporation (894.4 mg, 95%). This material was of sufficient purity for direct use in the next step.

Part D: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanecarboxaldehyde

[0404] A 100 mL flask was flame-dried and sealed under nitrogen. The flask was charged with dry methylene chloride (11 mL) and oxalyl chloride (0.44 mL, 5.07 mmol). The solution was cooled in a dry ice/acetone bath and dimethylsulfoxide was introduced (0.73 mL, 10.3 mmol). After stirring for 5 minutes, the starting material (1.065 g, 4.36 mmol) was added as a solution in methylene cholride (5.0 mL). After stirring for 20 minutes, triethylamine (3.1 mL, 22.4 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was then poured into 1 N HCl and extracted with ether. The organic layer was washed twice with water and once with brine. Drying with magnesium sulfate, filtration and evaporation then provided the crude product. This material was of sufficient purity for use in the next step.

Part E: Preparation of 1-Triisopropylsilylhydroxy-1-(2′,2′-dibromoethene)cyclopropane

[0405] A 500 mL flask was charged with carbon tetrabromide (2.89 g, 8.72 mmol) dissolved in dry methylene chloride (87 mL). The solution was cooled to −20° C. when triphenylphosphine (recrystallized from hexanes, 2.28 g, 8.72 mmol) was added and stirring continued for 45 minutes. The reaction was then cooled to −60 ° C. where the crude aldehyde (maximum of 4.36 mmol) dissolved in dry methylene chloride (40 mL) containing triethylamine (0.61 mL, 4.26 mmol) was added. Stiirring was continued overnight with warming to room temperature. The reaction was then diluted with hexanes (1 l) and filtered through a pad of magnesium sulfate. Evaporation and purification by flash column chromatography (silica, hexanes) gave the desired dibromoolefin (35%, 607.1 mg).

Part F: Preparation of (+/−)-4-(1′-Triisopropylsilylhydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0406] A 50 mL two-necked flasked was flame-dried in vacuo and sealed under nitrogen. The dibromoolefin was dissolved in dry tetrahydrofuran (8.0 mL) and transferred to the reaction flask. The reaction was cooled to -78° C. and a solution of n-butyllithium (2.5 M in hexanes, 1.2 mL, 2.96 mmol) was added dropwise. Stirring was continued for 20 minutes when a solution of the chlorobenzoxazinone (212 mg. 0.74 mmol) in dry tetrahydrofuran (2.0 mL) was added. The reaction was warmed to −60° C. and stirring continued for 30 minutes. The reaction was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine and then dried over magnesium sulfate. The crude product was isolated by filtration and evaporation. Flash chromatography (silica, 4:1 hexanes/ethyl acetate) gave the partially purified product (235 mg). A subsequent chromatography under similar conditions gave the desired material (35%, 118 mg) with suitable purity for the next step.

Part G: Preparation of 4-(1′-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0407] The starting material (53.0 mg, 0.117 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) under nitrogen. A solution of tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 0.12 mL, 0.12 mmol) was added and stirring continued for 15 minutes. The reaction was then diluted with 1:1 hexanes/ethyl acetate and washed twice with water and once with brine. Drying with magnesium sulfate, filtration, and evaporation gave the crude product. The compound was purified by flash chromatography (silica, 4:1 hexanes/ethyl acetate to 2:1 hexanes/ethyl acetate). The desired product was isolated in 74% yield (28.7 mg). m.p. 192-194° C. HRMS: calculated for C14H10ClF3NO3, M+H): 332.0301; found 332.0296.

Example 18

Preparation of (+/−)-4-isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Triphenylmethylamino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

[0408] To a solution of 3-methyl-1-butyne (0.16 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5-fluoro-2-trifluoroacetyl-triphenylmethylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. The reaction mixture was poured onto saturated NH4Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part B: Preparation of 2-Amino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

[0409] To a solution of the benzyl alcohol (crude product, approx. 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated hydrochloric acid (0.1 mL) and the resulting reaction mixture was allowed to stir at room temperature for 0.25 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO2, 15% EtOAc-hexanes eluant) provided 103 mg of the title compound (184 mg theoretical, 56% yield over two steps).

Part C: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0410] To a solution of amino-alcohol (103 mg 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.30 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO2, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

Example 19

Preparation of 4-Chloro-2-cyclopropylacetylaniline

[0411]

[0412] Cyclopropyllithium was prepared by the procedure of Dakkouri (Chem. Ber. 1979, 112, 3523.). To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a West condenser and a nitrogen line was charged 1.0 g (0.14 mol.) of freshly cleaned Li ribbon and 20 ml anhydrous ether. The mixture was cooled to 0° C. and 5.6 ml of cyclopropylbromide (70 mmol) in 10 ml of anhydrous ether was added dropwise. The bromide solution was added over 45 min. due to the exothermic nature of the metalation reaction. After the addition was complete the lithium reagent was aged for 30 min. then cooled to −65° C. A solution of 5.53 g (28 mmol.) of 5-chloroisatoic anhydride in 80 ml THF was prepared in a dry 3 neck flask and cooled to −40° C. The cyclopropyllithium solution was transfered via canula into the anhydride solution over 30 min. The resulting milky solution was aged for 1 h at −4° C. during which time the solution became clear with a pale green color. The anion solution was quenched by addition of 1 M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a tacky yellow solid which was chromatographed on silica gel with ethyl acetate/hexanes (3:1) to provide 3.56 g of the title compound in 65% yield. Crystallization from heptane provides the title compound as a pale yellow solid: m.p. 73.7° C.; 1H NMR (300 MHz, CDCl3) δ7.90 (d, J=1.5 Hz, 1 H), 7.22 (dd, J=2.3, 8.7 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.13 (brs, 2H), 2.56 (m, 1 H),. 1.18 (m, 2 H), 1.00 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ201.06, 148.23, 133.83, 130.41, 121.70, 119.69, 118.56, 17.37, 11.08; IR (cm−1) 3315, 3012, 1628, 1582, 1533, 1481, 1464, 1414, 1389, 1343, 1313, 1217, 1183, 1158, 1082, 1053, 1032, 985, 893, 868, 813.

Example 20

Preparation of 4-Chloro-2-((cyclopropylenthynyl)acetyl)aniline

[0413]

[0414] To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a solid addition funnel and a nitrogen line was charged 3.7 g (56.0 mmol.) of cyclopropylacetylene and 30 ml of anhydrous THF. The solution was cooled to −60° C. and 30 ml (53.1 mmol.) of 1.8 M hexyllithium in hexanes was added dropwise while maintaining the internal temperature below −20° C. The solution was aged at −40° C. for 30 min. and then 5 g (25.3 mmol.) of 5-chloroisatoic anhydride was added as a solid in small portions. The resulting solution was aged for 2 h at −40° C. during which time the solution became clear with a pale yellow color. The anion solution was quenched by addition of 1 M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a an orange solid. The product was triturated with heptanes to provides 9 as a tan solid: 1H NM (300 MHz, CDCl3) δ8.43 (m, 1 H), 8.02 (m, 1H), 7.36 (m, 1H), 1.48 (m, 1 H),. 0.99 (m, 2 H), 0.87 (m, 2 H); IR (cm−1) 2978, 2221, 1641, 1579, 1502, 1434, 1410, 1370, 1299, 1055, 906, 829, 731.

Example 21

Preparation of (S)-6-Chloro-4-(chloro)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0415]

[0416] To a 3 neck flask equipped with a magnetic stirrer, a thermocouple probe and a dry ice condenser was charged 25 g (0.11 mol.) of trifluoroketone 3 and 150 ml of anhydrous toluene. This yellow solution was then heated to gentle reflux and a solution (87 ml, 0.17 mol.) of phosgene (1.93 M) in toluene was added subsurface. The solution was heated to reflux (temperature range at 104 to 110° C.) for 3 h after which time the yellow color had dissipated and the starting ketone was not detected by 1H NMR. The solution was cooled to ambient temperature and then concentrated to provide a heterogeneous solution. The product was triturated with heptane (100 ml) and filtered to provide 29.24 g (92%) of the desired chlorobenzoxazinone as a white solid. m.p. 140.8° C.; 1H NMR (300 MHz) δ9.26 (b, 1H), 7.57 (s, 1H), 7.45 (dd, J=1.9, 8.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H) ; 13C NMR (75 MHz) δ146.32, 132.88, 132.42, 130.27, 125.80, 122.83, 119.06, 116.79, 115.85, 0.013; 19F NMR (282 MHz) δ−79.5; IR (cm−1) 3191, 1764, 1601, 1498, 1403, 1335, 1316, 1252, 1199, 1073, 991, 901, 874, 826, 683.

Example 22

Preparation of (+/−)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0417]

[0418] To a 50 ml 3 neck flask equipped with a magnetic stir bar, a thermocouple probe and nitrogen inlet was charged 10 ml anhydrous THF and 2.2 eq cyclopropylacetylene (0.23 g, 3.4 mmol.). The solution was cooled to −50 ° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8 M, 1.8 ml, 3.26 mmol.) was added dropwise via syringe. The internal temperature was maintained below −30 ° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 0.44 g (1.55 mmol.) of the chlorobenzoxazinone in 5 ml THF was added dropwise. The reaction solution was maintained below −20 ° C. during the addition. The mixture was aged at —20° C. for 4 h after which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a light yellow solid. The product was then triturated with heptanes to provide 0.47 g (95%) of racemic title product as a white solid. HPLC: 99.8 area %; m.p. 183-6° C.; 1H NMR (400 MHz, DMSO-d6) δ11.05 (s, 1H), 7.54 (dd, J=2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, −1.32; 19F NMR (282 MHz, DMSO-d6) δ−81.1; IR (cm−1) 3316, 3094, 2250, 1752, 1602, 1498, 1196, 1186. HRMS calcd. for C14H10F3ClNO2 (M+H) 316.0352, found 316.0338. Anal. Calcd. for C14H9F3ClNO2: C, 53.27; H, 2.87; N, 4.45; Cl 11.23; F, 18.05. Found: C, 53.15; H, 2.73; N, 4.37; Cl, 11.10; F, 17.84.

Example 23

Preparation of (S)-6-Chloro-4-(1-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0419]

[0420] To a 50 ml 3 neck flask equipped with a magnetic stir bar, thermocouple and nitrogen inlet was charged 20 ml anhydrous THF and 2.2 eq pyridylethyne (1.1 g, 10.2 mmol.). The solution was cooled to −50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8 M, 4.0 ml, 10.0 mmol.) was added dropwise via syringe. The internal temperature was maintained below −30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 1.5 g (5.2 mmol.) of the chlorobenzoxazinone from Example 21 in 15 ml THF was added dropwise. The reaction solution was maintained above −20° C. during the addition. The mixture was aged at −20° C. for 2 h at which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a brown solid. The product was purified by flash chromatography (hexanes/ethyl acetate; 3:1) and then triturated with heptanes to provide 1.06 g (57%) of the title compound as a white solid. HPLC: 99.8 area %; m.p. 185.8° C.; 1H NMR (300 MHz) δ9.62 (s, 1H), 8.68 (d, J=4.2 Hz, 1 H), 7.76 (dd, J=7.6, 9.5 Hz, 1H), 7.61 (d, J=5.7 Hz, 2H), 7.40 (m, 2 H), 6.91 (d, J=8.7 Hz, 1H; 13C NMR (75 MHz) δ150.38, 148.20, 140.32, 136.57, 133.43, 132.06, 129.34, 128.30, 127.60, 124.65, 123.94, 120.13, 116.37, 114.01, 88.72, 78.75; 19F NMR (282 MHz) δ−81.4; IR (cm−1)3245, 3157, 3069, 2946, 2876, 2252, 1757, 1603, 1581, 1498, 1467, 1428, 1401, 1305, 1256, 1243, 1186, 1142, 1401, 1304, 1256, 1243, 1186, 1142, 1103, 1072, 1037, 997, 971, 940, 866, 822, 780, 740. MS FIA/PCI (M+H) 353 m/z.

Example 24

Preparation of (+/−)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0421]

Part A: Preparation of 1-(t-Butyldimethylsilyl)-2-cyclopropylacetylene

[0422] To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5 M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g (663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH4Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g (42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39-42° C. at 0.5 torr). 1H NMR(CDCl3, 300 MHz) δ1.17-1.24(m, 1H) ; 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H)

Part B: Preparation of 1-Deutero-1-ethynylcyclpropane

[0423] To a stirred, cooled (−30° C.) solution of 130 g (720 mmol) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene in 400 mL of THF was added 403 mL (1.01 mol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred 1.5 h at −20° C. and then treated with 49 mL (1.2 mol) of CD3OD over 10 min. After stirring 10 min. at −100° C. the reaction was quenched with 10 mL of D2O, followed 15 min later with 1 L of 20% aq. citric acid. The mixture was extracted with 1 L of ether, and the organic extract was washed sequentially with water, sat'd aq. NaHCO3, and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and re-dissolved in 300 mL of THF. This solution was treated with 780 mL(350 mmol) of a 1 M solution of (n-Bu)4NF in THF and stirred 6 h at ambient temperature. The solution was cooled to 0° C., washed with 1 L of water, and the aqueous phase was extracted with 150 mL of p-xylene. The organic extract was washed with 500 mL of water, and the combined aqueous phases were extracted with 70 mL of p-xylene. The two organic phases were combined, and washed 5 times with water and once with brine, dried (MgSO4), and distilled. The fraction which boiled up to 105° C. at ambient pressure was collected to give 88g of a solution having a deuterocyclopropylacetylene concentration of c. 43%. The remainder is primarily THF with some xylene and some 1-butene.

Part C: Preparation of (+/−) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0424] To a stirred, cooled (−60° C.) solution of 12.6g of a 60% solution of 1-deutero-1-ethynylcyclpropane in 65 mL of anhydrous THF was added 41 mL(102 mmol) of a 2.5M solution of n-BuLi in hexanes over 20 min. The solution was stirred 30 min. and charged with 9.7 g (33.9 mmol) of 4,6-dichloro-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one in 10 mL of THF over 2 min. The solution was warmed to −30° C. over 1 h, whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO3 then brine. The solution was concentrated under reduced pressure, and the crude product was chromatographed on silica gel(elution with 2:1 hexanes-ether) to afford 5.8 g (54%) of (+/−) 6-chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 180-18120 C. 1H NMR(300 MHz, CDCl3) δ9.32(br. s, 1H); 7.50(m, 1H); 7.37(dd, 1H, J=8, 1 Hz); 6.95(d, 1H, J=8 Hz); 0.82-0.96(m, 4H). Chiral chromatographic resolution provides (−) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 133-134° C.

Example 25

Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Amino-6-fluoro-α-trifluoromethyl-benzyl alcohol

[0425] To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO4 and concentrated in vacuo. Chromatography (SiO2, 10% EtOAc-hexanes) provided 88mg of the title compound (108 mg theoretical, 82% yield).

Part B: Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

[0426] To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO2, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol

[0427] To a solution of 3-methyl-1-butyne (0.15 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 6-fluoro-2-trifluoroacetylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH4Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part D: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

[0428] To a solution of the crude trityl protected amino-alcohol (crude product, 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated HCl (0.1 mL) and the resulting reaction mixture is allowed to stir at room temperature for 0.25 h. The reaction mixture is concentrated in vacuo and the residue is taken up in ether (10 mL) and washed with saturated NaHCO3. The ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO2, 15% EtOAc-hexanes) provided 103 mg of the deprotected amino-alcohol (184 mg theoretical, 56% yield).

[0429] To a solution of amino-alcohol (103 mg, 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO2, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

1TABLE 1

Ex.#GR1R2m.p. (° C.)Mass Spec 16-Cl, 8-OHCF3C≡C-cycPr332.0301 2(-)6-Cl, 8-OHCF3C≡C-cycPr170-172 3(-)6-Cl, 8-OHCF3C≡C-cycPr 46-Cl, 8-FCF3C≡C-cycPr169-171334.0244 56-CH3iPrC≡C-cycPr138-138.5270.1494 66-CH3CF3C≡C-iPr198-199298.1047 76-COCH3CF3C≡C-cycPr197-200 85,6-diFCF33-methyl-1-buten-1-yl 95,6-diFCF3C≡C-iPr319.0616 126-Cl, 7-azaCF3C≡C-cycPr317.0322 136-ClCF3methoxyethoxy 146-ClCF3n-propylamino 156-ClCF3furan-2-yl-≡- 166-OMeCF3C≡C—Et161-162300.0841 176-ClCF3≡-(1′-OH-cycPr)332.0296 185-FCF3≡-iPr 226-ClCF3≡-cycPr316.0352 236-ClCF3≡-2-pyridyl353 (M + H) 246-ClCF3≡-(1-deutero-133-134cycloprop-1-yl) 255FCF3≡-iPr 266-Cl, 8-OMeCF3C≡C-cycPr346.0477 276-Cl, 7-OHCF3C≡C-cycPr332.0286 286-Cl, 8-FCF3C≡C—Et191-192339.0525(M + NH4+) 296-Cl, 8-FCF3CH2CH2CH(CH3)2160-162340 (MH+) 305,6-diFCF3C≡C-cycPr318.0550 (MH+) 315,6-diFCF3C≡C-iPramorphous 325,6-diFCF3C≡C-nPr320.0691 335,6-diFCF3C≡C—Et306.0550(MH+) 345,6-diFCF3C≡C—Me217 355,6-diFCF3CH2CH2CH2CH2CH3324.1008 365,6-diFCF3CH2CH2CH(CH3)2324.1003 375,6-diFCF3CH2CH2CH2CH3310.0878 385,6-OCH2O—CF3C≡C-cycPr223-4225326.0639 395,6-OCH2O—CF3C≡C-iPr240328.0797 405,6-OCH2O—CF3C≡C-nPr208-210 415,6-OCH2O—CF3C≡C—Et230-232 425,6-OCH2O—CF3CH2C≡C—CH2CH3215-217328.0800 435,6-OCH2O—CF3CH2C≡C—CH3207-208314.0640 445,6-OCH2O—CF3CH2CH2CH(CH3)2199-200 456-OMeCF3C≡C-cycPr155-157312.0835 466-OMeCF3C≡C-cycPr143-144312.0843 476-OMeCF3C≡C-cycPr142-144312.0836 486-OMeCF3C≡C-iPr158-159314.0998 496-OMeCF3C≡C-nPr148-150314.1007 506-OMeCF3C≡C—Me177-180286.0691 516-OMeCF3CH2C≡C—CH2CH3119-122314.0989 526-OMeCF3CH2CH2CH(CH3)2318 (MH+) 536-OMeCF3CH2CH2CH2CH3304.1167 546-OMeCF3CH2CH2—Ph352.1153 556-OMe, 8-FCF3C≡C-cycPr188-189330.0738 566-NMe2CF3C≡C-cycPr325.1173 576-NMe2CF3C≡C-iPr327.1322 586-NMe2CF3CH2CH2CH2CH2CH3331.1641 596-NMe2CF3CH2CH2CH(CH3)2331.1637 606-COCH3CF3C≡C—Et180-183 616-CH3CF3C≡C-cycPr189296.0905 626-CH3CF3C≡C—Et222284.0882 636,8-diClCF3C≡C-cycPr152-153348.9870 646,8-diClCF3CH2CH2—Ph389.0188(M+) 655,6,8-triFCF3C≡C-cycPramorphous 665,6,8-triFCF3C≡C-iPramorphous 675,6,8-triFCF3C≡C-nPramorphous 685,6,8-triFCF3C≡C—Etamorphous 695,8-diFCF3C≡C-cycPr335.0834(M + NH4+) 705,8-diFCF3C≡C-iPr320.0710(MH+) 715,8-diFCF3C≡C-nPr337.0970(M + NH4+) 725,8-diFCF3C≡C—Et323.8817(M + NH4+) 736-iPrCF3C≡C-cycPr324.1203 746-iPrCF3C≡C-iPr326.1361 756-iPrCF3C≡C—Ph360.1204 766-iPrCF3CH2CH2CH2CH2CH3330.1672 776-iPrCF3CH2CH2-iPr330.1673 786-iPrCF3CH2CH2-Ph364.1517 796-OCF3CF3C≡C-cycPr366.0561 806-OCF3CF3C≡C-iPr368.0712 816-OCF3CF3C≡C—Ph401.0475 826-OCF3CF3CH2CH2CH2CH2CH3372.1018 836-OCF3CF3CH2CH2-iPr372.1039 846-OCF3CF3CH2CH2-Ph405.0795 85HCF3CH2CH2-Ph282.0735 86HCF3C≡C-iPr284.0894 87HCF3C≡C—Ph318.0748 88HCF3CH2CH2CH2CH2CH3288.1201 89HCF3CH2CH2-iPr121-122 90HCF3CH2CH2—Ph322.1055 916-PhCF3C≡C-cycPr185-186358.1055 926-PhCF3C≡C-iPr179-4180360.1211 936-PhCF3C≡C-nPr143-4144360.1211 946-PhCF3C≡C-iBu163-164374.1352 956-PhCF3C≡C—Et195346.1055 966-PhCF3CH2CH2-iPr147-148364.1524 976-OMeiPrC≡C-cycPr286.1428 986-OMeiPrC≡C-iPr288.1583 996-CH3cycPrC≡C-iPr133-134270.14981006-CH3iPrC≡C-iPr133-134272.16481016-CH3EtC≡C-iPr138-139258.15051026-CH3EtC≡C—Et138.5-139244.13331036,7-diClcycPrC≡C-iPr1046,7-diCliprC≡C-iPramorphous1057-ClcycPrC≡C-cycPr288.07831067-ClcycPrC≡C-iPr290.09411077-ClcycPrC≡C-iBu117-118304.11101087-CliPrC≡C-cycPr290.09401097-CliPrC≡C-iPr292.11031106-Cl, 8-azaCF3C≡C-cycPr317.03171116-Cl, 8-azaCF3C≡C-iPr319 (MH+)1126-Cl, 8-azaCF3CH2CH2-Ph214-215357.06251136-OCH3,CF3C≡C-cycPr181-182313.08007-aza1146-azaCF3C≡C-cycPr*Unless otherwise noted, stereochemistry is (+/−)

