This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection. A representative compound of the invention is the compound of formula:
wherein r22 and r23 are allyl.
0. 21. A compound of formula (IIa):
or a pharmaceutically acceptable salt form thereof, wherein r22 is 3 -aminobenzyl and r23 is 3 1. A compound of the formula (I):
or a pharmaceutically acceptable salt form thereof wherein:
r4 and r7 are independently selected from the following groups: hydrogen; C1-C8 alkyl substituted with 0-3 r11; C2-C8 alkenyl substituted with 0-3 r11: ; C2-C8 alkynyl substituted with 0-3 r11; a C3-C14 carbocyclic ring system substituted with 0-3 r11 or 0-3 r12; a heterocyclic ring system selected independently from indolyl, furanyl, pyridyl, thienyl, pyrrolyl, benzothienyl, pyrazolyl, thiazolyl, benzofuranyl, tetrahydroisoquinolinvl tetrahydroisoquinolinyl, benzotriazolyl, benzimidazolyl, or imidazolyl, said heterocyclic ring system being substituted with 0-2 r12; CO2r13; r4A and r7A are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-6 halogen or 0-3 C1-C2 alkoxy; benzyl substituted with 0-6 halogen or 0-3 C1-C2 alkoxy; CO2r13; r4 and r4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 r12; r7 and r7A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 r12; n is 1; r5 is selected from H; , halogen; , C1-C6 alkyl substituted with 0-3 r11, --N(r20)2, --SR20, --OR20, or --N3; r6 is independently selected from: hydrogen, halogen, C1-C6 alkyl substituted with 0-3 r11, --N(r20)2, --SR20, --OR21, or --N3; r5 and r6 can alternatively join to form an epoxide or aziridine ring; --OCH2SCH2O--; --OC(═O)O--; --OCH2O--; --OC(═S)O--; --OC(═O)C(═O)O--; --OC(CH3)2O--; --OC((CH2)3NH2)(CH3)O--; --OC(OCH3)(CH2CH2CH3)O--; --OS(═O)O--; --NHC(═O)NH--; --OC(═O)NH--; --NHC(═O)O--; --NHCH2O--; --OCH2NH--; --NHC(═S)O--; --OS(═O)NH--; --NHC(═O)C(═O)O--; --OC(═O)C(═O)NH--; --NHC(═O)C(═O)NH--; --NHC(CH3)2O--; --OC(CH3)2NH--; r5a is selected from hydrogen, halogen, C1-C6 alkyl, --N(r20)2, --SR20, or --OR20; r6a is selected from: hydrogen, halogen, C1-C6 alkyl, --N(r20)2, --SR20 or --OR21; r5 and r5a can alternatively join to form ═O, ═S, or a ketal ring; r6 and r6a can alternatively join to form ═O, ═S, or a ketal ring; r20 and r21 are independently selected from: hydrogen; C1-C6 alkyl substituted with 0-3 r11; C3-C6 alkoxyalkyl substituted with 0-3 r11; C1-C6 alkylcarbonyl substituted with 0-3 r11; C1-C6 alkoxycarbonyl substituted with 0-3 r11; C1-C6 alkylaminocarbonyl substituted with 0-3 r11; benzoyl substituted with 0-3 r12; phenoxycarbonyl substituted with 0-3 r12; phenylaminocarbonyl substituted with 0-3 r12; or phosphate ester; r11 is selected from one or more of the following: H, keto, halogen, cyano, --CH2NR13r14, --NR13r14, --CO2r13, --OC(═O)r13, --OR13, --S(O)mr13, --NHC(═NH)NHR13, --C(═NH)NHR13, --C(═O)NR13r14, --NR14C(═O)r13, ═NOR14, --NR14C(═O)OR14, --OC(═O)NR13r14, --NR13C(═O)NR13r14, --NR14SO2NR13r14, --NR14SO2r13, --SO2NR13r14, --OP(O)(OR13)2, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cyclolkoxy, C1-C4 alkyl substituted with --NR13r14, cycloalkoxy, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1 C4 C1-C4haloalkyl, C1-C4 haloalkoxy, Cl-c4 alkoxycarbonyl, pyridylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --OCH2CO2H, 2-(1-morpholino)ethoxy, azido, or --C(r14)═N(OR14); 1-3 amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; C3-C10 cycloalkyl substituted with 0-2 r12; C1-C4 alkyl substitued substituted with 0-2 r12; aryl(C1-C3 alkyl)-, substituted with 0-2 r12; C2-C6 alkoxyalkyl-, substituted with 0-2 r12; C1-C4 alkylcarbonyloxy substituted with 0-2 r12, ; C6-C10 arylcarbonyloxy substituted with 0-2 r12, ; a C5-C14 carbocyclic residue substituted with 0-3 r12; a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 r12; r11A is selected from one or more of the following: H, keto, halogen, cyano, --CH2N(r13A)r(14A) --CH2N(r13A)(r14A), --N(r13A)r(14A) --N(r13A)(r14A), --CO2H, --OC(═O)(C1-C3 alkyl), --OH, C2-C6 alkoxyalkyl, --C(═O)NH2, --OC(═O)NH2, --NHC(═O)NH2, --SO2NH2, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with --NH2, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --OCH2CO2H, 2-(1-morpholino)ethoxy, azido, aryl(C1-C3 alkyl), a C5-C14 carbocyclic residue; a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 r12A; r12 when a substituent on carbon is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, --CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, --OR13, C1-C4 alkyl substituted with --NR13r14, --NR13r14, C2-C6 alkoxyalkylene optionally substituted with --Si(CH3)3, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --S(O)mr13, --SO2NR13r14, --NHSO2r14, --OCH2CO2r13, 2-(1-morpholino)ethoxy, --C(r14)═N(OR14); or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or r12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or --NR13r14; or, when r12 is attached to a saturated carbon atom, it may be ═O or ═S; or when r12 is attached to sulfur it may be ═O; r12, when a substituent on nitrogen is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, --CH2NR13r14, --NR13r14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, --CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, --C(r14)═N(OR14); r12A, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, --CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, --OR13, C1-C4 alkyl substituted with --NH2, --NH2, --NHMe, C2-C6 alkoxyalkyl optionally substituted with --Si(CH3)3, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --S(O)mMe, --SO2NH2, --NHSO2Me, --OCH2CO2r13, 2-(1-morpholino)ethoxy, --C(═NOH)NH2; or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or r12A may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or --NH2; or, when r12A is attached to a saturated carbon atom, it may be ═O or ═S; or when r12 r12A is attached to sulfur it may be ═O. ; r12A, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, --CH2NH2, --NH2, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, --CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, --C(═NOH)NH2; r13 is selected from: H; phenyl substituted with 0-3 r11A; benzyl substituted with 0-3 r11A; C1-C6 alkyl substituted with 0-3 r11A; C2-C4 alkenyl substituted with 0-3 r11A; C1-C6 alkylcarbonyl substituted with 0-3 r11A; C1-C6 alkoxycarbonyl substituted with 0-3 r11A; C1-C6 alkylaminocarbonyl substituted with 0-3 r11A; C3-C6 alkoxyalkyl substituted with 0-3 r11A; r14 is hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 groups selected from OH, C1-C4 alkoxy, and halogen, ; NH2, --NH(C1-C4 alkyl),C1-C6 C1-C4 alkoxy, C2-C6 C2-C4 alkenyl, phenyl, or benzyl; r13 and r14 can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2--, or --CH2CH2OCH2CH2--; r13A and r14A are independently selected from: H, C1-C6 alkyl; r13A and r14A can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2--, or --CH2CH2OCH2CH2--; r15 is H or CH3; m is 0, 1 or 2; W is selected from: --N(r22)C(═Z)N(r23)--; --N(r22)S(═Z')N(r23)--; --N(r22)S(═Z')2N(r23)--; --N(r22)P(═O)(r24a)N(r23)--; wherein:
Z is O, S, NR24; Z' is O or NR24; r22 and r23 are independently selected from the following: hydrogen; --OR22a; --N(r22a)(r22b); C1-C8 alkyl substituted with 0-3 r31; C2-C8 alkenyl substituted with 0-3 r31; C2-C8 alkynyl substituted with 0-3 r31; a C3-C14 carbocyclic ring system substituted with 0-5 r31 or 0-5 r32; a heterocyclic ring system selected independently from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, tetrazoyl, triazinyl, pyrazinyl, myridazinyl pyridazinyl, oxazolidinyl, and thiazolyl said heterocyclic ring system being substituted with 0-2 r32; r22a and r22b are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 r31; C2-C8 alkenyl substituted with 0-3 r31; C2-C8 alkynyl substituted with 0-3 r31; a C3-C14 carbocyclic ring system substituted with 0-5 r31 or 0-5 r32; a heterocyclic ring system selected independently from pyridinyl, furanyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl said heterocyclic ring system being substituted with 0-2 r32; r24 is selected from: hydrogen; hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy; mono- or di-(C1-C6 alkyl)amino; cyano; nitro; benzyloxy; --NHSO2aryl, aryl being optionally substituted with (C1-C6)alkyl; r24a is selected from: hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy; mono- or di-(C1-C6 alkyl)amino; cyano; nitro; benzyloxy; or phenoxy; alternatively, r22 can join with r4 or r4A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 r12, said heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine; or alternatively, r23 can join with r7 or r7A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 r12, said heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine; or alternatively, r22 or r23 can join with r5 or r6 to form a 0- to 7-membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 r12 and said heterocyclic ring being selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine; alternatively r23 can join with r7A to form a direct bond; alternatively r22 can join with r4A to form a direct bond; r31 is selected from one or more of the following: keto, halogen, cyano, --CH2NR13r14, --NR13r14, --CO2r3 --CO2r13, --C(═O)r11, --OC(═O)r13, --OR13, C2-C6 alkoxyalkyl, --S(O)mr13, --NHC(═NH)NHR13, --C(═NH)NHR13, --C(═O)NR13r14, --NR14C(═O)r13, ═NOR14, --NR14C(═O)OR14, --OC(═O)NR13r14, --NR13C(═O)NR13r14, --NR13C(═S)NR13r14, --NR14SO2NR13r14, --NR14SO2r13, --SO2NR13r14, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with --NR13r14, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --OCH2CO2r13, 2-(1-morpholino)ethoxy, azido, --C(r14)═N(OR14); or 1-3 amino acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; a C5-C14 carbocyclic residue substituted with 0-5 r32; or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 r32; r32, when a substituent on carbon, is selected from one or more of the following: phenethyl, phenoxy, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 alkylcarbonyloxy, --NHSO2r14, benzyloxy, halogen, 2-(1-morpholino) ethoxy, --CO2r13, hydroxamic acid, --CONR13NR13r14, cyano, sulfonamide, --CHO, C3-C6 cycloalkoxy, --NR13r14, --C(r14)═N(OR14), --NO2, --OR13, --NR40r41, --SOmr13, --SOmNR13r14, --C(═O)NR13r14, --OC(═O)NR13r14, --C(═O)r11, --OC(═O)r11, --OCO2r13, phenyl, --C(═O)NR13--(C1-C4 alkyl)-NR13r14, --C(═O)NR40r41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, Cl-C4 haloalkynyl C2-C4 haloalkynyl, or --C(═O)NR13C(r11)2NR13r14: --C(═O)NR13C(r11)2NR13CO2r13; --C(═O)NR13--(C1-C4 alkyl)-NR13CO2r13; --C(═O)N(r13)--(C1-C4 alkyl)-r11; or --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; or C1-C4 alkoxy substituted with 0-4 groups selected from: r11, C3-C6 cycloalkyl, --CO2r13, --C(═O)NR13r14, --NR13r14or OH ; C1-C4 alkyl substituted with 0-4 groups selected from: r11, ═NR14, ═NNR13C(═O)NR13r14, ═NNR13C(═O)OR13, or --NR13r14; C2-C4 alkenyl substituted with 0-4 r11; C2-C4 alkynyl substituted with 0-4 r11; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 r12; or r32 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or --NR13r14; or, when r32 is attached to a saturated carbon, it may be ═O, ═S, ═NOH; or when r32 attached to sulfur it may be ═O. ; r32, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, --CH2NR13r14, --NR13r14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, --CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, --C(r14)═N(OR14); r40 is selected from: H, C1-C3 alkyl; r41 is selected from: --C(═O)NR13r14; --C(═O)NR13NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)H; --C(═O)r11; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═C)--(C1-C4 alkyl)-NR13CO2r13; 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; wherein said aryl group is phenyl or naphthyl; provided that: r4, r4A, r7 and r7A are not all hydrogen; when r4 and r4A are hydrogen, r22 is not hydrogen. 2. A compound of
r4 and r7 are independently selected from the following groups: hydrogen; C1-C8 alkyl substituted with 0-3 r11; C2-C8 alkenyl substituted with 0-3 r11; C2-C8 alkynyl substituted with 0-3 r11; C3-C8 cycloalkyl substituted with 0-3 r11; C6-C10 bicycloalkyl substitutd with 0-3 r11; aryl substituited with 0-3 r12; a C6-C14 partially unsaturated carbocyclic residue substituted with 0-3 r12; a heterocyclic ring system selected independently from indolyl, furanyl, pyridyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, or imidazolyl, said heterocyclic ring system being substituted with 0-2 r12; r22 and r23 are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 r31; C2-C8 alkenyl substituted with 0-3 r31; C2-C8 alkynyl substituted with 0-3 r31; C3-C8 cycloalkyl substituted with 0-3 r31; C6-C10 bicycloalkyl substituted with 0-3 r31; aryl substituted with 0-5 r32; a C6-C14 partially unsaturated carbocyclic residue substituted with 0-3 r32; a heterocyclic ring system selected independently from pyridinyl, pyrimidinyl pyrazolyl, imidazolyl, tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl, and thiazolyl said heterocyclic ring system being substituted with 0-2 r32. 3. A compound of
or a pharmaceutically acceptable salt form thereof wherein:
r4 and r7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 r11; C3-C4 alkenyl substituted with 0-3 r11; C3-C4 alkynyl substituted with 0-3 r11; r4A and r7A are hydrogen; n is 1; r5 is selected from fluoro, --OR20, --N(r20)2; r6 is independently selected from: hydrogen, fluoro or --OR21; r5 and r6 can alternatively join to form an epoxide or aziridine ring; --OCH2SCH2O--; --OS(═O)O--; --OC(═O)O--; --OCH2O--; --OC(═S)O--; --OC(═O)C(═O)O--; --OC(CH3)2O-- --OC(CH3)2O--; --OC(OCH3)(CH2CH2CH3)O--; r5a is selected from hydrogen or fluoro; r6a is selected from: hydrogen or fluoro; r5 and r5a can alternatively join to form ═O, ═S, or a ketal ring; r6 and r6a can alternatively join to form ═O, ═S, or a ketal ring; r20 and r21 are independently selected from: hydrogen; C1-C6 alkylcarbonyl; C1-C6 alkoxycarbonyl; benzoyl; or phosphate ester; r11 is selected from one or more of the following: H, keto, halogen, cyano, --CH2NR13r14, --NR13r14, --CO2r13, --OC(═O)r13, --OR13, C2-C4 alkoxyalkyl, --S(O)mr13, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl; a C5-C14 saturated or partially unsaturated carbocyclic residue substituted with 0-3 r12; aryl(C1-C3 alkyl)-, substituted with 0-2 r12; aryl substituted with 0-3 r12; or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 r12; r12 when a substituent on carbon is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, 2-(1-morpholino)ethoxy, --CO2H, hydroxamic acid, hydrazide, --C(r14)═N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, --OR13, C1-C4 alkyl substituted with --NR13r14, --NR13r14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --S(O)mr13, --SO2NR13r14, --NHSO2r14; or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or r12 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or --NR13r14; or, when r12 is attached to a saturated carbon atom, it may be ═O or ═S; or when r12 is attached to sulfur it may be ═) ═O; r12, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, --CH2NR13r14, --NR13r14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, --CO2H; r13 is H, C1-C6 alkyl, C3-C6 alkoxyalkyl, C2-C4 alkenyl, phenyl, or benzyl; r14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, phenyl, or benzyl; r13 and r14 can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2--, or --CH2CH2OCH2CH2--; r15 is H or CH3: ; m is 0, 1 or 2; W is selected from: --N(r22)C(═Z)N(r23)--; --N(r22)S(═Z')N(r23)--; --N(r22)S(═Z')2N(r23)--; --N(r22)P(═O)(r24a)N(r23)--; wherein:
Z is O, S, N--CN, N--OH, N--OCH3; Z' is oxygen: ; r22 and r23 are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 r31; C3-C8 alkenyl substituted with 0-3 r31; C3-C8 alkynyl substituted with 0-3 r31; C3-C6 cycloalkyl substituted with 0-3 r31; r24a is selected from --OH, C1-C4 alkoxy, mono- or di-(C1-C6 alkyl)amino; r31 is selected from one or more of the following: keto, halogen, cyano, --CH2NR13RI4, --NR13r14, --CO2r13, --OC(═O)r13, --OR13, C2-C4 alkoxyalkyl, --S(O)mr13, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with --NR13r14, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, --OCH2CO2H, 2-(1-morpholino)ethoxy, --C(r14)═N(OR14); or a C5-C14 saturated or partially unsaturated carbocyclic residue substituted with 0-3 r32; aryl substituted with 0-3 r32; or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 r32; r32, when a substituent on carbon, is selected from one or more of the following: phenethyl, phenoxy, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 alkylcarbonyloxy, --NHSO2r14 benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO2r13, hydroxamic acid, --CONR13NR13r14, cyano, boronic acid, sulfonamide, --CHO, C3-C6 cycloalkoxy, --NR13r14, --C(r14)═N(OR14), NO2, --OR13, --NR40r41, --SOmr13, --SOmNR13r14, --C(═O)NR13r14, --OC(═O)NR13r14, --C(═O)r11, --OC(═O)r11, --OCO2r13, phenyl, --C(═O)NR13--(C1-C4 alkyl)NR13r14, --C(═O)NR40r41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, or --C(═O)NR13C(r11)2NR13r14; --C(═O)NR13C(r11)2NR13NR14; --C(═O)NR13C(r11)2NR13CO2r13; --C(═O)NR13--(C1-C4 alkyl)-NR13CO2r13; or --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14; --C(═O)C(r11)2NR13CO2r13; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; or C1-C4 alkoxy substituted with 0-3 groups selected from: r11, C3-C6 cycloalkyl, --CO2r13, --C(═O)NR13r14, --NR13r14or OH ; C1-C4 alkyl substituted with 0-3 groups selected from: r11, ═NR14, ═NNR13C(═O)NR13r14 or --NR13r14; C2-C4 alkenyl substituted with 0-3 r11; C2-C4 alkynyl substituted with 0-3 r11; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 r12; or r32 may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or --NR13r14; or, when r32 is attached to a saturated carbon atom, it may be ═O or ═S; or when r12 r32 is attached to sulfur it may be ═O. ; r32, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, --CH2NR13r14, --NR13r14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, --CO2H, --C(r14)═N(OR14); r40 is selected from: H, C1-C3 alkyl; r41 is selected from; --C(═O)NR13r14; --C(═O)NR13NR14 --C(═O)NR13NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14 --C(═O)C(r11)2NR13NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)H; --C(═O)r11; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; wherein said aryl group is phenyl or naphthyl; provided that: r4, r4A, r7, and r7A are not all hydrogen; when r4 and r4A are hydrogen, then r22 is not hydrogen. 4. A compound of
or a pharmaceutically acceptable salt form thereof wherein:
r4 and r7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 r11; C3-C4 alkenyl substituted with 0-3 r11; r5 is --OR20; r6 is hydrogen or --OR21; r20 and r21 are H; r11 is selected from one or more of the following: H, keto, halogen, --CH2NR13r14, --NR13r14, --OR13, C2-C4 alkoxyalkyl, C2-C4 alkenyl, ; C3-C10 cycloalkyl substituted with 0-2 r12; C1-C4 alkyl substituted with 0-2 r12; aryl(C1-C3 alkyl)-, substituted with 0-2 r12; aryl substituted with 0-3 r12; or a 5- or 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 r12; r12, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy, 2-(1-morpholino)ethoxy, --CO2H, hydroxamic acid, hydrazide, --C(r14)═N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, --OR13, C1-C4 alkyl substituted with --NR13r14, --NR13r14, methylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, hydroxy, hydroxymethyl; or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; r12, when a substituent on nitrogen, is selected from benzyl or methyl; r13 is H, C1-C4 alkyl, C3-C6 alkoxyalkyl, C2-C4 alkenyl, or benzyl; r14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl; r13 and r14 can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2--, or --CH2CH2OCH2CH2--; r15 is H or CH3; W is selected from: --N(r22)C(═Z)N(r23)--; --N(r22)S(═Z')N(r23)--; --N(r22)S(═Z')2N(r23)--; --N(r22)P(═O)(r24a)N(r23)-- --N(r22)P(═O)(r24a)N(r23)--; wherein:
Z is O, S, or N--CN; Z' is 0; r22 and r23 are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-2 r31; C2-C6 alkenyl substituted with 0-1 r31; C2-C4 alkynyl substituted with 0-1 r31; r24a is selected from --OH, C1-C4 alkoxy, mono- or di-(C1-C6 alkyl)amino; r31 is selected from one or more of the following: keto, halogen, --CH2NR13r14, --NR13r14, --OR13, C2-C4 alkoxyalkyl, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, --C(r14)═N(OR14), --CO2r13, --S(O)mr13; aryl substituted with 0-5 r32; or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 r32; r32, when a substituent on carbon, is selected from one or more of the following: phenethyl, phenoxy, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 alkylcarbonyloxy, --NHSO2r14, benzyloxy, halogen, 2-(1-morpholino) ethoxy, --CO2r13, hydroxamic acid, --CONR13NR13r14, cyano, boronic acid, sulfonamide, --CHO, C3-C6 cycloalkoxy, --NR13r14, --C(r14)═N(OR14), NO2, --OR13, --NR40r41, --SOmr13, --SOmNR13r14, --C(═O)NR13r14, --OC(═O)NR13r14, --C(═O)r11, --OC(═O)r11, --OCO2r13, phenyl, --C(═O)NR13--(C1--C4 alkyl)--NR13r14, --C(═O)NR40r41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, or --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)--(C1-C4 alkyl)--NR13r14; --C(═O)--(C1-C4 alkyl)--NR13CO2r13; or C1-C4 alkoxy substituted with 0-3 groups selected from: r11, C3-C6 cycloalkyl, --CO2r13, --C(═O)NR13r14, --NR13r14 or OH ; C1-C4 alkyl substituted with 0-3 groups selected from: r11, --NR14, ═NNR13C(═O)NR13r14 or --NR13r14; C2-C4 alkenyl substituted with 0-3 r11; C2-C4 alkynyl substituted with 0-3 r11; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-3 r12; r32, when a substituent on nitrogen, is selected from benzyl or methyl; m is 0, 1, or 2; r40 is selected from: H, C1-C3 alkyl; r41 is selected from: --C(═O)NR13r14; --C(═O)NR13NR14 --C(═O)NR13NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14 --C(═O)C(r11)2NR13NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)H; --C(═O)r11; --C(═O)--(C1--C4 alkyl)-NR13r14; --C(═O)--(C1--C4 alkyl)--NR13CO2r13; 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; wherein said aryl group is phenyl or naphthyl; provided that:
r4 and r7 are not both hydrogen; when r4 is hydrogen, then r22 is not hydrogen.
5. A compound of
r4 and r7 are independently selected from the following groups: hydrogen; C1-C3 alkyl substituted with 0-1 r11; r5 is --OR20; r6 is hydrogen or --OR21; r20 and r21 are H; r11 is selected from one or more of the following: H; halogen; --OR13; C3-C10 cycloalkyl substituted with 0-2 r12; C1-C4 alkyl substituted with 0-2 r12; aryl (C1-C3 alkylene) substituted with 0-2 r12; aryl substituted with 0-2 r12; or a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 r12; r12, when a substituent on carbon is selected from one or more of the following: benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(1-morpholino)ethoxy, --CO2H, hydroxamic acid, hydrazide, --C(r14)═N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with --NR13r14, --NR13r14, hydroxy, hydroxymethyl; or r12, when a substituent on nitrogen, is methyl; r13 is H, C1-C4 alkyl, C2-C4 alkenyl, or benzyl; r14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl; r13 and r14 can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2, or --CH2CH2OCH2CH2--; r15 is H or CH3; W is selected from: --N(r22)C(═Z)N(r23)--; --N(r22)C(═Z)O--; --N(r22)S(═Z')2N(r23)--; Z is O, S, or N--CN; Z' is O; r22 and r23 are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 r31; C2-C6 alkenyl substituted with 0-3 r31; C2-C4 alkynyl substituted with 0-3 r31; r31 is selected from one or more of the following: halogen, --OR13, C1-C4 alkyl, C3-C10 cycloalkyl, --C(r14)═N(OR14), --CO2r13, --S(O)mr13; aryl substituted with 0-5 r32; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring being substituted with 0-2 r32; r32, when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO2r13, hydroxamic acid, --CONR13NR13r14, cyano, boronic acid, sulfonamide, --CHO, C3-C6 cycloalkoxy, --NR13r14, --C(r14)═N(OR14), NO2, --OR13, --NR40r41, --SOmr13, --SOmNR13r14, --C(═O)NR13r14, --OC(═O)NR13r14, --C(═O)r11, --OC(═O)r11, --OCO2r13, phenyl, --C(═O)NR13--(C1-C4 alkyl)-NR13r14, --C(═O)NR40r41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, --C(═O)NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14; --C(═O)C(r11)2NR13CO2r13; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; or C1-C4 alkoxy substituted with 0-3 groups selected from: r11, C3-C6 cycloalkyl, --C(═O)NR13r14, --NR13r14or OH ; C1-C4 alkyl substituted with 0-3 groups selected from: r11, ═NR14, ═NNR13C(═O)NR13r14 or --NR13r14; C2-C4 alkenyl substituted with 0-3 r11; C2-C4 alkynyl substituted with 0-3 r11; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 r12; r32, when a substituent on nitrogen, is methyl; m is 0, 1, or 2; r40 is selected from: H, C1-C3 alkyl; r41 is selected from: --C (═O) NR13r14; --C(═O)NR13NR14 --C(═O)NR13NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14 --C(═O)C(r11)2NR13NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)H; --C(═O)r11; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; wherein said aryl group is phenyl or naphthyl; provided that:
r4 and r7 are not both hydrogen; when r4 is hydrogen, then r22 is not hydrogen.
6. A compound of
r4 and r7 are selected from benzyl, fluorobenzyl, methylbenzyl, dimethylbenzyl, ethylbenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, or naphthylmethyl; r5 is --OH; r6 is hydrogen or --OH; r13 is H, C1-C4 C1-C4 alkyl, C2-C4 alkenyl, or benzyl; r14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl; r13 and r14 can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2--, or --CH2CH2OCH2CH2--; W is selected from: --N(r22)C(═O)N(r23)--; --N(r22)C(═N--CN)N(r23)--; --N(r22)S(═O)2N(r23)--; --N(r22)C(═S)N(r23)--; r22 and r23 are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-2 r31; C2-C6 alkenyl substituted with 0-2 r31; C2-C4 alkynyl substituted with 0-2 r31; r31 is selected from one or more of the following: halogen, --OR13, C1-C4 alkyl, C3-C10 cycloalkyl, --C(r14)═N(OR14), --CO2r13, --S(O)mr13; aryl substituted with 0-5 r32; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, benzimidazolyl, benzotriazolyl, indazolyl, benzoxazolinyl, benzoxazolyl, said heterocyclic ring being substituted with 0-2 r32; r32 when a substituent on carbon, is selected from one or more of the following: --CONH2, --CO2H, --CHO, --CH2NHOH, --CH2NR13r14, --NR13r14, hydroxy, hydroxymethyl, --C(r14)═N(OR14), halogen, methoxy, methyl, nitro, cyano, allyloxy, --CO2CH3, --NHCHO, --NHCOCH3, --OCO2CH3, --CH═NCH2CH2OH, --OCONHCH2C6H5, --OCONHCH3, oxazolidinyl, --C≡C--CH2OH, --COCH3, hydroxyethyl, C1-C3 alkyl (said alkyl substituted with 0-4 halogen, or OH), tetrazolyl, --OCH2CONH2, CONHNH2, --CH═NNHCONH2, --CONHOCH3, --CH2CH(OH)CH2OH, adamantamido, hydroxyethoxy, dihydroxyethyl, --C(NH2)═NH, --CONHCH3, --B(OH)2, benzyloxy, --CONHCH2CH3, --CON(CH2CH3)2, methylthio, --SO2CH3, --NHCONH2, --NHCONHCH3, --NHCOCH2N(CH3)2, --NHCOCH2NHCH3, --NHCOCH2NHCO2CH2C6H5, --NHCOCH2NH2, --NHCOCH(CH3)NHCO2CH2C6H5, --NHCOCH(CH2C6H5)NHCO2CH2C6H5, --NHCOCH(CH3)NH2, --NHCOCH(CH2C6H5)NH2, --CO2CH2CH3, --CONHCH2CH2CH3, --CONHCH(CH3)2, --CH2-imidazole, --COC(CH3)3, --CH(OH)CF3, --CO-imidazole, --CO-pyrazolyl, --CO--CH2-pyridine, oxidiazolyl, --COCF3, --C(CH2CH3)═N(OH)or , --C(CF3)═N(OH), phenyl, acetoxy, hydroxyamino, --N(CH3)(CHO), cyclopropylmethoxy, --CONR13r14, --CONHOH, diethylaminoethyl)aminocarbonyl, (N-ethyl, N-methlaminoethyl) aminocarbonyl (N-ethyl,N-methylaminoethyl)aminocarbonyl, (4-methylpiperazinylethyl)aminocarbonyl, (pyrrolidinylethyl)aminocarbonyl, (piperidinylethyl)aminocarbonyl, --NHCOCH2NHCH3, N-(2-(4-morpholino)ethyl)aminocarbonyl, N-(2-N,N-dimethylamino)ethyl)aminocarbonyl, wherein said oxazolidinyl, tetrazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyrrolidinyl, and piperidinyl groups are optionally substituted with 1-2 groups independently selected from OH, --O(C1-C3 alkyl), NH2, --NH(C1-C3 alkyl), or halogen; r32, when a substituent on nitrogen, is methyl.
7. A compound of
wherein:
Z is O, S, or N--CN; r4 and r7 are independently selected from: benzyl, methylbenzyl, dimethylbenzyl, ethylbenzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, or naphthylmethyl; r22 and r23 are independently selected from the group consisting of: hydrogen, allyl, methyl, ethyl, propyrl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH═C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N═CH) -benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(═NOH) )-benzyl, (H2NNHC(═O))-benzyl, (H2NC(═O)NHN═CH)-benzyl, (CH3ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH3NHC(═O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)benzyl, hydroxyethoxybenzyl(oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl) alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl, (pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H2NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(═NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(═NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(═O)O)benzyl, CHBNHC(═O)O)benzyl (CH3NHC(═O)O)benzyl, (NH2C(═O)CH2O)benzyl, (NH2C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3C--C(═O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl, 3-aminoindazolylmethyl, 3-aminobenzoxazolylmethyl, aminopyrazolylbenzyl, imidazolylbenzyl, aminoimidozolylbenzyl aminoimidazolylbenzyl. 8. A compound of
or a pharmaceutically acceptable salt form thereof, wherein:
wherein r22 and r23 are independently selected from the group consisting of: hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH═C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N═CH) -benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(═NOH))-benzyl, (H2NNHC(═O))-benzyl, (H2NC(═O)NHN═CH)-benzyl, (CH3ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH3NHC(═O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl--C(═O))-benzyl, (pyrazolyl--C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H2NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(═NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(═NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(═O)O)benzyl, (CH3NHC(═O)O)benzyl, (NH2C(═O)CH2O)benzyl, (NH2C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3C--C(═O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl, 3-aminoindazolylmethyl, 3-aminobenzoxazolylmethyl, aminopyrazolylbenzyl, imidazolylbenzyl, aminoimidazolylbenzyl. 9. A compound of
or a pharmaceutically acceptable salt form thereof, selected from the group consisting of:
the compound of formula (IIa) wherein r22 is allyl and r23 is allyl; the compound of formula (IIa) wherein r22 is propyl and r23 is propyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is n-hexyl and r23 is n-hexyl; the compound of formula (IIa) wherein r22 is n-butyl and r23 is n-butyl; the compound of formula (IIa) wherein r22 is CH2CH═C(CH3)2 and r23 is CH2CH═C(CH3)2; the compound of formula (IIa) wherein r22 is CH2CH═C(CH3)2 and r23 is H; the compound of formula (IIa) wherein r22 is i-pentyl and r23 is i-pentyl; the compound of formula (IIa) wherein r22 is 2-methallyl and r23 is 2-methallyl; the compound of formula (IIa) wherein r22 is n-pentyl and r23 is n-pentyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is benzyl; the compound of formula (IIa) wherein r22 is i-hexyl and r23 is i-hexyl; the compound of formula (IIa) wherein r22 is allyl and r23 is isoprenyl; the compound of formula (IIa) wherein r22 is 1-cinnamyl and r23 is 1-cinnamyl; the compound of formula (IIa) wherein r22 is 4-fluorobenzyl and r23 is 4-fluorobenzyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is benzyl; the compound of formula (IIa) wherein r22 is allyl and r23 is benzyl; the compound of formula (IIa) wherein r22 is CH2CH═C(CH3)2 and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is 2-naphthylmethyl and r23 is 2-napthylmethyl; the compound of formula (IIa) wherein r22 is n-butyl and r23 is benzyl; the compound of formula (IIa) wherein r22 is allyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is n-butyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is CH2CH═C(CH3)2 and r23 is benzyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is ethyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is 4-pyridinylmethyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 4-pyridinylmethyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is cyclopentylmethyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is cyclopentylmethyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is n-propyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is cinnamyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is cyclopentylmethyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 2-pyridinylmethyl; the compound of formula (IIa) wherein r22 is 3-cyanobenzyl and r23 is 3-cyanobenzyl; the compound of formula (IIa) wherein r22 is allyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is n-propyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is n-butyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is hydrogen and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is 4-pyridinylmethyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is allyl and r23 is cyclopentylmethyl; the compound of formula (IIa) wherein r22 is allyl and r23 is 2-quinolinylmethyl; the compound of formula (IIa) wherein r22 is 3-pyridinylmethyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is 3-pyridinylmethyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is 3-hydroxybenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is vinylbenzyl and r23 is vinylbenzyl; the compound of formula (IIa) wherein r22 is 3-allyloxybenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-pyridinylmethyl and r23 is 3-pyridinylmethyl; the compound of formula (IIa) wherein r22 is 2-naphthylmethyl and r23 is 4-fluorobenzyl; the compound of formula (IIa) wherein r22 is 4-hydroxybenzyl and r23 is 4-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-carbomethoxybenzyl and r23 is 3-carbomethoxybenzyl; the compound of formula (IIa) wherein r22 is 4-hydroxymethylbenzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-formylbenzyl and r23 is 3-formylbenzyl; the compound of formula (IIa) wherein r22 is 4-cyanobenzyl and r23 is 4-cyanobenzyl; the compound of formula (IIa) wherein r22 is 4-formylbenzyl and r23 is 4-formylbenzyl; the compound of formula (IIa) wherein r22 is 4-hydroxybenzyl and r23 is 2-propyl; the compound of formula (IIa) wherein r22 is 3-hydroxybenzyl and r23 is 2-propyl; the compound of formula (IIa) wherein r22 is 3-carboxybenzyl and r23 is 3-carboxybenzyl; the compound of formula (IIa) wherein r22 is 3-formaldoximebenzyl and r23 is 3-formaldoximebenzyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 4-hydroxybenzyl; the compound of formula (IIa) wherein r22 is cyclobutylmethyl and r23 is cyclobutylmethyl; the compound of formula (IIa) wherein r22 is cyclopentylmethyl and r23 is cyclopentylmethyl; the compound of formula (IIa) wherein r22 is 3n-butyl n-butyl and r23 is CH2CH═C(CH3)2; the compound of formula (IIa) wherein r22 is n-butyl and r23 is cyclopentylmethyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is H; the compound of formula (IIa) wherein r22 is 3-fluorobenzyl and r23 is 3-fluorobenzyl; the compound of formula (IIa) wherein r22 is 3-methoxybenzyl and r23 is 3-methoxybenzyl; the compound of formula (IIa) wherein r22 is 3,4-difluorobenzyl and r23 is 3,4-difluorobenzyl; the compound of formula (IIa) wherein r22 is 4-methylbenzyl and r23 is 4-methylbenzyl; the compound of formula (IIa) wherein r22 is 4-chlorobenzyl and r23 is 4-chlorobenzyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 4-fluorobenzyl; the compound of formula (IIa) wherein r22 is 3-chlorobenzyl and r23 is 3-chlorobenzyl; the compound of formula (IIa) wherein r22 is 3-nitrobenzyl and r23 is 3-nitrobenzyl; the compound of formula (IIa) wherein r22 is 3-methylbenzyl and r23 is 3-methylbenzyl; the compound of formula (IIa) wherein r22 is 3-bromobenzyl and r23 is 3-bromobenzyl; the compound of formula (IIa) wherein r22 is 4-fluorobenzyl and r23 is H; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 3-chlorobenzyl; the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 3-aminobenzyl; the compound of formula (IIa) wherein r22 is 4-aminobenzyl and r23 is 4-aminobenzyl; the compound of formula (IIa) wherein r22 is 3-nitrobenzyl and r23 is H; the compound of formula (IIa) wherein r22 is 3-(NHCHO)benzyl and r23 is 3-(NHCHO)benzyl; the compound of formula (IIa) wherein r22 is 3-(NHCOCH3)benzyl and r23 is 3-(NHCOCH3)benzyl; the compound of formula (IIa) wherein r22 is 3,4-dihydroxybenzyl and r23 is 3,4-dihydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-formaldoximebenzyl and r23 is 3-(N-hydroxy)aminomethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(N-hydroxy)aminomethylbenzyl and r23 is 3-(N-hydroxy)aminomethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(CH3OC(═O)O-)benzyl and r23 is 3-(CH3OC(═O)O-)benzyl; the compound of formula (IIa) wherein r22 is 3-(1-hydroxyethyl)benzyl and r23 is 3-(1-hydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(HOCH2CH2N═CH)benzyl and r23 is 3-(HOCH2CH2N═CH)benzyl; the compound of formula (IIa) wherein r22 is 3-(HOCH2CH2N═CH)benzyl and r23 is 3-(2-oxazolidinyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(C6H5CH2NHC(═O)O)benzyl and r23 is 3-(C6H5CH2NHC(═O)O)benzyl; the compound of formula (IIa) wherein r22 is 3-(CH3NHC(═O)O)benzyl and r23 is 3-(CH3NHC(═O)O)benzyl; the compound of formula (IIa) wherein r22 is 3-(HOCH2CC)benzyl and r23 is 3-bromobenzyl; the compound of formula (IIa) wherein r22 is 3-acetylbenzyl and r23 is 3-bromobenzyl; the compound of formula (IIa) wherein r22 is 3-acetylbenzyl and r23 is 3-acetylbenzyl; the compound of formula (IIa) wherein r22 is 3-(CH3C(═NOH))benzyl and r23 is 3-(CH3C(═NOH))benzyl; the compound of formula (IIa) wherein r22 is 3-(1-hydroxyethyl)benzyl and r23 is 3-bromobenzyl; the compound of formula (IIa) wherein r22 is 3-(chloromethyl)benzyl and r23 is 3-(chloromethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(5-tetrazolyl)benzyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is 3-cyanobenzyl and r23 is 3-formylbenzyl; the compound of formula (IIa) wherein r22 is 4-acetoxybenzyl and r23 is 4-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-aminocarbonylbenzyl and r23 is 3-aminocarbonylbenzyl; the compound of formula (IIa) wherein r22 is 3-(H2NCOCH2O)benzyl and r23 is 3-(H2NCOCH2O)benzyl; the compound of formula (IIa) wherein r22 is 3-hydroxybenzyl and r23 is H; the compound of formula (IIa) wherein r22 is 3-methylbenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 2-naphthylmethyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-(H2NNHC(═O))-benzyl and r23 is 3-(H2NNHC(═O))-benzyl; the compound of formula (IIa) wherein r22 is 4-(H2NNHC(═O))-benzyl and r23 is 4-(H2NNHC(═O))-benzyl; the compound of formula (IIa) wherein r22 is 4-hydroxymethylbenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-(H2NC(═O)NHN═CH)-benzyl and r23 is 3-(H2NC(═O)NHN═CH)-benzyl; the compound of formula (IIa) wherein r22 is 3-[(N-methoxy)aminocarbonyl]-benzyl and r23 is 3-[(N-methoxy)aminocarbonyl]-benzyl; the compound of formula (IIa) wherein r22 is 4-[(N-methoxy)aminocarbonyl]-benzyl and r23 is 4-[(N-methoxy)aminocarbonyl]-benzyl; the compound of formula (IIa) wherein r22 is 3-(HOCH2CH(OH)CH2O)benzyl and r23 is 3-(HOCH2CH(OH)CH2O)benzyl; the compound of formula (IIa) wherein r22 is 3-(2-hydroxyethoxy)benzyl and r23 is 3-(2-hydroxyethoxy)benzyl; the compound of formula (IIa) wherein r22 is 3-(1,2-dihydroxyethyl)benzyl and r23 is 4-(1,2-dihydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-aminocarbonylbenzyl and r23 is 3-(H2NC(═NH))benzyl; the compound of formula (IIa) wherein r22 is 4-hydroxybenzyl and r23 is 3-formyl-4-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-carbomethoxybenzyl and r23 is 3-(N-methylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(N-methylaminocarbonyl)benzyl and r23 is 3-(N-methylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 2-naphthylmethyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(1,2-dihydroxyethyl)benzyl and r23 is 3-(1,2-dihydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 4-(1,2-dihydroxyethyl)benzyl and r23 is 4-(1,2-dihydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-(N-methylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 4-hydroxymethylbenzyl and r23 is hydrogen; the compound of formula (IIa) wherein r22 is 3-(boronic acid)benzyl and r23 is 3-(boronic acid)benzyl; the compound of formula (IIa) wherein r22 is 3-nitrobenzyl and r23 is 3-benzyloxybenzyl; the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 3-(N-ethylaminocarbonyl)benzyl and r23 is 3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-carbomethoxybenzyl and r23 is 3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-carbomethoxybenzyl and r23 is 3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 6-hydroxy-1-hexyl and r23 is hydrogen; the compound of formula (IIa) wherein r22 is 6-hydroxy-1-hexyl and r23 is 6-hydroxy-1-hexyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 6-hydroxy-1-hexyl; the compound of formula (IIa) wherein r22 is 5-carboxy-1-pentyl and r23 is 5-carboxy-1-pentyl; the compound of formula (IIa) wherein r22 is 3-iodobenzyl and r23 is 3-iodobenzyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is 2-(hydroxymethyl)-cyclopropylmethyl, the compound of formula (IIa) wherein r22 is 3-(thiomethyl)benzyl and r23 is 3-(thiomethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(methylsulfonyl)benzyl and r23 is 3-(methylsulfonyl)benzyl; the compound of formula (IIa) wherein r22 is 6-hexenyl and r23 is 6-hexenyl; the compound of formula (IIa) wherein r22 is 6-bromo-5-hydroxy-1-hexyl and r23 is 6-bromo-5-hydroxy-1-hexyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 5-hydroxy-1-pentyl; the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(H2NC(═O)NH)benzyl and r23 is 3-(H2NC(═O)NH)benzyl; the compound of formula (IIa) wherein r22 is 3-(N-methylamino)benzyl and r23 is 3-(N-methylamino)benzyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 3-aminobenzyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 3-nitrobenzyl; the compound of formula (IIa) wherein r22 is 3-(N,N-dimethylamino)benzyl and r23 is 3-(N,N-dimethylamino)benzyl; the compound of formula (IIa) wherein r22 is 3-nitrobenzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 3-(CH3NHC(═O)NH)benzyl; the compound of formula (IIa) wherein r22 is 3-(CH3NHC(═O)NH)benzyl and r23 is 3-(CH3NHC(═O)NH)benzyl; the compound of formula (IIa) wherein r22 is 3-(N-methylamino)benzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-((N,N-dimethylaminoglycyl)amino)benzyl and r23 is 3-((N,N-dimethylaminoglycyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 3-((N-methylaminoglycyl)amino)benzyl and r23 is I-((N-methylaminoglycyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 3-((N,N-dimethylaminoglycyl)amino)benzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl and r23 is 3-(N-phenylmethoxycarbonylaminoglycyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 3-(glycylamino)benzyl and r23 is 3-(glycylamino)benzyl; the compound of formula (IIa) wherein r22 is 3-(glycylamino)benzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl and r23 is 3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl and r23 is 3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 3-(L-alanyl)amino)benzyl and r23 is 3-(L-alanyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 3-(L-phenylalanyl)amino)benzyl and r23 is 3-(L-phenylalanyl)amino)benzyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is hydrogen; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is benzyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 6-hydroxy-1-hexyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 3-hydroxybenzyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is (5-methylsulfonyl)-1-pentyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 5-(CH3S(O))-1-pentyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 5-methoxy-1-pentyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 3-cyanobenzyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 3-carboethoxybenzyl; the compound of formula (IIa) wherein r22 is 4-hydroxy-1-hexyl and r23 is 4-hydroxy-1-hexyl; the compound of formula (IIa) wherein r22 is 4-hydroxy-1-hexyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is 4-oxime-1-hexyl and r23 is 4-oxime-1-hexyl; the compound of formula (IIa) wherein r22 is 5-hydroxy-1-pentyl and r23 is 3-hydroxyrethylbenzyl; the compound of formula (IIa) wherein r22 is 6-amino-1-hexyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(N,N-diethylaminocarbonyl)benzyl and r23 is 3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-carbomethoxybenzyl and r23 is 3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-carbomethoxybenzyl and r23 is 3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is hydrogen; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(N-propylaminocarbonyl)benzyl and r23 is 3-(N-propylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(HO2C)benzyl and r23 is 3-(N-isopropylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(HO2C)benzyl and r23 is 3-(N-propylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(HO2C)benzyl and r23 is benzyl; the compound of formula (IIa) wherein r22 is 3-(HO2C)benzyl and r23 is cyclopropylmethyl; the compound of formula (IIa) wherein r22 is 4-hydroxymethylbenzyl and r23 is 3-(HO2C)benzyl; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-pyridinylmethyl; the compound of formula (IIa) wherein r22 is 4-hydroxymethylbenzyl and r23 is 3-aminocarbonylbenzyl; the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 3-aminocarbonylbenzyl; the compound of formula (IIa) wherein r22 is 3-aminocarbonylbenzyl and r23 is hydrogen; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-(N-methylamino)benzyl; the compound of formula (IIa) wherein r22 is 3-methylamino)benzyl and r23 is 2-naphthylmethyl; the compound of formula (IIa) wherein r22 is 4-formylbenzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(1-hydroxy-1-ethyl)benzyl and r23 is 3-(1-hydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-pyridinylmethyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 3-(N-imidazolylmethyl)benzyl and r23 is 3-(N-imidazolylmethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(2,2-dimethyl-1-propionyl)benzyl and r23 is 3-(2,2-dimethyl-1-propionyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl and r23 is 3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(2-imidazolyl-C(═O))benzyl and r23 is 3-(2-imidazolyl-C(═O))benzyl; the compound of formula (IIa) wherein r22 is 3-(3-hydroxy-1-propyn-1-yl)benzyl and r23 is 3-(3-hydroxy-1-propyn-1-yl)benzyl; the compound of formula (IIa) wherein r22 is 3-(2,2,2-trifluoroacetyl)benzyl and r23 is 3-(2,2,2-trifluoroacetyl)benzyl; the compound of formula (IIa) wherein r22 is 3-propionylbenzyl and r23 is 3-propionylbenzyl; the compound of formula (IIa) wherein r22 is 3-(4-pyrazolyl)benzyl and r23 is 3-(4-pyrazolyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(CH3CH2C(═NOH))benzyl and r23 is 3-(CH3CH2C(═N--OH))benzyl; the compound of formula (IIa) wherein r22 is 3-sulfonamidobenzyl and r23 is 3-sulfonamidobenzyl; the compound of formula (IIa) wherein r22 is 3-(CF3CH2C(═NOH))benzyl and r23 is 3-(CF3CH2C(═N--OH))benzyl; the compound of formula (IIa) wherein r22 is 4-fluoromethylbenzyl and r23 is 4-fluoromethylbenzyl; the compound of formula (IIa) wherein r22 is 4-(1-hydroxyethyl)benzyl and r23 is 4-(1-hydroxyethyl)benzyl; the compound of formula (IIa) wherein r22 is 3-(5-methyl-1,2,3-oxadiazolyl)benzyl and r23 is 3-(5-methyl-1,2,3-oxadiazolyl)benzyl; the compound of formula (IIa) wherein r22 3-(H2NC(═NOH)benzyl 3-(H2NC(═NOH))benzyl and r23 is 3-(H2NC(═NOH)benzyl 3-(H2NC(═NOH))benzyl; the compound of formula (IIa) wherein r22 is 3-(H2NC(═NOH)-4-fluorobenzyl 3-(H2NC(═NOH))- the compound of formula (IIa) wherein r22 is 5-benzotriazolylmethyl and r23 is 5-benzotriazolylmethyl; the compound of formula (IIa) wherein r22 is 5-benzimidazolylmethyl and r23 is 5-benzimidazolylmethyl; the compound of formula (IIa) wherein r22 is 5-benzimidazolylmethyl and r23 is 5-benzimidazolylmethyl; the compound of formula (IIa) wherein r22 is 5-benzotriazolylmethyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein r22 is 5-benzotriazolylmethyl and r23 is 3-(3-pyrazolyl)benzyl; the compound of formula (IIa) wherein r22 is 5-indazolylmethyl and r23 is 5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-chloro-5-indazolylmethyl and r23 is 3-chloro-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-methylamino-5-indazolylmethyl and r23 is 3-methylamino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-ethylamino-5-indazolylmethyl and r23 is 3-ethylamino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 6-indazolylmethyl and r23 is 6-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-amino-5-benzisoxazolylmethyl and r23 is 3-amino-5-benzisoxazolylmethyl; the compound of formula (IIa) wherein r22 is 5-(2-aminobenzoxazolyl 5-(
10. A compound of
or a pharmaceutically acceptable salt form thereof wherein:
r4 and r7 are independently selected from: benzyl, methylbenzyl, dimethylbenzyl, ethylbenzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, hydroxybenzyl, thienylmethyl, pyridylmethyl, or naphthylmethyl; r22 and r23 are independently selected from: hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH═C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantyl ethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid, N-hyroxylaminomethylbenzyl N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(═NOH))-benzyl, (H2NNHC(═O))-benzyl, (H2NC(═O)NHN═CH)-benzyl, (CH3ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH3NHC(═O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)benzyl, hydroxyethoxybenzyl(oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl, (pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H2NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl, methoxylpentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(═NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(═NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(═O)O)benzyl, (CH3NHC(═O)O)benzyl, (NH2C(═O)CH2O)benzyl, (NH2C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3C--C(═O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl, 3-aminoindazolylmethyl, 3-aminobenzoxazolylmethyl, aminopyrazolylbenzyl, imidazolylbepzyl imidazolylbenzyl, aminoimidazolylbenzyl. 11. A compound of
or a pharmaceutically acceptable salt form thereof, selected from the group consisting of:
the compound of formula (IIaa) wherein r4 and r7 are isobutyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are isobutyl, r22 and r23 are allyl; the compound of formula (IIaa) wherein r4 is 4-nitrobenzyl, r7 is 2-nitrobenzyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 4-nitrobenzyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 is 4-nitrobenzyl, r7 is 2-nitrobenzyl, r22 and r23 are n-butyl; the compound of formula (IIaa) wherein r4 is 4-aminobenzyl, r7 is 2-aminobenzyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-hydroxybenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 4-hydroxymethylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-aminocarbonylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-acetylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-butyrylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-hydroxymethylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-(CH3C(═N--OH)benzyl; the compound of formula (IIaa) wherein r4 and r7 are 3-methoxybenzyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-(H2NC(═NOH)benzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-fluorobenzyl, r22 and r23 are 3-(H2NC(═NOH)-4-fluorobenzyl; the compound of formula (IIaa) wherein r4 and r7 are 3-methoxybenzyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 3-methoxybenzyl, r22 and r23 are 4-hydroxymethylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 3-methoxybenzyl, r22 and r23 are 3-methoxybenzyl; the compound of formula (IIaa) wherein r4 and r7 are 3-hydroxybenzyl, r22 and r23 are 3-hydroxybenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-methoxybenzyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 4-methoxybenzyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-methoxybenzyl, r22 and r23 are 2-naphthylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 4-methoxybenzyl, r22 and r23 are 4-hydroxymethylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-hydroxybenzyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-methoxybenzyl, r22 and r23 are allyl; the compound of formula (IIaa) wherein r4 and r7 are 4-(2-hydroxyethoxy)benzyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-(2-morpholinylethoxy)benzyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are 3-(H2NC(═O)CH20)benzyl, r22 and r23 are n-butyl; the compound of formula (IIaa) wherein r4 and r7 are 3,4-difluorobenzyl, r22 and r23 are 3-hydroxymethylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 3,4-difluorobenzyl, r22 and r23 are 4-hydroxymethylbenzyl; the compound of formula (IIaa) wherein r4 and r7 are 3,4-difluorobenzyl, r22 and r23 are 3-(H2NC(═O))benzyl; the compound of formula (IIaa) wherein r4 and r7 are 3,4-difluorobenzyl, r22 and r23 are 3-(H2NC(═NOH))benzyl; the compound of formula (IIaa) wherein r4 and r7 are 2-naphthylmethyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are 2-naphthylmethyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 2-thienylmethyl, r22 and r23 are cyclopropylmethyl; the compound of formula (IIaa) wherein r4 and r7 are 2-thienylmethyl, r22 and r23 are 3-(H2NC(═NOH))benzyl; the compound of formula (IIaa) wherein r4 and r7 are 4-methylthiobenzyl, r22 and r23 are benzyl; the compound of formula (IIaa) wherein r4 and r7 are isopropyl, r22 and r23 are n-hexyl; and the compound of formula (IIaa) wherein r4 and r7 are 4-pyridylmethyl, r22 and r23 are benzyl.
12. A compound of
or a pharmaceutically acceptable salt form thereof wherein
r22 and r23 are independently selected from the group consisting of: hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH═C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, mnethoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(═NOH))-benzyl, (H2NNHC(═O))-benzyl, (H2NC(═O)NHN═CH)-benzyl, (CH3ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH3NHC(═O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl(oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl)phenylalanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropyrnyl)benzyl, (imidazolyl--C(═O))-benzyl, (pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H2NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(═NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(═NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N, N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(═O)O)benzyl, (CH3NHC(═O)O)benzyl, (NH2C(═O)CH20)benzyl, (NH2C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3C--C(═O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl, 3-aminoindazolylmethyl, 3-aminobenzoxazolylmethyl, aminopyrazolylbenzyl, imidazolylbenzyl, aminoimidazolylbenzyl. 13. A compound of
or a pharmaceutically acceptable salt form thereof, selected from the group consisting of:
the compound of formula (IIb) wherein r22 is 4hydroxybenzyl and r23 is 4hydroxybenzyl; the compound of formula (IIb) wherein r22 is cyclopentylmethyl and r23 is cyclopentylmethyl; the compound of formula (IIb) wherein r22 is n-butyl and r23 is n-butyl; the compound of formula (IIb) wherein r22 is 3-hydroxybenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IIb) wherein r22 is 3-aminobenzyl and r23 is 3-aminobenzyl; the compound of formula (IIb) wherein r22 is cyclohexylmethyl and r23 is cyclohexylmethyl; the compound of formula (IIb) wherein r22 is cyclobutylmethyl and r23 is cyclobutylmethyl; the compound of formula (IIb) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-hydroxymethylbenzyl; the compound of formula (IIb) wherein r22 is 3-formylbenzyl and r23 is 3-formylbenzyl; the compound of formula (IIb) wherein r22 is 3-formaldoximebenzyl and r23 is 3-formaldoximebenzyl.
14. A compound of
or a pharmaceutically acceptable salt form thereof wherein:
r22 and r23 are independently selected from the group consisting of: hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH═C (CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylmethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═))-benzyl (H2NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(═NOH))-benzyl, (H2NNHC(═O))-benzyl, (H2NC(═O)NHH═CH)-benzyl (H2NC(═O)NHN═CH)-benzyl, (CH3ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH3NHC(═O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl(oxazolindinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl--C(═O))-benzyl, (pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H2NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(═NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(═NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(═O)O)benzyl, (CH3NHC(═O)O)benzyl, (NH2C(═O)CH2O)benzyl, (NH2C(═NH))-benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3C--C(═O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl, 3-aminoindazolylmethyl, 3-aminobenzoxazolylmethyl, aminopyrazolylbenzyl, imidazolylbenzyl, aminoimidazolylbenzyl. 15. A compound of
or a pharmaceutically salt form thereof, selected from the group consisting of:
the compound of formula (Ibb) wherein r22 is benzyl and r23 is hydrogen; the compound of formula (Ibb) wherein r22 is cyclopropylmethyl and r23 is cyclopropylmethyl; the compound of formula (Ibb) wherein r22 is benzyl and r23 is benzyl; the compound of formula (Ibb) wherein r22 is 3-hydroxybenzyl and r23 is 3-hydroxybenzyl; the compound of formula (Ibb) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-hydroxymethylbenzyl; the compound of formula (Ibb) wherein r22 is 4-hydroxybenzyl and r23 is 4-hydroxybenzyl; the compound of formula (Ibb) wherein r22 is 3-methoxybenzyl and r23 is 3-methoxybenzyl; the compound of formula (Ibb) wherein r22 is 3-(H2NC(═NOH))benzyl 3-(H2NC(═NOH))benzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (Ibb) wherein r22 is 3-(H2NC(═NOH))benzyl 3-(H2NC(═NOH))benzyl and r23 3-(H2NC(═NOH))benzyl 3-(H2NC(═NOH))benzyl; and the compound of formula (Ibb) wherein r22 is 3-(H2NC(═NOH))-4-fluorobenzyl 3-(H2NC(═NOH))-
16. A compound of
or a pharmaceutically acceptable salt form thereof wherein:
r22 and r23 are independently selected from the group consisting of: hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH═C(CH3)2, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamanmylethyl adamantylethyl, cyclopropyline thoxybenzyl cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH3C(═NOH))-benzyl, (H2NNHC(═O))-benzyl, (H2NC(═O)NHN═CH)-benzyl, (CH3ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH3NHC(═O))-benzyl, N,N-dimethylaminocarbonylbenzyl, (HOCH2CH(OH)CH2O)-benzyl, hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethlbenzyl N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl, (pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H2NSO2)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H2NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzyl, (CH3CH2C(═NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (CF3C(═NOH))-benzyl, (N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (benzyl-NHC(═O)O)benzyl, (CHBNHC(═O)O)benzyl (CH3NHC(═O)O)benzyl, (NH2C(═O)CH2O)benzyl, (NH2C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl, ((CH3)3C--C(═O))benzyl, (N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, furylmethyl, 3-aminoindazolylmethyl, 3-aminobenzoxazolylmethyl, aminopyrazolylbenzyl, imidazolylbenzyl, aminoimidazolylbenzyl. 17. A compound of
or a pharmaceutically acceptable salt form thereof, selected from the group consisting of:
the compound of formula (IId) wherein r22 is 4-hydroxymethylbenzyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IId) wherein r22 is 3-hydroxybenzyl and r23 is 3-hydroxybenzyl; the compound of formula (IId) wherein r22 is cyclopropylmethyl and r23 is cyclopropylmethyl; the compound of formula (IId) wherein r22 is 2-naphthylmethyl and r23 is 2-naphthylmethyl; the compound of formula (lid) wherein r22 is 4-hydroxybenzyl and r23 is 4-hydroxybenzyl; the compound of formula (IId) wherein r22 is 3-aminobenzyl and r23 is 3-aminobenzyl; the compound of formula (IId) wherein r22 is 3-hydroxymethylbenzyl and r23 is 3-hydroxymethylbenzyl; the compound of formula (IId) wherein r22 is 3-(Me2NCH2C(═O)NH)-benzyl and r23 is 3-(Me2NCH2C(═O)NH)benzyl; the compound of formula (IId) wherein r22 is 3-formaldoximebenzyl and r23 is 3-formaldoximebenzyl; the compound of formula (IId) wherein r22 is 3-(CH3C(═N--OH))-benzyl and r23 is 3-(CH3C═N--OH))-benzyl 3-(CH3C(═N--OH))-benzyl; the compound of formula (IId) wherein r22 is 3-(2-amino-4-thienyl)benzyl and r23 is 3-(2-amino-4-thienyl)benzyl; the compound of formula (IId) wherein r22 is 5-hydroxypentyl and r23 is 5-hydroxypentyl; the compound of formula (IId) wherein r22 is 6-hydroxypentyl and r23 is 6-hydroxypentyl; the compound of formula (IId) wherein r22 is 5-hydroxypentyl and r23 is 2-naphthylmethyl; the compound of formula (IId) wherein r22 is 5-hydroxypentyl and r23 is 4-hydroxymethylbenzyl; the compound of formula (IId) wherein r22 is 5-hydroxypentyl and r23 is 3-hydroxymethylbenzyl.
18. A compound of
or a pharmaceutically acceptable salt form thereof, wherein:
r22 is selected from: cyclopropylmethyl, n-butyl, allyl, benzyl, naphthylmethyl, carboxybenzyl, methoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, (1-hydroxy-2-propyl)benzyl, aminobenzyl, formylbenzyl, cyanobenzyl, 3-methylbutyl, 2-methylpropyl, n-pentyl, 3-N-N-dimethylaminobenzyl, 3,4-methylenedioxybenzyl, pyridinylmethyl, pyridinylethyl, fluorobenzyl, difluorobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC(═O))-benzyl, carbomethoxybenzyl, N,N-dimethylaminobenzyl, carboethoxybenzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylaminobenzyl, N-propylaminobenzyl, N-butylaminobenzyl, acetylbenzyl, (CH3C(═NOH))-benzyl, N-methylaminocarbonylbenzyl, N,N-diethylaminocarbonylbenzyl, N,N-dimethylaminocarbonylbenzyl, (hydroxyl)hexyl, (hydroxyl)pentyl, (methylthio)benzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (CH3CH2NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N, N-di-n-propylaminocarbonylbenzyl, (imidazolyl-C(═O))-benzyl, (pyrazolyl-C(═O))-benzyl, 3-phenylalanylaminobenzyl, 3-(N-methylglycyl)aminobenzyl, 3-(CH3C(═NOH))benzyl, 2-amino-5-benzoxazolylmethyl, 3-amino-5-benzisoxazolylmethyl, 3-methylamino-5-indazolylmethyl, 3-ethylamino-5-indazolylmethyl, 3,4-dihydroxybenzyl, (pyridylmethylaminocarbonyl)benzyl, (oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, acetylaminobenzyl, (CH3CH2C(═NOH))benzyl, (CF3C(═NOH))-benzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, (N,N-diethylaminoethyl)aminocarbonylbenzyl, (4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (NH2C(═NH))benzyl, (imidazolylmethyl)benzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, thiazolylmethyl, thiazolylethyl, furylmethyl, 3-aminoindazolylmethyl, 3-chloroindazolylmethyl, 3-methylaminoindazolylmethyl, 3-ethylaminoindazolylmethyl, 3-methoxyindazolylmethyl, 3-methylindazolylmethyl, 3-ethylindazolylmethyl, 3-methoxycarbonylindazolylmethyl; and r23 r23 is selected from: naphthylmethyl, hydroxymethylbenzyl, (1-hydroxy-2-propyl)benzyl, aminobenzyl, acetylbenzyl, (CH3C(═NOH))-benzyl, (pyrazolyl)benzyl, (CH3CH2C(═NOH))-benzyl, (CF3C(═NOH))-benzyl, (H2NC(═NOH))benzyl, (H2NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, 3-aminoindazolylmethyl, 3-chloroindazolylmethyl, 3-methylaminoindazolylmethyl, 3-ethylaminoindazolylmethyl, 3-methoxyindazolylmethyl, 3-methylindazolylmethyl, 3-ethylindazolylmethyl, or 3-methoxycarbonylindazolylmethyl. 19. A compound of
or a pharmaceutically acceptable salt form thereof, selected from the group consisting of:
the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 3-aminobenzyl; the compound of formula (IIa) wherein r22 is 3-(CH3C(═NOH))benzyl and r23 is 3-(CH3C(═NOH))benzyl; the compound of formula (IIa) wherein r22 is 3-(H2NC(═NOH)-4-fluorobenzyl 3-(H2NC(═NOH))- the compound of formula (IIa) wherein r22 is 3-(H2NC(═NOH)benzyl 3-(H2NC(═NOH))benzyl and r23 is 3-(H2NC(═NOH)benzyl 3-(H2NC(═NOH))benzyl; the compound of formula (IIa) wherein r22 is 3-(3-pyrazolyl)benzyl and r23 is 3-(3-pyrazolyl)benzyl; the compound of formula (IIa) wherein r22 is 5-indazolylmethyl and r23 is 5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-chloro-5-indazolylmethyl and r23 is 3-chloro-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-methylamino-5-indazolylmethyl and r23 is 3-methylamino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-ethylamino-5-indazolylmethyl and r23 is 3-ethylamino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 6-indazolylmethyl and r23 is 6-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-amino-5-indazolylmethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-methoxycarbonyl-5-indazolylmethyl and r23 is 3-methoxycarbonyl-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-cyclopropylmethylaminobenzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(1-hydroxy-2-propyl)benzyl and r23 is 3-(1-hydroxy-2-propyl)benzyl; the compound of formula (IIa) wherein r22 is n-butyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(n-propylamino)benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-[C3H7C(═NOH)]benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 5-indazolylymethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(H2NC(═NOH)-4-fluorobenzyl and r23 is 5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 2-naphthylmethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-aminobenzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(n-butylamino)benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(ethylamino)benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(dimethylamino)benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(2-phenylethylamino)benzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is cyclopropylmethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-thienylmethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-methoxy-5-indazolylmethyl and r23 is 3-methoxy-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-chloro-5-indazolylmethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-methyl-5-indazolylmethyl and r23 is 3-methyl-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-ethyl-5-indazolylmethyl and r23 is 3-ethyl-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-n-butyl-5-indazolylmethyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-methyoxybenzyl and r23 is 3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein r22 is 3-(isopropylamino)benzyl and r23 is 3-amino-5-indazolylmethyl .
20. A compound of
wherein
r4 and r7 are independently selected from the following groups: hydrogen; C1-C3 alkyl substituted with 0-r11 0-3 r11; r5 is --OR20; r6 is hydrogen or --OR21; r20 and r21 are H; r11 is selected from one or more of the following: H; halogen; --OR13; C3-C10 cycloalkyl substituted with 0-2 r12; C1-C4 alkyl substituted with 0-2 r12; aryl(C1-C3 alkyl) substituted with 0-2 r12; aryl substituted with 0-2 r12; or a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 r12; r12, when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(1-morpholino)ethoxy, --CO2H, hydroxamic acid, hydrazide, --C(r14)═N(OR14), cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with --NR13r14, --NR13r14, hydroxy, hydroxymethyl; or r12, when a substituent on nitrogen, is methyl; r13 is H, C1-C4 alkyl, C2-C4 alkenyl, or benzyl; r14 is OH, H, CF3, C1-C4 alkyl, C1-C4 alkoxy, NH2, C2-C4 alkenyl, or benzyl; r13 and r14 can alternatively join to form --(CH2)4--, --(CH2)5--, --CH2CH2N(r15)CH2CH2--, or --CH2CH2OCH2CH2--; r15 is H or CH3; r22 and r23 are independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 r31; C2-C6 alkenyl substituted with 0-3 r31; C2-C4 alkynyl substituted with 0-3 r31; r31 is selected from one or more of the following: halogen, --OR13, C1-C4 alkyl, C3-C10 cycloalkyl, --C(r14)═N(OR14), --CO2r13, --S(O)mr13; aryl substituted with 0-5 r32; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring being substituted with 0-2 r32; r32, when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO2r13, hydroxamic acid, --CONR13NR13r14, cyano, boronic acid, sulfonamide, --CHO, C3-C6 cycloalkoxy, --NR13r14, --C(r14)═N(OR14), NO2, --OR13, --NR40r41, --SOmr13, --SOmNR13r14, --C(═O)NR13r14, --OC(═O)NR13r14, --C(═O)r11, --OC(═O)r11, --OCO2r13, phenyl, --C(═O)NR13-(C1-C4 alkyl)--NR13r14, --C(═O)NR40r41, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C1-C4 haloalkynyl C2-C4 haloalkynyl, --C(═O)NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14; --C(═O)C(r11)2NR13CO2r13; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; or C1-C4 alkoxy substituted with 0-3 groups selected from: r11, C3-C6 cycloalkyl, --C(═O)NR13r14, --NR13r14or OH ; C1-C4 alkyl substituted with 0-3 groups selected from: r11, ═NR14, ═NNR13C(═O)NR13r14 or --NR13r14; C2-C4 alkenyl substituted with 0-3 r11; C2-C4 alkynyl substituted with 0-3 r11; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur substiuted with 0-2 r12; r32 when a substituent on nitrogen is methyl; m is 0, 1, or 2; r40 is selected from: H, C1-C3 alkyl; r41 is selected from: --C(═O)NR13r14; --C(═O)NR13NR14 --C(═O)NR13NR13r14; --C(═O)C(r11)2NR13r14; --C(═O)C(r11)2NR13NR14 --C(═O)C(r11)2NR13NR13r14; --C(═O)C(r11)2NR13CO2r13; --C(═O)H; --C(═O)r11; --C(═O)--(C1-C4 alkyl)-NR13r14; --C(═O)--(C1-C4 alkyl)-NR13CO2r13; or 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus. |
This application is 656)
Using the above-described techniques or variations thereon appreciated by those of skill in the art of chemical synthesis, the compounds of Tables 3-13 (shown below) can also be prepared.
For compounds of the present invention having reduceded water solubility it may be advantageous to prepare prodrugs to enhance the solubility and bioavailability of these compounds. For example, the addition of ionizable groups by derivatization of free hydroxy groups of compounds of formula (I) with bioreversible esters resulted in greatly improved water solubility. Solubility studies were performed by mixing an excess of solid compound in water or aqueous medium for at least 4 hours. Solubility was assessed either visually, if a weighed amount clearly dissolved in a measured volume of solvent (method A), or by HPLC assay of filtrates of saturated solutions (method B). Solubility results are summarized in Table A below.
TABLE A | ||||
Ex. | Solubility | |||
No. | Solvent | Method | (mg/ml) | |
5U | water | B | 0.01 | |
29A | water | B | 2.25 | |
29B | water | A | >100 | |
29C | 0.1M citric acid | A | >20 | |
29D | water | A | >200 | |
For such prodrugs of the present invention to be useful therapeutic agents (assuming that the intact esters have relatively little inherent pharmacologic activity), the ester must be hydrolyzed after dosing to yield the parent hydroxy compound. Compounds 29A-29E are hydrolyzed to parent compound 5U in biological fluids in vitro. This was shown as follows. Plasma was collected from rats, dogs, or human volunteer, and was used within 24 hours. Prodrug was added to plasma, which had been warmed to 37°C C. at concentrations of 2-10 μg/ml. After various times of incubation at 37°C C., the hydrolysis reaction was quenched with the addition of an organic solvent. The organic solvent was used for extraction of 5U, and concentrations of 5U in the plasma aliquots were determined using HPLC after extraction. Concentrations of 5U were thus measured vs. time of incubation of the prodrug in plasma at 37°C C. Similar studies were performed using a homogenate of rat intestinal tissue (10% w/v) as the hydrolysis medium. Results for in vitro hydrolysis of prodrug 29B in dog plasma and rat intestinal homogenate (10% w/v) are given in Table B. Results for in vitro hydrolysis of prodrug 29C in rat, dog and human plasma are given in Table C. Prodrugs 29B, 29C, and 29E were shown to readily convert to parent 5U when exposed to plasma or intestinal enzymes in vitro. The results indicate that these prodrugs will convert to 5U in vivo. Other salt forms of these compounds, such as prodrugs 29A and 29D, will be similar to their free acid or free base forms.
TABLE B | ||
% Converted to 5U | ||
Time | % Converted to 5U | (Rat intestine |
(min) | (Dog plasma) | homogenate) |
0 | 3.4 | 16.0 |
5 | 4.9 | 16.6 |
15 | 5.5 | 22.7 |
60 | 9.3 | 46.0 |
120 | 19.9 | 47.1 |
TABLE B | ||
% Converted to 5U | ||
Time | % Converted to 5U | (Rat intestine |
(min) | (Dog plasma) | homogenate) |
0 | 3.4 | 16.0 |
5 | 4.9 | 16.6 |
15 | 5.5 | 22.7 |
60 | 9.3 | 46.0 |
120 | 19.9 | 47.1 |
Improved water solubility can result in increasing the extent of oral bioavailability. Oral bioavailability studies were performed in fasted beagle dogs. Compounds were dosed orally using a solution vehicle or the solid drug powder filled into hard gelatin capsules. Periodic blood samples were taken from each dog and plasma was separated. Plasma drug concentrations were determined using extraction and HPLC analysis. Generally, after the administration of 5U or its prodrugs 29A-E, the plasma concentrations of 5U were determined, rather than unchanged prodrug concentrations. Oral bioavailability was estimated by comparing the dose-normalized area under the plasma 5U concentration vs. time curve (AUC) after oral dosing with the AUC after intravenous administration of 5U. Oral bioavailability is expressed as the percentage of the oral dose absorbed.
Compound 5U has reduced water soluble, and when administered as the solid powder gave low oral bioavailability. Therefore, in order to attain improved oral bioavailability, 5U was administered using a solution with polyethylene glycol 400 or propylene glycol as the vehicle. However, as the dose of 5U was increased, oral bioavailability was reduced, due to precipitation of 5U from the glycol vehicle upon mixing with the aqueous contents of the gastrointestinal tract. Improved oral bioavailability was attained when the water soluble prodrugs were administered in the solid form, with no added excipients or solvents. One advantage of these water soluble produgs is that they can be formulated in conventional solid oral dosage forms, whereas 5U gave low oral bioavailability when dosed in solid form. The advantage of the water soluble prodrugs is especially clear at high doses. Both prodrugs 29B and 29D yielded good oral bioavailability at relatively high doses, whereas the administration of a similar dose of 5U in a non-aqueous vehicle resulted in relatively poor oral bioavailability.
Prodrug 29E resulted in lower bioavailability then prodrugs 29B-D. Additional assays of the plasma samples for intact ester (total of mono and bis ester) was performed by treating plasma with NaOH to hydrolyze any intact esters. Samples were then extracted again and assayed for 5U concentration. The AUC of intact esters was approximately 2 fold greater than that of 5U. Thus, plasma levels of both intact prodrug and hydrolysis product can be attained using these water soluble prodrugs. The results of the comparison of the oral bioavailability in dogs of 5U and its water soluble prodrugs are shown in Table D.
TABLE D | |||
% Oral | |||
Ex. | Dose | Bioavailability of 5U | |
No. | Excipients | (mg/kg. 5U eq.) | (Mean ± SE) |
5U | glycol | 10-15 | 50 ± 20 |
5U | glycol | 40 | 5 ± 2 |
29B | none | 8 | 29 ± 2 |
28B | none | 27 | 27 ± 6 |
29D | none | 31 | 40 ± 12 |
29E | none | 8 | 12 ± 2 |
The compounds of this invention possess retroviral protease inhibitory activity, in particular, HIV inhibitory efficacy, as evidenced by their activity in the assays, as described below. The compounds of formula (I) possess HIV protease 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 protease inhibitory activity and are effective as inhibitors of HIV growth.
The protease inhibitory activity of the compounds of the present invention is demonstrated using standard assays of protease activity, for example, using the assay described below for assaying inhibitors of HIV protease activity. 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 assays described below. The compounds of the present invention inhibit HIV-protease activity in vivo as demonstrated using the animal models for HIV protease inhibition described below. The compounds of the present invention demonstrate in vivo HIV inhibitory activity, as shown in the animal models described below. The HIV inhibitory activity in the animal models I described below indicates that the presently claims compounds are useful for the treatment of HIV infection in humans.
As discussed above, the compounds provided by this invention are also useful as standards and reagents for use in tests or assays for determining the ability of a potential pharmaceutical to inhibit HIV protease and/or HIV growth, such as the assays described herein below. Thus, the compounds of the present invention may be provided in commercial kits or containers comprising a compound of this invention, for use pharmaceutical research.
Since the compounds of the present invention inhibit HIV growth and infectivity, they may be used as HIV antivirals for the inhibition of HIV in a biological sample which contains HIV or is suspect to contain HIV or to be exposed to HIV.
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.
A compound is considered to be active if it has an IC50 or Ki value of less than about 1 mM for the inhibition of HIV protease or HIV viral growth or infectivity.
HIV Protease Inhibition Assay--Spectroscopic Method
Materials:
Protease: Inclusion bodies of E. coli harboring plasmid containing HIV protease under the control of an inducible T7 promoter were prepared according to Cheng et. al (1990) Gene 87: 243. Inclusion bodies were solubilized in 8M urea, 50 mM tris pH 8∅ Protease activity was recovered by dilution 20-fold into buffer containing 50 mM sodium acetate pH 5.5, 1 mM EDTA, 10% glycerol and 5% ethylene glycol. Enzyme was used at a final concentration of 1.0-10 ug/ml.
Substrate: Peptide of sequence: Ala-Thr-His-Gln-Val-Tyr-Phe(NO2)-Val-Arg-Lys-Ala, containing p-nitrophenylalanine (Phe(NO2)), was prepared by solid phase peptide synthesis as previously described by Cheng et al. (1990) Proc. Natl. Acad. Sci. USA 87: 9660. Stock solutions of 10 mM were prepared in DMSO.
Inhibitory compounds were dissolved in sufficient DMSO to make 2.5 or 25 mM stock solutions. All further dilutions were done in DMSO.
Reactions:
Compound (1-5 uL) and HIV protease were mixed in buffer containing 50 mM MES, pH 6.5, 1 M NaCl, 1 mM EDTA, 1 mM dithiothreitol, 10% glycerol. Reactions were initiated by the addition of peptide substrate to a final concentration of 240 uM, and absorbance at 300 nM monitored for 10 min. Values of Ki for inhibitor binding were determined from percent activity measurements in the presence and absence of known concentration of inhibitor, using a value of 0.07 mM for the Km of the substrate (Cheng et al. (1990) Proc. Natl. Acad. Sci USA 87: 9660).
The HIV-1 protease inhibitory activity of representative compounds of the invention is shown in Table 1 and 2.
HIV Protease Inhibition Assay--HPLC Method
Materials:
Protease: Inclusion bodies of E. coli harboring plasmid containing plasmid T1718R with a synthetic gene coding for a single-chain tethered dimer of HIV protease were prepared as described in Cheng et al. (Proc. Natl. Acad. Sci. USA, 87, 9660-9664, 1990). Active protease was prepared as described therein by extraction with 67% acetic acid, dilution 33-fold with water, dialysis against water and then against a "refolding buffer" consisting of 20 mM MES, 1 mM dithiothreitol and 10% glycerol. Protease was stored as a stock preparation at 10 uM in refolding buffer.
Substrate: Peptide of sequence: aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr-Phe(NO2)-Val-Arg-Lys-Ala containing p-nitrophenylalanine, was prepared by solid phase synthesis as previously described Cheng et al., op.cit. Stock solutions of 2 mM substrate were prepared in DMSO.
Inhibitory compounds were dissolved in sufficient DMSO to make 3 mM stock solutions. All further dilutions were prepared in "assay buffer": 1M NaCl, 50 mM MES, pH 5.5, 1 mM EDTA, 1 mM DTT, 20T glycerol.
Reactions:
Enzyme reaction: In a 2 ml screw-cap centrifuge tube were added 50 ul protease (final concentration 0.25 nM) and 0.1 ml inhibitory compound (final concentration 0.1-12, 500). After 15 min preincubation at room temperature, the reaction was started with the addition of 0.05 ml substrate (final concentration 5 uM). Incubation was carried out at 30 C. for 1 hr. The reaction was stopped with 1 ml 0.1M ammonium hydroxide.
HPLC measurement of product formation: The product (aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr) was separated from substrate on a Pharmacia MonoQ anion exchange column. The injection volume was 0.2 ml. The mobile phases were: A (20 mM trisHCl, pH 9.0, 0.02% sodium Azide, 10% acetonitrile), B (20 mM tris HCl, pH 9.0, 0.02% sodium azide, 0.5M ammonium formate, 10% acetonitrile). The mobile phases were pumped at 1 ml/min, with a gradient from 0 to 30% B in 5 min, 100% B for 4 min to wash the column, and a re-equilibration for 4 min. The retention time of the product was 3.6 min. Detection with a Shimadzu model RF535 fluorescence monitor was at 330 nm (excitation) and 430 (emission). The Ki was calculated from the formula Ki=I/(((kM+S-FA*S)/(FA*Km))-1) where I=inhibitory concentration, S=substrate concentration, FA=fractional activity=cm peak height with inhibitor/cm peak height without inhibitor, and Km=Michaelis constant=20 uM.
HIV RNA Assay
DNA Plasmids and in vitro RNA transcripts:
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 C. The concentration of RNA was determined from the A260.
Probes:
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 0.5μM stocks in 2× SSC (0.3M NaCl, 0.03M sodium citrate), 0.05M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 10 μM stocks in water.
Streptavidin coated plates:
Nunc-immunomodule microtiter plate strips were coated by addition of 200 μL of streptavidin (30 ug/mL, Scripps, La Jolla, Calif.) in freshly prepared 10 mM sodium carbonate (pH 9.6). Plates were incubated overnight at 4°C C. Streptavidin solution was aspirated from the wells and a blocking buffer composed of phosphate buffered saline (PBS), 20 mg/mL bovine serum albumin (crystalline, nuclease and protease free, Calbiochem) and 100 mg/mL lactose (Sigma) was added to the plates for 3 hrs at room temperature. Blocking buffer was removed from the wells, which were allowed to dry overnight at room temperature and subsequently stored at 4°C C. in zip lock bags with desiccant. For the majority of the compound evaluation experiments, streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).
Cells and virus stocks:
MT-2, CEM, and H9 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS), 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. Laboratory strains of HIV-1 (RF, MN and IIIB) were propagated in H9 cells in the same medium. Virus stocks were prepared approximately 1 month after acute infection of H9 cells by clarification of the tissue culture medium and storage of aliquots at -70°C 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. In some cases, infected H9 cells were shifted to Dulbecco's modified Eagle's medium 3-10 days before collection of virus in order to generate virus stocks in medium with low biotin content. Clinical isolates of HIV that had been passaged once in MT-2 cells were used to infect fresh MT-2 cells in RPMI medium. Three days after infection, cells were pelleted, resuspended and culture continued in Dulbecco's modified Eagle's medium as above. Virus stocks of clinical isolates were prepaid 10-15 days after infection when cytopathic effects were apparent in the culture.
For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells wee resuspended at 5×105 cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×106/mL in either Dulbecco's modified Eagles medium, or RPMI 1640 medium minus biotin (Gibco, custom formulation) with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37°C C. In some experiments, virus was removed after an initial adsorption period.
Preparation of HIV-1 infected cell lysates:
HIV-1 infected cells were pelleted by centrifugation. After removal of the supernatant the cells were resuspended at a concentration of 1×107 cells/mL in 5M guanidinium isothiocyanate solution (GED: 5M guanidinium isothiocyanate (Sigma), 0.1M EDTA, 10% dextran sulfate). Alternately, cells grown in biotin free tissue culture medium were mixed with 5M GED to a final concentration of 3M guanidinium isothiocyanate, 0.06M EDTA and 6% dextran sulfate.
HIV RNA assay:
Cell lysates or purified RNA in 3M or 5M GED were mixed with 5M GED and capture probe to a final guanidinium isothiocyanate concentration of 3M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed microfuge tubes or in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37°C C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1M 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), 0.051% 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 ×100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37°C 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 (2.5M 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 C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.
Microplate based compound evaluation in HIV-1 infected MT-2 cells:
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, MT2 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 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.
After 3 days of culture at 37°C 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 5M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3M 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 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.
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 IC50 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 protease inhibitor should be less than 10% of the level achieved in an uninhibited infection.
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.
The HIV inhibitory activity of representative compounds of the present invention in the RNA assay described above is shown in TABLE 3. The IC90 values in TABLE 3 were determined using the assay conditions described above under HIV RNA Assay. The IC90 values are indicated as follows: +++=<10 ug/mL; ++=10 to 100 ug/mL; +=>100 ug/mL. The ++/+ is used in the cases where an IC90 was determined to be >50 ug/mL.
HIV Yield Reduction Cell Assay
Materials: MT-2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin. Human immunodeficiency virus strains, HIV (3B) and HIV(RF) were propagated in H-9 cells in RPMI with 5% FCS. Poly-L-lysine (Sigma) coated cell culture plates were prepared according to the method of Harada et al. (1985) Science 229: 563-566.MTT, 3-(4,5-dimethyl-thiazol-2yl)-2, 5-diphenyltetrazolium bromide, was obtained from Sigma.
Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/mL and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5×105/mL) in 2.3 mL were mixed with 0.3 ml of the appropriate test compound solution and allowed to sit for 30 minutes at room temperature. HIV (3B) or HIV (RF) (-5×105 plaque forming units/mL) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36°C C. The mixtures were centrifuged at 1000 rpm for 10 minutes and the supernatants containing unattached virus were discarded. The cell pellets were suspended in fresh RPMI containing the appropriate concentrations of test compound and placed in a 36°C C, 4% CO2 incubator. Virus was allowed to replicate for 3 days. Cultures were centrifuged for 10 minutes at 1000 rpm and the supernatants containing cell free progeny virus were removed for plaque assay.
The virus titers of the progeny virus produced in the presence or absence of test compounds were determined by plaque assay. Progeny virus suspensions were serially diluted in RPMI and 1.0 mL of each dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36°C C. to allow for efficient attachment of the virus to cells. Each virus and cell mixture was aliquoted equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 36°C C., 4% CO2. liquid and unattached cells were removed prior to the addition of 1.5 mL of RPMI with 0.75% (w/v) Seaplaque agarose (FMC Corp.) and 5% FCS. Plates were incubated for 3 days and a second RPMI/agarose overlay was added. After an additional 3 days at 36°C C. 4% CO2, a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and 1 mg MTT/mL was added. The plates were incubated overnight at 36°C C. Clear plaques on a purple background were counted and the number of plaque forming units of virus was calculated for each sample. The antiviral activity of test compounds was determined by the percent reduction in the virus titer with respect to virus grown in the absence of any inhibitors.
HIV Low Multiplicity Assay
Materials: MT-2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin (GIBCO). Human immunodeficiency virus strains HIV (3B) and HIV (RF) were propagated in H-9 cells in RPMI with 5% FCS. XTT, benzene-sulfonic acid, 3,3'-[1-[(phenylamino) carbonyl]-3,4-tetrazolium]bis (4-methoxy-6nitro)-, sodium salt, was obtained from Starks Associates, Inc.
Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/ml and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5×104/0.1 mL) were added to each well of a 96 well culture plate and 0.02 mL of the appropriate test compound solution was added to the cells such that each compound concentration was present in two wells. The cells and compounds were allowed to sit for 30 minutes at room temperature. HIV(3B) or HIV(RF) (-5×105 plaque foaming units/mL) was diluted in medium and added to the cell and compound mixtures to give a multiplicity of infection of 0.01 plaque forming unit/cell. The mixtures were incubated for 7 days at 36°C C., during which time the virus replicated and caused the death of unprotected cells. The percentage of cells protected from virus induced cell death was determined by the degree of metabolism of the tetrazolium dye, XTT. In living cells, XTT was metabolized to a colored formazan product which was quantitated spectrophotometrically at 450 nm. The amount of colored formazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC50) or 90% (IC90) with respect to an uninfected cell culture was determined.
The HIV inhibitory activity of representative compounds of the present invention in the whole cell infectivity assay described above is shown in Table E.
TABLE E | ||
Example Number | IC90 | |
1C | + + + | |
1X | + + + | |
1Z | + + + | |
1AC | + + + | |
1AF | + + + | |
1AH | + + + | |
1AQ | + + + | |
The IC90 values in Table 2 are indicated as: +++=<10 ug/mL.
In the Tables herein the Ki values were determined using the assay conditions described above under HIV Protease Inhibition Assay. The Ki values are indicated as follows: +++=<10 nM; ++=10 nM to 1 μM; +=>1 μM.
In the Tables herein the IC90 values were determined using the assay conditions described above under HIV RNA Assay. The IC90 values are indicated as follows: +++=<10 μg/mL; ++=10 to 100 μg/mL; +=>100 μg/mL. The ++/+ is used in the cases where an IC90 was determined to be >50 μg/mL.
The HIV inhibitory activity of the presently claimed compounds in an animal was demonstrated in an animal model wherein HIV-1 infected human CEM lymphcyte cells were xenotransplanted in nude mice and the growth of HIV in vivo in such xenotransplanted CEM cells was monitored. The in vivo assay using this model consisted of testing compound in a prophylactic manner, whereby the daily dose of agent was administered to a group of mice one day prior to HIV challenge. The test and control animals were followed with drug for a period of 25 days. Upon the experiment termination and animal sacrifice, serum p24 antigen levels, and relative percent indirect immunofluorescence assay (IFA) positive cell numbers were determined as the experimental endpoint (as described below).
Cell Line and HIV Culture: CCRF-CEM or CEM, a well characterized tumorigenic and HIV permissive cell line, was obtained from the American Type Culture Collection, Rockville, Md. (AYCC CCL 119) and maintained in RPMI 1640 medium with 15% heat inactivated fetal calf serum and 50 μg/ml gentamicin as described by Wetherall (In: Schellekens and Horzinek, eds., Animal Models in AIDS, Elsevier, Amsterdam, 1990, pp 291-302). The cells were propagated at 37°C C. in a humid 5% CO2 atmosphere. Stocks of the HIV-1 isolate HTLV-IIIB were acquired from Dr. Neal T. Wetherall, Vanderbilt University, and were harvested from cultures of chronically-infected CCRF-CEM (CEM) cells obtained from the American Type Culture Collection. For routine propagation, virus containing culture fluids were clarified of cells by low speed centrifugation and passed through 0.45 μm filters. Infectious visions were quantitated on MT-2 cells in microculture using cytopathic effect (CPE) as the end point for infection. (Scudiero et al., Cancer Res. 1988, 48, 4827-4833). The 50% tissue culture infectious dose (TCID50) was calculated by the method of Reed and Muench (Amer J. Hygiene, 1938, 27, 493-497). CCRF-CEM cells used for virus xenotransplantation were acutely infected with a stock dilution of HIV-1 at a MOI (input multiplicity of infection) of 0.01 followed by adsorption for 1 h at 37°C C.
Animals and Cell/HIV Transplantation: Sprague Dawley 21±2 day old female nude (nu/nu) mice were exposed to 450 Rad's of 137Cs irradiation. Twenty-four hours later, the drug dosing was started. CEM cell cultures, both HIV infected or uninfected, were harvested and washed with serum free media and reharvested. Cells of a specified number were suspended in 0.2 ml media and injected subcutaneously (s.c.) into the intrascapular region of the mice, 24 h after drug dosing commenced. The mice were observed the following day and at least three times a week for the duration of the experiment. At each of these time points the animal group weight is determined, and the inoculation site is gently palpated to determine the date of gross tumor onset. At the termination of an experiment, the animals were anesthesized and euthanized by exsanguination.
p24 Enzyme Immunoassay: The p24 enzyme immunoassay (EIA) used was the unmodified procedure commercially available from Coulter Corporation (Hialeah, Fla.), which uses a murine monoclonal antibody to the HIV core protein coated onto microwell strips. The assay detects p24 gag antigen in culture supernatants, plasma, and serum. Non-specific cross reactions with mouse serum are not seen with this assay.
Indirect Immunofluorescence Assay (IFA): HIV-1 antigen-expressing cells are detected by IFA using the method described by Montefiori and Mitchell (Virology 1986, 155, 726-731). Slides were prepared by air drying and fixing in a 50:50 mixture of acetone/methanol for 30 minutes, followed by adding a 1:200 dilution in PBS-BSA (phosphate buffered saline containing 0.1% globin-free bovine serum albumin) of high-titer serum from pooled HIV-1 positive individuals (positive by Western immunoblot for all HIV-1 antigens).
Anti-HIV IgG then will be detected using a 1:200 dilution of fluorescein-conjugated, IgG fraction of goat anti-human IgG (heavy and light chains specific, Cappel) containing Evan's blue counter stain. Slides were mounted using 50% glycerol and cells examined for fluorescence using a Zeiss KF-2 Epi-fluorescence microscope.
Preparation and Administration of Compounds: Compounds were mixed with 0.25% (wt/v) methylcellulose solution, warmed to 37°C C. and homogenized One drop of Tween 80 was added to the stock suspension (1 drop/10-20 ml) and mixed by vortexing. Dilutions of the stock suspension were made in methylcellulose/Tween 80 and stored at 4 ,C for no more than one week. The suspensions were gently warmed and vortexed after removal from the refrigerator and prior to injection to ensure proper suspension. The compounds were administered BID, i.p. at doses of 30, 100, and 300 mg/kg or 60, 200, and 600 mg/kg/day.
The HIV inhibitory activity in vivo in the HIV/CEM mouse xenotransplant animal model for a representative compound of the invention is shown in Table F below. Data in the p24 EIA and IFA is expressed as a percent of the control untreated levels.
TABLE F | |||
Compound | Dose | p24 E1A | IFA |
Ex. 5I | 300 mg/kg bid | 37.8 | 51.5 |
ip | |||
Ex. 5I | 100 mg/kg bid | 76.4 | 111.3 |
ip | |||
Ex. 5I | 30 mg/kg bid | 61.5 | 116.7 |
ip | |||
The in vivo HIV protease inhibitory activity of the presently claimed compounds was also demonstrated using a transgenic animal model system wherein the HIV-1 protease protein was expressed in the mouse lens using a transgene where the HIV-1 protease coding sequence was placed under the transcriptional control of the mouse alpha A-crystallin promoter. Such transgenic animals were found to display a HIV protease-mediated cataract phenotype. The HIV protease inhibitory activity of the presently claimed compounds was measured in this animal system as a delay or prevention of the onset of cataract appearance in the test animals.
Plasmid Construction: The mammalian expression vector pMSG (Pharmacia) was modified by replacing the MMTV LTR promoter with the 412-bp Bgl II-BamHI mouse alpha A-cryatallin promoter fragment (Chepelinsky et al. Proc. Natl. Acad. Sci. USA, 1985, 82, 2334-2338). The SV40 early splice and polyadenylation signals were retained and this plasmid was renamed pCSV 19. A single chain, tethered dimeric form of the active HIV-1 protease gene (BAA; Cheng et al., Proc. Natl. Acad. Sci. USA, 1990, 87, 9660-9664 and Cheng et al., Gene, 1990, 87, 243-248) was modified for mammalian cell expression by replacing nucleotides 7 to 90 with CGTAATAGAAGGAGATATAACCATGGAG. The gene was cut with EcoRI and Hind III and after blunt-end repair cloned into the Sma I site of the pCSV 19, thus producing PCSV 19-BAA. The mutant form of the construct (BA*A*) was produced by site directed mutagenesis (GAT to GGT) resulting in the change of aspartic acid (25th residue) to glycine in both monomers resulting in an inactive form of the protease.
Construction of Transgenic Mice: 2.5 kb Hind III fragments from the pCSV 19-BAA and pCSV 19-BA*A* plasmids were isolated (modified from Sambrook at al., Molecular Cloning, A Laboratory Manual, 2nd Ed., 1989, Cold Spring Harbor Laboratory) and used for the construction of transgenic mice using the pronuclei injection method (Hogan et al., Manipulating the Mouse Embryo. A Laboratory Manual, 1986, Cold Spring Harbor Laboratory). Mice were screened for the HIV-1 protease transgene by either Southern blot or Polymerase Chain Reaction (PCR) methods. Mice of the FVB/N strain (Taketo et al., Proc. Natl. Acad Sci. USA, 1991, 88, 2065-2069) were used for the construction and breeding of these transgenic mice, and were originally obtained from Dr. Carl Hansen (NIH) and bred in our facility. Subsequently, the mice were purchased from Charles River Laboratory (Portage, Mich.).
Identification of Transgenic Mice: Southern blot analysis (Sambrook et al. vide supra) was performed on DNA purified from tail biopsies (Hogan et al. vide supra) using the 2.5 kb Hind III fragment from pCSV 19-BAA as the probe (32P labeled). DNA for PCR was prepared from tail biopsies by overnight digestion with 0.5 mg of Proteinase K (Boehringer-Manheim GmbH) in 100 μl of water and 0.025% SDS. PCR primers specific for the mouse c-fos gene and and the transgene's SV40 segment were used as an internal control in some samples. Each PCR reaction contained 1-2 μl of tail digest, 60 μg of each primer, 200 μM of Perkin Elmer Cetus dATP, dCTP, dGTP,TTP (buffered at pH 8.8) and up to 5 units of Perkin Elmer Cetus Ampli/Taq polymerase. The reactions were run on a Perkin Elmer DNA Thermal Cycler as follows: 1 min at 94°C C., 3 min at 67°C C. (2 sec extension/cycle) for 35 cycles. The PCR products were analyzed by gel electrophoresis (1% agarose,0.5 μg/ml of ethidium bromide), and tail samples with a 625 PCR fragment (SV40 specific) were considered positive for the transgene. Mice bearing the active HIV-1 protease transgene were also identified by their cataract phenotype. Progeny of homozygous parent(s) were 100% positive for the transgene and did not require Southern/PCR analysis.
Dosing Regimen: Compounds to be tested were pulverized by manual grinding with mortar and pestle. Just prior to dosing of mice, the compound was suspended in 0.25% methylcellulose/Tween 80 solution, homogenized in a manual Dounce homogenizer and sonicated for 10 min in a sonicating water bath. The volume of suspension was adjusted so that the amount of compound required for dosing one mouse was 0.1-0.2 mL. In order to maintain the required mg/kg dose, an average mouse weight for each group was determined twice a week and the amount of compound adjusted accordingly. Intraperitoneal (ip) and oral (po) dosing was performed using 25 G ⅝ in. injection and 20 G 1½ in. feeding needles, respectively. The dosing was performed twice a day (bid) and the doses were administered 6-8 h apart. Eyes of control and dosed animals were examined daily by up to 3 individuals, and the day when cataracts became visible to the naked eye was recorded as the experimental end point (days after birth). Because cataracts do not always develop in both eyes of individual mice on the same day, each eye was scored as an independent observation. Results from individual eyes were used to calculate the average (mean) day of cataract development and its standard deviation for each group.
Eye Histology: Eyes were dissected from euthanized mice and fixed with 10% neutral buffered formalin. Eye histology was performed at the Experimental Pathology Laboratories (EPL), Inc., Sterling, Va.
Characterization of HIV-1 Protease Transgenic Mice:
Gross appearance: Three lines of mice with the active (BAA) and three lines with the mutant (BA*A*) form of HIV-1 protease gene were established. The eyes of mice with the mutant gene appear identical to those of normal mice (FIG. 1A), but bilateral cataracts develop in the eyes of mice with the active gene. This phenotype is easily detected even by an untried observer because the inside of cataract eye is opaque and white/gray in color (FIG. 1B). Cataracts appear similar in all transgenic lines.
Time of cataract development: The time when cataract develops varies among the three transgenic lines bearing the active HIV-1 protease gene (BAA, Appendix 2). Mice of the Tg 61 line develop the phenotype prenatally (day 18 in utero). Mice of the remaining two lines (Tg 62, and 72) develop the cataracts postnatally (at 24-30 days). Among the mice of each individual line, the time difference in cataract development is less than one week. None of the mice bearing the mutant form of the gene (BA*A*) have developed cataract. Based on this genetic evidence that cataracts develop only in transgenic mice with the active but not inactive form of HIV-1 protease we conclude this phenotype is caused by the protease's enzymatic activity.
Method:
A single homozygous male mouse (Tg 72-110) was mated with three non-transgenic FVB/N females. From each litter, 4-5 mice were used as controls, i.e., were dosed with vehicle only (ip or po route). The remaining mice of each litter (5-7) were dosed (ip or po) with test compound. When mice were 15 days old, dosing began in two groups of 5 mice each with ip injections of 100 mg/kg/BID. The compound was administered ip to the mice in the first group until all had bilateral cataracts. For the second group, the compound was administered ip for 5 days only and from day 20 via the po route until cataracts appeared. A third group (7 mice) was dosed ip starting on day 15 but with 400 mg/kg/bid. On day 41, when no cataracts had yet developed in this last group, three were removed from treatment, and the remaining four were dosed until day 52. All mice were observed daily for cataract formation.
The results for representative compounds of the present invention in the above HIV-1 transgenic mouse model are shown in Table G below. The results show that the representative compounds of the present invention effectively inhibit HIV protease activity in vivo.
TABLE G | ||||
Cataract | Delay in | |||
Density | Cataract | |||
(% of | (relative to | |||
Ex. No. | Dose/Route | Mouse | control) | control) |
1AQ | 60 mg/kg ip | Tg 61 | 46.6 | |
preg days 11-18 | ||||
1AQ | 85 mg/kg ip | Tg 61 | 20.6 | |
preg days 11-18; | ||||
17-18 | ||||
1X | 15 mg/kg ip | Tg 61 | 28.8 | |
preg days 11-18 | ||||
1X | 5 mg/kg ip | Tg 61 | 39.8 | |
preg days 11-18 | ||||
5I | 80 mg/kg bid | Tg 72 | 6 days | |
ip days 15-19/ | ||||
po days 20 & ff | ||||
51 | 50 mg/kg bid | Tg 72 | 3.6 days | |
ip days 15-20/ | ||||
po days 21 & ff | ||||
5U | 100 mg/kg bid ip | Tg 72 | 5 days | |
5U | 400 mg/kg bid ip | Tg 72 | 45 days | |
days 15-42 | ||||
The antiviral compounds of this invention can be administered as treatment for retroviral infections by any means that produces contact of the active agent with the agent's site of action, the retroviral protease, 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 generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The compounds of the present invention can be administered in oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pins, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present invention may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed for the inhibition of HIV and the treatment of HIV infection.
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.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses may range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
The compounds for the present invention may also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (compositions suitable for administration contain from about 1 milligram to about 100 milligrams of active ingredient per dosage 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 dosage forms.
Gelatin capsules may 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 forms for oral administration can contain coloring and flavoring to increase patient acceptance.
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, Mack Publishing Company, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable
A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension:
An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 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 mL of vanillin.
The compounds of formula (I) of the present invention may be administered in combination with a second therapeutic agent, such as a second HIV inhibitory agent or other therapeutic agent for treatment of HIV associated disease conditions. The compound of formula (I) and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above. The compound of formula (I) may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of formula (I) and the second therapeutic agent are not formulated together in a single dosage unit, the compound of formula (I) and the second therapeutic agent may be administered essentially at the same time, or in any order, for example the compound of formula (I) may be administered first, followed by administration of the second agent. When not administered at the same time, preferably the administration of the compound of formula (I) and the second therapeutic agent occurs less than about one hour apart, more preferably less than about 5 to 30 minutes apart.
The present invention also includes pharmaceutical kits useful, for example, for the treatment of HIV infection, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed 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.
In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.
The Tables below provide representative compounds of formula (I) of the present invention. Specifically incorporated herein by reference is the disclosure of PCT International Application Publication Number WO 93/07128, including Examples Number 1-5763, which are listed in Tables 3-12 of such reference.
Tables 2A through 2C and 2d through 2q below set forth representative compounds of the present invention.
TABLE 2A | ||||||
Example | ||||||
Number | R22 | R23 | MS (M + H) | Ki | IC90 | m.p. (°C C.) |
2A | CH2CHC(CH3)2 | CH2CHC(CH3)2 | 463 | +++ | +++ | 165.1 |
2B | CH2CH2CH2C6H5 | CH2CH2CH2C6H5 | 563 | ++ | +++ | 120.7 |
2C | CH2CHCH2 | CH2CHC(CH3)2 | 435 | +++ | +++ | 62 |
2D | CH2CHC(CH3)2 | CH3 | 409 | ++ | sin 65 | |
108 | ||||||
2E | CH2C6H4-p-F | CH2C6H4-p-F | 543 | +++ | +++ | |
2F | CH2C6H5 | 471 | +++ | +++ | ||
2G | CH2CHCH2 | CH2C6H5 | 457 | +++ | +++ | 226.5 |
2H | CH2C6H5 | CH3 | 431 | ++ | +++ | 81 |
2I | CH2CHC(CH3)2 | 440 | +++ | +++ | 76 | |
2J | CH2C6H4-m-OCF3 | CH2C6H4-m-OCF3 | 675 | ++ | +++ | 128.3 |
2K | CH2C6H5-m-CF3-p-F | CH2C6H5-m-CF3-p-F | 679 | ++ | +++ | 167.2 |
2L | CH2C6H4-p-OCF3 | CH2C6H4-p-OCF3 | 675 | ++ | +++ | 136.8 |
2M | CH2C6H3-m-F-m-CF3 | CH2C6H3-m-F-m-CF3 | 679 | ++ | 162.3 | |
TABLE 2A | ||||||
Example | ||||||
Number | R22 | R23 | MS (M + H) | Ki | IC90 | m.p. (°C C.) |
2A | CH2CHC(CH3)2 | CH2CHC(CH3)2 | 463 | +++ | +++ | 165.1 |
2B | CH2CH2CH2C6H5 | CH2CH2CH2C6H5 | 563 | ++ | +++ | 120.7 |
2C | CH2CHCH2 | CH2CHC(CH3)2 | 435 | +++ | +++ | 62 |
2D | CH2CHC(CH3)2 | CH3 | 409 | ++ | sin 65 | |
108 | ||||||
2E | CH2C6H4-p-F | CH2C6H4-p-F | 543 | +++ | +++ | |
2F | CH2C6H5 | 471 | +++ | +++ | ||
2G | CH2CHCH2 | CH2C6H5 | 457 | +++ | +++ | 226.5 |
2H | CH2C6H5 | CH3 | 431 | ++ | +++ | 81 |
2I | CH2CHC(CH3)2 | 440 | +++ | +++ | 76 | |
2J | CH2C6H4-m-OCF3 | CH2C6H4-m-OCF3 | 675 | ++ | +++ | 128.3 |
2K | CH2C6H5-m-CF3-p-F | CH2C6H5-m-CF3-p-F | 679 | ++ | +++ | 167.2 |
2L | CH2C6H4-p-OCF3 | CH2C6H4-p-OCF3 | 675 | ++ | +++ | 136.8 |
2M | CH2C6H3-m-F-m-CF3 | CH2C6H3-m-F-m-CF3 | 679 | ++ | 162.3 | |
TABLE 2C | ||||||||
Example | Mass Spec | |||||||
Number | Stereoisomer | R22 | R23 | Ki | IC90 | MP (°C C.) | M + 1 (%) | Notes |
3L | RSSR | CH2C≡CH | CH2C≡CH | ++ | ++ | 196-197 | 507 | |
3M | RSSR | 2-picolinyl | 2-picolinyl | ++ | ++ | 151-153 | 509 | |
3N | RSSR | CH2CH2OCH3 | CH2CH2OCH3 | ++ | + | 183-185 | 443 | |
3O | RSSR | CH2C6H12 | CH2C6H12 | ++ | + | -- | 519 | |
3P | RSSR | CH2CH2C(CH3)3 | CH2CH2C(CH3)3 | ++ | + | 242-245 | 495 | |
3Q | RSSR | CH2C6H9 | CH2C6H9 | |||||
3R | RSSR | CH2CH2OCH2CH3 | CH2CH2OCH2CH3 | + | + | 148-150 | 471 | |
3S | RSSR | 3-methyl-5- | H | ++ | + | -- | 464 | |
oxazolinyl-methyl | ||||||||
3T | RSSR | 1-naphthylmethyl | 1-naphthylmethyl | ++ | + | 231-233 | 607 (85%) | |
3U | RSSR | 2-naphthylmethyl | 2-naphthylmethyl | +++ | +++ | 202-204 | 607 | |
3V | RSSR | n-butyl | benzyl | +++ | +++ | 89-91 | 473 | |
3W | RSSR | CH2CH═CH2 | cyclopropylmethyl | +++ | +++ | 173-175 | 421 | |
3X | RSSR | n-butyl | cyclopropylmethyl | +++ | +++ | -- | 437 | |
3Y | RSSR | CH2CH═C(CH3)2 | benzyl | +++ | +++ | 173-174 | 485 | |
3Z | RSSR | 3-methyloxoy- | 3-methyloxoy- | + | -- | 527 | ||
olinylmethyl | olinylmethyl | |||||||
4A | RSSR | benzyl | ethyl | +++ | +++ | 190-193 | 445 | |
4B | RSSR | benzyl | 4-picolinyl | +++ | +++ | -- | 508 | |
4C | RSSR | cyclopropylmethyl | 4-picolinyl | +++ | +++ | -- | 472 | |
4D | RSSR | CH2CH2OCH═CH2 | CH2CH2OCH═CH2 | ++ | -- | 467 | ||
4E | RSSR | benzyl | cyclopentylmethyl | +++ | +++ | 198-200 | 499 | |
4F | RSSR | cyclopropylmethyl | cyclopentylmethyl | +++ | +++ | -- | 463 | |
4G | RSSR | benzyl | n-propyl | +++ | +++ | -- | 459 | |
4H | RSSR | benzyl-(D7) | benzyl-(D7) | +++ | +++ | -- | 521 | |
4I | RSSR | cyclopropylmethyl | cinnamyl | +++ | +++ | -- | 497 | |
4J | RSSR | 2,3,4,5,6-penta- | 2,3,4,5,6-penta- | + | +++ | 193-195 | 687 | |
fluoro-benzyl | fluoro-benzyl | |||||||
4K | RSSR | cyclopropylmethyl | 2-naphthylmethyl | +++ | +++ | 175-178 | 521 | |
4L | RSSR | cyclopentylmethyl | 2-naphthylmethyl | +++ | +++ | 89-92 | 549 | |
4M | RSSR | benzyl | 2-naphthylmethyl | +++ | +++ | 90-92 | 557 | |
4N | RSSR | cyclopropylmethyl | 2-picolinyl | +++ | +++ | 220-222 | 472 | |
4O | RSSR | benzyl | 2-quinolinylmethyl | ++ | +++ | -- | 558 | |
4P | RSSR | 3-cyanobenzyl | 3-cyanobenzyl | +++ | +++ | 225-227 | 557 | |
4Q | RSSR | 3-benzyloxybenzyl | 3-benzyloxybenzyl | ++ | +++ | 140-141 | 691 | |
4R | RSSR | 4-phenylbenzyl | 4-phenylbenzyl | ++ | 109-110 | 659 | ||
4S | RSSR | 3-allyl | 2-naphthylmethyl | +++ | +++ | 72-74 | 507 | |
4T | RSSR | n-propyl | 2-naphthylmethyl | +++ | +++ | 150-152 | 509 | |
4U | RSSR | n-butyl | 2-naphthylmethyl | +++ | +++ | 78-80 | 523 | |
4V | RSSR | H | 2-naphthylmethyl | +++ | +++ | 210-213 | 467 | |
4W | RSSR | 2-adamantylethyl | 2-adamantylethyl | ++ | 292-294 | 651 | ||
4X | RSSR | H | cyclopropylmethyl | ++ | 189-190 | 381 | ||
4Y | RSSR | 2-picolinyl | 2-naphthylmethyl | ++ | +++ | 165-166 | 558 | |
4Z | RSSR | 4-picolinyl | 2-naphthylmethyl | +++ | +++ | 118-121 | 558 | |
5A | RSSR | 3-allyl | H | + | 180-182 | 367 | ||
5B | RSSR | 3-allyl | cyclopentylmethyl | +++ | +++ | 190-191 | 449 | |
5C | RSSR | 3-allyl | 2-picolinyl | ++ | +++ | 160-162 | 458 | |
5D | RSSR | 3-allyl | 2-quinolinylmethyl | +++ | +++ | 145-146 | 507 | |
5E | RSSR | 3-allyl | 4-picolinyl | ++ | +++ | 458 | ||
5F | RSSR | 3-benzyloxybenzyl | 3-benzyloxybenzyl | ++ | 165-166 | |||
5G | RSSR | 3-picolinyl | cyclopropylmethyl | +++ | +++ | 193-195 | 472 | |
5H | RSSR | 3-picolinyl | 2-naphthylmethyl | +++ | +++ | 94-96 | 558 | |
5I | RSSR | 3-hydroxybenzyl | 3-hydroxybenzyl | +++ | +++ | 101-103 | 539 | |
5J | RSSR | vinylbenzyl | vinylbenzyl | +++ | +++ | 158-160 | 559 | |
5K | RSSR | 3-cyclopropyl- | 3-cyclopropyl- | + | 170-172 | 697 | ||
methoxy-benzyl | methoxy-benzyl | |||||||
5L | RSSR | 3-allyloxybenzyl | 3-allyloxybenzyl | +++ | + | 170-172 | 619 | |
5M | RSSR | 3-allyloxybenzyl | 3-hydroxybenzyl | +++ | +++ | 78-79 | 579 | |
5N | RSSR | 3-ethoxybenzyl | 3-ethoxybenzyl | ++ | + | 185-186 | 595 | |
5O | RSSR | 3-picolinyl | 3-picolinyl | +++ | +++ | -- | 509 | |
5P | RSSR | 4-benzyoxybenzyl | 4-benzyoxybenzyl | + | + | 80-81 | 719 | |
5Q | RSSR | 2-naphthylmethyl- | 4-fluorobenzyl | +++ | +++ | 105-107 | 575 | |
5R | RSSR | 4-hydroxybenzyl | 4-hydroxybenzyl | +++ | +++ | 115-117 | 539 (20%) | |
5S | RSSR | 3-hydroxymethyl- | 3-hydroxymethyl- | +++ | +++ | 94-95 | 567 (40%) | |
benzyl | benzyl | |||||||
5T | RSSR | 3-carbomethoxy- | 3-carbomethoxy- | +++ | +++ | -- | 623 (40%) | |
benzyl | benzyl | |||||||
5U | RSSR | 4-hydroxy- | 4-hydroxy- | +++ | +++ | 190-195 | 567 | |
methylbenzyl | methylbenzyl | |||||||
5V | RSSR | 3-formylbenzyl | 3-formylbenzyl | +++ | +++ | 175-176 | 563 (30%) | |
5W | RSSR | 4-cyanobenzyl | 4-cyanobenzyl | +++ | +++ | 140-143 | 557 (15%) | |
5X | RSSR | 4-formylbenzyl | 4-formylbenzyl | +++ | +++ | 90-91 | 563 (52%) | |
5Y | RSSR | 4-hydroxybenzyl | 2-propyl | +++ | +++ | 246-248 | 475 (80%) | |
5Z | RSSR | 3-hydroxybenzyl | 2-propyl | +++ | +++ | 212-213 | 475 (90%) | |
6A | RSSR | 3-carboxybenzyl | 3-carboxybenzyl | +++ | +++ | 190-195 | 189 | |
6B | RSSR | 4-carboxybenzyl | 4-carboxybenzyl | ++ | ++ | 210-211 | 189 | |
6C | RSSR | 3-formaldoxime- | 3-formaldoxime- | +++ | +++ | 185-189 | 593 (2%) | |
benzyl | benzyl | |||||||
6D | RSSR | cyclopropylmethyl | 3-hydroxybenzyl | +++ | +++ | 233-234 | 486 | |
6E | RSSR | cyclopropylmethyl | 4-hydroxybenzyl | +++ | +++ | 234-236 | 486 | |
6F | RSSR | 5-chloro-2- | 5-chloro-2- | ++ | +++ | 587 | ||
thienyl-methyl | thienyl-methyl | |||||||
6G | RSSR | cyclobutylmethyl | cyclobutylmethyl | +++ | +++ | 463 | ||
6H | RSSR | cyclopentylmethyl | cyclopentylmethyl | +++ | +++ | 491 | ||
6I | RSSR | n-butyl | CH2CH═C(CH3)2 | +++ | +++ | |||
6J | RSSR | n-butyl | cyclopentylmethyl | +++ | +++ | 465 | ||
6K | RSSR | 2-quinolinyl- | 2-quinolinyl- | ++ | + | 609 | ||
methyl | methyl | |||||||
6L | RSSR | 2-propyl | 2-picolinyl | ++ | +++ | 460 | 1 | |
6M | RSSR | p-CH3OC6H4CH2-- | p-CH3OC6H4CH2-- | ++ | +++ | 567.29 | 1 | |
6N | RSSR | (CH3)2NCH2CH2-- | (CH3)2NCH2CH2-- | + | + | 469.32 | 1 | |
6o | RSSR | benzyl | H | +++ | +++ | 417.22 | 1 | |
6P | RSSR | o-F--C6H4CH2-- | o-F--C6H4CH2-- | ++ | +++ | 543.25 | 1 | |
6Q | RSSR | m-CH3O--C6H4CH2-- | m-CH3O--C6H4CH2-- | +++ | +++ | 567.29 | 1 | |
6R | RSSR | (CH3)2NCH2CH2-- | (CH3)2NCH2CH2-- | + | + | 468.62 | 1 | |
6S | RSSR | m,p-F2--C6H4CH2-- | m,p-F2--C6H4CH2-- | +++ | +++ | 579.23 | 1 | |
6T | RSSR | p-CH3--C6H4CH2-- | p-CH3--C6H4CH2-- | +++ | +++ | 535.30 | 1 | |
6U | RSSR | p-Cl--C6H4CH2-- | p-Cl--C6H4CH2-- | +++ | +++ | 575.19 (35Cl) | 1 | |
6V | RSSR | p-F--C6H4CH2-- | +++ | +++ | 183.4 | 489.26 | 1a | |
6W | RSSR | p-CF3--C6H4CH2-- | p-CF3--C6H4CH2-- | ++ | + | 643.24 | 1 | |
6X | RSSR | m-Cl--C6H4CH2 | m-Cl--C6H4CH2 | +++ | +++ | 210.3 | 575.19 (35Cl) | 1 |
6Y | RSSR | m-CF3--C6H4CH2 | m-CF3--C6H4CH2 | ++ | + | 643.24 | 1 | |
6Z | RSSR | M-NO2--C6H4CH2-- | m-NO2--C6H4CH2-- | +++ | +++ | 248.3 | 597.23 | 1 |
6ZA | RSSR | m-CH3--C6H4CH2-- | m-CH3--C6H4CH2-- | +++ | +++ | 535.30 | 1 | |
6ZB | RSSR | o-CH3O--C6H4CH2-- | o-CH3O--C6H4CH2-- | + | ++ | 567.29 | 1 | |
6ZC | RSSR | m,m-F2--C6H4CH2-- | m,m-F2--C6H4CH2-- | ++ | ++ | 167.9 | 579.23 | 1 |
6ZD | RSSR | o-Cl--C6H4CH2-- | o-Cl--C6H4CH2-- | ++ | +++ | 575.56 (35Cl) | 1 | |
6ZE | RSSR | m-Br--C6H4CH2-- | m-Br--C6H4CH2-- | +++ | +++ | 210.7 | 665.00 | 1 |
6ZF | RSSR | p-F--C6H4CH2-- | H | +++ | +++ | 188.9 | 435.21 | 1 |
6ZG | RSSR | p-Br--C6H4CH2-- | p-Br--C6H4CH2-- | ++ | +++ | 663.09 (79Br) | 1 | |
6ZH | RSSR | m-Cl--C6H4CH2-- | +++ | +++ | 126.0 | 505.23 (35Cl) | 1 | |
6ZI | RSSR | m-NH2C6H4CH2--(HCl) | m-NH2C6H4CH2--(HCl) | +++ | +++ | 537.29 | 2 | |
6ZJ | RSSR | m,m-Cl2--C6H4CH2-- | m,m-Cl2--C6H4CH2-- | ++ | ++ | 231.1 | 642.10 (35Cl) | |
6ZK | RSSR | m-(NH2CH2)-- | m-(NH2CH2)-- | ++ | ++ | 565.32 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
6ZL | RSSR | m-NO2C6H4CH2-- | H | +++ | +++ | 462.20 | ||
6ZM | RSSR | m-(NHCHO)--C6H4CH2-- | m-(NHCHO)--C6H4CH2-- | +++ | +++ | 593.28 | 3 | |
6ZN | RSSR | m-(NHCOCH3)-- | m-(NHCOCH3)-- | +++ | +++ | 621.31 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
6ZQ | RSSR | m,p-(HO)2--C6H4CH2-- | m,p-(HO)2--C6H4CH2-- | +++ | +++ | 571.24 | ||
6ZP | RSSR | + | ++ | 667.34 | ||||
# Upon successful alkylation, liberation of the desired functional group would take place based on the aforementioned reference. | ||||||||
Synthesis of compounds of the invention in Table 2d is described in further detail below.
To a solution of bis m-(HO--N═CH)--C6H4CH2 cyclic urea (0.297, 0.502 mmol) in methanol (5 ml) was added borane-pyridine complex (0.464 g, 5.02 mmol) at -10°C C. and the resultant mixture was stirred for 15 minutes. After treated with 4M HCl in dioxane (5 ml), the reaction mixture was allowed to stir to room temperature for additional 1.5 hours. The solution was neutralized with sat. NaHCO3 to pH=8, washed with water and dried over MgSO4. After removal of solvents, the residue was purified on silica gel plate with ethyl acetate: dichloromethane: methanol (50:50:2) to give 60 mg of a solid, M.P. 214°C-216°C C. 1H NMR (CD3OD): δ8.03(s, 1H), 7.46-7.06 (m, 18H), 4.74 (d, J=13.9 Hz, 1H), 4.73 (d J=13.9Hz, 1H), 3.92 (S, 2H), 3.62-3.59 (bs, 4H), 3.07-2.91(m, 6H) 13C NMR (CD3OD): 163.88, 149.70, 141.26, 141.23, 139.92, 139.39, 138.73, 134.91, 131.50, 131.41, 130.64, 130.00 129.72, 129.64, 129.57, 129.53, 128.47, 127.45 127.42, 127.31, 71.96, 71.92, 67.42, 67.11, 58.65, 57.09, 57.03, 33.62, 33.57, MS: 594 (100%) 595 (M+H, 60%).
To a stirred solution of bis m-(HO--N═CH)--C6H4CH2 cyclic urea (257 mg, 0.434 mmol), sodium cyanoborohydride (290 mg, 4.6 mmol) and trace amount of methyl orange in methanol (10 ml) at room temperature was added dropwise 2N HCl at a rate sufficient to maintain a pH of 3-4 over 3 hours. The methanol was removed by rotary evaporation. The residue was purified on a reverse phase TLC plate with 90% methanol in water to give the product. 1H NMR (CD3OD): δ7.33-7.09 (m, 18H), 4.75 (d, J=13.9Hz, 2H), 3.93 (s, 4H), 3.61-3.56 (m, 4H), 3.06-2.94 (m, 6H); 13C NMR (CD3OD): 162.42, 139.72, 137.88, 137.79, 129.92, 129.20, 128.31, 128.14, 128.06, 126.02, 70.36, 65.49, 57.40, 55.59, 32.09.
A solution of Example 9C (30 mg) in methanol was treated with 4M HCl in dioxane at room temperature. All solvents were removed under vacuum to give hydroxylamine hydrochloride. 1H NMR (CD3OD): δ7.44-7.23 (m, 14H), 6.99 (d, J=6.2Hz, 4H), 4.65 (d, J=14.3 Hz,2H), 4.35(S, 4H), 3.70-3.66 (m, 4H), 3.12-3.05 (m, 4H), 2.89-2.85 (m, 2H); 13C NMR(CD3OD): δ163.68, 141.13, 140.39, 123.09, 132.03, 131.06, 130.59, 130.50, 129.59, 127.48, 71.82, 68.23, 57.40, 56.12, 33.70.
An unpurified sample of example 9C was purified on TLC plate using acetic acid: ethyl acetate: dichloromethane (5:50:45) to give the acetic acid salt. 1H NMR (CD3OD): δ7.35-7.08 (m, 18H), 4.74 (d, J=13.9Hz, 2H), 3.97(s, 4H), 3.62-3.53(m, 4H), 3.06-2.88 (m, 6H), 1.97 (s, 6H).
A solution of bis (m-CHO--C6H4CH2) cyclic urea (119 mg, 0.212 mml) and O-benzylhydroxylamine hydrochloride (203 mg, 1.27 mmol) in pyridine/ethanol (6 ml 1:1) was refluxed for 3 hours. After removal of solvent, the residue was purified on T.L.C. plate with 15% ethyl acetate in dichloromethane to give the product (164 mg) as a solid, M.P. 170.5°C-171°C C. 1H NMR(CDCl3): δ8.01 (s, 2H), 7.39-7.07 (m, 28H), 5.09 (s, 4H), 4.81 (d, J=14.3Hz, 2H), 3.59 (bs, 2H), 3.52 (d, J=11.0Hz, 2H), 3.07-2.89 (m, 8H); 13C NMR(CDCl3): 162.14, 148.55, 139.40, 138.62, 137.39, 132.50, 130.50, 129.43, 128.87, 138.62, 128.35, 128.27, 128.87, 127.57, 126.56, 126.46, 76.34, 71.32, 64.55, 55.57, 32.70; MS 790 (M+NH4, 100%).
By the procedure given above Example 9C, a solution of Example 9D (60 mg, 0.078 mmol), sodium cyanoborohydride (70 mg, 1.1 mml), trace amounts of methyl orange mn methanol was treated with 2N HCl (approx. 0.5 ml). Purification on T.L.C. plate with 40% ethyl acetate in methylene chloride gave the product (30 mg). 1H NMR (CDCl3):δ8.05 (s,1H), 7.43-7.06 (m, 28H), 5.13 (s, 2H), 4.90 (d, J=14.3Hz, 1H), 4.87(d, J=14.3Hz, 1H), 4.61(s, 2H), 3.98 (s, 2H), 3.59-3.49 (m, 4H), 3.07-2.95 (m, 6H). 13C NMR(CDCl3): δ161.98, 148.59, 139.48, 138.86, 138.32, 138.05, 137.74 137.48, 132.56 130.61, 129.87, 129.51, 128.91, 128.67, 128.65, 128.44, 128.37, 128.11, 127.91, 127.86, 127.66, 126.59, 126.56, 126.40, 77.20, 76.41, 76.15, 71.52, 71.48, 64.33, 64.11, 56.26, 55.58, 55.57, 33.79, 32.47. MS: 792 (M+NH4, 40%) 775 (M+H, 100%).
To a suspension solution of bis (m-(HO)--C6H4CH2) cyclic urea (280 mg, 0.52 mmol) and Cs2CO3 (1.5 g, 4.6 mmol) in THF (4 ml) was added methylchloroformate (122.9 mg, 1.3 mm) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered through celite and concentrated to give a residue which was purified on T.L.C. plate with 15% ethyl acetate in methylene chloride to give the product (220 mg). as a solid, M.P. 146°C-147°C C. 1H NMR (CD3OD): δ7.34-6.95 (m, 18 m), 4.78 (d.J=14.3Hz, 2H), 3.78 (s. 6H), 3.68 (bs, 2H), 3.61 (d, J=11.4Hz, 2H), 3.10-2.83 (m, 6H). 13C NMR (CD3OD): 162.22, 154.08, 151.28 139.74, 129.28, 129.14 128.11, 126.52, 125.99, 121.63, 119.85, 70.44, 66.14, 55.46, 54.51, 32.22; MS: 655 (M+H, 100%).
A solution of Example 9P (50 mg, 0.085) in methanol (2 ml) was treated with sodium borohydride (32 mg, 0.85 mmol) at room temperature overnight. After removing the solvent, the mixture is purified on T.L.C. plate with EtOAc/CH2Cl2 (1:1) to give a good yield of the desired product (two stereoisomers) : MS=612 (M+NH4+, 100%); HRMS: 595.3177 for C37H43N2O5 (M+H); 1NMR (CD3OD): δ7.36-7.06 (M, 18H), 4.82 (d, J=6.3 Hz, 1H) 4.78 (d, J=6.6Hz, 1H), 4.77 (d, J=13.9Hz, 2H), 3.64-3.57 (m, 4H), 2.10-2.92 (m, 6Hz), 1.41 (d,J=6.6Hz, 3H), 1.40 (d,J=6.3Hz, 3H); 13C NMR (CD3OD): δ163.93, 148.07, 141.33, 139.36, 130.69, 129.59, 129.55, 127.62, 127.59, 126.01, 125.90, 72.04, 70.60, 70.56, 67.30, 67.05, 57.27, 57.12, 33.66, 25.55.
To a solution of Example 9S (100 mg) in tetrahydrofuran (1 ml) was added methyl amine (0.4 ml, 40% in water) and the resulting solution was stirred overnight. After concentration and purification on the plate, the product was obtained in good yield. 1H NMR (CD3OD) δ7.40 (m, 18H) 4.69 (d, J=14.3Hz, 2H) 3.93 (s, 4H) 3.66-3.64 (m, 4H) 3.35-3.02 (m, 4H) 2.90-2.81 (m, 2H) 2.52 (s,6H); 13CNMR(CD3OD) δ163.75, 141.31, 140.86, 139.58, 130.70, 130.64, 129.79, 129.51, 129.33, 128.86, 127.41, 71.91, 67.55, 57.22, 56.21, 35.51, 33.63.
By the procedure described previously for preparation of Example 9D, and substituting b-ethanolamine and trace amounts of molecular sieves (powder) in ethanol. The reaction mixture was filtered through Celite and concentrated to give a residue, which was purified on reverse phrase T.L.C. plate with 90% methanol in water to the desired compounds.
1H NMR (CD3OD):δ8.31 (s, 2H), 7.67 (d, J=7.7Hz, 2H), 7.59 (s, 2H), 7.43-7.03 (m, 14H), 4.74 (d, J=14Hz, 2H), 3.81-3.58 (m, 12H), 3.10-2.86 (m, 6H); 13C NMR (CD3OD): 164.97, 163.73, 141.22, 140.14 137.66, 133.06, 130.65, 130.53, 130.06, 129.56, 128.50, 127.46, 71.93, 67.90, 64.26, 62.29, 57.20, 33.68, MS: 649 (M+H, 100%).
1H NMR (CD3OD): δ8.31 (s,1H), 7.68-7.03 (m, 18H), 5.33 (s, 1H), 4.76 (d, J=13.9Hz, 1H), 4.75 (d, J=14.3Hz, 1H), 3.81-3.55 (m, 10H), 3.12-2.7 (m, 8H); 13C NMR (CD3OD): 164,97, 163.78, 141.29, 141.24, 140.18, 139.39, 137.63, 133.06, 130.67, 130.64, 130.53, 130.48, 130.05, 129.55, 129.50, 128.86, 128.49, 127.47, 127.45, 127.20, 104.35, 71.98, 67.90, 67.40, 64.25 62.39, 57.22, 57.11, 53.23, 33.67; M.S.: 649 (M+H, 100%).
To a solution of Example 5I (0.7 g, 1.3 mmol) and triethylamine (0.263 g, 2.6 mmol) in THF (5 ml) was added benzyl isocyanate (0.346 g, 2.6 mmol) and the resulting solution was stirred at room temperature overnight. After removal of all the volatiles, the residue was purified on T.L.C. plate to give 0.7 g of a solid, M.P. 150°C C. (decompose). 1H NMR (CD3OD): δ7.33-6.83 (m, 28H), 4.74 (d, J=13.9Hz, 2H), 4.30 (s, 4H), 3.64-3,57 (m, 4H), 3.13-2.91 (m, 6H); 13C NMR (CD3OD): 162.54, 155.68, 151.33, 139.88, 139.30, 138.64, 129.29, 129.20, 128.24, 128.18, 127.02, 126.90, 126.13, 125.81, 122.44, 120.55, 70.44, 65.28, 55.20, 44.31, 32.28; M.S: 805 (M+H, 100%).