[0430]

2

TABLE 2

Ex. #
G
R1
R2

201
6-Cl, 8-F
CF3
C≡C-iPr

202
6-Cl, 8-F
CF3
C≡C-nPr

203
6-Cl, 8-F
CF3
C≡C—Bu

204
6-Cl, 8-F
CF3
C≡C-iBu

205
6-Cl, 8-F
CF3
C≡C-tBu

206
6-Cl, 8-F
CF3
C≡C—Me

207
6-Cl, 8-F
CF3
C≡C—Ph

208
6-Cl, 8-F
CF3
C≡C-(2-Cl)Ph

209
6-Cl, 8-F
CF3
C≡C-(3-Cl)Ph

210
6-Cl, 8-F
CF3
C≡C-(2-F)Ph

211
6-Cl, 8-F
CF3
C≡C-(3-F)Ph

212
6-Cl, 8-F
CF3
C≡C-(2-OH)Ph

213
6-Cl, 8-F
CF3
C≡C-(3-OH)Ph

214
6-Cl, 8-F
CF3
C≡C-(2-OMe)Ph

215
6-Cl, 8-F
CF3
C≡C-(3-OMe)Ph

216
6-Cl, 8-F
CF3
C≡C-(2-CN)Ph

217
6-Cl, 8-F
CF3
C≡C-(3-CN)Ph

218
6-Cl, 8-F
CF3
C≡C-(2-NH2)Ph

219
6-Cl, 8-F
CF3
C≡C-(3-NH2)Ph

220
6-Cl, 8-F
CF3
C≡C-(2-NMe2)Ph

221
6-Cl, 8-F
CF3
C≡C-(3-NMe2)Ph

222
6-Cl, 8-F
CF3
C≡C-2-Pyridyl

223
6-Cl, 8-F
CF3
C≡C-3-Pyridyl

224
6-Cl, 8-F
CF3
C≡C-4-Pyridyl

225
6-Cl, 8-F
CF3
C≡C-2-furanyl

226
6-Cl, 8-F
CF3
C≡C-3-furanyl

227
6-Cl, 8-F
CF3
C≡C-2-thienyl

228
6-Cl, 8-F
CF3
C≡C-3-thienyl

229
6-Cl, 8-F
CF3
CH═CH-cycPr

230
6-Cl, 8-F
CF3
CH═CH-iPr

231
6-Cl, 8-F
CF3
CH═CH-nPr

232
6-Cl, 8-F
CF3
CH═CH—Bu

233
6-Cl, 8-F
CF3
CH═CH-iBu

234
6-Cl, 8-F
CF3
CH═CH-tBu

235
6-Cl, 8-F
CF3
CH═CH—Et

236
6-Cl, 8-F
CF3
CH═CH—Me

237
6-Cl, 8-F
CF3
CH═CH—Ph

238
6-Cl, 8-F
CF3
CH═CH-2-Pyridyl

239
6-Cl, 8-F
CF3
CH═CH-3-Pyridyl

240
6-Cl, 8-F
CF3
CH═CH-4-Pyridyl

241
6-Cl, 8-F
CF3
CH═CH-2-furanyl

242
6-Cl, 8-F
CF3
CH═CH-3-furanyl

243
6-Cl, 8-F
CF3
CH═CH-2-thienyl

244
6-Cl, 8-F
CF3
CH═CH-3-thienyl

245
6-Cl, 8-F
CF3
CH2CH2CH2CH2CH3

246
6-Cl, 8-F
CF3
CH2CH2CH2CH3

247
6-Cl, 8-F
CF3
CH2CH2-cycPr

248
6-Cl, 8-F
CF3
CH2CH2-tBu

249
6-Cl, 8-F
CF3
CH2CH2-Ph

250
6-Cl, 8-F
CF3
CH2CH2-2-Pyridyl

251
6-Cl, 8-F
CF3
CH2CH2-3-Pyridyl

252
6-Cl, 8-F
CF3
CH2CH2-4-Pyridyl

253
6-Cl, 8-F
CF3
CH2CH2-2-furanyl

254
6-Cl, 8-F
CF3
CH2CH2-3-furanyl

255
6-Cl, 8-F
CF3
CH2CH2-2-thienyl

256
6-Cl, 8-F
CF3
CH2CH2-3-thienyl

257
5,6-diF
CF3
C≡C—Bu

258
5,6-diF
CF3
C≡C-iBu

259
5,6-diF
CF3
C≡C-tBu

260
5,6-diF
CF3
C≡CCH2CH2OH

261
5,6-diF
CF3
C≡C—CH(OH)Me

262
5,6-diF
CF3
C≡C—Ph

263
5,6-diF
CF3
C≡C-(2-Cl)Ph

264
5,6-diF
CF3
C≡C-(3-Cl)Ph

265
5,6-diF
CF3
C≡C-(4-Cl)Ph

266
5,6-diF
CF3
C≡C-(2-F)Ph

267
5,6-diF
CF3
C≡C-(3-F)Ph

268
5,6-diF
CF3
C≡C-(4-F)Ph

269
5,6-diF
CF3
C≡C-(2-OH)Ph

270
5,6-diF
CF3
C≡C-(3-OH)Ph

271
5,6-diF
CF3
C≡C-(4-OH)Ph

272
5,6-diF
CF3
C≡C-(2-OMe)Ph

273
5,6-diF
CF3
C≡C-(3-OMe)Ph

274
5,6-diF
CF3
C≡C-(4-OMe)Ph

275
5,6-diF
CF3
C≡C-(2-CN)Ph

276
5,6-diF
CF3
C≡C-(3-CN)Ph

277
5,6-diF
CF3
C≡C-(4-CN)Ph

278
5,6-diF
CF3
C≡C-(2-NO2)Ph

279
5,6-diF
CF3
C≡C-(3-NO2)Ph

280
5,6-diF
CF3
C≡C-(4-NO2)Ph

281
5,6-diF
CF3
C≡C-(2-NH2)Ph

282
5,6-diF
CF3
C≡C-(3-NH2)Ph

283
5,6-diF
CF3
C≡C-(4-NH2)Ph

284
5,6-diF
CF3
C≡C-(2-NMe2)Ph

285
5,6-diF
CF3
C≡C-(3-NMe2)Ph

286
5,6-diF
CF3
C≡C-(4-NMe2)Ph

287
5,6-diF
CF3
C≡C-2-Pyridyl

288
5,6-diF
CF3
C≡C-3-Pyridyl

289
5,6-diF
CF3
C≡C-4-Pyridyl

290
5,6-diF
CF3
C≡C-2-furanyl

291
5,6-diF
CF3
C≡C-3-furanyl

292
5,6-diF
CF3
C≡C-2-thienyl

293
5,6-diF
CF3
C≡C-3-thienyl

294
5,6-diF
CF3
C═C-2-oxazolyl

295
5,6-diF
CF3
C≡C-2-thiazolyl

296
5,6-diF
CF3
C≡C-4-isoxazolyl

297
5,6-diF
CF3
C≡C-2-imidazolyl

298
5,6-diF
CF3
CH2C≡C—CH3

299
5,6-diF
CF3
CH2C≡C—CH2CH3

300
5,6-diF
CF3
CH═CH-cycPr

301
5,6-diF
CF3
CH═CH-iPr

302
5,6-diF
CF3
CH═CH-nPr

303
5,6-diF
CF3
CH═CH—Bu

304
5,6-diF
CF3
CH═CH-iBu

305
5,6-diF
CF3
CH═CH-tBu

306
5,6-diF
CF3
CH═CH—Et

307
5,6-diF
CF3
CH═CH—Me

308
5,6-diF
CF3
CH═CH—Ph

309
5,6-diF
CF3
CH═CH-2-Pyridyl

310
5,6-diF
CF3
CH═CH-3-Pyridyl

311
5,6-diF
CF3
CH═CH-4-Pyridyl

312
5,6-diF
CF3
CH═CH-2-furanyl

313
5,6-diF
CF3
CH═CH-3-furanyl

314
5,6-diF
CF3
CH═CH-2-thienyl

315
5,6-diF
CF3
CH═CH-3-thienyl

316
5,6-diF
CF3
CH2CH2CH3

317
5,6-diF
CF3
CH2CH2-cycPr

318
5,6-diF
CF3
CH2CH3-tBu

319
5,6-diF
CF3
CH2CH2CH2CH2OH

320
5,6-diF
CF3
CH2CH2—CH(OH)Me

321
5,6-diF
CF3
CH2CH2Ph

322
5,6-diF
CF3
CH2CH2-(2-Cl)Ph

323
5,6-diF
CF3
CH2CH2-(3-Cl)Ph

324
5,6-diF
CF3
CH2CH2-(4-Cl)Ph

325
5,6-diF
CF3
CH2CH2-(2-F)Ph

326
5,6-diF
CF3
CH2CH2-(3-F)Ph

327
5,5-diF
CF3
CH2CH2-(4-F)Ph

328
5,6-diF
CF3
CH2CH2-(2-OH)Ph

329
5,6-diF
CF3
CH2CH2-(3-OH)Ph

330
5,6-diF
CF3
CH2CH2-(4-OH)Ph

331
5,6-diF
CF3
CH2CH2-(2-OMe)Ph

332
5,6-diF
CF3
CH2CH2-(3-OMe)Ph

333
5,6-diF
CF3
CH2CH2-(4-OMe)Ph

334
5,6-diF
CF3
CH2CH2-(2-CN)Ph

335
5,6-diF
CF3
CH2CH2-(3-CN)Ph

336
5,6-diF
CF3
CH2CH2-(4-CN)Ph

337
5,6-diF
CF3
CH2CH2-(2-NO2)Ph

338
5,6-diF
CF3
CH2CH2-(3-NO2)Ph

339
5,6-diF
CF3
CH2CH2-(4-NO2)Ph

340
5,6-diF
CF3
CH2CH2-(2-NH2)Ph

341
5,6-diF
CF3
CH2CH2-(3-NH2)Ph

342
5,6-diF
CF3
CH2CH2-(4-NH2)Ph

343
5,6-diF
CF3
CH2CH2-(2-NMe2)Ph

344
5,6-diF
CF3
CH2CH2-(3-NMe2)Ph

345
5,6-diF
CF3
CH2CH2-(4-NMe2)Ph

346
5,6-diF
CF3
CH2CH2-2-Pyridyl

347
5,6-diF
CF3
CH2CH2-3-Pyridyl

348
5,6-diF
CF3
CH2CH2-4-Pyridyl

349
5,6-diF
CF3
CH2CH2-2-furanyl

350
5,6-diF
CF3
CH2CH2-3-furanyl

351
5,6-diF
CF3
CH2CH2-2-thienyl

352
5,6-diF
CF3
CH2CH2-3-thienyl

353
5,6-diF
CF3
CH2CH2-2-oxazolyl

354
5,6-diF
CF3
CH2CH2-2-thiazolyl

355
5,6-diF
CF3
CH2CH2-4-isoxazolyl

356
5,6-diF
CF3
CH2CH2-2-imidazolyl

357
5,6-diCl
CF3
C≡C-cycPr

358
5,6-diCl
CF3
C≡C-iPr

359
5,6-diCl
CF3
C≡C-nPr

360
5,6-diCl
CF3
C≡C—Bu

361
5,6-diCl
CF3
C≡C-iBu

362
5,6-diCl
CF3
C≡C-tBu

363
5,6-diCl
CF3
C≡C—Et

364
5,6-diCl
CF3
C≡C—Me

365
5,6-diCl
CF3
C≡CCH2CH2OH

366
5,6-diCl
CF3
C≡C—CH(OH)Me

367
5,6-diCl
CF3
C≡C—Ph

368
5,6-diCl
CF3
C≡C-(2-Cl)Ph

369
5,6-diCl
CF3
C≡C-(3-Cl)Ph

370
5,6-diCl
CF3
C≡C-(4-Cl)Ph

371
5,6-diCl
CF3
C≡C-(2-F)Ph

372
5,6-diCl
CF3
C≡C-(3-F)Ph

373
5,6-diCl
CF3
C≡C-(4-F)Ph

374
5,6-diCl
CF3
C≡C-(2-OH)Ph

375
5,6-diCl
CF3
C≡C-(3-OH)Ph

376
5,6-diCl
CF3
C≡C-(4-OH)Ph

377
5,6-diCl
CF3
C≡C-(2-OMe)Ph

378
5,6-diCl
CF3
C≡C-(3-OMe)Ph

379
5,6-diCl
CF3
C≡C-(4-OMe)Ph

380
5,6-diCl
CF3
C≡C-(2-CN)Ph

381
5,6-diCl
CF3
C≡C-(3-CN)Ph

382
5,6-diCl
CF3
C≡C-(4-CN)Ph

383
5,6-diCl
CF3
C≡C-(2-NO2)Ph

384
5,6-diCl
CF3
C≡C-(3-NO2)Ph

385
5,6-diCl
CF3
C≡C-(4-NO2)Ph

386
5,6-diCl
CF3
C≡C-(2-NH2)Ph

387
5,6-diCl
CF3
C≡C-(3-NH2)Ph

388
5,6-diCl
CF3
C≡C-(4-NH2)Ph

389
5,6-diCl
CF3
C≡C-(2-NH2)Ph

390
5,6-diCl
CF3
C≡C-(3-NH2)Ph

391
5,6-diCl
CF3
C≡C-(4-NMe2)Ph

392
5,6-diCl
CF3
C≡C-2-Pyridyl

393
5,6-diCl
CF3
C≡C-3-Pyridyl

394
5,6-diCl
CF3
C≡C-4-Pyridyl

395
5,6-diCl
CF3
C≡C-2-furanyl

396
5,6-diCl
CF3
C≡C-3-furanyl

397
5,6-diCl
CF3
C≡C-2-thienyl

398
5,6-diCl
CF3
C≡C-3-thienyl

399
5,6-diCl
CF3
CH═CH-cycPr

400
5,6-diCl
CF3
CH═CH-iPr

401
5,6-diCl
CF3
CH═CH-nPr

402
5,6-diCl
CF3
CH═CH—Bu

403
5,6-diCl
CF3
CH═CH-iBu

404
5,6-diCl
CF3
CH═CH-tBu

405
5,6-diCl
CF3
CH═CH—Et

406
5,6-diCl
CF3
CH═CH—Me

407
5,6-diCl
CF3
CH═CH—Ph

408
5,6-diCl
CF3
CH═CH-2-Pyridyl

409
5,6-diCl
CF3
CH═CH-3-Pyridyl

410
5,6-diCl
CF3
CH═CH-4-Pyridyl

411
5,6-diCl
CF3
CH═CH-2-furanyl

412
5,6-diCl
CF3
CH═CH-3-furanyl

413
5,6-diCl
CF3
CH═CH-2-thienyl

414
5,6-diCl
CF3
CH═CH-3-thienyl

415
5,6-diCl
CF3
CH2CH2CH2CH2CH3

416
5,6-diCl
CF3
CH2CH2CH(CH3)2

417
5,6-diCl
CF3
CH2CH2CH2CH3

418
5,6-diCl
CF3
CH2CH2-cycPr

419
5,6-diCl
CF3
CH2CH2-tBu

420
5,6-diCl
CF3
CH2CH2CH2CH2OH

421
5,6-diCl
CF3
CH2CH2—CH(OH)Me

422
5,6-diCl
CF3
CH2CH2-Ph

423
5,6-diCl
CF3
CH2CH2-2-Pyridyl

424
5,6-diCl
CF3
CH2CH2-3-Pyridyl

425
5,6-diCl
CF3
CH2CH2-4-Pyridyl

426
5,6-diCl
CF3
CH2CH2-2-furanyl

427
5,6-diCl
CF3
CH2CH2-3-furanyl

428
5,6-diCl
CF3
CH2CH2-2-thienyl

429
5,6-diCl
CF3
CH2CH2-3-thienyl

430
5-Cl, 6-F
CF3
C≡C-cycPr

431
5-Cl, 6-F
CF3
C≡C-iPr

432
5-Cl, 6-F
CF3
C≡C-nPr

433
5-Cl, 6-F
CF3
C≡C—Bu

434
5-Cl, 6-F
CF3
C≡C-iBu

435
5-Cl, 6-F
CF3
C≡C-tBu

436
5-Cl, 6-F
CF3
C≡C—Et

437
5-Cl, 6-F
CF3
C≡C—Me

438
5-Cl, 6-F
CF3
C≡CCH2CH2OH

439
5-Cl, 6-F
CF3
C≡C—CH(OH)Me

440
5-Cl, 6-F
CF3
C≡C—Ph

441
5-Cl, 6-F
CF3
C≡C-(2-Cl)Ph

442
5-Cl, 6-F
CF3
C≡C-(3-Cl)Ph

443
5-Cl, 6-F
CF3
C≡C-(4-Cl)Ph

444
5-Cl, 6-F
CF3
C≡C-(2-F)Ph

445
5-Cl, 6-F
CF3
C≡C-(3-F)Ph

446
5-Cl, 6-F
CF3
C≡C-(4-F)Ph

447
5-Cl, 6-F
CF3
C≡C-(2-OH)Ph

448
5-Cl, 6-F
CF3
C≡C-(3-OH)Ph

449
5-Cl, 6-F
CF3
C≡C-(4-OH)Ph

450
5-Cl, 6-F
CF3
C≡C-(2-OMe)Ph

451
5-Cl, 6-F
CF3
C≡C-(3-OMe)Ph

452
5-Cl, 6-F
CF3
C≡C-(4-OMe)Ph

453
5-Cl, 6-F
CF3
C≡C-(2-CN)Ph

454
5-Cl, 6-F
CF3
C≡C-(3-CN)Ph

455
5-Cl, 6-F
CF3
C≡C-(4-CN)Ph

456
5-Cl, 6-F
CF3
C≡C-(2-NO2)Ph

457
5-Cl, 6-F
CF3
C≡C-(3-NO2)Ph

458
5-Cl, 6-F
CF3
C≡C-(4-NO2)Ph

459
5-Cl, 6-F
CF3
C≡C-(2-NH2)Ph

460
5-Cl, 6-F
CF3
C≡C-(3-NH2)Ph

451
5-Cl, 6-F
CF3
C≡C-(4-NH2)Ph

462
5-Cl, 6-F
CF3
C≡C-(2-NMe2)Ph

463
5-Cl, 6-F
CF3
C≡C-(3-NMe2)Ph

464
5-Cl, 6-F
CF3
C≡C-(4-NMe2)Ph

465
5-Cl, 6-F
CF3
C≡C-2-Pyridyl

466
5-Cl, 6-F
CF3
C≡C-3-Pyridyl

467
5-Cl, 6-F
CF3
C≡C-4-Pyridyl

468
5-Cl, 6-F
CF3
C≡C-2-furanyl

469
5-Cl, 6-F
CF3
C≡C-3-furanyl

470
5-Cl, 6-F
CF3
C≡C-2-thienyl

471
5-Cl, 6-F
CF3
C≡C-3-thienyl

472
5-Cl, 6-F
CF3
CH═CH-cycPr

473
5-Cl, 6-F
CF3
CH═CH-iPr

474
5-Cl, 6-F
CF3
CH═CH-npr

475
5-Cl, 6-F
CF3
CH═CH—Bu

476
5-Cl, 6-F
CF3
CH═CH-iBu

477
5-Cl, 6-F
CF3
CH═CH-tBu

478
5-Cl, 6-F
CF3
CH═CH—Et

479
5-Cl, 6-F
CF3
CH═CH—Me

480
5-Cl, 6-F
CF3
CH═CH—Ph

481
5-Cl, 6-F
CF3
CH═CH-2-Pyridyl

482
5-Cl, 6-F
CF3
CH═CH-3-Pyridyl

483
5-Cl, 6-F
CF3