To a solution of Example 5I (100 mg, 0.186 mmol) triethylamine (38 mg. 0.39 mmol) in THF (1 ml) was added methyl isocyanate (27 mg. 0.47 mmol) at room temperature and the resulting mixture was stirred overnight. After removal of all volatile reagents, a residue was purified on T.L.C. plate with 40% ethyl acetate in dichloromehane to give 51 mgs of a solid, M.P. 150°C C. (decompose). 1H NMR (CD3OD) δ7.44-6.99 (m, 18H), 4.82 (d, J=14.2Hz, 2H), 3.69-3.65 (m, 4H), 3.15-2.95 (m, 6H), 2.84 (s, 6H). 13C NMR (CD3OD): 163.96, 157.56, 152.92, 141.31 140.83, 130.66, 130.55, 129.58, 127.46, 127.17, 123.70, 121.95, 71.88, 67.02, 56.67, 33.65, 27.57. M.S.: 670 (M+NH, 100%).
A solution of bis (m-bromobenzyl) cyclic urea (MEM-protected) (0.84 g, 1 mmol), propargyl alcohol (0.224 g, mmol), tetrakis (triphenylphoshine) palladium (0.116 g, 0.1 mmol), copper iodide (0.019 g, 0.1 mmol) in triethylamine (5 ml) was refluxed under nitrogen overnight. After evaporation of all volatiles, a residue was diluted with ether (20 ml) and filtered through Celite. The filtrate was concentrated and purified on T.L.C. plate to give 400 mg of MEM-protected-mono/coupling product. Deprotection of 170 mg of the coupled product by the standard procedure gave 130 mg of the desired product. 1H NMR (CD3OD): δ7.50-7.09 (m, 18H), 4.72 (d, J=13.9Hz, 1H), 4.69 (d, J=13.4Hz, 1H), 4.46 (s, 2H), 3.75-3.68 (m, 4H), 3.18-2.86 (m, 6H). 13C NMR (CD3OD): 163.61, 141.99, 141.07, 139.73, 133.64, 133.54, 131.91, 131.76, 131.47, 130.57, 130.50, 129.81, 129.59, 129.19, 127.51, 124.69, 123.46, 89.28, 85.09, 71.93, 71.91, 68.12, 67.75, 57.07, 57.03, 51.15, 33.60, 33.59;; M.S.: 639/641 (M+H, 100%), 656/658 (M+NH4, 100%).
A solution of bis (m-Br-C6H4CH2) cyclic urea (425, mg, 0.64 mmol), 1-ethoxy-1-trimethylstannyl ethylene (833 mg, 3.84 mmol) and Pd(PPh3)4 (37 mg, 0.032 mmol) in THF (5 ml) was refluxed under N2 overnight. After cooling to room temperature, the reaction mixture was diluted with ether (10 ml) and filtered through silica gel to give two products. Further purification on T.L.C. plate with 20% ethyl acetate in methylene chloride gave Example 9O (107 mg, M.P. 190°C-191°C C.) and Example 9P (225 mg, M.P. 158°C-159°C C.).
1H NMR (CDCl3): δ7.78 (d, J=7.3Hz, 1H), 7.71 (s, 1H), 7.42-7.02 (m, 16H), 4.81 (d, J=13.9Hz, 1H), 4.77 (d, J=13.9H, 1H), 3.71 (bs, 2H), 3.62-3.54 (m, 2H), 3.20-2.85(m, 8H), 2.50 (s, 3H); 13C NMR (CDCl3): 198.27, 161.86, 140.38, 139.29, 139.22, 138.81, 137.22, 133.99, 132.36, 130.65, 130.09, 129.36, 129.32, 128.99, 128.86, 128.66, 127.70, 127.55, 126.61, 122.53, 71.38, 65.24, 65.12, 55.83, 55.59, 32.77, 26.58, M.S: 644/646 (M+NH4, 100%).
1H NMR (CDCl3): δ7.78-7.03 (m, 18H), 4.83 (d, J=14.3Hz, 2H), 3.73-3.62 (m, 4H), 3.17-3.08 (m, 4H), 2.92-2.89 (m, 2H), 2.49 (s, 6H); 13C NMR (CDCl3): 198.03, 161.83, 139.40, 138.78, 137.12, 133.87, 129.29, 129.04, 128.74, 128.52, 127.36, 126.46, 71.25, 71.15, 65.32, 55.82, 30.73, 26.51; M.S.: 608 (M+NH4, 100%).
A solution of Example 9P (84 mg, 0.142 mmol) and hydroxylamine hydrochloride (59.4 mg, 0. 854 mmol) in pyridine/ethanol (6 ml, 1:1) was refluxed overnight. Evaporation of all solvents under vacuum gave a residue which was purified on preparative T.L.C. plates with ethyl acetate: methylene chloride: methanol (50:50:2) to give 71 mg of a solid, M.P. 200°C-202°C C. 1H NMR (CD3OD): δ7.67-7.07 (m, 18H), 4.74 (d, J=13.9Hz, 2H), 3.64-3.62 (m, 4H), 3.09-2.89 (m, 6H), 2.17 (s, 6H); 13C NMR(CD3OD): 163.94, 155.43, 141.23, 139.46, 138.97, 130.77, 130.65, 129.69, 129.37, 128.10, 127.47, 126.32, 72.02, 67.16, 57.08, 33.62, 11.96; M.S.: 621, (M+H, 100%).
A solution of Example 9O (50 mg, 0.066 mmol) in methanol (2 ml) was treated with sodium borohydride (25 mg, 0.66 mmol). After the reactions was completed, the mixture was washed with hydrochloric acid(2N), water and dried with magnesium sulfate. Concentration gave a residue which was purified to give a good yield of the desired product: MS 629.2015 for C31H38N2OrBr; 1H NMR (CD3OD); δ7.42-7.01 (m, 18H), 4.79-4.60 (m, 3H), 3.65-3.58 (m, 4H), 3.08-2.78 (m, 6H), 1.40-1.37 (m, 3H); 13CNMR (CD3OD): δ163.73, 148.11, 142.08, 141.19, 139.26, 133.64, 131.75, 131.45, 130.61, 129.62, 129.57, 129.19, 129.15, 127.61, 127.49, 127.17, 126.05, 123.46, 72.06, 71.92, 70.59, 68.20, 6.27, 57.12, 57.04, 53.68, 25.55.
Prepared according to the general alkylation and deprotection procedures (see procedure 5) MS: 603.2163 (M+H+), 100%); HR Mass Spec: 603.2163 for C35H37N2O3Cl2 (M+H); 1HNMR (CD3OD) 57.39,-7.02 (m, 18H), 4.68 (d,J=14.3 H2, 2H), 4.55 (S, 4H), 3.65-3.59 (m, 4H), 3.09(d, 3.04 (m, 2H), 3.00 (d,J=14.3 H2, 2H), 2.93-2.84 (m, 2H), 13HNMR (CD3OD, ppm): 162.26, 139.74, 138.47, 138.16, 139.35, 129.16, 128.82, 128.48, 128.09, 127.38, 125.97, 70.47, 66.14, 55.69, 45.19, 32.20.
A solution of Example 9S (100 mg., 0.166 mmol) in tetrahydrofuran (1 ml) was treated with methyl amine (40% in H2O, 1 ml) and the resulting solution was stirred at room temperature overnight. After the solution was concentrated on a rotary evaporator, the residue was obtained and was purified on Prep. T.L.C. to give a good yield of a neutral product which was acidified with 4M HCl in ether to give the desired product. MS: 593 (M+H+, 100%); HRMS: 593.2483 for C37H45N4O3; 1H NMR (CD3OD) δ7.38-7.07 (m, 18H), 4.69 (d, J=14.3 Hz, 2H), 3.93 (S, 4H), 3.66-3.64 (m, 4H), 3.09-3.02 (m, 4H), 2.90-2.81 (m, 2H), 2.52 (S, 6H); 13CNMR (CD3OD, ppm) 163.75, 141.30, 140.85, 139.58, 130.70, 130.64, 129.79, 129.51, 129.32, 128.85, 127.41, 71.91, 67.55, 57.22, 56.21, 35.50, 33.63.
To a suspension of Nail (240 mg, 60% in mineral oil, 6 mmol) in DMF (4 mL) was added MEM-protected Example 11N (694 mg. 0.98 mmol), and 3-chloromethylpyridine (492 mg., 3 mmol); and the resulting mixture was stirred at room temperature overnight. After the reaction mixture was filtered through Buchner funnel, the filtrate was treated with 4M HCl in dioxane(15 ml) for 16 hours and then was neutralized with sat. NaHCO3, to pH=7. After general workup, the resulting crude was purified on T.L.C. plate using ethyl acetate to give the product in a good yield. MS: 538 (M+H+, 100%); HRMS 538.2693 for C33H36O4N3 13C NMR (CD3OD) ppm 163.67, 151.07, 149.16, 141.11, 139.33, 135.91, 130.59, 130.51, 130.48, 129.62, 128.53, 138.24, 127.51, 127.47, 135.28, 71.96. 71.80, 68.68, 66.98, 64.81, 56.71, 55.10, 33.73, 33.66.
To a solution of Example 9S (100 mg, 0.166 mmol) in DMF (2 ml) was added K2CO3 (138 mg, 1.0 mmol) and diethylamine hydrochloride (80 mg, 1.0 mmol) and the resulting mixture was stirred for 24 hrs. The mixture was diluted with EtOAc and washed with water. After the organic layer was dried over MgSO4, the solution was concentrated under vacuum to give 70 mg. of the product. MS: 677 (M+H, 100%); HRMS: 677.4444 for C43H57N4O3; 1H NMR (CDCl3): δ7.26-6.96 (m, 18H), 4.84 (d, J=14.3 Hz, 2H), 3.50-3.46 (m, 4H), 3.35 (s, 4H), 2.97-2.78 (m, 6H), 2.36 (q, J=6.9 Hz, 4H), 0.90 (t, J=6.9 Hz, 6H), 13C NMR (CDCl3,) δ161.98, 139.52, 138.52, 138.17, 129.99, 129.46, 128.46, 128.25, 128.84, 127.84, 126.30, 71.09, 64.23, 56.98, 55.54, 46.42, 32.62, 11.31.
The experimental procedure is similar as preparation of Example 15XF. MS: 667. (MtH, 100%); HRMS: 666.3394 for C41H43N6O3; 13C NMR (CD3OD, ppm): 163.76, 141.27, 141.21, 138.82, 130.62, 130.28, 129.70, 129.56, 127.88, 127.45, 71.93, 67.37, 57.11, 51.36, 33.75; 1H NMR (CD3OD): δ7.69, (s, 2H), 7.35-6.92 (m, 22H), 5.19 (s, 4H), 4.62 (d, J=14.3 Hz, 2H), 3.52-3.50 (m, 4H), 3.03-2.70 (m, 6H).
To a solution of MEM-protected Example 4P (366 mg, 0.5 mmol) in THF (15 mL) at -78°C C. was dropwise added tBuli (1.7M, 2.59 ml, 4.4 mmol), and the resulting solution was allowed to warm to room temperature. The mixture was diluted with ether washed with saturated NH4Cl, water, and dried ever MgSO4. After concentrated on a rotary evaporator, a residue was obtained and was purified on T.L.C. plate with 10% EtOAc in CH2Cl2 to give a good yield of the product; MS: 675.5 (M+H), 100%) HRMS: 675.3805 for C43H51N2O5; 1H NMR (CDCl3): δ7.56-7.54 (m, 2H), 7.43 (s,2H), 7.33-7.25 (s,10H), 7.08-7.06 (m, 4H), 4.88 (d, J=14.3 Hz, 2H, 3.64-3.53 (m, 4H), 3.09-2.87 (m, 6H), 1.29 (s, 18H); 13C NMR (CDCl3): δ209.24, 161.87, 139.35, 139.05, 138.23, 131.66, 129.43, 128.70, 128.36, 126.96, 126.62, 71.58, 64.76, 55.80, 44.21, 32.89, 27.94.
To a solution of trifluoromethyl trimethylsilane (312 mg. 2.2 mmol), in THF (3 ml) in an ice-water bath was added a solution of MEM-protected Example 5V (400 mg, 0.55 mmol) in THF (2 mL); and then to the resulting solution was added tetrabutylammonium fluoride catalyst (TBAF, 3 mg, 0.011 mmol. After the reaction mixture was stirred at 0°C C. for 40 min., the cooling bath was removed and the reaction mixture was brought to room temperature and was continued for an additional hour. The reaction mixture was then treated with 4M HCl in dioxane (5 mL) overnight. General workup and purification on TLC plate with 20% EtOAc in CH2Cl2 to furnish a quantitative yield of Example 15XI: MS: 703 (M+H, 100%); HRMS: 703.2611 for C37H37N2O5F6; 13C NMR (CDCl3, ppm) 162.40, 139.70, 138.02, 135.76, 129.61, 129.18, 128.30, 128.14, 126.74, 126.58, 126.03, 71.39 (q, J=32.4 Hz), 70.55, 65.88 (d, J=6.2 Hz), 55.66, 32.12; 19F NMR (CDCl3) 79.72 (q.J=6.0 H2); 1H NMR (CDCl3): δ7.83-7.04 (m, 18H), 5.01-4.98 (m, 2H), 4.72 (d,J=14.2 Hz, 2H), 3.67-3.58 (m 4H), 3.09-2.92 (m, 6H).
To a solution of N-SEM protected imidazole (552 mg., 2.78 mmol) in THF (10 ml) at -78°C C. was added n-Buli (1.6M, 2.5 mL, 4 mmol) dropwise and the resulting solution was allowed to warm to -20°C C. over one hour. After a solution of MEM-protected 5V(510 mg., 0.697 mmol) in THF (10 mL) was added, the reaction mixture was allowed to warm to room temperature and was stirred for an additional hour. Workup by general procedure and purification on T.L.C. plate with 50% ether in CH2Cl2 gave an oily intermediate (160 mg., 21.3% of yield), which was deprotected with 4M HCl in dioxane to give the product in good yield: MS: 695 (M+H, 100%); HRMS: 695.2977 for C41H39N6O5, 13C NMR (CD3OD, ppm): 183.16, 164.07, 146.27, 141.34, 139.59, 137.92, 135.08, 133.06, 130.70, 130.53, 120.74, 120.57, 127.45, 71.92, 66.93, 56.72, 33.72; 1H NMR (CD3OD): δ8.50 (s, 2H), 8.29-8.27 (m, 2H), 7.61-7.21 (m, 18H), 4.94 (d, J=14.3 Hz, 2H), 3.77-3.72 (m, 4H), 3.20-3.09 (m, 6H).
A solution of Example 15XE in MeOH was acidified with 4M HCl in dioxane to give the product: 1H NMR (CD3OD): δ8.58 (d, J=1.1 Hz, 2H), 8.42 (dd, J,=1.1 Hz, J=4.0 Hz, 1H), 7.78 (bs, 1H), 7.30-7.00 (m, 12H), 6.78 (d,J=6.4 Hz, 2H), 4.61 (d,J=14.2 Hz, 1H), 4.32 (dd, J=39.8Hz, J=14.2Hz, 2H), 4.03-3.99 (m, 1H), 3.71-3.62 (m, 4H), 3.21 (d,J=13.2 Hz, 1H), 3.02-2.90 (m, 4H), 2.72-2.66 (m, 1H), 13C NMR (CD3OD, ppm) 163.80, 148.66, 143.75, 142.32, 141.38, 140.85, 140.44, 137.59, 130.46, 129.60, 129.54, 128.43, 128.20, 127.66, 127.53, 71.54, 70.84, 68.41, 67.56, 64.67, 56.67, 54.02, 34.36, 33.05.
The experimental procedures is similar as preparations Example 9N: MS: 632 (M+N14, 100%); HRMS: 615.2853 for C39H39N2O5; 1H NMR (CD3OD): δ7.32-6.99 (M, 18H), 4.82 (d, J=1.3 Hz, 2H), 4.65 (d, J=13.9 Hz, 2H), 4.37 (s, 2H), 3.31-3.30 (m, 4H); 3.08-3.04 (m, 2H), 3.98 (d, J=13.9 Hz, 2H), 2.89-2.84 (m, 2H).
To a solution of MEM-protected-m-iodobenzyl cyclic urea (980 mg., 1.07 mmol) in THF (10 ml) at -78°C C. was added t-BuLi (1.7M in hexane, 2.64 mL, 4.5 mmol) and the resulting solution was stirred for another 30 mins. The N,N-dimethyl trifluoroacetamide (560 mg., 4 mmol) was added and the mixture was stirred for 2.5 hours. The mixture was diluted with ether and acidified with 2N HCl to pH=1. The ether layer was neutralized and washed with water, brine, and dried over MgSO4. The solution was concentrated to give a residue which was purified on silica gel column with gradient solvents (0-20% ethyl acetate in CH2Cl2) to give an oily intermediate (350 mg).
The oil was dissolved in CH2Cl2 (5 ml) and was treated with 4M HCl in dioxane overnight. General workup and purification on Prep. T.L.C. plate with 40% EtOAc in CH2Cl2 gave the the product (300 mg) in 40.2% yield. MS: 699.4 (M+H, 100%); HRMS: 699.2286 for C37H33N2O5F6; 1H NMR (CD3COCD3): δ7.97 (bs, 4H), 7.73-7.59 (m, 4H), 7.14-6.96 (m, 10H), 4.75 (d,J=13.9 Hz, 2H), 3.72-3.63 (m, 4H), 3.32 (d,J=14.3 Hz, 2H), 3.18-3.13 (m, 2H), 2.95-2.79 (m, 4H); 19FNMR (CD3COCD3): δ72.54; 13C NMR (CD3COCD3) 180.83 (q,J=34.3 Hz), 162.39, 141.27, 141.06, 137.90, 131.60, 130.43, 130.35, 130.23, 129.73, 129.16, 127.05, 117.62 (q, J=291.4 Hz), 71.83, 67.40, 56.55, 33.59.
To a solution of MEM-protected 4P (750 mg, 1.02 mmol) in THF (20 mL) was added ethyl magnesium bromide (2M in Et2O, 4 mL) and the resulting mixture was allowed to reflux for 2 hours. After removing all solvents on rotary evaporator, the resulting residue was dissolved in MeOH (15 mL) and was treated with 4M HCl in dioxane overnight. After general workup and purification on T.L.C. plate with 40% EtOAc in CH2Cl2. Example 15XN was obtained (600 mg) in 95.2% yield. MS: 636 (M+N H4, 100%); HRMS: 619.3181 for C39H43N2O5; 1H NMR (CDCl3): δ7.77-7.71 (m, 4H), 7.39-7.22 (m, 10H), 7.06-7.03 (m, 4H), 4.83 (d,J=14.3 Hz, 2H), 3.75 (bs,2H) 3.64-3.60 (m,2H), 3.53 (S, 2H), 3.14 (d,J=14.31 Hz, 2H), 3.10 (d,J=11.6 Hz, 2H), 2.95-2.86 (m, 2H), 2.87 (q,J=7.3 Hz, 4H), 1.12 (t,J=7.3 Hz, 6H); 13C NMR (CDCl3, ppm) 200.85. 161.88, 139.36, 138.72, 136.92, 133.70, 129.31, 128.75, 128.66, 128.54, 127.09, 126.50, 71.28, 65.28, 55.84, 32.70, 31.70, 8.04.
The experimental procedure of Note 5, Table 2D was followed: MS: 649 (M+H+, 100%); 1H NMR (CD3OD):δ7.62-7.08 (m, 18H), 4.76 (d,J=13.9Hz, 2H), 3.63-3.60 (m, 4H), 3.10-2.91 (m, 4H), 2.97 (d, J=13.9 Hz, 2H), 2.78 (q,J=7.7 Hz, 4H), 1.06 (t,J=7.7 Hz, 6H); 13C NMR(CD3OD, ppm) 162.46, 158.95, 139.71, 138.00, 136.45, 129.31, 129.17, 128.29, 128.11, 126.81, 126.02, 125.09, 70.53, 65.63, 55.57, 32.17, 18.67, 9.88.
To a solution of MEM-protected-m-iodobenzyl cyclic urea (1 g, 1.07 mmol) in THF (15 mL) at -78°C C. was dropwise added t-Buli (1.7M in hexane, 2.5 mL) and the resulting solution was stirred for another 30 minutes. Sulfur dioxide gas was introduced into the basic solution at the same temperature for 15 mins. The mixture was allowed to warm to R.T. over 2 hours and then was cooled to -78°C C. again. Sulfuryl chloride (0.72 g., 5.35 mmol) was added and the resulting mixture was allowed to warm to R.T. and stirred overnight. After all volatile reagents and solvents were removed under vacuum, the residue was dissolved in THF (10 mL) at -60°C C. and was treated with excess ammonia gas for 10 minutes. The final mixture was diluted with EtOAc and washed with water, brine and dried over anhydrous MgSO4 followed by filtration. The solvents were removed on a rotary evaporator and the residue was deprotected by general procedure. Finally, the crude was purified on T.L.C. plate and further purified on HPLC to give the desired product in moderated yield. MS: 682 (M+NH4, 10%); HRMS: 665.2103 for C33H37N4O7S2; 13C NMR (CD3CCD3, ppm) 162.33, 145.25, 141.16, 140.81, 133.59, 130.38, 129.86, 129.21, 127.77, 126.95, 125.85, 71.87, 67.52, 56.78, 33.56; 1H NMR (CD3OD): δ8.19-7.32 (m, 18H), 5.06 (d,=14.3 Hz, 2H), 4.08-3.95 (m, 4H), 3.49-3.16 (m, 6H)
The experimental procedure in Note 5 of Table 2d was followed. MS: 745 (M+18, 100%); HRMS: 729.2500 for C37H35N4O5N6; 1H NMR (CD3OD): δ7.47-7.39 (m, 6H ), 7.29-7.24 (m, 8H), 7.06-7.03 (m, 4H), 4.71 (d,J=13.9 Hz, 2H ), 3.66 (S, 2H), 3.62 (d, J=11.7 Hz, 2H), 3.08 (d, J=12.5 Hz, 2H), 2.98 (d,J=14.2 Hz, 2H), 2.95-2.89 (m, 2H), 13C NMR (CD3OD, ppm) 163.87, 141.26, 139.71, 132.08, 131.04, 130.64, 129.75, 129.56, 128.95, 128.92, 127.45, 122.57 (q,J=273.1 Hz), 72.02, 67.42, 57.02, 33.67; 19F NMR (CD3OD) 67.75.
The experimental procedure of Note 5, Table 2D was followed. The obtained product was further purified on chiral-HPLC to give the product: MS: 621 (M+H+, 100%); 1H NMR [CDCl3+CD3OD(1:1)]: δ7.26-6.76 (m, 18H), 4.47 (d,J=14.3 Hz, 2H), 3.24-3.03 (m, 4H), 2.76-2.56 (m, 6H,) 1.86 (s, 6H); 13C NMR [CDCl3+CD3OD(1:1), ppm]163.28, 155.56, 140.48, 138.78, 138.18, 130.34, 130.09, 129.22, 129.12, 127.62, 127.04, 125.84, 71.45, 66.00, 56.42, 33.15, 12.25;
To a stirred mixture of cyclic urea Example 5I (Table 2c) (300 mg, 0.56 mmol) and anhydrous cesium carbonate (912 mg, 2.8 mmol) in dioxane, free base of N-(2-chloroethyl) morpholine (2.5 g, 16.8 mmol) was added (prepared by dissolving 3.1 g of the hydrochloride in 5 mL of water and 5 mL of sat'd NaHCO3, extracting with 100 mL of Hexane, drying over MgSO4, and concentrating) (Thompson; et al. J. Med. Chem. 1992, 35, 1698) and heated up to 80°C C. for 2 days. The mixture was filtered, rinsed with chloroform and purified on silica gel (1:5 Methanol : Chloroform) to give 339 mg (79%) pure product. M.P. 110°C-112°C C. M. S. 765(M+1, 100%).
The intermediate was prepared by alkylating the appropriate monoalkylated compound with m-cyanobenzyl chloride. Lithium aluminum hydride (158 mg, 4.18 mmol) was added to AlCl3 (180 mg, 1.39 mmol) in ether at 0°C C. The mixture was warmed up to RT and stirred for 15 min. Then a solution of the above intermediate (950 mg, 1.16 mmol) in ether was added dropwise. The mixture was stirred at RT for 1 h, quenched with 1 mL of H2O, 1 mL of 5% NaOH and washed with H2O, sat'd NaCl and dried over MgSO4. Following the same hydrolysis procedure, the product was isolated (70 mg) in 10% yield. M.P. 132°C-134°C C. M.S. 566 (M+1, 100%).
To the mixture of 1 mL of DMF and 4 mL CH2Cl2, oxalyl chloride (0.72 mL, 2M in CH2Cl2) was added dropwise at -20°C C. under N2. After 20 min, 500 mg (0.65 mmol) of bis(N-m-benzoic acid) cyclic urea Example 6A (Table 2c) and 0.14 mL (2 mmol) of N-methyl-morpholine were added. The mixture was stirred at -20°C C. for 20 min. N-methyl-hydroxylamine hydrochloride (217 mg, 4 mmol) and an additional 0.56 mL (8 mmol) of N-methylmorpholine were added. The reaction mixture was diluted with ethyl acetate, washed with cold 5% HCl, sat'd NaHCO3, H2O, brine and purified on silica gel (1:95 Methanol : chloroform). Following the same hydrolysis procedure, the product (80 mg) was isolated in 20% yield. M.P. 223°C-224°C C.
Using an analogous procedure to that reported by Paul Unangst, et al. (in J. Med. Chem. 1992, 35, 3691-3698) the title compound can be prepared from the hydroxyamidine. To a stirred solution of hydroxyamidine analog (150 mg, 0.19 mmol) containing triethylamine (0.13 mL, 0.95 mmol), ethyl chloroformate in 10 mL chloroform was added dropwise at 0°C C. The mixture was stirred at RT for 2 h and washed with water, brine and dried over MgSO4. The residue was purified on silica gel (1:1 ethyl acetate: methylene chloride). The product (137 mg, 76% yield) was isolated as ester intermediate.
To the above ester intermediate, toluene was added and the solution was heated up to 110°C C. for 48 h. The solvent was removed on rotary evaporator. Following the same hydrolysis procedure. The product (45 mg) was isolated in 35% yield. M.P. 223°C-224°C C. (decomp.).
A solution of bis(N-m-benzaldehyde) cyclic urea Example 5V (Table 2c)(120 mg, 0.21 mmol) containing small amount of 3A molecular sieves was treated with toluenesulfonylhydrazide dropwise at 0°C C. under N2. The mixture was stirred at RT for overnight. The solvent was removed on rotary evaporator and purified on silica gel (1:4 ethyl acetate : methylene chloride) to give 92 mg (52%) pure product. M.P. 169°C-171°C C.
To a solution of N-SEM-imidazole (396 mg, 2 mmol) in THF (10 mL) at -78°C C. was added n-BuLi (5 mmol, 3.1 mL) dropwise and the resultant mixture was stirred for 30 minutes, and to this was added a solution of zinc chloride (410 mg, 3 mmol) in THF (5 mL). After the resulting solution was allowed to warm to room temperature, a solution of m-iodobenzyl cyclic urea (466 mg, 0.5 mmol) in THF (2 mL) and Pd(PPh3)4 (77 mg, 0.07 mmol) were added under nitrogen and resultant mixture was allowed to reflux overnight. Work-up and deprotection by general procedure, followed by purification on TLC plate with 50% EtOAc in CH2Cl2 gave Example 15YK as a solid. 1H NMR (CD3OD) δ7.74-7.09 (m, 22 H), 5.34 (s, 2H), 4.84 (d, J=13.3 Hz, 1H), 4.68 (d, J=14.3 Hz, 1H), 3.76-3.69 (m, 4H), 3.60 (t, J=8.0 Hz, 2H), 3.18-3.03 (m, 4H), 2.96-2.88 (m, 2H), 0.90 (t, J=8.0 Hz, 2H), 0 00 (s, 9H); 13C NMR (CD3OD): ppm 164.91, 150.71, 143.28, 142.52, 142.43, 141.37, 141.11, 139.14, 135.08, 135.06, 134.43, 134.33, 133.13, 132.84, 132.72, 132.34, 131.96, 131.38, 131.35, 131.22, 131.03, 130.94, 130.91, 130.84, 129.79, 128.84, 128.80, 124.79, 96.36, 77.82, 73.27, 73.24, 69.49, 68.97, 68.84, 58.54, 58.32, 35.16, 34.91, 19.94, 0.00.
To a solution of N-SEM protected pyrazole (1.98 g., 10 mmol) in THF (40 mL) at -78°C C. was added n-BuLi (1.6 M, 7.5 mL, 12 mmol) dropwise and the resulting solution was stirred for an additional half hour, and then triisopropylborate (9.4 g, 50 mmol) was added. After being allowed to warm to room temperature over 2 hours, the reaction mixture was acidified with 2N HCl, extracted with ether, washed with water and brine, and dried over MgSO4. Filtration and concentration gave N-SEM-3-hydroxyboricpyrazole (2.4 g, 100%) as a solid. 1H NMR (CD3OD) δ7.57 (S, 1H), 6.80 (s, 1H), 5.70 (s, 2H), 3.57 (t, J=7.8 Hz, 2H), 0.89 (t, J=8.0 Hz, 2H), 0.00 (s, 9H); 13C NMR (CD3OD): ppm 138.54, 115.65, 78.98, 65.98, 17.31, -2.30.
To a solution of m-iodobenzyl cyclic urea (932 mg, 1 mmol) in THF (5 mL) was added N-SEM-3-hydroxyboricpyrazole (968 mg, 4 mmol), Pd(PPh3)4 (57.8 mg, 5%) and Na2CO3 (1.7 g in H2O (4 mL) under nitrogen and the resultant mixture was allowed to reflux over 48 hours. The organic layer was concentrated on rotary evaporation to give a residue, which was deprotected by the general procedure, followed by purification on TLC plate with 20% EtOH in hexane to give Example 15YL (560 mg, 87.8%) as a solid. MS 639 (M+H+, 100%); HRMS calcd for C39H39N6O3 639.3084, Found 639.3081; 1H NMR (CD3OD) δ7.76-7.69 (m, 6H), 7.45-7.15 (m, 14H), 6.66 (s, 2H), 4.87 (d, J=14.3 Hz, 2H), 3.77 (b, 4H), 3.19-2.98 (m, 6H); 13C NMR (CD3OD) ppm 162.82, 140.19, 139.01, 129.67, 129.22, 128.96, 128.59, 127.06, 126.49, 125.03, 102.41, 71.02, 66.69, 56.37, 32.65.
A solution of Example 15YL (200 mg) in methanol (5 mL) was treated with HCl gas for 2 seconds and the solvent was removed under full vacuum to give Example 15YM as a solid. 1H NMR (CD3OD) δ8.34-8.32 (m, 2H), 7.76-7.74 (m, 2H), 7.73-7.66 (m, 2H), 7.55-7.50 (m, 4H), 7.15-7.09 (m, 8 H), 6.89-6.86 (m, 4H), 4.58 (d, J=13.9 Hz, 2H), 3.88-3.78 (m, 4H), 3.32 (d, J=13.9 Hz, 2H), 3.08-3.04 (m, 2H), 2.78-2.69 (m, 2H); 13C NMR (CD3OD) ppm 161.86, 147.23, 139.72, 139.50, 135.07, 132.00, 129.53, 129.04, 128.00, 127.92, 126.03, 125.97, 125.74, 104.78, 70.21, 67.75, 56.28, 32.27.
To a solution of N-SEM protected pyrazole (780 mg., 3.9 mmol) in THF (40 mL) at -78°C C. was added t-BuLi (1.7 M, 2.8 mL, 4.7 mmol) dropwise and the resulting solution was stirred for an additional 30 minutes. The solution was transferred to another solution of MEM-protected m-cyanobenzyl cyclic urea (732 mg., 1 mmol) in THF (10 mL) at -78°C C. and the resulting reaction mixture was allowed to warm to room temperature and was stirred overnight. After evaporation of all volatiles, the residue was diluted with methanol (20 mL) and then treated with 4M HCl in dioxane (20 mL) overnight. Workup by general procedure and purification on reverse phase T.L.C. plate with 70% MeOH in H2O gave Example 15YN in good yield: MS: 695 (M+H, 100%); HRMS calcd for C41H39N6O5 695.2983, Found 695.2967; 13C NMR (CD3OD): ppm 183.16, 164.07, 146.27, 141.34, 139.59, 137.92, 135.08, 133.06, 130.70, 130.53, 120.74, 120.57, 127.45, 71.92, 66.93, 56.72, 33.72; 1H NMR (CD3OD) 58.50 (s, 2H), 8.29-8.27 (m, 2H), 7.61-7.21 (m, 18H), 4.94 (d, J=14.3 Hz, 2H), 3.77-3.72 (m, 4H), 3.20-3.09 (m, 6H).
A solution of MEM-protected compound 12J (0.94 g, 1.0 mmol) was treated with n-BuLi (1.6M, 1.6 mL) at -78°C C. for 20 minutes, followed by quenching with N-methoxy-N-methyl benzyloxyacetamide (1.35 g, 6 mmol), prepared by a reaction of benzyloxyacetyl chloride with N-methoxy-N-methylamine in pyridine and CH2Cl2 at room temperature. Removal of MEM-groups by general hydrolysis procedure followed by purification by preparative T.L.C. gave compound 15BI in moderate yield. 1H NMR (CDCl3) 87.72-7.66 (m, 4H), 7.42-7.00 (m, 24H), 4.79 (d, J=14.6 Hz, 2H), 4.64 (s, 2H), 4.57 (d, J=2.5 Hz, 2H), 3.71-2.82 (m, 14 H); 13C NMR (CDCl3) δ196.08, 161.84, 139.30, 138.95, 136.89, 134.40, 129.45, 129.40, 129.29, 128.92, 128.58, 128.48, 128.02, 127.96, 126.97, 126.54, 73.26, 72.29, 71.12, 65.40, 55.82, 32.72; HRMS: calcd. for C51H51N2O7: 803.3696; found 803.3693.
To a solution of SEM protected imidazole (2 g) in THF (20 mL) was added t-BuLi (1.7 M, 6.9 mL) at -78°C C. and the mixture was stirred for 20 minutes. After addition of TMSCl (1.25 g), the resulting mixture was allowed to warm to 0°C C. over 2 hours, and then cooled to -78°C C. again. The mixture was treated with t-BuLi (1.7 M, 6.9 mL), stirred for 20 minutes, followed by addition of B(OMe)3 (10.4 g). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was poured into EtOAc/H2O and the organic layer was washed to PH 7, dried with NaSO4, and purified on column with MeOH to give pure N-SEM-5-borono-imidazole (2.3 g 95%) as a solid. 1H NMR (CD3OD) δ7.63 (d, J=0.74 Hz, 1H), 6.87 (d, J=1.1 Hz, 1H), 5.47 (s, 2H), 3.55 (t, J=8.4 Hz, 2H), 0.93 (t, J=8.4 Hz, 2H, 0.00 (s, 9H); 13C NMR (CD3OD) δ138.97, 134.54, 77.89, 68.00, 20.19, 0.00.
A solution of the borono-imidazole prepared above (1.3 g, 5.37 mmol), MEM-protected cpd 12J (0.937 g, 1.01 mmol), Pd (Ph3P)4 (0.18 g, 0.16 mmol) and K2CO3 (7.5 g) in THF (20 mL) and H2O (20 mL) was degassed, and then was heated to reflux under N2 overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc/H2O. The organic layer was dried over MgSO4 and concentrated to give a residue, which was deprotected by general hydrolysis procedures and purified on T.L.C. plate with 5% MeOH in EtOAc to give the coupling product, 15BJ (0.4 g, 37.2%). 1H NMR (CD3OD) δ7.97 (s, 2H), 7.61-7.11 (m, 20H), 5.37 (s, 4H), 4.83 (d, J=13.9 Hz, 2H), 3.78-3.73 (m, 4H), 3.59 (t, J=8.0 Hz, 4H), 3.18-2.97 (m, 6H), 0.90 (t, J=8.0 Hz, 4H), 0.00 (s, 18H).
Compound 15BJ was treated with 4M HCl in dioxane under reflux overnight. After the solvent was removed under full vacuum, the residue was purified on reverse phase T.L.C. plate to give the desired compound as a solid in moderate yield. 1H NMR (CD3OD) δ7.71 (sb, 2H), 7.61 (d, J=7.7 Hz, 2H), 7.52 (s, 2H), 7.35-7.19 (m, 10H), 7.10-7.08 (m, 6H), 4.78 (d, J=13.9 Hz, 2H), 3.71-3.65 (m, 4H), 3.32-3.00 (m, 4H), 2.96-2.87 (m, 2H); 13C NMR (CD3OD) δ163.80, 141.26, 139.94, 137.20, 134.78, 130.67, 130.11, 129.52, 128.88, 127.40, 127.08, 125.22, 72.00, 67.72, 57.38, 33.60; HRMS: calcd. for C39H39N6O3: 639.3084; found 639.3089.
Compound 15BK in MeOH was treated with 4M HCl in dioxane and the resulting solvents ware evaporated under full vacuum to give the hydrochloride salt. 1H NMR (CD3OD) δ9.02 (d, J=1.1 Hz, 2H), 7.87 (d, J=1.1 Hz, 2H), 7.65-7.38 (m, 8H), 7.19-7.17 (m, 6H), 6.93-6.90 (m, 4H), 4.65 (d, J=14.3 Hz, 2H), 3.78-3.72 (m, 4H), 3.25 (d, J=14.3, 2H), 3.06-3.02 (m, 2H), 2.81-2.7 (m, 2H); 13C NMR (CD3OD) δ163.41, 141.11, 141.04, 135.91, 134.97, 131.95, 130.89, 130.51, 129.47, 128.16, 128.10, 127.43, 126.09, 116.38, 71.80, 69.21, 57.87, 33.73.
2-Trimethyltin-N-dimethylsulfamoyl-imidazole was prepared in situ by lithiation of N-dimethylsulfamoylimidazole (1.75 g, 10 mmol) in THF (30 mL) at -78°C C. with n-BuLi (1.6M, 7.5 mL), followed by quenching with trimethyltin chloride (2.19 g, 11 mmol). A coupling reaction of the tin reagent (1.2 g, crude) and MEM-protected compound 12J (0.8 g, 0.86 mmol) in the presence of Pd(Ph3P)4 (0.18 g, 0.16 mmol) was carried out under reflux overnight. After being cooled to room temperature, the reaction mixture was poured into EtOAc/H2O. The organic layer was dried over MgSO4 and concentrated on a rotary evaporator. The residue was dissolved in MeOH, saturated with HCl (gas) at 0°C C. for 5 minutes and then stirred at that temperature for 1 hour. The resulting mixture was worked up and purified on column with EtOAc to give compound 15BM as a solid(450 mg, 61%). 1H NMR (CD3OD) δ7.61-7.11 (m, 22H), 4.86 (d, J=14.3 Hz, 2H), 3.61-3.59 (m, 4H), 3.10-2.92 (m, 6H), 2.54 (s, 6H); 13C NMR (CD3OD) δ163.98, 148.97, 141.21, 139.37, 132.57, 132.17, 131.55, 130.98, 130.69, 129.63, 129.50, 128.30, 127.53, 123.61, 71.92, 66.99, 56.66, 38.23, 33.74. HRMS: calcd. for C43H49N8O7S2: 853.3166; found 853.3163.
A solution of 4-iodopyrazole (1.54 g, 8 mmol) in THF (20 mL), was treated with Nail (4.3 g, 10.6 mmol), followed by quenching with dimethylsulfamoyl chloride (1.38 g, 9.6 mmol) to form the N-protected pyrazole (2.4 g, 92%). This intermediate (1.5 g, 5 mmol) was reacted with hexamethylditin (1.8 g, 5.5 mmol) in the presence of Pd(Ph3P)4 (0.055 g, 0.01 mmol) in THF (25 mL) at 78°C C. overnight to give crude 4-trimethyltin-N-dimethylsulfamoyl-pyrazole.
The crude tin compound was reacted with MEM-protected cpd 12J (0.932 g, 1.0 mmol) in the presence of Pd (Ph3P)4 (0.18 g, 0.16 mmol) under reflux to form the coupled product, which was deprotected by general hydrolysis procedure, followed by purification on reverse phase TLC plate with 85% MeOH in water to give compound 15BN as a solid. 1H NMR (CD3OD) δ7.77-7.12 (m, 4H), 7.38-6.95 (m, 18H), 4.72 (d, J=14.3 Hz, 2H), 3.59-3.55 (m, 4H), 3.02-2.88 (m, 6H); 13C NMR (CD3OD) δ163.36, 140.63, 139.40, 133.75, 130.19, 129.83, 129.18, 127.87, 127.38, 127.12, 125.47, 122.79, 71.64, 66.46, 56.76, 33.23;
MEM-protected mono-m-bromobenzyl cyclic urea was made by general procedure for preparation of monoalkylated cyclic ureas. The monoalkyated intermediate (2.4 g, 3.56 mmol) was dissolved in DMF (15 mL) and treated with NaH (0.43 g, 10.75 mmol), followed by addition of methyl m-bromomethylbenzoate (1.63 g, 7.1 mmol) to give pure desired asymmetric cyclic urea (1.6 g, 55%).
This asymmetric urea (1.6 g, 2 mmol) was coupled with 5-borono-N-SEM-Pyrazole (0.48 g, 2 mmol) by the same procedure described for example 15BJ above to provide pure coupled product, which was further deprotected by general hydrolysis procedure to form compound 15BP (0.9 g, 73.2% for the two steps). 1H NMR (CD3OD) δ7.85-7.82 (m, 2H), 7.66-7.57 (m, 4H), 7.35-7.01 (m, 13H), 6.56 (s, 1H), 4.76 (d, J=14.3 Hz, 1H), 4.69 (d, J=14.3 Hz, 1H), 3.77 (s, 3H), 3.72-3.58 (m, 4H), 3.11-3.02 (m, 4H), 2.94-2.84 (m, 2H); 13C NMR (CD3OD) δ166.79, 162.24, 139.69, 139.59, 138.56, 138.50, 133.63, 130.09, 129.16, 128.78, 128.61, 128.46, 128.29, 128.16, 126.59, 126.08, 124.60, 102.00, 70.50, 66.36, 66.31, 55.99, 55.63, 51.32, 32.23, 32.15; LRMS: 631.4 (M+1, 100%); HRMS: calcd. for C38H39N4O5: 631.2920; found 631.2916.
To a solution of compound 15BP (63 mg, 0.1 mmol) in THF (1 mL) was added LiBH4 (2M in THF, 0.3 mL) and MeOH (57.6 mg, 1.8 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 1 with 2N HCl and extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated. The residue was purified on TLC plate with EtOAc to give the desired compound (46 mg, 76.3%). 1H NMR (CD3OD) δ7.78-7.60 (m, 4H), 7.50-7.07 (m, 15H), 6.68 (d, J=2.2 Hz, 1H), 4.90-4.81 (m, 2H), 4.66 (bs, 2H), 3.79-3.63 (m, 4H), 3.18-3.00 (m, 6H); 13C NMR (CD3OD) 5163.92, 143.24, 141.32, 141.23, 139.41, 130.67, 130.17, 129.93, 129.69, 129.57, 129.53, 129.30, 129.04, 128.04, 127.45, 127.41, 127.25, 126.01, 103.33, 72.02, 71.96, 67.04, 64.97, 57.30, 57.07, 33.63, 33.57; LRMS: 603.2 (M+1, 100%); HRMS: calcd. for C37H39N4O4: 603.291; found 603.2968.
N-dimethylsulfamoyl-imidaz-2-yl zinc chloride was prepared in situ by lithiation of N-dimethylsulfamoylimidazole (0.97 g, 5.5 mmol) in THF (20 mL) with t-BuLi ( 1.7M, 6.7 mL), followed by quenching with zinc chloride (1.87 g, 13.75 mmol).
A coupling reaction of the zinc reagent (crude) and MEM-protected cpd 12J (0.932 g, 1.0 mmol) in the presence of Pd(Ph3P)4 (0.12 g, 0.1 mmol) was carried out under reflux overnight. After cooling to room temperature, the reaction mixture was poured into EtOAc/H2O. The organic layer was dried over MgSO4 and concentrated on a rotary evaporator. The residue was dissolved in MeOH, and treated with 4M HCl in dioxane under reflux for 2 hours. The resulting mixture was worked up and purified on a reverse phase TLC plate with 75% MeOH in water to give compound 15BR as a solid. 1H NMR (CD3OD) δ7.75-7.70 (m, 4H), 7.42-7.33 (m, 2H), 7.28-7.12 (m, 12H), 7.00-6.94 (m, 4H), 4.73 (d, J=14.3 Hz, 2H), 3.71 (bs, 4H), 3.14 (d, J=13.9 Hz, 2H), 3.04-2.99 (m, 2H), 2.89-2.77 (m, 2H); 13C NMR (CD3OD) δ162.00, 146.27, 139.58, 138.87, 130.23, 129.36, 129.11, 128.80, 128.00, 126.20, 125.89, 124.36, 122.64, 70.39, 67.14, 56.29, 32.22; HRMS: calcd. for C39H39N6O3: 639.3084; found 639.3069.
Compound 15BR was dissolved in MeOH, and treated with 4M HCl in dioxane at r.t. for 1 minute. The resulting mixture was concentrated in vacuo to give the solid dihydrochloride salt. 1H NMR (CD3OD) δ7.81-7.79 (m, 2H), 7.73 (s, 2H), 7.65 (s, 4H), 7.61-7.57 (m, 4H), 7.13-7.11 (m, 6H), 6.86-6.84 (m, 4H), 4.59 (d, J=13.9 Hz, 2H), 3.84 (s, 2H), 3.76 (d, J=11.7 Hz, 2H), 3.45 (d, J=14.1 Hz, 2H), 3.06 (d, J=12.2 Hz, 2H), 2.75-2.68 (m, 2H); 13C NMR (CD3OD) δ163.39, 145.94, 141.63, 140.94, 134.79, 131.28, 130,46, 129.44, 129.13, 127.38, 127.14, 124.31, 121.37, 71.58, 69.54, 57.82, 33.84.
To compound 15BP (63 mg, 0.1 mmol) was added 4-(2-aminoethyl)morpholine (0.13 g, 1 mmol) and the resulting mixture was stirred at 110°C C. overnight. The mixture was evaporated in vacuo to remove the excess 4-(2-aminoethyl)morpholine, and the residue was purified on TLC plate with 10% MeOH in EtOAc to give pure product (44 mg, 60.4%). 1H NMR (CD3OD) δ8.04 (s, 1H), 7.73-6.99 (m, 18H), 6.59 (d, J=2.2 Hz, 1H), 4.72 (d, J=14.4 Hz, 2H), 3.69-3.64 (m, 8H), 3.36 (t, J=6.6 Hz, 2H), 3.14 (J=14.2 Hz, 2H), 3.08-2.85 (m, 4H), 2.54 (t, J=6.6 Hz, 2H), 2.51-2.45 (m, 4H); 13C NMR (CD3OD) δ169.84, 163.68, 141.25, 141.12, 140.09, 136.07, 133.65, 130.63, 129.87, 129.56, 129.51, 128.02, 127.44, 103.31, 71.98, 71,91, 68.26, 67.75, 58.62, 58.37, 58.45, 54.68, 37.76, 35.76, 33.69, 33.62; HRMS: calcd. for C43H49N6O5: 729.3764; found 729.3753.
MEM-protected mono-m-bromobenzyl cyclic urea was made by general procedure for preparation of monoalkylated cyclic ureas. The mono cyclic urea (2.4 g, 3.56 mmol) in DMF (15 mL) was coupled with 5-borono-N-SEM-pyrazole by the same procedure used to make compound 20AX to provide pure coupled product, MEM-protected mono m-(N-SEM-pyraz-5-yl)benzyl cyclic urea.
This intermediate (0.2 g, 0.25 mmol) in DMF (5 mL) was treated with NaH (0.04 g, 1.0 mmol), followed by quenching with m-picolyl chloride hydrochloride (0.123 g, 0.75 mmol) to give desired asymmetric cyclic urea, which was further deprotected by general hydrolysis procedure to form compound 15BU. 1H NMR (CD3OD) δ8.51-8.46 (m, 2H), 7.83-7.63 (m, 4H), 7.48-7.03 (m, 13H), 6.68 (d, J=2.2 Hz, 1H), 4.84 (d, J=14.3 Hz, 1H), 4.66 (d, J=14.3 Hz, 1H), 3.85-3.76 (m, 4H), 3.20-2.83 (m, 6H); 13C NMR (CD3OD) δ163.63, 151.12, 149.22, 141.12, 141.07, 139.41, 135.98, 130.60, 130.55, 130.24, 129.63, 129.60, 128.04, 127.54, 126.08, 125.34, 103.35, 71.94, 71.81, 68.72, 55.13, 33.75, 33.61; HRMS: calcd for C35H36N5O3: 574.2818; found 574.2811.
The MEM-protected mono m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea (788 mg, 1 mmol), described in procedure of example 15U was dissolved in DMF (8 mL) and treated with NaH (0.16 g, 4.0 mmol, 60% in mineral oil), followed by quenching with α-bromo-m-tolunitrile (0.392 g, 2.0 mmol) to give desired asymmetric cyclic urea, which was further deprotected by general hydrolysis procedure to form compound 15BV. 1H NMR (CD3OD) δ7.99-7.07 (m, 19H), 6.68 (bs, 1H), 4.70 (d, J=13.9 Hz, 1H), 4.64 (d, J=13.9 Hz, 1H), 3.93-3.70 (m, 4H), 3.21-2.83 (m, 6H); 13C NMR (CD3OD) δ163.82, 141.40, 141.24, 141.14, 135.42, 134.42, 133.90, 132.52, 130.85, 130.67, 130.15, 130.03, 129.82, 129.71, 128.16, 127.66, 119.67, 113.62, 103.40, 71.92, 71.87, 68.67, 57.14, 33.79, 33.62; HRMS: calcd. for C37H36N5O3: 598.2818; found 598.2813.
To a solution of compound 15BV (50 mg, 0.084 mmol) in pyridine (3 mL) was added hydroxylamine hydrochloride (36 mg, 5.2 mmol) and the resulting mixture was refluxed overnight. After being cooled to room temperature, the mixture was evaporated in vacuo to remove pyridine. The resulting residue was worked up and purified on TLC plate with EtOAc to give pure amidoxime (32 mg, 60.6%). 1H NMR (CD3OD)δ7.96-7.05 (m, 19H), 6.59 (d, J=2.2 Hz, 1H), 4.78 (d, J=14.3 Hz, 1H), 4.75 (d, J=14.3 Hz, 1H), 3.70-3.59 (m, 4H), 3.11-3.03 (m, 4H), 2.96-2.88 (m, 2H); 13C NMR (CD3OD)δ163.82, 141.25, 141.14, 140.02, 139.77, 134.52, 134.00, 131.68, 130.62, 130.18, 129.93, 129.69, 129.56, 129.54, 128.04, 127.44, 126.01, 103.32, 71.97, 67.65, 67.58, 57.31, 56.97, 33.67, 33.56.
Mono-m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea prepared above in procedure of Example 15BU was deprotected by general hydrolysis procedure to give compound XS618. 1H NMR (CD3OD) δ7.67-7.05 (M, 15H), 6.58 (d, J=4.0 Hz, 1H), 4.80 (d, J=14.7 Hz, 1H), 3.86-3.82 (m, 1H), 3.71-3.62 (m, 2H), 3.51-3.48 (m, 1H), 3.18-2.99 (m, 4H), 2.80-2.72 (m, 1H); 13C NMR (CD3OD) δ163.90, 141.47, 140.89, 130.63, 130.49, 130.09, 130.01, 129.64, 129.49, 129.27, 127.52, 127.25, 125.85, 103.33, 72.99, 72.55, 66.50, 66.47, 55.27, 35.13, 34.32; HRMS: calcd. for C29H31N4O3: 483.2400; found 483.2401.
MEM-protected mono m-(N-SEM-pyraz-5-yl) benzyl cyclic urea described above (220 mg, 0.28 mmol) was dissolved in DMF (3 mL) and treated with NaH (0.045 g, 1.12 mmol, 60% in mineral oil), followed by quenching with p-benzyloxybenzyl chloride (0.13 g, 0.56 mmol) to give the desired asymmetric cyclic urea, which was deprotected by general hydrolysis procedure to give compound 15BY. 1H NMR (CD3OD) δ7.68-6.91 (m, 24H), 6.58 (d, J=2.2 Hz, 1H), 5.02 (s, 2H), 4.78 (d, J=13.9 Hz, 1H), 4.66 (d, J=13.9 Hz, 1H), 3.67-3.54 (m, 4H), 3.08-2.88 (m, 6H); 13C NMR (CD3OD) δ163.88, 159.84, 141.29, 138.63, 131.73, 131.58, 130.69, 130.64, 130.15, 129.56, 129.49, 129.46, 128.82, 128.50, 128.03, 127.46, 127.37, 125.99, 116.07, 103.32, 72.05. 72.02, 66.81, 56.45, 33.62, 33.59; HRMS: calcd. for C43H43N4O4: 6779.3284; found 679.3284.
To compound 15BP (45 mg, 0.071 mmol) was added 3-(aminomethyl)pyridine (0.077 g, 0.71 mmol) and the resulting mixture was stirred at 110°C C. overnight. The mixture was evaporated in vacuo to remove the excess 3-(aminomethyl)-pyridine. The residue was purified on TLC plate with 15% MeOH in EtOAc to give pure product (37 mg, 73.8%). 1H NMR (CD3OD)δ7.80-6.95 (m, 23 H), 6.59 (d, J=2.2 Hz, 1H), 4.77-4.72 (m, 1H), 4.68 (d, J=14.3Hz, 1H), 4.58 (d, J=2.2 Hz, 2H), 3.66-3.64 (m, 4H), 3.15 (d, J=14.3 Hz, 1H), 3.06-2.82 (m, 5H); 13C NMR (CD3OD) δ170.09, 163.83, 152.96, 149.63, 141.32, 141.23, 140.30, 137.40, 136.94, 135.80, 134.04, 130.71, 130.29, 130.09, 129.75, 129.66, 128.12, 127.67, 127.54, 126.14, 125.34, 125.19, 103.38, 72.00, 71.93, 68.47, 57.56, 42.02, 33.62.
Hydrogenation of compound 15BY in MeOH in the presence of catalytic amount of 10% Pd/C produced the hydroxymethyl compound in good yield. 1H NMR (CD3OD) δ7.68-7.58 (m, 3H), 7.39-7.05 (m, 12H), 6.98 (d, J=8.4 Hz, 2H), 6.73 (d, J=8.4 Hz, 2H), 6.58 (d, J=2.2 Hz, 1H), 4.78 (d, J=14.3 Hz, 1H), 4.66 (d, J=13.9 Hz, 1H), 3.68-3.50 (m, 4H), 3.08-2.83 (m, 6H); 13C NMR (CD3OD) δ163.94, 158.15, 141.31, 140.11, 131.73, 130.69, 130.65, 130.16, 129.96, 129.56, 129.48, 128.04, 127.46, 127.35, 125.98, 116.39, 103.32, 72.10, 72.02, 66.42, 57.22, 56.37, 33.56; HRMS: calcd. for C36H37N4O4: 589.2815; found 589.2811.
To compound 15BP (44 mg, 0.07 mmol) was added 2-(aminomethyl)pyridine (0.077 g, 0.71 mmol) and the resulting mixture was stirred at 110°C C. overnight. The mixture was evaporated in vacuo to remove the excess 2-(aminomethyl)pyridine. The residue was purified on a TLC plate with 20% MeOH in EtOAc to give pure product (35 mg, 71%). 1H NMR (CD3OD)δ8.45 (d, J=4.8 Hz, 1H), 7.80-6.98 (m, 22H), 6.58 (d, J=1.5 Hz, 1H), 4.77 (d, J =14.3 Hz, 1H), 4.71 (d, J=14.3 Hz, 1H), 4.66 (d, J=4.8 Hz, 2H), 3.68-3.65 (m, 4H), 3.17-2.82 (m, 6H); 13C NMR (CD3OD) δ169.99, 163.71, 159.28, 149.75, 141.25, 141.14, 140.17, 139.98, 138.80, 135.79, 133.94, 130.63, 130.18, 129.96, 129.92, 129.57, 128.03, 127.64, 127.45, 126.03, 123.72, 122.76, 103.32, 71.99, 71.92, 68.32, 67.72, 57.50, 57.30, 45.92, 33.69, 33.65; HRMS: calcd. for C43H43N6O4: 707.3346; found 707.3344.
MEM-protected mono m-(N-SEM-pyraz-5-yl)benzyl cyclic urea (200 mg, 0.254 mmol) was dissolved in DMF (5 mL) and treated with NaH (0.041 g, 1.02 mmol, 60% in mineral oil), followed by quenching with m,p-dibenzyloxy-benzyl chloride (0.172 g, 0.51 mmol) to give the desired asymmetric cyclic urea. After deprotection by general hydrolysis procedure, the urea was hydrogenated to give the dihydroxy compound. 1H NMR (CD3OD) δ7.83-7.07 (m, 15H), 6.81-6.71 (m, 3H), 6.53 (s, 1H), 4.86 (d, J=13.9 Hz, 1H), 4.72 (d, J=13.6 Hz, 1H), 3.80-3.66 (m, 4H), 3.19-2.82 (m, 6H); 13C NMR (CD3OD) δ164.10, 149.97, 146.56, 146.12, 141.43, 141.32, 140.29, 134.53, 133.55, 130.82, 130.71, 130.67, 130.29, 129.64, 129.53, 128.23, 127.51, 127.42, 126.14, 122.22, 117.49, 116.39, 103.59, 72.13, 72.01, 67.77, 65.89, 57.28, 56.35, 33.61, 33.45; HRMS: calcd. for C36H37N4O5: 605.2764; found 605.2750.
MEM-protected mono m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea (560 mg, 0.71 mmol) was dissolved in DMF (10 mL) was treated with Nail (0.114 g, 2.84 mmol, 60% in mineral oil), followed by quenching of m-nitrobenzyl chloride (0.360 g, 2.13 mmol) to give desired asymmetric cyclic urea. After deprotection by general de-MEM procedure, the urea was purified on TLC plate with EtOAc to give pure product. 1H NMR (CD3OD) δ8.11-8.06 (m, 2H), 7.69-7.15 (m, 13H), 7.06-6.95 (m, 4H), 6.59 (d, J=2.2 Hz, 1H), 4.76 (d, J=13.9 Hz, 1H), 4.61 (d, J=14.3 Hz, 1H), 3.78-3.56 (m, 4H), 3.15-2.79 (m, 6H); 13C NMR (CD3OD) δ163.75, 149.67, 141.75, 141.12, 140.97, 136.71, 130.78, 130.53, 130.21, 129.93, 129.73, 129.57, 128.04, 127.53, 127.43, 126.07, 125.37, 123.51, 103.33, 71.84, 68.28, 57.31, 56.86, 33.85, 33.58; HRMS: calcd. for C36H36N5O5: 618.2716; found 618.2703.
Hydrogenation of compound 15CD (210 mg, o.34 mmol) in MeOH (5 mL) and 1N HCl (1 mL) in the presence of 10% Pd/C was carried out at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified on TLC plate with EtOAc to give the amino compound (140 mg, 61%). 1H NMR (CD3OD) δ8.31 (s, 1H), 7.81-6.88 (m, 19H), 4.60 (d, J=13.6 Hz, 2H), 3.80-3.57 (m, 4H), 3.16-2.68 (m, 6H); 13C NMR (CD3OD) δ163.99, 149.09, 141.38, 141.23, 140.01, 130.73, 130.65, 130.35, 130.15, 129.93, 129.55, 129.46, 128.04, 127.42, 127.35, 125.97, 120.06, 117.33, 115.81, 103.32, 72.11, 71.99, 66.39, 57.28, 56.97, 33.66, 33.53; HRMS: calcd. for C36H38N5O3: 588.2975; found 588.2983.
MEM-protected mono m-(N-SEM-pyraz-5-yl) -benzyl cyclic urea (240 mg, 0.3 mmol) was dissolved in DMF (5 mL) and treated with NaH (0.049 g, 1.2 mmol, 60% in mineral oil), followed by addition of m-cyano-p-fluorobenzyl bromide (0.128 g, 0.6 mmol) to give desired asymmetric cyclic urea. After deprotection by general hydrolysis procedure, the urea was purified on TLC plate with EtOAc to give pure compound 15CF (72 mg, 39%). 1H NMR (CD3OD) δ7.68-6.86 (m, 18H), 6.57 (d, J=0.7 Hz, 1H), 4.72 (d, J=14.1 Hz, 1H), 4.36 (d, J=13.8 Hz, 1H), 3.82-3.55 (m, 4H), 3.16-2.69 (m, 6H); HRMS: calcd. for C37H35N5O3F: 616.2713; found 616.2710.
A solution of compound 15BX in MeOH was treated with 4M HCl in dioxane, and the resulting solution was evaporated to dryness in vacuo to give the hydrochloride salt. 1H NMR (CD3OD) δ8.31 (d, J=2.6 Hz, 1H), 7.72-7.06 (m, 15H), 4.68 (d, J=15 Hz, 1H), 3.83-3.75 (m, 3H), 3.73-3.60 (m, 1H), 3.59-3.41 (m, 1H), 3.23-3.03 (m, 3H), 2.69-2.65 (m, 1H); 13C NMR (CD3OD) δ163.52, 148.75, 141.15, 140.30, 136.47, 132.50, 130.88, 130.49, 130.35, 129.62, 129.46, 128.32, 127.53, 127.35, 127.04, 106.27, 73.14, 72.49, 67.06, 58.97, 55.16, 35.61, 34.93.
A solution of the compound of Example 9P (0.11 g, 0.2 mmol) and hydroxylamine hydrochloride (0.014 mg, 0.2 mmol) in pyridine (2 mL) was refluxed overnight. Workup and purification using HPLC with a solvent gradient from hexane in EtOH to 100% of EtOH provided compound 15GH (28 mg). 1H NMR (CD3OD) δ7.89-7.86 (m, 1H), 7.81 (s, 1H), 7.54 (d, J=4.0 Hz, 1H), 7.45-7.00 (m, 15H), 4.73 (d, J=14.1 Hz, 1H), 4.71 (d, J=14.2 Hz, 1H), 3.62-3.55 (m, 4H), 3.17 (d, J=14.2 Hz, 1H), 3.08-3.05 (m, 2H), 2.98 (d, J=14.1 Hz, 1H), 2.96-2.83 (m, 2H), 2.54 (s, 3H), 2.16 (s, 3H); 13C NMR (CD3OD) δ200.03, 163.85, 155.42, 141.19, 141.16, 140.19, 139.40, 139.00, 138.63, 135.31, 130.77, 130,62, 130.59, 130.48, 130.07, 129.71, 129.60, 129.57, 128.71, 128.11, 127.50, 126.35, 71.99, 71.93, 67.81, 67.24, 57.15, 57.09, 33.65, 26.72, 11.94; HRMS: calcd. for C37H40N3O5: 606.2968; found 6.2971.
Bis-m-cyano-p-fluorobenzyl cyclic urea was prepared using general alkylation and deprotection procedures. The urea (0.47 g, 0.79 mmol) in THF (20 mL) was treated with MeMgBr (3M, 2.5 mL, 0.5 mmol) under reflux for 3 hours. General workup and purification on TLC plate with EtOAc in CH2Cl2, followed by further purification on HPLC with 85% hexane in EtOH gave compound 15CI (40 mg) and compound 15CJ (80 mg).
Example 15CI: 1H NMR (CDCl3) δ7.64 (dd, J=7.0 Hz, J=2.2 Hz, 2H), 7.40-7.00 (m, 14H), 4.72 (dd, J=14.6 Hz, 2H), 3.75 (s, 2H), 3.55 (d, J=11.4 Hz, 2H), 3.22 (d, J=14.6 Hz, 2H), 3.08 (dd, J=13.6 Hz, J=2.6 Hz, 2H), 2.83 (dd, J=13.2 Hz, J=11.0 Hz, 2H), 2.59 (d, J=4.8 Hz, 6H), 2.51 (b, 2H); 13C NMR (CDCl3) δ196.31 (d, J=3.1 Hz), 161.71, 161.46 (d, J=255.6 Hz), 139.39, 135.78 (d, J=9.2 Hz), 134.74, 130.82 (d, J=2.3 Hz), 129.31, 128.60, 126.48, 125.38 (d, J=13.0 Hz), 116.97 (d, J=14.4 Hz), 70.89, 65.58, 55.08, 32.78, 31.26 (d, J=7.6 Hz); HRMS: calcd. for C37H37N2O5F2: 627.2671; found 62.2670.
Example 15CJ: 1H NMR (CDCl3) 7.74 (dd, J=7.0 Hz, J=2.2 Hz, 2H), 7.57-7.00 (m, 14H), 4.80 (d, J=14.3 Hz, 1H), 4.62 (d, J=14.3 Hz, 1H), 3.90 (bs, 2H), 3.71-3.61 (m, 2H), 3.53 (d, J=14.6 Hz, 1H), 3.29 (d, J=14.3 Hz, 1H), 3.25-3.17 (m, 4H), 2.93-2.82 (m, 2H), 2.68 (s, 3H), 2.66 (s, 3H); 13C NMR (CDCl3) δ196.48 (d, J=2.3 Hz), 162.37 (d, J=259.4 Hz), 161.75, 161.58 (d, J=255.6 Hz), 139.21, 139.15, 136.02 (d, J=8.4 Hz), 135.85 (d, J=8.4 Hz), 135.34 (d, J=3.8 Hz), 134.62 (d, J=3.0 Hz), 134.31, 130.76, 129.24, 128.68, 128.62, 126.63, 126.59, 125.42, (d, J=13.0 Hz), 117.03 (d, J=14.4 Hz), 116.41 (d, J=19.9 Hz), 113.67, 101.28 (d, J=15.3 Hz), 70.85, 65.96, 65.75, 55.09, 54.95, 32.96, 32.79, 31.25 (d, J=6.9 Hz); HRMS: calcd. for C36H34N3O4F2: 610.2517; found 610.2534.