CH═CH-4-Pyridyl

484
5-Cl, 6-F
CF3
CH═CH-2-furanyl

485
5-Cl, 6-F
CF3
CH═CH-3-furanyl

486
5-Cl, 6-F
CF3
CH═CH-2-thienyl

487
5-Cl, 6-F
CF3
CH═CH-3-thienyl

488
5-Cl, 6-F
CF3
CH2CH2CH2CH2CH3

489
5-Cl, 6-F
CF3
CH2CH2CH(CH3)2

490
5-Cl, 6-F
CF3
CH2CH2CH2CH3

491
5-Cl, 6-F
CF3
CH2CH2-cycPr

492
5-Cl, 6-F
CF3
CH2CH2-tBu

493
5-Cl, 6-F
CF3
CH2CH2CH2CH2OH

494
5-Cl, 6-F
CF3
CH2CH2-CH(OH)Me

495
5-Cl, 6-F
CF3
CH2CH2-Ph

496
5-Cl, 6-F
CF3
CH2CH2-2-Pyridyl

497
5-Cl, 6-F
CF3
CH2CH2-3-Pyridyl

498
5-Cl, 6-F
CF3
CH2CH2-4-Pyridyl

499
5-Cl, 6-F
CF3
CH2CH2-2-furanyl

500
5-Cl, 6-F
CF3
CH2CH2-3-furanyl

501
5-Cl, 6-F
CF3
CH2CH2-2-thienyl

502
5-Cl, 6-F
CF3
CH2CH2-3-thienyl

503
5,6-OCH2O—
CF3
C≡C—Bu

504
5,6-OCH2O—
CF3
C≡C-iBu

505
5,6-OCH2O—
CF3
C≡C-tBu

506
5,6-OCH2O—
CF3
C≡C—Me

507
5,6-OCH2O—
CF3
C≡CCH2CH2OH

508
5,6-OCH2O—
CF3
C≡C—CH(OH)Me

509
5,6-OCH2O—
CF3
C≡C—Ph

510
5,6-OCH2O—
CF3
C≡C-(2-Cl)Ph

511
5,6-OCH2O—
CF3
C≡C-(3-Cl)Ph

512
5,6-OCH2O—
CF3
C≡C-(4-Cl)Ph

513
5,6-OCH2O—
CF3
C≡C-(2-F)Ph

514
5,6-OCH2O—
CF3
C≡C-(3-F)Ph

515
5,6-OCH2O—
CF3
C≡C-(4-F)Ph

516
5,6-OCH2O—
CF3
C≡C-(2-OH)Ph

517
5,6-OCH2O—
CF3
C≡C-(3-OH)Ph

518
5,6-OCH2O—
CF3
C≡C-(4-OH)Ph

519
5,6-OCH2O—
CF3
C≡C-(2-OMe)Ph

520
5,6-OCH2O—
CF3
C≡C-(3-OMe)Ph

521
5,6-OCH2O—
CF3
C≡C-(4-OMe)Ph

522
5,6-OCH2O—
CF3
C≡C-(2-CN)Ph

523
5,6-OCH2O—
CF3
C≡C-(3-CN)Ph

524
5,6-OCH2O—
CF3
C≡C-(4-CN)Ph

525
5,6-OCH2O—
CF3
C≡C-(2-NO2)Ph

526
5,6-OCH2O—
CF3
C≡C-(3-NO2)Ph

527
5,6-OCH2O—
CF3
C≡C-(4-NO2)Ph

528
5,6-OCH2O—
CF3
C≡C-(2-NH2)Ph

529
5,6-OCH2O—
CF3
C≡C-(3-NH2)Ph

530
5,6-OCH2O—
CF3
C≡C-(4-NH2)Ph

531
5,6-OCH2O—
CF3
C≡C-(2-NMe2)Ph

532
5,6-OCH2O—
CF3
C≡C-(3-NMe2)Ph

533
5,6-OCH2O—
CF3
C≡C-(4-NMe2)Ph

534
5,6-OCH2O—
CF3
C≡C-2-Pyridyl

535
5,6-OCH2O—
CF3
C≡C-3-Pyridyl

536
5,6-OCH2O—
CF3
C≡C-4-Pyridyl

537
5,6-OCH2O—
CF3
C≡C-2-furanyl

538
5,6-OCH2O—
CF3
C≡C-3-furanyl

539
5,6-OCH2O—
CF3
C≡C-2-thienyl

540
5,6-OCH2O—
CF3
C≡C-3-thienyl

541
5,6-OCH2O—
CF3
CH═CH-cycPr

542
5,6-OCH2O—
CF3
CH═CH-iPr

543
5,6-OCH2O—
CF3
CH═CH-nPr

544
5,6-OCH2O—
CF3
CH═CH—Bu

545
5,6-OCH2O—
CF3
CH═CH-iBu

546
5,6-OCH2O—
CF3
CH═CH-tBu

547
5,6-OCH2O—
CF3
CH═CH—Et

548
5,6-OCH2O—
CF3
CH═CH—Me

549
5,6-OCH2O—
CF3
CH═CH—Ph

550
5,6-OCH2O—
CF3
CH═CH-2-Pyridyl

551
5,6-OCH2O—
CF3
CH═CH-3-Pyridyl

552
5,6-OCH2O—
CF3
CH═CH-4-Pyridyl

553
5,6-OCH2O—
CF3
CH═CH-2-furanyl

554
5,6-OCH2O—
CF3
CH═CH-3-furanyl

555
5,6-OCH2O—
CF3
CH═CH-2-thienyl

556
5,6-OCH2O—
CF3
CH═CH-3-thienyl

557
5,6-OCH2O—
CF3
CH2CH2CH2CH2CH3

558
5,6-OCH2O—
CF3
CH2CH2CH2CH3

559
5,6-OCH2O—
CF3
CH2CH2-cycPr

560
5,6-OCH2O—
CF3
CH2CH2-tBu

561
5,6-OCH2O—
CF3
CH2CH2CH2CH2OH

562
5,6-OCH2O—
CF3
CH2CH2-CH(OH)Me

563
5,6-OCH2O—
CF3
CH2CH2-Ph

564
5,6-OCH2O—
CF3
CH2CH2-2-Pyridyl

565
5,6-OCH2O—
CF3
CH2CH2-3-Pyridyl

566
5,6-OCH2O—
CF3
CH2CH2-4-Pyridyl

567
5,6-OCH2O—
CF3
CH2CH2-2-furanyl

568
5,6-OCH2O—
CF3
CH2CH2-3-furanyl

569
5,6-OCH2O—
CF3
CH2CH2-2-thienyl

570
5,6-OCH2O—
CF3
CH2CH2-3-thienyl

571
5-F
CF3
C≡C-cycPr

572
5-F
CF3
C≡C-iPr

573
5-F
CF3
C≡C-nPr

574
5-F
CF3
C≡C—Bu

575
5-F
CF3
C≡C-iBu

576
5-F
CF3
C≡C-tBu

577
5-F
CF3
C≡C—Et

578
5-F
CF3
C≡C—Me

579
5-F
CF3
C≡CCH2CH2OH

580
5-F
CF3
C≡C—CH(OH)Me

581
5-F
CF3
C≡C—Ph

582
5-F
CF3
C≡C-(2-Cl)Ph

583
5-F
CF3
C≡C-(3-Cl)Ph

584
5-F
CF3
C≡C-(4-Cl)Ph

585
5-F
CF3
C≡C-(2-F)Ph

586
5-F
CF3
C≡C-(3-F)Ph

587
5-F
CF3
C≡C-(4-F)Ph

588
5-F
CF3
C≡C-(2-OH)Ph

589
5-F
CF3
C≡C-(3-OH)Ph

590
5-F
CF3
C≡C-(4-OH)Ph

591
5-F
CF3
C≡C-(2-OMe)Ph

592
5-F
CF3
C≡C-(3-OMe)Ph

593
5-F
CF3
C≡C-(4-OMe)Ph

594
5-F
CF3
C≡C-(2-CN)Ph

595
5-F
CF3
C≡C-(3-CN)Ph

596
5-F
CF3
C≡C-(4-CN)Ph

597
5-F
CF3
C≡C-(2-NO2)Ph

598
5-F
CF3
C≡C-(3-NO2)Ph

599
5-F
CF3
C≡C-(4-NO2)Ph

600
5-F
CF3
C≡C-(2-NH2)Ph

601
5-F
CF3
C≡C-(3-NH2)Ph

602
5-F
CF3
C≡C-(4-NH2)Ph

603
5-F
CF3
C≡C-(2-NMe2)Ph

604
5-F
CF3
C≡C-(3-NMe2)Ph

605
5-F
CF3
C≡C-(4-NMe2)Ph

606
5-F
CF3
C≡C-2-Pyridyl

607
5-F
CF3
C≡C-3-Pyridyl

608
5-F
CF3
C≡C-4-Pyridyl

609
5-F
CF3
C≡C-2-furanyl

610
5-F
CF3
C≡C-3-furanyl

611
5-F
CF3
C≡C-2-thienyl

612
5-F
CF3
C≡C-3-thienyl

613
5-F
CF3
CH═CH-cycPr

614
5-F
CF3
CH═CH-iPr

615
5-F
CF3
CH═CH-nPr

616
5-F
CF3
CH═CH—Bu

617
5-F
CF3
CH═CH-iBu

618
5-F
CF3
CH═CH-tBu

619
5-F
CF3
CH═CH—Et

620
5-F
CF3
CH═CH—Me

621
5-F
CF3
CH═CH—Ph

622
5-F
CF3
CH═CH-2-Pyridyl

623
5-F
CF3
CH═CH-3-Pyridyl

624
5-F
CF3
CH═CH-4-Pyridyl

625
5-F
CF3
CH═CH-2-furanyl

626
5-F
CF3
CH═CH-3-furanyl

627
5-F
CF3
CH═CH-2-thienyl

628
5-F
CF3
CH═CH-3-thienyl

629
5-F
CF3
CH2CH2CH2CH2CH3

630
5-F
CF3
CH2CH2CH(CH3)2

631
5-F
CF3
CH2CH2CH2CH3

632
5-F
CF3
CH2CH2-cycPr

633
5-F
CF3
CH2CH2-tBu

634
5-F
CF3
CH2CH2CH2CH2OH

635
5-F
CF3
CH2CH2-CH(OH)Me

636
5-F
CF3
CH2CH2-Ph

637
5-F
CF3
CH2CH2-2-Pyridyl

638
5-F
CF3
CH2CH2-3-Pyridyl

639
5-F
CF3
CH2CH2-4-Pyridyl

640
5-F
CF3
CH2CH2-2-furanyl

641
5-F
CF3
CH2CH2-3-furanyl

642
5-F
CF3
CH2CH2-2-thienyl

643
5-F
CF3
CH2CH2-3-thienyl

644
5-Cl
CF3
C≡C-cycPr

645
5-Cl
CF3
C≡C-iPr

646
5-Cl
CF3
C≡C-nPr

647
5-Cl
CF3
C≡C—Bu

648
5-Cl
CF3
C≡C-iBu

649
5-Cl
CF3
C≡C-tBu

650
5-Cl
CF3
C≡C—Et

651
5-Cl
CF3
C≡C—Me

652
5-Cl
CF3
C≡CCH2CH2OH

653
5-Cl
CF3
C≡C—CH(OH)Me

654
5-Cl
CF3
C≡C—Ph

655
5-Cl
CF3
C≡C-(2-Cl)Ph

656
5-Cl
CF3
C≡C-(3-Cl)Ph

657
5-Cl
CF3
C≡C-(4-Cl)Ph

658
5-Cl
CF3
C≡C-(2-F)Ph

659
5-Cl
CF3
C≡C-(3-F)Ph

660
5-Cl
CF3
C≡C-(4-F)Ph

661
5-Cl
CF3
C≡C-(2-OH)Ph

662
5-Cl
CF3
C≡C-(3-OH)Ph

663
5-Cl
CF3
C≡C-(4-OH)Ph

664
5-Cl
CF3
C≡C-(2-OMe)Ph

665
5-Cl
CF3
C≡C-(3-OMe)Ph

666
5-Cl
CF3
C≡C-(4-OMe)Ph

667
5-Cl
CF3
C≡C-(2-CN)Ph

668
5-Cl
CF3
C≡C-(3-CN)Ph

669
5-Cl
CF3
C≡C-(4-CN)Ph

670
5-Cl
CF3
C≡C-(2-NO2)Ph

671
5-Cl
CF3
C≡C-(3-NO2)Ph

672
5-Cl
CF3
C≡C-(4-NO2)Ph

673
5-Cl
CF3
C≡C-(2-NH2)Ph

674
5-Cl
CF3
C≡C-(3-NH2)1Ph

675
5-Cl
CF3
C≡C-(4-NH2)Ph

676
5-Cl
CF3
C≡C-(2-NMe2)Ph

677
5-Cl
CF3
C≡C-(3-NMe2)Ph

678
5-Cl
CF3
C≡C-(4-NMe2)Ph

679
5-Cl
CF3
C≡C-2-Pyridyl

680
5-Cl
CF3
C≡C-3-Pyridyl

681
5-Cl
CF3
C≡C-4-Pyridyl

682
5-Cl
CF3
C≡C-2-furanyl

683
5-Cl
CF3
C≡C-3-furanyl

684
5-Cl
CF3
C≡C-2-thienyl

685
5-Cl
CF3
C≡C-3-thienyl

686
5-Cl
CF3
CH═CH-cycPr

687
5-Cl
CF3
CH═CH-iPr

688
5-Cl
CF3
CH═CH-nPr

689
5-Cl
CF3
CH═CH—Bu

690
5-Cl
CF3
CH═CH-iBu

691
5-Cl
CF3
CH═CH-tBu

692
5-Cl
CF3
CH═CH—Et

693
5-Cl
CF3
CH═CH—Me

694
5-Cl
CF3
CH═CH—Ph

695
5-Cl
CF3
CH═CH-2-Pyridyl

696
5-Cl
CF3
CH═CH-3-Pyridyl

697
5-Cl
CF3
CH═CH-4-Pyridyl

698
5-Cl
CF3
CH═CH-2-furanyl

699
5-Cl
CF3
CH═CH-3-furanyl

700
5-Cl
CF3
CH═CH-2-thienyl

701
5-Cl
CF3
CH═CH-3-thienyl

702
5-Cl
CF3
CH2CH2CH2CH2CH3

703
5-Cl
CF3
CH2CH2CH(CH3)2

704
5-Cl
CF3
CH2CH2CH2CH3

705
5-Cl
CF3
CH2CH2-cycPr

706
5-Cl
CF3
CH2CH2-tBu

707
5-Cl
CF3
CH2CH2CH2CH2OH

708
5-Cl
CF3
CH2CH2—CH(OH)Me

709
5-Cl
CF3
CH2CH2-Ph

710
5-Cl
CF3
CH2CH2-2-Pyridyl

711
5-Cl
CF3
CH2CH2-3-Pyridyl

712
5-Cl
CF3
CH2CH2-4-Pyridyl

713
5-Cl
CF3
CH2CH2-2-furanyl

714
5-Cl
CF3
CH2CH2-3-furanyl

715
5-Cl
CF3
CH2CH2-2-thienyl

716
5-Cl
CF3
CH2CH2-3-thienyl

717
6-OMe
CF3
C≡C—Bu

718
6-OMe
CF3
C≡C-iBu

719
6-OMe
CF3
C≡C-tBu

720
6-OMe
CF3
C≡CCH2CH2OH

721
6-OMe
CF3
C≡C—CH(OH)Me

722
6-OMe
CF3
C≡C—Ph

723
6-OMe
CF3
C≡C-(2-Cl)Ph

724
6-OMe
CF3
C≡C-(3-Cl)Ph

725
6-OMe
CF3
C≡C-(4-Cl)Ph

726
6-OMe
CF3
C≡C-(2-F)Ph

727
6-OMe
CF3
C≡C-(3-F)Ph

728
6-OMe
CF3
C≡C-(4-F)Ph

729
6-OMe
CF3
C≡C-(2-OH)Ph

730
6-OMe
CF3
C≡C-(3-OH)Ph

731
6-OMe
CF3
C≡C-(4-OH)Ph

732
6-OMe
CF3
C≡C-(2-OMe)Ph

733
6-OMe
CF3
C≡C-(3-OMe)Ph

734
6-OMe
CF3
C≡C-(4-OMe)Ph

735
6-OMe
CF3
C≡C-(2-CN)Ph

736
6-OMe
CF3
C≡C-(3-CN)Ph

737
6-OMe
CF3
C≡C-(4-CN)Ph

738
6-OMe
CF3
C≡C-(2-NO2)Ph

739
6-OMe
CF3
C≡C-(3-NO2)Ph

740
6-OMe
CF3
C≡C-(4-NO2)Ph

741
6-OMe
CF3
C≡C-(2-NH2)Ph

742
6-OMe
CF3
C≡C-(3-NH2)Ph

743
6-OMe
CF3
C≡C-(4-NH2)Ph

744
6-OMe
CF3
C≡C-(2-NMe2)Ph

745
6-OMe
CF3
C≡C-(3-NMe2)Ph

746
6-OMe
CF3
C≡C-(4-NMe2)Ph

747
6-OMe
CF3
C≡C-2-Pyridyl

748
6-OMe
CF3
C≡C-3-Pyridyl

749
6-OMe
CF3
C≡C-4-Pyridyl

750
6-OMe
CF3
C≡C-2-furanyl

751
6-OMe
CF3
C≡C-3-furanyl

752
6-OMe
CF3
C≡C-2-thienyl

753
6-OMe
CF3
C≡C-3-thienyl

754
6-OMe
CF3
C≡C-2-oxazolyl

755
6-OMe
CF3
C≡C-2-thiazolyl

756
6-OMe
CF3
C≡C-4-isoxazolyl

757
6-OMe
CF3
C≡C-2-imidazolyl

758
6-OMe
CF3
CH2C≡C—CH3

759
6-OMe
CF3
CH═CH-cycPr

760
6-OMe
CF3
CH═CH-iPr

761
6-OMe
CF3
CH═CH-nPr

762
6-OMe
CF3
CH═CH—Bu

763
6-OMe
CF3
CH═CH-iBu

764
6-OMe
CF3
CH═CH-tBu

765
6-OMe
CF3
CH═CH—Et

766
6-OMe
CF3
CH═CH-Ne

767
6-OMe
CF3
CH═CH—Ph

768
6-OMe
CF3
CH═CH-2-Pyridyl

769
6-OMe
CF3
CH═CH-3-Pyridyl

770
6-OMe
CF3
CH═CH-4-Pyridyl

771
6-OMe
CF3
CH═CH-2-furanyl

772
6-OMe
CF3
CH═CH-3-furanyl

773
6-OMe
CF3
CH═CH-2-thienyl

774
6-OMe
CF3
CH═CH-3-thienyl

775
6-OMe
CF3
CH2CH2CH2CH2CH3

776
6-OMe
CF3
CH2CH2CH3

777
6-OMe
CF3
CH2CH2-cycPr

778
6-OMe
CF3
CH2CH2-tBu

779
6-OMe
CF3
CH2CH2CH2CH2OH

780
6-OMe
CF3
CH2CH2—CH(OH)Me

781
6-OMe
CF3
CH2CH2-(2-Cl)Ph

782
6-OMe
CF3
CH2CH2-(3-Cl)Ph

783
6-OMe
CF3
CH2CH2-(4-Cl)Ph

784
6-OMe
CF3
CH2CH2-(2-F)Ph

785
6-OMe
CF3
CH2CH2-(3-F)Ph

786
6-OMe
CF3
CH2CH2-(4-F)Ph

787
6-OMe
CF3
CH2CH2-(2-OH)Ph

788
6-OMe
CF3
CH2CH2-(3-OH)Ph

789
6-OMe
CF3
CH2CH2-(4-OH)Ph

790
6-OMe
CF3
CH2CH2-(2-OMe)Ph

791
6-OMe
CF3
CH2CH2-(3-OMe)Ph

792
6-OMe
CF3
CH2CH2-(4-OMe)Ph

793
6-OMe
CF3
CH2CH2-(2-CN)Ph

794
6-OMe
CF3
CH2CH2-(3-CN)Ph

795
6-OMe
CF3
CH2CH2-(4-CN)Ph

796
6-OMe
CF3
CH2CH2-(2-NO2)Ph

797
6-OMe
CF3
CH2CH2-(3-NO2)Ph

798
6-OMe
CF3
CH2CH2-(4-NO2)Ph

799
6-OMe
CF3
CH2CH2-(2-NH2)Ph

800
6-OMe
CF3
CH2CH2-(3-NH2)Ph

801
6-OMe
CF3
CH2CH2-(4-NH2)Ph

802
6-OMe
CF3
CH2CH2-(2-NMe2)Ph

803
6-OMe
CF3
CH2CH2-(3-NMe2)Ph

804
6-OMe
CF3
CH2CH2-(4-NMe2)Ph

805
6-OMe
CF3
CH2CH2-2-Pyridyl

806
6-OMe
CF3
CH2CH2-3-Pyridyl

807
6-OMe
CF3
CH2CH2-4-Pyridyl

808
6-OMe
CF3
CH2CH2-2-furanyl

809
6-OMe
CF3
CH2CH2-3-furanyl

810
6-OMe
CF3
CH2CH2-2-thienyl

811
6-OMe
CF3
CH2CH2-3-thienyl

812
6-OMe
CF3
CH2CH2-2-oxazolyl

813
6-OMe
CF3
CH2CH2-2-thiazolyl

314
6-OMe
CF3
CH2CH2-4-isoxazolyl

815
6-OMe
CF3
CH2CH2-2-imidazolyl

816
6-OMe, 8-F
CF3
C≡C-iPr

817
6-OMe, 8-F
CF3
C≡C-nPr

818
6-OMe, 8-F
CF3
C≡C—Et

819
6-OMe, 8-F
CF3
C≡C—Me

820
6-OMe, 8-F
CF3
C≡C—Ph

821
6-OMe, 8-F
CF3
C≡C-2-Pyridyl

822
6-OMe, 8-F
CF3
C≡C-3-Pyridyl

823
6-OMe, 8-F
CF3
C≡C-4-Pyridyl

824
6-OMe, 8-F
CF3
C≡C-2-furanyl

825
6-OMe, 8-F
CF3
C≡C-3-furanyl

826
6-OMe, 8-F
CF3
C≡C-2-thienyl

827
6-OMe, 8-F
CF3
C≡C-3-thienyl

828
6-OMe, 8-F
CF3
CH═CH-cycPr

829
6-OMe, 8-F
CF3
CH═CH-iPr

830
6-OMe, 8-F
CF3
CH═CH-nPr

831
6-OMe, 8-F
CF3
CH═CH—Et

832
6-OMe, 8-F
CF3
CH═CH—Me

833
6-OMe, 8-F
CF3
CH═CH—Ph

834
6-OMe, 8-F
CF3
CH═CH-2-Pyridyl

835
6-OMe, 8-F
CF3
CH═CH-3-Pyridyl

836
6-OMe, 8-F
CF3
CH═CH-4-Pyridyl

837
6-OMe, 8-F
CF3
CH═CH-2-furanyl

838
6-OMe, 8-F
CF3
CH═CH-3-furanyl

839
6-OMe, 8-F
CF3
CH═CH-2-thienyl

840
6-OMe, 8-F
CF3
CH═CH-3-thienyl

841
6-OMe, 8-F
CF3
CH2CH2CH2CH2CH3

842
6-OMe, 8-F
CF3
CH2CH2CH(CH3)2

843
6-OMe, 8-F
CF3
CH2CH2CH2CH3

844
6-OMe, 8-F
CF3
CH2CH2-cycPr

845
6-OMe, 8-F
CF3
CH2CH2-Ph

846
6-OMe, 8-F
CF3
CH2CH2-2-Pyridyl

847
6-OMe, 8-F
CF3
CH2CH2-3-Pyridyl

848
6-OMe, 8-F
CF3
CH2CH2-4-Pyridyl

849
6-OMe, 8-F
CF3
CH2CH2-2-furanyl

850
6-OMe, 8-F
CF3
CH2CH2-3-furanyl

851
6-OMe, 8-F
CF3
CH2CH2-2-thienyl

852
6-OMe, 8-F
CF3
CH2CH2-3-thienyl

853
5-F, 6-OMe
CF3
C≡C-cycPr

854
5-F, 6-OMe
CF3
C≡C-iPr

855
5-F, 6-OMe
CF3
C≡C-nPr

856
5-F, 6-OMe
CF3
C≡C—Bu

857
5-F, 6-OMe
CF3
C≡C-iBu

858
5-F, 6-OMe
CF3
C≡C-tBu

859
5-F, 6-OMe
CF3
C≡C—Et

860
5-F, 6-OMe
CF3
C≡C—Me

861
5-F, 6-OMe
CF3
C≡C—Ph

862
5-F, 6-OMe
CF3
C≡C-(2-Cl)Ph

863
5-F, 6-OMe
CF3
C≡C-(3-Cl)Ph

864
5-F, 6-OMe
CF3
C≡C-(2-F)Ph

865
5-F, 6-OMe
CF3
C≡C-(3-F)Ph

866
5-F, 6-OMe
CF3
C≡C-(2-OH)Ph

867
5-F, 6-OMe
CF3
C≡C-(3-OH)Ph

868
5-F, 6-OMe
CF3
C≡C-(2-OMe)Ph

869
5-F, 6-OMe
CF3
C≡C-(3-OMe)Ph

870
5-F, 6-OMe
CF3
C≡C-(2-CN)Ph

871
5-F, 6-OMe
CF3
C≡C-(3-CN)Ph

872
5-F, 6-OMe
CF3
C≡C-(2-NH2)Ph

873
5-F, 6-OMe
CF3
C≡C-(3-NH2)Ph

874
5-F, 6-OMe
CF3
C≡C-(2-NMe2)Ph

875
5-F, 6-OMe
CF3
C≡C-(3-NMe2)Ph

876
5-F, 6-OMe
CF3
C≡C-2-Pyridyl

877
5-F, 6-OMe
CF3
C≡C-3-Pyridyl

878
5-F, 6-OMe
CF3
C≡C-4-Pyridyl

879
5-F, 6-OMe
CF3
C≡C-2-furanyl

880
5-F, 6-OMe
CF3
C≡C-3-furanyl

881
5-F, 6-OMe
CF3
C≡C-2-thienyl

882
5-F, 6-OMe
CF3
C≡C-3-thienyl

883
5-F, 6-OMe
CF3
CH═CH-cycPr

884
5-F, 6-OMe
CF3
CH═CH-iPr

885
5-F, 6-OMe
CF3
CH═CH-nPr

886
5-F, 6-OMe
CF3
CH═CH—Bu

887
5-F, 6-OMe
CF3
CH═CH-iBu

888
5-F, 6-OMe
CF3
CN═CH-tBu

889
5-F, 6-OMe
CF3
CH═CH—Et

890
5-F, 6-OMe
CF3
CH═CH—Me

891
5-F, 6-OMe
CF3
CH═CH—Ph

892
5-F, 6-OMe
CF3
CH═CH-2-Pyridyl

893
5-F, 6-OMe
CF3
CH═CH-3-Pyridyl

894
5-F, 6-OMe
CF3
CH═CH-4-Pyridyl

895
5-F, 6-OMe
CF3
CH═CH-2-furanyl

896
5-F, 6-OMe
CF3
CH═CH-3-furanyl

897
5-F, 6-OMe
CF3
CH═CH-2-thienyl

898
5-F, 6-OMe
CF3
CH═CH-3-thienyl

899
5-F, 6-OMe
CF3
CH2CH2CH2CH2CH3

900
5-F, 6-OMe
CF3
CH2CH2CH(CH3)2

901
5-F, 6-OMe
CF3
CH2CH2CH2CH3

902
5-F, 6-OMe
CF3
CH2CH2-cycPr

903
5-F, 6-OMe
CF3
CH2CH2-tBu

904
5-F, 6-OMe
CF3
CH2CH2-Ph

905
5-F, 6-OMe
CF3
CH2CH2-2-Pyridyl

906
5-F, 6-OMe
CF3
CH2CH2-3-Pyridyl

907
5-F, 6-OMe
CF3
CH2CH2-4-Pyridyl

908
5-F, 6-OMe
CF3
CH2CH2-2-furanyl

909
5-F, 6-OMe
CF3
CH2CH2-3-furanyl

910
5-F, 6-OMe
CF3
CH2CH2-2-thienyl

911
5-F, 6-OMe
CF3
CH2CH2-3-thienyl

912
6-NMe2
CF3
C≡C-nPr

913
6-NMe2
CF3
C≡C—Bu

914
6-NMe2
CF3
C≡C-iBu

915
6-NMe2
CF3
C≡C-tBu

916
6-NMe2
CF3
C≡C—Et

917
6-NMe2
CF3
C≡C—Me

918
6-NMe2
CF3
C≡C—Ph

919
6-NMe2
CF3
C≡C-(2-Cl)Ph

920
6-NMe2
CF3
C≡C-(3-Cl)Ph

921
6-NMe2
CF3
C≡C-(2-F)Ph

922
6-NMe2
CF3
C≡C-(3-F)Ph

923
6-NMe2
CF3
C≡C-(2-OH)Ph

924
6-NMe2
CF3
C≡C-(3-OH)Ph

925
6-NMe2
CF3
C≡C-(2-OMe)Ph

926
6-NMe2
CF3
C≡C-(3-OMe)Ph

927
6-NMe2
CF3
C≡C-(2-CN)Ph

928
6-NMe2
CF3
C≡C-(3-CN)Ph

929
6-NMe2
CF3
C≡C-(2-NH2)Ph

930
6-NMe2
CF3
C≡C-(3-NH2)Ph

931
6-NMe2
CF3
C≡C-(2-NMe2)Ph

932
6-NMe2
CF3
C≡C-(3-NMe2)Ph

933
6-NMe2
CF3
C≡C-2-Pyridyl

934
6-NMe2
CF3
C≡C-3-Pyridyl

935
6-NMe2
CF3
C≡C-4-Pyridyl

936
6-NMe2
CF3
C≡C-2-furanyl

937
6-NMe2
CF3
C≡C-3-furanyl

938
6-NMe2
CF3
C≡C-2-thienyl

939
6-NMe2
CF3
C≡C-3-thienyl

940
6-NMe2
CF3
CH═CH-cycPr

941
6-NMe2
CF3
CH═CH-iPr

942
6-NMe2
CF3
CH═CH-nPr

943
6-NMe2
CF3
CH═CH—Bu

944
6-NMe2
CF3
CH═CH-iBu

945
6-NMe2
CF3
CH═CH-tBu

946
6-NMe2
CF3
CH═CH—Et

947
6-NMe2
CF3
CH═CH—Me

948
6-NMe2
CF3
CH═CH—Ph

949
6-NMe2
CF3
CH═CH-2-Pyridyl

950
6-NMe2
CF3
CH═CH-3-Pyridyl

951
6-NMe2
CF3
CH═CH-4-Pyridyl

952
6-NMe2
CF3
CH═CH-2-furanyl

953
6-NMe2
CF3
CH═CH-3-furanyl

954
6-NMe2
CF3
CH═CH-2-thienyl

955
6-NMe2
CF3
CH═CH-3-thienyl

956
6-NMe2
CF3
CH2CH2CH2CH3

957
6-NMe2
CF3
CH2CH2-cycPr

958
6-NMe2
CF3
CH2CH2-tBu

959
6-NMe2
CF3
CH2CH2-Ph

960
6-NMe2
CF3
CH2CH2-2-Pyridyl

961
6-NMe2
CF3
CH2CH2-3-Pyridyl

962
6-NMe2
CF3
CH2CH2-4-Pyridyl

963
6-NMe2
CF3
CH2CH2-2-furanyl

964
6-NMe2
CF3
CH2CH2-3-furanyl

965
6-NMe2
CF3
CH2CH2-2-thienyl

966
6-NMe2
CF3
CH2CH2-3-thienyl

967
6-COCH3
CF3
C≡C-iPr

968
6-COCH3
CF3
C≡C-nPr

969
6-COCH3
CF3
C≡C—Bu

970
6-COCH3
CF3
C≡C-iBu

971
6-COCH3
CF3
C≡C-tBu

972
6-COCH3
CF3
C≡C—Me

973
6-COCH3
CF3
C≡C—Ph

974
6-COCH3
CF3
C≡C-(2-Cl)Ph

975
6-COCH3
CF3
C≡C-(3-Cl)Ph

976
6-COCH3
CF3
C≡C-(2-F)Ph

977
6-COCH3
CF3
C≡C-(3-F)Ph

978
6-COCH3
CF3
C≡C-(2-OH)Ph

979
6-COCH3
CF3
C≡C-(3-OH)Ph

980
6-COCH3
CF3
C≡C-(2-OMe)Ph

981
6-COCH3
CF3
C≡C-(3-OMe)Ph

982
6-COCH3
CF3
C≡C-(2-CN)Ph

983
6-COCH3
CF3
C≡C-(3-CN)Ph

984
6-COCH3
CF3
C≡C-(2-NH2)Ph

985
6-COCH3
CF3
C≡C-(3-NH2)Ph

986
6-COCH3
CF3
C≡C-(2-NMe2)Ph

987
6-COCH3
CF3
C≡C-(3-NMe2)Ph

988
6-COCH3
CF3
C≡C-2-Pyridyl

989
6-COCH3
CF3
C≡C-3-Pyridyl

990
6-COCH3
CF3
C≡C-4-Pyridyl

991
6-COCH3
CF3
C≡C-2-furanyl

992
6-COCH3
CF3
C≡C-3-furanyl

993
6-COCH3
CF3
C≡C-2-thienyl

994
6-COCH3
CF3
C≡C-3-thienyl

995
6-COCH3
CF3
CH═CH-cycPr

996
6-COCH3
CF3
CH═CH-iPr

997
6-COCH3
CF3
CH═CH-nPr

998
6-COCH3
CF3
CH═CH—Bu

999
6-COCH3
CF3
CH═CH-iBu

1000
6-COCH3
CF3
CH═CH-tBu

1001
6-COCH3
CF3
CH═CH—Et

1002
6-COCH3
CF3
CH═CH—Me

1003
6-COCH3
CF3
CH═CH—Ph

1004
6-COCH3
CF3
CH═CH-2-Pyridyl

1005
6-COCH3
CF3
CH═CH-3-Pyridyl

1006
6-COCH3
CF3
CH═CH-4-Pyridyl

1007
6-COCH3
CF3
CH═CH-2-furanyl

1008
6-COCH3
CF3
CH═CH-3-furanyl

1009
6-COCH3
CF3
CH═CH-2-thienyl

1010
6-COCH3
CF3
CH═CH-3-thienyl

1011
6-COCH3
CF3
CH2CH2CH2CH2CH3

1012
6-COCH3
CF3
CH2CH2CH(CH3)2

1013
6-COCH3
CF3
CH2CH2CH2CH3

1014
6-COCH3
CF3
CH2CH2-cycPr

1015
6-COCH3
CF3
CH2CH2-tBu

1016
6-COCH3
CF3
CH2CH2-Ph

1017
6-COCH3
CF3
CH2CH2-2-Pyridyl

1018
6-COCH3
CF3
CH2CH2-3-Pyridyl

1019
6-COCH3
CF3
CH2CH2-4-Pyridyl

1020
6-COCH3
CF3
CH2CH2-2-furanyl

1021
6-COCH3
CF3
CH2CH2-3-furanyl

1022
6-COCH3
CF3
CH2CH2-2-thienyl

1023
6-COCH3
CF3
CH2CH2-3-thienyl

1024
6-CH3
CF3
C≡C-nPr

1025
6-CH3
CF3
C≡C—Bu

1026
6-CH3
CF3
C≡C-iBu

1027
6-CH3
CF3
C≡C-tBu

1028
6-CH3
CF3
C≡C—Me

1029
6-CH3
CF3
C≡C—Ph

1030
6-CH3
CF3
C≡C-(2-Cl)Ph

1031
6-CH3
CF3
C≡C-(3-Cl)Ph

1032
6-CH3
CF3
C≡C-(2-F)Ph

1033
6-CH3
CF3
C≡C-(3-F)Ph

1034
6-CH3
CF3
C≡C-(2-OH)Ph

1035
6-CH3
CF3
C≡C-(3-OH)Ph

1036
6-CH3
CF3
C≡C-(2-OMe)Ph

1037
6-CH3
CF3
C≡C-(3-OMe)Ph

1038
6-CH3
CF3
C≡C-(2-CN)Ph

1039
6-CH3
CF3
C≡C-(3-CN)Ph

1040
6-CH3
CF3
C≡C-(2-NH2)Ph

1041
6-CH3
CF3
C≡C-(3-NH2)Ph

1042
6-CH3
CF3
C≡C-(2-NMe2)Ph

1043
6-CH3
CF3
C≡C-(3-NMe2)Ph

1044
6-CH3
CF3
C≡C-2-Pyridyl

1045
6-CH3
CF3
C≡C-3-Pyridyl

1046
6-CH3
CF3
C≡C-4-Pyridyl

1047
6-CH3
CF3
C≡C-2-furanyl

1048
6-CH3
CF3
C≡C-3-furanyl

1049
6-CH3
CF3
C≡C-2-thienyl

1050
6-CH3
CF3
C≡C-3-thienyl

1051
6-CH3
CF3
CH═CH-cycPr

1052
6-CH3
CF3
CH═CH-iPr

1053
6-CH3
CF3
CH═CH-nPr

1054
6-CH3
CF3
CH═CH—Bu

1055
6-CH3
CF3
CH═CH-iBu

1056
6-CH3
CF3
CH═CH-tBu

1057
6-CH3
CF3
CH═CH—Et

1058
6-CH3
CF3
CH═CH—Me

1059
6-CH3
CF3
CH═CH—Ph

1060
6-CH3
CF3
CH═CH-2-Pyridyl

1061
6-CH3
CF3
CH═CH-3-Pyridyl

1062
6-CH3
CF3
CH═CH-4-Pyridyl

1063
6-CH3
CF3
CH═CH-2-furanyl

1064
6-CH3
CF3
CH═CH-3-furanyl

1065
6-CH3
CF3
CH═CH-2-thienyl

1066
6-CH3
CF3
CH═CH-3-thienyl

1067
6-CH3
CF3
CH2CH2CH2CH2CH3

1068
6-CH3
CF3
CH2CH2CH(CH3)2

1069
6-CH3
CF3
CH2CH2CH2CH3

1070
6-CH3
CF3
CH2CH2-cycPr

1071
6-CH3
CF3
CH2CH2-tBu

1072
6-CH3
CF3
CH2CH2-Ph

1073
6-CH3
CF3
CH2CH2-2-Pyridyl

1074
6-CH3
CF3
CH2CH2-3-Pyridyl

1075
6-CH3
CF3
CH2CH2-4-Pyridyl

1076
6-CH3
CF3
CH2CH2-2-furanyl

1077
6-CH3
CF3
CH2CH2-3-furanyl

1078
6-CH3
CF3