In the synthesis of compound 9Q, compound 15CK was a minor stereoisomer and was isolated on HPLC with 80% hexane in EtOH. 1H NMR (CD3OD) δ7.55-7.53 (m, 2H), 7.48 (s, 2H), 7.33-7.14 (m, 10H), 7.10-7.07 (m, 4H), 4.75 (d, J=14.6 Hz, 2H), 3.61-3.58 (m, 4H), 3.08-3.04 (m, 2H), 2.99 (d, J=14.3 Hz, 2H), 2.96-2.90 (m, 2H), 2.17 (s, 6H); 13C NMR (CD3OD) δ163.94, 155.44. 141.22, 139.43, 138.96, 130.76, 130.63, 129.68, 129.56, 128.09, 127.46, 126.30, 72.00, 67.09, 57.03, 33.59, 11.97; HRMS: calcd. for C37H41N4O5: 621.3077; found 620.3091.
By the same procedure used to make Example 9Q, compound 15CL was obtained from compound 15CI in good yield. 1H NMR (CD3OD) δ 7.31-7.02 (m, 16H), 4.63 (d, J=13.9 Hz, 2H), 3.62-3.56 (m, 4H), 3.09-2.99 (m, 4H), 2.90-2.82 (m, 2H), 2.16 (d, J=2.2 Hz, 6H); 13C NMR (CD3OD) δ 163.76, 161.28 (d, J=248.7 Hz), 153.70, 141.18, 135.44 (d, J=3.8 Hz), 132.57 (d, J=8.4 Hz), 131.86 (d, J=3.8 Hz), 130.60, 129.59, 127.49, 127.13 (d, J=13.7 Hz), 117.21 (d, J=22.9 Hz), 71.90, 67.41, 56.34, 33.66, 14.8 (d, J=4.6 Hz); HRMS: calcd. for C37H39N4O5F2: 657.2889; found 657.2874.
Compound 15CM was obtained from compound XS534 by the same procedure used to make Example 9Q. 1H NMR (CD3OD) δ 7.34-7.02 (m, 16H), 4.66 (d, J=14.2 Hz, 1H), 4.64 (d, J=14.2 Hz, 1H), 3.64-3.54 (m, 4H), 3.09-2.83 (m, 6H), 2.15 (d, J=2.4 Hz, 3H); 13C NMR (CD3OD) δ 163.83, 161.29 (d, J=248.0 Hz), 161.08 (d, J=250.3 Hz), 153.67, 151.69, 141.21, 141.16, 135.44, 133.40 (d, J=9.2 Hz), 132.58 (d, J=8.4 Hz), 132.20, 131.98 (d, J=3.8 Hz), 130.61, 129.63, 127.49, 127.14 (d, J=13.7 Hz), 122.37 (d, J=13.77 Hz), 117.43 (d, J=22.9 Hz), 117.20 (d, J=22.9 Hz), 71.84, 67.41, 66.99, 56.38, 56.98, 33.74, 33.58, 14.78 (d, J=5.3 Hz); HRMS: calcd. for C36H38N5O5F2: 658.2841; found 658.2838.
To a stirred solution of 3.66 g(10 mmol) of compound XXVIIIf in 15 mL of DMF and 7 mL of THF, cooled to 0°C C., was added 1.2 g (40 mmol) of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred 5 min., and 4.66 g (40 mmol) of 3-furylmethylchloride was added. The mixture was warmed to ambient temperature over 30 min. and then recooled to 0°C C. The reaction was quenched by the addition of 0.4N HCl, and the resulting mixture was extracted with Et2O. The organic extract was washed with sat'd aq. NaHCO3, then brine, dried (MgSO4), and concentrated under reduced pressure to afford 4.92 g (93%) of alkylated intermediate. 1H NMR (CDCl3) δ 7.11-7.42 (m, 7H); 6.32 (s, 1H); 4.72 (d, 1H); 3.88(s, 1H); 3.82(m, 1H); 3.03(d, 1H); 2.79-2.97(m, 2H); 1.40 (s, 6H).
To 0.20 g (0.38 mmol) of acetonide protected bis(N-3-furylmethyl cyclic urea above was added 8 mL of MeOH and 1 mL of conc. aq. HCl. The solution was stirred 1 h at ambient temperature and poured into water. The white colloidal suspension was extracted with 1:1 Et2O-EtOAc, and the organic extract was washed with sat'd aq. NaHCO3, brine, dried (MgSO4), and concentrated under reduced pressure to afford an off-white solid. This material was dissolved in 7 mL of EtOAc and warmed to boiling. Hexane, 20 mL, was introduced, and the solution was concentrated to ∼6 mL. The product was triturated with 3 mL of hexanes and allowed to cool. Solvent was removed by pipette, and the white crystalline solid was washed with 9:1 hexanes-EtOAc. The diol 15FN, following removal of residual solvent at vacuum pump pressure, weighed 111 mg (60% of theoretical).
To 0.22 mL (2.3 mmol) of stirred, cooled POCl3 was added 0.20 mL (2.5 mmol) of DMF. The solution was stirred 5 min., and a solution of 530 mg (1.0 mmol) of acetonide protected bis (N-3-furylmethyl)cyclic urea, described in example 15FN above, in 0.5 mL of THF and 0.5 mL of DMF was introduced. The solution was warmed to ambient temperature with stirring over 25 min., whereupon an additional 0.10 mL of POCl3 was introduced. The reaction was heated to reflux for 30 min., cooled, and poured into water. The resulting colloidal solid was extracted with 1:1 Et2O-EtOAc, and the organic extract was washed with sat'd aq. NaHCO3, water, then brine. Drying (MgSO4), and concentration under reduced pressure afforded a brown oil. Chromatography on silica gel (gradient elution with 3:1 to 1:1 hexanes-EtOAc) afforded 120 mg (22%) of monoaldehyde intermediate as an oil. 1H NMR (CDCl3) δ 9.41(s, 1H, CHO); 7.52(s, 1H, furyl); 7.00-7.38(m, 12H, aryl); 6.59(s, 1H, furyl); 6.31 (s, 1H, furyl); 4.80 (d, 1H, J=14.6 Hz, one of NCH2); 4.69(d, 1H, J=14.6 Hz, NCH2); 3.77-4.03(m, 5H, 2×Hα, one of NCH2, CHOC(CH3)2OCH); 2.68-302 (m, 5H, one of NCH2, 4×Hβ); 1.44(s, 3H, CH3); 1.42(s, 3H, CH3).
To a stirred solution of 100 mg (0.18 mmol) of the monoaldehyde intermediate in 10 mL of MeOH and 1 mL of water was added 0.5 mL of conc. aq. HCl. The solution was stirred for 1 h at ambient temperature, poured into water, and extracted with 1:1 Et2O-EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford diol 15FO as an oil. 1H NMR (CDCl3) δ 9.43(s, 1H); 7.51(s, 1H); 6.98-7.36 (m, 12H); 6.64 (s, 1H); 6.32 (s, 1H); 4.73 (d, 1H, J=15 Hz); 4.64(d, 1H, J=15 Hz); 3.55-3.78(m, 5H); 2.62-3.14 (m, 6H).
To a stirred solution of 530 mg (1.00 mmol) of acetonide protected bis(N-3-furylmethyl cyclic urea, described in example 15FN above, in 8 mL of THF, cooled to -78°C C., was added 1.6 mL (2.5 mmol) of a 1.6M solution of n-BuLi in THF. The solution was stirred 20 min. at -78°C C., and DMF was added. The reaction was stirred 1 h at -78°C C., whereupon it was quenched with 1N HCl. The mixture was extracted with Et2O, and the organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with 1:1 EtOAc-hexanes) afforded, after removal of solvent, 310 mg (53%) of dialdehyde intermediate as an oil. 1H NMR (CDCl3) δ 9.42 (s, 1H); 7.52 (d, 1H, J=2 Hz); 7.20-7.36 (m, 5H); 6.58 (d, 1H, J=2H); 4.18(ABq, 2H, JAB=13 Hz, Δv=330 Hz); 4.00(br. s, 1H); 3.90(d, 1H, J=11 Hz); 2.84(ABx, 2H, JAB=13.5 Hz, JAX=1.7 Hz, JBX=11.3 Hz, Δv=78 Hz); 1.45(s, 6H).
To a stirred, cooled (-78°C C.) solution of 120 mg (0.21 mmol) of the dialdehyde intermediate in 4 mL of Et2O was added 2 mL (2 mmol) of 1M diisobutylaluminum hydride in CH2Cl2. The solution was stirred 15 min at -78°C C., the dry ice bath was removed, and the reaction was quenched with saturated aqueous sodium potassium tartrate. The mixture was diluted with Et2O, and the two phases were stirred together for 30 min. The phases were separated, and the organic phase was dried (MgSO4), concentrated, and chromatographed on silica gel. The product was eluted with EtOAc, concentrated, and redissolved in 8 mL of MeOH. This solution was treated with 0.4 mL of con. aq. HCl, stirred 1 h, and poured into water. The colloidal suspension was extracted with EtOAc, and the organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with EtOAc) afforded a glass which was lyophilized from benzene-acetronitrile to give 62 mg (57%) of tetraol 15FP as a powder. 1H NMR (CD3OD) δ 7.43 (d, 1H, J=2 Hz); 7.20-7.37(m, 3H); 7.11(dd, 2H, J=8.1, 1.1 Hz); 6.37(d, 1H, J=2H); 4.22(ABq, 2H, JAB=13.3 Hz, Δv=33 Hz); 3.76(ABq, 2H, J=14.6 Hz, Δv=460 Hz); 3.65(br. s, 1H); 3.56(br. d, 1H, J=11 Hz); 2.98(ABx, 2H, JAB=13.3 Hz, JAX=1.8 Hz, JBX=12.1 Hz, Δv=54 Hz). Mass spec. (NH3-CI/DDIP): 529((M+H--H2O)+, 100%).
To a stirred solution of 55 mg (0.1 mmol) of monoaldehyde intermediate prepared in example 15FO in 2 mL of EtOH and 1 mL of water was added 35 mg (0.5 mmol) of hydroxylamine hydrochloride. The solution was stirred 25 h at ambient temperature, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 33 mg (58%) of oxime 15FQ as an amorphous solid. Mass Spec. (NH3-CI/DDIP): 530 ((M+H)+, 8%); 512 ((M+H--H2O)+, 100%). 1H NMR (CDCl3) δ 7.76(s, 1H); 7.01-7.38(m, 13H); 6.47(s, 1H); 6.32(s, 1H); 4.59-4.76(m, 2H); 3.55-3.84(m, 4H); 3.25(d, 1H, J=15 Hz); 2.75-3.09 (m, 5H).
c.) To a stirred solution of 50 mg (0.097 mmol) of compound of example 15FO in 6 mL of EtOH was added 20 mg (excess) sodium borohydride. The solution was stirred 3 h at ambient temperature, kept at -23°C C. for 15 h, and rewarmed to ambient temperature with stirring over 6 h. The reaction was quenched with 10% aq. HOAc, stirred for 30 min., and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with EtOAc) followed by lyophilization afforded 45 mg (90%) of triol 15FR as a white powder. 1H NMR (CDCl3) δ 7.05-7.38(m, 11H); 6.85(s, 1H); 6.82(s, 1H); 6.30(s, 2H); 4.51-4.61(m, 2H); 4.31(d, 1H, J=13 Hz); 3.93(dd, J=14, 5 Hz); 3.65-3.77(m, 2H) 3.51-3.60(m, 1H); 2.74-3.12(m, 6H). Mass Spec. (NH3-CI/DDIP): 517((M+NH4--H2O)+, 7%); 499 ((M+H--H2O)+, 100%).
A flask was charged with lithium chloride (1.02 g, 24.0 mmol, 1.2 equiv.) and flame dried in vacuo. A nitrogen atmosphere was introduced and dry dimethylformamide (12.0 ml) was added. The flask was cooled to 0°C C. and the starting alcohol, 2-furylmethanol (1.7 ml, 20.0 mmol) was added via syringe. The reagents, 2,6-lutidine (3.5 ml, 30.0 mmol, 1.5 equiv., distilled from calcium hydride) and methanesulfonyl chloride (1.7 ml, 22.0 mmol, 1.1 equiv.), were added and stirring continued for one hour. The reaction was poured onto ice and extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium carbonate, whereupon a precipitate formed. The precipitate was removed by filtration and the layers separated. The organic layer was dried with anhydrous sodium carbonate. The product was isolated by filtration and removal of solvent on an ice cooled rotary evaporator. When the volume neared 20 ml, the flask was removed from the rotary evaporator, flushed with nitrogen and diluted with dry dimethylformamide (20.0 ml). This solution containing 2-chloromethylfuran was used without characterization in the next reaction.
The cyclic urea acetonide XXVIIIf (1.02 g, 2.79 mmol) was added to the solution of 2-chloromethylfuran. Sodium hydride (490 mg, 16.3 mmol, 5.9 equiv., 80% oil dispersion) was added and stirring continued for one hour. The reaction was then quenched by the addition of water and extracted with ethyl acetate-hexanes (1:1). The organic phase was washed twice with water, once with brine, and dried over anhydrous magnesium sulfate. Filtration and evaporation gave the crude product which was purified by flash column chromatography (30% ethyl acetate-70% hexanes). The column provided two major fractions: a nonpolar fraction containing the significantly contaminated bis-alkylated product and a polar fraction containing adequately pure mono-alkylated cyclic urea intermediate (343 mg). 1H-NMR (300 MHz, CDCl3) δ 7.28(11H, m), 6.27(1H, t), 6.05(1H, d), 5.07(1H, d), 4.83(1H, d), 4.22(1H, dd), 3.88(2H, m), 3.48(1H, m), 3.15-2.88(4H, m), 2.70(1H, t), 1.48(3H, s), 1.46 (3H, s). HRMS (NH3 CI) Calculated for C27H31N2O4 (M+H): 447.2284; observed: 447.2277. The nonpolar fraction was further purified by flash column chromatography (15% ethyl acetate-85% hexanes) to give pure bis-alkylated intermediate (73.4 mg, 5% ). 1H-NMR (300 MHz, CDCl3) δ 7.37-7.09(11H, m), 6.27 (2H, dd), 6.08(2H, d), 4.94(2H, d), 3.90(2H, s), 3.82(2H, b), 3.03(2H, d), 2.90(4H, m), 1.41(6H, s). 13C NMR (75.4 MHz, CDCl3) δ 160.74, 151.93, 142.19, 138.86, 129.45, 128.57, 126.46, 110.21, 108.71, 75.26, 61.49, 48.45, 32.87, 26.71. MS (NH3 CI) m/e 527 (M+H).
The monoalkylated cyclic urea acetonide above (33.5 mg, 0.075 mmol) was dissolved in methanol (3.0 ml). p-Toluenesulfonic acid monohydrate (2.9 mg) was added and stirring continued for four hours. The reaction was quenched by the addition of saturated aqueous sodium carbonate. The solvent was removed on a rotary evaporator and the residue applied to a flash silica gel column. The column was eluted with initially 50% ethyl acetate-50% hexanes and finally 100% ethyl acetate. This provided 15FS (27.8 mg, 91%) in excellent yield. 1H-NMR (300 MHz, CD3OD) δ 7.43(1H, s), 7.34-7.12(10H, m), 6.31(1H, m), 6.10(1H, d), 4.75(1H, d), 3.86(1H, dd), 3.65(2H, m), 3.39(1H, m), 3.11(2H, m), 3.01(1H, dd), 2.88(1H, d), 2.77(1H, dd). 13C NMR (75.4 MHz, CD3OD) δ 162.17, 151.45, 142.30, 139.79, 139.74, 129.10, 129.06, 128.08, 127.91, 125.96, 125.64, 109.80, 108.15, 70.90, 70.53, 65.28, 58.73, 32.70, 31.94. HRMS(NH3 CI) Calculated for C24H27N2O4 (M+H): 407.1971; Observed 407.1961.
The bisalkylated acetonide was deprotected using the same procedure. Flash silica gel chromatography using 50% ethyl acetate-50% hexanes gave 15FT in 83% yield. 1H-NMR (400 MHz, CD3OD) δ 7.44 (2H, dd), 7.32-7.13(10H, m), 6.33 (2H, dd), 6.15 (2H, d), 4.75 (2H, d), 3.64(2H, bd), 3.60(2H, s), 3.05-2.89(6H, m). 13C NMR (100.6 MHz, CD3OD) δ 163.11, 153.01, 143.93, 130.63, 129.4 7, 127.38, 111.36, 110.01, 71.75, 67.24, 48.88, 32.99. HRMS(NH3 CI): Calculated for C29H31N2O5 (M+H): 487.2233; Observed: 487.2226.
The starting 3-carbomethoxy-2,5-dihydrothiophene was prepared from 1,4-dithiane-2,5-diol, trimethylphosphonoacrylate and triethylamine as described in the literature [J. Org. Chem. 43 (23) 4431 (1978)]. The resulting ester (1.03 g, 7.15 mmol) was dissolved in dry methylene chloride (16.0 ml) and cooled to -78°C C. under a nitrogen atmosphere. A solution of diisobutylaluminum hydride (11.9 ml, 17.88 mmol, 2.5 equiv., 1.5M in toluene) was added and stirring continued for two hours. The reaction was then briefly warmed to room temperature then recooled to -78°C C. Excess reagent was then quenched with methanol (5.0 ml) and the reaction was allowed to warm to room temperature. The reaction was diluted with ether and treated with a saturated solution of sodium potassium tartrate. The clarified aqueous phase was extracted with two additional portions of ether. The combined organic layers were dried with magnesium sulfate, filtered and evaporated. Purification was accomplished by flash silica gel chromatography (5% methanol 95% methylene chloride). The resulting 3-hydroxymethyl-2,5-dihydrothiophene was isolated in 91% yield (753.7 mg). 1H-NMR (300 MHz, CDCl3) δ 5.77(1H, bs), 4.22(2H, d), 3.74(4H, m), 2.09(1H, t). 13C NMR (75.4 MHz, CDCl3) δ 142.77, 124.13, 61.39, 38.45, 38.21. MS(CH4 CI) m/e 117 (M+H).
Ths alcohol (663.0 mg, 5.72 mmol) was dissolved in dry methylene chloride (20 ml) under a nitrogen atmosphere. Dry triethylamine (1.2 ml, 8.7 mmol, 1.5 equiv.) was added and the reaction cooled to 0°C C. Methanesulfonic anhydride (1.2 g, 6.86 mmol, 1.2 equiv.) was added and reaction continued for 0.5 hours. The reaction was diluted with methylene chloride and washed with dilute hydrochloric acid and brine. Drying over magnesium sulfate, filtration and evaporation gave the crude mesylate which was used without purification.
The residue was dissolved in dry dimethylformamide (5.0 ml) and the cyclic urea acetonide XXVIIIf (524.5 mg, 1.43 mmol) was added. Sodium hydride (172 mg, 5.72 mmol, circa 4 equiv., 80% oil dispersion) was added and stirring continued overnight. The reaction was quenched by the careful addition of water and extracted with 50% ethyl acetate-50% hexanes. The organic phase was washed twice with water, once with brine, and dried over magnesium sulfate. Filtration and evaporation gave the crude product which was purified by flash silica gel chromatography (15% ethyl acetate-85% hexanes). The desired bisalkylated product was obtained in excellent yield (720.1 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.29(6H, m), 7.14(4H, d), 5.40(2H, s), 4.32(2H, d), 4.08(2H, s), 3.83(2H, d), 3.78-3.49(8H, m),3.06(2H, dd), 2.87 (2H, d), 2.83 (2H, dd), 1.31 (6H, s). HRMS (NH3 CI) Calculated for C32H39N2O3S2 (M+H)+: 563.2402; Observed: 563.2394.
Removal of the acetonide protecting group using the hydrolysis procedure described in the procedure of example 15FS gave compound 15FU. (34.1 mg, 78%). 1H-NMR (300 MHz, CDCl3) δ 7.36-7.11(10H, m), 5.45(2H, bs), 4.27(2H, d), 3.93(2H, bs), 3.82-3.49(10H, m), 3.16(2H, dd), 2.87 (2H, dd), 2.84 (2H, d), 2.62 (2H, bs). 13C-NMR (75.43 MHz, CDCl3) δ 162.14, 139.66, 139.10, 129.36, 128.66, 128.51, 126.70, 71.81, 63.01, 50.97, 39.70, 38.31, 32.91. HRMS(NH3 CI) Calculated for C29H35N2O3S2 (M+H): 523.2089; Observed: 523.2071.
Compound 15FU, protected as the acetonide, (53.2 mg, 0.0947 mmol) was dissolved in dry methylene chloride (2.0 ml) under a nitrogen atmosphere. The reaction was cooled to 0°C C. and solid m-chloroperoxybenzoic acid (83.7 mg, 0.388 mmol, 4.1 equiv., circa 80% active) was added and stirring continued for three hours with gradual warming to room temperature. The reaction was then diluted with methylene chloride and washed successively with saturated sodium bisulfite, saturated sodium carbonate, and brine. The organic phase was dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash silica gel chromatography (50% ethyl acetate-50% hexanes) to give the bis-sulfone acetonide (61.5 mg, slightly more than theoretical). This material was of sufficient purity for the subsequent transformations. 1H-NMR (300 MHz, CDCl3) δ 7.39-6.95 (10H, m), 5.60 (2H, bs), 4.22 (2H, d), 4.06 (2H, s), 3.83-3.47 (10H, m), 3.13 (2H, d), 2.99 (2H, d), 2.73(2H, dd), 1.31(6H, s). MS(NH3 CI) m/e 563(M+H-SO2), 499 (M+H--2SO2).
Removal of the acetonide protecting group using the hydrolysis procedure described in the procedure of example 15FS gave compound 15FV (17.4 mg, 65%). 1H-NMR (300 MHz, CDCl3) δ 7.28(6H, m), 7.11(4H, d), 5.57(2H, bs), 4.16 (2H, d), 3.92 (2H, s), 3.83-3.45 (10H, m), 3.23 (2H, d ), 2.92(2H, d), 2.74(2H, t). 13C-NMR (100.6 MHz, CDCl3) δ 161.99, 139.00, 135.52, 129.32, 128.84, 127.04, 123.28, 71.04, 6 3.84, 56.53, 53.07, 33.14. HRMS(FAB (glycerol/TFA): Calculated for C29H35N2O7S2 (M+H): 587.1886; Observed: 587.1889.
Compound 15FU, protected as the acetonide, (46.6 mg, 0.0829 mmol) was dissolved in dry 1,2-dichloroethane (2.0 ml). Addition of 2,3-dichloro-5,6-dicyanobenzoquinone (41.4 mg, 0. 182 mmol, 2.2 equiv.) resulted in an instantaneous conversion to product. The reaction was applied to a flash silica gel column and eluted with first methylene chloride then 5% methanol-95% methylene chloride. The desired bis-thiophene intermediate was isolated in 92% yield (42.4 mg). 1H-NMR (300 MHz, CDCl3) δ 7.37-7.20(8H, m), 7.10(4H, d), 6.98(2H, d), 6.95(2H, b), 4.88(2H, d), 3.83(2H, bs), 3.80(2H, bd (obscured)), 3.16(2H, d), 2.92(2H, dd), 2.82(2H, dd), 1.37(6H, s). 13C-NMR (75.4 MHz, CDCl3) δ 161.29, 139.01, 138.84, 129.43, 128.71, 127.74, 126.53, 126.37, 123.87, 110.19, 75.59, 60.89, 51.00, 33.58, 26.79. MS(NH3 CI) m/e 559 (M+H).
After deprotection of the acetonide as described for example 15FS, the resulting residue was applied to a preparative silica gel plate (0.25 mm) and eluted with 50% ethyl acetate-50% hexanes. Isolation of the appropriate fractions gave compound 15FW (12.9 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 7.38(8H, m), 7.12(4H, d), 7.00 (2H, dd), 6.97 (2H, bd), 4 . 82 (2H, d), 3.64 (2H, s), 3.58(2H, bd), 3.16(2H, d), 3.04(2H, dd), 2.89(2H, dd), 2.34(2H, bs). 13C-NMR (75.4 MHz, CDCl3) δ 161.69, 139.4, 138.92, 129.46, 128.68. 127.98, 126.58, 126.43, 124.07, 71.77, 64.04, 50.20, 32.81. MS(NH3 CI) m/e 519(M+H).
Compound 15FV, protected as the acetonide, (15.5 mg, 0.024 mmol) was dissolved in dry toluene (5.0 ml) under nitrogen. The reaction was heated at reflux for seven hours then allow to cool overnight. The solvent was removed under reduced pressure and the residue applied to a preparative silica gel plate (0.25 mm) and eluted with 25% ethyl acetate-75% hexanes. The bis-diene intermediate was isolated in 61% yield (7.5 mg). 1H-NMR (300 MHz, CDCl3) δ 7.37-7.17(10H, m), 6.31(2H, dd), 5.35(2H, s), 5.13 (2H, d), 4.83 (2H, d), 4.70(2H, s), 3.88(2H, s), 3.85 (2H, m), 2.89 (4H, m), 2.64(2H, d), 1.44(6H, s) 13C-NMR (100.6 MHz, CDCl3) δ 161.68, 142.93, 139.49, 136.85, 129.39, 128.64, 126.49, 120.23, 115.46, 110.22, 75.76, 59.19, 52.81, 33.40, 26.90. MS (NH3 CI) m/e 499 (M+H).
After deprotection of the acetonide as described for example 15FS, the resulting residue was applied to a preparative silica gel plate (0.25 mm) and eluted with 50% ethyl acetate-50% hexanes. Isolation of the appropriate fractions gave compound 15FX (2.9 mg, 42%). 1H-NMR (400 MHz, CDCl3) δ 7.37-7.16(10H, m), 6.31(2H, dd), 5.34(2H, d), 5.17(2H, s), 5.12(2H, d), 4.79(2H, s), 4.74(2H, d), 3.76(2H, s), 3.64(2H, d), 3.06-2.88(4H, m), 2.67(2H, d), 2.28(2H, s). 13C-NMR (100.6 MHz, CDCl3) δ 162.02, 143.05, 139.93, 136.88, 129.48, 128.68, 126.47, 120.08, 115.61, 71.89, 63.06, 52.42, 32.68. HRMS(NH3 CI): Calculated for C29H35N2O3 (M+H): 459.2648; Observed: 459.2653.
TABLE 2d | ||||||||
MS | ||||||||
Ex. | Stereo | HPLC | M + H | |||||
No. | 2:3:4:5 | R22 | R23 | K1 | IC90 | mp, °C C. | (M + NH4) | Notes |
9A | RSSR | m-(HO-- | m-(HONHCH2)-- | ++ | +++ | 214-216 | 595 | |
N═CH)C6H4CH2-- | C6H4CH2-- | + | ||||||
9B | RSSR | m-(HONHCH2)-- | m-(HONHCH2)-- | ++ | +++ | |||
C6H4CH2--.HOAC | C6H4CH2--.HOAC | + | ||||||
9C | RSSR | m(HONHCH2)-- | m-(HONHCH20)-- | ++ | +++ | 610 | ||
C6H4CH2-- | C6H4CH3-- | + | ||||||
9D | RSSR | m-(C6H5CH2ON═CH)-- | m-(C6H5CH2ON═CH)-- | ++ | ++ | 170.5-171 | 790 | |
C6H4CH2-- | C6H4CH2-- | |||||||
9E | RSSR | m-(HONCH2)-- | m-(HONHCH2)-- | ++ | +++ | |||
C6H4CH2--HCl | C6H4CH2--.HCl | + | + | |||||
9F | RSSR | m-(C6H5CH2ONHCH2)-- | m-(C6H5CH2ONHCH3)-- | ++ | + | 775 | ||
C6H4CH2-- | C6H4CH2-- | (792) | ||||||
9G | RSSR | m-(CH3OC(═O)--)-- | m-(CH3OC(═O)--O)-- | ++ | +++ | 146-147 | 655 | |
C6H4CH2-- | C6H4CH2-- | + | ||||||
9H | RSSR | m-(CH3CH(OH))-- | m-(CH3CH(OH)) | ++ | +++ | 612 | ||
C6h4CH2-- | C6H4CH2-- | + | ||||||
9I | RSSR | m-(CH3NHCH2)-- | m-(CH3NHCH2)-- | 593 | ||||
C6H4CH2 | C6H4CH2 | |||||||
9J | RSSR | m-(HOCH2CH2N═CH)-- | m-(HOCH2CH2N═CH)-- | ++ | +++ | 649 | ||
C6H4CH2-- | C6H4CH2-- | + | ||||||
9K | RSSR | m-(HOCH2CH2N═CH)-- C6H4CH2-- | ++ | +++ | 649 | |||
+ | ||||||||
9L | RSSR | m-(C6H5CH2NHC(═O)-- | m-(C6H5CH2NHC(═)-- | ++ | +++ | 150(dec) | 805 | |
O)--C6H4CH2-- | O)--C6H4CH2-- | + | ||||||
9M | RSSR | m-(CH3NHC(═O))--O)-- | m-(CH3NHC(═O))--O)-- | ++ | +++ | 150(dec) | 670 | |
C6H4CH2-- | C6h4CH2-- | + | ||||||
9N | RSSR | m-(HOCH2CC)-- | m-Br--C6H4CH2-- | ++ | +++ | 639/641(656/658) | ||
C6H4CH2-- | + | |||||||
9o | RSSR | m-(CH3C(═O))-- | m-Br--C6H4CH2-- | ++ | +++ | 190-191 | 644/646 | |
C6R4CH2-- | + | |||||||
9P | RSSR | m-(CH3C(═O))-- | m-(CH3C(═))-- | ++ | +++ | 158-159 | 608 | |
C6H4CH2-- | C6H4CH2-- | + | ||||||
9Q | RSSR | m-(CH3C(═NOH))-- | m-(CH3C(═NOH))-- | ++ | +++ | 200-202 | 621 | |
C6H4CH2-- | C6H4CH2-- | + | ||||||
9R | RSSR | m-(CH3CH(OH))-- | m-Br--C6H4CH2-- | ++ | +++ | 629/631 | ||
C6H4CH2-- | + | |||||||
9S | RSSR | m-(ClCH2)--C6H4CH2-- | m-(ClCH2)--C6H4CH2-- | ++ | +++ | 156-157 | 603 | |
9T | RSSR | m-(5-tetrazolyl) | m-(5-tetrazolyl) | +++ | + | 159.4 | 643.2893 | |
--C6H4CH2-- | C6H4CH2-- | |||||||
9U | RSSR | m-(5-tetrazolyl) | cyclopropyl-methyl | +++ | +++ | 171.6 | 539.2771 | |
--C6H4l CH2-- | ||||||||
10A | RSSR | m-(CO2H)-- | H | +++ | + | 141-143 | 2 | |
C6H4CH2 | ||||||||
10C | RSSR | m-(N)-- | m-(OHC)--C6H4CH2-- | +++ | +++ | 189-191 | 560(577) | 4 |
C6H4CH2-- | ||||||||
10D | RSSR | m-(CH3ON═CH)-- | m-(CH3ON--CH)-- | ++ | + | 183-185 | (638) | 5 |
C6H4CH2-- | C6H4CH2-- | |||||||
10E | RSSR | p-(CH3C(═O)O)-- | p-(HO)--C6H4CH2-- | +++ | +++ | 110-112 | 623 | 6 |
C6H4CH2-- | ||||||||
10F | RSSR | m-(CH3C(═O)O)-- | m-(CH3C(═O)O)-- | ++ | +++ | 623 | 8 | |
C6H4CH2-- | C6H4CH2-- | |||||||
10G | RSSR | m-(NH2C(═O))-- | m-(NH2C(═O))-- | +++ | +++ | (610) | 7 | |
C6H4CH2-- | C6H4CH2-- | |||||||
10H | RSSR | m-(NH2C(═O) | m-(NH2C(═O) | +++ | +++ | NMR only | ||
--CH2O)--C6H4CH2-- | --CH2O)--C6H4CH2-- | |||||||
10I | RSSR | m-(HO)--C6H4CH2-- | H | +++ | +++ | 193-914 | 433 | 2 |
10J | RSSR | m-(CH3)--C6H4CH2-- | m-(HO)--C6H4CH2-- | +++ | +++ | 536 | 3 | |
10K | RSSR | 2-Naphthylmethyl | m-(HO)--C6H4CH2-- | +++ | +++ | 137-138 | 573 | 3 |
10L | RSSR | p-(CH3C(═O)--O)-- | p-(CH3C(═O)--O)-- | ++ | +++ | 623 | 8 | |
C6H4CH2-- | C6H4CH3-- | |||||||
10M | RSSR | m-(NH2NHC(═O))-- | m-(NH2NHC(═O))-- | +++ | +++ | 205 | 623 | 7 |
C6h4CH2-- | C6H4CH2-- | |||||||
10N | RSSR | p-(NH2NHC(═O))-- | m-(NH2NHC(═O)-- | +++ | +++ | 215-217 | 623 | 7 |
C6H4CH2-- | C6H4CH2-- | |||||||
10o | RSSR | p-(HOCH2) | m-(HO)--C6H4CH2-- | +++ | +++ | 141-144 | 553 | 3 |
--C6H4CH2-- | ||||||||
10P | RSSR | m-(NH2C(═O)--NHN═CH)-- | m-(NH2C(═O)--NHN═CH)-- | +++ | +++ | 301-303 | 5 | |
C6H4CH2-- | C6H4CH2-- | |||||||
10Q | RSSR | 2-picolinyl- | m-(HO)--C6H4CH2-- | ++ | +++ | 524 | 3 | |
10R | RSSR | m-(CH3ONHC(═O))-- | m-(CH3ONHC(═O))-- | +++ | +++ | 150-158 | (670) | 7 |
C6H4CH2-- | C6H4CH2-- | |||||||
10S | RSSR | p-(CH3ONHC(═O))-- | p-(CH3ONHC(═O))-- | +++ | +++ | 186-189 | 653 | 7 |
C6H4CH2-- | C6H4CH2-- | |||||||
10T | RSSR | m-(HOCH2CH(OH)-- | m-(HOCH2CH(OH)-- | +++ | +++ | 113-115 | 9 | |
CH2O)--C6H6CH2-- | CH2O)--C6H4CH2-- | |||||||
10U | RSSR | m-(adamantamido)- | m-(adamantamido)- | + | +++ | 183-184 | 893 | 8 |
C6H4CH2-- | C6H4CH3-- | |||||||
10V | RSSR | m-(HO)--C6H4CH2-- | m-(adamatamido)- | ++ | +++ | 196-198 | 716 | 6 |
C6H4CH2-- | ||||||||
10W | RSSR | m-(CH3CH2OC(═O)) | m-(CH3CH2OC(═O)) | +++ | + | 139-143 | 11 | |
--C6H4CH2-- | --C6H4CH2-- | |||||||
10X | RSSR | m-(HONHC(═O))-- | m-(HONHC(═O))-- | +++ | + | 139-143 | 11 | |
C6H4CH2-- | C6H4CH2-- | |||||||
10Y | RSSR | m-(HOCH2CH2O)-- | m-(HOCH2CH2O)-- | +++ | +++ | 245-247 | 627 | 9 |
C6H4CH2-- | C6H4CH2-- | |||||||
10Z | SRRS | p-(HOCH2)C6H4CH2 | p-(HOCH2)C6H4CH2 | + | ++ | 198-199 | 567 | 1 |
11A | RSSR | m-(NH2C(═NH))-- | m-(NH2C(═NH)-- | ++ | + | 224-226 | 591 | 13 |
C6H4CH2--HOAc | C6H4CH2--HOAc | |||||||
11B | RSSR | (HOCH2--CH(OH)-- | (HOCH2--CH)OH))-- | +++ | +++ | 135-137 | 627 | 9 |
C6H4CH2-- | ||||||||
m, p, positions | ||||||||
mixture | ||||||||
11C | RSSR | m-(NH2C(═))-- | m-(NH2C(═NH)-- | +++ | +++ | 229-231 | 4 | |
C6H4CH2l -- | C6H4CH2--HOAc | |||||||
11D | RSSR | p-(HO)--C6H4CH2-- | p-(HO)-m-(HOCH2)-- | +++ | ++ | 178-180 | 14 | |
C6H5CH2-- | ||||||||
11E | RSSR | p(HO)--C6H4CH2-- | p-(HO)-m-(OHC)-- | +++ | +++ | 567 | 14 | |
C6H5CH2-- | ||||||||
11F | RSSR | p-(CH3CH2OC(═))-- | p-(CH3CH2OC(═O))-- | ++ | + | 174-178 | 651 | 10 |
C6H4CH2-- | C6H4CH2-- | |||||||
11G | RSSR | m-(CH3OC(═O))-- | m-(CH3NHC(═O))-- | +++ | +++ | 158-161 | 622(639) | 4 |
C6H4CH213 | C6H4CH2-- | |||||||
11H | RSSR | m-(CH3NHC(═O))-- | m-(CH3NHC(═O))-- | +++ | +++ | 1601∝163 | 621 | 7 |
C6H4CH2-- | C6H4CH2-- | |||||||
11I | RSSR | benzyl | m-(HO)--C6H4CH2-- | +++ | +++ | 189-193 | 523 | 3 |
11J | RSSR | 2-Naphthylmethyl | p-(HOCH2)--C6H4CH2 | +++ | +++ | 199-201 | 5587 | 3 |
11K | RSSR | m-(HOCH2--CH(OH) | m-(HOCH2--CH(OH)) | +++ | +++ | 627 | 9 | |
--C6H4CH2-- | --C6H4CH2-- | |||||||
11L | RSSR | p-(HOCH2--CH(OH) | p-(HOCH2--CH(OH) | +++ | +++ | 627 | 9 | |
--C6H4CH2-- | --C6H4CH2-- | |||||||
11M | RSSR | m-(HOCH2) | m-(CH3NHC(═O))-- | +++ | +++ | 107-109 | (611)594 | 4 |
--C6h4CH2-- | C6H4CH3-- | |||||||
11N | RSSR | p-(HOCH2)-- | H | +++ | +++ | 112-114 | 447 | 2 |
C6H4CH2-- | ||||||||
11o | RSSR | m-((HO)2B)-- | m-((HO)2B)-- | +++ | +++ | 263-267 | 15 | |
C6H4CH2-- | C6H4CH2-- | |||||||
11P | RSSR | m-(NO2)--C6H4CH2-- | m-(C6H5CH2O)--C6H4CH2-- | +++ | +++ | 173-176 | (675) | 3 |
11Q | RSSR | m-(NH2)--C6H4CH2-- | m-(HO)--C6H4CH2 | +++ | +++ | 116-120 | 538 | 3 |
11R | RSSR | m-(CH3CH2NHC | m-(CH3CH2NHC(═O))-- | +++ | +++ | 135-138 | 649 | 7 |
(═O))--C6H4CH2-- | C6H4CH2-- | |||||||
11S | RSSR | m-((CH3)2N | m-((CH3)2NH(═))-- | ++ | +++ | 132-134 | 649 | 7 |
C(═O))--C6H4CH2-- | C6H4CH2-- | |||||||
11T | RSSR | m-(CH3O2C)--C6H4CH3 | m-((CH3CH2)2NC | +++ | +++ | (681) | 4 | |
(═))--C6H4CH2-- | ||||||||
11U | RSSR | m-(CH3O2C)-- | m-(CH3CH2NHC | +++ | +++ | (653) | 4 | |
C6H4CH2-- | (═O))--C6H4CH2-- | |||||||
12A | RSSR | 6-amino-1-hexyl | 6-amino-1-hexyl | + | + | 525 | ||
12B | RSSR | 6-amino-1-hexyl | benzyl | ++ | + | 516 | ||
12C | RSSR | 6-hydroxy-1-hexyl | H | +++ | +++ | 427 | ||
12D | RSSR | 6-hydroxy-1-hexyl | 6-hydroxy-1-hexyl | +++ | +++ | 527 | ||
12E | RSSR | cyclopropyl methyl | 6-hyrdoxy-1-hexyl | +++ | +++ | 481 | ||
12F | RSSR | 4-hydroxy-1-butyl | 4-hydroxy-1-butyl | ++ | ++ | 471 | ||
12G | RSSR | 5-carboxy-1-pentyl | 5-carboxy-1-pentyl | +++ | +++ | 555 | ||
12H | RSSR | 5-carbomethoxy-1- | 5-carbomethyl-1- | ++ | ++ | 583 | ||
pentyl | pentyl | |||||||
12I | RSSR | 5-carbomethoxy-1- | 5-carboxy-1-pentyl | +++ | + | |||
pentyl | ||||||||
12J | RSSR | 3-iodobenzyl | 3-iodobenzyl | +++ | +++ | 759 | ||
12K | RSSR | 8-hydroxy-1-octyl | 8-hydroxy-1-octyl | ++ | +++ | 583 | ||
12L | RSSR | 2-(hyrdoxy | 2-(hydroxy | + | 495 | |||
methyl)- | methyl)- | |||||||
cyclopropyl-methyl | cyclopropyl- | |||||||
methyl | ||||||||
12M | RSSR | benzyl | 2-(hydroxy | +++ | +++ | 501 | ||
methyl)- | ||||||||
cyclopropyl- | ||||||||
methyl | ||||||||
12N | RSSR | 2-(hydroxy | H | ++ | + | 411 | ||
methyl)- | ||||||||
cyclopropyl- | ||||||||
methyl | ||||||||
12o | RSSR | 7-hydroxy-1-heptyl | H | ++ | ++ | 411 | ||
12P | RSSR | 7-hydroxy-1-heptyl | 7-hydroxy-1-heptyl | ++ | +++ | 555 | ||
12Q | RSSR | 3-(carbanoyl | 3-(carbamoyl | +++ | + | 185 | 655 | |
thio)benzyl | thio)benzyl | |||||||
12R | RSSR | (3-methylthio) | (3-methylthio) | +++ | +++ | 169 | 599 | |
benzyl | benzyl | |||||||
12S | RSSR | 3- | 30 | +++ | +++ | 633 | ||
(methylsulfonyl) | (methylsulfonyl) | |||||||
benzyl | benzyl | |||||||
12T | RSSR | 2-[(2-hydroxy | H | ++ | + | 415 | ||
ethyl)oxy]ethyl | ||||||||
12U | RSSR | 2-[(2-hydroxy | 2-[(2-hydroxy | + | ++ | 503 | ||
ethyl)oxy]ethyl | ethyl)oxy]ethyl | |||||||
12V | RSSR | 6-acetoxy-1-hexyl | 6-hydroxy-1-hexyl | ++ | +++ | 569 | ||
12W | RSSR | 6-(N-methylamino | 6-(N-methylamino | ++ | ++ | 641 | ||
carboxy)-1-hexyl | carboxy)-1-hexyl | |||||||
12X | RSSR | 6-(N-methylamino | 6-acetoxy-1-hexyl | ++ | +++ | 626 | ||
carboxy)-1-hexyl | ||||||||
12Y | RSSR | 6-(N-methylamino | 6-acetoxy-1-hexyl | +++ | 584 | |||
carboxy)-1-hexyl | ||||||||
12Z | RSSR | 2-(2-hydroxy | H | ++ | 425 | |||
ethyl) | ||||||||
cyclopropyl- | ||||||||
methyl | ||||||||
13A | RSSR | 2-(3- | H | ++ | 439 | 16 | ||
hydroxypropyl)- | ||||||||
cyclopropyl- | ||||||||
methyl | ||||||||
13B | RSSR | [2-(2- | H | ++ | 481 | 16 | ||
hydroxypropyl] | ||||||||
3,3-dimethyl] | ||||||||
13C | RSSR | [2-(2- | [2-(2- | + | 635 | |||
hydroxypropyl)- | hydroxypropyl)- | |||||||
3,3-dimethyl] | 3,3-dimethyl] | |||||||
cyclopropyl- | cyclopropyl- | |||||||
methyl | methyl | |||||||
13D | RSSR | 6-hexenyl | 6-hexenyl | +++ | +++ | 491 | ||
13E | RSSR | 5,6-epoxy-1-hexyl | 5,6-epoxy-1-hexyl | ++ | +++ | 523 | ||
13F | RSSR | 5,6-dibromo-1- | 5,6-dibromo-1- | ++ | + | 811 | ||
hexyl | hexyl | |||||||
13G | RSSR | 6-bromo-5-hydroxy- | 6-bromo-5-hydroxy- | +++ | +++ | 685 | ||
1-hexyl | 1-hexyl | |||||||
13H | RSSR | 5-hydroxy-1-pentyl | 5-hydroxy-1-pentyl | +++ | +++ | 499 | ||
13I | RSSR | 5,6-dihydroxy-1- | 5,6-dihydroxy-1- | +++ | + | 559 | ||
hexyl | hexyl | |||||||
13J | RRSR | cyclopropyl- | cycloproypl | +++ | +++ | 435 | ||
methyl | methyl | |||||||
13K | RRSR | allyl | allyl | +++ | +++ | 407 | ||
13L | RRSR | benzyl | benzyl | +++ | +++ | 507 | ||
13M | RRSR | 4-(hydroxy | 4-(hydroxy) | +++ | +++ | 567 | ||
methyl)benzyl | methyl)benzyl | |||||||
13N | RRRR | allyl | allyl | + | ++ | 407 | ||
13o | RRRR | cyclopropyl-methyl | cyclopropyl-methyl | + | ++ | 435 | ||
13P | RRRR | H | H | + | + | 327 | ||
13Q | RRRR | benzyl | benzyl | + | +++ | 507 | ||
13R | RRRR | n-butyl | n-butyl | ++ | +++ | 439 | ||
13S | RRRR | 4-(hydroxy | 4-(hydroxy | ++ | ++ | 567 | ||
methyl)benzyl | methyl)benzyl | |||||||
13T | RSSR | (1,2,3,4- | (1,2,3,4- | ++ | + | 617 | ||
tetrahydro)-6- | tetrahydro)-6- | |||||||
isoquinolyl-methyl | isoquinolyl-methyl | |||||||
13U | RSSR | 6-isoquinolyl | 6-isoquinolyl- | ++ | + | 264-6 | 609 | |
13V | RSSR | 2-thiazolyl-methyl | 2-thiazolyl-methyl | ++ | ++ | 521 | ||
13W | RSSR | (5-t- | (5-t- | + | +++ | 182-4 | 687 | |
butoxycarbonyl)-2- | butoxycarbonyl)-2- | |||||||
furanylmethyl | furanylmethyl | |||||||
13X | RSSR | (5-hydroxymethyl)- | (5-hydroxymethyl)- | ++ | + | 547 | ||
2-furanylmethyl | 2-furanylmethyl | |||||||
13Y | RRRS | benzyl | benzyl | + | +++ | 507 | ||
13Z | RSSR | 4-chloro-3- | 4-chloro-3- | ++ | +++ | 577(594) | ||
pyridylmethyl | pyridylmethyl | |||||||
14A | RSSR | 2-chloro-3- | 2-chloro-3- | ++ | ++ | |||
pyridylmethyl | pyridylmethyl | |||||||
14B | RSSR | 2-(t-butylthio)-3- | 2-(t-butylthio)-3- | ++ | +++ | 685 | ||
pyridylmethyl | pyridylmethyl | |||||||
14C | RSSR | 4-hydroxy-3- | 4-hydroxy-3- | ++ | + | 541 | ||
pyridylmnethyl | pyridylmethyl | |||||||
14D | RSSR | cyclopropyl-methyl | 2-pyridyl | ++ | +++ | 458 | ||
14E | RSSR | cot-2-yn-1-yl | oct-2-yn-1-yl | ++ | 543 | |||
14F | RSSR | 3,3-diphenyl-2(R)- | 3,3-diphenyl-2(R)- | ++ | 739 | 16 | ||
cyclopropylmethyl | cyclopropylmethyl | |||||||
14G | RSSR | phenyl | phenyl | ++ | 479 | |||
14H | RSSR | 3(S)-phenyl-2(R)- | 3(S)-phenyl-2(R)- | ++ | 587 | 16 | ||
cyclopropyl-methyl | cyclopropylmethyl | |||||||
14I | RSSR | 3(S)-phenyl-2(R)- | H | ++ | 457 | 16 | ||
cyckopropyl-methyl | ||||||||
14J | RSSR | 3-benzyloxy-5- | 3-benzyloxy-5- | ++ | ||||
methyl-4- | methyl-4- | |||||||
pyridylmethyl | pyridylmethyl | |||||||
14K | RSSR | 3-hydroxy-5- | 3-hydroxy-5- | ++ | + | |||
methyl-4- | methyl-4- | |||||||
pyridylmethyl | pyridylmethyl | |||||||
15A | RSSR | m-(H2N)--C6H4CH2-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 552.29 | 17 | |
15B | RSSR | m-(CF3O2SNH)-- | m-(CF3O2SNH)-- | +++ | ++ | 141.8 | 801.19 | 18 |
C6H4CH2-- | C6H4CH2-- | |||||||
15C | RSSR | m-(H2NCONH)-- | m-(H2NCONH)-- | +++ | +++ | 19 | ||
C4H4CH2-- | C6H4CH2-- | |||||||
15D | RSSR | m-(CH3NH)--C6H4CH2-- | m-(CH3NH)--C6H4CH2-- | +++ | +++ | 180.3 | 565.32 | 20 |
15E | RSSR | m-(C6H5CH2OCONH)-- | m-(C6H5CH2OCONH)-- | ++ | + | 190.7 | 822.39 | 21 |
C6H4CH2-- | C6H4CH2-- | |||||||
15F | RSSR | m-(CH3(OHC)N)-- | m-(CH3(OHC)N)-- | ++ | +++ | 82.0 | 621.31 | 22 |
C6H4CH2-- | C6H4CH2-- | |||||||
15G | RSSR | cyclopropyl-methyl | m-(H2N)--C6H4CH2-- | +++ | +++ | 108.9 | 486.27 | 23 |
HCl | ||||||||
15H | RSSR | cyclopropyl-methyl | m-(O2N)--C6H4CH2-- | +++ | +++ | 516.25 | ||
15I | RSSR | m-(CH3)2N)-- | m-((CH3)2N)-- | +++ | +++ | 199.9 | 593.25 | 24 |
15J | RSSR | m-(O2N)--C6H4CH2-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 92.0 | (599) | |
15K | RSSR | m-(H2N)C6H4CH2-- | m-(CH2NHCONH)-- | +++ | 173.7 | (651.4) | 25 | |
C6H4CH2-- | ||||||||
15L | RSSR | m-(CH3NHCONH)-- | m-(CH3NHCONH)-- | +++ | 173.7 | (651.4) | 25 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15M | RSSR | m-(NHCH3)--C6H4CH2-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 107.6 | 566.30 | 26 |
. . . HCl | ||||||||
15N | RSSR | m-(CH3)2NCH2-- | m-((CH3)2NCH2-- | +++ | +++ | 92.8 | 707.39 | 27 |
C(O)NH)--C6H4CH2-- | C(O)NH)--C6H4CH2-- | |||||||
. . . HCl | . . . HCl | |||||||
15O | RSSR | m-(CH3NHCH3-- | m-(CH3NHCH2-- | +++ | +++ | 202.6 | 679.36 | 27 |
C(O)NH)--C6H4CH2-- | C(O)NH)--C6H4CH2-- | |||||||
. . . HCl | . . . HCl | |||||||
15P | RSSR | m-((CH3)2NCH2-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 108.1 | 637.34 | 27 |
C(ON)NH)--C6H4CH2-- | ||||||||
. . . HCl | ||||||||
15Q | RSSR | m-(C6H5CH2O-- | m-(C6H5CH2O-- | +++ | +++ | 114.6 | 27 | |
C(O)NHCH2C(O)NH)-- | C(O)NHCH2C(O)NH)-- | |||||||
C6H4CH2-- | ||||||||
15R | RSSR | m-(H2NCH2C(O)NH)-- | m-(H2NCH2C(O)NH)-- | +++ | +++ | 233.7 | 651.3 | 27 |
C6H4CH2-- . . . HCl | C6H4CH2-- . . . HCl | |||||||
15S | RSSR | m-(L-- | m-(L-- | +++ | 100.6 | 947.43 | 27 | |
C6H5CH2OC(O)NH-- | C6H5CH2C(O)NH-- | |||||||
CH(CH3)C(O)NH)-- | CH(CH3)C(O)NH)-- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15T | RSSR | m-(L--C6H5CH2O-- | m-(L--C6H5CH2O-- | +++ | 107.9 | 1099.50 | 27 | |
C(O)NHCH(CH2C6H5)C | C(O)NHCH(CH2C6H5)C | |||||||
(O)NH--C6H4CH2-- | (O)NH--C6H4CH2-- | |||||||
15U | RSSR | m-(L-- | m-(L-- | +++ | 112.3 | 679.36 | 27 | |
H2NCH(CH3)C(O)NH)-- | H2NCH(CH3)C(O)NH)-- | |||||||
C6H4CH3-- . . . HCl | C6H4CH2-- . . . HCl | |||||||
15V | RSSR | m-(L-- | M-(L-13 | +++ | 210.6 | 831.42 | 27 | |
H2NCH(CH2C6H5)-- | H2NCH(CH2C6H5)-- | |||||||
C(O)NH)--C6H4CH2-- | C(O)NH)--C6H4CH2-- | |||||||
. . . HCl | . . . HCl | |||||||
15VA | RSSR | H | 4-oxocyclohexyl- | ++ | ++/+ | 437 | ||
methyl | ||||||||
15VB | RSSR | H | 4,4-dimethoxy- | ++ | ++/+ | 452(469) | ||
15VC | RSSR | H | 4-(oxime)- | ++ | ++/+ | 451 | ||
cyclohexylmethyl | (M + H-- | |||||||
OCH3) | ||||||||
15VD | RSSR | CH3NHC(═O)--(CH2)3-- | CH3NHC(═O)--(CH2)3 | ++ | ++ | 581(598) | ||
15VE | RSSR | HO(CH2)6 | Cl(CH2)6-- | ++ | +++ | 545 | 28 | |
15VF | RSSR | HO(CH2)6-- | CH3NHSO3(CH2)4-- | ++ | +++ | 620(637) | 28 | |
15VG | RSSR | H | HO(CH2)5-- | +++ | +++ | 413 | 29 | |
15VH | RSSR | HO(CH2)5-- | b-Naphthyl-CH2-- | +++ | +++ | 84.6 | 553 | 28 |
15VI | RSSR | HO(CH2)5-- | C6H5CH2-- | +++ | +++ | 503 | 28 | |
15VJ | RSSR | HO(CH2)5-- | CH3S(CH2)3-- | ++ | +++ | 529 | 28 | |
15VK | RSSR | HO(CH2)5-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 533 | ||
15VL | RSSR | H | CH3CH2CH(OH)--CH2-- | + | ++/+ | 399 | 30 | |
15VM | RSSR | H | CH3(CH2)3CH(OH)--CH2-- | + | ++/+ | 427 | 31 | |
15VN | RSSR | CH3CH2CH(OH)--CH2-- | CH3CH2CH(OH)--CH2-- | + | ++/+ | 99.2 | 471 | 30 |
15VO | RSSR | CH3CH2C(═O)CH2-- | CH3CH2C(═O)CH3-- | ++ | ++/+ | 467 | 32 | |
15VP | RSSR | CH3CH2C(═NOH)--CH2-- | CH3CH2C(═NOH)--CH2 | ++ | ++ | 497 | 33 | |
15VQ | RSSR | HO(CH2)6-- | b-Naphthyl-CH3-- | +++ | +++ | 567 | ||
15VR | RSSR | HO(CH2)5-- | m-HOC6H4CH2-- | +++ | +++ | 519 | ||
15VS | RSSR | HO(CH2)5-- | CH3SO(CH2)5-- | +++ | +++ | 561(578) | ||
15VT | RSSR | HO(CH2)5-- | CH3SO2(CH2)5-- | +++ | +++ | 545(562) | ||
15VU | RSSR | HO(CH2)5-- | C3H5CH2-- | +++ | +++ | 467 | ||
15VV | RSSR | CH3O(CH2)5-- | CH3O(CH2)5-- | ++ | ++ | 527(544) | 34 | |
15VW | RSSR | HO(CH2)5-- | CH3O(CH3)5-- | +++ | +++ | 513 | 35 | |
15VX | RSSR | HO(CH2)5-- | m-CN--C6H4CH3-- | +++ | +++ | 528(545) | ||
15VY | RSSR | HO(CH2)5-- | m-(C2H5OC(═O))-- | +++ | +++ | 575(592) | ||
C6H4CH2-- | ||||||||
15VZ | RSSR | CH3CH(OH)(CH2)4-- | CH3CH(OH)(CH2)4-- | +++ | +++ | 527(544) | 36 | |
15WA | RSSR | CH3CH(OH)(CH2)4-- | n-Naphthyl-CH2-- | +++ | +++ | 80.7 | 567(584) | 36 |
15WB | RSSR | CH3C(═O)(CH2)4-- | CH3C(50 )(CH2)4-- | ++ | ++ | 523 | 32 | |
15WC | RSSR | CH3C(═NOH)--(CH2)4-- | CH3C(═NOH)--(CH2)4-- | ++ | +++ | 553 | ||
15WD | RSSR | H2N(CH2)6-- | p-(HOCH2)--C6H4CH2-- | ++ | +++ | 546 | 37 | |
15WE | RSSR | HO(CH2)5-- | m-(HOCH2)--C6H4CH2-- | +++ | +++ | 533(550) | ||
15WF | RSSR | m-(Et2NC(O))-- | m-(Et2NC(O))-- | +++ | +++ | 89-91 | (722) | 38 |
C6H4CH2-- | C6H4CH2-- | |||||||
15WG | RSSR | m-(MeO2C)--C6H4CH2-- | m-(Et2NC(O))-- | +++ | +++ | (681) | 39 | |
C6H4CH2-- | ||||||||
15WH | RSSR | m-(MeO2C)--C6H4CH2-- | m-((EtNHC(O))-- | +++ | +++ | (653) | 39 | |
C6H4CH2-- | ||||||||
15WI | RSSR | H | m-(HOCH2)--C6H4CH2-- | +++ | +++ | 176-177 | 447 | 40 |
15WJ | RSSR | m-(HOCH2)--C6H4CH2-- | m-Et2NC(O)-- | +++ | +++ | 88.9-90.0 | 636(20%) | 39 |
C6H4CH2-- | ||||||||
15WK | RSSR | m-(HOCH2)--C6H4CH2-- | m-(EtNHC(O))-- | +++ | +++ | 608 | 39 | |
C6H4CH2-- | ||||||||
15WL | RSSR | m-(iPr2NC(O))-- | m-(iPr2NC(O))-- | + | + | 165-167 | 678 | 39 |
C6H4CH2-- | C6H4CH2-- | |||||||
15WM | RSSR | m-(PrNHC(O))-- | m-(PrNHC(O))-- | +++ | +++ | 677 | 38 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15WN | RSSR | m-(HO2C)C6H4CH2-- | m-(iPrNHC(O))-- | +++ | +++ | 164-167 | 636 | 39 |
C6H4CH2-- | ||||||||
15WO | RSSR | m-(HO2C)C6H4CH2-- | m-(PrNHC(O))-- | +++ | +++ | 151-153 | 636(32%) | 39 |
C6H4CH2-- | ||||||||
15WP | RSSR | m-(HO2C)C6H4CH2-- | Benzyl | +++ | +++ | 122-124 | (568) | 39 |
15WQ | RSSR | m-(HO2C)C6H4CH2-- | Cyclopropyl-methyl | +++ | +++ | 135-137 | (532) | 39 |
15WR | RSSR | p-(HOCH2)--C6H4CH2-- | m-(HO3C)C6H4CH2-- | +++ | +++ | 130-132 | (598) | 39 |
15WS | RSSR | m-(HOCH2)--C6H4CH2-- | 3-picolinyl | +++ | +++ | 538 | 39 | |
15WT | RSSR | p-(HOCH2)--C6H4CH2-- | m-(H2NH(O))-- | +++ | +++ | 123-124 | 580 | 39 |
C6H4CH2-- | ||||||||
15WU | RSSR | m-(H2N)C6H4CH2-- | 2-naphthylmethyl | +++ | +++ | 572 | 39 | |
15WV | RSSR | Cyclopropyl-methyl | m-(H2NC(O))-- | +++ | +++ | 128-130 | 514 | 39 |
C6H4CH2-- | ||||||||
15WW | RSSR | H | m-(H2NC(O))-- | +++ | +++ | 114-116 | 460 | 39 |
15WX | RSSR | m-(HOCH2)--C6H4CH2-- | m-(EtNHC(O))-- | +++ | +++ | 88-89 | 580 | 39 |
C6H4CH2-- | ||||||||
15WY | RSSR | m-(HOCH2)--C6H4CH2-- | m-(MeNH)C6H4CH2-- | +++ | +++ | 111-113 | 552 | 39 |
15WZ | RSSR | m-(MeNH)C6H4CH2-- | 2-Naphthylmethyl | +++ | +++ | 98-100 | 586 | 39 |
15XA | RSSR | p-(HO2C)C6H4CH2-- | p-(HOCH2)--C6H4CH2-- | +++ | ++ | (598) | 41 | |
15XB | RSSR | p-(HC(O))--C6H4CH2-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 565 | 42 | |
15XC | RSSR | m-(MeNHCH2)-- | m-(MeNHCH2)-- | ++ | +++ | 593.3483 | ||
C6H4CH2--.HCl | C6H4CH2--.HCl | |||||||
15XD | RSSR | m-(CH3CHOH)-- | m-(CH3CHOH)-- | +++ | +++ | 595.3177 | ||
C6H4CH2-- | C6H4CH2-- | (612) | ||||||
15XE | RSSR | 3-picolinyl | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 538.2693 | ||
15XF | RSSR | m-(Et2NCH2)-- | m-(Et2NCH2)-- | ++ | +++ | 677.444 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15XG | RSSR | m-(N-imidazol- | m-(N-imidazol- | +++ | +++ | 667.3394 | ||
methyl)C6H4CH3-- | methyl)C6H4CH2-- | |||||||
15XH | RSSR | m-(tBuC(OO)-- | m-(tBuC(O))-- | +++ | +++ | 675.3394 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15XI | RSSR | m-(CF3CHOH)-- | m-(CF3CHOH)-- | +++ | +++ | 703.2611 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15XJ | RSSR | m-[2-imidazolyl- | m-[2-imidazolyl- | +++ | +++ | 695.2977 | ||
C(O)]C6H4CH2-- | C(O)]C6H4CH2-- | |||||||
16XK | RSSR | 3-picolinyl.HCl | p-(HOCH2)--C6H4CH2-- | +++ | +++ | (538) | ||
15XL | RSSR | m-(HOCH2CC)-- | m-(HOCH2CC)-- | +++ | +++ | 615.2853 | ||
C6H4CH2-- | C6H4CH2-- | (632) | ||||||
15XM | RSSR | m-(CF3C(O))-- | m-(CF3C(O))-- | +++ | +++ | 699.2286 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15XN | RSSR | m-(CH3CH2C(O))-- | m-(CH3CH2C(O))-- | +++ | +++ | 639.3181 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15Xo | RSSR | m-[3-pyrazolyl)- | m-[(3-pyrazolyl)- | +++ | +++ | 639.3100 | ||
C6H4CH2-- | C6H4CH2-- | (656) | ||||||
15XP | RSSR | m-[Et--C(═N--OH)]-- | m-[Et--C(═N--OH)]-- | +++ | +++ | (649) | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15XQ | RSSR | m-(NH2SO2)-- | m-(NH2SO2)-- | +++ | +++ | 665.2103 | ||
C6H4CH2-- | C6H4CH2-- | (682) | ||||||
15XR | RSSR | m-[CF3--C(═N-- | m-[CF3--C(═N-- | +++ | +++ | 729.2500 | ||
OH)]C6H4CH2-- | OH)]C6H4CH2-- | (746) | ||||||
15XS | RSSR | m-[Me--C(═N--OH)-- | m-[Me--C(═N--OH)]-- | +++ | +++ | 621.3070 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15XT | RSSR | m-(H2NCH2C(═O)NH) | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 645.20 | ||
--C6H4CH3-- . . . HCl | ||||||||
15XU | RSSR | m-(2-(4- | m-(2-(4- | +++ | +++ | 102-105 | 819.4435 | |
morpholino)ethylNHC | morpholino)ethylNHC | |||||||
(═O))C6H4CH2-- | (═O))C6H4CH2-- | |||||||
15XV | RSSR | m-(2-(N,N- | m-(2-(N,N- | +++ | 735.4226 | |||
dimethylamino)- | dimethylamino)- | |||||||
ethylNHC(═O))-- | ethylNHC(═O))-- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15XW | RSSR | m-(2-(N,N- | m-(2-(N,N- | +++ | ++ | 100-103 | 735.4226 | |
dimethylamino)- | dimethylamino)- | |||||||
ethylNHC(═O))-- | ethylNHC(═O))-- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15XX | RSSR | CH3 | m-(2-(N,N- | ++ | 101-103 | |||
dimethylamino)- | ||||||||
ethylNHC(═O))-- | ||||||||
C6H4CH2-- | ||||||||
15XY | RSSR | CH3 | m-(2-(N,N- | ++ | +/++ | 118-120 | 587.3234 | |
dimethylamino)- | ||||||||
ethylNHC(═O))-- | ||||||||
C6H4CH2-- | ||||||||
15XZ | RSSR | CH3 | benzyl(3- | ++ | +/++ | 134-136 | 571.3276 | |
(pyrrolidino | ||||||||
ethyl)benzamido) | ||||||||
methyl | ||||||||
15YA | RSSR | cyclopropylmethyl | m-(2-(N,N- | +++ | +++ | 97-99 | 585.3430 | |
dimethylamino)- | ||||||||
ethylNHC(═O))-- | ||||||||
C6H4CH2-- | ||||||||
15YB | RSSR | cyclopropylmethyl | m-(2-(4- | +++ | +++ | 103-105 | 627.3546 | |
morphholino)ethylNHC | ||||||||
(═O))C6H4CH2-- | ||||||||
15YC | RSSR | cyclopropylmethyl | benzyl)3- | +++ | +++ | 110-112 | 611.3598 | |
(pyrolidino | ||||||||
ethyl)benzamido) | ||||||||
methyl | ||||||||
15YD | RSSR | cyclopropylmethyl | m-((3-pyridyl)- | +++ | 115-117 | 605.3113 | ||
methylNHC(═O))-- | ||||||||
C6H4CH2-- | ||||||||
15YE | RSSR | cyclopropylmethyl | m-((2-pyridyl)- | |||||
methylNHC(═O))-- | ||||||||
C6H4CH2-- | ||||||||
15YF | RSSR | m-(p-toluyl | m-(p-toluyl | ++ | +++ | 169-171 | ||
sulfonylhydra-zone) | sulfonhydra- | |||||||
C6H4CH2 | zone)C6H4CH2 | |||||||
15YG | RSSR | m-(N-morpholino | m-(N-morpholino | ++ | +++ | 110-112 | 765 | |
ethoxy)C6H4CH2-- | ethoxy)C6H4CH2-- | |||||||
15YH | RSSR | p-HOCH2C6H4CH2 | p-H2NCH2C6H4CH2 | ++ | ++ | 132-134 | 566 | |
15YI | RSSR | m-(CH3NHOC═O)-- | m-(CH3NHOC═)-- | +++ | +++ | 223-224 | ||
C6H4CH2 | C6H4CH2 | |||||||
15YJ | RSSR | m-(1,2,4-oxadia | m-(1,2,4-oxadia | +++ | 202(dec) | |||
zolidinon-3-yl)- | zolidinon-3-yl)- | |||||||
C6H4CH2 | C6H4CH2 | |||||||
15YK | RSSR | m-(2-imidazole)- | m-(N-SEM-2- | ++ | +++ | 769 | ||
C6H4CH2-- | imidazole)- | |||||||
C6H4CH2-- | ||||||||