CH2CH2-2-thienyl

1079
6-CH3
CF3
CH2CH2-3-thienyl

1080
6,8-diCl
CF3
C≡C-ipr

1081
6,8-diCl
CF3
C≡C-nPr

1082
6,8-diCl
CF3
C≡C—Et

1083
6,8-diCl
CF3
C≡C—Me

1084
6,8-diCl
CF3
C≡C—Ph

1085
6,8-diCl
CF3
C≡C-2-Pyridyl

1086
6,8-diCl
CF3
C≡C-3-Pyridyl

1087
6,8-diCl
CF3
C≡C-4-Pyridyl

1088
6,8-diCl
CF3
C≡C-2-furanyl

1089
6,8-diCl
CF3
C≡C-3-furanyl

1090
6,8-diCl
CF3
C≡C-2-thienyl

1091
6,8-diCl
CF3
C≡C-3-thienyl

1092
6,8-diCl
CF3
CH═CH-cycPr

1093
6,8-diCl
CF3
CH═CH-iPr

1094
6,8-diCl
CF3
CH═CH-nPr

1095
6,8-diCl
CF3
CH═CH—Et

1096
6,8-diCl
CF3
CH═CH—Me

1097
6,8-diCl
CF3
CH═CH—Ph

1098
6,8-diCl
CF3
CH═CH-2-Pyridyl

1099
6,8-diCl
CF3
CH═CH-3-Pyridyl

1100
6,8-diCl
CF3
CH═CH-4-Pyridyl

1101
6,8-diCl
CF3
CH═CH-2-furanyl

1102
6,8-diCl
CF3
CH═CH-3-furanyl

1103
6,8-diCl
CF3
CH═CH-2-thienyl

1104
6,8-diCl
CF3
CH═CH-3-thienyl

1105
6,8-diCl
CF3
CH2CH2CH2CH2CH3

1106
6,8-diCl
CF3
CH2CH2CH(CH3)2

1107
6,8-diCl
CF3
CH2CH2CH2CH3

1108
6,8-diCl
CF3
CH2CH2-cycPr

1109
6,8-diCl
CF3
CH2CH2-2-Pyridyl

1110
6,8-diCl
CF3
CH2CH2-3-Pyridyl

1111
6,8-diCl
CF3
CH2CH2-4-Pyridyl

1112
6,8-diCl
CF3
CH2CH2-2-furanyl

1113
6,8-did
CF3
CH2CH2-3-furanyl

1114
6,8-diCl
CF3
CH2CH2-2-thienyl

1115
6,8-diCl
CF3
CH2CH2-3-thienyl

1116
5,6,8-triF
CF3
C≡C—Me

1117
5,6,8-triF
CF3
C≡C—Ph

1118
5,6,8-triF
CF3
C≡C-2-Pyridyl

1119
5,6,8-triF
CF3
C≡C-3-Pyridyl

1120
5,6,8-triF
CF3
C≡C-4-Pyridyl

1121
5,6,8-triF
CF3
C≡C-2-furanyl

1122
5,6,8-triF
CF3
C≡C-3-furanyl

1123
5,6,8-triF
CF3
C≡C-2-thienyl

1124
5,6,8-triF
CF3
C≡C-3-thienyl

1125
5,6,8-triF
CF3
CH═CH-cycPr

1126
5,6,8-triF
CF3
CH═CH-iPr

1127
5,6,8-triF
CF3
CH═CH-nPr

1128
5,6,8-triF
CF3
CH═CH—Et

1129
5,6,8-triF
CF3
CH═CH—Me

1130
5,6,8-triF
CF3
CH═CH—Ph

1131
5,6,8-triF
CF3
CH═CH-2-Pyridyl

1132
5,6,8-triF
CF3
CH═CH-3-Pyridyl

1133
5,6,8-triF
CF3
CH═CH-4-Pyridyl

1134
5,6,8-triF
CF3
CH═CH-2-furanyl

1135
5,6,8-triF
CF3
CH═CH-3-furanyl

1136
5,6,8-triF
CF3
CH═CH-2-thienyl

1137
5,6,8-triF
CF3
CH═CH-3-thienyl

1138
5,6,8-triF
CF3
CH2CH2CH2CH2CH3

1139
5,6,8-triF
CF3
CH2CH2CH(CH3)2

1140
5,6,8-triF
CF3
CH2CH2CH2CH3

1141
5,6,8-triF
CF3
CH2CH2-cycPr

1142
5,6,8-triF
CF3
CH2CH2-Ph

1143
5,6,8-triF
CF3
CH2CH2-2-Pyridyl

1144
5,6,8-triF
CF3
CH2CH2-3-Pyridyl

1145
5,6,8-triF
CF3
CH2CH2-4-Pyridyl

1146
5,6,8-triF
CF3
CH2CH2-2-furanyl

1147
5,6,8-triF
CF3
CH2CH2-3-furanyl

1148
5,6,8-triF
CF3
CH2CH2-2-thienyl

1149
5,6,8-triF
CF3
CH2CH2-3-thienyl

1150
5,8-diF
CF3
C≡C—Me

1151
5,8-diF
CF3
C≡C—Ph

1152
5,8-diF
CF3
C≡C-2-Pyridyl

1153
5,8-diF
CF3
C≡C-3-Pyridyl

1154
5,8-diF
CF3
C≡C-4-Pyridyl

1155
5,8-diF
CF3
C≡C-2-furanyl

1156
5,8-diF
CF3
C≡C-3-furanyl

1157
5,8-diF
CF3
C≡C-2-thienyl

1158
5,8-diF
CF3
C≡C-3-thienyl

1159
5,8-diF
CF3
CH═CH-cycPr

1160
5,8-diF
CF3
CH═CH-iPr

1161
5,8-diF
CF3
CH═CH-nPr

1162
5,8-diF
CF3
CH═CH—Et

1163
5,8-diF
CF3
CH═CH—Me

1164
5,8-diF
CF3
CH═CH—Ph

1165
5,8-diF
CF3
CH═CH-2-Pyridyl

1166
5,8-diF
CF3
CH═CH-3-Pyridyl

1167
5,8-diF
CF3
CH═CH-4-Pyridyl

1168
5,8-diF
CF3
CH═CH-2-furanyl

1169
5,8-diF
CF3
CH═CH-3-furanyl

1170
5,8-diF
CF3
CH═CH-2-thienyl

1171
5,8-diF
CF3
CH═CH-3-thienyl

1172
5,8-diF
CF3
CH2CH2CH2CH2CH3

1173
5,8-diF
CF3
CH2CH2CH(CH3)2

1174
5,8-diF
CF3
CH2CH2CH2CH3

1175
5,8-diF
CF3
CH2CH2-cycPr

1176
5,8-diF
CF3
CH2CH2-Ph

1177
5,8-diF
CF3
CH2CH2-2-Pyridyl

1178
5,8-diF
CF3
CH2CH2-3-Pyridyl

1179
5,8-diF
CF3
CH2CH2-4-Pyridyl

1180
5,8-diF
CF3
CH2CH2-2-furanyl

1181
5,8-diF
CF3
CH2CH2-3-furanyl

1182
5,8-diF
CF3
CH2CH2-2-thienyl

1183
5,8-diF
CF3
CH2CH2-3-thienyl

1184
6-iPr
CF3
C≡C-nPr

1185
6-iPr
CF3
C≡C—Et

1186
6-iPr
CF3
C≡C—Me

1187
6-iPr
CF3
C≡C-3-Pyridyl

1188
6-iPr
CF3
C≡C-2-furanyl

1189
6-iPr
CF3
C≡C-3-furanyl

1190
6-iPr
CF3
C≡C-2-thienyl

1191
6-iPr
CF3
C≡C-3-thienyl

1192
6-iPr
CF3
CH═CH-cycPr

1193
6-iPr
CF3
CH═CH-iPr

1194
6-iPr
CF3
CH═CH-nPr

1195
6-iPr
CF3
CH═CH—Et

1196
6-iPr
CF3
CH═CH—Me

1197
6-iPr
CF3
CH═CH—Ph

1198
6-iPr
CF3
CH═CH-2-furanyl

1199
6-iPr
CF3
CH═CH-3-furanyl

1200
6-iPr
CF3
CH═CH-2-thienyl

1201
6-iPr
CF3
CH═CH-3-thienyl

1202
6-iPr
CF3
CH2CH2CH2CH3

1203
6-iPr
CF3
CH2CH2-cycPr

1204
6-OCF3
CF3
C≡C-nPr

1205
6-OCF3
CF3
C≡C—Et

1206
6-OCF3
CF3
C≡C—Me

1207
6-OCF3
CF3
C≡C-3-Pyridyl

1208
6-OCF3
CF3
C≡C-2-furanyl

1209
6-OCF3
CF3
C≡C-3-furanyl

1210
6-OCF3
CF3
C≡C-2-thienyl

1211
6-OCF3
CF3
C≡C-3-thienyl

1212
6-OCF3
CF3
CH═CH-cycPr

1213
6-OCF3
CF3
CH═CH-iPr

1214
6-OCF3
CF3
CH═CH-nPr

1215
6-OCF3
CF3
CM═CH—Et

1216
6-OCF3
CF3
CH═CH—Me

1217
6-OCF3
CF3
CH═CH—Ph

1218
6-OCF3
CF3
CH═CH-3-Pyridyl

1219
6-OCF3
CF3
CH═CH-2-furanyl

1220
6-OCF3
CF3
CH═CH-3-furanyl

1221
6-OCF3
CF3
CH═CH-2-thienyl

1222
6-OCF3
CF3
CH═CH-3-thienyl

1223
6-OCF3
CF3
CH2CH2CH2CH3

1224
6-OCF3
CF3
CH2CH2-cycPr

1225
6-(pyrazol-5-yl)
CF3
C≡C-cycPr

1226
6-(pyrazol-5-yl)
CF3
C≡C-iPr

1227
6-(pyrazol-5-yl)
CF3
C≡C-nPr

1228
6-(pyrazol-5-yl)
CF3
C≡C—Et

1229
6-(pyrazol-5-yl)
CF3
C≡C—Me

1230
6-(pyrazol-5-yl)
CF3
C≡C—Ph

1231
6-(pyrazol-5-yl)
CF3
C≡C-3-Pyridyl

1232
6-(pyrazol-5-yl)
CF3
C≡C-2-furanyl

1233
6-(pyrazol-5-yl)
CF3
C≡C-3-furanyl

1234
6-(pyrazol-5-yl)
CF3
C≡C-2-thienyl

1235
6-(pyrazol-5-yl)
CF3
C≡C-3-thienyl

1236
6-(pyrazol-5-yl)
CF3
CH═CH-cycPr

1237
6-(pyrazol-5-yl)
CF3
CH═CH-iPr

1238
6-(pyrazol-5-yl)
CF3
CH═CH-nPr

1239
6-(pyrazol-5-yl)
CF3
CH═CH—Et

1240
6-(pyrazol-5-yl)
CF3
CH═CH—Me

1241
6-(pyrazol-5-yl)
CF3
CH═CH—Ph

1242
6-(pyrazol-5-yl)
CF3
CH═CH-3-Pyridyl

1243
6-(pyrazol-5-yl)
CF3
CH═CH-2-furanyl

1244
6-(pyrazol-5-yl)
CF3
CH═CH-3-furanyl

1245
6-(pyrazol-5-yl)
CF3
CH═CH-2-thienyl

1246
6-(pyrazol-5-yl)
CF3
CH═CH-3-thienyl

1247
6-(pyrazol-5-yl)
CF3
Pentyl

1248
6-(pyrazol-5-yl)
CF3
CH2CH2-iPr

1249
6-(pyrazol-5-yl)
CF3
CH2CH2CH2CH3

1250
6-(pyrazol-5-yl)
CF3
CH2CH2-cycPr

1251
H
CF3
C≡C-nPr

1252
H
CF3
C≡C—Et

1253
H
CF3
C≡C—Me

1254
H
CF3
C≡C-3-Pyridyl

1255
H
CF3
C≡C-2-furanyl

1256
H
CF3
C≡C-3-furanyl

1257
H
CF3
C≡C-2-thienyl

1258
H
CF3
C≡C-3-thienyl

1259
H
CF3
CH═CH-cycPr

1260
H
CF3
CH═CH-iPr

1261
H
CF3
CH═CH-nPr

1262
H
CF3
CH═CH—Et

1263
H
CF3
CH═CH—Me

1264
H
CF3
CH═CH—Ph

1265
H
CF3
CH═CH-3-Pyridyl

1266
H
CF3
CH═CH-2-furanyl

1267
H
CF3
CH═CH-3-furanyl

1268
H
CF3
CH═CH-2-thienyl

1269
H
CF3
CH═CH-3-thienyl

1270
H
CF3
CH2CH2CH2CH3

1271
H
CF3
CH2CH2-cycPr

1272
6-Ph
CF3
C≡C—Me

1273
6-Ph
CF3
C≡C—Ph

1274
6-Ph
CF3
C≡C-3-Pyridyl

1275
6-Ph
CF3
C≡C-2-furanyl

1276
6-Ph
CF3
C≡C-3-furanyl

1277
6-Ph
CF3
C≡C-2-thienyl

1278
6-Ph
CF3
C≡C-3-thienyl

1279
6-Ph
CF3
CH═CH-cycPr

1280
6-Ph
CF3
CH═CH-iPr

1281
6-Ph
CF3
CH═CH-nPr

1282
6-Ph
CF3
CH═CH—Et

1283
6-Ph
CF3
CH═CH—Me

1284
6-Ph
CF3
CH═CH—Ph

1285
6-Ph
CF3
CH═CH-3-Pyridyl

1286
6-Ph
CF3
CH═CH-2-furanyl

1287
6-Ph
CF3
CH═CH-3-furanyl

1288
6-Ph
CF3
CH═CH-2-thienyl

1289
6-Ph
CF3
CH═CH-3-thienyl

1290
6-Ph
CF3
Pentyl

1291
6-Ph
CF3
CH2CH2CH2CH3

1292
6-Ph
CF3
CH2CH2-cycPr

1293
6-CN
CF3
C≡C-cycPr

1294
6-CN
CF3
C≡C-iPr

1295
6-CN
CF3
C≡C-nPr

1296
6-CN
CF3
C≡C—Et

1297
6-CN
CF3
C≡C-3-Pyridyl

1298
6-CN
CF3
C≡C-2-furanyl

1299
6-CN
CF3
C≡C-3-furanyl

1300
6-CN
CF3
C≡C-2-thienyl

1301
6-CN
CF3
C≡C-3-thienyl

1302
6-CN
CF3
CH═CH-cycPr

1303
6-CN
CF3
CH═CH-iPr

1304
6-CN
CF3
CH═CH-nPr

1305
6-CN
CF3
CH═CH—Et

1306
6-CN
CF3
CH═CH-3-Pyridyl

1307
6-CN
CF3
CH═CH-2-furanyl

1308
6-CN
CF3
CH═CH-3-furanyl

1309
6-CN
CF3
CH═CH-2-thienyl

1310
6-CN
CF3
CH═CH-3-thienyl

1311
6-NO2
CF3
C≡C-cycPr

1312
6-NO2
CF3
C≡C-iPr

1313
6-NO2
CF3
C≡C-nPr

1314
6-NO2
CF3
C≡C—Et

1315
6-NO2
CF3
C≡C-3-Pyridyl

1316
6-NO2
CF3
C≡C-2-furanyl

1317
6-NO2
CF3
C≡C-3-furanyl

1318
6-NO2
CF3
C≡C-2-thienyl

1319
6-NO2
CF3
C≡C-3-thienyl

1320
6-NHMe
CF3
C≡C-cycPr

1321
6-NHMe
CF3
C≡C-iPr

1322
6-NHMe
CF3
C≡C-nPr

1323
6-NHMe
CF3
C≡C—Et

1324
6-NHMe
CF3
C≡C-3-Pyridyl

1325
6-NHMe
CF3
C≡C-2-furanyl

1326
6-NHMe
CF3
C≡C-3-furanyl

1327
6-NHMe
CF3
C≡C-2-thienyl

1328
6-NHMe
CF3
C≡C-3-thienyl

1329
6-NHMe
CF3
CH═CH-cycPr

1330
6-NHMe
CF3
CH═CH-iPr

1331
6-NHMe
CF3
CH═CH-nPr

1332
6-NHMe
CF3
CH═CH—Et

1333
6-NHMe
CF3
CH═CH-3-Pyridyl

1334
6-NHMe
CF3
CH═CH-2-furanyl

1335
6-NHMe
CF3
CH═CH-3-furanyl

1336
6-NHMe
CF3
CN═CH-2-thienyl

1337
6-NHMe
CF3
CH═CH-3-thienyl

1338
6,7-OCH2O—
CF3
C≡C-cycPr

1339
6,7-OCH2O—
CF3
C≡C-iPr

1340
6,7-OCH2O—
CF3
C≡C-nPr

1341
6,7-OCH2O—
CF3
C≡C—Et

1342
6,7-OCH2O—
CF3
C≡C-3-Pyridyl

1343
6,7-OCH2O—
CF3
C≡C-2-furanyl

1344
6,7-OCH2O—
CF3
C≡C-3-furanyl

1345
6,7-OCH2O—
CF3
C≡C-2-thienyl

1346
6,7-OCH2O—
CF3
C≡C-3-thienyl

1347
6,7-diCl
CF3
C≡C-cycPr

1348
6,7-diCl
CF3
C≡C-iPr

1349
6,7-diCl
CF3
C≡C-nPr

1350
6,7-diCl
CF3
C≡C—Et

1351
6,7-diCl
CF3
C≡C-3-Pyridyl

1352
6,7-diCl
CF3
C≡C-2-furanyl

1353
6,7-diCl
CF3
C≡C-3-furanyl

1354
6,7-diCl
CF3
C≡C-2-thienyl

1355
6,7-diCl
CF3
C≡C-3-thienyl

1356
7-Cl
CF3
C≡C-cycPr

1357
7-Cl
CF3
C≡C-iPr

1358
7-Cl
CF3
C≡C-nPr

1359
7-Cl
CF3
C≡C—Et

1360
7-Cl
CF3
C≡C-3-Pyridyl

1361
7-Cl
CF3
C≡C-2-furanyl

1362
7-Cl
CF3
C≡C-3-furanyl

1363
7-Cl
CF3
C≡C-2-thienyl

1364
7-Cl
CF3
C≡C-3-thienyl

*Unless otherwise noted, stereochemistry is (+/−).

[0431]