15YL | RSSR | m-(3-pyrazole)- | m-(3-pyrazole- | +++ | +++ | 208-210 | 639.4 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15YM | RSSR | m-(3-pyrazole)- | m-(3-pyrazole)- | +++ | +++ | 195-197 | ||
C6H4CH2-- | C6H4CH2--.HCl | |||||||
15YN | RSSR | m-(3-pyrazole-CO)-- | m-(3-pyrazole-CO)-- | +++ | +++ | 695 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15AA | RSSR | m-(ClCH2C(O)NH | m-(ClCH2C(O)NH | +++ | +++ | 51 | ||
C(O)NH)--C6H4CH2 | C(O)NH--C6H4CH2 | |||||||
15AB | RSSR | m-H2NC6H4CH3.HCl | m-isonicotinamido- | +++ | +++ | 205(dec) | 747 | 47 |
C5H4CH2.HCl | ||||||||
15AC | RSSR | m-isonicotinamdio- | m-isoicotinamido- | +++ | +++ | 205(dec) | 747 | 47 |
C6H4CH2.HCl | C6H4CH2.HCl | |||||||
15AD | RSSR | m-((CH3)2NCH2CH2 | m-CH3C(O)C6H4CH2 | +++ | +++ | 170(dec) | 646 | 4 |
C(O))--C6H4CH2 | ||||||||
15AE | RSSR | m-((CH3)2NCH2CH2 | m-((CH3)2NCH2CH2 | +++ | +++ | 164(dec) | 701 | 43 |
C(O))--C6H4CH2 | C(O))--C6H4CH2 | |||||||
15AF | RSSR | m-(H2NC(═NOH))-- | cyclopropylmethyl | +++ | +++ | 183-186 | 529 | 44 |
C6H4CH2 | ||||||||
15AG | RSSR | m,p-dihydroxy- | cyclopropylmethyl | +++ | +++ | 141 | 503 | 2 |
C6H4CH2 | ||||||||
15AH | RSSR | m-(H2NC(═NOH))-- | p-hydroxymethyl- | +++ | +++ | 198-199 | 595 | 44 |
C6H4CH2 | ||||||||
15AI | RSSR | p-(H2NC(═NOH))-- | p-hydroxymethyl | ++ | +++ | 215 | 595 | 44 |
C6H4CH2 | C6H4CH2 | |||||||
15AJ | RSSR | m-(5-amino- | m-(5-amino- | +++ | +++ | 208-209 | 690 | 49 |
1,3,4-oxadiazo- | 1,3,4-oxadiazo- | |||||||
2-yl)-C6H4CH2 | 2-yl)-C6H4CH2 | |||||||
15AK | RSSR | m-hydraxide- | cyclopropylmethyl | +++ | +++ | 176-177 | 529 | 48 |
C6H4CH2 | ||||||||
15AL | RSSR | m-((CH3)3COC(O)-- | m-((CH3)3COC(O)-- | ++ | +++ | 227-228 | 808 | 50 |
NHN═CH--C6H4CH2 | NHN═CH)═C6H4CH2 | |||||||
15AM | RSSR | m-(C2H5OC(O))-- | m-(5-amino- | 661 | 53 | |||
C6H4CH2 | 1,3,4-oxadiazo- | |||||||
2-yl)-C6H4CH2 | ||||||||
15AN | RSSR | m-(H2NC(═NOH))-- | 2-naphthylmethyl | +++ | +++ | 192-193 | 615 | 44 |
C6H4CH2 | ||||||||
15AO | RSSR | 3-((5-(CH3)2NCH2)- | 3-((5-(CH3)2NCH2)- | +++ | +++ | 165(dec) | 56 | |
1,2,4-oxadiazol | 1,2,4-oxadiazol | |||||||
yl)-C6H4CH2.HCl | yl)-C6H4CH2.HCl | |||||||
15AP | RSSR | m-(N-methyl-N'- | H | + | 147-149 | 467 | 2 | |
piperazinyl) | ||||||||
propyl.HCl | ||||||||
15AQ | RSSR | m-cyanoC6H4CH2 | p-hydroxyC6H4CH2 | +++ | +++ | 548 | 54 | |
15AR | RSSR | m-cyanoC6H4CH2 | m-3-pyridylmethyl | +++ | +++ | 533 | 55 | |
15AS | RSSR | m-(N-methyl-N'- | H | + | +/++ | 150 | 467 | 2 |
piperazinyl) | ||||||||
propyl.HCl | ||||||||
15AT | RSSR | m-(H2NH(═NOH))-- | H | +++ | +++ | 172-179 | 475 | 2 |
C6H4CH2 | ||||||||
15AU | RSSR | m-(H2NH(═NOH))-- | p-hydroxyC6H4CH2 | +++ | +++ | 195-197 | 581 | 44 |
C6H4CH2 | C6H4CH2 | |||||||
15AW | RSSR | m-(H2NC(═NOH))-- | 4-pyridylmethyl | 178-192 | 566 | 44 | ||
C6H4CH2 | ||||||||
15AX | RSSR | m-(2- | m-(2- | ++ | 205 | 739 | 46 | |
benzimidazolyl)- | benzimidazolyl)- | |||||||
C6H4CH2 | C6H4CH2 | |||||||
15AY | RSSR | m-(2- | m-(2- | ++ | 217-219 | 739 | 46 | |
benzimidazolyl)- | benzimidazolyl)- | |||||||
C6H4CH2.HCl | C6H4CH2.HCl | |||||||
15AZ | RSSR | m-(CH2NHC(═NOH))-- | m-(CH3N--HC(═NOH))-- | +++ | +++ | 192(dec) | 651 | 46 |
CC6H4CH2-- | C6H4CH2-- | |||||||
15BA | RSSR | m-(C3H7NHC(═NOH)-- | m-(C3H7NHC(═NOH))-- | +++ | +++ | 177 | 707 | 46 |
C6H4CH2-- | C6H4CH2-- | |||||||
15BB | RSSR | m-(2-amino- | m-(2-amino- | ++ | 226-227 | 693 | 45 | |
pyrimidin-5-yl)- | pyrimidin-4-yl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15BC | RSSR | cyclopropylmethyl | 4-fluoro-4-cyano- | ++ | 514 | 44 | ||
C6H4CH2-- | ||||||||
15BD | RSSR | m-(2-amino-4- | m-(2-amino-4- | +++ | +++ | 151-160 | 703 | |
thienyl)-C6H4CH2-- | thienyl)-C6H4CH2-- | |||||||
15BE | RSSR | cyclopropylmethyl | m-(2-amino-4- | +++ | +++ | 118-127 | 569 | |
thienyl)-C6H4CH2-- | ||||||||
15BF | RSSR | m-(2-chloromethyl- | m-(2-chloromethyl- | ++ | ++ | 178-181 | 503 | |
2-propenyl)- | 2-propenyl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15BG | RSSR | m- | m- | + | 73-80 | 467 | ||
(2-hydroxymethyl- | (2-hydroxymethyl- | |||||||
2-propenyl)- | 2-propenyl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15BH | RSSR | cyclopropylmethyl | ((2- | +++ | +++ | 155-164 | 643 | |
benzimidazolyl)- | ||||||||
CH2NHC(O))-- | ||||||||
C6H4CH2-- | ||||||||
15BI | RSSR | m-(benzyloxy- | m-(benzyloxy | +++ | +++ | 803.5 | ||
methylcarbonyl)- | methylcarbonyl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15BJ | RSSR | m-(1-SEM-5- | m-(1-SEM-5- | +++ | +++ | 899.5 | ||
imidazoyl)- | imidazoyl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15BK | RSSR | m-(5-imidazoyl)- | m-(5-imidazoyl)- | +++ | +++ | 171-175 | 639 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15BL | RSSR | m-(5-imidazoyl)- | m-(5-imidazoyl)- | +++ | +++ | |||
C6H4CH2--.HCl | C6H4CH2.HCl | |||||||
15BM | RSSR | m-(1-(N,N-dimethyl | m-(1-(N,N-dimethyl | ++ | +++ | 853 | ||
sylfamoyl)-2- | sulfamoyl)-2- | |||||||
imidazoyl)- | imidazoyl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15BN | RSSR | m-(4-pyrazole)- | m-(4-pyrazole)- | +++ | +++ | |||
C6H4CH2--.HCl | C6H4CH2--.HCl | |||||||
15BP | RSSR | m-carbomethoxy- | m-(3-pyrazole)- | +++ | +++ | 127-130 | 631.4 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15BQ | RSSR | m-hydroxymethyl- | m-(3-pyraole)- | +++ | +++ | 603.2 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15BR | RSSR | (2-imidazoyl)- | m-(2-imidazoyl)- | +++ | +++ | 178-180 | 639.4 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15BS | RSSR | m-(2-imidazoyl)- | m-(2-imidazoyl)- | +++ | +++ | 191-194 | ||
C6H4CH2--.HCl | C6H4CH2--.HCl | |||||||
15BT | RSSR | m-((2-morpholino | m-(3-pyrazole)- | +++ | +++ | 729.5 | ||
ethyl)amino | C6H4CH2-- | |||||||
carbonyl)-C6H4CH2-- | ||||||||
15BU | RSSR | 3-pyridinylmethyl | m-(3-pyrazole)- | +++ | +++ | 133-136 | 574.2 | |
C6H4CH2-- | ||||||||
15BV | RSSR | m-cyano-C6H4CH2-- | m-(3-pyrazole)- | +++ | +++ | 598.2 | ||
C6H4CH2-- | ||||||||
15BW | RSSR | m-(H2NC(═NOH)-- | m-(3-pyrazole)- | +++ | +++ | |||
C6H4CH2-- | C6H4CH2-- | |||||||
15BX | RSSR | H | m-(3-pyrazole)- | +++ | +++ | 483.2 | ||
C6H4CH2-- | ||||||||
15BY | RSSR | p-(benzyloxy)- | m-(3-pyrazole)- | +++ | +++ | 679.3 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15BZ | RSSR | m-((3-pyridinyl | m-(3-pyrazole)- | +++ | +++ | 707.5 | ||
methyl)amino | C6H4CH2-- | |||||||
carbonyl)-C6H4CH2-- | ||||||||
15CA | RSSR | p-hydroxy-C6H4CH2-- | m-(3-pyrazole)- | +++ | +++ | 1501∝153 | 589.3 | |
C6H4CH2-- | ||||||||
15CB | RSSR | m-((2-pyridinyl | m-(3-pyrazole)- | +++ | +++ | 707 | ||
methyl)amino | C6H4CH2-- | |||||||
carbonyl)-C6H4CH2-- | ||||||||
15CC | RSSR | m,p-dihydroxy- | m-(3-pyrazole)- | +++ | +++ | 177-180 | 622 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15CD | RSSR | m-nitro-C6H4CH2-- | m-(3-pyrazole)- | +++ | +++ | (635) | ||
C6H4CH2-- | ||||||||
15CE | RSSR | m-amino-C6H4CH2-- | m-(3-pyrazole)- | +++ | +++ | 136-138 | 605 | |
C6H4CH2-- | ||||||||
15CF | RSSR | m-cyano-p-fluoro- | m-(3-pyrazole)- | +++ | +++ | 118-120 | 616 | |
C6H4CH2-- | C6H4CH2-- | |||||||
15CG | RSSR | H | m-(3-pyrazole)- | +++ | +++ | 152-154 | ||
C6H4CH2--.HCl | ||||||||
15CH | RSSR | m-acetyl-C6H4CH2-- | m-(CH3C(═NOH))-- | 186-188 | 606.4 | |||
C6H4CH2-- | ||||||||
15CI | RSSR | m-acetyl-p-fluoro | m-acetly-p-fluoro | 203-204 | 649.3 | |||
C6H4CH2-- | C6H4CH2-- | (M + Na) | ||||||
15CJ | RSSR | m-cyano-p-fluor- | m-acetyl-p-fluoro | 192-193 | 632.3 | |||
C6H4CH2-- | C6H4CH2-- | (M + Na) | ||||||
15CK | RSSR | m-(CH3C(═NOH))-- | m-(CH3C(═NOH))-- | 621.4 | ||||
C6H4CH2-- | C6H4CH2-- | (M + Na) | ||||||
15CL | RSSR | m-(CH3C(═NOH))- | m-(CH3C(═NOH))- | 657.3 | ||||
p-fluoro-C6H4CH2-- | p-fluoro-C6H4CH2-- | |||||||
15CM | RSSR | m-(H2NC(═NOH)- | m-(CH3C(═NOH))- | 658.4 | ||||
p-fluoro-C6H4CH2-- | p-fluoro-C6H4CH2-- | |||||||
15CN | RSSR | 2-naphthylmethyl | 5-methyl-5- | +++ | +++ | 627 | ||
carbomethoxy | ||||||||
hexyl | ||||||||
15CO | RSSR | 2-naphthylmethyl | 5-methyl-5- | +++ | +++ | 595 | ||
carboxyhexyl | ||||||||
15CP | RSSR | 5,5-dimethyl-6- | 5,5-dimethyl-6- | ++ | +++ | 583 | ||
hydroxyhexyl | hydroxyhexyl | |||||||
15CQ | RSSR | p-aminobenzyl | p-aminobenzyl | +++ | +++ | 114-116 | ||
15CS | RSSR | 5-benzimidazolyl | 5-benzimidazolyl | ++ | ++ | 209-212 | ||
methyl | methyl | |||||||
15CT | RSSR | 5-benzotriazolyl | 5-benzotriazolyl | +++ | +++ | >310 | ||
methyl | methyl | |||||||
15CU | RSSR | 3-hydroxy-5- | 3-hydroxy-5- | ++ | 185-192 | |||
benzotriazolyl | benzotriazolyl | |||||||
methyl | methyl | |||||||
15CV | RSSR | 2-oxo-5- | 2-oxo-5- | +++ | ++ | 240-245 | ||
benzimidazolyl- | benzotriazolyl | |||||||
methyl | methyl | |||||||
15CW | RSSR | 5-(2,2-dioxo- | 5-(2,2-dioxo- | +++ | ++ | 210(dec) | ||
benz-2,1,3- | benz-2,1,3- | |||||||
thiadiazolyl)- | thiadiazolyl)- | |||||||
methyl | methyl | |||||||
15CX | RSSR | 5-indazolylmethyl | 5-indazolylmethyl | +++ | +++ | 165-170 | ||
15CY | RSSR | 6-indazolylmethyl | 6-indazolylmethyl | +++ | +++ | 170-175 | ||
15CZ | RSSR | (2-methyl-2-oxo- | (2-methyl-2-oxo- | +++ | +++ | 192-200 | ||
5-benzimidazolyl)- | 5-benzimidazolyl)- | |||||||
methyl | methyl | |||||||
15DA | RSSR | 5-isatinylmethyl | 5-isatinylmethyl | +++ | +++ | 196-200 | ||
15DB | RSSR | (3-hydroxyimino-5- | 3-hydroxyimino-5- | +++ | +++ | 242-245 | ||
oxindolyl)methyl | oxindolylmethyl | |||||||
15DC | RSSR | (2-oxo-5-benz | (2-oxo-5-benz | +++ | +++ | 181-185 | ||
oxazolin-2-yl)- | oxazolin-2-yl)- | |||||||
methyl | methyl | |||||||
15DD | RSSR | 5-oxindolylmethyl | 5-oxindolylmethyl | +++ | +++ | 170-175 | ||
15DE | RSSR | 5-indolylmethyl | 5-indolylmethyl | +++ | +++ | 170(dec) | ||
15DF | RSSR | (3-amino-5- | (3-amino-5- | +++ | +++ | 180-184 | ||
indazolyl)methyl | indazolyl)methyl | |||||||
15DG | RSSR | (3-amino-5- | (3-amino-5- | +++ | +++ | 153-158 | ||
benzisoxazolyl) | benzisoxazolyl) | |||||||
methyl | methyl | |||||||
15DH | RSSR | (3-methylamino-5- | (3-methylamino-5- | +++ | +++ | 174-177 | ||
indazolyl)methyl | indazolyl)methyl | |||||||
15DI | RSSR | (3-chloro-5- | (3-chloro-5- | +++ | +++ | 290(dec) | ||
indazolyl)methyl | indazolyl)methyl | |||||||
15DJ | RSSR | (3-ethylamino-5- | (3-ethylamino-5- | +++ | +++ | 158-162 | ||
indazolyl)methyl | indazolyl)methyl | |||||||
15DK | RSSR | (3-methylamino-5- | (3-methylamino-5- | +++ | 150-153 | |||
benzisoxazolyl) | benzisoxazolyl) | |||||||
methyl | methyl | |||||||
15DM | RSSR | H | 5-benzotriazolyl | +++ | 188-190 | |||
methyl | ||||||||
15DN | RSSR | benzyl | 5-benzotriazolyl | +++ | +++ | 268-270 | ||
methyl | ||||||||
15DO | RSSR | 2-naphthylmethyl | 5-benzotriazolyl | +++ | +++ | 155-159 | ||
methyl | ||||||||
15DP | RSSR | cyclopropylmethyl | 5-benzotriazolyl | +++ | +++ | 155-159 | ||
methyl | ||||||||
15DQ | RSSR | p-hydroxymethyl | 5-benzotriazolyl | +++ | +++ | 151-153 | ||
C6H4CH2-- | methyl | |||||||
15DR | RSSR | m-hydroxyC6H4CH2-- | 5-benzotriazolyl | +++ | +++ | 296-298 | ||
methyl | ||||||||
15DS | RSSR | m-(3-pyrazolyl) | 5-benzotriazolyl | +++ | +++ | 183-186 | ||
C6H4CH2-- | methyl | |||||||
15DT | RSSR | m-iodoC6H4CH2-- | 5-benzotriazolyl | +++ | 153-156 | |||
methyl | ||||||||
15DU | RSSR | m-cyanomethyl | m-cyanomethyl | ++ | +++ | 585.2 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15DV | RSSR | m-(H2NC(O)CH2)-- | m-(H2NC(O)CH2)-- | +++ | +++ | 621.4 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15DW | RSSR | m-(carbomethyoxy | m-(carbomethoxy | +++ | +++ | 651.4 | ||
methyl)-C6H4CH2-- | methyl)-C6H4CH2-- | |||||||
15DX | RSSR | m- | m- | +++ | +++ | 595.4 | ||
(2-hydroxymethoxy | (2-hydroxyethyl)- | |||||||
C6H4CH2-- | C6H4CH2-- | |||||||
15DY | RSSR | o-hydroxy | o-hydroxy- | +++ | +++ | 5939.4 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15DZ | RSSR | H | m-(methylamino)- | +++ | +++ | 500.2 | ||
p-fluoroC6H4CH2-- | ||||||||
15EA | RSSR | o-hydroxy- | p-hydroxymethyl | +++ | +++ | 553.3 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15EB | RSSR | o-hydroxy- | m-hydroxymethyl | ++ | +++ | 553.3 | ||
C6H4CH2-- | C6H4CH2-- | |||||||
15EC | RSSR | m-cyano-p-fluoro- | m-cyano-p-fluoro- | ++ | +++ | (610.2) | ||
C6H4CH2-- | C6h4CH2-- | |||||||
15ED | RSSR | m-H2NC(O))-p- | m-(H2NC(O))-p- | +++ | ++ | (646.4) | ||
fluoro-C6H4CH2-- | fluoro-C6H4CH2-- | |||||||
15EE | RSSR | m-carbomethoxy-p- | m-carbomethoxy-p- | +++ | + | (676.3) | ||
fluoro-C6H4CH2-- | fluoro-C6H4CH2-- | |||||||
15EF | RSSR | m-(H2NC(═NOH))- | m-(H2NC(═NOH))- | +++ | +++ | 659.1 | ||
p-fluoro-C6H4CH2-- | p-fluoro-C6H4CH2-- | |||||||
15EG | RSSR | m-(hydroxymethyl) | m-(hydroxymethyl) | +++ | +++ | 603.3 | ||
p-fluoro-C6H4CH2-- | p-fluoro-C6H4CH2-- | |||||||
15EH | RSSR | m-(H2NC(O))- | m-(H2NC(═NOH))- | +++ | +++ | 644.0 | ||
p-fluoroC6H4CH2-- | p-fluoroC6H4CH2-- | |||||||
15EI | RSSR | p-methylC6H4CH2-- | p-hydroxymethyl- | +++ | 174-175 | 551 | ||
C6H4CH2-- | ||||||||
15EK | RSSR | 5-(methylamino | 5-(methylamino | ++ | ++ | 613 | ||
carbonyloxy) | carbonyloxy) | |||||||
pentyl | pentyl | |||||||
15EL | RSSR | 7-(1,1,4,4-tetra | 7-(1,1,4,4-tetra | + | ++/+ | 727 | ||
methyl-1,2,3,4- | methyl-1,2,3,4- | |||||||
tetrahydro | tatrehydro | |||||||
naphthyl)methyl | naphthyl)methyl | |||||||
15EM | RSSR | 5-azidopentyl | 5-azidopentyl | ++ | +++ | 549 | ||
(566) | ||||||||
15EN | RSSR | 5-(methylsulfonyl | 5-(methylsulfonyl | ++ | ++/+ | (670) | ||
amino)-pentyl | amino)-pentyl | |||||||
15EO | RSSR | 5-(p-methylphenyl | 5-(p-methylphenytl | ++ | ++/+ | (822) | ||
sulfonyl)pentyl | sulfonyl)pentyl | |||||||
15EP | RSSR | 5-aminophenyl | 5-aminophenyl | + | ++/+ | 497 | ||
15EQ | RSSR | 5-methoxycarbonyl | 5-methoxycarbobyl | ++ | ++/+ | (630) | ||
aminopentyl | aminopentyl | |||||||
15ER | RSSR | 5-(phenylamino | 5-(phenylamino | ++ | ++/+ | |||
carbonylamino | carbonylamino | |||||||
pentyl | pentyl | |||||||
15ES | RSSR | 5-(methylamino | 5-(methylamino | ++ | ++/+ | 611 | ||
carbobylamino) | carbonylamino) | (628) | ||||||
pentyl | pentyl | |||||||
15ET | RSSR | 5-(acetylamino) | 5-(acetylamino) | ++ | ++/+ | (598) | ||
pentyl | pentyl | |||||||
15EU | RSSR | 5-((3-pyridinyl | 5-((3-pyridinyl | +++ | +++ | 767 | ||
methoxy)carbonyl | methoxy)carbonyl | |||||||
amino)pentyl.HCl | amino)pentyl.HCl | |||||||
15EV | RSSR | 5-((methylamino) | 5-((methylamino) | ++ | ++/+ | 643 | ||
thiocarbonyl | thiocarbonyl | |||||||
amino)-pentyl | amino)-pentyl | |||||||
15EW | RSSR | 5-((phenylamino) | 5-((phenylamino) | ++ | ++/+ | 767 | ||
thiocarbonyl | thiocarbonyl | |||||||
amino)-pentyl | amino)-pentyl | |||||||
15EX | RSSR | 5-(benzoylamino)- | 5-(benzoylamino)- | ++ | ++/+ | (722) | ||
pentyl | pentyl | |||||||
15EY | RSSR | 5-((3-fluoro | 5-((3-fluoro | ++ | +++ | 741 | ||
benzoyl)amino)- | benzoyl)amino)- | |||||||
pentyl | pentyl | |||||||
15EZ | RSSR | 5-(N-methylglycyl | 5-(N-methylglycyl | ++ | ++/+ | 639 | ||
amino)pentyl.HCl | amino)pentyl.HCl | |||||||
15FA | RSSR | 5-(4-pyridinyl | 5-(4-pyridinyl | ++ | +++ | 707 | ||
carbonylamino)- | carbonylamino)- | |||||||
pentyl.HCl | pentyl.HCl | |||||||
15FB | RSSR | 5-((2-fluoro | 5(2-fluoro | ++ | +++ | 741 | ||
benzoyl)amino)- | benzoylamino)- | |||||||
pentyl | pentyl | |||||||
15FC | RSSR | 5-((4-fluoro | 5-((2-fluoro | ++ | ++/+ | 741 | ||
benzoyl)amino)- | benzoyl)amino)- | (758) | ||||||
pentyl | pentyl | |||||||
15FD | RSSR | 4-cyanobutyl | 4-cyanobutyl | ++ | ++ | 489 | ||
(506) | ||||||||
15FE | RSSR | 5-(4-morpholinyl | 5-(4-morpholinyl | ++ | ++/+ | 751 | ||
methylcarbonyl | methylcarbonyl | |||||||
amino)-pentyl.HCl | amino)-pentyl.HCl | |||||||
15FF | RSSR | 5-(2-pyrazinyl | 5-(2-pyrazinyl | + | ++/+ | (726) | ||
carbonylamino)- | carbonylamino)- | |||||||
pentyl | pentyl | |||||||
15FG | RSSR | 5-(3,5-difluoro | 5-((3,5-difluoro | ++ | ++/+ | (794) | ||
benzoyl)amino)- | benzoyl)amino)- | |||||||
pentyl | pentyl | |||||||
15FH | RSSR | 4-(dimethylamino) | 4-(dimethylamino) | ++ | ++/+ | 525 | ||
butyl.HCl | butyl.HCl | |||||||
15FI | RSSR | 4-aminobutyl.HCl | 4-aminobutyl.HCl | + | ++/+ | 469 | ||
15FJ | RSSR | 5-((3-trifluoro | 5-((3-trifluoro | ++ | ++/+ | 841 | ||
methylbenzoyl) | methylbenzoyl) | |||||||
amino)- | amino)- | |||||||
pentyl | pentyl | |||||||
15FK | RSSR | 4-(1-imidazolyl)- | 4-(1-imidazolyl)- | + | 599 | |||
pentyl.HCl | pentyl.HCl | |||||||
15FL | RSSR | 5-(1-pyrazolyl)- | 5-(1-pyrazolyl)- | + | 599 | |||
pentyl | pentyl | |||||||
15FM | RSSR | 5-(4-morpholinyl) | 5-(4-morpholinyl) | + | 637 | |||
pentyl.HCl | pentyl.HCl | |||||||
15FN | RSSR | 3-furylmethyl | 3-furylmethyl | +++ | +++ | 152.5-153 | ||
furyl)-methyl | oil | |||||||
15FO | RSSR | 3-furylmethyl | (5-carbonyl-3- | |||||
furyl)-methyl | ||||||||
15FP | RSSR | (5-hydroxymethyl- | (5-hydroxymethyl- | +++ | ||||
3-furyl)-methyl | 3-furyl)-methyl | |||||||
15FQ | RSSR | (5-hydroxyimino | (5-hydroxyimino | +++ | +++ | |||
methyl-3-furyl)- | methyl-3-furyl)- | |||||||
methyl | methyl | |||||||
15FR | RSSR | 3-furylmethyl | (5-hydroxymethyl- | +++ | +++ | |||
3-furyl)-methyl | ||||||||
15FS | RSSR | (2,5-dihydro)-3- | (2,5-dihydro)-3- | ++ | ||||
thienylmethyl | thienylmethyl | |||||||
15FT | RSSR | 3-thienylmethyl | 3-thienylmethyl | +++ | 519 | |||
dihydro-3- | dihydro-3- | |||||||
thienyl)-methyl | thienyl)-methyl | |||||||
15FV | RSSR | 2-furylmethyl | H | +++ | ||||
15FW | RSSR | 2-furylmethyl | 2-furylmethyl | +++ | ||||
15FX | RSSR | 2-methylene-3- | 2-methylene-3- | ++ | ||||
butenyl | butenyl | |||||||
15FY | RSSR | 5-hydroxymethyl- | 5-hydroxymethyl- | ++ | ||||
2-furylmethyl | 2-furylmethyl | |||||||
Notes (for Table 2d):
(1) Prepared according to the general alkylation procedure.
(2) Monoalkylated compounds were prepared by following the procedure 5 under the title of synthesis of monoalkyl cyclic urea. Further functional group elaboration is similar to the corresponding dialkylated cyclic ureas described herein.
(3) Prepared by the alkylating the appropriate monoalkylated compound. Further functional group elaboration is similar to the corresponding dialkylated compounds described herein.
(4) Isolated as the side product due to incomplete reaction.
(5) Methoxylamine hydrochloride (92 mg, 1.08 mmol) was added to bis(N-m-benzaldehyde) cyclic urea (100 mg, 0.18 mmol) in a mixture of 2 mL pyridine and 2 mL ethanol. The mixture was heated to reflux for 4 hr and the solvent was removed on a rotary evaporator. The residue was purified on silica gel (0.2:3:7 methanol:ethyl acetate:methylene chloride) to provide the product (93 mg) in 83% yield. Other amines such as, but not limited to, hydrazine and semicarbazides, can be used instead of methoxylamine. E.g. hydroxylamine was used to make formaldoxime as in 6C in Table 2C.
(6) Preparation of monoacyl compounds were favored by using one equivalent of acylating agent.
(7) A solution of bis(N-m-benzoic acid) cyclic urea (1.2 g, 1.56 mmol) in 1:1 benzene: methylene chloride containing 1 drop of DMF and pyridine (0.75 mL, 9.36 mmol) was treated with oxalyl chloride (2M in methylene chloride, 4.87 ml, 9.36 mmol) at zero degree and stirred at room temperature for overnight. The solvent removed on a rotary evaporator and the resulting residue was dried under pump for 2 hr. To the residue 20 mL methylene chloride was added followed by pyridine (0.75 mL, 9.36 mmol) and methylamine (8.03M in ethanol 1.17 nL, 9.36 mmol). Stirred at room temperature for overnight. The mixture was extracted with EtOAc, dried over MgSO4 and purified on silica gel (1:19 methanol chloroform). Following the same hydrolysis procedure, the product (66 mg) was isolated in 68% yield. Other alkylamines or ammonia can be used instead of methylamine.
(8) A solution of bis(N-m-hydroxy-benzyl)cyclic urea (500 mg, 0.93 mmol) in methylene chloride was treated with triethylamine (0.23 mL, 1.67 mmol) at -20°C C. Then a solution of 1-adamantyl isocyanate (252 mg, 1.4 mmol) in 5 mL methylene chloride was added dropwise. The mixture was stirred at -20°C C. for 10 min, 0°C C. for 1 hr, room temperature for overnight and washed with cooled 5% HCl, sat'd NaHCO3, water, and dried over MgSO4. The residue was purified on silica gel (2:8 ethylene acetate:methylene chloride). The product was isolated (150 mg) in 18% yield. Other acylating agents besides isocyanates can be used.
(9) 2 drops of OsO4 (25% in t-BuOH) was added into the mixture of bis(N-allyloxy-benzyl) cyclic urea (120 mg, 0.19 mmol) and N-methyl-morpholine N-oxide (77 mg, 0.57 mmol) in 5 mL acetone. The mixture was stirred at RT for overnight. The solvent was removed on a totary evaporator and the residue was purified on silica gel (2:8 methanol:chloroform). The product was isolated (145 mg) in 100% yield.
(10) The ethyl ester was prepared by refluxing the appropriate acid with 4M HCl (in dioxane) in ethanol.
(11) To the appropriate ethyl ester (139 mg, 0.21 mmol) and hydroxylamine hydrochloride (118 mg, 1.71 mmol) mixture (10 mL methanol was used as the solvent), a 5M (2.4 mL, 2.1 mmol) solution of potassium hydroxide in methanol was added dropwisely at room temperature. After stirring for 24 hr, methanol was evaporated and the solid residue acidified with acetic acid and extracted with ethyl acetate which was purified on silica gel (0.1:3:7 acetic acid:methanol:ethyl acetate). The product was isolated (90 mg) in 69% yield
(12) To the bis(N-m-allyloxy-benzyl) cyclic urea (100 mg, 0.16 mmol) in 10 mL methanol, ozone was bubbled through for 10 min at -78°C C. After warmed up to RT, sodium borohydride (60.5 mg, 1.6 mmol) was added and stirred at RT for overnight. The reaction was worked up by quenching with acetic acid, the solvent was removed on rotary evaporator and purified on silica gel (0.3:9.7 methanol:ethyl acetate). The product was isolated (88 mg) in 88% yield.
(13) A solution of the bis-cyano compound (400 mg, 0.55 mmol) in absolute methanol was saturated with hydrochloric acid and left at zero degree for 3 hr followed by TLC until completed. After evaporation of the solvent, the resulting was solubilized in 2M ammonia in methanol. After one week stirring at room temperature, the solvent was removed under reduced pressure and the residue was purified on silica gel (by 0.2:1:9 acetic acid:methanol:ethyl acetate) to give a solid. The overall yield was 53% (171 mg).
(14) To the bis(N-p-hydroxy-benzyl) cyclic urea (600 mg, 1.11 mmol) in ethanol, NaOH (622 mg, 15.54 mmol) in 2 mL water was added dropwise. The mixture was heated up to 80°C C. for 1 hr, then 2 mL chloroform was added following additional heating at 80°C C. for overnight. The reaction was worked up by neutralizing with 5% cooled HCl, washed with sat'd sodium bicarbonate, water and dried over MgSO4. The residue was purified on silica gel (1.5:8.5 methanol:chloroform) to give 11E as a solid (59 mg, 11%). To this solid, ethanol was added followed by excess sodium borohydride (10 equiv). The mixture was heated up to reflux for 2 hr. The reaction was worked up by quenching with acetic acid, the solvent was removed on rotary evaporator and the purified on silica gel (2:8 methanol:chloroform). The product was isolated (36 mg) in 63% yield.
(15) n-Butyllithium (1.6M in hexane, 1.6 mL, 2.5 mmol) was added dropwise to bis(N-m-bromo-benzyl) cyclic urea (840 mg, 1 mmol) in THF at -78°C C. After stirring for 0.5 hr, trimethyl borate (0.58 mL, 5 mmol) was added. The mixture slowly warmed up to room temperature and remained stirring for 4 hr. The reaction mixture was decomposed by the addition of 5% HCl, diluted with ethyl acetate, washed 2 time with water and dried over MgSO4. The residue was purified on silica gel (0.1:0.5:9.5 acetic acid:methanol:chloroform). Following the same hydrolysis procedure, the product was isolated (176 mg) in 53% yield.
(16) Required alkylating agents were prepared in a three step sequence: 1.) Asymmetric cyclopropanation [D. A. Evans et al., J. Amer. Chem. Soc. 1991, 113, 726-728]. 2.) Reduction with lithium aluminum hydride. 3.) Conversion to the bromide with CBr4, Ph3P, and imidazole.
(17) Prepared from Example 15J using the conditions described for Example 6ZI in Table 2C.
(18) Prepared from the compound of Table 2C, Example 6ZI using methanesulfonic anhydride.
(19) Prepared from Example 6ZI using isocyanic acid.
(20) A solution (60ml) of borane in tetrahydrofuran (THF, 2M) was added dropwise into a cooled solution (0°C C.) of bis-formamide 6ZM (9.18 g, 15.5 mmoles) in anhydrous THF (200 ml). The mixture was stirred for 16 hours at room temperature, followed by dropwise addition of methanol (50 ml). When the effervescence had subsided, hydrochloric acid (conc., 35 ml) was added. The residue was stirred for 30 minutes, evaporated to dryness, and partitioned between ethyl acetate and sodium hydroxide (1N). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 8.65 g of the product.
(21) Prepared from Example 6ZI using benzyl chloroformate.
(22) Prepared from Example 15D using the conditions described of 6ZM.
(23) Premed from Example 15H using the conditions described for Example 6ZI.
(24) Prepared from Example 15F using the procedure described for Example 15D.
(25) Prepared form Example 6ZI using methyl isocyanate.
(26) The formamide of Example 15A was prepared by the procedure Example 6ZM, followed by reduction described for Example 15D.
(27) The amide bond is formed between an amino acid and aminobenzyl cyclic urea using dicyclohexylcarbodiimide/catalytic 1-hydroxybenzotriazale in N,N-dimethylformamide in the proper proportions. When the desired product is to be a primary or secondary amine, the N-terminus of the amino acid was first suitably protected, based on the comparability with later reactions (see T. W. Greene and P. G. M. Wuts, "Protecting Groups in Organic Synthesis", 2nd edition, Wiley (1991)) and then later removed.
(28) Cyclic urea XXIIc was alkylated with sodium hydride (2.5 equiv) and THPO(CH2)5Br (prepared in 2 steps from HO(CH2)5OH)(4 equiv) in DMF to give the monoalkylated product. Where upon further treatment with sodium hydride and a second bromo-alkylating agent provided an intermediate which was deprotected using methanolic HCl in dioxane to provide the product.
(29) Prepared by acidic detection of the monoalkylated intermediate.
(30) Prepared from intermediate (XXII) by treatment with phenyllithium, boron trifluoride and 1,2-epoxybutane, followed by acidic deprotection.
(31) Prepared from intermediate (XXII) by treatment with phenyllithium, boron trifluoride and 1,2-epoxyhexane, followed by acidic deprotection.
(32) Prepared by pyridinium chlorochromate oxidation of the corresponding alcohol.
(33) Prepared from Example 15VQ using hydroxylamine hydrochloride.
(34) See preparation of Example 15VW using excess reagents.
(35) Prepared by selective monoalkylation of the dialkylated diol using sodium hydride/methyl iodide.
(36) Prepared by substituting CH3CH(OTHP)(CH2)4Br in the procedure described for Example 15VE. Bromide is prepared from CH3CH(OH)(CH2)4OH by the following sequence: (1) Ac2o; (2) THP, H+; (3) NaOH; (4) CBr4, Ph3P.
(37) Prepared by substituting Ph2C═N(CH2)2Br in the procedure described for Example 15VE. Bromide is prepared from H2N(CH2)2OH by the following sequence: (1) Ph2CO; (2) CBr4, Ph3P.
(38) See note 7, Table 2d.
(39) See note 3, Table 2d.
(40) See note 2, Table 2d.
(41) The intermediate was prepared by following Procedure 5 under the title of synthesis of monoalkyl cyclic urea. This was followed by alkylation with Bromo-m-tolunitrile. This intermediate (670 mg, 0.82 mmol) was treated with potassium hydroxide (0.4 g, 7.13 mmol) in ethylene glycol at 140°C C. overnight. The solution was acidified with pre-cooled hydrochloric acid (1N) and extracted with ethyl acetate. The organic phase was concentrated to give 415 mg (61%) of MEM-protected diol. Procedure for hydrolysis of this product is covered under procedure 5.
(42) The intermediate was prepared by following Procedure 5 under the title of synthesis of monoalkyl cyclic urea followed by alkylation with Bromo-m-tolunitrile. This intermediate (210 mg, 0.26 mmol) was treated with DIBAL-H (0.19 mL, 1.5M in toluene, 0.286 mmol) at -78°C C. under nitrogen, stirred at -78°C C. for 1 hour and RT for 3 hours. The reaction was quenched with cooled hydrochloric acid (1N) and worked up in the usual manner to give 180 mg (87%) of the MEM-protected product. Hydrolysis of this product is covered under procedure 5.
(43) N,N-dimethylformamide dimethyl acetal (2.1 ml, 15.9 mmol) was added to a solution of ketone 9P (940 mg, 1.59 mmol) in ethanol. The mixture was heated at reflux overnight, and the solvent was removed on a rotary evaporator. The residue was purified on silica gel (15% methanol/chloroform) to provide the product (940 mg, 84%).
(44) The intermediate was prepared by following procedure 5 under the title of synthesis of monoalkyl cyclic urea. The monoalkylation product was further alkylated with bromo-m-tolunitrile. This intermediate (185 mg, 0.24 mmol) was treated with hydroxylamine.HCl (25 mg, 0.37 mmol), and triethylamine (0.05 ml, 0.37 mml) in refluxing ethanol for 16 h. The resulting solution was partitioned between ethyl acetate/water. The organic layer was washed twice with water and concentrated to give MEM-protected product which can be further hydrolyzed as described above to yield 90 mg (58%) product 9C.
(45) Guanidine carbonate (7.2 g, 40.23 mmol) was added to Ex 15AE in xylene. The mixture was heated at 130°C C. until no starting material was left. The solution was partitioned between ethyl acetate/water and the organic layer washed with water twice. The organic residue was purified on silica gel (10% methanol/ethyl acetate) to provide the pure product(347 mg, 37%).
(46) To a solution of MEM-protected formaldoxime 6C (0.5 g, 0.65 mol) in DMF was added ⅓ of N-chlorosuccinimide (173 mg, 1.3 mmol). The mixture was stirred for 10 min followed by 2 min of heating at 40°C-50°C C. After stirring for another 10 min, the rest of NCS was added. The mixture was stirred at room temperature for overnight. The solution was then partitioned between ethyl acetate/water. The organic layer was washed with water and dried over MgSO4. Treatment of the hydroximoyl chloride with 3 equivalents of o-phenylenediamine in ethanol gave a single product which can be further hydrolyzed to the product (126 mg, 43%).
(47) To a solution of aniline 3K (146 mg, 0.27 mmol) in methylene chloride, was added isonicotinoyl chloride hydrochloride (110 mg, 0.59 mmol) followed by potassium carbonate (187 mg, 1.35 mmol) at 0°C C. The mixture was stirred for 2 h and then slowly warmed up to room temperature overnight. The mixture was partitioned between ethyl acetate/water. The organic layer was washed twice with water and dried over MgSO4. The residue was purified on silica gel (5% methanol/ethyl acetate) to gave the product (52 mg, 26%).
(48) The benzoyl chloride intermediate (0.51 g, 0.72 mmol) was prepared by following procedure (41) & (7) without removing MEM-protecting group. To the residue, 20 ml methylene chloride was added, followed by pyridine (0.11 ml, 1.44 mmol) and tert-butyl carbazate (190 mg, 1.44 mmol). The mixture was stirred at room temperature overnight. The mixture was washed with water & dried over MgSO4. The residue was purified on silica gel (10% ethyl acetate/methylene chloride). Following the hydrolysis procedure described above, the product (182 mg) was isolated in 47% yield.
(49) To the MEM-protected hydrazide 10M (450 mg, 0.72 mmol) in dioxane was added 165 mg (1.5 mmol) of CNBr followed by a solution of 125 mg (1.5 mmol) of sodium bicarbonate in 10 ml water. The resulting mixture was stirred 2 h at room temperature. The solution was concentrated to ½ volume in vacuo. The mixture was diluted with 10 ml of water and the resulting solid isolated by filtration and purified on silica gel (15% methanol/chloroform) to provide (38.4 mg, 8%).
(50) t-Butyl carbazate (264 mg, 2 mmol) was added to aldehyde 5V (450 mg, 0.8 mmol) in ethanol. The mixture was stirred at room temperature for 2 h and heated at reflux overnight. The residue was purified on silica gel (20% ethyl acetate/methylene chloride) to provide the product (179 mg, 28%).
(51) To a solution of aniline 3K (160 mg, 0.3 mmol) in THF, chloroacetyl isocyanate was added dropwise at 0°C C. The mixture was stirred for 0.5 h and then slowly warmed up to room temperature overnight. The solution was partitioned between ethyl acetate/water. The organic phase was washed with water and dried over MgSO4. The residue was purified on silica gel (5% methanol/chloroform) to gave 217 mg in 93% yield.
(53) To a solution of 333 mg (6.16 mmol) of anhydrous NaOCH3 in 20 ml of anhydrous methanol at 0°C C. was added 855 mg (6.16 mmol) of aminoguanidine carbonate followed by 2 ml methanol. The resulting mixture was treated dropwise with 500 mg (0.77 mmol) of ethyl ester 11F which was made by following procedure (10) in 5 ml of methanol. The mixture was heated at reflux overnight, then poured into ice water, brought to PH 7 with 5% aqueous HCl, filtered, and purified on silica gel (10% methanol.chloroform) to give 20 mg (4%) product.
(54) A solution of MEM-protected cyclic urea wherein R22 and R23 are (H2NC(═NOH))benzyl (210 mg, 0.26 mmol) and Et3N (0.18 ml, 1.3 mmol) was treated dropwise with a solution of chloroacetyl chloride (0.046 ml, 0.57 mmol) in CHCl3. The mixture was stirred at room temperature for 2 days and then evaporated, and the residue was redissolved in ethyl acetate. The solution was washed with water, brine, dried over Na2SO4. The residue was purified on silica gel (10% ethyl acetate/methylene chloride) to provide 140 mg (59%) intermediate. The intermediate was dissolved in DMF and treated with excess dimethylamine gas. The mixture was stirred overnight, then poured into ice water, and extracted with ethyl acetate. The extracts were washed with water, dried over MgSO4. Following the usual hydrolysis procedure, the product (15.6 mg) was isolated in 10% yield.
Listed below are a representative list of data for compounds listed in Table 2d:
Example 12A: MS: 525 (M+1). NMR (CD3OD): δ 7.30-7.10 (m, 10H), 3.96-3.88 (m, 2H), 3.58-3.42 (m, 4H), 3.37=3.28 (m, 4H), 3.17-3.10 (m, 2H), 2.94-2.78 (m, 6H), 2.20-2.08 (m, 2H), 1.72-1.10 (br m, 14H).
Example 12B: MS: 516 (M+1, 100). NMR (CD3OD): δ 6.96-7.72 (br m, 15H), 4.68 (d, 1H), 3.78-3.89 (m, 1H), 3.43-3.64 (m, 3H), 3.28-3.34 (m, 2H), 3.10-3.19 (m, 1H), 2.81-3.02 (m, 6H), 2.12-2.26 (m, 1H), 1.10-1.84 (br m, 9H).
Example 12C: MS: 427 (M+1, 100). NMR (CDCl3): δ 7.16-7.36 (m, 10H), 4.82 (d, 1H), 3.88-3.98 (m, 2H), 3.37-3.69 (m, 8H), 3.04-3.19 (m, 3H), 2.63-2.77 (m, 1H), 2.08-2.22 (m, 1H), 1.74-1.88 (m, 2H), 1.10-1.64 (br m, 6H).
Example 12D: MS: 527 (M+1, 100). NMR (CDCl3): δ 7.17-7.38 (m, 10H), 3.99 (s, 2H), 3.45-3.75 (m, 8H), 3.03-3.14 (m, 2H), 2.89-3.01 (m, 2H), 2.60-2.68 (m, 2H), 2.12-2.24 (m, 2H), 1.12-1.62 (br m, 18H).
Example 12E: MS: 481 (M+1, 100). NMR (CDCl3): δ 7.17-7.37 (m, 10H), 3.94-4.13 (m, 2H), 3.61-3.75 (m, 2H), 3.43-3.61 (m, 4H), 3.05-3.20 (m, 3H), 2.73-3.03 (m, 3H), 2.10-2.23 (m, 1H), 1.98-2.08 (m, 1H), 1.02-1.75 (br m, 9H ), 0.82-0.97 (m, 1H), 0.30-0.47 (m, 2H), 0.02-0.13 (m, 2H).
Example 12F: MS: 471 (M+1, 100). NMR (DMSO-d6): δ 7.06-7.33 (m, 10H), 5.25 (s, 2H) 4.34 (t, 2H), 3.71 (s, 2H), 3.44-3.58 (m, 2H), 3.20-3.42 (m, 6H), 2.96-3.06 (m, 2H), 2.79-2.91 (m, 2H), 1.83-1.97 (m, 2H), 1.08-1.42 (br m, 8H).
Example 12G: FABMS: 555 (M+1, 100). NMR (DMSO-d6): δ 8.41 (s, 4H), 7.06-7.33 (m, 10H), 3.71 (s, 2H), 3.33-3.50 (m, 5H), 3.00-3.09 (m, 2H), 2.75-2.88 (m, 2H), 2.11-2.21 (m, 2H), 2.03-2.11 (m, 3H), 1.90-2.03 (m, 2H), 1.02-1.54 (br m, 10 H).
Example 12H: MS: 583 (M+1, 100). NMR (CDCl3): δ 7.12-7.35 (m, 10H), 3.98 (s, 2H), 3.61 (s, 6H), 3.60-3.74 (m, 2H), 3.45-3.58 (m, 2H), 3.03-3.13 (m, 2H), 2.84-3.03 (m, 4H), 2.07-2.28 (m, 6H), 1.08-1.81 (br m, 12H).
Example 12I: MS: 555 (M--CH2+1, 100). NMR (CDCl3): δ 7.12-7.34 (m, 10H), 3.98 (s, 2H), 3.62 (s, 3H), 3.45-3.76 (m, 6H), 3.04-3.13 (m, 2H), 2.85-2.99 (m, 3H), 2.79 (s, 1H), 2.10-2.28 (m, 4H), 1.08-1.64 (br m, 12H).
Example 12J: MS: 759 (M+1, 100), 633 (M--I+1, 33), 507 M--2I+1, 17). NMR (CDCl3): δ 7.00-7.64 (br m, 18H), 4.77 (d, 2H), 3.70 (s, 2H), 3.49-3.57 (m, 2H), 2.99-3.12 (m, 4H), 2.81-2.93 (m, 2H), 2.29 (s, 2H).
Example 12K: MS: 583 (M+1, 100). NMR (CDCl3): δ 7.15-7.35 (m, 10H), 3.98 (s, 2H), 3.44-3.74 (m, 8H), 3.02-3.22 (m, 2H), 2.88-3.02 (m, 2H), 2.02-2.20 (m, 2H), 0.94-1.92 (br m, 28H).
Example 12L: MS: 495 (M+1,100) NMR (CDCl3): δ 7.31 (m,10H) 4.22 (m. 4H) 3.76-4.05 (m. 6H) 3.60 (m, 2H) 3.03-3.37 (m, 6H) 1.89 (m, 2H) 0.95 (m, 2H) 0.80 (m, 2H), 0.45 (m, 2H) 0.30 (m, 2H).
Example 12M: MS: 501 (M+1,100) NMR (CDCl3): δ 7.05-7.38 (m, 15H) 4.84 (dd, 1H) 4.04 (m, 1H) 3.93 (m, 1H) 3.49-3.75 (m. 3H) 3.05 (m, 6H) 1.74 (m, 2H) 0.70-0.98 (m, 2H) 0.40 (m, 1H) 0.28 (m, 1H).
Example 12N: MS: 411 (M+1, 100) NMR (CDCl3): δ 7.25 (m, 10H) 4.72 (bs, 1H) 3.95 (m, 5H) 3.53 (m. 2H) 3.11 (m. 6H) 2.94 (t, 1H) 2.76 (m. 1H) 0.84 (m. 2H) 0.39 (m, 1H) 0.24 (m. 1H).
Example 12o: MS: 441 (M+1, 100). NMR (CDCl3): δ 7.17-7.36 (m, 10H), 4.70 (d, 1H), 3.90-4.01 (m, 2H), 3.53-3.68 (m, 4H), 3.37-3.45 (m, 1H), 3.04-3.20 (m, 3H), 2.78-3.03 (m, 1H), 2.68-2.77 (m, 1H), 2.09-2.24 (m, 1H), 1.10-1.95 (br m, 12H).
Example 12P: MS: 555 (M+1, 100). NMR (CDCl3): δ 7.13-7.37 (m, 10H), 3.98 (s, 2H), 3.44-3.77 (m, 10H), 3.03-3.14 (m, 2H), 2.80-3.01 (m, 4H), 2.06-2.21 (m, 2H), 1.00-1.75 (br m, 20H).
Example 12Q: m. p. 185.7°C C. FABMS: 655 (M+1, 100), 613 (M--HNCNH+1, 80). NMR (DMSO-d6): δ 8.99 (br s, 8H), 6.87-7.62 (br m, 18H), 5.08-5.35 (m, 2H), 4.44-4.62 (m, 2H), 3.41-3.61 (m, 4H), 2.96-3.18 (m, 4H), 2.64-2.81 (m, 2H). Reference: K. Takagi, Chemistry Letters (1985), pp. 1307-1308.
Example 12R: m. p. 169.3°C C. MS: 599 (M+1, 100). NMR (CDCl3): δ 6.90-7.40 (m, 18H), 4.88 (d, 2H), 3.63 (s, 2H), 3.49-3.58 (m, 2H), 2.91-3.12 (m, 6H), 2. 42 (s, 6H), 2.22 (s, 2H).
Example 12S: MS: 663 (M+1), 680 (M+NH3+1). NMR (CDCl3): δ 6.93-7.83 (br m, 18H), 4.78 (d, 2H), 3.71 (s, 2H), 3.53-3.59 (m, 2H), 3.19 (d, 2H), 3.00-3.14 (m, 4H), 2.98 (s, 6H), 2.75-2.83 (m, 2H).
Example 12T: MS: 415 (M+1). NMR (Acetone-d6): δ 7.15-7.30 (m, 10H), 5.29 (s, 1H), 4.41 (s, 1H), 4.25 (s, 1H), 3.81-4.05 (m, 3H), 3.63-3.78 (m, 2H), 3.56-3.63 (m, 2H), 3.37-3.47 (m, 5H), 3.05-3.25 (m, 3H), 2.79-2.94 (m, 1H), 2.20 (br s, 1H).
Example 12U: MS: 503 (M+1). NMR (Acetone-d6): δ 7.15-7.28 (m, 10H), 4.29 (s, 1H), 3.95-4.07 (m, 4H), 3.49-3.66 (m, 8H), 3.35-3.49 (m, 8H), 3.14-3.22 (m, 2H), 3.02-3.09 (m, 2H), 2.08-2.21 (m, 3H).
Example 12V: MS: 569 (M+1). NMR (CDCl3): δ 7.14-7.34 (m, 10H), 3.90-4.03 (m, 4H), 3.42-3.74 (m, 8H), 3.03-3.14 (m, 2H), 2.86-3.01 (m, 2H), 2.68-2.86 (m, 2H), 2.05-2.23 (m, 2H), 2.01 (s, 3H), 0.98-1.75 (br m, 15 H).
Example 12W: MS: 641 (M+1), 584 (M--CONHCH2+1), 27 (M--2CONHCH2+1). NMR (CDCl3): δ 7.10-7.35 (m, 10H), 4.77 (br s, 2H), 3.89-4.12 (m, 6H), 3.60-3.80 (m, 2H), 3.35-3.47 (m, 2H), 3.04-3.16 (m, 2H), 2.87-3.01 (m, 2H), 2.78 (d, 6H), 2.01-2.16 (m, 2H), 0.98-1.80 (br m, 18H).
Example 12X: MS: 626 (M+1), 569 (M--CONHCH2+1). NMR (CDCl13): δ 7.0 9-7.35 (m, 10H), 4.79 (br s, 1H), 3.82-4.14 (m, 6H), 3.38-3.81 (m, 4H), 3.01-3.22 (m, 2H), 2.83-3.01 (m, 2H), 2.79 (d, 3H), 2.04-2.20 (m, 2H), 2.01 (s, 3H), 0.96-1.84 (br m, 18 H).
Example 12Y: MS: 584 (M+1), 527 (M--CONHCH2+1). NMR (CDCl3): δ 7.11-7.41 (m, 10H), 4.81 (br s, 1H), 3.87-4.10 (m, 4H), 3.41-3.76 (m, 6H), 3.02-3.16 (m, 2H), 2.81-3.02 (m, 2H), 2.78 (d, 3H), 2.00-2.21 (m, 2H), 1.79 (br s, 1H), 0.95-1.63 (br m, 18H).
Example 12Z: MS: 425 (M+1, 100).
Example 13A: MS: 439 (M+1, 100).
Example 13B: MS: 481 (M+1, 100).
Example 13C: MS: 635 (M+1, 100) 652 (M+NH4).
Example 13D: MS: 491 (M+1,100); NMR (CDCl3): δ 7.24 (m,10H), 5.68 (m,2H), 4.90 (m,4H), 3.98 (s,2H), 3.66 (m,2H), 3.50 (m,2H), 3.04 (m,4H), 2.19 (m,2H), 1.95 (m,4H), 1.22 (m,8H).
Example 13E: MS: 523 (M+1, 100); NMR (CDCl3): δ 7.19 (m,10H), 3.98 (s,2H), 3.66 (m,2H), 3.53 (m,2H), 3.23 (s,2H), 3.14-2.66 (m,8H), 2.40 (m,2H), 2.21 (m,2H), 1.55-1.23 (m,12H).
Example 13F: MS: 811 (M+1,100); NMR (CDCl3): δ 7.22 (m,10H), 4.00 (m,4H), 3.77 (dd,2H), 3.56 (m,6H), 3.13 (m,4H), 2.93 (m,2H), 2.23 (m,2H), 2.00 (m,2H), 1.65 (m,2H), 1.50-1.23 (m,8H).
Example 13G: MS: 685 (M+1, 100); NMR (CDCl3): δ 7.22 (m,10H), 4.01 (m,2H), 3.72-3.26 (m,12H), 3.14 (d,2H), 2.96-2.70 (m,6H), 2.26 (m,2H), 1.43-1.18 (m,8H).
Example 13H: MS: 499 (M+1,100); NMR (CDCl3): 7.23 (m,10H), 3.99 (s,2H), 3.54 (m,8H), 3.12 (m,2H), 2.94 (m,4H), 2.22 (m,2H), 1.47-1.20 (m,12H).
Example 13I: MS: 559 (M+1, 100); NMR (CDCl3/CD3OD): δ 7.02 (m,10H), 3.79 (s,2H), 3.69 (s,2H), 3.28 (m,6H), 3.13 (m,4H), 2.86 (m,2H), 2.67 (m,2H), 1.95 (m,2H), 1.09-0.90 (m,12H).
Example 13J: MS: 435 (M+1, 100); NMR (CDCl3): δ 7.26 (m,10H), 4.15 (m,1H), 3.86 (m,1H), 3.76 (m,1H), 3.64 (m,1H), 3.53 (m,2H), 3.23-2.97 (m,4H), 2.78 (m, 2H), 2.16 (d,1H), 1.92 (m,1H), 1.18 (m,1H), 0.88 (m,1H), 0.58 (m,2H), 0.46 (m,2H), 0.29 (d,1H), 0.07 (d,1H).
Example 13K: MS: 407 (M+1, 100); NMR (CDCl3): δ 7.23 (m,10H), 6.05 (m,1H), 5.67 (m,1H), 5.25 (m,2H), 5.05 (dd,2H), 4.17 (m,2H), 3.96 (m,1H), 3.83 (m,1H), 3.65 (m,1H), 3.55 (m,1H), 3.12-2.79 (m,5H), 2.59 (br s,1H), 2.35 (d,1H).
Example 13L: MS: 507 (M+1, 100); NMR (CDCl3): δ 7.28 (m,18H), 6.91 (d,2H), 4.10 (d,2H), 3.92 (d,1H), 3.58 (m,4H), 3.18-2.63 (m,5H).
Example 13M: MS: 567 (M+1,100); NMR (CDCl3): δ 7.46-6.95 (m,18H), 4.90 (dd,2H), 4.67 (br d,4H), 3.84 (d,1H), 3.53 (m,4H), 3.09-2.75 (m,5H), 2.44 (d,1H).
Example 13N: MS: 407 (M+1,100); NMR (CDCl3): δ 7.24 (m,10H), 5.55 (m,2H), 5.14 (m,4H), 4.07 (dd,2H), 3.74 (m,2H), 3.27 (m,2H), 3.12-2.84 (m,6H), 2.09 (s,2H).
Example 13o: MS: 435 (M+1,100); NMR (CDCl3): δ 7.26 (m,10H), 3.85 (s,2H), 3.41 (m,4H), 3.01 (ddd,4H), 2.28 (dd,2H), 2.19 (s,2H), 0.93 (m,2H), 0.50 (m,2H), 0.16 (m,2H).
Example 13P: MS:327 (M+1,100); NMR (CDCl3): δ 7.28 (m,10H), 4.25 (m,2H), 3.35 (m,6H), 2.81 (m,2H), 2.65 (m,2H).
Example 13Q: MS: 507 (M+1,100): NMR (CDCl3): δ 7.24 (m,20H), 4.74 (d,2H), 3.55 (m,4H), 3.20 (m,2H), 2.96 (m,2H), 2.77 (m,2H).
Example 13R: MS: 439 (M+1,100); NMR (CDCl3): δ 7.26 (m,10H), 3.75 (s,2H), 3.62 (m,2H), 3.20 (m,2H), 3.08 (m,2H), 2.84 (m,2H), 2.38 (m,2H), 1.38-1.23 (m,8H), 0.90 (m,6H).
Example 13S: MS: 567 (M+1,100); NMR (CDCl3): δ 7.34-7.07 (m,18H), 4.68 (m,6H), 3.57 (m,4H), 3.17 (m,2H), 2.96 (m,2H), 2.79 (m,2H).
Example 13T: MS: 617 (M+H, 100%); NMR (CDCl3, 300 MHz): δ 7.3 (m,10H), 6.7 (m,4H), 6.35 (m,2H), 4.75 (d,2H), 3.5 (s,4H), 3.3 (m,4H), 3.0 (m,6H), 2.7 (m,4H), 1.9 (m,4H).
Example 13U: m.p. 264°C-266°C C.; MS: 609 (M+H, 100%); NMR (CDCl3, 300 MHz): δ 8.6 (d,2H), 7.95 (d,2H), 7.8 (d,2H), 7.6 (d,2H), 7.3 (m,14H), 5.1 (d,2H), 3.7 (m,4H), 3.2 (m,6H).
Example 13V: MS: 521 (M+H, 100%); NMR (CDCl3, 300MHz): δ 8.8(s,2H), 7.2(m, 12H), 4.15(s,2H), 3.8 (t, 2H), 3.6 (m, 4H), 2.9(m, 4H).
Example 13W: m.p. 182°C-184°C C.; MS: 687 (M+H, 100%); NMR (CDCl3,300 MHz): δ 7.2 (m,10H), 6.95 (d,2H), 6.2 (d,2H), 4.9(d,2H), 4.15(d,2H), 3.9(bs,2s), 3.7(d,2H), 3.0(m, 6H), 1.45(s,18H).
Example 13X: MS: 547 (M+H, 100%); NMR (CDCl3,300 MHz): δ 7.2(m,10H), 6.2(d,2H), 6.0(d,2H), 4.8(d,2H), 4.5(bs,2H), 3.8(s,2H), 3.5(d,2H), 3.1(m, 6H).
Example 13Y: MS: 507 (M+1, 100% ); NMR (CDCl3, 300 MHz): δ 7.0-7.4 (m, 20H), 4.7-4.8 (d, 2H), 4.5 (m, 2H), 3.45 (m, 4H), 3.1 (m, 4H), 2.9 (m, 2H).
Example 13Z: MS: 577 ((M+H)+, 100%); 594 ((M+NH4)+, 80%). NMR (CDCl3): δ 8.08(s 1H), 7.48(dd, 1H, J=8.4, 1.9 Hz), 7.25-7.38 (m, 3H); 7.19 (d, 1H, J=8.4 Hz), 7.00-7.03(m, 2H), 3.96(ABq, 2H), 3.73(d, 1H, J=1.1 Hz), 3.50(dd, 1H, J=11.4, 1.1 Hz), 3.23(br.s., 1H), 2.98 (ABx, 2H).
Example 14A: NMR (CDCl3): δ 8.27(dd, 1H, J=4.9, 2.0 Hz), 7.66(dd, 1H, J=7.5, 2.0 Hz), 7.14-7.27 (m, 4H), 6.68(dd, 2H, J=7.5, 3.6 Hz), 4.16(d, 1H, J=0.8 Hz), 3.90 (ABq, 2H), 3.72(dd, 1H, J=11.3, 1.1 Hz), 3.14(br. s., 1H), 2.87(ABx, 2H).
Example 14B: MS: 685 ((M+H)+, 100%). NMR (CDCl3): δ 8.34(dd, 1H, J=4.8, 1.9 Hz), 7.16-7.37(m, 4H), 6.93(dd, 1H, J=7.6. 4.8 Hz), 6.87(dd, 2H, J=7.5, 1.7 Hz), 4.14(s, 1H), 3.90(ABq, 2H), 3.68(td, 1H, J=6.3, 0.7 Hz), 2.99(d, 2H, J=6.3 Hz), 2.43(br. s., 1H).
Example 14C: MS: 541 ((M+H)+, 100%) NMR (CD3OD): δ 7.53(dd, 1H, J=9.5, 2.6 Hz), 7.15-7.26(m, 3H), 7.06(d, 1H, J=2.6 Hz), 6.96-6.99 (m, 2H), 6.42 (d, 1H, J=9.5 Hz), 3.80 (s, 1H), 3.71(ABq, 2H), 3.62(dd, 1H, J=11.7, 0.7 Hz), 2.92(ABx, 2H).
Example 14D: MS: 458 (M+H+, 100%).
Example 14E: MS: 543(M+H+, 100%) NMR (CDCl3): δ 7.4-7.1(m, 5H), 4.42(d, J=17.5 Hz, 1H), 4.10(s, 1H), 3.83(d, J=10.6 Hz), 3.2-3.0(m, 2H), 2.82 (d, J=17.6 Hz, 1H), 2.36(s, 1H), 2.14(m, 2H), 1.5-1.2(m, 6H), 0.85(t, J=7.0 Hz, 3H).
Example 14F: MS: 739.5 (M+H+) NMR (CDCl3): δ 7.4-7.0(m, 15H), 3.90(s, 1H), 3.3-3.1(m, 2H), 3.04(m, 2H), 2.43(dd, J=14.7, 5.7 Hz, 1H), 2.17(s, 1H), 1.824(m, 1H), 1.26(t, J=6.0 Hz, 1H), 1.02(dd, J=9.0, 5.1 Hz, 1H)
Example 14G: MS: 479 (M+H+, 100%) NMR (CDCl3): δ 7.24(bs, 5H), 7.15-6.9(m, 3H), 6.72(d, J=7.5 Hz, 2H), 4.15(s, 1H), 4.06(d, J=10.5 Hz, 1H), 3.5-3.2 (m, 2H), 2.98 (s, 1H).
Example 14H: MS: 587 (M+H+, 100%) NMR (CDCl3): δ 7.4-6.9(m, 10H), 3.92(s, 1H), 3.8-3.6(m, 2H), 3.03(m, 2H), 2.50(bs, 1H), 2.19(dd, J=14.3, 7.0 Hz, 1H), 1.57 (m, 1H), 1.0-0.7 (m, 2H).
Example 14I: MS: 457 (M+H+, 100%), 474(M+NH4+, 15%) NMR (CDCl3): δ 7.4-6.9(m, 15H), 4.69(d, J=6.2 Hz, 1H), 3.95(m, 2H), 3.77(m, 2H), 3.37(m, 1H), 3.25-3.0(m, 3H), 2.15(b, 1H), 1.61(m, 2H), 1.24(m, 1H), 1.0-0.7 (m, 2H).
Example 14J: NMR (CDCl3): δ 7.42 (d, 2H, J=7.3 Hz), 7.22-7.38(m, 6H), 7.11(d, 2H, J=6.6 Hz), 6.54(s, 1H), 6.35(s, 1H), 5.31(s, 2H), 3.84(ABq, 2H), 3.72(s, 1H), 3.49(d, 1H, J=10.4 Hz), 2.90-3.01(m, 2H), 2.39(s, 3H).
Example 14K: NMR ((CD3)2SO): δ 7.00-7.33(m, 7H), 3.61(s, 1H), 3.55(ABq, 2H), 3.45(d, 1H, J=11.0 Hz), 2.95(ABx, 2H), 2.09(s, 3H).
Example 15VA: NMR (CDCl3): δ 7.19-7.40 (m, 10H), 4.66 (d, 1H) 3.99-4.12 (m, 2H) 3.59-3.69 (m, 2H) 3.37-3.49 (m, 2H) 3.10-3.21 (m, 2H) 2.25-2.38(m, 3H) 1.90-2.00 (m, 2H) 0.85-0.92 (m, 8H).
Example 15VB: NMR (CD3OD): δ 7.50-7.70 (m, 1H) 7.10-7.35 (m, 9H) 3.95 (m, 2H) 3.53-3.70 (m, 2H) 3.40-3.50 (m, 2H) 3.00-3.20 (m, 3H) 2.75 (t, 1H) 2.30 (m, 1H) 1.60-2.10 (m, 7H) 1.28 (m, 2H) 0.81-1.10 (m, 2H).
Example 15VC: NMR (CDCl3): δ 7.15-7.40 (m, 10H) 4.70 (d, 1H) 4.05 (m, 2H) 3.50-3.70 (m, 3H) 3.57 (m, 1H) 3.20 (m, 1H) 3.07 3H) 3.05 (s, 3H )2.75 (t, 1H) 2.59 (s, 2H) 2.93 (m, 2H) 1.40-1.55 (m, 5H) 1.17-1.32 (m, 2H) 1.00-1.15 (m, 2H).
Example 15VD: NMR (CDCl3): δ 7.05-7.30 (m, 10H), 5.55 (br s, 2H), 3.93 (s, 2H) 3.66-3.80 (m, 4H), 3.53 (d, 2H), 3.09 (d, 2H), 2.85-2.92 (m, 2H), 2.81 (d, 6H), 1.98-2.26 (m, 6H), 0.96-1.52 (br m, 12H).
Example 15VE: NMR (CDCl3): δ 7.17-7.34 (m, 10H), 3.99 (s, 2H), 3.55-3.73 (m, 4H), 3.43-3.53 (m, 4H), 3.05-3.13 (m, 2H), 2.90-3.00 (m, 2H), 2.58 (br d, 2H), 2.15-2.28 (m, 2H), 1.12-1.80 (br m, 17H).
Example 15VF: NMR (CDCl3): δ 7.17-7.34 (m, 10H), 4.57 (br s, 1H), 4.08 (t, 2H), 3.99 (s, 2H), 3.60-3.72 (m, 2H), 3.59 (t, 2H), 3.46-3.54 (m, 2H), 3.05-3.13 (m, 2H), 2.89-3.00 (m, 2H), 2.78 (d, 3H), 2.70 (br s, 2H), 2.14-2.24 (m, 2H), 1.12-1.80.(br m, 17H).
Example 15VG: NMR (CDCl3): δ 7.10-7.37 (m, 10H), 4.80 (d, 1H), 3.92 (s, 2H), 3.20-3.70 (br m, 6H), 3.00-3.19 (m, 4H), 3.61-3.77 (m, 1H), 2.21 (br s, 1H), 1.10-1.50 (br m, 7H).
Example 15VH: NMR (CDCl3); δ 7.64-7.84 (m, 3H), 7.05-7.57 (m, 14H), 4.96 (d, 1H), 3.92 (m, 1H), 3.38-3.80 (m, 6H), 3.21 (d, 1H), 2.99-3.18 (m, 3H), 2.75-2.98 (m, 2H), 2.43 (br s, 1H), 2.20-2.35 (m, 1H), 1.10-1.88 (br m, 7H).
Example 15VI: NMR (CDCl3): δ 7.04-7.40 (m, 15H), 4.80 (d, 1H), 3.94 (m, 1H), 3.42-3.80 (m, 7H), 2.83-3.17 (m, 6H), 2.64 (br s, 1H), 2.19-2.31 (m, 1H), 1.16-1.50 (br m, 6H).
Example 15VJ: NMR (CDCl3): δ 7.11-7.35 (m, 10H), 3.99 (s, 2H), 3.43-3.69 (m, 6H), 3.10 (m, 2H), 2.95 (m, 3H), 2.80 (s, 1H), 2.38 (t, 2H), 2.20 (m, 2H), 2.02 (s, 3H), 1.18-1.56 (br m, 13H).
Example 15VK: NMR (CDCl3): δ 7.05-7.40 (m, 14H), 4.79 (d, 1H), 4.58-4.70 (m, 2H), 4.50 (d, 1H), 3.91 (m, 1H), 3.40-3.75 (m, 6H), 2.98-3.14 (m, 4H), 2.81-2.95 (m, 2H), 2.72 (s, 1H), 2.25 (m, 1H), 2.07 (br s, 1H), 1.16-1.50 (br m, 6H).
Example 15VL: NMR (CDCl3): δ 7.18-7.36 (10H, m) 4.53 (1H,s) 3.95 (2H,s): 3.79 (1H,m) 3.51 (1H,m) 3.33 (2H,m) 3.13 (6H,m) 2.72 (1H,t) 2.60 (1H, s) 1.33 (2H,m) 0.84 (3H, t).
Example 15VM: NMR (CDCl3): δ 7.20-7.34 (10H,m) 4.57 (1H, s) 3.94 (2H, s) 3.79 (1H,m) 3.52 (1H,m) 3.38 (1H,m) 3.33 (1H, d) 3.13 (5H, m) 2.94 (2H,.bs) 2.72 (1H, t) 1.26 (6H, m) 0.86 (3H, t).
Example 15VO: NMR (CDCl3): δ 7.14-7.35 (10H, m) 4.63 (2H,d) 4.41 (2H, s) 3.49 (2H,d) 3.34 (2H, m) 3.14.(2H,m) 2.85 (2H,d) 2.45 (2H, s) 2.10-2.32 (4H,m) 0.99 (6H,t).
Example 15VP: NMR(CDCl3): δ 8.81 (2H, s) 7.23 (10H, m) 4.80 (2H,d) 4.14 (4H, m) 3.68 (2H, m) 3.14 (2H, m) 2.60 (2H.d) 2.44 (2H,m) 2.03 (2H,m) 0.98 (6H,t).
Example 15VQ: NMR (CDCl3): δ 7.64-7.82 (m, 3H), 7.07-7.53 (m, 14H), 4.96 (d, 1H), 3.88-3.96 (m, 1H), 3.44-3.80 (m, 7H), 3.21 (d, 1H), 2.99-3.16 (m, 3H), 2.84-2.98 (m, 1H), 2.70 (s, 1H), 2.19-2.33 (m, 2H), 1.08-1.56 (br m,8H).
Example 15VR: NMR (Acetone-d6): δ 8.38 (s, 1H), 7.02-7.40 (m, 11H), 6.70 (m, 2H), 6.52 (d, 1H), 4.73 (d, 1H), 4.34 (s, 2H), 3.84-3.96 (m, 1H), 3.38-3.76 (br m, 7H), 2.80-3.21 (br m, 5H), 2.07-2.19 (m, 1H), 1.16-1.52 (br m, 6H).
Example 15VS: NMR (CDCl3): δ 7.15-7.33 (m, 10H), 4.00 (s, 2H), 3.44-3.69 (m, 5H), 3.10 (d, 2H), 2.88-2.98 (m, 3H), 2.85 (s, 3H), 2.56-2.76 (m, 2H), 2.17-2.35 (m, 2H), 1.18-1.80 (m, 15H).
Example 15VU: NMR (CDCl3): δ 7.10-7.36 (m, 10H), 4.04 (m, 2H), 3.3 9-3.7 9 (br m, 7H), 2.78-3.22 (br m, 6H), 2.17-2.29 (m, 1H), 2.03 (m, 1H), 1.15-1.52 (br m, 6H), 0.91 (m, 1H), 0.41 (m 2H), 0.06 (m, 2H).
Example 15VV: NMR (CDCl3): δ 7.15-7.33 (m, 10H), 3.99 (s, 2H), 3.65 (m, 2H), 3.49 (d, 2H), 3.25 (s, 6H), 3.21-3.33 (m, 4H), 3.04-3.14 (m, 2H), 2.89-3.00 (m, 2H), 2.63 (s, 2H), 2.18 (m, 2H), 1.72 (br s, 2H), 1.15-1.52 (br m, 10H).
Example 15VW: NMR (CDCl3): δ 7.13-7.33 (m, 10H), 3.99 (s, 2H), 3.45-3.71 (br m, 6H), 3.24 (s, 3H), 3.20-3.33 (m, 3H), 3.10 (d, 3H), 2.89-3.00 (m, 2H), 2.10-2.28 (m, 2H), 1.85 (br d, 2H), 1.15-1.53 (br m, 11H).
Example 15VX: NMR (CDCl3): δ 7.13-7.57 (br, m, 11H), 6.98 (d, 3H), 4.68 (d, 1H), 3.98 (m, 1H),3.74-3.89 (m, 2H), 3.46-3.69 (m, 3H), 3.22 (d, 1H), 3.01-3.18 (m, 3H), 2.81-2.93 (m, 3H), 2.66 (br d, 2H), 2.23 (m, 1H), 1.18-1.56 (br m, 6H).
Example 15VY: NMR (CDCl3): δ 7.91 (m, 1H), 7.83 (s, 1H), 7.17-7.39 (m, 10H), 7.09 (d, 2H), 4.84 (d, 1H), 4.31 (q, 2H), 3.95 (dd, 1H), 3.62-3.72 (m, 2H), 3.48-3.60 (m, 4H), 2.86-3.16 (br m, 5H), 2.57 (br s, 1H), 2.39 (br s, 1H), 2.29 (m, 1H), 1.05-1.52 (br m, 10H).
Example 15VZ: NMR (CDCl3): δ 7.17-7.32 (10H,m) 3.99 (2H,s) 3.68 (4H,m) 3.50 (2H,d) 3.09 (2H,dd) 2.94 (2H,t) 2.62 (2H,s) 2.23 (2H,m) 1.33 (14H,m) 1.12 (6H,d).
Example 15WB: NMR (CDCl3): δ 7.13-7.33 (m, 10H), 4.02 (s, 2H), 3.61 (m, 2H), 3.50 (d, 2H), 3.10 (dd, 2H), 2.85-2.97 (m, 2H), 2.82 (s, 2H), 2.33 (t, 4H), 2.19 (m, 2H), 2.06 (s, 6H), 1.18-1.50 (br m, 8H).
Example 15WC: NMR (DMSO-d6): δ 10.17, 10.09 (2 singlets, 2H-3:1 mixture of isomers), 7.08-7.32 (m, 10H), 5.21 (s, 2H), 3.70 (s, 2H), 3.48 (m, 2H), 3.38 (d, 2H), 3.03 (d, 2H), 2.81 (m, 2H), 1.91-2.19 (br m, 6H), 1.61-1.71 (m, 6H), 1.15-1.39 (m, 8H).
Example 15WD: NMR (DMSO-d6): δ 6.91-7.40 (br m, 14H), 5.01-5.22 (m, 1H), 4.61 (m, 1H), 4.42-4.50 (m, 1H), 3.66 (m, 1H), 3.12-3.54 (br m, 7H), 3.06 (d, 1H), 2.75-2.99 (m, 4H), 2.32-2.57 (m, 4H), 1.94-2.07 (m, 1H), 1.05-1.38 (br m, 8H).
Example 15WE: NMR (CDCl3): δ 7.18-7.38 (m, 10H), 7.33 (s, 1H), 7.06 (m, 3H), 4.80 (d, 1H), 4.60 (d, 2H), 3.94 (m, 1H), 3.46-3.75 (m, 7H), 2.80-3.15 (m, 7H), 2.23-2.42 (m, 2H), 1.18-1.50 (br m, 6H).
15BC; MS (DCI): 514 (M+H+, 100%). 1H NMR (CD3OD, 300 MHz) δ 0.1 (m, 2H), 0.4 (m, 2H), 0.8 (m, 1H), 1.9 (m, 1H), 3.0 (m, 4H), 3.3 (d, 1H), 3.4 (m, 2H), 3.6 (m, 1H), 3.75 (m,1H), 4.0 (m, 1H), 4.4 (d,1H), 6.8-7.4 (m,13H).
15AA 1H NMR (CD3OD, 300 MHz) δ 3.00(m, 6H), 3.6 (m, 4H), 4.4 (s, 4H), 4.7 (d, 2H), 6.9-7.5 (m, 18H).
15AM MS (DCI): 661 (M+H,100%). 1H NMR (CD3OD, 300 MHz) δ 1.2 (t, 3H), 3.0 (m, 6H), 3.6 (m, 4H), 4.3 (q, 2H), 4.8 (d,2H), 7.0-7.4 (m, 18),7.8-8.0 (m, 3H).
15AQ: MS (DCI): 548 (M+H, 100%). 1H NMR (CD3OD, 300 MHz) δ 3.0 (m, 6H), 3.6 (m, 4H), 4.8 (m, 2H), 6.8-7.8 (m, 18H).
15AR: MS (DCI): 533 (M+H, 100%). 1H NMR (CD3OD, 300 MHz) δ 3.0 (m, 6H), 3.7 (m, 4H), 4.7 (d, 2H), 4.8 (d, 1H), 7.0-8.4 (m, 18H).
15AO: 1H NMR (CD3OD, 300 MHz) δ 2.4 (s, 12H), 3.0 (m, 6H), 3.6 (s,4H), 3.9 (s, 4H), 4.8 (d, J=15Hz,2H), 7.05-7.50(m, 14H) 7.96(d, J=7.5 Hz, 2H), 8.0(s, 2H).
The structures of the Examples below are shown in Table 2e.
Lithium borohydride (1.2 gr, 56.2 mmol) was added in four portions to a suspension of L-mannonic-g-lactone (5 gr, 28.1 mmol) in methanol (250 mL) at 0°C C. over 10 min. Ice bath was removed and reaction stirred at room temperature for 30 min. Reaction was quenched at 0°C C. with 2N HCl. Solvent was evaporated and residue taken up in acetone (75 mL) to which 2,2-dimethoxypropane (20 mL, 168.6 mmol) and camphorsulphonic acid (20 gr, 84.3 mmol) were added in four portions. Reaction becomes clear for a few minutes and then a precipitate forms. Reaction stirred at room temperature for 14 h. Solvent volume then reduced by ⅔ at reduced pressure and then poured into EtOAc, washed with saturated NaHCO3, dried (MgSO4) and concentrated. Solid residue taken up in hexane and filtered thru a pad of silica gel. Filtrate concentrated to give triacetonide (XXVIa) as a yellowish solid (7.1 gr, 80%). m.p. 72°C-74°C C.; MS: 303 (M+H, 100%); NMR (CDCl3, 300 MHz): δ 4.25 (m, 2H), 4.15 (m, 2H), 4.05 (m, 4H), 1.5 (s, 6H), 1.45 (s, 6H), 1.4 (s, 6H).
Compound (XXVIa) (14 gr) in 70% AcOH (200 mL) was stirred at 45°C C. for 2 h. Solvent removed at reduced pressure with a bath temperature of 45°C C. Residue recrystalized from ether. Mother liquors concentrated and chromatographed (silica, 10% methanol in methylene chloride) to give the desired product as a white solid (8.2 gr, 80%). m.p. 91°C-93°C C.; [a]D=-26.40 (c=3, H2O); MS: 240 (M+NH4,100%); NMR (CDCl3, 300 MHz): δ 3.95 (m, 6H), 3.75 (m, 4H), 2.5 (bs, 2H), 1.4 (s,6H).
A solution of Compound (XXVIb) (1 g, 4.5 mmol) in pyridine (5 mL) was cooled to -20°C C. and treated with p-toluenesulfonyl chloride (1.89 g, 10 mmol). Stirring continued at -20°C C. for 20 min, 0°C C. for 20 min, and 23°C C. for 20 min. The reaction was then diluted with methylene chloride and washed with 2N HCl and NaHCO3. The organic extract was dried over MgSO4 and concentrated The crude product was then taken up in methanol (14 mL) and cooled to 0°C C. Next, K2CO3 (3.11 g. 22 mmol) was added and the reaction stirred at room temperature for 30 min. The methanol was then stripped off (do not evaporate to dryness, epoxide is volatile) and the crude was washed with water, extracted with ether, dried over MgSO4, filtered, and concentrated. The compound was purified on SiO2 and eluted with 30-60% ether/petroleum ether to afford the diepoxide (0.63 g, 75%) as an oil. NMR (CDCl3, 300 MHz): 83.81 (m, 2H), 3.10 (m, 2H), 2.80 (t, 2H), 2.68 (m, 2H), 1.40 (s, 6H, CH3).
To a suspension of cuprous bromide-dimethyl sulfide complex (1.8 g, 8.7 mmol) in anhydrous THF (5 mL) at -20°C C. was added 8.5 ml benzylmagnesium chloride (2M in THF, 17 mmol). Reaction stirred at -20°C C. for 30 min and at 0°C C. for 1 h. Next, Compound (XXVIc) (0.54 g, 3 mmol) in THF (5 mL) was added, and the reaction stirred at 0°C C. for 1 h. The excess reagent was quenched with saturated NH4Cl solution and allowed to warm to room temperature. The contents were then washed with water and brine, extracted with ether, dried over MgSO4, filtered, and concentrated. Crude material was then purified by flash chromatography (30-60% ether/petroleum ether) to yield 0.84 g (78%) of an oil. MS: 371 (M+H, 66%); NMR (CDCl3,300 MHz): δ 7.2-7.4 (m, 10H), 4.65 (s, 2H), 3.6-3.8 (m, 4H), 2.6-3.0 (m, 4H), 1.8-2.2 (m, 4H), 1.4 (s, 6H).
To a solution of Compound (XXVId) (0.48 g, 1.3 mmol) and triphenyl phosphine (1.0 g, 3.9 mmol) in THF (5 mL) at 0°C C. was added diethylazodicarboxylate (0.61 mL, 3.9 mmol) and diphenylphosphorylazide (0.84 mL, 3.9 mmol). Contents were allowed to warm to room temperature in the ice bath for 1 h. The excess reagents were quenched by the addition of methanol (0.2 mL, 5 mmol) at 0°C C. The mixture was then stirred at room temperature for 30 min and then concentrated to a small volume. Crude was then purified on SiO2 using 1:40 ethyl acetate/hexane giving 0.245 g (45%) of an oil. MS: 438 (M+NH4, 8%); NMR (CDCl3,300 MHz): δ 7.2-7.4 (m, 10H), 4.18 (s, 2H), 2.7-3.0 (m, 6H), 2.0-2.3 (m, 4H), 1.58 (s, 6H).
To Compound (XXVIe) (0.245 g, 0.58 mmol) in ethanol (6 mL) under N2 was added 10% Pd/C (735 mg, 30%/weight). Reaction stirred under H2 atmosphere at room temperature overnite. Crude was then filtered through celite and concentrated. 0.21 g (98%) of the diamine was collected as an oil and taken onto next step without further purification. MS: 369 (M+H, 100%); NMR (CDCl3,300 MHz): δ 7.05-7.3 (m, 10H), 3.9 (bs, 2H), 3.05 (bs. 4H), 2.8 (m, 2H), 2.6 (m, 4H), 1.7 (bs, 4H), 1.35 (s, 6H).
The diamine (0.21 g, 0.57 mmol) was dissolved in methylene chloride (50 mL) and carbonyldiimidazole (0.102 g, 0.63 mmol) was added and the reaction stirred at 23°C C. overnite. The solution was then concentrated and purified on SiO2 using 75% ethyl acetate/hexane as elutent which gave 85 mg (38%) of (XXVIf) as a foam. MS: 395 (M+H, 100%); NMR (CDCl3, 300 MHz): δ 7.0-7.2 (m, 10H), 3.6-4.0 (m, 4H), 3.6-2.7 (m, 4H), 1.8-1.9 (m, 4H), 1.3 (s. 6H).
To Compound (XXVIf) (85 mg, 0.22 mmol) in dry DMF (3 mL) was added 60% NaH (0.07 g, 1.7 mmol). The solution was stirred for 5 min at room temperature. Next, benzyl bromide (0.1 mL, 0.86 mmol) was added and the reaction stirred at 23°C C. overnite. Reaction was then quenched with methanol (several drops), washed with H2O, extracted with ether, dried (MgSO4), and concentrated. Crude was then purified on silica gel using 1:1 hexane/ethyl acetate affording 0.03 g (25%) of the bis-alkylated urea as a foam. MS: 575 (M+H, 100% ); NMR (CDCl3, 300 MHz): δ 7.1-7.4 (m, 20H), 5.1 (d,2H), 4.0 (d, 2H), 3.75 (bs, 2H), 3.6 (m, 2H), 2.7 (m, 2H), 2.6 (m, 2H), 1.9-2.0 (m, 4H), 1.25 (s, 6H).
To above prepared bis-alkylated cyclic urea (0.03 g, 0.05 mmol) in THF (2 mL) at room temperature was added several drops of concentrated HCl. Reaction stirred at room temperature for 2 h. Reaction was then washed with 1N NaOH, extracted with ethyl acetate, dried (MgSO4), and concentrated. Chromatography (silica, 1-5% methanol in methylenechloride) gave 0.024 g (85%) of example 16A as a foam. MS: 535 (M+H, 100%); NMR (CDCl3, 300 MHz): δ 7.1-7.3 (m, 20H), 5.15 (d, 2H), 3.9 (d, 2H), 3.5 (bs, 2H), 3.3-3.4 (m, 2H), 2.7-2.8 (m, 2H), 2.5-2.6 (m, 2H), 2.0-2.1 (m, 6H ).
Ester Hydrolysis: Synthesis of diacid LIVa
To a solution of 100.7 g (458.0 mmol) of (4R, 5R)-(-)-dimethyl-2,3-O-isopropylidine-L-tartrate in 450 mL of ethanol was added 450 ml of 15% sodium hydroxide in water. After stirring 5 h the solvent was partially removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The aqueous layer was then acidified with conc. HCl, saturated with NaCl, and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the solid residue was triturated with CH2Cl2 and hexanes to give 72.2 g (83%) of the diacid LIVa as a white solid. mp 98°C-100°C C. 1H NMR (300 MHz, CD3OD) δ 4.83 (s, 2H, CH), 1.54 (s, 6H, CH3).
Preparation of Weinreb Amide: Synthesis of LIVb
To a solution of 30 g (157.8 mmol) of LIVa in 1 L of methylene chloride was added 60 g (370.0 mmol) of 1,1'-carbonyldiimidazole. After stirring 6h, 34.0 g (350 mmol) of N,O-dimethylhydroxylamine hydrochloride was added and the resulting solution was stirred overnight. The solvent was partially removed under reduced pressure and the residue was diluted with ethyl acetate, The solution was then acidified with 4N HCl, saturated with NaCl, and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was triturated with ethyl acetate and hexanes to give 35.6 g (82%) of the bis-Weinreb amide LIVb as a tan solid. mp. 78°C-80°C C. 1H NMR (300 MHz, CDCl3) δ 5.16 (s, 2H, CH), 3.70 (s, 6H, OCH3), 3.22 (s, 6H, CH3), 1.52 (s, 6H, CH3); MS (CI,NH3) m/e 277 (M+1).
Addition of Grignard Reagent: Synthesis of diketone LIVc
To a solution of 4.0 g (14.5 mmol) of the LIVb in 100 mL of THF was added 20 mL (40 mmol) of 2M octylmagnesium bromide in THF dropwise. After stiring 3.5 h, the solution was quenched with saturated NH4Cl, acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 7.5% ethyl acetate in hexanes gave 4.86 g (88%) of the bis-octyl ketone LIVc as an oil. 1H NMR (300 MHz, CDCl3) δ 4.55 (s, 2H, CH), 2.64 (dt, 4H, CH2), 1.62 (m, 4H, CH2), 1.42 (s, 6H, CH3), 1.27 (broad s, 20H, CH2), 0.88 (t, 6H, CH3); MS (CI,NH3) m/e 383 (M+1).
Oxime Formation: Synthesis of LIVd
To a solution of 4.65 g (12.2 mmol) of LIVc in 140 mL of ethanol and 35 ml of water was added 2.22 g (32.2 mmol) of hydroxylamine hydrochloride. After stirring overnight the solvent was partially removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 15% ethyl acetate in hexanes gave 3.76 g (75%) of the bis-octyl oxime LIVd as a mix of isomers. MS (CI,NH3) m/e 413 (M+1).
Reduction of Oxime: Synthesis of diamine LIVe
To a solution of 3.68 g (8.9 mmol) of LIVd in 70 mL of toluene at 0°C C. was added 53 mL (80 mmol) of 1.5M diisobutylaluminum hydride in toluene over 15 min. and the solution was allowed to warm to room temperature. After stirring overnight the solution was quenched with saturated Rochelle's salt and gently stirred at mom temperature. After stirring overnight the solution was extracted with EtOAc and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 10% methanol in methylene chloride gave 2.33 g (68%) of the diamine LIVe as an oil. 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 2H, CH), 2.68 (m, 2H, CH), 1.43 (m, 4H, CH2), 1.41 (s, 6H, CH3), 1.27 (broad s, 24H, CH2), 0.88 (t, 6H, CH3).
To a solution of 135 g (3.5 mmol) of LIVe in 50 mL of 1,1,2,2-tetrachloroethane was added 620 mg (3.8 mmol) of 1,1'-carbonyldiimidazole. After stirring 10 min the solution was added dropwise over 30 min to 150 mL of refluxing 1,1,2,2-tetrachloroethane. The solution was cooled and was washed with dilute HCl, water, brine, and was dried over MgSO4 The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 33% ethyl acetate in hexanes increasing to 50% ethyl acetate in hexanes gave 379 mg (27%) of the cyclic urea XXVIf. 1H NMR (300 MHz, CDCl3) δ 5.24 (d, 2H, NH), 4.07 (s, 2H, CH),3.33 (m, 2H, CH), 1.60 (m, 4H, CH2), 1.43 (s, 6H, CH3), 1.26 (broad s, 24H, CH2), 0.88 (t, 6H, CH3); MS (CI,NH3)m/e 411 (M+1).
Alkylation of the cyclic urea XXVIf and removal of the acetonide protecting group was carried out using the procedures described above to give compound 15AJ in a 68% yield. mp. 66°C-70°C C. 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 10H, aromatic),5.15 (d, 2H, CH2), 3.87 (d, 2H, CH2), 3.46 (s, 2H, CH), 3.26 (br d, 2H, CH), 1.96 (s, 2H, OH), 1.60 (m, 4H, CH2), 1.26 (m, 24H, CH2), 0.89 (t, 6H, CH3); MS (CI,NH3) m/e 551 (M+1).
TABLE 2e | ||||||
Ex. | Stereo | K4 | ||||
No. | 2:3:4:5 | R22 | R23 | R4═R7 | HPLC | Note |
16A | RSSR | benzyl | benzyl | phenethyl | ++ | 1 |
16B | RSSR | allyl | allyl | phenethyl | + | 1 |
16C | RSSR | allyl | allyl | isopropyl | ++ | 2 |
16D | RSSR | cyclopropyl | cyclopropyl | isopropyl | ++ | 2 |
methyl | methyl | |||||
16E | RSSR | allyl | allyl | methyl | + | 2 |
16F | RSSR | allyl | n-butyl | methyl | + | 2 |
16G | RSSR | benzyl | benzyl | methyl | + | 2 |
16H | RSSR | 2-naphthyl- | 2-naphthyl- | methyl | + | 2 |
methyl | methyl | |||||
16I | RSSR | allyl | allyl | isobutyl | +++ | 2 |
16J | RSSR | cyclopropyl | cyclopropyl | isobutyl | +++ | 2 |
methyl | methyl | |||||
16K | RSSR | benzyl | benzyl | 2-naphthyl | +++ | 1 |
methyl | ||||||
16L | RSSR | cyclopropyl | cyclopropyl | 2-naphthyl | +++ | 1 |
methyl | methyl | methyl | ||||
16M | RSSR | 3-cyanobenzyl | 3-cyanobenzyl | 2-naphthyl | 1 | |
methyl | ||||||
16N | RSSR | 3,4-dihydroxy | 3,4-dihydroxy | 2-naphthyl | 1 | |
benzyl | benzyl | methyl | ||||
16O | RSSR | cyclopropyl | cyclopropyl | 2-thienyl | +++ | 2 |
methyl | methyl | methyl | ||||
16P | RSSR | 3- | 3- | 2-thienyl | +++ | 2 |
(H2NC(═NOH))- | (H2NC(═NOH))- | methyl | ||||
benzyl | benzyl | |||||
16Q | RSSR | benzyl | benzyl | 4- | +++ | 1 |
methylthio | ||||||
benzyl | ||||||
16R | RSSR | 3- | 3- | 2-methoxy | ++ | 1 |
methoxybenzyl | methoxybenzyl | benzyl | ||||
16S | RSSR | cyclopropyl | cyclopropyl | 2-methoxy | ++ | 1 |
methyl | methyl | benzyl | ||||
16T | RSSR | benzyl | benzyl | 2-methoxy | ++ | 1 |
benzyl | ||||||
16U | RSSR | benzyl | benzyl | 4- | 1 | |
methylsulfo | ||||||
nylbenzyl | ||||||
16V | RSSR | benzyl | benzyl | 3- | 1 | |
aminobenzyl | ||||||
16W | RSSR | benzyl | benzyl | 4- | 1 | |
aminobenzyl | ||||||
16X | RSSR | n-hexyl | n0hexyl | isopropyl | +++ | 2 |
16Y | RSSR | benzyl | benzyl | 3- | ++ | 2 |
indolylmethyl | ||||||
yl | ||||||
16Z | RSSR | benzyl | benzyl | isobutyl | ++ | 2 |
16AA | RSSR | benzyl | benzyl | 2- | + | 2 |
methylthio | ||||||
ethyl | ||||||
16AB | RSSR | cyclopropyl | cyclopropyl | 2- | + | 2 |
methyl | methyl | methylthio | ||||
ethyl | ||||||
16AC | RSSR | benzyl | benzyl | 1-benzyl-3- | ++ | 2 |
indolyl | ||||||
16AD | RSSR | benzyl | benzyl | isobutyl | +++ | 2 |
16AE | RSSR | n-butyl | n-butyl | isobutyl | ++ | 2 |
16AF | RSSR | 4- | 4- | 2- | + | 2 |
hydroxymethyl | hydoxymethyl | methylthio | ||||
benzyl | nemzyl | ethyl | ||||
16AG | RSSR | benzyl | benzyl | n-butyl | + | 3 |
16AH | RSSR | benzyl | benzyl | n-pentyl | ++ | 3 |
16AI | RSSR | benzyl | benzyl | n-hexyl | ++ | 3 |
16AJ | RSSR | benzyl | benzyl | n-octyl | + | 3 |
16AK | RSSR | benzyl | benzyl | 3-butenyl | + | 3 |
16AL | RSSR | benzyl | benzyl | 4-pentenyl | + | 3 |
16AM | RSSR | benzyl | benzyl | 2- | ++ | 3 |
ethylbutyl | ||||||
16AN | RSSR | benzyl | benzyl | 5-hydroxy | + | 3,4 |
pentyl | ||||||
16AO | RSSR | benzyl | benzyl | 4-hydroxy | + | 3,4 |
butyl | ||||||
16AP | RSSR | allyl | allyl | n-octyl | ++ | 3 |
16AQ | RSSR | allyl | allyl | n-hexyl | + | 3 |
16AR | RSSR | allyl | allyl | 4-pentenyl | + | 3 |
16AS | RSSR | allyl | allyl | 3-butenyl | + | 3 |
16AT | RSSR | 4- | 4- | n-butyl | ++ | 3 |
hydroxymethyl | hydroxymethyl | |||||
benzyl | benzyl | |||||
Listed below are physical data for representative compounds of the invention.
Example 16A: MS: 535 (M+1, 100%); NMR (CDCl3,300 MHz): δ 7.1-7.3 (m, 20H),5.15 (d, 2H), 3.9 (d, 2H), 3.5 (bs, 2H), 3.3-3.4 (m, 2H), 2.7-2.8 (m, 2H), 2.5-2.6 (m, 2H), 2.0-2.1 (m, 6H).
Example 16B: MS: 435 (M+1, 100%); NMR (CDCl3,300 MHz): δ 7.1-7.3 (m, 10H), 5.8 (m, 2H), 5.15 (s, 2H), 5.1 (d, 2H), 4.5-4.6 (m, 2H), 3.8 (s, 2H), 3.3-3.5 (m, 4H), 2.5-2.9 (m, 4H), 2.2 (m, 2H), 2.0 (m, 4H).
Example 16C: MS: 312 (22, M+2),311 (100, M+1), 267 (1). HRMS: Calc. 311.2334. Found: 311.2330. NMR (CDCl3): δ 5.81(m, 2H), 5.2(m, 4H), 4.4(m, 2H), 4.0(br s, 2H), 3.4(m, 2H), 3.1 (br s, 2H), 3.0(m, 2H), 2.4(m, 2H), 1.2(d, 6H), 0.9(d, 6H).
Example 16D: MS: 341 (4), 340 (25), 339 (100, M+1), 321 (1), 295 (2), 256 (2). HRMS: Calc. 339.2647. Found: 339.2652. NMR (CDCl3): δ 4.2(brs, 2H), 3.65(m, 2H), 3.20(m, 4H), 2.6(m, 4H), 1.2(d, 6H), 1.0(m, 2H), 0.9(d, 6H), 0.5(m, 4H), 0.2(m, 4H).
Example 16E: MS: 256 (15, M+2), 255 (100, M+1). HRMS: Calc. 255.1706. Found: 255.1708.NMR (CDCl3) δ 5.8(m, 2H), 5.2(m, 4H), 4.0(m, 2H), 3.8(br s, 2H), 3.65(m, 2H), 3.4(m, 2H), 2.8(m, 2H), 1.2(d, 6H).
Example 16F: MS: 272 (16, M+2), 271 (100, M+1). HRMS: Calc. 271.2021. Found: 271.2036. NMR (CDCl3): δ 5.8(m, 1H), 5.2(m, 2H), 4.0(m, 2H), 3.8(br s, 2H), 3.6-3.3(3H), 3.0(m, 2H), 2.45(m, 2H), 1.35(m, 2H), 1.2(d, 6H), 0.9(m, 4H).
Example 16G: MS: 356 (23, M+2),355 (100, M+1). HRMS: Calc. 355.2021. Found: 355.2012. NMR (CDCl3): δ 7.4-7.2(m, 10H), 4.9(d, 2H), 4.2(d, 2H), 3.6(br s, 2H), 3.3(m, 2H), 2.2(m, 2H), 1.2(d, 6H).
Example 16H: mp 236°C-238°C C. MS: 456 (29, M+2), 455 (100, M+1), 315 (10), 158 (5). HRMS: 455.2334. Found: 55.2333.NMR (CDCl3): δ 7.9-7.8(m, 8H), 7.6-7.5(m, 6H), 5.0(d, 2H), 4.4(m, 2H), 3.6(br, s, 2H), 3.4(m, 2H), 1.9(m, 2H), 1.2(m, 2H).
Example 16I: MS 339 (100, M+1), 311 (4). HRMS 339.265377 (calc. mass=339.264768). NMR (CDCl3): δ 5.91-5.79 (m), 5.29-5.18 (m, 4H), 4.53-4.46 (m, 2H), 3.76 (s, 2H), 3.41-3.33 (m, 4H), 2.13 (s, 2H), 1.81-1.71 (m, 2H), 1.71-1.62 (m, 2H), 1.45-1.35 (m, 2H), 0.90 (t, 12H).
Example 16J: m.p. 137°C-139°C C. MS 367 (100, M+1). HRMS 367.295357 (calc. mass=367.296068). NMR (CDCl3): δ 3.94 (s, 2H), 3.82 (d, 2H), 3.77 (d, 2H), 3.48 (d, 2H), 2.91 (bs, 2H), 2.63 (d, 2H), 2.61 (d, 2H), 1.99 (m, 2H), 1.70-1.61 (m, 2H), 1.43 (m, 2H) 1.26 (s, 2H), 1.07-0.98 (m, 2H), 0.91 (t, 12H), 0.52 (m, 2H) 0.22 (m, 2H).
Example 16Q: mp 214°C C.
Example 16R: mp 192°C-193°C C.
Example 16S: mp 155°C-156°C C.
Example 16T: mp 194°C-195°C C.
Example 16U: mp 244°C C.
Example 16X: mp 112°C-113°C C. MS 427, (100, M+1)
Example 16Y: MS: 585.2 (100, M+H). NMR(CDCl3) δ 8.02 (s, 2H), 7.55 (d, 2H), 7.4 (d, 2H), 7.01 (m, 4H), 6.79 (s, 2H), 4.84 (d, 2H), 3.78 (s, 4H), 3.2, (m, 6H)
Example 16Z: MS: 475.2 (100, M+H), NMR (CDCl3) δ 7.48-7.22 (m, 10H), 4.76-4.4 (dd, 4H), 3.8 (s, 2H), 62 (m, 2H), 2.23 (s, 2H), 1.73 (m, 2H), 1.59 (m, 4H), 6 (m, 4H), 0.76 (d, 6H), 0.61 (d, 6H)
Example 16AA: MS: 475.0 (100, M+H). NMR(CDCl3) δ 7.41-7.18 (m, 10H), 5.01 (d, 2H), 4.01 (d, 2H), 3.65-3.41 (m, 5H), 3.01 (dd, 1H), 2.6-2.3 (m, 6H), 2.0 (m, 6H), 1.25 (m, 2H)
Example 16AB: MS: 403.2 (100, M+H). NMR (CDCl3) δ 3.97 (s, 2H), 3.8-3.6 (m, 4H), 2.8-2.4 (m, 8H), 2.24 (m, 2H), 1.62 (s, 2H), 1.03 (m, 2H), 0.52 (m, 4H), 0.32-0.14 (m, 4H)
Example 16AC: MS: 765.5 (59, M+H) 382.1 (100), 274 (97). NMR (CDCl3) δ 7.53 (d, 2H), 7.35-7.0 (m, 26H), 6.63 (s, 2H), 5.24 (s, 2H), 5.23 (s, 2H), 4.82 (d, 2H), 3.8 (s, 4H), 3.3-3.08 (m, 6H), 2.37 (s, 2H)
Example 16AD: MS: 439.2 (M+H) NMR (CDCl3) δ 7.39-7.28 (m, 10H), 5.19 (d, 4H), 3.85 (d, 4H), 3.50 (s, 2H), 3.38 (d, 2H), 1.95 (s, 2H), 1.75 (m, 4H), 1.38 (m, 2H), 0.92 (d, 6H), 0.85 (d, 6H)
Example 16AD: MS: 439.2 (M+H). NMR(CDCl3) δ 7.39-7.28 (m,10H), 5.19 (d, 4H), 3.85 (d, 4H), 3.50 (s, 2H), 3.38 (d, 2H), 1.95 (s, 2H), 1.75 (m, 4H), 1.38 (m, 2H), 0.92 (d, 6H), 0.85 (d, 6H) MS: (M+H)+=439.2
Example 16AE: MS: 371 (M+H). NMR (CDCl3) δ 4.0 (m, 2H), 3.85 (s, 2H), 3.35 (d, 2H), 2.65 (m, 2H), 2.35 (s, 2H), 1.82 (m, 2H), 1.75-1.24 (m, 12H), 0.91 (m, 18H)
Example 16F: MS: 552 (100, M+NH4), 535 (61, M+H), 516 (81). NMR(CDCl3) δ 7.38 (d, 8H), 5.05 (d, 2H), 4.68 (s, 4H), 3.98 (d, 2H), 3.65 (s, 2H), 3.52 (m, 2H), 3.43 (s, 2H), 2.57 (m, 2H), 2.42 (m, 2H), 2.03 (s, 6H), 1.97 (m, 4H), 0.84 (m, 4H)
Example 16AG: mp 109°C-114°C C. MS m/e 439 (M+H)
Example 16AH: mp 94°C-97°C C. MS m/e 467 (M+H)
Example 16AI: mp 79°C-82°C C. MS m/e 495 (M+H)
Example 16AJ: mp 66°C-70°C C. MS m/e 551 (M+H)
Example 16AK: mp 123°C-126°C C. MS m/e 435 (M+H)
Example 16AL: MS m/e 463 (M+H).
Example 16AM: mp 91°C-94°C C. MS m/e 495 (M+H)
Example 16AN: mp 111°C-116°C C. MS m/e 499 (M+H)
Example 16AO: MS m/e 483 (M+H)
Example 16AP: mp 73°C-74°C C. MS m/e 451 (M+H)
Example 16AQ: mp 73°C-75°C C. MS m/e 395 (M+H)
Example 16AR: mp 108°C-111°C C. MS m/e 363 (M+H)
Example 16AS: mp 110°C-114°C C. MS m/e 335 (M+H)
Example 16AT: mp 114°C-116°C C. MS m/e 499 (M+H)
The structures of the Examples below are shown in Table 2 f-h
Diaminodimem Compound (XXIc) (22.45 g, 47.1 mmol) was dissolved in 200 mL of tetrahydrofuran and to this solution was added 9.23 g (51.8 mmol) of thiocarbonyl diimidazole. After stirring the mixture for 18 hours at room temperature TLC (10:1:10 ethyl acetate: ethanol: hexane) indicated complete reaction. The reaction mixture was taken to dryness and the solid residue purified by flash chromatography (silica gel, 250 g, 1:1 ethyl acetate: hexane) to provide solid which was triturated with hexane to provide 17.8 g (73% yield) of XXVIIa as a white solid.
Compound (XXVIIa) (3.108 g, 6 mmol) was dissolved in 15 ml acetonitrile and to this solution was added methyl iodide 1.5 ml (24 mmol) via syringe and stirred at room temperature for one hour. The contents were then taken to dryness. The residue was dissolved in 30 ml dimethylformamide and to this solution, cooled in a 0°C C. ice bath, was added NaH (60% in oil) 720 mg (18 mmol) slowly (EVOLUTION!). The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C C. ice bath and benzyl bromide (2.052 g, 12 mmol) was added via syringe and stirred at room temperature for 18 hours. TLC (2:3 EtOAc:Hexane Rf=0.25) indicated a complete reaction. The reaction was worked up by diluting with water (300 ml) and extracting with diethyl ether (3×50 ml). The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (200 g; 2:3 EtOAc:Hexane) to provide 2.923 g (78.2% yield) of XXVIIb as a colorless oil.
Compound (XXVIIb) (2.900 g, 4.65 mmol) was dissolved in 25 ml pyridine and to this solution was added 742 mg (4.65 mmol) benzylhydroxylamine hydrochloride. The contents were refluxed in a 125°C C. oil bath for 18 hours. (Caution: Methyl mercaptan is a by-product and the reaction should be vented to a Clorox scrubber). TLC indicated a complete reaction. The reaction was diluted with 150 ml dichloromethane. The organic layer was washed with 1N HCl (2×300 ml) followed by sat. sodium bicarbonate solution (100 ml). It was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (130 g; using 1:3 EtOAc:Hexane) to provide 584 mg (18.0% yield) of Compound (XXVIIc) as a colorless oil. 1:2 EtOAc:Hexane was used to provide 2.113 g of a side product thiourea (XXVIId).
Compound (XXVIIc) (584 mg, 0.84 mmmol) was dissolved in 5 ml dimethylformamide and to this solution, cooled in a 0°C C. ice bath, was added NaH(60% in oil) 80 mg (2 mmol) slowly (EVOLUTION!). The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C C. ice bath and benzyl bromide (0.24 ml, 2 mmol) was added via syringe and stirred at room temperature for 18 hours. TLC (1:3 EtOAc:Hexane Rf=0.26) indicated a complete reaction. The reaction was worked up by diluting with water (50 ml) and extracting with diethyl ether (2×25 ml). The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (33 g; 1:3 EtOAc:Hexane) to provide 491 mg (74.2% yield) of a colorless oil.
Compound (XXVIId) (450 mg, 0.57 mmol) was placed in a 25 ml R.B. Flask and cooled in a 0°C C. ice bath. To this flask was added 4M HCl in dioxane (5 ml, 20 mmol) and the mixture stirred at room temperature for 18 hours. TLC (2:3 EtOAc:Hexane Rf=0.29) indicated a complete reaction. The mixture was worked up by quenching in sat.sodium bicarbonate solution (50 ml) and extracting with dichloromethane (2×50 ml). The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (33 g; 2:3 EtOAc:Hexane) to provide 246 mg (70.5% yield) of Example 18A as a waxy solid.
Example 18A (160 mg, 0.26 mmol) was dissolved in 5 ml ethanol. To this mixture was added 50 mg of 10% palladium hydroxide on Carbon and the suspension stirred for 18 hours under hydrogen(1 atm). TLC (10:1:10 EtOAc:EtOH: Hexane Rf=0.3) indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue was purified on SiO2 gel (33 g; 10:1:10 EtOAc:EtOH:Hexane) to provide 97 mg of Example 17A (69.5% yield) as a white solid.
Compound (XXVIId) (500 mg, 0.82 mmol) was placed in a 25 ml R.B. Flask and cooled in a 0°C C. ice bath. To this flask was added 4M HCl in dioxane (7.5 ml, 30 mmol) and the mixture stirred at room temperature for 18 hours. TLC (1:2 EtOAc:Hexane Rf=0.29) indicated a complete reaction. The mixture was worked up by quenching in sat.sodium bicarbonate solution (50 ml) and extracting with dichloromethane (2×50 ml). The organic exacts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (33 g; 1:2 EtOAc:Hexane) to provide 181 mg (51.1% yield) of Example 19A as a white solid.
TABLE 2f | |||||
Ex. | HPLC | MS | |||
No. | R | Ki | IC90 | m.p. °C C. | M + H |
17A | CH2C6H5 | ++ | 120.1 | 522.275 | |
TABLE 2f | |||||
Ex. | HPLC | MS | |||
No. | R | Ki | IC90 | m.p. °C C. | M + H |
17A | CH2C6H5 | ++ | 120.1 | 522.275 | |
TABLE 2f | |||||
Ex. | HPLC | MS | |||
No. | R | Ki | IC90 | m.p. °C C. | M + H |
17A | CH2C6H5 | ++ | 120.1 | 522.275 | |
The structures of the Examples below are shown in Table 2i.
Example 1X (3.517 g, 7.58 mmol) was dissolved in 25 ml pyridine and to this solution, cooled in a 0°C C. ice bath, was added 350 mg 4-Dimethylaminopyridine and 7.16 ml (75.85 mmol) acetic anhydride. The contents were stirred at room temperature for 18 hours. TLC (1:4 EtOAc:Hexane Rf=0.3) indicated a complete reaction. The reaction was diluted with 250 ml dichloromethane. The organic layer was washed with 1N HCl (2×300 ml) followed by sat. sodium bicarbonate solution (100 ml). It was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (200 g; 1:5 EtOAc:Hexane) to provide 2.632 g (67.0%) of XXVIIIa as a white solid.
Compound (XXVIIIa) (518 mg, 1 mmol) was dissolved in 4 ml acetonitrile and to this solution, cooled in a -40°C C. dry ice-acetone bath, was added 4.4 ml (2.2 mmol) 0.5M Nitronium tetrafluoroborate in sulfolane. The contents were stored in a -40°C C. freezer for 18 hours. TLC indicated a complete reaction. The reaction was diluted with 100 ml ether and washed with water (2×50 ml). Tho organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel (75 g; 1:3 EtOAC:Hexane for XXVIIIb, 1:2 EtOAc:Hexane for XXVIIIc) to provide 106 mg (17.4% yield) of XXVIIIb as a white solid and 159 mg (26.2% yield) of XXVIIIc as a white solid.
Compound (XXVIIIb) (106 mg, 0.174 mmol) was dissolved in 5 ml methanol and to this solution was added 0.5 ml 0.5M sodium methoxide in methanol via syringe. The contents were stirred at room temperature for 30 minutes. TLC indicated a complete reaction. The mixture was quenched by adding 500 mg of AG50W-X8 acid resin and stirring the suspension at room temperature for 5 minutes. The filtrate was taken to dryness and the residue purified on SiO2 gel (33 g; 1:2 EtOAc:Hexane) to provide 43 mg (47.1% yield) of Example 20A as a white solid.
Compound (XXVIIIc) (159 mg, 0.261 mmol) was dissolved in 5 ml methanol and to this solution was added 0.5 ml 0.5M sodium methoxide in methanol via syringe. The contents were stirred at room temperature for 30 minutes. A white precipitate started forming after 15 minutes. TLC indicated a complete reaction. The mixture was quenched by adding 500 mg of AG50W-X8 acid resin and stirring the suspension at room temperature for 5 minutes. 10 ml dichloromethane was then added to solubilize the solid. The filtrate was taken to dryness and the residue provided 111 mg (81.1% yield) of Example 20B as a white solid.
Example 20A (100 mg, 0.191 mmol) was dissolved in 5 ml ethanol. To this mixture was added 50 mg of 5% palladium on Carbon and the suspension stirred for 18 hours under hydrogen (1 atm). TLC indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue provided 47 mg (53.0% yield) of Example 20E as a white solid.
Example 20B (100 mg, 0.191 mmol) was suspended in 5 ml ethanol. To this mixture was added 50 mg of 5% palladium on Carbon and the suspension stirred for 18 hours under hydrogen (1 atm). The starting material went into solution as the reaction progressed. TLC indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue provided 49 mg (55.2% yield) of example 20F as a white solid.
The synthesis of 4-fluorobenzyl cyclic urea is outlined in Scheme 7. N-acetyl-D4-fluorophenylalanine methyl ester (23.9 g. 0.1 mol), obtained using the procedure of M. J. Burk (J. Am. Chem. Soc. 1991, 113, 8518), was dissolved in 40 mL of acetic acid and treated with 100 mL of concentrated HCl, 40 mL of water and heated to reflux for 5 hrs. The solution was cooled to room temperature and then made basic (pH=10) with 50% NaOH while cooling in an ice bath. Benzyl chloroformate (25 mL, 29 g, 0.17 mol) and NaOH are added in four portions and the solution is maintained alkaline by the addition of NaOH. The mixture is then stirred at rt for 30 min. The alkaline solution is extracted with ether (2×500 mL) and the solution acidified with conc HCl to pH 1. The precipitate is extruted into methylene chloride and dried over MgSO4. The solution is filtered and concentrated to give 20 g of the N-Cbz-D-4-fluorophenylalanine as a white solid that is used without further purification.
A solution of N,O-dimethylhydroxylamine hydrochloride (8.0 g, 0.082 mol) in DMF is prepared by gentle warming. The solution is allowed to cool slightly and treated with N-methylmorpholine (8.2 g, 0.082 mol) and diluted with THF to facilitate transfering of the resulting thick suspension.
A solution of N-Cbz-D -4-fluorophenylalanine (20 g, 0.063 mol) in THF is treated with N-methylmorpholine (9.0 g 0.09 mol) and cooled to 0°C C. in an ice bath. To the stirred cold solution is added isobutyl chloroformate (8.6 g, 0.063 mol) in small portions over a period of 10 mins. Then the solution of N,O-dimethylhydroxylamine in DMF prepared above is added and the reaction mixture is stirred for 20 mins. Most of the solvent is removed on a rotorary evaporator and the residue is partitioned between water and methylene chloride. The organic layer is washed successively with 1N HCl, 1N NaOH, water, brine and then dried over MgSO4. The solution is then filtered and concentrated and the residue chromatographed on silica gel (50% EtOAc/Hex) to give 16 g of the amide.
Using the procedure of by J-A. Febrentz and B. Castro (Synthesis, 1983, 676) 11 g (0.031 mol) of N-Cbz-D-4-fluorophenyl-alanine N,O-dimethylhydroxylamide was converted to 9.0 g of N-Cbz-D-4-fluorophenylalaninal obtained as a thick oil that was used without further purification.
N-Cbz-D4-fluorophenylalaninal (9.0 g, 0.031 mol) was converted, using procedure 1, to (2R, 3S, 4S, 5R)-2.5-bis(N-Cbz-amino)-3,4-dihydroxy-1,6-di(4-fluorophenyl-)hexane (4 g) obtained as a white solid. MS: (CI, NH3) (M+H)+=605.
The (2R,3S,4S,5R)-2,5-bis(N-Cbz-amino)3,4-dihydroxy-1,6-di(4-fluorophenyl)hexane (4.0 g, 0.0066 mol) was converted, as described in procedure 4, to 1.3 g of the 4-fluorobenzyl cyclic urea (XXXI) obtained as a white solid. MS: (CI, NH3) (M+H)+=539.3
B. The 4-fluorobenzyl cyclic urea (XXXI) (270 mg, 0.5 mmol) was alkylated with 3-benzoxybenzyl chloride (350 mg, 1.5 mmol) according to general procedure 5. The resulting intermediate was dissolved in TBF and hydrogenated for 12 hours (200 mg 10% Pd/C, 55 psi) to remove the benzyl protecting groups. The MEM group was then removed, according to general procedure 5, to give, after chromatography on HPLC (silica gel, 10% MeOH/CHCl3), 140 mg of Example 20G as a white foam. MS: (CI, NH3) (M+H)+=575.2 (100%).
By variation of the above-described methods, the title compound was prepared. NMR (CDCl3): δ 7.12-7.32 (m, 12H) 6.61-6.83 (m, 6H) 4.91 (d, 2H) 3.80 (s, 6H) 3.64 (m,2H) 3.55 (m, 2H) 3.10 (d, 2H) 3.00 (m, 4H) 2.11 (s, 2H).
TABLE 2i | |||||||
Mass | |||||||
Spec | |||||||
Ex. | HPLC | m.p. | M + H | ||||
No. | R22, R23 | R4 | R7 | Ki | IC90 | °C C. | (M + NH4) |
20A | cyclopropyl- | 4-nitro- | 2-nitro- | +++ | +++ | 209.8 | 525.234 |
methyl | benzyl | benzyl | |||||
20B | cyclopropyl- | 4-nitro- | 4-nitro- | +++ | +++ | 227.5 | 525.234 |
methyl | benzyl | benzyl | |||||
20C | n-butyl | 4-nitro- | 2-nitro- | +++ | +++ | 165.0 | 529.266 |
benzyl | benzyl | ||||||
20D | n-butyl | 4-nitro- | 4-nitro- | 245.0 | 529.266 | ||
benzyl | benzyl | (dec) | |||||
20E | cyclopropyl- | 4-amino- | 2-amino- | +++ | +++ | 465.286 | |
methyl | benzyl | benzyl | |||||
20F | cyclopropyl- | 4-amino- | 4-amino- | ++ | +++ | 465.286 | |
methyl | benzyl | benzyl | |||||
20G | 3-hydroxy | 4-fluoro | 4-fluoro | +++ | 575.2 | ||
benzyl | benzyl | benzyl | |||||
20H | cyclopropyl- | 4-fluoro | 4-fluoro | +++ | 471.2 | ||
methyl | benzyl | benzyl | |||||
20I | 4-hydroxy | 4-fluoro | 4-fluoro | +++ | 603.2 | ||
methylbenzyl | benzyl | benzyl | |||||
20J | 4-acetyl | benzyl | benzyl | ++ | (608) | ||
benzyl | |||||||
20K | 4-fluoro | benzyl | benzyl | +++ | +++ | 571 | |
methylbenzyl | |||||||
20L | 3-(H2NC(O))- | 4-fluoro | 4-fluoro | +++ | +++ | (646.4) | |
benzyl | benzyl | benzyl | |||||
20M | 4-(CH3CH(OH))- | benzyl | benzyl | +++ | +++ | 595.2 | |
benzyl | |||||||
20N | 3-(CH3C(O))- | 4-fluoro | 4-fluoro | +++ | +++ | (644.4) | |
benzyl | benzyl | benzyl | |||||
20O | 3-cyano-benzyl | 4-fluoro | 4-fluoro | ++ | +++ | (610.2) | |
benzyl | benzyl | ||||||
20P | 3-(CH3CH2CH2-- | 4-fluoro | 4-fluoro | +++ | +++ | (700.5) | |
(CO))-benzyl | benzyl | benzyl | |||||
20Q | benzyl | benzyl | +++ | +++ | 671.4 | ||
20R | benzyl | benzyl | ++ | +++ | 779.4 | ||
20S | 4-fluoro benzyl | 4-fluoro benzyl | ++ | ++ | 815.5 | ||
20T | 3-(HOCH2)- | 4-fluoro | 4-fluoro | +++ | +++ | 603.3 | |
benzyl | benzyl | benzyl | |||||
20U | 3-(CH3C(NOH))- | 4-fluoro | 4-fluoro | +++ | +++ | 657.5 | |
benzyl | benzyl | benzyl | |||||
20V | 3-(H2NC(═NOH))- | benzyl | benzyl | +++ | +++ | 623.3 | |
benzyl | |||||||
20W | benzyl | 3- | 3- | +++ | +++ | ||
methoxy- | methoxy- | ||||||
benzyl | benzyl | ||||||
20X | 3-(H2NC(═NOH))- | 4-fluoro | 4-fluoro | +++ | +++ | 659.3 | |
benzyl | benzyl | benzyl | |||||
20Y | 3- | 3,4- | 3,4- | +++ | +++ | 695.4 | |
carbomethoxy- | difluoro | difluoro | |||||
benzyl | benzyl | benzyl | |||||
20Z | 4- | 3,4- | 3,4- | ++ | +++ | (712.4) | |
carbomethoxy- | difluoro | difluoro | |||||
benzyl | benzyl | benzyl | |||||
20AA | 3-hydroxymethyl | 3,4- | 3,4- | +++ | +++ | 639.4 | |
benzyl | difluoro | dilfuoro | |||||
benzyl | benzyl | ||||||
20AB | 4-hydroxymethyl | 3,4- | 3,4- | +++ | +++ | 639.4 | |
benzyl | difluoro | difluoro | |||||
benzyl | benzyl | ||||||
20AC | 3-(H2NC(O))- | 3,4- | 3,4- | +++ | +++ | 665.2 | |
benzyl | difluoro | difluoro | |||||
benzyl | benzyl | ||||||
20AD | 3-(H2NC(═NOH)- | 3,4- | 3,4- | +++ | +++ | 695. | |
benzyl | difluoro | difluoro | |||||
benzyl | benzyl | ||||||
20AE | R22 = | 4-fluoro | 4-fluoro | +++ | +++ | 123- | 573.2 |
cyclopropyl | benzyl | benzyl | 126 | ||||
methy | |||||||
R23 = | |||||||
3-(3-pyrazolyl | |||||||
benzyl | |||||||
20AF | cyclopropyl | 4-methoxy | 4-methoxy | +++ | 145- | 495 | |
methyl | benzyl | benzyl | 147 | ||||
20AG | benzyl | 4-methoxy | 4-methoxy | +++ | 567 | ||
benzyl | benzyl | ||||||
20AH | 2-naphthyl | 4-methoxy | 4-methoxy | +++ | 667 | ||
methyl | benzyl | benzyl | |||||
20AI | 4-carbomethoxy | 4-methoxy | 4-methoxy | + | 700 | ||
benzyl | benzyl | benzyl | |||||
20AJ | 4-hydroxymethyl | 4-methoxy | 4-methoxy | +++ | 644 | ||
benzyl | benzyl | benzyl | |||||
20AK | benzyl | 4-hydroxy | 4-hydroxy | +++ | 179- | 539 | |
benzyl | benzyl | 180 | |||||
20AL | allyl | 4-methoxy | 4-methoxy | +++ | 467 | ||
benzyl | benzyl | ||||||
20AM | benzyl | 4-(2- | 4-(2- | +++ | 129- | 627 | |
hydroxy | hydroxy | 131 | (644) | ||||
ethoxy) | ethoxy) | ||||||
benzyl | benzyl | ||||||
20AN | benzyl | 4-(2-mor- | 4-(2- | +++ | 101- | 765 | |
pholinyl | hydroxy | 103 | |||||
ethoxy) | ethoxy) | ||||||
benzyl | benzyl | ||||||
20AO | H | 3-methoxy | 3-methoxy | ++ | ++ | 205.4 | 387 |
benzyl | benzyl | ||||||
20AP | n-butyl | 3-hydroxy | 3-hydroxy | ++ | + | 182.1 | 541 |
benzyl | benzyl | ||||||
20AQ | 3-hydroxy | 3-hydroxy | 3-hydroxy | +++ | +++ | 181.2 | 571 |
benzyl | benzyl | benzyl | |||||
20AR | n-butyl | 3- | 3- | +++ | 101.3 | 581 | |
(H2NC(O) | (H2NC(O) | ||||||
CH2O) | CH2O) | ||||||
benzyl | benzyl | ||||||
20AS | cyclopropyl | 3-methoxy | 3-methoxy | +++ | +++ | 495 | |
methyl | benzyl | benzyl | |||||
20AT | 4-hydroxy | 3-methoxy | 3-methoxy | +++ | +++ | 627 | |
methylbenzyl | benzyl | benzyl | |||||
20AU | 3-methoxy | 3-methoxy | 3-methoxy | +++ | +++ | 627 | |
benzyl | benzyl | benzyl | |||||
20AV | cyclopropyl | 3- | 3- | ++ | 639 | ||
methyl | (EtOC(O) | (EtOC(O) | |||||
CH2O) | CH2O) | ||||||
benzyl | benzyl | ||||||
The structures of the Examples below are shown in Table 2j.
A solution of Example 1A (5.3 g, 0.016 mol) in pyridine was treated with acetic anhydride (3.3 g, 0.033 mol) and stirred at room temperature for 3 hrs. 10 mL of MeOH was added and the mixture was evaporated to dryness. The residue was extracted into methylene chloride and washed sequentially with water, 1N HCl, brine, and dried over MgSO4. The solution was filtered, concentrated and the residue chromatographed on silica gel (5%MeOH/CHCl3) to give 2.0 g of the corresponding monoacetate product as a white solid. The solid obtained was dissolved in methylene chloride and cooled in an ice bath under nitrogen. To this was added DAST (0.875 g, 0.005 mol) via syringe and the solution stirred for 10 mins. The mixture was quenched with sat'd NaHCO3 and the organic layer washed with water and brine. The solution is dried over MgSO4 then filtered and concentrated to give 1.9 g of the acetate aziridine (XXXIIa) which is used without further purification.
B. The acetate aziridine (XXXIIa) (100 mg. 0.29 mmol) is dissolved in MeOH (2 mL) and treated with 1N NaOH (0.5 ml) and stirred at rt for 30 min. The mixture is diluted with water (20 mL) and extracted into CH2Cl2. The extract is washed with water and brine, dried over MgSO4 then filtered and concentrated to give 30 mg of Example 21A as a white solid. MS: (CI; NH3) (M+H)+=309.0
The acetate aziridine (XXXIIa) (200 mg, 0.57 mmol) is alkylated with benzyl bromide (120 mg, 0.69 mmol) according to Procedure 5 to give a mixture of products. This was HPLC chromatographed on silica gel (50% EtOAc/Hex) to give first 50 mg of Example 21B as a white solid. MS: (CI, NH3) (M+H)+=309∅ This was followed by 30 mg of Example 21C, obtained as a colorless oil. MS: (CI, NH3) (M+H)+=489.2.
TABLE 2j | |||||
MS | |||||
Ex | M + H | ||||
No. | R22 | R | Ki | IC90 | (M + NH4) |
21A | H | H | + | ++/+ | 309.0 |
21B | benzyl | Ac | + | ++/+ | 441.0 |
21C | benzyl | ben- | ++ | 489.2 | |
zyl | |||||
21D | benzyl | H | + | ++/+ | 399.1 |
21E | 3-benzyloxy | H | + | ++/+ | 505.2 |
benzyl | |||||
21F | 3- | H | + | + | 424.2 |
cyanobenzyl | |||||
21G | 3-(H2NC(O)) | H | ++ | ++ | 442.0 |
benzyl | |||||
21H | 3- | H | ++ | +++ | (474) |
H2NC(═NOH) | |||||
benzyl | |||||
The structures of the Examples below are shown in Table 2k.
A. Preparation of 4-Amino-2-(t-butoxycarbonylamino)-1,5-diphenyl-3-(2-methoxyethoxymethyl)pentane.
A mixture of 595 mg (1.50 mmole) of 4azido-2-(t-butoxycarbonylamino-1,5-diphenyl-3-hydroxypentane (EP 0 402 646 A1), 10 ml of dioxane, 0.2 ml (1.75 mmole) of MEM chloride, and 0.32 ml (1.83 mmole) of diisopropylethylamine was heated at 80°C C. for 16 hrs. Evaporated the solvent and purified the residue by flash chromatography on silica gel with 85:15 hexane-ethyl acetate to give 0.64 g (88%) of an oil. Mass spec (M+H)+=485.2. This was reduced to the title compound with hydrogen using 100 mg of 10 % Pd on carbon in 60 ml of ethyl acetate and 0.6 ml of acetic acid in 49% yield
B. Preparation of 2,4-diamino-1,5-diphenyl-3-hydroxypentane.
The product from Part A (218 mg) was dissolved in 2 ml of ice cold 1:1 trifluoroacetic acid dichloromethane. After 1 hr the solution was poured into a mixture of sodium bicarbonate solution and ethyl acetate. The ethyl acetate extract yielded 163 mg of the desired diamino compound.