3

TABLE 3

Ex. #
G
R1
R2

1401
6-Cl, 8-F
cycPr
C≡C-cycPr

1402
6-Cl, 8-F
cycPr
C≡C-iPr

1403
6-Cl, 8-F
cycPr
C≡C-nPr

1404
6-Cl, 8-F
cycPr
C≡C-Et

1405
6-Cl, 8-F
cycPr
C≡C-3-Pyridyl

1406
6-Cl, 8-F
cycPr
C≡C-2-furanyl

1407
6-Cl, 8-F
cycPr
C≡C-3-furanyl

1408
6-Cl, 8-F
cycPr
C≡C-2-thienyl

1409
6-Cl, 8-F
cycPr
C≡C-3-thienyl

1410
6-Cl, 8-F
iPr
C≡C-cycPr

1411
6-Cl, 8-F
iPr
C≡C-iPr

1412
6-Cl, 8-F
iPr
C≡C-nPr

1413
6-Cl, 8-F
iPr
C≡C-Et

1414
6-Cl, 8-F
iPr
C≡C-3-Pyridyl

1415
6-Cl, 8-F
iPr
C≡C-2-furanyl

1416
6-Cl, 8-F
iPr
C≡C-3-furanyl

1417
6-Cl, 8-F
iPr
C≡C-2-thienyl

1418
6-Cl, 8-F
iPr
C≡C-3-thienyl

1419
6-Cl, 8-F
Et
C≡C-cycPr

1420
6-Cl, 8-F
Et
C≡C-iPr

1421
6-Cl, 8-F
Et
C≡C-nPr

1422
6-Cl, 8-F
Et
C≡C-Et

1423
5,6-diF
cycPr
C≡C-cycPr

1424
5,6-diF
cycPr
C≡C-iPr

1425
5,6-diF
cycPr
C≡C-nPr

1426
5,6-diF
cycPr
C≡C-Et

1427
5,6-diF
cycPr
C≡C-3-Pyridyl

1428
5,6-diF
cycPr
C≡C-2-furanyl

1429
5,6-diF
cycPr
C≡C-3-furanyl

1430
5,6-diF
cycPr
C≡C-2-thienyl

1431
5,6-diF
cycPr
C≡C-3-thienyl

1432
5,6-diF
iPr
C≡C-cycPr

1433
5,6-diF
iPr
C≡C-iPr

1434
5,6-diF
iPr
C≡C-nPr

1435
5,6-diF
iPr
C≡C-Et

1436
5,6-diF
iPr
C≡C-3-Pyridyl

1437
5,6-diF
iPr
C≡C-2-furanyl

1438
5,6-diF
iPr
C≡C-3-furanyl

1439
5,6-diF
iPr
C≡C-2-thienyl

1440
5,6-diF
iPr
C≡C-3-thienyl

1441
5,6-diF
Et
C≡C-cycPr

1442
5,6-diF
Et
C≡C-iPr

1443
5,6-diF
Et
C≡C-nPr

1444
5,6-diF
Et
C≡C-Et

1445
5,6-diCl
cycPr
C≡C-cycPr

1446
5,6-diCl
cycPr
C≡C-iPr

1447
5,6-diCl
cycPr
C≡C-nPr

1448
5,6-diCl
cycPr
C≡C-Et

1449
5,6-diCl
cycPr
C≡C-3-Pyridyl

1450
5,6-diCl
cycPr
C≡C-2-furanyl

1451
5,6-diCl
cycPr
C≡C-3-furanyl

1452
5,6-diCl
cycPr
C≡C-2-thienyl

1453
5,6-diCl
cycPr
C≡C-3-thienyl

1454
5,6-diCl
iPr
C≡C-cycPr

1455
5,6-diCl
iPr
C≡C-iPr

1456
5,6-diCl
iPr
C≡C-nPr

1457
5,6-diCl
iPr
C≡C-Et

1458
5,6-diCl
iPr
C≡C-3-Pyridyl

1459
5,6-diCl
iPr
C≡C-2-furanyl

1460
5,6-diCl
iPr
C≡C-3-furanyl

1461
5,6-diCl
iPr
C≡C-2-thienyl

1462
5,6-diCl
iPr
C≡C-3-thienyl

1463
5,6-diCl
Et
C≡C-cycPr

1464
5,6-diCl
Et
C≡C-iPr

1465
5,6-diCl
Et
C≡C-nPr

1466
5,6-diCl
Et
C≡C-Et

1467
3-Cl,6-F
cycPr
C≡C-cycPr

1468
5-Cl,6-F
cycPr
C≡C-iPr

1469
5-Cl,6-F
cycPr
C≡C-nPr

1470
5-Cl,6-F
cycPr
C≡C-Et

1471
5-Cl,6-F
cycPr
C≡C-3-Pyridyl

1472
5-Cl,6-F
cycPr
C≡C-2-furanyl

1473
5-Cl,6-F
cycPr
C≡C-3-furanyl

1474
5-Cl,6-F
cycPr
C≡C-2-thienyl

1475
5-Cl,6-F
cycPr
C≡C-3-thienyl

1476
5-Cl,6-F
iPr
C≡C-cycPr

1477
5-Cl,6-F
iPr
C≡C-iPr

1478
5-Cl,6-F
iPr
C≡C-nPr

1479
5-Cl,6-F
iPr
C≡C-Et

1480
5-Cl,6-F
iPr
C≡C-3-Pyridyl

1481
5-Cl,6-F
iPr
C≡C-2-furanyl

1482
5-Cl,6-F
iPr
C≡C-3-furanyl

1483
5-Cl,6-F
iPr
C≡C-2-thienyl

1484
5-Cl,6-F
iPr
C≡C-3-thienyl

1485
5-Cl,6-F
Et
C≡C-cycPr

1486
5-Cl,6-F
Et
C≡C-iPr

1487
5-Cl,6-F
Et
C≡C-nPr

1488
5-Cl,6-F
Et
C≡C-Et

1489
5,6-OCH2O—
cycPr
C≡C-cycPr

1490
5,6-OCH2O—
cycPr
C≡C-iPr

1491
5,6-OCH2O—
cycPr
C≡C-nPr

1492
5,6-OCH2O—
cycPr
C≡C-Et

1493
5,6-OCH2O—
cycPr
C≡C-3-Pyridyl

1494
5,6-OCH2O—
cycPr
C≡C-2-furanyl

1495
5,6-OCH2O—
cycPr
C≡C-3-furanyl

1496
5,6-OCH2O—
cycPr
C≡C-2-thienyl

1497
5,6-OCH2O—
cycPr
C≡C-3-thienyl

1498
5,6-OCH2O—
iPr
C≡C-cycPr

1499
5,6-OCH2O—
iPr
C≡C-iPr

1500
5,6-OCH2O—
iPr
C≡C-nPr

1501
5,6-OCH2O—
iPr
C≡C-Et

1502
5,6-OCH2O—
iPr
C≡C-3-Pyridyl

1503
5,6-OCH2O—
iPr
C≡C-2-furanyl

1504
5,6-OCH2O—
iPr
C≡C-3-furanyl

1505
5,6-OCH2O—
iPr
C≡C-2-thienyl

1506
5,6-OCH2O—
iPr
C≡C-3-thienyl

1507
5,6-OCH2O—
Et
C≡C-cycPr

1508
5,6-OCH2O—
Et
C≡C-iPr

1509
5,6-OCH2O—
Et
C≡C-nPr

1510
5,6-OCH2O—
Et
C≡C-Et

1511
5-F
cycPr
C≡C-cycPr

1512
5-F
cycPr
C≡C-iPr

1513
5-F
cycPr
C≡C-nPr

1514
5-F
cycPr
C≡C-Et

1515
5-F
cycPr
C≡C-3-Pyridyl

1516
5-F
cycPr
C≡C-2-furanyl

1517
5-F
cycPr
C≡C-3-furanyl

1518
5-F
cycPr
C≡C-2-thienyl

1519
5-F
cycPr
C≡C-3-thienyl

1520
5-F
iPr
C≡C-cycPr

1521
5-F
iPr
C≡C-iPr

1522
5-F
iPr
C≡C-nPr

1523
5-F
iPr
C≡C-Et

1524
5-F
iPr
C≡C-3-Pyridyl

1525
5-F
iPr
C≡C-2-furanyl

1526
5-F
iPr
C≡C-3-furanyl

1527
5-F
iPr
C≡C-2-thienyl

1528
5-F
iPr
C≡C-3-thienyl

1529
5-F
Et
C≡C-cycPr

1530
5-F
Et
C≡C-iPr

1531
5-F
Et
C≡C-nPr

1532
5-F
Et
C≡C-Et

1533
5-Cl
cycPr
C≡C-cycPr

1534
5-Cl
cycPr
C≡C-iPr

1535
5-Cl
cycPr
C≡C-nPr

1536
5-Cl
cycPr
C≡C-Et

1537
5-Cl
cycPr
C≡C-3-Pyridyl

1538
5-Cl
cycPr
C≡C-2-furanyl

1539
5-Cl
cycPr
C≡C-3-furanyl

1540
5-Cl
cycPr
C≡C-2-thienyl

1541
5-Cl
cycPr
C≡C-3-thienyl

1542
5-Cl
iPr
C≡C-cycPr

1543
5-Cl
iPr
C≡C-iPr

1544
5-Cl
iPr
C≡C-nPr

1545
5-Cl
iPr
C≡C-Et

1546
5-Cl
iPr
C≡C-3-Pyridyl

1547
5-Cl
iPr
C≡C-2-furanyl

1548
5-Cl
iPr
C≡C-3-furanyl

1549
5-Cl
iPr
C≡C-2-thienyl

1550
5-Cl
iPr
C≡C-3-thienyl

1551
5-Cl
Et
C≡C-cycPr

1552
5-Cl
Et
C≡C-iPr

1553
5-Cl
Et
C≡C-nPr

1554
5-Cl
Et
C≡C-Et

1555
6-OMe
cycPr
C≡C-cycPr

1556
6-OMe
cycPr
C≡C-iPr

1557
6-OMe
cycPr
C≡C-nPr

1558
6-OMe
cycPr
C≡C-Et

1559
6-OMe
cycPr
C≡C-3-Pyridyl

1560
6-OMe
cycPr
C≡C-2-furanyl

1561
6-OMe
cycPr
C≡C-3-furanyl

1562
6-OMe
cycPr
C≡C-2-thienyl

1563
6-OMe
cycPr
C≡C-3-thienyl

1564
6-OMe
iPr
C≡C-nPr

1565
6-OMe
iPr
C≡C-Et

1566
6-OMe
iPr
C≡C-3-Pyridyl

1567
6-OMe
iPr
C≡C-2-furanyl

1568
6-OMe
iPr
C≡C-3-furanyl

1569
6-OMe
iPr
C≡C-2-thienyl

1570
6-OMe
iPr
C≡C-3-thienyl

1571
6-OMe
Et
C≡C-cycPr

1572
6-OMe
Et
C≡C-iPr

1573
6-OMe
Et
C≡C-nPr

1574
6-OMe
Et
C≡C-Et

1575
5-F, 6-OMe
cycPr
C≡C-cycPr

1576
5-F, 6-OMe
cycPr
C≡C-iPr

1577
5-F, 6-OMe
cycPr
C≡C-nPr

1578
5-F, 6-OMe
cycPr
C≡C-Et

1579
5-F, 6-OMe
cycPr
C≡C-3-Pyridyl

1580
5-F, 6-OMe
cycPr
C≡C-2-furanyl

1581
5-F, 6-OMe
cycPr
C≡C-3-furanyl

1582
5-F, 6-OMe
cycPr
C≡C-2-thienyl

1583
5-F, 6-OMe
cycPr
C≡C-3-thienyl

1584
5-F, 6-OMe
iPr
C≡C-cycPr

1585
5-F, 6-OMe
iPr
C≡C-iPr

1586
5-F, 6-OMe
iPr
C≡C-nPr

1587
5-F, 6-OMe
iPr
C≡C-Et

1588
5-F, 6-OMe
iPr
C≡C-3-Pyridyl

1589
5-F, 6-OMe
iPr
C≡C-2-furanyl

1590
5-F, 6-OMe
iPr
C≡C-3-furanyl

1591
5-F, 6-OMe
iPr
C≡C-2-thienyl

1592
5-F, 6-OMe
iPr
C≡C-3-thienyl

1593
5-F, 6-OMe
Et
C≡C-cycPr

1594
5-F, 6-OMe
Et
C≡C-iPr

1595
5-F, 6-OMe
Et
C≡C-nPr

1596
5-F, 6-OMe
Et
C≡C-Et

1597
6-NMe2
cycPr
C≡C-cycPr

1598
6-NMe2
cycPr
C≡C-iPr

1599
6-NMe2
cycPr
C≡C-nPr

1600
6-NMe2
cycPr
C≡C-Et

1601
6-NMe2
cycPr
C≡C-3-Pyridyl

1602
6-NMe2
cycPr
C≡C-2-furanyl

1603
6-NMe2
cycPr
C≡C-3-furanyl

1604
6-NMe2
cycPr
C≡C-2-thienyl

1605
6-NMe2
cycPr
C≡C-3-thienyl

1606
6-NMe2
iPr
C≡C-cycPr

1607
6-NMe2
iPr
C≡C-iPr

1608
6-NMe2
iPr
C≡C-nPr

1609
6-NMe2
iPr
C≡C-Et

1610
6-NMe2
iPr
C≡C-3-Pyridyl

1611
6-NMe2
iPr
C≡C-2-furanyl

1612
6-NMe2
iPr
C≡C-3-furanyl

1613
6-NMe2
iPr
C≡C-2-thienyl

1614
6-NMe2
iPr
C≡C-3-thienyl

1615
6-NMe2
Et
C≡C-cycPr

1616
6-NMe2
Et
C≡C-iPr

1617
6-NMe2
Et
C≡C-nPr

1618
6-NMe2
Et
C≡C-Et

1619
6-COCH3
cycPr
C≡C-cycPr

1620
6-COCH3
cycPr
C≡C-iPr

1621
6-COCH3
cycPr
C≡C-nPr

1622
6-COCH3
cycPr
C≡C-Et

1623
6-COCH3
cycPr
C≡C-3-Pyridyl

1624
6-COCH3
cycPr
C≡C-2-furanyl

1625
6-COCH3
cycPr
C≡C-3-furanyl

1626
6-COCH3
cycPr
C≡C-2-thienyl

1627
6-COCH3
cycPr
C≡C-3-thienyl

1628
6-COCH3
iPr
C≡C-cycPr

1629
6-COCH3
iPr
C≡C-iPr

1630
6-COCH3
iPr
C≡C-nPr

1631
6-COCH3
iPr
C≡C-Et

1632
6-COCH3
iPr
C≡C-3-Pyridyl

1633
6-COCH3
iPr
C≡C-2-furanyl

1634
6-COCH3
iPr
C≡C-3-furanyl

1635
6-COCH3
iPr
C≡C-2-thienyl

1636
6-COCH3
iPr
C≡C-3-thienyl

1637
6-COCH3
Et
C≡C-cycPr

1638
6-COCH3
Et
C≡C-iPr

1639
6-COCH3
Et
C≡C-nPr

1640
6-COCH3
Et
C≡C-Et

1641
6-CH3
cycPr
C≡C-cycPr

1642
6-CH3
cycPr
C≡C-nPr

1643
6-CH3
cycPr
C≡C-Et

1644
6-CH3
cycPr
C≡C-3-Pyridyl

1645
6-CH3
cycPr
C≡C-2-furanyl

1646
6-CH3
cycPr
C≡C-3-furanyl

1647
6-CH3
cycPr
C≡C-2-thienyl

1648
6-CH3
cycPr
C≡C-3-thienyl

1649
6-CH3
iPr
C≡C-nPr

1650
6-CH3
iPr
C≡C-Et

1651
6-CH3
iPr
C≡C-3-Pyridyl

1652
6-CH3
iPr
C≡C-2-furanyl

1653
6-CH3
iPr
C≡C-3-furanyl

1654
6-CH3
iPr
C≡C-2-thienyl

1655
6-CH3
iPr
C≡C-3-thienyl

1656
6-CH3
Et
C≡C-cycPr

1657
6-CH3
Et
C≡C-nPr

1658
6,8-diCl
cycPr
C≡C-cycPr

1659
6,8-diCl
cycPr
C≡C-iPr

1660
6,8-diCl
cycPr
C≡C-nPr

1661
6,8-diCl
cycPr
C≡C-Et

1662
6,8-diCl
cycPr
C≡C-3-Pyridyl

1663
6,8-diCl
cycPr
C≡C-2-furanyl

1664
6,8-diCl
cycPr
C≡C-3-furanyl

1665
6,8-diCl
cycPr
C≡C-2-thienyl

1666
6,8-diCl
cycPr
C≡C-3-thienyl

1667
6,8-diCl
iPr
C≡C-cycPr

1668
6,8-diCl
iPr
C≡C-iPr

1669
6,8-diCl
iPr
C≡C-nPr

1670
6,8-diCl
iPr
C≡C-Et

1671
6,8-diCl
iPr
C≡C-3-Pyridyl

1672
6,8-diCl
iPr
C≡C-2-furanyl

1673
6,8-diCl
iPr
C≡C-3-furanyl

1674
6,8-diCl
iPr
C≡C-2-thienyl

1675
6,8-diCl
iPr
C≡C-3-thienyl

1676
6,8-diCl
Et
C≡C-cycPr

1677
6,8-diCl
Et
C≡C-iPr

1678
6,8-diCl
Et
C≡C-nPr

1679
6,8-diCl
Et
C≡C-Et

1680
5,6,8-triF
cycPr
C≡C-cycPr

1681
5,6,8-triF
cycPr
C≡C-iPr

1682
5,6,8-triF
cycPr
C≡C-nPr

1683
5,6,8-triF
cycPr
C≡C-Et

1684
5,6,8-triF
cycPr
C≡C-3-Pyridyl

1685
5,6,8-triF
cycPr
C≡C-2-furanyl

1686
5,6,8-triF
cycPr
C≡C-3-furanyl

1687
5,6,8-triF
cycPr
C≡C-2-thienyl-

1688
5,6,8-triF
cycPr
C≡C-3-thienyl

1689
5,6,8-triF
iPr
C≡C-cycPr

1690
5,6,8-triF
iPr
C≡C-iPr

1691
5,6,8-triF
iPr
C≡C-nPr

1692
5,6,8-triF
iPr
C≡C-Et

1693
5,6,8-triF
iPr
C≡C-3-Pyridyl

1694
5,6,8-triF
iPr
C≡C-2-furanyl

1695
5,6,8-triF
iPr
C≡C-3-furanyl

1696
5,6,8-triF
iPr
C≡C-2-thienyl

1697
5,6,8-triF
iPr
C≡C-3-thienyl

1698
5,6,8-triF
Et
C≡C-cycPr

1699
5,6,8-triF
Et
C≡C-iPr

1700
5,6,8-triF
Et
C≡C-nPr

1701
5,6,8-triF
Et
C≡C-Et

1702
5,8-diF
cycPr
C≡C-cycPr

1703
5,8-diF
cycPr
C≡C-iPr

1704
5,8-diF
cycPr
C≡C-nPr

1705
5,8-diF
cycPr
C≡C-Et

1706
5,8-diF
cycPr
C≡C-3-Pyridyl

1707
5,8-diF
cycPr
C≡C-2-furanyl

1708
5,8-diF
cycPr
C≡C-3-furanyl

1709
5,8-diF
cycPr
C≡C-2-thienyl

1710
5,8-diF
cycPr
C≡C-3-thienyl

1711
5,8-diF
iPr
C≡C-cycPr

1712
5,8-diF
iPr
C≡C-iPr

1713
5,8-diF
iPr
C≡C-nPr

1714
5,8-diF
iPr
C≡C-Et

1715
5,8-diF
iPr
C≡C-3-Pyridyl

1716
5,8-diF
iPr
C≡C-2-furanyl

1717
5,8-diF
iPr
C≡C-3-furanyl

1718
5,8-diF
iPr
C≡C-2-thienyl

1719
5,8-diF
iPr
C≡C-3-thienyl

1720
5,8-diF
Et
C≡C-cycPr

1721
5,8-diF
Et
C≡C-iPr

1722
5,8-diF
Et
C≡C-nPr

1723
5,8-diF
Et
C≡C-Et

1724
6-iPr
cycPr
C≡C-cycPr

1725
6-iPr
cycPr
C≡C-iPr

1726
6-iPr
cycPr
C≡C-nPr

1727
6-iPr
cycPr
C≡C-Et

1728
6-iPr
cycPr
C≡C-3-pyridyl

1729
6-iPr
cycPr
C≡C-2-furanyl

1730
6-iPr
cycPr
C≡C-3-furanyl

1731
6-iPr
cycPr
C≡C-2-thienyl

1732
6-iPr
cycPr
C≡C-3-thienyl

1733
6-iPr
iPr
C≡C-cycPr

1734
6-iPr
iPr
C≡C-iPr

1735
6-iPr
iPr
C≡C-nPr

1736
6-iPr
iPr
C≡C-Et

1737
6-iPr
iPr
C≡C-3-Pyridyl

1738
6-iPr
iPr
C≡C-2-furanyl

1739
6-iPr
iPr
C≡C-3-furanyl

1740
6-iPr
iPr
C≡C-2-thienyl

1741
6-iPr
iPr
C≡C-3-thienyl

1742
6-iPr
Et
C≡C-cycPr

1743
6-iPr
Et
C≡C-iPr

1744
6-iPr
Et
C≡C-nPr

1745
6-iPr
Et
C≡C-Et

1746
6-OCF3
cycPr
C≡C-cycPr

1747
6-OCF3
cycPr
C≡C-iPr

1748
6-OCF3
cycPr
C≡C-nPr

1749
6-OCF3
cycPr
C≡C-Et

1750
6-OCF3
cycPr
C≡C-3-pyridyl

1751
6-OCF3
cycPr
C≡C-2-furanyl

1752
6-OCF3
cycPr
C≡C-3-furanyl

1753
6-OCF3
cycPr
C≡C-2-thienyl

1754
6-OCF3
cycPr
C≡C-3-thienyl

1755
6-OCF3
iPr
C≡C-cycPr

1756
6-OCF3
iPr
C≡C-iPr

1757
6-OCF3
iPr
C≡C-nPr

1758
6-OCF3
iPr
C≡C-Et

1759
6-OCF3
iPr
C≡C-3-pyridyl

1760
6-OCF3
iPr
C≡C-2-furanyl

1761
6-OCF3
iPr
C≡C-3-furanyl

1762
6-OCF3
iPr
C≡C-2-thienyl

1763
6-OCF3
iPr
C≡C-3-thienyl

1764
6-OCF3
Et
C≡C-cycPr

1765
6-OCF3
Et
C≡C-iPr

1766
6-OCF3
Et
C≡C-nPr

1767
6-OCF3
Et
C≡C-Et

1768
6-(pyrazol-
cycPr
C≡C-cycPr

5-yl)

1769
6-(pyrazol-
cycPr
C≡C-iPr

5-yl)

1770
6-(pyrazol-
cycPr
C≡C-nPr

5-yl)

1771
6-(pyrazol-
cycPr
C≡C-Et

5-yl)

1772
6-(pyrazol-
cycPr
C≡C-3-Pyridyl

5-yl)

1773
6-(pyrazol-
cycPr
C≡C-2-furanyl

5-yl)

1774
6-(pyrazol-
cycPr
C≡C-3-furanyl

5-yl)

1775
6-(pyrazol-
cycPr
C≡C-2-thienyl

5-yl)

1776
6-(pyrazol-
cycPr
C≡C-3-thienyl

5-yl)

1777
6-(pyrazol-
iPr
C≡C-cycPr

5-yl)

1778
6-(pyrazol-
iPr
C≡C-iPr

5-yl)

1779
6-(pyrazol-
iPr
C≡C-nPr

5-yl)

1780
6-(pyrazol-
iPr
C≡C-Et

5-yl)

1781
6-(pyrazol-
iPr
C≡C-3-Pyridyl

5-yl)

1782
6-(pyrazol-
iPr
C≡C-2-furanyl

5-yl)

1783
6-(pyrazol-
iPr
C≡C-3-furanyl

5-yl)

1784
6-(pyrazol-
iPr
C≡C-2-thienyl

5-yl)

1785
6-(pyrazol-
iPr
C≡C-3-thienyl

5-yl)

1786
6-(pyrazol-
Et
C≡C-cycPr

5-yl)

1787
6-(pyrazol-
Et
C≡C-iPr

5-yl)

1788
6-(pyrazol-
Et
C≡C-nPr

5-yl)

1789
6-(pyrazol-
Et
C≡C-Et

5-yl)

1790
H
cycPr
C≡C-cycPr

1791
H
cycPr
C≡C-iPr

1792
H
cycPr
C≡C-nPr

1793
H
cycPr
C≡C-Et

1794
H
cycPr
C≡C-3-Pyridyl

1795
H
cycPr
C≡C-2-furanyl

1796
H
cycPr
C≡C-3-furanyl

1797
H
cycPr
C≡C-2-thienyl

1798
H
cycPr
C≡C-3-thienyl

1799
H
iPr
C≡C-cycPr

1800
H
iPr
C≡C-iPr

1801
H
iPr
C≡C-nPr

1802
H
iPr
C≡C-Et

1803
H
iPr
C≡C-3-Pyridyl

1804
H
iPr
C≡C-2-furanyl

1805
H
iPr
C≡C-3-furanyl

1806
H
iPr
C≡C-2-thienyl

1807
H
iPr
C≡C-3-thienyl

1808
H
Et
C≡C-cycPr

1809
H
Et
C≡C-iPr

1810
H
Et
C≡C-nPr

1811
H
Et
C≡C-Et

1812
6-Ph
cycPr
C≡C-cycPr

1813
6-Ph
cycPr
C≡C-iPr

1814
6-Ph
cycPr
C≡C-nPr

1815
6-Ph
cycPr
C≡C-Et

1816
6-Ph
cycPr
C≡C-3-Pyridyl

1817
6-Ph
cycPr
C≡C-2-furanyl

1818
6-Ph
cycPr
C≡C-3-furanyl

1819
6-Ph
cycPr
C≡C-2-thienyl

1820
6-Ph
cycPr
C≡C-3-thienyl

1821
6-Ph
iPr
C≡C-cycPr

1822
6-Ph
iPr
C≡C-iPr

1823
6-Ph
iPr
C≡C-nPr

1824
6-Ph
iPr
C≡C-Et

1825
6-Ph
iPr
C≡C-3-Pyridyl

1826
6-Ph
iPr
C≡C-2-furanyl

1827
6-Ph
iPr
C≡C-3-furanyl

1828
6-Ph
iPr
C≡C-2-thienyl

1829
6-Ph
iPr
C≡C-3-thienyl

1830
6-Ph
Et
C≡C-cycPr

1831
6-Ph
Et
C≡C-iPr

1832
6-Ph
Et
C≡C-nPr

1833
6-Ph
Et
C≡C-Et

1834
6-CN
cycPr
C≡C-cycPr

1835
6-CN
cycPr
C≡C-iPr

1836
6-CN
cycPr
C≡C-nPr

1837
6-CN
cycPr
C≡C-Et

1838
6-CN
cycPr
C≡C-3-Pyridyl

1839
6-CN
cycPr
C≡C-2-furanyl

1840
6-CN
cycPr
C≡C-3-furanyl

1841
6-CN
cycPr
C≡C-2-thienyl

1842
6-CN
cycPr
C≡C-3-thienyl

1843
6-CN
iPr
C≡C-cycPr

1844
6-CN
iPr
C≡C-iPr

1845
6-CN
iPr
C≡C-nPr

1846
6-CN
iPr
C≡C-Et

1847
6-CN
iPr
C≡C-3-Pyridyl

1848
6-CN
iPr
C≡C-2-furanyl

1849
6-CN
iPr
C≡C-3-furanyl

1850
6-CN
iPr
C≡C-2-thienyl

1851
6-CN
iPr
C≡C-3-thienyl

1852
6-CN
Et
C≡C-cycPr

1853
6-CN
Et
C≡C-iPr

1854
6-CN
Et
C≡C-nPr

1855
6-CN
Et
C≡C-Et

1856
6-NO2
cycPr
C≡C-cycPr

1857
6-NO2
cycPr
C≡C-iPr

1858
6-NO2
cycPr
C≡C-nPr

1859
6-NO2
cycPr
C≡C-Et

1860
6-NO2
cycPr
C≡C-3-Pyridyl

1861
6-NO2
cycPr
C≡C-2-furanyl

1862
6-NO2
cycPr
C≡C-3-furanyl

1863
6-NO2
cycPr
C≡C-2-thienyl

1864
6-NO2
cycPr
C≡C-3-thienyl

1865
6-NO2
iPr
C≡C-cycPr

1866
6-NO2
iPr
C≡C-iPr

1867
6-NO2
iPr
C≡C-nPr

1868
6-NO2
iPr
C≡C-Et

1869
6-NO2
iPr
C≡C-3-Pyridyl

1870
6-NO2
iPr
C≡C-2-furanyl

1871
6-NO2
iPr
C≡C-3-furanyl

1872
6-NO2
iPr
C≡C-2-thienyl

1873
6-NO2
iPr
C≡C-3-thienyl

1874
6-NO2
Et
C≡C-cycPr

1875
6-NO2
Et
C≡C-iPr

1876
6-NO2
Et
C≡C-nPr

1877
6-NO2
Et
C≡C-Et

1878
6-NHMe
cycPr
C≡C-cycPr

1879
6-NHMe
cycPr
C≡C-iPr

1880
6-NHMe
cycPr
C≡C-nPr

1881
6-NHMe
cycPr
C≡C-Et

1882
6-NHMe
cycPr
C≡C-3-Pyridyl

1883
6-NHMe
cycPr
C≡C-2-furanyl

1884
6-NHMe
cycPr
C≡C-3-furanyl

1885
6-NHMe
cycPr
C≡C-2-thienyl

1886
6-NHMe
cycPr
C≡C-3-thienyl

1887
6-NHMe
iPr
C≡C-cycPr

1888
6-NHMe
iPr
C≡C-iPr

1889
6-NHMe
iPr
C≡C-nPr

1890
6-NHMe
iPr
C≡C-Et

1891
6-NHMe
iPr
C≡C-3-Pyridyl

1892
6-NHMe
iPr
C≡C-2-furanyl

1893
6-NHMe
iPr
C≡C-3-furanyl-

1894
6-NHMe
iPr
C≡C-2-thienyl

1895
6-NHMe
iPr
C≡C-3-thienyl

1896
6-NHMe
Et
C≡C-cycPr

1897
6-NHMe
Et
C≡C-iPr

1898
6-NHMe
Et
C≡C-nPr

1899
6-NHMe
Et
C≡C-Et

1900
6,7-diCl
cycPr
C≡C-cycPr

1901
6,7-diCl
cycPr
C≡C-nPr

1902
6,7-diCl
cycPr
C≡C-Et

1903
6,7-diCl
cycPr
C≡C-3-Pyridyl

1904
6,7-diCl
cycPr
C≡C-2-furanyl

1905
6,7-diCl
cycPr
C≡C-3-furanyl

1906
6,7-diCl
cycPr
C≡C-2-thienyl

1907
6,7-diCl
cycPr
C≡C-3-thienyl

1908
6,7-diCl
iPr
C≡C-cycPr

1909
6,7-diCl
iPr
C≡C-nPr

1910
6,7-diCl
iPr
C≡C-Et

1911
6,7-diCl
iPr
C≡C-3-Pyridyl

1912
6,7-diCl
iPr
C≡C-2-furanyl

1913
6,7-diCl
iPr
C≡C-3-furanyl

1914
6,7-diCl
iPr
C≡C-2-thienyl

1915
6,7-diCl
iPr
C≡C-3-thienyl

1916
6,7-diCl
Et
C≡C-cycPr

1917
6,7-diCl
Et
C≡C-iPr

1918
6,7-diCl
Et
C≡C-nPr

1919
6,7-diCl
Et
C≡C-Et

1920
7-Cl
cycPr
C≡C-nPr

1921
7-Cl
cycPr
C≡C-Et

1922
7-Cl
cycPr
C≡C-3-Pyridyl

1923
7-Cl
cycPr
C≡C-2-furanyl

1924
7-Cl
cycPr
C≡C-3-furanyl

1925
7-Cl
cycPr
C≡C-2-thienyl

1926
7-Cl
cycPr
C≡C-3-thienyl

1927
7-Cl
iPr
C≡C-nPr

1928
7-Cl
iPr
C≡C-Et

1929
7-Cl
iPr
C≡C-3-Pyridyl

1930
7-Cl
iPr
C≡C-2-furanyl

1931
7-Cl
iPr
C≡C-3-furanyl

1932
7-Cl
iPr
C≡C-2-thienyl

1933
7-Cl
iPr
C≡C-3-thienyl

1934
7-Cl
Et
C≡C-cycPr

1935
7-Cl
Et
C≡C-iPr

1936
7-Cl
Et
C≡C-nPr

1937
7-Cl
Et
C≡C-Et

*Unless otherwise noted, stereochemistry is (+/−)