C. Cyclization of the Diamine.
The product from Part B (146 mg), 75 mg of carbonyl diimidazole, and 0.15 ml of diisopropylethylamine were dissolved in 2.5 ml of anydrous THF and stirred at room temperature for 16 hrs. The solvent was evaporated. The residue was purified by preparative TLC on silica gel with 90:10 dichloromethane-methanol to give 108 mg (69%) of the cyclic urea. Mass spec (M+H)+=385.1.
D. The product from Part C (93 mg) was dissolved in 2.5 ml of anhydrous DMF, and 100 mg of 60% NaH in mineral oil was added. The mixture was stirred for one hr. m-Benzyloxbenzyl chloride (350 mg) was added, and the mixture was stirred for 16 hrs at room temperature. Water and ethyl acetate were added. The ethyl acetate extract was washed with water, dried and evaporated. The residue was purified by prep TLC on silica gel with 60:40 hexane/ethyl acetate to give 105 mg (54%) of the desired bis-alkylated product Mass spec (M+H)+=777.5
The product from part δ (103 mg) was dissolved in 4N HCl/dioxane for 16 hrs. The solution was evaporated and purified by prep TLC on silica gel with 60:40 hexane-ethyl acetate. Mass spec (M+H)+=689.4. The purified material was hydrogenated for 16 hrs in the presence of 3 ml ethanol. 0.2 ml of acetic acid, and 35 mg of 10% Pd on carbon to give Example 22A Mass spec (M+H)+=509.25; calculated, 509.24.
TABLE 2k | |||||
MS | |||||
Ex No. | R22 | R23 | Ki | IC90 | M + H |
22A | m-(HO)-- | m-(HO)-- | ++ | 509.25 | |
C6H4CH2-- | C6H4CH2-- | ||||
The structures of the Examples below are shown in Table 2m.
Synthesis of Intermediate (XXXIVa): Compound XXIc (2.846 g, 5.95 mmol) was dissolved in pyridine (37.5 mL) and to this solution was added sulfamide (572 mg, 5.95 mmol). The contents were refluxed in a 125°C C. oil bath for 18 hours. (Caution: Ammonia is a by-product and the reaction should be well vented). TLC(1:1 EtOAc:Hexane Rf=0.2) indicated a complete reaction. The reaction was diluted with 200 ml diethyl ether and the organic layer was washed with water(300 ml), followed by 1N HCL (2×100 ml) and sat. sodium bicarbonate solution (25 ml). The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Silica gel (130 g; using 1:1 EtOAc:Hexane followed by 20:1:20 EtOAc:EtOH:Hexane) to provide 2.412 g (75.3% yield) of the desired intermediate (XXXIVa) as a white solid.
Intermediate (XXXIVa) (269 mg, 0.5 mmol) was dissolved in dimethylformamide (3mL) and to this solution, cooled in a 0°C C. ice bath, was slowly added sodium hydride (60% in oil, 80 mg, 2 mmol) (EVOLUTION!). The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C C. ice bath and (bromomethyl-)cyclopropane (0.19 mL, 2 mmol) was added via syringe and stirred at room temperature for 18 hours. TLC (1:1 EtOAc:Hexane Rf=0.3) indicated a complete reaction. The reaction was worked up by diluting with water (50 mL) and extracting with diethyl ether (2×25 mL). The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was placed in a 50 ml R.B. flask and dissolved in methanol (3 mL) and to the flask was added 4M HCl in dioxane (3 mL, 12 mmol) and the mixture stirred at room temperature for 18 hours. TLC (2:3 EtOAc:Hexane Rf=0.3) indicated a complete reaction. The mixture was worked up by quenching in sat. sodium bicarbonate (25 ml) and extracting with dichloromethane (2×25 mL). The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on silica gel (55 g; 1:2 EtOAc:Hexane followed by 1:1) to provide 129 mg (54.8% yield) of the tide compound as a white solid. m.p. 71°C-72°C C.
Intermediate (XXXIVa) from Example 23F (538 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL) and to this solution, cooled in a 0°C C. ice bath, was slowly added sodium hydride (60% in oil, 160 mg, 4 mmol) (EVOLUTION!). The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C C. ice bath and m-benzyloxybenzyl chloride (931 mg, 4 mmol) was added as a solid and the mixture stirred at room temperature for 18 hours. TLC (1:2 EtOAc:Hexane Rf=0.25) indicated a complete reaction. The reaction was worked up by diluting with water (100 mL) and extracting with diethyl ether (2×50 mL). The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on silica gel (75 g; 1:2 followed by 1:1 EtOAc:Hexane) to provide 785 mg (84.3% yield) of the intermediate (XXXIVb) (where R22=R23=m-benzyloxybenzyl) as a colorless foam.
Intermediate (XXXIVb) (700 mg, 0.75 mmol) was dissolved in methanol (3.5 mL) and to this solution cooled in a 0°C C. ice bath, was added 4M HCl in dioxane (3.5 mL, 14 mmol) and the mixture stirred at room temperature for 18 hours. TLC (1:2 EtOAc:Hexane Rf=0.26) indicated a complete reaction. The mixture was worked up by quenching in sat.sodium bicarbonate (50 mL) and extracting with dichloromethane (2×50 mL). The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on silica gel (75 g; 1:2 followed by 2:3 EtOAc:Hexane) to provide 357 mg (63.1% yield) of the title compound as a white solid. m.p. 194°C-195°C C.
Example 23C (257 mg, 0.34 mmol) was dissolved in a mixture of ethanol (5 mL) and dioxane (5 mL). To the mixture was added palladium hydroxide on Carbon (20%, 100 mg) and the suspension stirred for 18 hours under hydrogen (1 atm). TLC(10:1:10 EtOAc:EtOH:Hexane Rf=0.3) indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue was purified on silica gel (33 g; 1:1 EtOAc:Hexane followed by 20:1:20 EtOAc:EtOH:Hexane) to provide 162 mg (82.9% yield) of the desired compound as a white solid. m.p. 123°C-124°C C.
TABLE 2m | |||||||
MassSpec | |||||||
Ex. | Stereo | M + H | |||||
No. | 2,3,4,5 | R22 | R23 | HPLC Ki | IC90 | mp, °C C. | (M + NH4) |
23A | RSSR | H | H | + | ++ | 253-255 | 363.1387 |
23B | RSSR | p-(HOCH2)--C6H4CH2-- | p-(HOCH2)--C6H4CH2-- | +++ | +++ | 189-190 | 603.2528 |
23C | RSSR | m-(C6H5CH2O)--C6H4CH2-- | m-(C6H5CH2O)--C6H4CH2-- | ++ | ++ | 194-195 | 755.3155 |
23D | RSSR | m-(HO)--C6H4CH2-- | m-(HO)--C6H4CH2-- | +++ | +++ | 123-124 | 575.2216 |
23E | RSSR | allyl | allyl | ++ | +++ | 112-113 | 443.2005 |
23F | RSSR | cyclopropylmethyl | cyclopropylmethyl | +++ | +++ | 71-72 | 471.2318 |
23G | RSSR | n-butyl | n-butyl | +++ | +++ | oil | 475.2631 |
23H | RSSR | 2-naphthylmethyl | 2-naphthylmethyl | +++ | +++ | 211-212 | 643.2631 |
23I | RSSR | benzyl | benzyl | ++ | +++ | 159-161 | 543.2306 |
23J | RSSR | p-(C6H5CH2O)--C6H4CH2-- | p-(C6H5CH2O)--C6H4CH2-- | + | ++ | 755.3147 | |
23K | RSSR | p-(HO)--C6H4CH2-- | p-(HO)--C6H4CH2-- | +++ | +++ | 223-225 | (592.2486) |
23L | RSSR | m-nitrobenzyl | m-nitrobenzyl | ++ | +++ | 196-198 | 633.2014 |
23M | RSSR | m-aminobenzyl | m-aminobenzyl | +++ | +++ | 212-214 | 573.2535 |
23N | RSSR | m-(HOCH2)--C6H4CH2-- | m-(HOCH2)--C6H4CH2-- | +++ | +++ | 603.2540 | |
23O | RSSR | m-((CH3)2NCH2CO)-- | m-((CH3)2NCH2CO)-- | +++ | +++ | 137-139 | 743.3596 |
C6H4CH2-- | C6H4CH2-- | ||||||
23P | RSSR | m-(CH3OCH2)--C6H4CH2-- | m-(CH3OCH2)--C6H4CH2-- | ++ | ++ | 152-154 | 631.2832 |
23Q | RSSR | m-(CHO)--C6H4CH2-- | m-(CHO)--C6H4CH2-- | +++ | +++ | 91-93 | 599.2211 |
23R | RSSR | CH2-tetrahydro- | CH2-tetrahydro- | ++ | +++ | 97-99 | 531.2533 |
furan-3-yl | furan-3-yl | ||||||
23S | RSSR | m-(HON═CH)--C6H4CH2-- | m-(HON═CH)--C6H4CH2-- | +++ | +++ | 105-107 | (646.2708) |
23T | RSSR | m-(CH3CO)--C6H4CH2-- | m(CH3CO)--C6H4CH2-- | +++ | +++ | 96-99 | 627.2523 |
23U | RSSR | m- | m- | +++ | +++ | 110-113 | 657.2739 |
(HON═C(CH3))--C6H4CH2-- | (HON═C(CH3))--C6H4CH2-- | ||||||
23V | RSSR | CH3 | CH3 | + | ++/+ | 200-203 | 391.1696 |
23W | RSSR | CH2CH3 | CH2CH3 | ++ | ++ | 182-185 | 419.2007 |
23X | RSSR | CH2CH2CH3 | CH2CH2CH3 | +++ | +++ | 145-148 | 447.2316 |
23Y | RSSR | m-(CN)--C6H4CH2-- | m-(CN)--C6H4CH2-- | ++ | +++ | 146-149 | 593.2227 |
23Z | RSSR | m-(2-(4-morpholino)- | m-(2-(4-morpholino)- | ++ | +/++ | 119-122 | 855.4111 |
ethylNHC(═O))C6H4CH2-- | ethylNHC(═O))C6H4CH2-- | ||||||
23AA | RSSR | m-(2-(N,N-dimethyl- | m-(2-(N,N-dimethyl- | ++ | ++ | 127-130 | 771.3903 |
amino)-ethylNHC(═O))-- | amino)-ethylNHC(═O))-- | ||||||
C6H4CH2-- | C6H4CH2-- | ||||||
23AB | RSSR | m-(2-amino-4-thienyl)- | m-(2-amino-4-thienyl)- | +++ | +++ | 185-190 | 739 |
C6H4CH2-- | C6H4CH2-- | ||||||
23AC | RSSR | 5-hydroxypentyl | 5-hydroxyphenyl | +++ | +++ | (552) | |
23AD | RSSR | 6-hydroxypentyl | 6-hydroxyphenyl | +++ | +++ | (580) | |
23AE | RSSR | 5-hydroxypentyl | H | ++ | ++/+ | (466) | |
23AF | RSSR | 5-hydroxypentyl | 2-naphthylmethyl | +++ | +++ | (606) | |
23AG | RSSR | 5-hydroxypentyl | p-(HOCH2)--C6H4CH2-- | +++ | +++ | (586) | |
23AH | RSSR | 5-hydroxypentyl | m-(HOCH2)--C6H4CH2-- | +++ | +++ | (586) | |
The structures of the Examples below are shown in Table 2n.
Intermediate (XXXIVb): To a solution of diamine (XXIc) (100 mg, 0.21 mmol.) in ethanol (3 mL), was added p-toluenesulfonic acid monohydrate (39 mg, 0.21 mmol.). After stirring for 10 min., dimethylacetamide dimethyl acetal (0.034 mL, 0.21 mmol.) was added. The reaction was then stirred at room temperature for 25 min. and then refluxed for 2 h. After cooling to room temperature, the reaction was evaporated in vacuo and partitioned between 5% NaOH and CH2Cl2. The organic phase was then washed with saturated NaCl, dried (Na2SO4) and evaporated leaving 100 mg of Intermediate (XXXIXb) as a yellow oil (95% yield).
To a suspension of 60% NaH (160 mg, 4.0 mmol; washed twice with hexane) in DMF (3 mL) was added a solution of Intermediate (XXXIVb) (100 mg, 0.20 mmol.) in DMF (7 mL). After stirring for 35 min., a solution of 4tetrahydro-pyranyloxymethylbenzyl chloride (XXXIVc) (0.53 g, 2.20 mmol.) in DMF (2 mL) was added followed by addition of potassium iodide (0.33 g, 2.0 mmol.). After stirring overnight, additional chloride (XXXIVc) (0.53 g, 2.20 mmol.) was added and the reaction was heated to 50°C C. and stirred overnight. The reaction was quenched by addition of acetic acid (1 mL) in Et2O (100 mL). After basification with 5% NaOH, the organic phrase was washed with water (2×), brine (2×), dried (Na2SO4), and evaporated leaving 2.1 g of a yellow oil. This material was taken up in methanol (10 mL) and 4N HCl in dioxane (5 mL) was added. After stirring overnight, the reaction was evaporated in vacuo and partitioned between 5% NaOH and CH2Cl2. The organic phase was dried and evaporated leaving 1.1 g of an orange oil. Column chromatography (flash silica gel; 5% MeOH/CH2Cl2 and 0.1% NH4OH) gave 182 mg of Example 24B and 300 mg of Example 24C, both as white solids.
Example 24B: Mass spec. MH+=445.2; mp=105°C-110°C C. (HCl salt)
Example 24C: Mass spec. M+=565.5; mp=72°C-75°C C. (Note: The mass spec is M+since this is already a charged species.)
By an analogous process reported above, and instead using benzyl chloride, the desired product was obtained. The acid deprotection step was not performed in this instance.
Example 24A: 1H NMR (300MHz, CDCl3): δ 6.90-7.35 (m, 15 H), 4.09-4.14 (m, 2 H), 3.56 (dd, 2 H), 3.13 (dd, 1 H), 2.50-2.95 (m, 5 H), 1.97 (s, 3 H). Mass spec. MH+=415.1, mp=130°C-137°C C.
TABLE 2n | ||||||
MS | ||||||
Ex No | R22 | R23 | R4 = R7 | R5 = R6 | Ki | (M + H)+ |
24A | . . . | benzyl | benzyl | OMEM | 415.1 | |
24B | HCl | m-(HO)-- | benzyl | OH | 445.2 | |
C6H4CH2-- | ||||||
24C | m-(HO)-- | m-(HO)-- | benzyl | OH | (565.2) | |
C6H4CH2-- | C6H4CH2-- | |||||
The structures of the Examples below are shown in Table 2o.
Intermediate (XLVa), (3S,5R)-5-[(1'R)-1'-[(t-Butyloxycarbonyl) amino]-2'-phenethyl]-3-phenylmethyltetrahydrofuran2-one, can be prepared from N-Boc-phenylalanine following the 8-step procedure of G. B. Dreyer, et al [Biochem. 1992, 31, 6646-6659]. This is converted to the acid (XLVb) using the procedure of B. E. Evans, et al [J. Org. Chem 1985, 50, 4615-4625], wherein a solution of (3S,5R)-5-[(1'R)-1'-[(t-Butyloxycarbonyl) amino]-2'-phenethyl]-3-phenylmethyltetrahydrofuran-2-one (XLVa) (11.0 g, 2.5 mmol) in 15 mL of dioxane/7.5 mL of water was treated with 2.7 mL of 1N NaOH dropwise. The mixture was stirred at room temperature for 30 min. and then concentrated at rt on a rotary evaporator. The residue was acidified with 10% citric acid and extracted into ether. The ether extract was washed with water, brine and dried over MgSO4. The solution was filtered and concentrated to give the hydroxy acid as white solid.
The hydroxy acid was immediately dissolved in dry DMF and treated with t-butyldimethylsilyl chloride (2.6 g, 17.5 mmol) and imidazole (2.2 g). The mixture was stirred overnight at room temperature. Analysis by TLC (50:50 EtOAc/Hex) showed no starting material remained, at which time the solution was concentrated in vacuo and the residue acidified to pH 4 with 10% citric acid and extracted into ether. The ether extract was washed with water, brine and dried over MgSO4. The solution was filtered and concentrated to give 1.7 g of the silyl ether-silyl ester as a colorless syrup.
A solution of the silyl ether-silyl ester in tetrahydrofuran (THF, 10 mL) was treated with 10 mL of glacial acid and water (3 mL). The solution was stirred at room temperature for 2.5 hrs until analysis by TLC showed complete conversion to silyl ether-acid (XLVb). The solution was concentrated in vacuo and the resulting residue diluted with water and extracted into ether. The ether extract was washed with water, brine and dried over MgSO4. The solution was filtered and concentrated to give the acid (XLVb) as a solid.
A solution of the acid (XLVb) in dioxane was treated with N-hydroxy succinimide (290 mg, 2.5 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 500 mg, 2.5 mmol) and stirred overnight. The solution was cooled in an ice bath and the solids were filtered off. The filtrate was concentrated to give the activated ester (XLVc) as a sticky foam. MS (M+H)+=625.5 (41%); (M+H-BOC)+=525.4 (100%).
The above activated ester (XLVc) was dissolved in ether, cooled in a nice bath and treated with HCl (g for 15 minutes and stirred at 0°C C. for an additional hour. The solution was concentrated in vacua at RT to give a white foam. This was dissolved in THF (100 mL) and made basic, with triethyamine (3 mL). The resulting suspension was stirred at room temperature overnight. The solution was concentrated and the residue was chromatographed on silica gel (medium pressure LC, ethyl acetate). This was filter purified by HPLC chromatography on silica gel (50:50 EtOAc/Hex) to give 170 mg (17% overall yield/6 steps) of the lactam (XLVd) as a colorless oil. MS (M+H)+=410.2 (100%)
A solution of (XLVd) (170 mg, 0.42 mmol) in DMF was cooled to 0°C C. and treated with 60% NaH in oil dispersion (25 mg, 0.62 mmol) and stirred at 0°C C. for 30 minutess. Benzyl bromide (105 mg, 0.44 mmol) was added and stirred for 1 hour and the reaction was allowed to warm to room temperature. The mixture was cooled to 0°C C. and quenched with 1N HCl and diluted with water. The suspension was extracted into ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated. The residue was HPLC chromatographed on silica gel (30% EtOAc/Hex) to give 130 mg of (XLVf) as a colorless film. MS (M+H)+=500.2 (100%).
The silyl ether-lactam (XLVf) (130 mg, 0.26 mmol) was dissolved in tetrabutylammonium fluoride (TBAF, 1M in THF, 5 mL) solution and stirred at room temperature for 30 minutes. The solution was diluted with water and extracted into ethyl acetate. The extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was HPLC chromatographed on silica gel (65% EtOAc/Hex) to give 79 mg of Example 25A (XLVg) as a white foam. MS (M+H)+=386.2 (100%).
TABLE 2o | ||||||
MS | ||||||
Ex No | R22 | R23 | R4 | Ki | (M + H)+ | |
25A | benzyl | benzyl | benzyl | + | 386.2 | |
The structures of the Examples below are shown in Table 2p.
5H-dibenzo [A,D] cyclohepten-5-one-10,11-dihydro-10, 11-diol
A mixture of 5H-dibenzo [AD] cyclohepten-5-one-10, 11-dihydro-10,11-diolacetate (ester) (100 mg, 0.31 mmol) and sodium hydroxide 50% aqueous solution (5 drops) was disolved in methanol (10 ml). The mixture was stirred at room temperature for 5 minutes, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate twice. The organic layer was washed with water, brine, dried with magnesium sulfate and then concentrated in vacuo. The concentrate was dissolved with a minimum amount of methylene chloride and hexane was added to the cloudy point. The resulting precipitate was filtered to give opaque fine needle crystals (47 mg, 64%). mp 107.5°C-107.9°C C., Mass Spec 241.1 (M+H)+; Analysis Calc. for C15H12O3: C, 74.99; H, 5.03; Found: C, 74.70; H, 5.01. 1H NMR (CDCl3/TMS) δ 87.85 (2H, m), 7.67 (2H, m), 7.57 (2H, m), 7.44 (2H, m), 5.02 (2H, m), 3.03 (2H, m).
TABLE 2p | |||||
MS | |||||
Ex No | R22-R4 | R23-R7 | Ki | mp, °C C. | (M + H)+ |
26A | fused | fused | + | 107.5-108 | 241 |
aromatic | aromatic | ||||
The structures of the Examples below are shown in Table 2q.
Compound XXIIb (3.0 g, 4.8 mmol) was dissolved in of anhydrous acetonitrile (40 ml) and to this solution was added benzyl bromide (820 mg) and tetrabutylammonium iodide (20 mg). The contents were heated at reflux under a nitrogen atmosphere for 14 h and the solvent was removed under reduced pressure. The crude residue was chromatographed on silica gel using ethyl acetate-hexane (1;1) as the eluent. The major fraction contained 2.5 g (76% yield) of Intermediate (LIIIa) as a white solid. MS: (M+H)+699.4, (100%); 1H NMR (CDCl3): δ7.25 (m, 12 H), 6.99 (m, 3H), 4.95 (d, 1H), 4.82 (d, 1H), 4.65 (d, 1H), 4.50 (d, 1H), 4.15 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.60 (m, 1H), 3.56 (m, 1H), 3.4 (s, 3H), 3.39 (m, 1H), 3.35 (s, 3H), 3.12 (m, 1H), 2.92 (m, 1H), 2.10 (s, 3H).
Intermediate (LIIIa) (300 mg, 0.48 mmol) was dissolved in methanol (5 ml) and a solution of hydrochloric acid in dioxane (4M, 5 ml) was added. This mixture was stirred at room temperature for 4 h and then the solvent was removed under reduced pressure (the excess HCl can be removed by extensive washing with methanol followed by evaporation). The crude residue was chromatographed on silica gel using a 10% ethyl acetate in methylene chloride as the eluent. The major product contained 175 mg (81%) of Example 27A. top: 91°C-93°C C. MS: (M+H)+523.2, (100%). IR (KBr, cm-1): 3416, 3086, 1584 and 1282. 1H NMR (CDCl3): δ7.25 (m, 10 H), 5.85 (d, 1H), 3.80 (m, 1H), 3.65 (d, 1H), 3.38 (s, 1H), 3.12-2.90 (m. 2H), 2.21 (s, 1H). 13C NMR (CDCl3, ppm) 193.6, 139.9, 137.6, 130.2, 130.1, 129.1, 128.8, 128.3, 127.0, 72.0, 67.7, 62.2, 32.8.
The above reaction (removal of the MEM protecting group) can also be done by dissolving the starting material in methanol followed by bubbling HCl gas into the solution for 5 min at -10°C C. and then stirring at room temperature for 20 min. Similar work up of the first procedure leads to the desired Example 27A.
By substituting cyclopropylmethyl bromide into procedure of Example 27A and using the appropriate monoalkylated cyclic thiourea, Example 27B was prepared in good yield. mp: 84°C-86°C C.; MS: (M+H)+451.1; 1H NMR (CDCl3):δ7.35-7.20 (m, 5H), 5.0 (d, 1H), 4.85 (d, 1H), 4.10 (m, 2H), 3.95 (m, 1H), 3.75 (m, 1H), 3.45 (m, 2H), 3.38 (s, 3H), 3.2 (m, 1H), 3.0 (m, 1H), 2.78 (m, 1H), 1.20 (m, 1H), 0.21 (m, 2H), 0.17 (m, 2H)
Using an analogous procedure to that described for Example 27B, Example 27C was prepared in good yield. mp: 257°C-259°C C.; MS: (M+H)+583.2; 1H NMR (CDCl3):δ7.25-7.15 (m, 9H), 5.80 (m, 2H), 4.75 (s, 2H), 3.82 (m, 1H), 3.42 (m, 1H), 3.35 (m, 2H), 2.95 (m, 2H).
Using an analogous procedure to that described for Example 27A, Example 27D was prepared in good yield (m-MEMOCH2C6H5CH2Br was the alkylating agent). mp: 253°C-255°C C.; MS(CDI):m/e 583.3 (100%, M+H); 1H NMR (CD3OD, 300 MHz) δ2.95 (m, 2H), 3.20 (m, 1H), 3.40 (m, 1H), 3.78 (m. 1H), 5.82 (m, 1H) and 7.15-7.30 (m, 9H).
By using the appropriate alkylating agent (m-cyanobenzylbromide), Example 27E was prepared in an anologous procedure to Example 27A; mp: 154°C-155°C C.; MS(CDI): m/e 548.2 (100%, M+H); 1H NMR (CD3OD, 300 MHz) δ2.81 (m, 1H), 2.95 (m, 2H), 3.20 (m, 1H), 3.25 (m, 2H), 3.85 (m, 1H), 3.90 (m, 1H), 5.25 (m, 1H), 5.80 (m, 1H), 7.10 (m, 5H), 7.15 (m, 10H) and 7.25 (m, 4H).
Example 27F was made by using p-MEMOC6H5CH2Br as the alkylating agent in the procedure of Example 27A. mp: 162°C C.; MS(CDI): m/e 555.2 (100%, M+H);1H NMR (CD3OD) δ2.85 (m, 2H), 3.12 (m, 2H), 3.8 (m, 1H), 5.80 (m, 1H), 6.75 (m, 2H), 6.95 (m, 2H) and 7.15 (m, 5H).
Example 27G was prepared according to the procedure described for Example 27A, using m-MEMOC6HSCH2Br as the alkylating agent. mp: 82°C C.; MS(CDI): m/e 583.2 (100%, M+H); 1H NMR (CD3OD, 300 MHz) 52.85 (m, 2H), 3.25 (m, 2H), 3.62 (s, 3H), 3.90 (m, 1H), 5.80 (m, 1H), 6.80 (m, 3H) and 7.10-7.20 (m, 6H).
Example 27H was prepared using an analogous procedure to that described for Example 27A by employing m-NCC6H5CH2Br as the alkylating agent. mp: 110°C C.; MS(CDI): m/e 577.2 (M+H); 1H NMR (CD3OD, 300 MHz) δ2.8 (m, 2H), 3.15 (m, 2H), 3.45 (m, 2H), 3.65 (m, 1H), 3.70 (m, 1H), 3.82 (m, 1H), 4.15 (m, 1H), 5.28 (m, 1H),5.82 (m, 1H), 7.25 (m, 41H), 7.40 (m, 10 H) and 7.80 (m, 4H).
Example 27K was prepared by treating Example 27H with hydroxylamine. HCl, using an analogous procedure to that described for Example 27N. mp: 130°C-132°C C.; MS(CDI): m/e 611.2 (100%, M+H); 1H NMR (CD3OD, 300 MHz) δ2.81 (m, 2H), 3.21 (m, 2H), 3.45 (m, 2H), 3.8 (m, 2H), 4.72 (m, 2H), 5.85 (m, 2H) and 7.25 (m, 18 H).
Example 27L was synthesized in a similar fashion to that described for Example 27F by using m-MEMOC6H5CH2Br as the alkylating agent. mp: 125°C C.; MS(CDI): m/e 555.3 (100%, M+H); 1H NMR (CD3OD, 300 MHz) δ3.05-3.20 (m, 2H), 3.41-3.60 (m, 2H), 3.95 (m, 1H), 5.82 (m, 1H), 6.80 (m, 3H) and 7.20-7.45 (m, 6H).
Example 27M was prepared using an analogous procedure to that described for Example 27A by using m-NCC6H5CH2Br as the alkylating agent. mp: 102°C C.; MS(CDI): m/e 573.3 (100%, M+H); 1H NMR (CD3OD, 300 MHz) δ2.80 (m, 1H), 3.05 (m, 1H), 3.20 (m, 1H), 3.42 (m, 1H), 3.78 (m, 1H), 5.15 (m, 1H), 7.15 (m, 2H), 7.25 (m, 3H), 7.45 (m, 1H) and 7.60 (m, 3H).
To a solution containing 200 mg (0.34 mmol) of Example 27M in 10 mL of anhydrous ethanol was added 60 mg (0.87 mmol) of hydroxylamine.HCl and 87 mg (0.87 mmol) of triethylamine. The reaction mixture was heated at reflux until the starting material could not be detected by TLC), and then the solvent was removed under reduced pressure. The residue was chromatographed on a C18 silica column using a 20% solution of water in methanol as the eluent. The major fraction isolated contained 97 mg (45% yield) of thiourea, Example 27N. mp: 150°C C.; MS(DCI): m/e 639.2 (100%, M+H); 1H NMR (CD3OD, 300 MHz)δ2.85 (m, 2H), 3.15 (m, 1H), 3.25 (m, 1H), 3.80 (m, 1H), 5.82 (m, 1H), 7.15 (m, 5H) and 7.45 (m, 4H).
To a solution of containing 5.0 g (10.5 mmol) of Di-amino-Di-MEM compound III in 75 ml of THF was added 2.20 g (22.0 mmol) of K2CO3 and 4.48 g (23.0 mmol) of 4-fluoro-3-cyanobenzyl bromide. The reaction mixture was stirred at room temperature for 18 h and then 100 mL of water was added. The mixture was extracted with CH2Cl2 and the organic layer was dried over MgSO4 and filtered. The filtrate was treated with 1.73 g (15.0 mmol) of thiophosgene and 2.0 g (20.0 mmol) of triethylamine. The reaction was stirred at room temperature overnight and then washed with 100 mL of 10% citric acid. The organic layer was washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using a 50% solution of ethyl acetate in hexane as the eluent to give 2.45 g (30% yield) of the alkylated intermediate. Removal of the the MEM groups was done by using analogous procedure to that described for intermediate LIIIa. The thiourea compound obtained from the previous step was converted to example 27P by applying the same procedure described for Example 27N. mp 154°C C.; MS(DCI): m/e 675.2 (100%, M+H); 1H NMR (CD3OD, 300 MHz) 2.85 (m, 2H). 3.35 (m, 1H), 3.52 (m, 1H), 3.78 (m, 1H), 5.61 (m, 1H), 7.10 (m, 1H) and 7.25 (m, 8H).
TABLE 2q | |||||||
Ex. | Stereo | HPLC | Mass Spec | ||||
No. | 2,3,4,5 | R22 | R23 | Ki | IC90 | mp, °C C. | (M + H) |
27A | RSSR | C6H5CH2-- | C6H5CH2-- | +++ | +++ | 92-94 | 523.2 |
27B | RSSR | (C3H5)CH2-- | (C3H5)CH2-- | +++ | +++ | 84-86 | 451.1 |
27C | RSSR | p-HOCH2C6H4CH2-- | C6H5CH2-- | +++ | +++ | 257-258 | 583.2 |
27D | RSSR | m-HOCH2-- | m-HOCH2-- | +++ | +++ | 253-355 | 583.3 |
C6H4CH2-- | C6H4CH2-- | ||||||
27E | RSSR | m-cyano- | C6H4CH2-- | +++ | +++ | 154-155 | 548.2 |
C6H4CH2-- | |||||||
27F | RSSR | p-HOC6H4CH2-- | p-HO-- | +++ | +++ | 162 | 555.2 |
C6H4CH2-- | |||||||
27G | RSSR | m-CH3O-- | m-CH3O-- | +++ | +++ | 82 | 583.2 |
C6H4CH2-- | C6H4CH2-- | ||||||
27H | RSSR | m-cyano- | p-HOCH2-- | +++ | +++ | 110 | 577.2 |
C6H4CH2-- | C6H4CH2-- | ||||||
27I | RSSR | m-HONNH2-- | p-HOCH2-- | +++ | +++ | 130-132 | 611.2 |
C6H4CH2-- | C6H4CH2-- | ||||||
27J | RSSR | m-HO-- | m-HO-- | +++ | +++ | 125 | 555.3 |
C6H4CH2-- | C6H4CH2-- | ||||||
27K | RSSR | m-cyano- | m-cyano- | +++ | +++ | 102 | 573.3 |
C6H4CH2-- | C6H4CH2-- | ||||||
27L | RSSR | m- | m- | +++ | +++ | 150 | 639.2 |
(H2NC(═NOH)) | (H2NC(═NOH)) | ||||||
C6H4CH2-- | C6H4CH2-- | ||||||
27M | RSSR | m- | m- | +++ | +++ | 152-153 | 675.2 |
(H2NC(═NOH))- | (H2NC(═NOH))- | ||||||
p-fluoro- | p-fluoro- | ||||||
C6H4CH2-- | p-HOCH2C6H4CH2-- | ||||||
27N | RSSR | p-H2NC6H4CH2-- | p-H2NC6H4CH2-- | +++ | +++ | 625.7 | |
The structures of the Examples below are shown in Table 2r. Compounds in Table 2r were prepared as shown in Scheme 28.
Preparation of Diamine (La):
To a suspension of 10 g of (2R, 3S, 4S, 5R) -2,5-bis-(N-Cbz-amino)-3,4-(dihydroxy)-1,6-diphenylhexane in 200 mL of methylene chloride was added 10.8 mL of 2,2-dimethoxypropane and 0.41 g of camphorsulfonic acid. The mixture was stirred at room temperature for 48 hr, then washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The residue was crystallized from ether/hexane (1/10 v/v) to give 6.6 g (60% yield) acetonide as white needles, mp 76°C-77°C C.
To a solution of 6.6 g of this acetonide in 100 mL of tetrahydrofuran/ethanol (1/1 v/v) was added 0.7 g of 10% Pd/C. The mixture was stirred vigorously under 1 atmosphere of hydrogen gas for 18 hr. The catalyst was isolated by filtration and washed with tetrahydrofuran. The combined filtrate and washings were concentrated on a rotary evaporator. The residue consisted of 3.6 g (100% yield) of diamine, La, which was used without further purification.
To a solution of 2 g of compound La in 15 mL of anhydrous tetrahydrofuran, maintained at 0°C-10°C C. under a nitrogen atmosphere with efficient stirring, was added 1.8 mL (2.2 eq) of triethylamine followed by dropwise addition of a solution of 0.9 mL (1 eq) of phenyldichlorophosphate in 4 mL of tetrahydrofuran. The mixture was stirred for 16 hr at room temperature. The resulting triethylamine hydrochloride was isolated by filtration and washed with tetrahydrofuran. The combined filtrate and washings were concentrated on a rotary evaporator, taken up in methylene chloride/ethyl ether (1/1 v/v), and washed successively with water (2×), and saturated sodium chloride solution (1X). After drying over anhydrous magnesium sulfate the organic layer was concentrated on a rotary evaporator. Purification of the residue by column chromatography using a short pad of silica gel eluting with hexane/ethyl acetate (1/1 v/v) gave 1.8 g (64% yield) of the cyclic phosphoramide, Lb, as a sticky white foam.
To a solution of 0.1 g of compound Lb in 3 mL of anhydrous N,N-dimethylformamide, maintained under a nitrogen atmosphere at room temperature, was added 35 mg of 60% NaH (by weight, dispersed in oil). The mixture was stirred for 10-15 min followed by addition of 0.16 mL bromomethylcyclopropane. The mixture was stirred for 48 hr at room temperature, then quenched by water addition. The product was extracted with ethyl acetate (3×). The combined extracts were washed successively with water (2×) and saturated sodium chloride solution (1×), dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified using rotary preparative tlc eluting with hexane/ethyl acetate (4/1 v/v) to give 97 mg (79% yield) of the bisalkylated product as an amber oil. To a solution of 97 mg of this bisalkylated product in 2 mL of anhydrous methylene chloride, maintained under an argon atmosphere at -78°C C., was added 0.5 mL of a 2.0 M solution of dimethylboron bromide in methylene chloride by dropwise addition. The addition was completed in 10-15 min, and the mixture was thereafter stirred for 1 hr at -78°C C. The mixture was then transferred via syringe to a rapidly stirring mixture of 1 mL tetrahydrofuran and 0.5 mL aqueous saturated sodium hydrogen carbonate solution. After stirring for 5 min, the mixture was extracted with ethyl acetate (3×). The combined extracts were washed successively with 10% aqueous potassium hydrogen sulfate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic layer was concentrated by rotary evaporation. The residue was purified by rotary preparative tlc eluting with hexane/ethyl acetate (4/1 v/v) to give 70 mg (78% yield) of compound 28D as an amorphous white solid. MS 547 (M+H)+453 (100%, M+H)--C6H5OH)+. 1H NMR(CDCl3) δ0.24 (4H, m) 0.44 (4H,m) 0.95 (2H,m) 2.22 (1H, d) 2.52 (1H,m) 3.18 (4H,m) 3.38 (2H,m) 3.63 (1H, m) 3.90 (1H, t) 4.03 (2H, m) 7.00 (1H, m) 7.06 (2H, t) 7.24 (10 H,m) 7.50 (2H,m)
Compound of example 28M was prepared from compound Lb using the alkylation procedure described for example 28D by replacing the bromomethylcyclopropane with 3-(N-methyl-N-trifluoroacetamido)benzyl bromide. A solution of 0.27 g of the bisalkylation product, thus prepared, in 7 mL of methanol was treated with 4 eq of solid potassium carbonate. The mixture was stirred for 48 hr at room temperature, diluted with water, and extracted with methylene chloride. The extract was washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. Concentration by rotary evaporation and purification of the residue by column chromatography using silica gel eluting with hexane/ethyl acetate (1/1 v/v) gave the free amino compound in 57% yield.
To a solution of this diamine in 3 mL of methanol was added 0.01 g p-toluenesulfonic acid monohydrate. The solution was stirred for 1 hr at room temperature, then concentrated by rotary evaporation. The residue was taken up in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. Concentration by rotary evaporation and purification by column chromatography on silica gel using methylene chloride/ethyl acetate/ethanol (10/10/0.5 volume ratios) gave a 19% yield of compound 28M. MS: 583 (M+H--C6H5OH) 1H NMR (CDCl3): δ2.58-2.77 (m, 2H); 2.70 (s, 3H): 2.78 (s, 3H); 3.02 (d, 2H); 3.20-3.39 (m, 2H); 3.42 (d of d, 2H); 3.50-3.73 (m, 2H); 3.88 (s, 2H); 4.30-4.59 (m, 4H); 6.42-6.52 (m, 4H); 6.55-6.62 (m, 3H); 6.95 (d, 2H); 7.00-7.37 (m, 10 H); 7.52 (d, 2H).
TABLE 2r | |||||||
Ex. | Ki | Mass Spec | |||||
No. | R22 = R23 | R4 = R7 | R24A | HPLC | IC90 | mp, °C C. | (M + H) |
28A | H | benzyl | phenyloxy | + | ++ | 456 | |
(M + NH4) | |||||||
28B | 2-naphthyl | benzyl | phenyloxy | ++ | +++ | ||
methyl | |||||||
28C | cyclopropyl | benzyl | phenyloxy | ++ | +++ | 547 | |
methyl | |||||||
28D | n-butyl | benzyl | phenyloxy | ++ | +++ | 551 | |
28E | 4-(HOCH2)- | benzyl | phenyloxy | ++ | +++ | ||
benzyl | |||||||
28F | H | benzyl | ethoxy | + | ++/+ | 245-246 | 408 |
(M + NH4) | |||||||
391 | |||||||
28G | cyclopropyl | benzyl | dimethyl | + | ++ | 498 | |
methyl | amino | ||||||
28H | 4-(HOCH2)- | benzyl | methoxy | ++ | ++ | 617 | |
benzyl | |||||||
28I | 4-(HOCH2)- | benzyl | dimethyl | ++ | ++ | 159-160 | 630 |
benzyl | amino | ||||||
28J | 3-(HOCH2)- | benzyl | phenoxy | ++ | ++ | 109-110 | |
benzyl | |||||||
28K | benzyl | benzyl | methyl | ++ | 541 | ||
28L | 3-(CH3NH)- | benzyl | phenoxy | ++ | ++ | ||
benzyl | |||||||
The examples below are representative procedures for the preparation of the compounds shown in Table 2s below.
Compound of example 5U (11.340 g, 20 mmol) was dissolved in 60 ml tetrahydrofuran and cooled to 0°C C.. di-t-butyl-N,N-diethylphosphoramidite 13.000 g(52 mmol) in 40 tetrahydrofuran was added followed by additon of 7.28 g(104 mmol) of tetrazole. The contents were stirred for 5 minutes in the 0°C C. ice bath and then for 15 minutes in a water bath at approximately 23°C C. The contents were cooled in a -40°C C. bath and 21.5 g(62.4 mmol) of 50% m-chloroperoxybenzoic acid in 100 ml dichloromethane added over a 10 minute period and stirred for 5 minutes in the same bath and then 15 minutes in a water bath at approximately 23°C C. The reaction was quenched with 250 ml of 10% aqueous sodium bisulfite at 0°C C. The aqueous layer was extracted with ether (100 ml). The organic extracts were combined and washed with sat. sodium bicarbonate (100 ml), 10% aqueous sodium bisulfite (250 ml) and then sat. sodium bicarbonate (100 ml). The organic layer was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO2 gel [750 g; using chloroform (500 ml) followed by 1% Methanol:Chloroform (4 liters) followed by 1.5% (4 liters)] to provide 14.410 g (75.8% yield) of the bisphosphate ester as a white solid. Caution! The "flash chromatography" column should be done as fast as possible to avoid any decomposition on the column support. 1H NMR (300 MHz) (CDCl3) δ1.441 (36H, d, J=4Hz), 2.974(6H,m), 3.353 (2H, s), 3.49(4H,m), 4.865(2H, d,J=8Hz), 4.919 (4H, d, J=14Hz), 7.111(10H, t,J=8Hz), 7.293(8H,m); 31P NMR(121MHz) (CDCl3) δ-9.8 (s, decoupled).
This diester intermediate (36 g, 37.85 mmol) was dissolved in 200 ml methanol and to this solution was added 3.6 g of Amberlyst 15 ion exchange resin. The contents were stirred at reflux for 5 hours. The mixture was filtered through a celite pad and concentrated to afford 27 g (98.2% ) of Compound 29A as a white solid. 1H NMR (DMSOd6) δ2.842(4H,m), 2.955 (2H,m), 3.336(2H, s), 3.420 (2H, d, J=11 Hz), 4.662 (2H, d, J=4.2 Hz), 4.822 (4H, d, J=6.9Hz), 7.016 (4H, , d, J=6.9Hz), 7.084(4H,d,J=7.7 Hz), 7.266(10H, m); 31p NMR (DMSO-d6) δ-0.48(s,decoupled).
Compound 29A (2.178 g, 3 mmol) was treatd slowly with 11.71 ml (12 mmol) of 1.024N Potassium bicarbonate solution. After the addition was complete the solution was filtered through a sintered glass filter funnel and lyophilized to afford 2.433 g (92.3% yield) of desired tetrapotassium salt as a white solid.
Compound 5U (8.2 g, 14.4 mmol) was dissolved in methylene chloride (170 ml) under a nitrogen atmosphere. N,N-Dimethylglycine (1.78 g, 17.3 mmol, 1.2 equiv.) was added followed by the reagents, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.32 g, 17.3 mmol, 1.2 equiv.) and 4-dimethylaminopyridine (2.11 g, 17.3 mmol, 1.2 equiv.). After stirring overnight, silica gel (40 g, 230-400 mesh) was added and the solvent removed on a rotary evaporator. The residue was applied to the top of flash silica gel column and eluted with 20% methanol-80% ether to give partially purified D. Further chromatography using 15% isopropanol-85% methylene chloride gave the desired monoester (2.54 g, 27%). 1H NMR (300 MHz, CDCl3)δ7.35-7.02(18H, m), 5.06(2H, s), 4.85(1H, d), 4.80(1H, d), 4.50(2H, s), 3.46(6H, m), 3.07(2H, s), 2.96(7H, m), 2.22(6H, s). 13C NMR (75.4 MHz, CDCl3) δ170.2. 162.1, 140.2, 139.6, 138.4, 137.3, 134.8, 129.5, 129.4, 128.9, 1285, 128.5, 128.1, 127.1, 126.4, 71.1, 71.0, 66.0, 64.3, 63.8, 60.1, 55.3, 55.1, 45.1, 32.6.
This mono-ester (1.39 g, 2.14 mmol) was dissolved in a mixed solvent system (88 ml, 9% isopropanol-91% ether). A solution of hydrochloric acid (0.59 ml, 2.35 mmol, 1.1 equiv., 4.0M in dioxane) was added dropwise. After stirring for 1.5 hours, the reaction was filtered under nitrogen. The filtrate was rinsed into a flask with water and frozen. The frozen solution was lyophilized to give 29D as its monohydrochloride monohydrate (1.39 g, 92% for the monohydrate). 1H NMR (300 MHz, CD3OD) δ7.38-7.01(18H, m), 5.26(2H, s), 4.82(1H, d), 4.78(1H, d), 4.56(2H, s), 4.12(2H, dd), 3.58(4H, m), 3.09-2.78(6H, m), 2.91(6H, s). 13C NMR (100.6 MHz, CD30D) δ166,89, 163.83, 142.37, 141.30, 141.24, 140.17, 138.14, 135.64, 130.86, 130.65, 130.48, 129.93, 129.67, 129.57, 128.24, 127.48, 72.05, 71.90, 68.81, 67.81, 66.93, 64.79, 57.99, 57.07, 56.72, 44.49, 33.64, 33.58. MS (NH3 CI) m/e 652 (M+H-HCI).
Compound 5U (5.0 g, 8.82 mmol) was dissolved in methylene chloride (50 ml) under a nitrogen atmosphere. An excess of 2,2-dimethoxypropane (10 ml) and a catalytic amount of p-toluenesulfonic acid monohydrate (250 mg) were then added. After stirring for one hour, water (25 ml) was added and stirring continued for ten minutes. The reaction was then transferred to a separatory funnel where the layers were separated. The organic phase was was successively with a saturated aqueous solution of sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the crude product was isolated by filtration and evaporation. Purification was accomplished by flash silica gel column chromatography (5% methanol-95% methylene chloride). The acetonide was obtained in 90% yield (4.75 g). 1H NMR (300 MHz, CDCl3) δ7.37-7.23(10H, m), 7.09(8H, d), 4.88(2H, d), 4.65(4H, d), 3.82(2H, s), 3.76(2H, b), 3.04(2H, d), 2.92(4H, m), 1.94(2H, t), 1.34(6H, s). 13C NMR (75.4 MHz, CDCl3) δ161.7, 140.2, 138.8, 137.6, 129.4, 129.3, 129.2, 128.7, 127.2, 126.6, 110.2, 75.5, 65.0, 60.8, 56.0, 33.5, 26.7.
This acetonide (999 mg, 1.67 mmol) was dissolved in methylene chloride (10.0 ml) under a nitrogen atmosphere. N,N-Dimethylglycine (431 mg, 4.18 mmol, 2.5 equiv.) and the reagents 1-(3-dimethylaminopropyrl)3-ethylcarbodiimide hydrochloride (802 mg, 4.18 mmol, 2.5 equiv.) and 4-dimethylaminopyridine (511 mg, 4.18 mmol, 2.5 equiv.) were added and stirring continued overnight. The reaction was applied directly to a flash silica gel cohumn and eluted with 10% methanol-90% ether. The desired bis-ester was obtained in 73% yield (0.95 g). 1H NMR (300 MHz, CDCl3) δ7.36-7.04(18H, m), 5.14(4H, s), 4.92(2H, d), 3.86(2H, s), 3.77(2H, d), 3.18(4H, s), 3.08(2H, d), 2.92(4H, m), 2.33(12H, s), 1.37(6H, s). MS (NH3 CI) m/e 777(M+H).
This bis-ester (402 mg, 0.518 mnmol) was dissolved in methanol (5.0 ml) and hydrochloric acid (1.0 ml, 1.0 N solution) was added. After stirring for 0.5 hour the solvent was removed by rotary evaporation and the residue azeotropically dried with toluene. Further drying in vacuo gave 29E (383 mg).
TABLE 2s | |||||
Ki | Mass Spec | ||||
Ex. No. | R42 = 43 | (HPLC) | IC90 | mp, °C C. | (M + H) |
29A | PO3H2 | ||||
29B | PO3" (K+) | ||||
29C | Me2NCH2C(O)-- | ||||
29D | R22 = H, R23 = Me2NCH2C(O)--.HCl | 652 | |||
29E | Me2NCH2C(O)--.HCl | 737 | |||
29F | (3-pyridinyl)-CH2C(O)-- | 805 | |||
29G | (4-pyridinyl)-CH2C(O)-- | 777 | |||
29H | (1-morpholinyl)-CH2C(O)-- | 821 | |||
29I | (3-pyridinyl)-CH═CHC(O)-- | 829 | |||
29J | (1-morpholinyl)-(CH2)3C(O)-- | 877 | |||
29K | (4-methyl-1-piperazinyl)-(CH2)3C(O)-- | 903 | |||
29L | (1-piperidinyl)-(CH2)3C(O)-- | 837 | |||
29M | (4-methyl-1-piperazinyl)-CH2C(O)-- | 847 | |||
29N | (1-piperidinyl)-CH2C(O)-- | 817 | |||
29O | (4-phenyl-1-piperazinyl)-CH2C(O)-- | 971 | |||
29P | (1-morpholinyl)-(CH2)2C(O)-- | 849 | |||
29Q | (CH3)2C(NH2)C(O)-- | 737 | |||
29R | CH3CH(NH2)C(O)-- | 709 | |||
29S | 3-(1-morpholinyl methyl)C6H4C(O)--.HCl | + | +++ | 167-168 | |
29T | 4-(1-morpholinyl methyl)C6H4C(O)--.HCl | + | +++ | 165-167 | |
29U | 3-(EtNHCH2)--C6H4C(O)--.HCl | + | +++ | 124-126 | |
29V | 4-(EtNHCH2)--C6H4C(O)--.HCl | + | +++ | 134-136 | |
29W | 4-(2-HOCH2CH2NHCH2)--C6H4C(O)--.HCl | ++ | +++ | 169-170 | |
29X | 4-(4-methyl-1-piperazinyl methyl)- | ++ | +++ | 224-225 | |
C6H4C(O)--.2HCl | |||||
29Y | 3-(4-methyl-1-piperazinyl methyl)-C6H4(O)--.2HCl | ++ | +++ | 195-196 | |
The examples shown in Table 2t were prepared according to Scheme 34.
TABLE 2t | ||||||
Ex. No. | W | R22 = R23 | n | X, Y | Ki | mp, °C C. |
30A | C═O | benzyl | 1 | H, OH | + | 52-56 |
(±) | ||||||
30B | C═O | 4-(HOCH2)-benzyl | 1 | H, OH | + | 70-76 |
30C | C═O | 3-cyanobenzyl | 1 | H, OH | + | 56-65 |
30D | C═O | 4-hydroxybenzyl | 1 | H, OH | + | 78-85 |
30E | C═O | cyclopropyl methyl | 1 | H, OH | + | |
30F | C═O | 2-naphthylmethyl | 1 | H, OH | + | 59-66 |
30G | C═O | 6-hydroxyhexyl | 1 | H, OH | + | |
30H | SO2 | benzyl | 1 | H, OH | 123-125 | |
30I | SO2 | 2-naphthylmethyl | 1 | H, OH | ++ | 188.5-190 |
30J | SO2 | cyclopropyl methyl | 1 | H, OH | + | |
30K | SO2 | 4-hydroxymethyl | 1 | H, OH | + | |
30L | C═O | benzyl | 2 | H, OH | + | 134-136 |
30M | C═O | 2-naphthylmethyl | 2 | H, OH | + | 179-181 |
30N | C═O | 4-(HOCH2)-benzyl | 2 | H, OH | ++ | 72-75 |
30O | C═O | cyclopropyl methyl | 2 | H, OH | + | |
30P | C═O | 3-cyanobenzyl | 2 | H, OH | + | 142.5-144 |
30Q | SO2 | benzyl | 2 | H, OH | + | 118-120 |
30R | C═O | 3-(H2NC(═NOH)- | 2 | H, OH | +++ | |
benzyl | ||||||
30S | C═O | benzyl | 2 | ═O | + | |
30T | C═O | benzyl | 2 | ═NOH | + | |
30U | C═O | benzyl | 1 | H, OH | + | |
(R) | ||||||
30V | C═O | benzyl | 1 | H, OH | + | |
(S) | ||||||
The examples in Table 2u were prepared using the procedures outlined in Example 23f above. Compounds where R4=R7=4-fluorobenzyl were prepared from (2R, 2S,4S,4R)-2,5-bis(N-Cbzamino)-3,4-dimethoxyethoxymethoxy-1,6-di-(4-fluorophenyl)hexane. Further manipulations to X and Y were carried out using methods weln known to one of ordinary skill in organic chemistry.