[0432]

4

TABLE 4

Ex. #
W
X
Y
Z
R1
R2

2001
CH
CCl
CH
N
CF3
C≡C-nPr

2002
CH
CCl
CH
N
CF3
C≡C-Bu

2003
CH
CCl
CH
N
CF3
C≡C-iBu

2004
CH
CCl
CH
N
CF3
C≡C-tBu

2005
CH
CCl
CH
N
CF3
C≡C-Et

2006
CH
CCl
CH
N
CF3
C≡C-Me

2007
CH
CCl
CH
N
CF3
C≡C-Ph

2008
CH
CCl
CH
N
CF3
C≡C-2-Pyridyl

2009
CH
CCl
CH
N
CF3
C≡C-3-Pyridyl

2010
CH
CCl
CH
N
CF3
C≡C-4-Pyridyl

2011
CH
CCl
CH
N
CF3
C≡C-2-furanyl

2012
CH
CCl
CH
N
CF3
C≡C-3-furanyl

2013
CH
CCl
CH
N
CF3
C≡C-2-thienyl

2014
CH
CCl
CH
N
CF3
C≡C-3-thienyl

2015
CH
CCl
CH
N
CF3
CH═CH-cycPr

2016
CH
CCl
CH
N
CF3
CH═CH-iPr

2017
CH
CCl
CH
N
CF3
CH═CH-nPr

2018
CH
CCl
CH
N
CF3
CH═CH-Bu

2019
CH
CCl
CH
N
CF3
CH═CH-iBu

2020
CH
CCl
CH
N
CF3
CH═CH-tBu

2021
CH
CCl
CH
N
CF3
CH═CH-Et

2022
CH
CCl
CH
N
CF3
CH═CH-Me

2023
CH
CCl
CH
N
CF3
CH═CH-Ph

2024
CH
CCl
CH
N
CF3
CH═CH-2-Pyridyl

2025
CH
CCl
CH
N
CF3
CH═CH-3-Pyridyl

2026
CH
CCl
CH
N
CF3
CH═CH-4-Pyridyl

2027
CH
CCl
CH
N
CF3
CH═CH-2-furanyl

2028
CH
CCl
CH
N
CF3
CH═CH-3-furanyl

2029
CH
CCl
CH
N
CF3
CH═CH-2-thienyl

2030
CH
CCl
CH
N
CF3
CH═CH-3-thienyl

2031
CH
CCl
CH
N
CF3
CH2CH2CH2CH2CH3

2032
CH
CCl
CH
N
CF3
CH2CH2CH(CH3)2

2033
CH
CCl
CH
N
CF3
CH2CH2CH2CH3

2034
CH
CCl
CH
N
CF3
CH2CH2CH3

2035
CH
CCl
CH
N
CF3
CH2CH2cycPr

2036
CH
CCl
CH
N
CF3
CH2CH2-tBU

2037
CH
CCl
CH
N
CF3
CH2CH2-2-Pyridyl

2038
CH
CCl
CH
N
CF3
CH2CH2-3-Pyridyl

2039
CH
CCl
CH
N
CF3
CH2CH2-4-Pyridyl

2040
CH
CCl
CH
N
CF3
CH2CH2-2-furanyl

2041
CH
CCl
CH
N
CF3
CH2CH2-3-furanyl

2042
CH
CCl
CH
N
CF3
CH2CH2-2-thienyl

2043
CH
CCl
CH
N
CF3
CH2CH2-3-thienyl

2044
CH
C(OCH3)
CH
N
CF3
C≡C-cycPr

2045
CH
C(OCH3)
CH
N
CF3
C≡C-iPr

2046
CH
C(OCH3)
CH
N
CF3
C≡C-nPr

2047
CH
C(OCH3)
CH
N
CF3
C≡C-Bu

2048
CH
C(OCH3)
CH
N
CF3
C≡C-iBu

2049
CH
C(OCH3)
CH
N
CF3
C≡C-tBu

2050
CH
C(OCH3)
CH
N
CF3
C≡C-Et

2051
CH
C(OCH3)
CH
N
CF3
C≡C-Me

2052
CH
C(OCH3)
CH
N
CF3
C≡C-Ph

2053
CH
C(OCH3)
CH
N
CF3
C≡C-2-Pyridyl

2054
CH
C(OCH3)
CH
N
CF3
C≡C-3-Pyridyl

2055
CH
C(OCH3)
CH
N
CF3
C≡C-4-Pyridyl

2056
CH
C(OCH3)
CH
N
CF3
C≡C-2-furanyl

2057
CH
C(OCH3)
CH
N
CF3
C≡C-3-furanyl

2058
CH
C(OCH3)
CH
N
CF3
C≡C-2-thienyl

2059
CH
C(OCH3)
CH
N
CF3
C≡C-3-thienyl

2060
CH
C(OCH3)
CH
N
CF3
CH═CH-cycPr

2061
CH
C(OCH3)
CH
N
CF3
CH═CH-iPr

2062
CH
C(OCH3)
CH
N
CF3
CH═CH-nPr

2063
CH
C(OCH3)
CH
N
CF3
CH═CH-Bu

2064
CH
C(OCH3)
CH
N
CF3
CH═CH-iBu

2065
CH
C(OCH3)
CH
N
CF3
CH═CH-tBu

2066
CH
C(OCH3)
CH
N
CF3
CH═CH-Et

2067
CH
C(OCH3)
CH
N
CF3
CH═CH-Me

2068
CH
C(OCH3)
CH
N
CF3
CH═CH-Ph

2069
CH
C(OCH3)
CH
N
CF3
CH═CH-2-Pyridyl

2070
CH
C(OCH3)
CH
N
CF3
CH═CH-3-Pyridyl

2071
CH
C(OCH3)
CH
N
CF3
CH═CH-4-Pyridyl

2072
CH
C(OCH3)
CH
N
CF3
CH═CH-2-furanyl

2073
CH
C(OCH3)
CH
N
CF3
CH═CH-3-furanyl

2074
CH
C(OCH3)
CH
N
CF3
CH═CH-2-thienyl

2075
CH
C(OCH3)
CH
N
CF3
CH═CH-3-thienyl

2076
CH
C(OCH3)
CH
N
CF3
CH2CH2CH2CH2CH3

2077
CH
C(OCH3)
CH
N
CF3
CH2CH2CH(CH3)2

2078
CH
C(OCH3)
CH
N
CF3
CH2CH2CH2CH3

2079
CH
C(OCH3)
CH
N
CF3
CH2CH2CH3

2080
CH
C(OCH3)
CH
N
CF3
CH2CH2-cycPr

2081
CH
C(OCH3)
CH
N
CF3
CH2CH2-tBu

2082
CH
C(OCH3)
CH
N
CF3
CH2CH2-Ph

2083
CH
C(OCH3)
CH
N
CF3
CH2CH2-2-Pyridyl

2084
CH
C(OCH3)
CH
N
CF3
CH2CH2-3-Pyridyl

2085
CH
C(OCH3)
CH
N
CF3
CH2CH2-4-Pyridyl

2086
CH
C(OCH3)
CH
N
CF3
CH2CH2-2-furanyl

2087
CH
C(OCH3)
CH
N
CF3
CH2CH2-3-furanyl

2088
CH
C(OCH3)
CH
N
CF3
CH2CH2-2-thienyl

2089
CH
C(OCH3)
CH
N
CF3
CH2CH2-3-thienyl

2090
CH
CH
CH
N
CF3
C≡C-cycPr

2091
CH
CH
CH
N
CF3
C≡C-iPr

2092
CH
CH
CH
N
CF3
C≡C-nPr

2093
CH
CH
CH
N
CF3
C≡C-Et

2094
CH
CH
CH
N
CF3
C≡C-3-Pyridyl

2095
CH
CH
CH
N
CF3
C≡C-2-furanyl

2096
CH
CH
CH
N
CF3
C≡C-3-furanyl

2097
CH
CH
CH
N
CF3
C≡C-2-thienyl

2098
CH
CH
CH
N
CF3
C≡C-3-thienyl

2099
CH
CCl
N
CH
CF3
C≡C-iPr

2100
CH
CCl
N
CH
CF3
C≡C-nPr

2101
CH
CCl
N
CH
CF3
C≡C-Bu

2102
CH
CCl
N
CH
CF3
C≡C-iBu

2103
CH
CCl
N
CH
CF3
C≡C-tBu

2104
CH
CCl
N
CH
CF3
C≡C-Et

2105
CH
CCl
N
CH
CF3
C≡C-Me

2106
CH
CCl
N
CH
CF3
C≡C-Ph

2107
CH
CCl
N
CH
CF3
C≡C-2-Pyridyl

2108
CH
CCl
N
CH
CF3
C≡C-3-Pyridyl

2109
CH
CCl
N
CH
CF3
C≡C-4-Pyridyl

2110
CH
CCl
N
CH
CF3
C≡C-2-furanyl

2111
CH
CCl
N
CH
CF3
C≡C-3-furanyl

2112
CH
CCl
N
CH
CF3
C≡C-2-thienyl

2113
CH
CCl
N
CH
CF3
C≡C-3-thienyl

2114
CH
CCl
N
CH
CF3
CH═CH-cycPr

2115
CH
CCl
N
CH
CF3
CH═CH-iPr

2116
CH
CCl
N
CH
CF3
CH═CH-nPr

2117
CH
CCl
N
CH
CF3
CH═CH-Bu

2118
CH
CCl
N
CH
CF3
CH═CH-iBu

2119
CH
CCl
N
CH
CF3
CH═CH-tBu

2120
CH
CCl
N
CH
CF3
CH═CH-Et

2121
CH
CCl
N
CH
CF3
CH═CH-Me

2122
CH
CCl
N
CH
CF3
CH═CH-Ph

2123
CH
CCl
N
CH
CF3
CH═CH-2-Pyridyl

2124
CH
CCl
N
CH
CF3
CH═CH-3-Pyridyl

2125
CH
CCl
N
CH
CF3
CH═CH-4-Pyridyl

2126
CH
CCl
N
CH
CF3
CH═CH-2-furanyl

2127
CH
CCl
N
CH
CF3
CH═CH-3-furanyl-

2123
CH
CCl
N
CH
CF3
CH═CH-2-thienyl

2129
CH
CCl
N
CH
CF3
CH═CH-3-thienyl

2130
CH
CCl
N
CH
CF3
CH2CH2CH2CH2CH3

2131
CH
CCl
N
CH
CF3
CH2CH2CH(CH3)2

2132
CH
CCl
N
CH
CF3
CH2CH2CH2CH3

2133
CH
CCl
N
CH
CF3
CH2CH2CH3

2134
CH
CCl
N
CH
CF3
CH2CH2-cycPr

2135
CH
CCl
N
CH
CF3
CH2CH2-Bu

2136
CH
CCl
N
CH
CF3
CH2CH2-Ph

2137
CH
CCl
N
CH
CF3
CH2CH2-2-Pyridyl

2138
CH
CCl
N
CH
CF3
CH2CH2-3-Pyridyl

2139
CH
CCl
N
CH
CF3
CH2CH2-4-Pyridyl

2140
CH
CCl
N
CH
CF3
CH2CH2-2-furanyl

2141
CH
CCl
N
CH
CF3
CH2CH2-3-furanyl

2142
CH
CCl
N
CH
CF3
CH2CH2-2-thienyl

2143
CH
CCl
N
CH
CF3
CH2CH2-3-thienyl

2144
CH
C(OCH3)
N
CH
CF3
C≡C-iPr

2145
CH
C(OCH3)
N
CH
CF3
C≡C-nPr

2146
CH
C(OCH3)
N
CH
CF3
C≡C-Bu

2147
CH
C(OCH3)
N
CH
CF3
C≡C-iBu

2148
CH
C(OCH3)
N
CH
CF3
C≡C-tBu

2149
CH
C(OCH3)
N
CH
CF3
C≡C-Et

2150
CH
C(OCH3)
N
CH
CF3
C≡C-Me

2151
CH
C(OCH3)
N
CH
CF3
C≡C-Ph

2152
CH
C(OCH3)
N
CH
CF3
C≡C-2-Pyridyl

2153
CH
C(OCH3)
N
CH
CF3
C≡C-3-Pyridyl

2154
CH
C(OCH3)
N
CH
CF3
C≡C-4-Pyridyl

2155
CH
C(OCH3)
N
CH
CF3
C≡C-2-furanyl

2156
CH
C(OCH3)
N
CH
CF3
C≡C-3-furanyl

2157
CH
C(OCH3)
N
CH
CF3
C≡C-2-thienyl

2158
CH
C(OCH3)
N
CH
CF3
C≡C-3-thienyl

2159
CH
C(OCH3)
N
CH
CF3
CH═CH-cycPr

2160
CH
C(OCH3)
N
CH
CF3
CH═CH-iPr

2161
CH
C(OCH3)
N
CH
CF3
CH═CH-nPr

2162
CH
C(OCH3)
N
CH
CF3
CH═CH-Bu

2163
CH
C(OCH3)
N
CH
CF3
CH═CH-iBu

2164
CH
C(OCH3)
N
CH
CF3
CH═CH-tBu

2165
CH
C(OCH3)
N
CH
CF3
CH═CH-Et

2166
CH
C(OCH3)
N
CH
CF3
CH═CH-Me

2167
CH
C(OCH3)
N
CH
CF3
CH═CH-Ph

2168
CH
C(OCH3)
N
CH
CF3
CH═CH-2-Pyridyl

2169
CH
C(OCH3)
N
CH
CF3
CH═CH-3-Pyridyl

2170
CH
C(OCH3)
N
CH
CF3
CH═CH-4-Pyridyl

2171
CH
C(OCH3)
N
CH
CF3
CH═CH-2-furanyl

2172
CH
C(OCH3)
N
CH
CF3
CH═CH-3-furanyl

2173
CH
C(OCH3)
N
CH
CF3
CH═CH-2-thienyl

2174
CH
C(OCH3)
N
CH
CF3
CH═CH-3-thienyl

2175
CH
C(OCH3)
N
CH
CF3
CH2CH2CH2CH2CH3

2176
CH
C(OCH3)
N
CH
CF3
CH2CH2CH(CH3)2

2177
CH
C(OCH3)
N
CH
CF3
CH2CH2CH2CH3

2178
CH
C(OCH3)
N
CH
CF3
CH2CH2CH3

2179
CH
C(OCH3)
N
CH
CF3
CH2CH2-cycPr

2180
CH
C(OCH3)
N
CH
CF3
CH2CH2-tBu

2181
CH
C(OCH3)
N
CH
CF3
CH2CH2-Ph

2182
CH
C(OCH3)
N
CH
CF3
CH2CH2-2-Pyridyl

2183
CH
C(OCH3)
N
CH
CF3
CH2CH2-3-Pyridyl

2184
CH
C(OCH3)
N
CH
CF3
CH2CH2-4-Pyridyl

2185
CH
C(OCH3)
N
CH
CF3
CH2CH2-2-furanyl

2186
CH
C(OCH3)
N
CH
CF3
CH2CH2-3-furanyl

2187
CH
C(OCH3)
N
CH
CF3
CH2CH2-2-thienyl

2188
CH
C(OCH3)
N
CH
CF3
CH2CH2-3-thienyl

2189
CH
CH
N
CH
CF3
C≡C-cycPr

2190
CH
CH
N
CH
CF3
C≡C-iPr

2191
CH
CH
N
CH
CF3
C≡C-nPr

2192
CH
CH
N
CH
CF3
C≡C-Et

2193
CH
CH
N
CH
CF3
C≡C-3-Pyridyl

2194
CH
CH
N
CH
CF3
C≡C-2-furanyl

2195
CH
CH
N
CH
CF3
C≡C-3-furanyl

2196
CH
CH
N
CH
CF3
C≡C-2-thienyl

2197
CH
CH
N
CH
CF3
C≡C-3-thienyl

2198
CCl
N
CH
CH
CF3
C≡C-cycPr

2199
CCl
N
CH
CH
CF3
C≡C-iPr

2200
CCl
N
CH
CH
CF3
C≡C-nPr

2201
CCl
N
CH
CH
CF3
C≡C-Bu

2202
CCl
N
CH
CH
CF3
C≡C-iBu

2203
CCl
N
CH
CH
CF3
C≡C-tBu

2204
CCl
N
CH
CH
CF3
C≡C-Et

2205
CCl
N
CH
CH
CF3
C≡C-Me

2206
CCl
N
CH
CH
CF3
C≡C-Ph

2207
CCl
N
CH
CH
CF3
C≡C-2-Pyridyl

2208
CCl
N
CH
CH
CF3
C≡C-3-Pyridyl

2209
CCl
N
CH
CH
CF3
C≡C-4-Pyridyl

2210
CCl
N
CH
CH
CF3
C≡C-2-furanyl

2211
CCl
N
CH
CH
CF3
C≡C-3-furanyl

2212
CCl
N
CH
CH
CF3
C≡C-2-thienyl

2213
CCl
N
CH
CH
CF3
C≡C-3-thienyl

2214
CCl
N
CH
CH
CF3
CH═CH-cycPr

2215
CCl
N
CH
CH
CF3
CH═CH-iPr

2216
CCl
N
CH
CH
CF3
CH═CH-nPr

2217
CCl
N
CH
CH
CF3
CH═CH-Bu

2218
CCl
N
CH
CH
CF3
CH═CH-iBu

2219
CCl
N
CH
CH
CF3
CH═CH-tBu

2220
CCl
N
CH
CH
CF3
CH═CH-Et

2221
CCl
N
CH
CH
CF3
CH═CH-Me

2222
CCl
N
CH
CH
CF3
CH═CH-Ph

2223
CCl
N
CH
CH
CF3
CH═CH-2-Pyridyl

2224
CCl
N
CH
CH
CF3
CH═CH-3-Pyridyl

2225
CCl
N
CH
CH
CF3
CH═CH-4-Pyridyl

2226
CCl
N
CH
CH
CF3
CH═CH-2-furanyl

2227
CCl
N
CH
CH
CF3
CH═CH-3-furanyl

2228
CCl
N
CH
CH
CF3
CH═CH-2-thienyl

2229
CCl
N
CH
CH
CF3
CH═CH-3-thienyl

2230
CCl
N
CH
CH
CF3
CH2CH2CH2CH2CH3

2231
CCl
N
CH
CH
CF3
CH2CH2CH(CH3)2

2232
CCl
N
CH
CH
CF3
CH2CH2CH2CH3

2233
CCl
N
CH
CH
CF3
CH2CH2CH3

2234
CCl
N
CH
CH
CF3
CH2CH2-cycPr

2235
CCl
N
CH
CH
CF3
CH2CH2-tBu

2236
CCl
N
CH
CH
CF3
CH2CH2-Ph

2237
CCl
N
CH
CH
CF3
CH2CH2-2-Pyridyl

2238
CCl
N
CH
CH
CF3
CH2CH2-3-Pyridyl

2239
CCl
N
CH
CH
CF3
CH2CH2-4-Pyridyl

2240
CCl
N
CH
CH
CF3
CH2CH2-2-furanyl

2241
CCl
N
CH
CH
CF3
CH2CH2-3-furanyl

2242
CCl
N
CH
CH
CF3
CH2CH2-2-thienyl

2243
CCl
N
CH
CH
CF3
CH2CH2-3-thienyl

2244
CH
N
CH
CH
CF3
C≡C-iPr

2245
CH
N
CH
CH
CF3
C≡C-nPr

2246
CH
N
CH
CH
CF3
C≡C-Et

2247
CH
N
CH
CH
CF3
C≡C-3-Pyridyl

2248
CH
N
CH
CH
CF3
C≡C-2-furanyl

2249
CH
N
CH
CH
CF3
C≡C-3-furanyl

2250
CH
N
CH
CH
CF3
C≡C-2-thienyl

2251
CH
N
CH
CH
CF3
C≡C-3-thienyl

2252
N
CCl
CH
CH
CF3
C≡C-cycPr

2253
N
CCl
CH
CH
CF3
C≡C-iPr

2254
N
CCl
CH
CH
CF3
C≡C-nPr

2255
N
CCl
CH
CH
CF3
C≡C-Bu

2256
N
CCl
CH
CH
CF3
C≡C-iBu

2257
N
CCl
CH
CH
CF3
C≡C-tBu

2258
N
CCl
CH
CH
CF3
C≡C-Et

2259
N
CCl
CH
CH
CF3
C≡C-Me

2260
N
CCl
CH
CH
CF3
C≡C-Ph

2261
N
CCl
CH
CH
CF3
C≡C-2-Pyridyl

2262
N
CCl
CH
CH
CF3
C≡C-3-Pyridyl

2263
N
CCl
CH
CH
CF3
C≡C-4-Pyridyl

2264
N
CCl
CH
CH
CF3
C≡C-2-furanyl

2265
N
CCl
CH
CH
CF3
C≡C-3-furanyl

2266
N
CCl
CH
CH
CF3
C≡C-2-thienyl

2267
N
CCl
CH
CH
CF3
C≡C-3-thienyl

2268
N
CCl
CH
CH
CF3
CH═CH-cycPr

2269
N
CCl
CH
CH
CF3
CH═CH-iPr

2270
N
CCl
CH
CH
CF3
CH═CH-nPr

2271
N
CCl
CH
CH
CF3
CH═CH-Bu

2272
N
CCl
CH
CH
CF3
CH═CH-iBu

2273
N
CCl
CH
CH
CF3
CH═CH-tBu

2274
N
CCl
CH
CH
CF3
CH═CH-Et

2275
N
CCl
CH
CH
CF3
CH═CH-Me

2276
N
CCl
CH
CH
CF3
CH═CH-Ph

2277
N
CCl
CH
CH
CF3
CH═CH-2-Pyridyl

2278
N
CCl
CH
CH
CF3
CH═CH-3-Pyridyl

2279
N
CCl
CH
CH
CF3
CH═CH-4-Pyridyl

2280
N
CCl
CH
CH
CF3
CH═CH-2-furanyl

2281
N
CCl
CH
CH
CF3
CH═CH-3-furanyl

2282
N
CCl
CH
CH
CF3
CH═CH-2-thienyl

2283
N
CCl
CH
CH
CF3
CH═CH-3-thienyl

2284
N
CCl
CH
CH
CF3
CH2CH2CH2CH2CH3

2285
N
CCl
CH
CH
CF3
CH2CH2CH(CH3)2

2286
N
CCl
CH
CH
CF3
CH2CH2CH2CH3

2287
N
CCl
CH
CH
CF3
CH2CH2CH3

2288
N
CCl
CH
CH
CF3
CH2CH2-cycPr

2289
N
CCl
CH
CH
CF3
CH2CH2-tBU

2290
N
CCl
CH
CH
CF3
CH2CH2-Ph

2291
N
CCl
CH
CH
CF3
CH2CH2-2-Pyridyl

2292
N
CCl
CH
CH
CF3
CH2CH2-3-Pyridyl

2293
N
CCl
CH
CH
CF3
CH2CH2-4-Pyridyl

2294
N
CCl
CH
CH
CF3
CH2CH2-2-furanyl

2295
N
CCl
CH
CH
CF3
CH2CH2-3-furanyl

2296
N
CCl
CH
CH
CF3
CH2CH2-2-thienyl

2297
N
CCl
CH
CH
CF3
CH2CH2-3-thienyl

2298
N
C(OCH3)
CH
CH
CF3
C≡C-cycPr

2299
N
C(OCH3)
CH
CH
CF3
C≡C-iPr

2300
N
C(OCH3)
CH
CH
CF3
C≡C-nPr

2301
N
C(OCH3)
CH
CH
CF3
C≡C-Bu

2302
N
C(OCH3)
CH
CH
CF3
C≡C-iBu

2303
N
C(OCH3)
CH
CH
CF3
C≡C-tBu

2304
N
C(OCH3)
CH
CH
CF3
C≡C-Et

2305
N
C(OCH3)
CH
CH
CF3
C≡C-Me

2306
N
C(OCH3)
CH
CH
CF3
C≡C-Ph

2307
N
C(OCH3)
CH
CH
CF3
C≡C-2-Pyridyl

2308
N
C(OCH3)
CH
CH
CF3
C≡C-3-Pyridyl

2309
N
C(OCH3)
CH
CH
CF3
C≡C-4-Pyridyl

2310
N
C(OCH3)
CH
CH
CF3
C≡C-2-furanyl

2311
N
C(OCH3)
CH
CH
CF3
C≡C-3-furanyl

2312
N
C(OCH3)
CH
CH
CF3
C≡C-2-thienyl

2313
N
C(OCH3)
CH
CH
CF3
C≡C-3-thienyl

2314
N
C(OCH3)
CH
CH
CF3
CH═CH-cycPr

2315
N
C(OCH3)
CH
CH
CF3
CH═CH-iPr

2316
N
C(OCH3)
CH
CH
CF3
CH═CH-nPr

2317
N
C(OCH3)
CH
CH
CF3
CH═CH-Bu

2318
N
C(OCH3)
CH
CH
CF3
CH═CH-iBu

2319
N
C(OCH3)
CH
CH
CF3
CH═CH-tBu

2320
N
C(OCH3)
CH
CH
CF3
CH═CH-Et

2321
N
C(OCH3)
CH
CH
CF3
CH═CH-Me

2322
N
C(OCH3)
CH
CH
CF3
CH═CH-Ph

2323
N
C(OCH3)
CH
CH
CF3
CH═CH-2-Pyridyl

2324
N
C(OCH3)
CH
CH
CF3
CH═CH-3-Pyridyl

2325
N
C(OCH3)
CH
CH
CF3
CH═CH-4-Pyridyl

2326
N
C(OCH3)
CH
CH
CF3
CH═CH-2-furanyl

2327
N
C(OCH3)
CH
CH
CF3
CH═CH-3-furanyl

2328
N
C(OCH3)
CH
CH
CF3
CH═CH-2-thienyl

2329
N
C(OCH3)
CH
CH
CF3
CH═CH-3-thienyl

2330
N
C(OCH3)
CH
CH
CF3
CH2CH2CH2CH2CH3

2331
N
C(OCH3)
CH
CH
CF3
CH2CH2CH(CH3)2

2332
N
C(OCH3)
CH
CH
CF3
CH2CH2CH2CH3

2333
N
C(OCH3)
CH
CH
CF3
CH2CH2CH3

2334
N
C(OCH3)
CH
CH
CF3
CH2CH2-cycPr

2335
N
C(OCH3)
CH
CH
CF3
CH2CH2-tBu

2336
N
C(OCH3)
CH
CH
CF3
CH2CH2-Ph

2337
N
C(OCH3)
CH
CH
CF3
CH2CH2-2-Pyridyl

2338
N
C(OCH3)
CH
CH
CF3
CH2CH2-3-Pyridyl

2339
N
C(OCH3)
CH
CH
CF3
CH2CH2-4-Pyridyl

2340
N
C(OCH3)
CH
CH
CF3
CH2CH2-2-furanyl

2341
N
C(OCH3)
CH
CH
CF3
CH2CH2-3-furanyl

2342
N
C(OCH3)
CH
CH
CF3
CH2CH2-2-thienyl

2343
N
C(OCH3)
CH
CH
CF3
CH2CH2-3-thienyl

2344
N
CH
CH
CH
CF3
C≡C-cycPr

2345
N
CH
CH
CH
CF3
C≡C-iPr

2346
N
CH
CH
CH
CF3
C≡C-nPr

2347
N
CH
CH
CH
CF3
C≡C-Et

2348
N
CH
CH
CH
CF3
C≡C-3-Pyridyl

2349
N
CH
CH
CH
CF3
C≡C-2-furanyl

2350
N
CH
CH
CH
CF3
C≡C-3-furanyl

2351
N
CH
CH
CH
CF3
C≡C-2-thienyl

2352
N
CH
CH
CH
CF3
C≡C-3-thienyl

*Unless otherwise noted, stereochemistry is (+/−)

[0433]

5

TABLE 5

m.p.

Ex. #
G
R1
R2
(° C.)
Mass Spec

2401
6-Cl
cycPr
C≡C-Et
137-138.5

2402
6-Cl
CF3
C≡C-Et
178

2403
6-Cl
Et
C≡C-Et
175-176

2404
6-Cl
CH3
CH3
202
212.0440

2405
6-Cl
CH3
C≡C-cycPr
184

2406
6-Cl
CH3
CH3
221-222
228.0262

2407
6-Cl
CH3
C≡C-iPr
168
264.0790

2408
6-Cl
CF3
CH═CH-cycPr(cis)

2409
6-Cl
CF3
C≡C-iPr
167-168

2410
6-Cl
CF3
CH═CH-iPr(cis)
146-147

2411
6-Cl
CF3
CH2CH2-iPr
129-131

2412
6-Cl
CF3
C≡C-iPr
116-118

2413
6-Cl
CF3
CH═CH-iPr(trans)
127-129

2414
6-Cl
OMe
CH2CH2-Ph

318.0897

2415
6-Cl
OEt
Ph

304

(MH+)

2416
6-Cl
CF3
C≡C-1-d-cycPr
180-181
317.0406

2417
6-Cl
CF3
C≡C-1-d-cycPr
133-134
317.0417

2418
6-Cl
CF3
C≡C-1-Me-cycPr
158-159
347.0785

2419
6-Cl
CF3
Butyl
135-136

2420
6-Cl
CF3
C≡C-cycBu
183-185
330.0495

2421
6-Cl
CF3
C(Me)2CC≡CCH

2422
6-Cl
CF3
CF3
148-149

2423
6-Cl
CF3
C≡C—CF3
155-156

2424
6-Cl
CF3
Pentyl

2425
6-Cl
CF3
C≡C-Ph

352.0353

2426
6-Cl
CF3
C≡C-3-py

2427
6-Cl
CF3
C≡C-2-thiazole

2428
6-Cl
CF3
NH-iBu
182-133

2429
6-Cl
CF3
C≡C-4-py

2430
6-Cl
CH3
C≡C-Ph
181-182
298.0620

2431
6-Cl
iPr
C≡C-iPr
oil
292.1106

2432
6-Cl
iPr
C≡C-iBu
oil
306.1268

2433
6-Cl
iPr
C≡C-cycPr
amorphous
290.0938

2434
6-Cl
iPr
C≡C-Ph
177-178
326.0955

2435
6-Cl
Et
C≡C-cycPr
183-184
276.0792

2436
6-Cl
Et
C≡C-iPr
143-144
278.0958

2437
6-Cl
Et
C≡C-Ph
165-166
312.0790

2438
6-Cl
Et
C≡C-iBu
136-137
292.1100

2439
6-Cl
cycPr
C≡C-cycPr
142-143
288.0789

2440
6-Cl
cycPr
C≡C-iPr
152-153
290.0950

2441
6-Cl
cycPr
C≡C-Ph
156-157
324.0778

2442
6-Cl
cycPr
C≡C-iBu
142-143
304.1102

2443
6-Cl
iPr
CH2CH2-iPr
oil
296.1417

2444
6-Cl
cycPr
CH2CH2CH═CH2
oil
278.0946

2445
6-Cl
C≡C-
C≡C-cycPr
129-131
312.0786

cycPr

2446
6-Cl
CF3
C≡C-iBu
176-177
332.0664

2447
6-Cl
C≡C-iPr
C≡C-iPr
139
316.1104

2448
6-Cl
iPr
CH2CH2CH═CH2
oil
280.1109

2449
6-Cl
C≡CH
C≡C-iPr
161-162
274.0638

2450
6-Cl
CF3
C(Me)2CH═CH2
113-114
320.0662

2451
6-Cl
CF3
C≡C-2-Py

2452
6-Cl
CF3
C≡C-nPr
193-194
318.0500

(MH+)

2453
6-Cl
CF3
C≡C-1-OH-cycPr

2454
6-Cl
C≡CH
C≡C-Et
157-159
260.0483

2455
6-Cl
CF3
CH2-iPr
177-178
308.0659

2456
6-Cl
iPr
CH2-iPr
132-133
282.1261

2457
6-Cl
cycPr
CH2-iPr
136-137
280.1104

2458
6-Cl
iPr
C≡C-Et
amorphous

2459
6-Cl
CF3
C≡C-Et
142-146

2460
6-Cl
CF3
C≡C-Et
143-147

2461
6-Cl
CF3
CH2CH2-iPr
amorphous

2462
6-Cl
CF3
CH2CH2-iPr
amorphous

2463
6-Cl
iPr
C≡C-cycPr
amorphous

2464
6-Cl
iPr
C≡C-cycPr
amorphous

2465
6-Cl
CF3
CH2—C≡C-Me
196-199

2466
6-Cl
CF3
CH2—C≡C-Et
140-145

2467
6-Cl
CF3
NHCH2CH2CH3
184-185
309.0628

2468
6-Cl
CF3
C≡C-2-furanyl
170-171

2469
6-Cl
CF3
C≡C-3-thienyl
176.7-178

2470
6-Cl
CF3
C≡C-3-furanyl
155-156

2471
6-Cl
CF3
OBu
132-133

2472
6-Cl
CF3
C≡C-5-thiazolyl
196-196.5

2473
6-Cl
CF3
CH═CH-3-Py (t)
188-189

2474
6-Cl
CF3
C≡C-3-py
183.5

2475
6-Cl
CF3
C≡C-3-py

2476
6-Cl
CF3
CH═CH-iPr(t)

2477
6-Cl
CF3
CH═CH-iPr(t)

2478
6-Cl
CF3
OCH2CH2-iPr

338.0766

2479
6-Cl
CF3
OCH2CH2-OMe
127-128
326.0391

2480
6-Cl
CF3
CH═CH-cycPr(t)
136-137

2481
6-Cl
CF3
CH═CH-cycPr(t)
amorphous

2482
6-Cl
CF3
CH═CH-cycPr(t)
amorphous

2483
6-Cl
CF3
CH═CH-nPr(t)
127-128

2484
6-Cl
CF3
CH═CH-Et(t)
146-147

2485
6-Cl
CF3
C≡C—Me
243-244

2486
6-Cl
CF3
C≡C-iPr
116-118

2487
6-F
iPr
C≡C-iPr

276.1400

2488
6-F
iPr
C≡C-cycPr

274.1243

2489
6-F
CF3
C≡C-iPr

302.0797

2490
6-F
CF3
CH2CH2-iPr

306.1111

2491
6-F
CF3
C≡C-cycPr

300.0638

2492
6-F
CF3
C≡C-Ph

336.0648

2493
6-F
CF3
Pentyl

306.1106

2494
6-F
CF3
C≡C-iPr

2495
6-F
CF3
C≡C-iPr

302.0792

2496
6-F
CF3
C≡C-Et

288.0650

(MH+ )

2497
6-F
CF3
C≡C-nPr

302.0796

2498
6-F
CF3
Butyl

292.0947

*Unless otherwise noted, stereochemistry is (+/−)

Utility

[0434] The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

[0435] 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 expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

[0436] The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

[0437] Since the compounds of the present invention exhibit specificity 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, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

[0438] As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

[0439] DNA Plasmids and in Vitro RNA Transcripts

[0440] Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at −70° C. The concentration of RNA was determined from the A260.

[0441] Probes

[0442] Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5′ terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3′) was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5′-biotin-CCCTATCATTTTTGGTTTCCAT 3′) was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5′ CTGTCTTACTTTGATAAAACCTC 3′) was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5′ CCCAGTATTTGTCTACAGCCTTCT 3′) was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

[0443] Streptavidin Coated Plates

[0444] Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).

[0445] Cells and Virus Stocks

[0446] MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at −70° C. Infectious titers of HIV-1 (RF) stocks were 1-3×107 PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

[0447] For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×105 cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×106/mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

[0448] HIV RNA Assay

[0449] Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ(2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl2, 5 mM zinc acetate dihydrate 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) exciting at 365 nM.

[0450] Microplate Based Compound Evaluation in HIV-1 Infected MT-2 Cells

[0451] Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×105 per mL (1×105 per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO2 incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

[0452] After 3 days of culture at 37° C. in a humidified chamber inside a CO2 incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

[0453] In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC90 value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC90 values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×105 PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC90 values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC90 for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC90 was found to be less than 20 μM.

[0454] For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2×concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

HIV-1 RT Assay Materials and Methods

[0455] This assay measures HIV-1 RT RNA dependent DNA polymerase activity by the incorporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:

[0456] Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.

[0457] Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAE) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

[0458] Materials and Reagents

[0459] The template primer Poly (rA) oligo (dT)12-18 and dTTP were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/ml and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 μl/aliquot, dTTP at 9 μl/aliquot) and frozen at −20 C.

[0460] The 3H dTTP (2.5 mCi/ml in 10 mM Tricine at pH 7.6; specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 μl in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50% glycerol) were purchased from DuPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37 C. The 3H dTTP was aliquoted at 23.2 μl/microfuge tube (58 μCi) and frozen at −20 C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT buffer (80 mM KCl, 50 mM Tris HCl, 12 mM MgCl2, 1 mM DTT, 50 μM EGTA, 5 mg/ml BSA, 0.01% Triton-X 100, pH 8.2) and aliquoted at 10 μl/microfuge tube (10 Units/10 μl). One aliquot (enough for 8 assays) was diluted further to 10 Units/100 μl and aliquoted into 8 tubes (1.25 Units/12.5 μl) All aliquots were frozen at −70 C.

[0461] The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing film were purchased from Millipore. The filter plate containing 0.65 μm pore size diethyl amino ethyl cellulose (DEAE) paper disks was pretreated with 0.3 M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 μl/well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were purchased from Skatron Instruments. Microscint 20 scintillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Beckman.

[0462] HIV-1 RT Assay

[0463] The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was diluted with RT buffer (containing 5 mg/ml BSA) to a concentration of 0.05 Units/10 μl or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 units or 0.14 nM and 1 mg/ml respectively. The inhibitor and substrate mixture were diluted with RT buffer containing no BSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at −20 C. after use. A Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two times (10 fold/dilution) from 31.25 μM to 3125 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 μM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 μM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 μM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 μg/ml of Poly (rA) oligo (dT)12-18 and 12.5 μM of dTTP (58 μCi 3H dTTP). The final substrate concentrations were 2.5 μg/ml and 5 μM respectively.

[0464] Using the Beckman Instruments Biomek robot, 10 μl of HIV-1 RT was combined with 20 μl of inhibitor in a 96 well U bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 μl of the substrate mixture was added to each well to initiate the reaction (total volume was 50 μl). The reactions were incubated at 37 C. and terminated after 45 minutes.

[0465] For method 1, 200 μl of an ice-cold solution of 13% trichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyrophosphate. The filter disks were washed 3 times (2.0 ml/wash) with 1 N HCl and 10 mM sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 ml of Beckman Ready Flow III scintillant was added, and the vials were counted for radioactivity for 1 minute.

[0466] For method 2, the assay was terminated with the addition of 175 μl/well of 50 mM EDTA at pH 8.0. Then 180 μl of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was applied to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAE filter disks. Each well was washed 3 times with 200 μl of 0.3 M ammonium formate and 10 mM sodium pyrophosphate at pH 8.0. 50 μl of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.

[0467] The IC50 values are calculated with the equation:

IC50=[Inh]/(1/fractional activity−1)

[0468] where the fractional activity=RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the IC50 values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The IC50 values in this range (generally 2 values) were averaged. A compound was considered active if its IC50 was found to be less than 12 μM.

Protein Binding and Mutant Resistance

[0469] In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

[0470] 1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

[0471] 2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

[0472] Dosage and Formulation

[0473] The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0474] The dosage administered will, of course, vary depending upon 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 kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

[0475] Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid usage forms.

[0476] Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage formed for oral administration can contain coloring and flavoring to increase patient acceptance.

[0477] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions 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, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

[0478] Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

[0479] Capsules

[0480] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

[0481] Soft Gelatin Capsules

[0482] A mixture of 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 into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

[0483] Tablets

[0484] A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon 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 palatability or delay absorption.

[0485] Suspension

[0486] An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

[0487] Injectable

[0488] A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

[0489] Combination of Components (a) and (b)

[0490] Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

[0491] Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the 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 they may be administered in the revserse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

[0492] As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various 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 kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

[0493] The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

[0494] The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

[0495] Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one 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 placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

[0496] These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

[0497] Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and me or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invent. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

[0498] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

	Number	Date	Country
	60045138	Apr 1997	US
	60027137	Oct 1996	US

	Number	Date	Country
Parent	09627213	Jul 2000	US
Child	09919065	Jul 2001	US
Parent	09176491	Oct 1998	US
Child	09627213	Jul 2000	US
Parent	08942031	Oct 1997	US
Child	09176491	Oct 1998	US

4,4-disubstituted-1, 4-dihydro-2H-3, 1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

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