TABLE 2u | |||||||
Mass | |||||||
Ex. | stereo | K1 | Spec | ||||
No. | 2, 3, 4, 5 | R22═R23 | R4═R7 | X, Y | (HPLC) | IC90 | (M + H) |
31A | RSSR | 3-carbomethoxy | 4-fluoro | OH, OH | ++ | +++ | 12.4 |
benzyl | benzyl | (M + NH4) | |||||
31B | RSSR | 4-carbomethoxy | 4-fluoro | OH, OH | ++ | +++ | 695.4 |
benzyl | benzyl | ||||||
31C | RSSR | 3-hydroxymethyl | 4-fluoro | OH, OH | +++ | +++ | 639.4 |
benzyl | benzyl | ||||||
31D | RSSR | 4-hydroxymethyl | 4-fluoro | OH, OH | +++ | +++ | 656.2 |
benzyl | benzyl | (M + NH4) | |||||
31E | RSSR | benzyl | 4-fluoro | OH, H | ++ | +++ | 527.2 |
benzyl | |||||||
31F | RSRR | benzyl | benzyl | epoxy | + | ++/+ | 525.2 |
TABLE 2u | |||||||
Mass | |||||||
Ex. | stereo | K1 | Spec | ||||
No. | 2, 3, 4, 5 | R22═R23 | R4═R7 | X, Y | (HPLC) | IC90 | (M + H) |
31A | RSSR | 3-carbomethoxy | 4-fluoro | OH, OH | ++ | +++ | 12.4 |
benzyl | benzyl | (M + NH4) | |||||
31B | RSSR | 4-carbomethoxy | 4-fluoro | OH, OH | ++ | +++ | 695.4 |
benzyl | benzyl | ||||||
31C | RSSR | 3-hydroxymethyl | 4-fluoro | OH, OH | +++ | +++ | 639.4 |
benzyl | benzyl | ||||||
31D | RSSR | 4-hydroxymethyl | 4-fluoro | OH, OH | +++ | +++ | 656.2 |
benzyl | benzyl | (M + NH4) | |||||
31E | RSSR | benzyl | 4-fluoro | OH, H | ++ | +++ | 527.2 |
benzyl | |||||||
31F | RSRR | benzyl | benzyl | epoxy | + | ++/+ | 525.2 |
TABLE 14 | |||
Ex. | |||
No. | R4 | R7 | R22 |
5456 | benzyl | benzyl | 2-methallyl |
5457 | 1-pyrolylmethyl | 1-pyrolylmethyl | 4-methylpentyl |
5458 | 1-pyrazolylmethyl | 1-pyrazolylmethyl | 3-methallyl |
5459 | 1-imidazolylmethyl | 1-imidazolylmethyl | 3-methylbutyl |
5460 | 1-indolylmethyl | 1-indolylmethyl | 3-methylpentyl |
5461 | 2-pyridylmethyl | 2-pyridylmethyl | 3-pentyl |
5462 | 3-pyridylmethyl | 3-pyridylmethyl | 4-methylpentyl |
5463 | 4-pyridylmethyl | 4-pyridylmethyl | 3,3-dimethallyl |
5464 | cyclohexylamethyl | cyclohexylamethyl | 3,3-dimethylbutyl |
5465 | 2-thiophenylmethyl | 2-thiophenylmethyl | allyl |
5466 | (3,4-methylenedioxyphenyl)methyl | (3,4-methylenedioxyphenyl)methyl | cyclobutylmethyl |
5467 | 2-thienylmethyl | 2-thienylmethyl | cyclopropylmethyl |
5468 | 4-biphenylmethyl | 4-biphenylmethyl | isobutyl |
5469 | 2-thiomethylethyl | 2-thiomethylethyl | n-butyl |
5470 | p-hydroxyphenylmethyl | p-hydroxyphenylmethyl | n-pentyl |
5471 | p-nitrophenylmethyl | p-nitrophenylmethyl | propyl |
5472 | benzyl | benzyl | 2-methallyl |
5473 | 1-pyrolylmethyl | 1-pyrolylmethyl | 4-methylpentyl |
5474 | 1-pyrazolylmethyl | 1-pyrazolylmethyl | 3-methallyl |
5475 | 1-imidazolylmethyl | 1-imidazolylmethyl | 3-methylbutyl |
5476 | 1-indolylmethyl | 1-indolylmethyl | 3-methylpentyl |
5477 | 2-pyridylmethyl | 2-pyridylmethyl | 3-pentyl |
5478 | 3-pyridylmethyl | 3-pyridylmethyl | 4-methylpentyl |
5479 | 4-pyridylmethyl | 4-pyridylmethyl | 3,3-dimethallyl |
5480 | cyclohexylamethyl | cyclohexylamethyl | 3,3-dimethylbutyl |
5481 | 2-thiophenylmethyl | 2-thiophenylmethyl | allyl |
5482 | (3,4-methylenedioxyphenyl)methyl | (3,4-methylenedioxyphenyl)methyl | cyclobutylmethyl |
5483 | 2-thienylmethyl | 2-thienylmethyl | cyclopropylmethyl |
5484 | 4-biphenylmethyl | 4-biphenylmethyl | isobutyl |
5485 | 2-thiomethylethyl | 2-thiomethylethyl | n-butyl |
5486 | p-hydroxyphenylmethyl | p-hydroxyphenylmethyl | n-pentyl |
5487 | p-nitrophenylmethyl | p-nitrophenylmethyl | propyl |
5488 | benzyl | p-nitrophenylmethyl | 2-methallyl |
5489 | 1-pyrolylmethyl | benzyl | 4-methylpentyl |
5490 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
5491 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-methylbutyl |
5492 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methylpentyl |
5493 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl |
5494 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylpentyl |
5495 | 4-pyridylmethyl | 3-pyridylmethyl | 3,3-dimethallyl |
5496 | cyclohexylamethyl | 4-pyridylmethyl | 3,3-dimethylbutyl |
5497 | 2-thiophenylmethyl | cyclohexylamethyl | allyl |
5498 | (3,4-methylenedioxyphenyl)methyl | 2-thiophenylmethyl | cyclobutylmethyl |
5499 | 2-thienylmethyl | (3,4-methylenedioxyphenyl)methyl | cyclopropylmethyl |
5500 | 4-biphenylmethyl | 2-thienylmethyl | isobutyl |
5501 | 2-thiomethylethyl | 4-biphenylmethyl | n-butyl |
5502 | p-hydroxyphenylmethyl | 2-thiomethylethyl | n-pentyl |
5503 | p-nitrophenylmethyl | p-hydroxyphenylmethyl | propyl |
5504 | benzyl | p-nitrophenylmethyl | 2-methallyl |
5505 | 1-pyrolylmethyl | benzyl | 4-methylpentyl |
5506 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
5507 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-methylbutyl |
5508 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methylpentyl |
5509 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl |
5510 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylpentyl |
5511 | 4-pyridylmethyl | 3-pyridylmethyl | 3,3-dimethallyl |
5512 | cyclohexylamethyl | 4-pyridylmethyl | 3,3-dimethylbutyl |
5513 | 2-thiophenylmethyl | cyclohexylamethyl | allyl |
5514 | (3,4-methylenedioxyphenyl)methyl | 2-thiophenylmethyl | cyclobutylmethyl |
5515 | 2-thienylmethyl | (3,4-methylenedioxyphenyl)methyl | cyclopropylmethyl |
5516 | 4-biphenylmethyl | 2-thienylmethyl | isobutyl |
5517 | 2-thiomethylethyl | 4-biphenylmethyl | n-butyl |
5518 | p-hydroxyphenylmethyl | 2-thiomethylethyl | n-pentyl |
5519 | p-nitrophenylmethyl | p-hydroxyphenylmethyl | propyl |
5520 | benzyl | p-nitrophenylmethyl | 2-methallyl |
5521 | 1-pyrolylmethyl | benzyl | 4-methylpentyl |
5522 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
5523 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-methylbutyl |
5524 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methylpentyl |
5525 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl |
5526 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylpentyl |
5527 | 4-pyridylmethyl | 3-pyridylmethyl | 3,3-dimethallyl |
5528 | cyclohexylamethyl | 4-pyridylmethyl | 3,3-dimethylbutyl |
5529 | 2-thiophenylmethyl | cyclohexylamethyl | allyl |
5530 | (3,4-methylenedioxyphenyl)methyl | 2-thiophenylmethyl | cyclobutylmethyl |
5531 | 2-thienylmethyl | (3,4-methylenedioxyphenyl)methyl | cyclopropylmethyl |
5532 | 4-biphenylmethyl | 2-thienylmethyl | isobutyl |
5533 | 2-thiomethylethyl | 4-biphenylmethyl | n-butyl |
5534 | p-hydroxyphenylmethyl | 2-thiomethylethyl | n-pentyl |
5535 | p-nitrophenylmethyl | p-hydroxyphenylmethyl | propyl |
TABLE 15 | |||
Ex. | |||
No. | R4 | R7 | R22 |
5536 | benzyl | benzyl | 2-methallyl |
5537 | 1-pyrolylmethyl | 1-pyrolylmethyl | 4-methylpentyl |
5538 | 1-pyrazolylmethyl | 1-pyrazolylmethyl | 3-methallyl |
5539 | 1-imidazolylmethyl | 1-imidazolylmethyl | 3-methylbutyl |
5540 | 1-indolylmethyl | 1-indolylmethyl | 3-methylpentyl |
5541 | 2-pyridylmethyl | 2-pyridylmethyl | 3-pentyl |
5542 | 3-pyridylmethyl | 3-pyridylmethyl | 4-methylpentyl |
5543 | 4-pyridylmethyl | 4-pyridylmethyl | 3,3-dimethallyl |
5544 | cyclohexylamethyl | cyclohexylamethyl | 3,3-dimethylbutyl |
5545 | 2-thiophenylmethyl | 2-thiophenylmethyl | allyl |
5546 | (3,4-methylenedioxyphenyl)methyl | (3,4-methylenedioxyphenyl)methyl | cyclobutylmethyl |
5547 | 2-thienylmethyl | 2-thienylmethyl | cyclopropylmethyl |
5548 | 4-biphenylmethyl | 4-biphenylmethyl | isobutyl |
5549 | 2-thiomethylethyl | 2-thiomethylethyl | n-butyl |
5550 | p-hydroxyphenylmethyl | p-hydroxyphenylmethyl | n-pentyl |
5551 | p-nitrophenylmethyl | p-nitrophenylmethyl | propyl |
5552 | benzyl | benzyl | 2-methallyl |
5553 | 1-pyrolylmethyl | 1-pyrolylmethyl | 4-methylpentyl |
5554 | 1-pyrazolylmethyl | 1-pyrazolylmethyl | 3-methallyl |
5555 | 1-imidazolylmethyl | 1-imidazolylmethyl | 3-methylbutyl |
5556 | 1-indolylmethyl | 1-indolylmethyl | 3-methylpentyl |
5557 | 2-pyridylmethyl | 2-pyridylmethyl | 3-pentyl |
5558 | 3-pyridylmethyl | 3-pyridylmethyl | 4-methylpentyl |
5559 | 4-pyridylmethyl | 4-pyridylmethyl | 3,3-dimethallyl |
5560 | cyclohexylamethyl | cyclohexylamethyl | 3,3-dimethylbutyl |
5561 | 2-thiophenylmethyl | 2-thiophenylmethyl | allyl |
5562 | (3,4-methylenedioxyphenyl)methyl | (3,4-methylenedioxyphenyl)methyl | cyclobutylmethyl |
5563 | 2-thienylmethyl | 2-thienylmethyl | cyclopropylmethyl |
5564 | 4-biphenylmethyl | 4-biphenylmethyl | isobutyl |
5565 | 2-thiomethylethyl | 2-thiomethylethyl | n-butyl |
5566 | p-hydroxyphenylmethyl | p-hydroxyphenylmethyl | n-pentyl |
5567 | p-nitrophenylmethyl | p-nitrophenylmethyl | propyl |
5568 | benzyl | p-nitrophenylmethyl | 2-methallyl |
5569 | 1-pyrolylmethyl | benzyl | 4-methylpentyl |
5570 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
5571 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-methylbutyl |
5572 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methylpentyl |
5573 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl |
5574 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylpentyl |
5575 | 4-pyridylmethyl | 3-pyridylmethyl | 3,3-dimethallyl |
5576 | cyclohexylamethyl | 4-pyridylmethyl | 3,3-dimethylbutyl |
557 | 2-thiophenylmethyl | cyclohexylamethyl | allyl |
5578 | (3,4-methylenedioxyphenyl)methyl | 2-thiophenylmethyl | cyclobutylmethyl |
5579 | 2-thienylmethyl | (3,4-methylenedioxyphenyl)methyl | cyclopropylmethyl |
5580 | 4-biphenylmethyl | 2-thienylmethyl | isobutyl |
5581 | 2-thiomethylethyl | 4-biphenylmethyl | n-butyl |
5582 | p-hydroxyphenylmethyl | 2-thiomethylethyl | n-pentyl |
5583 | p-nitrophenylmethyl | p-hydroxyphenylmethyl | propyl |
5584 | benzyl | p-nitrophenylmethyl | 2-methallyl |
5585 | 1-pyrolylmethyl | benzyl | 4-methylpentyl |
5586 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
5587 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-methylbutyl |
5588 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methylpentyl |
5589 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl |
5590 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylpentyl |
5591 | 4-pyridylmethyl | 3-pyridylmethyl | 3,3-dimethallyl |
5592 | cyclohexylamethyl | 4-pyridylmethyl | 3,3-dimethylbutyl |
5593 | 2-thiophenylmethyl | cyclohexylamethyl | allyl |
5594 | (3,4-methylenedioxyphenyl)methyl | 2-thiophenylmethyl | cyclobutylmethyl |
5595 | 2-thienylmethyl | (3,4-methylenedioxyphenyl)methyl | cyclopropylmethyl |
5596 | 4-biphenylmethyl | 2-thienylmethyl | isobutyl |
5597 | 2-thiomethylethyl | 4-biphenylmethyl | n-butyl |
5598 | p-hydroxyphenylmethyl | 2-thiomethylethyl | n-pentyl |
5599 | p-nitrophenylmethyl | p-hydroxyphenylmethyl | propyl |
5600 | benzyl | p-nitrophenylmethyl | 2-methallyl |
5601 | 1-pyrolylmethyl | benzyl | 4-methylpentyl |
5602 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
5603 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-methylbutyl |
5604 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methylpentyl |
5605 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl |
5606 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylpentyl |
5607 | 4-pyridylmethyl | 3-pyridylmethyl | 3,3-dimethallyl |
5608 | cyclohexylamethyl | 4-pyridylmethyl | 3,3-dimethylbutyl |
5609 | 2-thiophenylmethyl | cyclohexylamethyl | allyl |
5610 | (3,4-methylenedioxyphenyl)methyl | 2-thiophenylmethyl | cyclobutylmethyl |
5611 | 2-thienylmethyl | (3,4-methylenedioxyphenyl)methyl | cyclopropylmethyl |
5612 | 4-biphenylmethyl | 2-thienylmethyl | isobutyl |
5613 | 2-thiomethylethyl | 4-biphenylmethyl | n-butyl |
5614 | p-hydroxyphenylmethyl | 2-thiomethylethyl | n-pentyl |
5615 | p-nitrophenylmethyl | p-hydroxyphenylmethyl | propyl |
TABLE 16 | ||
Example | ||
Number | ||
5616 | ||
5617 | ||
5618 | ||
5619 | ||
TABLE 17 | |||
Ex. No. | R22 | R23 | R4═R7 |
5620 | (m-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | benzyl |
5621 | (p-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | benzyl |
5622 | (m-hydroxy)benzyl | (m-tetrazolyl)benzyl | benzyl |
5623 | (p-hydroxy)benzyl | (m-tetrazolyl)benzyl | benzyl |
5624 | (m-carboxamido)benzyl | (m-tetrazolyl)benzyl | benzyl |
5625 | (m-(N-methyl | (m-tetrazolyl)benzyl | benzyl |
carboxyamido))benzyl | |||
5626 | (m-hydroxymethyl)benzyl | (m-imidazolyl)benzyl | benzyl |
5627 | (p-hydroxymethyl)benzyl | (m-imidazolyl)benzyl | benzyl |
5628 | (m-hydroxy)benzyl | (m-imidazolyl)benzyl | benzyl |
5629 | (p-hydroxy)benzyl | (m-imidazolyl)benzyl | benzyl |
5630 | (m-carboxamido)benzyl | (m-imidazolyl)benzyl | benzyl |
5631 | (m-(N-methyl | (m-imidazolyl)benzyl | benzyl |
carboxyamido))benzyl | |||
5632 | (m-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)benzyl |
5633 | (p-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)benzyl |
5634 | (m-hydroxy)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)benzyl |
5635 | (p-hydroxy)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)benzyl |
5636 | (m-carboxamido)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)benzyl |
5637 | (m-(N-methyl | (m-tetrazolyl)benzyl | (p-fluoro)benzyl |
carboxyamido))benzyl | |||
5638 | (m-hydroxymethyl)benzyl | (m-imidazolyl)benzyl | (p-fluoro)benzyl |
5639 | (p-hydroxymethyl)benzyl | (m-imidazolyl)benzyl | (p-fluoro)benzyl |
5640 | (m-hydroxy)benzyl | (m-imidazolyl)benzyl | (p-fluoro)benzyl |
5641 | (p-hydroxy)benzyl | (m-imidazolyl)benzyl | (p-fluoro)benzyl |
5642 | (m-carboxamido)benzyl | (m-imidazolyl)benzyl | (p-fluoro)benzyl |
5643 | (m-(N-methyl | (m-imidazolyl)benzyl | (p-fluoro)benzyl |
carboxyamido))benzyl | |||
5644 | (m-carboxy)benzyl | (m-hydroxy)benzyl | benzyl |
5645 | (m-carboxy)benzyl | (p-hydroxy)benzyl | benzyl |
5646 | (m-carboxy)benzyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
5647 | (m-carboxy)benzyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
5648 | (m-carboxy)benzyl | (m-carboxamido) | benzyl |
benzyl | |||
5649 | (m-carboxy)benzyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
5650 | (m-carboxy)benzyl | (m-acetyl)benzyl | benzyl |
5651 | (m-carboxy)benzyl | (m-glycolyl)benzyl | benzyl |
5652 | (m-carboxy)benzyl | (m-sulfonamido) | benzyl |
benzyl | |||
5653 | (m-carboxy)benzyl | (m-(N-methylamino) | benzyl |
benzyl | |||
5654 | (m-carboxamido)benzyl | (m-hydroxy)benzyl | benzyl |
5655 | (m-carboxamido)benzyl | (p-hydroxy)benzyl | benzyl |
5656 | (m-carboxamido)benzyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
5657 | (m-carboxamido)benzyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
5658 | (m-carboxamido)benzyl | (m-carboxamido) | benzyl |
benzyl | |||
5659 | (m-carboxamido)benzyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
5660 | (m-carboxamido)benzyl | (m-acetyl)benzyl | benzyl |
5661 | (m-carboxamido)benzyl | (m-glycolyl)benzyl | benzyl |
5662 | (m-carboxamido)benzyl | (m-sulfonamido) | benzyl |
benzyl | |||
5663 | (m-carboxamido)benzyl | (m-(N-methylamino) | benzyl |
benzyl | |||
5664 | (m-(N-methyl | (m-hydroxy)benzyl | benzyl |
carboxamido))benzyl | |||
5665 | (m-(N-methyl | (p-hydroxy)benzyl | benzyl |
carboxamido))benzyl | |||
5666 | (m-(N-methyl | (m-hydroxymethyl) | benzyl |
carboxamido))benzyl | benzyl | ||
5667 | (m-(N-methyl | (p-hydroxymethyl) | benzyl |
carboxamido))benzyl | benzyl | ||
5668 | (m-(N-methyl | (m-carboxamido) | benzyl |
carboxamido))benzyl | benzyl | ||
5669 | (m-(N-methyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | carboxamido))benzyl | ||
5670 | (m-(N-methyl | (m-acetyl)benzyl | benzyl |
carboxamido))benzyl | |||
5671 | (m-(N-methyl | (m-glycolyl)benzyl | benzyl |
carboxamido))benzyl | |||
5672 | (m-(N-methyl | (m-sulfonamido) | benzyl |
carboxamido))benzyl | benzyl | ||
5673 | (m-(N-methyl | (m-(N-methylamino) | benzyl |
carboxamido))benzyl | benzyl | ||
5674 | (m-sulfonamido)benzyl | (m-hydroxy)benzyl | benzyl |
5675 | (m-sulfonamido)benzyl | (p-hydroxy)benzyl | benzyl |
5676 | (m-sulfonamido)benzyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
5677 | (m-sulfonamido)benzyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
5678 | (m-sulfonamido)benzyl | (m-carboxamido) | benzyl |
benzyl | |||
5679 | (m-sulfonamido)benzyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
5680 | (m-sulfonamido)benzyl | (m-acetyl)benzyl | benzyl |
5681 | (m-sulfonamido)benzyl | (m-glycolyl)benzyl | benzyl |
5682 | (m-sulfonamido)benzyl | (m-sulfonamido) | benzyl |
benzyl | |||
5683 | (m-sulfonamido)benzyl | (m-(N-methylamino) | benzyl |
benzyl | |||
5684 | m-(N-ethylcarboxamido) | (m-hydroxy)benzyl | benzyl |
benzyl | |||
5685 | m-(N-ethylcarboxamido) | (p-hydroxy)benzyl | benzyl |
benzyl | |||
5686 | m-(N-ethylcarboxamido) | (m-hydroxymethyl) | benzyl |
benzyl | benzyl | ||
5687 | m-(N-ethylcarboxamido) | (p-hydroxymethyl) | benzyl |
benzyl | benzyl | ||
5688 | m-(N-ethylcarboxamido) | (m-carboxamido) | benzyl |
benzyl | benzyl | ||
5689 | m-(N-ethylcarboxamido) | (m-(N-methyl | benzyl |
benzyl | carboxamido))benzyl | ||
5690 | m-(N-ethylcarboxamido) | (m-acetyl)benzyl | benzyl |
benzyl | |||
5691 | m-(N-ethylcarboxamido) | (m-glycolyl)benzyl | benzyl |
benzyl | |||
5692 | m-(N-ethylcarboxamido) | (m-sulfonamido) | benzyl |
benzyl | benzyl | ||
5693 | m-(N-ethylcarboxamido) | (m-(N-methylamino) | benzyl |
benzyl | benzyl | ||
5694 | 3-pyridylmethyl | (m-hydroxy)benzyl | benzyl |
5695 | 3-pyridylmethyl | (p-hydroxy)benzyl | benzyl |
5696 | 3-pyridylmethyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
5697 | 3-pyridylmethyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
5698 | 3-pyridylmethyl | (m-carboxamido) | benzyl |
benzyl | |||
5699 | 3-pyridylmethyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
5700 | 3-pyridylmethyl | (m-acetyl)benzyl | benzyl |
5701 | 3-pyridylmethyl | (m-glycolyl)benzyl | benzyl |
5702 | 3-pyridylmethyl | (m-sulfonamido) | benzyl |
benzyl | |||
5703 | 3-pyridylmethyl | (m-(N-methylamino) | benzyl |
benzyl | |||
5704 | (m-carboxy)benzyl | (m-hydroxy)benzyl | (p-fluoro)benzyl |
5705 | (m-carboxy)benzyl | (p-hydroxy)benzyl | (p-fluoro)benzyl |
5706 | (m-carboxy)benzyl | (m-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5707 | (m-carboxy)benzyl | (p-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5708 | (m-carboxy)benzyl | (m-carboxamido) | (p-fluoro)benzyl |
benzyl | |||
5709 | (m-carboxy)benzyl | (m-(N-methyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5710 | (m-carboxy)benzyl | (m-acetyl)benzyl | (p-fluoro)benzyl |
5711 | (m-carboxy)benzyl | (m-glycolyl)benzyl | (p-fluoro)benzyl |
5712 | (m-carboxy)benzyl | (m-sulfonamido) | (p-fluoro)benzyl |
benzyl | |||
5713 | (m-carboxy)benzyl | (m-(N-methylamino) | (p-fluoro)benzyl |
benzyl | |||
5714 | (m-carboxamido)benzyl | (m-hydroxy)benzyl | (p-fluoro)benzyl |
5715 | (m-carboxamido)benzyl | (p-hydroxy)benzyl | (p-fluoro)benzyl |
5716 | (m-carboxamido)benzyl | (m-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5717 | (m-carboxamido)benzyl | (p-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5718 | (m-carboxamido)benzyl | (m-carboxamido) | (p-fluoro)benzyl |
benzyl | |||
5719 | (m-carboxamido)benzyl | (m-(N-methyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5720 | (m-carboxamido)benzyl | (m-acetyl)benzyl | (p-fluoro)benzyl |
5721 | (m-carboxamido)benzyl | (m-glycolyl)benzyl | (p-fluoro)benzyl |
5722 | (m-carboxamido)benzyl | (m-sulfonamido) | (p-fluoro)benzyl |
benzyl | |||
5723 | (m-carboxamido)benzyl | (m-(N-methylamino) | (p-fluoro)benzyl |
benzyl | |||
5724 | (m-(N-methyl | (m-hydroxy)benzyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5725 | (m-(N-methyl | (p-hydroxy)benzyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5726 | (m-(N-methyl | (m-hydroxymethyl) | (p-fluoro)benzyl |
carboxamido))benzyl | benzyl | ||
5727 | (m-(N-methyl | (p-hydroxymethyl) | (p-fluoro)benzyl |
carboxamido))benzyl | benzyl | ||
5728 | (m-(N-methyl | (m-carboxamido) | (p-fluoro)benzyl |
carboxamido))benzyl | benzyl | ||
5729 | (m-(N-methyl | (m-(N-methyl | (p-fluoro)benzyl |
carboxamido))benzyl | carboxamido))benzyl | ||
5730 | (m-(N-methyl | (m-acetyl)benzyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5731 | (m-(N-methyl | (m-glycolyl)benzyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5732 | (m-(N-methyl | (m-sulfonamido) | (p-fluoro)benzyl |
carboxamido))benzyl | benzyl | ||
5733 | (m-(N-methyl | (m-(N-methylamino) | (p-fluoro)benzyl |
carboxamido))benzyl | benzyl | ||
5734 | (m-sulfonamido)benzyl | (m-hydroxy)benzyl | (p-fluoro)benzyl |
5735 | (m-sulfonamido)benzyl | (p-hydroxy)benzyl | (p-fluoro)benzyl |
5736 | (m-sulfonamido)benzyl | (m-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5737 | (m-sulfonamido)benzyl | (p-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5738 | (m-sulfonamido)benzyl | (m-carboxamido) | (p-fluoro)benzyl |
benzyl | |||
5739 | (m-sulfonamido)benzyl | (m-(N-methyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5740 | (m-sulfonamido)benzyl | (m-acetyl)benzyl | (p-fluoro)benzyl |
5741 | (m-sulfonamido)benzyl | (m-glycolyl)benzyl | (p-fluoro)benzyl |
5742 | (m-sulfonamido)benzyl | (m-sulfonamido) | (p-fluoro)benzyl |
benzyl | |||
5743 | (m-sulfonamido)benzyl | (m-(N-methylamino) | (p-fluoro)benzyl |
benzyl | |||
5744 | m-(N-ethylcarboxamido) | (m-hydroxy)benzyl | (p-fluoro)benzyl |
benzyl | |||
5745 | m-(N-ethylcarboxamido) | (p-hydroxy)benzyl | (p-fluoro)benzyl |
benzyl | |||
5746 | m-(N-ethylcarboxamido) | (m-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | benzyl | ||
5747 | m-(N-ethylcarboxamido) | (p-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | benzyl | ||
5748 | m-(N-ethylcarboxamido) | (m-carboxamido) | (p-fluoro)benzyl |
benzyl | benzyl | ||
5749 | m-(N-ethylcarboxamido) | (m-(N-methyl | (p-fluoro)benzyl |
benzyl | carboxamido))benzyl | ||
5750 | m-(N-ethylcarboxamido) | (m-acetyl)benzyl | (p-fluoro)benzyl |
benzyl | |||
5751 | m-(N-ethylcarboxamido) | (m-glycolyl)benzyl | (p-fluoro)benzyl |
benzyl | |||
5752 | m-(N-ethylcarboxamido) | (m-sulfonamido) | (p-fluoro)benzyl |
benzyl | benzyl | ||
5753 | m-(N-ethylcarboxamido) | (m-(N-methylamino) | (p-fluoro)benzyl |
benzyl | benzyl | ||
5754 | 3-pyridylmethyl | (m-hydroxy)benzyl | (p-fluoro)benzyl |
5755 | 3-pyridylmethyl | (p-hydroxy)benzyl | (p-fluoro)benzyl |
5756 | 3-pyridylmethyl | (m-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5757 | 3-pyridylmethyl | (p-hydroxymethyl) | (p-fluoro)benzyl |
benzyl | |||
5758 | 3-pyridylmethyl | (m-carboxamido) | (p-fluoro)benzyl |
benzyl | |||
5759 | 3-pyridylmethyl | (m-(N-methyl | (p-fluoro)benzyl |
carboxamido))benzyl | |||
5760 | 3-pyridylmethyl | (m-acetyl)benzyl | (p-fluoro)benzyl |
5761 | 3-pyridylmethyl | (m-glycolyl)benzyl | (p-fluoro)benzyl |
5762 | 3-pyridylmethyl | (m-sulfonamido) | (p-fluoro)benzyl |
benzyl | |||
5763 | 3-pyridylmethyl | (m-(N-methylamino) | (p-fluoro)benzyl |
benzyl | |||
TABLE 18 | ||
Example | ||
Number | R4 = R7 | R22 = R23 |
5764 | benzyl | allyl |
5765 | 1-pyrolylmethyl | allyl |
5766 | 1-pyrazolylmethyl | allyl |
5767 | 1-imidazolylmethyl | allyl |
5768 | 1-indolylmethyl | allyl |
5769 | 1-triazolylmethyl | allyl |
5770 | 1-tetrazolylmethyl | allyl |
5771 | 2-pyridylmethyl | allyl |
5772 | 3-pyridylmethyl | allyl |
5773 | 4-pyridylmethyl | allyl |
5774 | cyclohexylmethyl | allyl |
5775 | 2-naphthylmethyl | allyl |
5776 | 3-naphthylmethyl | allyl |
5777 | 2-thiophenylmethyl | allyl |
5778 | 4-(1-methyl)piperidinyl- | allyl |
methyl | ||
5779 | "(3,4- | allyl |
methylenedioxyphenyl)methyl" | ||
5780 | 2-thienylmethyl | allyl |
5781 | 4-biphenylmethyl | allyl |
5782 | pyrimidinylmethyl | allyl |
5783 | 2-benzothiazolylmethyl | allyl |
5784 | 2-benzothiophenylmethyl | allyl |
5785 | 2-thiomethylethyl | allyl |
5786 | 2-thiomethylmethyl | allyl |
5787 | 2-methylpropyl | allyl |
5788 | 2-methylbutyl | allyl |
5789 | 3-methylbutyl | allyl |
5790 | cyclopropylmethyl | allyl |
5791 | cyclobutylmethyl | allyl |
5792 | cyclopentylmethyl | allyl |
5793 | p-hydroxyphenylmethyl | allyl |
5794 | p-nitrophenylmethyl | allyl |
5795 | p-aminophenylmethyl | allyl |
5796 | "4-(N,N- | allyl |
dimethylamino)phenylmethyl" | ||
5797 | benzyl | propyl |
5798 | 1-pyrolylmethyl | propyl |
5799 | 1-pyrazolylmethyl | propyl |
5800 | 1-imidazolylmethyl | propyl |
5801 | 1-indolylmethyl | propyl |
5802 | 1-triazolylmethyl | propyl |
5803 | 1-tetrazolylmethyl | propyl |
5804 | 2-pyridylmethyl | propyl |
5805 | 3-pyridylmethyl | propyl |
5806 | 4-pyridylmethyl | propyl |
5807 | cyclohexylmethyl | propyl |
5808 | 2-naphthylmethyl | propyl |
5809 | 3-naphthylmethyl | propyl |
5810 | 2-thiophenylmethyl | propyl |
5811 | 4-(1-methyl)piperidinyl- | propyl |
methyl | ||
5812 | "(3,4- | propyl |
methylenedioxyphenyl)methyl" | ||
5813 | 2-thienylmethyl | propyl |
5814 | 4-biphenylmethyl | propyl |
5815 | pyrimidinylmethyl | propyl |
5816 | 2-benzothiazolylmethyl | propyl |
5817 | 2-benzothiophenylmethyl | propyl |
5818 | 2-thiomethylethyl | propyl |
5819 | 2-thiomethylmethyl | propyl |
5820 | 2-methylpropyl | propyl |
5821 | 2-methylbutyl | propyl |
5822 | 3-methylbutyl | propyl |
5823 | cyclopropylmethyl | propyl |
5824 | cyclobutylmethyl | propyl |
5825 | cyclopentylmethyl | propyl |
5826 | p-hydroxyphenylmethyl | propyl |
5827 | p-nitrophenylmethyl | propyl |
5828 | p-aminophenylmethyl | propyl |
5829 | "4-(N,N- | propyl |
dimethylamino)phenylmethyl" | ||
5830 | benzyl | n-butyl |
5831 | 1-pyrolylmethyl | n-butyl |
5832 | 1-pyrazolylmethyl | n-butyl |
5833 | 1-imidazolylmethyl | n-butyl |
5834 | 1-indolylmethyl | n-butyl |
5835 | 1-triazolylmethyl | n-butyl |
5836 | 1-tetrazolylmethyl | n-butyl |
5837 | 2-pyridylmethyl | n-butyl |
5838 | 3-pyridylmethyl | n-butyl |
5839 | 4-pyridylmethyl | n-butyl |
5840 | cyclohexylmethyl | n-butyl |
5841 | 2-naphthylmethyl | n-butyl |
5842 | 3-naphthylmethyl | n-butyl |
5843 | 2-thiophenylmethyl | n-butyl |
5844 | 4-(1-methyl)piperidinyl- | n-butyl |
methyl | ||
5845 | "(3,4- | n-butyl |
methylenedioxyphenyl)methyl" | ||
5846 | 2-thienylmethyl | n-butyl |
5847 | 4-biphenylmethyl | n-butyl |
5848 | pyrimidinylmethyl | n-butyl |
5849 | 2-benzothiazolylmethyl | n-butyl |
5850 | 2-benzothiophenylmethyl | n-butyl |
5851 | 2-thiomethylethyl | n-butyl |
5852 | 2-thiomethylmethyl | n-butyl |
5853 | 2-methylpropyl | n-butyl |
5854 | 2-methylbutyl | n-butyl |
5855 | 3-methylbutyl | n-butyl |
5856 | cyclopropylmethyl | n-butyl |
5857 | cyclobutylmethyl | n-butyl |
5858 | cyclopentylmethyl | n-butyl |
5859 | p-hydroxyphenylmethyl | n-butyl |
5860 | p-nitrophenylmethyl | n-butyl |
5861 | p-aminophenylmethyl | n-butyl |
5862 | "4-(N,N- | n-butyl |
dimethylamino)phenylmethyl" | ||
5929 | benzyl | "3,3-dimethyallyl" |
5930 | 1-pyrolylmethyl | "3,3-dimethyallyl" |
5931 | 1-pyrazolylmethyl | "3,3-dimethyallyl" |
5932 | 1-imidazolylmethyl | "3,3-dimethyallyl" |
5933 | 1-indolylmethyl | "3,3-dimethyallyl" |
5934 | 1-triazolylmethyl | "3,3-dimethyallyl" |
5935 | 1-tetrazolylmethyl | "3,3-dimethyallyl" |
5936 | 2-pyridylmethyl | "3,3-dimethyallyl" |
5937 | 3-pyridylmethyl | "3,3-dimethyallyl" |
5938 | 4-pyridylmethyl | "3,3-dimethyallyl" |
5939 | cyclohexylmethyl | "3,3-dimethyallyl" |
5940 | 2-naphthylmethyl | "3,3-dimethyallyl" |
5941 | 3-naphthylmethyl | "3,3-dimethyallyl" |
5942 | 2-thiophenylmethyl | "3,3-dimethyallyl" |
5943 | 4-(1-methyl)piperidinyl- | "3,3-dimethyallyl" |
methyl | ||
5944 | "(3,4- | "3,3-dimethyallyl" |
methylenedioxyphenyl)methyl" | ||
5945 | 2-thienylmethyl | "3,3-dimethyallyl" |
5946 | 4-biphenylmethyl | "3,3-dimethyallyl" |
5947 | pyrimidinylmethyl | "3,3-dimethyallyl" |
5948 | 2-benzothiazolylmethyl | "3,3-dimethyallyl" |
5949 | 2-benzothiophenylmethyl | "3,3-dimethyallyl" |
5950 | 2-thiomethylethyl | "3,3-dimethyallyl" |
5951 | 2-thiomethylmethyl | "3,3-dimethyallyl" |
5952 | 2-methylpropyl | "3,3-dimethyallyl" |
5953 | 2-methylbutyl | "3,3-dimethyallyl" |
5954 | 3-methylbutyl | "3,3-dimethyallyl" |
5955 | cyclopropylmethyl | "3,3-dimethyallyl" |
5956 | cyclobutylmethyl | "3,3-dimethyallyl" |
5957 | cyclopentylmethyl | "3,3-dimethyallyl" |
5958 | p-hydroxyphenylmethyl | "3,3-dimethyallyl" |
5959 | p-nitrophenylmethyl | "3,3-dimethyallyl" |
5960 | p-aminophenylmethyl | "3,3-dimethyallyl" |
5961 | "4-(N,N- | "3,3-dimethyallyl" |
dimethylamino)phenylmethyl" | ||
5962 | benzyl | 3-methallyl |
5963 | 1-pyrolylmethyl | 3-methallyl |
5964 | 1-pyrazolylmethyl | 3-methallyl |
5965 | 1-imidazolylmethyl | 3-methallyl |
5966 | 1-indolylmethyl | 3-methallyl |
5967 | 1-triazolylmethyl | 3-methallyl |
5968 | 1-tetrazolylmethyl | 3-methallyl |
5969 | 2-pyridylmethyl | 3-methallyl |
5970 | 3-pyridylmethyl | 3-methallyl |
5971 | 4-pyridylmethyl | 3-methallyl |
5972 | cyclohexylmethyl | 3-methallyl |
5973 | 2-naphthylmethyl | 3-methallyl |
5974 | 3-naphthylmethyl | 3-methallyl |
5975 | 2-thiophenylmethyl | 3-methallyl |
5976 | 4-(1-methyl)piperidinyl- | 3-methallyl |
methyl | ||
5977 | "(3,4- | 3-methallyl |
methylenedioxyphenyl)methyl" | ||
5978 | 2-thienylmethyl | 3-methallyl |
5979 | 4-biphenylmethyl | 3-methallyl |
5980 | pyrimidinylmethyl | 3-methallyl |
5981 | 2-benzothiazolylmethyl | 3-methallyl |
5982 | 2-benzothiophenylmethyl | 3-methallyl |
5983 | 2-thiomethylethyl | 3-methallyl |
5984 | 2-thiomethylmethyl | 3-methallyl |
5985 | 2-methylpropyl | 3-methallyl |
5986 | 2-methylbutyl | 3-methallyl |
5987 | 3-methylbutyl | 3-methallyl |
5988 | cyclopropylmethyl | 3-methallyl |
5989 | cyclobutylmethyl | 3-methallyl |
5990 | cyclopentylmethyl | 3-methallyl |
5991 | p-hydroxyphenylmethyl | 3-methallyl |
5992 | p-nitrophenylmethyl | 3-methallyl |
5993 | p-aminophenylmethyl | 3-methallyl |
5994 | "4-(N,N- | 3-methallyl |
dimethylamino)phenylmethyl" | ||
5995 | benzyl | 2-methallyl |
5996 | 1-pyrolylmethyl | 2-methallyl |
5997 | 1-pyrazolylmethyl | 2-methallyl |
5998 | 1-imidazolylmethyl | 2-methallyl |
5999 | 1-indolylmethyl | 2-methallyl |
6000 | 1-triazolylmethyl | 2-methallyl |
6001 | 1-tetrazolylmethyl | 2-methallyl |
6002 | 2-pyridylmethyl | 2-methallyl |
6003 | 3-pyridylmethyl | 2-methallyl |
6004 | 4-pyridylmethyl | 2-methallyl |
6005 | cyclohexylmethyl | 2-methallyl |
6006 | 2-naphthylmethyl | 2-methallyl |
6007 | 3-naphthylmethyl | 2-methallyl |
6008 | 2-thiophenylmethyl | 2-methallyl |
6009 | 4-(1-methyl)piperidinyl- | 2-methallyl |
methyl | ||
6010 | "(3,4- | 2-methallyl |
methylenedioxyphenyl)methyl" | ||
6011 | 2-thienylmethyl | 2-methallyl |
6012 | 4-biphenylmethyl | 2-methallyl |
6013 | pyrimidinylmethyl | 2-methallyl |
6014 | 2-benzothiazolylmethyl | 2-methallyl |
6015 | 2-benzothiophenylmethyl | 2-methallyl |
6016 | 2-thiomethylethyl | 2-methallyl |
6017 | 2-thiomethylmethyl | 2-methallyl |
6018 | 2-methylpropyl | 2-methallyl |
6019 | 2-methylbutyl | 2-methallyl |
6020 | 3-methylbutyl | 2-methallyl |
6021 | cyclopropylmethyl | 2-methallyl |
6022 | cyclobutylmethyl | 2-methallyl |
6023 | cyclopentylmethyl | 2-methallyl |
6024 | p-hydroxyphenylmethyl | 2-methallyl |
6025 | p-nitrophenylmethyl | 2-methallyl |
6026 | p-aminophenylmethyl | 2-methallyl |
6027 | "4-(N,N- | 2-methallyl |
dimethylamino)phenylmethyl" | ||
6094 | benzyl | cyclopropylmethyl |
6095 | 1-pyrolylmethyl | cyclopropylmethyl |
6096 | 1-pyrazolylmethyl | cyclopropylmethyl |
6097 | 1-imidazolylmethyl | cyclopropylmethyl |
6098 | 1-indolylmethyl | cyclopropylmethyl |
6099 | 1-triazolylmethyl | cyclopropylmethyl |
6100 | 1-tetrazolylmethyl | cyclopropylmethyl |
6101 | 2-pyridylmethyl | cyclopropylmethyl |
6102 | 3-pyridylmethyl | cyclopropylmethyl |
6103 | 4-pyridylmethyl | cyclopropylmethyl |
6104 | cyclohexylmethyl | cyclopropylmethyl |
6105 | 2-naphthylmethyl | cyclopropylmethyl |
6106 | 3-naphthylmethyl | cyclopropylmethyl |
6107 | 2-thiophenylmethyl | cyclopropylmethyl |
6108 | 4-(1-methyl)piperidinyl- | cyclopropylmethyl |
methyl | ||
6109 | "(3,4- | cyclopropylmethyl |
methylenedioxyphenyl)methyl" | ||
6110 | 2-thienylmethyl | cyclopropylmethyl |
6111 | 4-biphenylmethyl | cyclopropylmethyl |
6112 | pyrimidinylmethyl | cyclopropylmethyl |
6113 | 2-benzothiazolylmethyl | cyclopropylmethyl |
6114 | 2-benzothiophenylmethyl | cyclopropylmethyl |
6115 | 2-thiomethylethyl | cyclopropylmethyl |
6116 | 2-thiomethylmethyl | cyclopropylmethyl |
6117 | 2-methylpropyl | cyclopropylmethyl |
6118 | 2-methylbutyl | cyclopropylmethyl |
6119 | 3-methylbutyl | cyclopropylmethyl |
6120 | cyclopropylmethyl | cyclopropylmethyl |
6121 | cyclobutylmethyl | cyclopropylmethyl |
6122 | cyclopentylmethyl | cyclopropylmethyl |
6123 | p-hydroxyphenylmethyl | cyclopropylmethyl |
6124 | p-nitrophenylmethyl | cyclopropylmethyl |
6125 | p-aminophenylmethyl | cyclopropylmethyl |
6126 | "4-(N,N- | cyclopropylmethyl |
dimethylamino)phenylmethyl" | ||
6127 | benzyl | n-pentyl |
6128 | 1-pyrolylmethyl | n-pentyl |
6129 | 1-pyrazolylmethyl | n-pentyl |
6130 | 1-imidazolylmethyl | n-pentyl |
6131 | 1-indolylmethyl | n-pentyl |
6132 | 1-triazolylmethyl | n-pentyl |
6133 | 1-tetrazolylmethyl | n-pentyl |
6134 | 2-pyridylmethyl | n-pentyl |
6135 | 3-pyridylmethyl | n-pentyl |
6136 | 4-pyridylmethyl | n-pentyl |
6137 | cyclohexylmethyl | n-pentyl |
6138 | 2-naphthylmethyl | n-pentyl |
6139 | 3-naphthylmethyl | n-pentyl |
6140 | 2-thiophenylmethyl | n-pentyl |
6141 | 4-(1-methyl)piperidinyl- | n-pentyl |
methyl | ||
6142 | "(3,4- | n-pentyl |
methylenedioxyphenyl)methyl" | ||
6143 | 2-thienylmethyl | n-pentyl |
6144 | 4-biphenylmethyl | n-pentyl |
6145 | pyrimidinylmethyl | n-pentyl |
6146 | 2-benzothiazolylmethyl | n-pentyl |
6147 | 2-benzothiophenylmethyl | n-pentyl |
6148 | 2-thiomethylethyl | n-pentyl |
6149 | 2-thiomethylmethyl | n-pentyl |
6150 | 2-methylpropyl | n-pentyl |
6151 | 2-methylbutyl | n-pentyl |
6152 | 3-methylbutyl | n-pentyl |
6153 | cyclopropylmethyl | n-pentyl |
6154 | cyclobutylmethyl | n-pentyl |
6155 | cyclopentylmethyl | n-pentyl |
6156 | p-hydroxyphenylmethyl | n-pentyl |
6157 | p-nitrophenylmethyl | n-pentyl |
6158 | p-aminophenylmethyl | n-pentyl |
6159 | "4-(N,N- | n-pentyl |
dimethylamino)phenylmethyl" | ||
6292 | benzyl | propargyl |
6293 | 1-pyrolylmethyl | propargyl |
6294 | 1-pyrazolylmethyl | propargyl |
6295 | 1-imidazolylmethyl | propargyl |
6296 | 1-indolylmethyl | propargyl |
6297 | 1-triazolylmethyl | propargyl |
6298 | 1-tetrazolylmethyl | propargyl |
6299 | 2-pyridylmethyl | propargyl |
6300 | 3-pyridylmethyl | propargyl |
6301 | 4-pyridylmethyl | propargyl |
6302 | cyclohexylmethyl | propargyl |
6303 | 2-naphthylmethyl | propargyl |
6304 | 3-naphthylmethyl | propargyl |
6305 | 2-thiophenylmethyl | propargyl |
6306 | 4-(1-methyl)piperidinyl- | propargyl |
methyl | ||
6307 | "(3,4- | propargyl |
methylenedioxyphenyl)methyl" | ||
6308 | 2-thienylmethyl | propargyl |
6309 | 4-biphenylmethyl | propargyl |
6310 | pyrimidinylmethyl | propargyl |
6311 | 2-benzothiazolylmethyl | propargyl |
6312 | 2-benzothiophenylmethyl | propargyl |
6313 | 2-thiomethylethyl | propargyl |
6314 | 2-thiomethylmethyl | propargyl |
6315 | 2-methylpropyl | propargyl |
6316 | 2-methylbutyl | propargyl |
6317 | 3-methylbutyl | propargyl |
6318 | cyclopropylmethyl | propargyl |
6319 | cyclobutylmethyl | propargyl |
6320 | cyclopentylmethyl | propargyl |
6321 | p-hydroxyphenylmethyl | propargyl |
6322 | p-nitrophenylmethyl | propargyl |
6323 | p-aminophenylmethyl | propargyl |
6324 | "4-(N,N- | propargyl |
dimethylamino)phenylmethyl" | ||
6358 | benzyl | cyclobutylmethyl |
6359 | 1-pyrolylmethyl | cyclobutylmethyl |
6360 | 1-pyrazolylmethyl | cyclobutylmethyl |
6361 | 1-imidazolylmethyl | cyclobutylmethyl |
6362 | 1-indolylmethyl | cyclobutylmethyl |
6363 | 1-triazolylmethyl | cyclobutylmethyl |
6364 | 1-tetrazolylmethyl | cyclobutylmethyl |
6365 | 2-pyridylmethyl | cyclobutylmethyl |
6366 | 3-pyridylmethyl | cyclobutylmethyl |
6367 | 4-pyridylmethyl | cyclobutylmethyl |
6368 | cyclohexylmethyl | cyclobutylmethyl |
6369 | 2-naphthylmethyl | cyclobutylmethyl |
6370 | 3-naphthylmethyl | cyclobutylmethyl |
6371 | 2-thiophenylmethyl | cyclobutylmethyl |
6372 | 4-(1-methyl)piperidinyl- | cyclobutylmethyl |
methyl | ||
6373 | "(3,4- | cyclobutylmethyl |
methylenedioxyphenyl)methyl" | ||
6374 | 2-thienylmethyl | cyclobutylmethyl |
6375 | 4-biphenylmethyl | cyclobutylmethyl |
6376 | pyrimidinylmethyl | cyclobutylmethyl |
6377 | 2-benzothiazolylmethyl | cyclobutylmethyl |
6378 | 2-benzothiophenylmethyl | cyclobutylmethyl |
6379 | 2-thiomethylethyl | cyclobutylmethyl |
6380 | 2-thiomethylmethyl | cyclobutylmethyl |
6381 | 2-methylpropyl | cyclobutylmethyl |
6382 | 2-methylbutyl | cyclobutylmethyl |
6383 | 3-methylbutyl | cyclobutylmethyl |
6384 | cyclopropylmethyl | cyclobutylmethyl |
6385 | cyclobutylmethyl | cyclobutylmethyl |
6386 | cyclopentylmethyl | cyclobutylmethyl |
6387 | p-hydroxyphenylmethyl | cyclobutylmethyl |
6388 | p-nitrophenylmethyl | cyclobutylmethyl |
6389 | p-aminophenylmethyl | cyclobutylmethyl |
6390 | "4-(N,N- | cyclobutylmethyl |
dimethylamino)phenylmethyl" | ||
6424 | benzyl | cyclopentylmethyl |
6425 | 1-pyrolylmethyl | cyclopentylmethyl |
6246 | 1-pyrazolylmethyl | cyclopentylmethyl |
6427 | 1-imidazolylmethyl | cyclopentylmethyl |
6428 | 1-indolylmethyl | cyclopentylmethyl |
6429 | 1-triazolylmethyl | cyclopentylmethyl |
6430 | 1-tetrazolylmethyl | cyclopentylmethyl |
6431 | 2-pyridylmethyl | cyclopentylmethyl |
6432 | 3-pyridylmethyl | cyclopentylmethyl |
6433 | 4-pyridylmethyl | cyclopentylmethyl |
6434 | cyclohexylmethyl | cyclopentylmethyl |
6435 | 2-naphthylmethyl | cyclopentylmethyl |
6436 | 3-naphthylmethyl | cyclopentylmethyl |
6437 | 2-thiophenylmethyl | cyclopentylmethyl |
6438 | 4-(1-methyl)piperidinyl- | cyclopentylmethyl |
methyl | ||
6439 | "(3,4- | cyclopentylmethyl |
methylenedioxyphenyl)methyl" | ||
6440 | 2-thienylmethyl | cyclopentylmethyl |
6441 | 4-biphenylmethyl | cyclopentylmethyl |
6442 | pyrimidinylmethyl | cyclopentylmethyl |
6443 | 2-benzothiazolylmethyl | cyclopentylmethyl |
6444 | 2-benzothiophenylmethyl | cyclopentylmethyl |
6445 | 2-thiomethylethyl | cyclopentylmethyl |
6446 | 2-thiomethylmethyl | cyclopentylmethyl |
6447 | 2-methylpropyl | cyclopentylmethyl |
6448 | 2-methylbutyl | cyclopentylmethyl |
6449 | 3-methylbutyl | cyclopentylmethyl |
6450 | cyclopropylmethyl | cyclopentylmethyl |
6451 | cyclobutylmethyl | cyclopentylmethyl |
6452 | cyclopentylmethyl | cyclopentylmethyl |
6453 | p-hydroxyphenylmethyl | cyclopentylmethyl |
6454 | p-nitrophenylmethyl | cyclopentylmethyl |
6455 | p-aminophenylmethyl | cyclopentylmethyl |
6456 | "4-(N,N- | cyclopentylmethyl |
dimethylamino)phenylmethyl" | ||
6457 | benzyl | 1-hexyl |
6458 | 1-pyrolylmethyl | 1-hexyl |
6459 | 1-pyrazolylmethyl | 1-hexyl |
6460 | 1-imidazolylmethyl | 1-hexyl |
6461 | 1-indolylmethyl | 1-hexyl |
6462 | 1-triazolylmethyl | 1-hexyl |
6463 | 1-tetrazolylmethyl | 1-hexyl |
6464 | 2-pyridylmethyl | 1-hexyl |
6465 | 3-pyridylmethyl | 1-hexyl |
6466 | 4-pyridylmethyl | 1-hexyl |
6467 | cyclohexylmethyl | 1-hexyl |
6468 | 2-naphthylmethyl | 1-hexyl |
6469 | 3-naphthylmethyl | 1-hexyl |
6470 | 2-thiophenylmethyl | 1-hexyl |
6471 | 4-(1-methyl)piperidinyl- | 1-hexyl |
methyl | ||
6472 | "(3,4- | 1-hexyl |
methylenedioxyphenyl)methyl" | ||
6473 | 2-thienylmethyl | 1-hexyl |
6474 | 4-biphenylmethyl | 1-hexyl |
6475 | pyrimidinylmethyl | 1-hexyl |
6476 | 2-benzothiazolylmethyl | 1-hexyl |
6477 | 2-benzothiophenylmethyl | 1-hexyl |
6478 | 2-thiomethylethyl | 1-hexyl |
6479 | 2-thiomethylmethyl | 1-hexyl |
6480 | 2-methylpropyl | 1-hexyl |
6481 | 2-methylbutyl | 1-hexyl |
6482 | 3-methylbutyl | 1-hexyl |
6483 | cyclopropylmethyl | 1-hexyl |
6484 | cyclobutylmethyl | 1-hexyl |
6485 | cyclopentylmethyl | 1-hexyl |
6486 | p-hydroxyphenylmethyl | 1-hexyl |
6487 | p-nitrophenylmethyl | 1-hexyl |
6488 | p-aminophenylmethyl | 1-hexyl |
6489 | "4-(N,N- | 1-hexyl |
dimethylamino)phenylmethyl" | ||
6622 | benzyl | 2-phenylethyl |
6623 | 1-pyrolylmethyl | 2-phenylethyl |
6624 | 1-pyrazolylmethyl | 2-phenylethyl |
6625 | 1-imidazolylmethyl | 2-phenylethyl |
6626 | 1-indolylmethyl | 2-phenylethyl |
6627 | 1-triazolylmethyl | 2-phenylethyl |
6628 | 1-tetrazolylmethyl | 2-phenylethyl |
6629 | 2-pyridylmethyl | 2-phenylethyl |
6630 | 3-pyridylmethyl | 2-phenylethyl |
6631 | 4-pyridylmethyl | 2-phenylethyl |
6632 | cyclohexylmethyl | 2-phenylethyl |
6633 | 2-naphthylmethyl | 2-phenylethyl |
6634 | 3-naphthylmethyl | 2-phenylethyl |
6635 | 2-thiophenylmethyl | 2-phenylethyl |
6636 | 4-(1-methyl)piperidinyl- | 2-phenylethyl |
methyl | ||
6637 | "(3,4- | 2-phenylethyl |
methylenedioxyphenyl)methyl" | ||
6638 | 2-thienylmethyl | 2-phenylethyl |
6639 | 4-biphenylmethyl | 2-phenylethyl |
6640 | pyrimidinylmethyl | 2-phenylethyl |
6641 | 2-benzothiazolylmethyl | 2-phenylethyl |
6642 | 2-benzothiophenylmethyl | 2-phenylethyl |
6643 | 2-thiomethylethyl | 2-phenylethyl |
6644 | 2-thiomethylmethyl | 2-phenylethyl |
6645 | 2-methylpropyl | 2-phenylethyl |
6646 | 2-methylbutyl | 2-phenylethyl |
6647 | 3-methylbutyl | 2-phenylethyl |
6648 | cyclopropylmethyl | 2-phenylethyl |
6649 | cyclobutylmethyl | 2-phenylethyl |
6650 | cyclopentylmethyl | 2-phenylethyl |
6651 | p-hydroxyphenylmethyl | 2-phenylethyl |
6652 | p-nitrophenylmethyl | 2-phenylethyl |
6653 | p-aminophenylmethyl | 2-phenylethyl |
6654 | "4-(N,N- | 2-phenylethyl |
dimethylamino)phenylmethyl" | ||
6655 | benzyl | 3-phenylpropyl |
6656 | 1-pyrolylmethyl | 3-phenylpropyl |
6657 | 1-pyrazolylmethyl | 3-phenylpropyl |
6658 | 1-imidazolylmethyl | 3-phenylpropyl |
6659 | 1-indolylmethyl | 3-phenylpropyl |
6660 | 1-triazolylmethyl | 3-phenylpropyl |
6661 | 1-tetrazolylmethyl | 3-phenylpropyl |
6662 | 2-pyridylmethyl | 3-phenylpropyl |
6663 | 3-pyridylmethyl | 3-phenylpropyl |
6664 | 4-pyridylmethyl | 3-phenylpropyl |
6665 | cyclohexylmethyl | 3-phenylpropyl |
6666 | 2-naphthylmethyl | 3-phenylpropyl |
6667 | 3-naphthylmethyl | 3-phenylpropyl |
6668 | 2-thiophenylmethyl | 3-phenylpropyl |
6669 | 4-(1-methyl)piperidinyl- | 3-phenylpropyl |
methyl | ||
6670 | "(3,4- | 3-phenylpropyl |
methylenedioxyphenyl)methyl" | ||
6671 | 2-thienylmethyl | 3-phenylpropyl |
6672 | 4-biphenylmethyl | 3-phenylpropyl |
6673 | pyrimidinylmethyl | 3-phenylpropyl |
6674 | 2-benzothiazolylmethyl | 3-phenylpropyl |
6675 | 2-benzothiophenylmethyl | 3-phenylpropyl |
6676 | 2-thiomethylethyl | 3-phenylpropyl |
6677 | 2-thiomethylmethyl | 3-phenylpropyl |
6678 | 2-methylpropyl | 3-phenylpropyl |
6679 | 2-methylbutyl | 3-phenylpropyl |
6680 | 3-methylbutyl | 3-phenylpropyl |
6681 | cyclopropylmethyl | 3-phenylpropyl |
6682 | cyclobutylmethyl | 3-phenylpropyl |
6683 | cyclopentylmethyl | 3-phenylpropyl |
6684 | p-hydroxyphenylmethyl | 3-phenylpropyl |
6685 | p-nitrophenylmethyl | 3-phenylpropyl |
6686 | p-aminophenylmethyl | 3-phenylpropyl |
6687 | "4-(N,N- | 3-phenylpropyl |
dimethylamino)phenylmethyl" | ||
6853 | benzyl | 2-(1-pyrolyl)ethyl |
6854 | 1-pyrolylmethyl | 2-(1-pyrolyl)ethyl |
6855 | 1-pyrazolylmethyl | 2-(1-pyrolyl)ethyl |
6856 | 1-imidazolylmethyl | 2-(1-pyrolyl)ethyl |
6857 | 1-indolylmethyl | 2-(1-pyrolyl)ethyl |
6858 | 1-triazolylmethyl | 2-(1-pyrolyl)ethyl |
6859 | 1-tetrazolylmethyl | 2-(1-pyrolyl)ethyl |
6860 | 2-pyridylmethyl | 2-(1-pyrolyl)ethyl |
6861 | 3-pyridylmethyl | 2-(1-pyrolyl)ethyl |
6862 | 4-pyridylmethyl | 2-(1-pyrolyl)ethyl |
6863 | cyclohexylmethyl | 2-(1-pyrolyl)ethyl |
6864 | 2-naphthylmethyl | 2-(1-pyrolyl)ethyl |
6865 | 3-naphthylmethyl | 2-(1-pyrolyl)ethyl |
6866 | 2-thiophenylmethyl | 2-(1-pyrolyl)ethyl |
6867 | 4-(1-methyl)piperidinyl- | 2-(1-pyrolyl)ethyl |
methyl | ||
6868 | "(3,4- | 2-(1-pyrolyl)ethyl |
methylenedioxyphenyl)methyl" | ||
6869 | 2-thienylmethyl | 2-(1-pyrolyl)ethyl |
6870 | 4-biphenylmethyl | 2-(1-pyrolyl)ethyl |
6871 | pyrimidinylmethyl | 2-(1-pyrolyl)ethyl |
6872 | 2-benzothiazolylmethyl | 2-(1-pyrolyl)ethyl |
6873 | 2-benzothiophenylmethyl | 2-(1-pyrolyl)ethyl |
6874 | 2-thiomethylethyl | 2-(1-pyrolyl)ethyl |
6875 | 2-thiomethylmethyl | 2-(1-pyrolyl)ethyl |
6876 | 2-methylpropyl | 2-(1-pyrolyl)ethyl |
6877 | 2-methylbutyl | 2-(1-pyrolyl)ethyl |
6878 | 3-methylbutyl | 2-(1-pyrolyl)ethyl |
6879 | cyclopropylmethyl | 2-(1-pyrolyl)ethyl |
6880 | cyclobutylmethyl | 2-(1-pyrolyl)ethyl |
6881 | cyclopentylmethyl | 2-(1-pyrolyl)ethyl |
6882 | p-hydroxyphenylmethyl | 2-(1-pyrolyl)ethyl |
6883 | p-nitrophenylmethyl | 2-(1-pyrolyl)ethyl |
6884 | p-aminophenylmethyl | 2-(1-pyrolyl)ethyl |
6885 | "4-(N,N- | 2-(1-pyrolyl)ethyl |
dimethylamino)phenylmethyl" | ||
6886 | benzyl | 2-(1-imidazolyl)ethyl |
6887 | 1-pyrolylmethyl | 2-(1-imidazolyl)ethyl |
6888 | 1-pyrazolylmethyl | 2-(1-imidazolyl)ethyl |
6889 | 1-imidazolylmethyl | 2-(1-imidazolyl)ethyl |
6890 | 1-indolylmethyl | 2-(1-imidazolyl)ethyl |
6891 | 1-triazolylmethyl | 2-(1-imidazolyl)ethyl |
6892 | 1-tetrazolylmethyl | 2-(1-imidazolyl)ethyl |
6893 | 2-pyridylmethyl | 2-(1-imidazolyl)ethyl |
6894 | 3-pyridylmethyl | 2-(1-imidazolyl)ethyl |
6895 | 4-pyridylmethyl | 2-(1-imidazolyl)ethyl |
6896 | cyclohexylmethyl | 2-(1-imidazolyl)ethyl |
6897 | 2-naphthylmethyl | 2-(1-imidazolyl)ethyl |
6898 | 3-naphthylmethyl | 2-(1-imidazolyl)ethyl |
6899 | 2-thiophenylmethyl | 2-(1-imidazolyl)ethyl |
6900 | 4-(1-methyl)piperidinyl- | 2-(1-imidazolyl)ethyl |
methyl | ||
6901 | "(3,4- | 2-(1-imidazolyl)ethyl |
methylenedioxyphenyl)methyl" | ||
6902 | 2-thienylmethyl | 2-(1-imidazolyl)ethyl |
6903 | 4-biphenylmethyl | 2-(1-imidazolyl)ethyl |
6904 | pyrimidinylmethyl | 2-(1-imidazolyl)ethyl |
6905 | 2-benzothiazolylmethyl | 2-(1-imidazolyl)ethyl |
6906 | 2-benzothiophenylmethyl | 2-(1-imidazolyl)ethyl |
6907 | 2-thiomethylethyl | 2-(1-imidazolyl)ethyl |
6908 | 2-thiomethylmethyl | 2-(1-imidazolyl)ethyl |
6909 | 2-methylpropyl | 2-(1-imidazolyl)ethyl |
6910 | 2-methylbutyl | 2-(1-imidazolyl)ethyl |
6911 | 3-methylbutyl | 2-(1-imidazolyl)ethyl |
6912 | cyclopropylmethyl | 2-(1-imidazolyl)ethyl |
6913 | cyclobutylmethyl | 2-(1-imidazolyl)ethyl |
6914 | cyclopentylmethyl | 2-(1-imidazolyl)ethyl |
6915 | p-hydroxyphenylmethyl | 2-(1-imidazolyl)ethyl |
6916 | p-nitrophenylmethyl | 2-(1-imidazolyl)ethyl |
6917 | p-aminophenylmethyl | 2-(1-imidazolyl)ethyl |
6918 | "4-(N,N- | 2-(1-imidazolyl)ethyl |
dimethylamino)phenylmethyl" | ||
6919 | benzyl | 2-pyridylmethyl |
6920 | 1-pyrolylmethyl | 2-pyridylmethyl |
6921 | 1-pyrazolylmethyl | 2-pyridylmethyl |
6922 | 1-imidazolylmethyl | 2-pyridylmethyl |
6923 | 1-indolylmethyl | 2-pyridylmethyl |
6924 | 1-triazolylmethyl | 2-pyridylmethyl |
6925 | 1-tetrazolylmethyl | 2-pyridylmethyl |
6926 | 2-pyridylmethyl | 2-pyridylmethyl |
6927 | 3-pyridylmethyl | 2-pyridylmethyl |
6928 | 4-pyridylmethyl | 2-pyridylmethyl |
6929 | cyclohexylmethyl | 2-pyridylmethyl |
6930 | 2-naphthylmethyl | 2-pyridylmethyl |
6931 | 3-naphthylmethyl | 2-pyridylmethyl |
6932 | 2-thiophenylmethyl | 2-pyridylmethyl |
6933 | 4-(1-methyl)piperidinyl- | 2-pyridylmethyl |
methyl | ||
6934 | "(3,4- | 2-pyridylmethyl |
methylenedioxyphenyl)methyl" | ||
6935 | 2-thienylmethyl | 2-pyridylmethyl |
6936 | 4-biphenylmethyl | 2-pyridylmethyl |
6937 | pyrimidinylmethyl | 2-pyridylmethyl |
6938 | 2-benzothiazolylmethyl | 2-pyridylmethyl |
6939 | 2-benzothiophenylmethyl | 2-pyridylmethyl |
6940 | 2-thiomethylethyl | 2-pyridylmethyl |
6941 | 2-thiomethylmethyl | 2-pyridylmethyl |
6942 | 2-methylpropyl | 2-pyridylmethyl |
6943 | 2-methylbutyl | 2-pyridylmethyl |
6944 | 3-methylbutyl | 2-pyridylmethyl |
6945 | cyclopropylmethyl | 2-pyridylmethyl |
6946 | cyclobutylmethyl | 2-pyridylmethyl |
6947 | cyclopentylmethyl | 2-pyridylmethyl |
6948 | p-hydroxyphenylmethyl | 2-pyridylmethyl |
6949 | p-nitrophenylmethyl | 2-pyridylmethyl |
6950 | p-aminophenylmethyl | 2-pyridylmethyl |
6951 | "4-(N,N- | 2-pyridylmethyl |
dimethylamino)phenylmethyl" | ||
TABLE 19 | |||
Example | |||
Number | R4 | R7 | R22 = R23 |
6984 | benzyl | "4-(N,N- | allyl |
dimethylamino)phenyl- | |||
methyl" | |||
6985 | 1-pyrolylmethyl | benzyl | allyl |
6986 | 1-pyrazolylmethyl | 1-pyrolylmethyl | allyl |
6987 | 1-imidazolylmethyl | 1-pyrazolylmethyl | allyl |
6988 | 1-indolylmethyl | 1-imidazolylmethyl | allyl |
6989 | 1-triazolylmethyl | 1-indolylmethyl | allyl |
6990 | 1-tetrazolylmethyl | 1-triazolylmethyl | allyl |
6991 | 2-pyridylmethyl | 1-tetrazolylmethyl | allyl |
6992 | 3-pyridylmethyl | 2-pyridylmethyl | allyl |
6993 | 4-pyridylmethyl | 3-pyridylmethyl | allyl |
6994 | cyclohexylmethyl | 4-pyridylmethyl | allyl |
6995 | 2-naphthylmethyl | cyclohexylmethyl | allyl |
6996 | 3-naphthylmethyl | 2-naphthylmethyl | allyl |
6997 | 2-thiophenylmethyl | 3-naphthylmethyl | allyl |
6998 | 4-(1-methyl)piper- | 2-thiophenylmethyl | allyl |
idinylmethyl | |||
6999 | "(3,4-methylenedioxy- | 4-(1-methyl)piperi- | allyl |
phenyl)methyl" | dinyl-methyl | ||
7000 | 2-thienylmethyl | "(3,4-methylenedioxy- | allyl |
phenyl)methyl" | |||
7001 | 4-biphenylmethyl | 2-thienylmethyl | allyl |
7002 | pyrimidinylmethyl | 4-biphenylmethyl | allyl |
7003 | 2-benzothiazolyl- | pyrimidinylmethyl | allyl |
methyl | |||
7004 | 2-benzothiophenyl- | 2-benzothiazolyl- | allyl |
methyl | methyl | ||
7005 | 2-thiomethylethyl | 2-benzothiophenyl- | allyl |
methyl | |||
7006 | 2-thiomethylmethyl | 2-thiomethylethyl | allyl |
7007 | 2-methylpropyl | 2-thiomethylmethyl | allyl |
7008 | 2-methylbutyl | 2-methylpropyl | allyl |
7009 | 3-methylbutyl | 2-methylbutyl | allyl |
7010 | cyclopropylmethyl | 3-methylbutyl | allyl |
7011 | cyclobutylmethyl | cyclopropylmethyl | |
7012 | cyclopentylmethyl | cyclobutylmethyl | allyl |
7013 | p-hydroxyphenyl-methyl | cyclopentylmethyl | allyl |
7014 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | allyl |
7015 | p-aminophenyl-methyl | p-nitrophenylmethyl | allyl |
7016 | "4-(N,N-dimethyl- | p-aminophenyl-methyl | allyl |
amino)phenylmethyl" | |||
7017 | benzyl | "4-(N,N-dimethyl- | propyl |
amino)-phenyl-methyl" | |||
7018 | 1-pyrolylmethyl | benzyl | propyl |
7019 | 1-pyrazolylmethyl | 1-pyrolylmethyl | propyl |
7020 | 1-imidazolylmethyl | 1-pyrazolylmethyl | propyl |
7021 | 1-indolylmethyl | 1-imidazolylmethyl | propyl |
7022 | 1-triazolylmethyl | 1-indolylmethyl | propyl |
7023 | 1-tetrazolylmethyl | 1-triazolylmethyl | propyl |
7024 | 2-pyridylmethyl | 1-tetrazolylmethyl | propyl |
7025 | 3-pyridylmethyl | 2-pyridylmethyl | propyl |
7026 | 4-pyridylmethyl | 3-pyridylmethyl | propyl |
7027 | cyclohexylmethyl | 4-pyridylmethyl | propyl |
7028 | 2-naphthylmethyl | cyclohexylmethyl | propyl |
7029 | 3-naphthylmethyl | 2-napthylmethyl | propyl |
7030 | 2-thiophenylmethyl | 3-naphthylmethyl | propyl |
7031 | 4-(1-methyl)- | 2-thiophenylmethyl | propyl |
piperidinyl-methyl | |||
7032 | "(3,4-methylene- | 4-(1-methyl)- | propyl |
dioxyphenyl)methyl" | piperidinyl-methyl | ||
7033 | 2-thienylmethyl | "(3,4-methylene- | propyl |
dioxyphenyl)methyl" | |||
7034 | 4-biphenylmethyl | 2-thienylmethyl | propyl |
7035 | pyrimidinylmethyl | 4-biphenylmethyl | propyl |
7036 | 2-benzothiazolylmethyl | pyrimidinylmethyl | propyl |
7037 | 2- | 2-benzothiazolylmethyl | propyl |
benzothiophenylmethyl | |||
7038 | 2-thiomethylethyl | 2- | propyl |
benzothiophenylmethyl | |||
7039 | 2-thiomethylmethyl | 2-thiomethylethyl | propyl |
7040 | 2-methylpropyl | 2-thiomethylmethyl | propyl |
7041 | 2-methylbutyl | 2-methylpropyl | propyl |
7042 | 3-methylbutyl | 2-methylbutyl | propyl |
7043 | cyclopropylmethyl | 3-methylbutyl | propyl |
7044 | cyclobutylmethyl | cyclopropylmethyl | propyl |
7045 | cyclopentylmethyl | cyclobutylmethyl | propyl |
7046 | p-hydroxyphenyl-methyl | cyclopentylmethyl | propyl |
7047 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | propyl |
7048 | p-aminophenyl-methyl | p-nitrophenylmethyl | propyl |
7049 | "4-(N,N-dimethyl- | p-aminophenyl-methyl | propyl |
amino)phenyl)methyl" | |||
7050 | benzyl | "4-(N,N-dimethyl- | n-butyl |
amino)phenylmethyl" | |||
7051 | 1-pyrolylmethyl | benzyl | n-butyl |
7052 | 1-pyrazolylmethyl | 1-pyrolylmethyl | n-butyl |
7053 | 1-imidazolylmethyl | 1-pyrazolylmethyl | n-butyl |
7054 | 1-indolylmethyl | 1-imidazolylmethyl | n-butyl |
7055 | 1-triazolylmethyl | 1-indolylmethyl | n-butyl |
7056 | 1-tetrazolylmethyl | 1-triazolylmethyl | n-butyl |
7057 | 2-pyridylmethyl | 1-tetrazolylmethyl | n-butyl |
7058 | 3-pyridylmethyl | 2-pyridylmethyl | n-butyl |
7059 | 4-pyridylmethyl | 3-pyridylmethyl | n-butyl |
7060 | cyclohexylmethyl | 4-pyridylmethyl | n-butyl |
7061 | 2-naphthylmethyl | cyclohexylmethyl | n-butyl |
7062 | 3-naphthylmethyl | 2-naphthylmethyl | n-butyl |
7063 | 2-thiophenylmethyl | 3-naphthylmethyl | n-butyl |
7064 | 4-(1-methyl- | 2-thiophenylmethyl | n-butyl |
piperidinyl-methyl | |||
7065 | "(3,4- | 4-(1-methyl)- | n-butyl |
methylenedioxyphenyl)- | piperidinyl-methyl | ||
methyl" | |||
7066 | 2-thienylmethyl | "(3,4-methylene- | n-butyl |
dioxyphenyl)methyl" | |||
7067 | 4-biphenylmethyl | 2-thienylmethyl | n-butyl |
7068 | pyrimidinylmethyl | 4-biphenylmethyl | n-butyl |
7069 | 2-benzothiazolylmethyl | pyrimidinylmethyl | n-butyl |
7070 | 2- | 2-benzothiazolylmethyl | n-butyl |
benzothiophenylmethyl | |||
7071 | 2-thiomethylethyl | 2- | n-butyl |
benzothiophenylmethyl | |||
7072 | 2-thiomethylmethyl | 2-thiomethylethyl | n-butyl |
7073 | 2-methylpropyl | 2-thiomethylmethyl | n-butyl |
7074 | 2-methylbutyl | 2-methylpropyl | n-butyl |
7075 | 3-methylbutyl | 2-methylbutyl | n-butyl |
7076 | cyclopropylmethyl | 3-methylbutyl | n-butyl |
7077 | cyclobutylmethyl | cyclopropylmethyl | n-butyl |
7078 | cyclopentylmethyl | cyclobutylmethyl | n-butyl |
7079 | p-hydroxyphenyl-methyl | cyclopentlymethyl | n-butyl |
7080 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | n-butyl |
7081 | p-aminophenyl-methyl | p-nitrophenyl-methyl | n-butyl |
7082 | "4-(N,N-dimethyl- | p-aminophenyl-methyl | n-butyl |
amino)phenyl-methyl" | |||
7149 | benzyl | "4-(N,N-dimethyl- | "3,3- |
amino)phenylmethyl" | dimethallyl" | ||
7150 | 1-pyrolylmethyl | benzyl | "3,3- |
dimethallyl" | |||
7151 | 1-pyrazolylmethyl | 1-pyrolylmethyl | "3,3- |
dimethallyl" | |||
7152 | 1-imidazolylmethyl | 1-pyrazolylmethyl | "3,3- |
dimethallyl" | |||
7153 | 1-indolylmethyl | 1-imidazolylmethyl | "3,3- |
dimethallyl" | |||
7154 | 1-triazolylmethyl | 1-indolylmethyl | "3,3- |
dimethallyl" | |||
7155 | 1-tetrazolylmethyl | 1-triazolylmethyl | "3,3- |
dimethallyl" | |||
7156 | 2-pyridylmethyl | 1-tetrazolylmethyl | "3,3- |
dimethallyl" | |||
7157 | 3-pyridylmethyl | 2-pyridylmethyl | "3,3- |
dimethallyl" | |||
7158 | 4-pyridylmethyl | 3-pyridylmethyl | "3,3- |
dimethallyl" | |||
7159 | cyclohexylmethyl | 4-pyridylmethyl | "3,3- |
dimethallyl" | |||
7160 | 2-naphthylmethyl | cyclohexylmethyl | "3,3- |
dimethallyl" | |||
7161 | 3-naphthylmethyl | 2-naphthylmethyl | "3,3- |
dimethallyl" | |||
7162 | 2-thiophenylmethyl | 3-naphthylmethyl | "3,3- |
dimethallyl" | |||
7163 | 4-(1- | 2-thiophenylmethyl | "3,3- |
methyl)piperidinyl- | dimethallyl" | ||
methyl | |||
7164 | "(3,4- | 4-(1- | "3,3- |
methylenedioxyphenyl)- | methyl)piperidinyl- | dimethallyl" | |
methyl" | methyl | ||
7165 | 2-thienylmethyl | "(3,4-methylene- | "3,3- |
dioxyphenyl)methyl" | dimethallyl" | ||
7166 | 4-biphenylmethyl | 2-thienylmethyl | "3,3- |
dimethallyl" | |||
7167 | pyrimidinylmethyl | 4-biphenylmethyl | "3,3- |
dimethallyl" | |||
7168 | 2-benzothiazolylmethyl | pyrimidinylmethyl | "3,3- |
dimethallyl" | |||
7169 | 2- | 2-benzothiazolylmethyl | "3,3- |
benzothiophenylmethyl | dimethallyl" | ||
7170 | 2-thiomethylethyl | 2- | "3,3- |
benzothiophenylmethyl | dimethallyl" | ||
7171 | 2-thiomethylmethyl | 2-thiomethylethyl | "3,3- |
dimethallyl" | |||
7172 | 2-methylpropyl | 2-thiomethylmethyl | "3,3- |
dimethallyl" | |||
7173 | 2-methylbutyl | 2-methylpropyl | "3,3- |
dimethallyl" | |||
7174 | 3-methylbutyl | 2-methylbutyl | "3,3- |
dimethallyl" | |||
7175 | cyclopropylmethyl | 3-methylbutyl | "3,3- |
dimethallyl" | |||
7176 | cyclobutylmethyl | cyclopropylmethyl | "3,3- |
dimethallyl" | |||
7177 | cyclopentylmethyl | cyclobutylmethyl | "3,3- |
dimethallyl" | |||
7178 | p-hydroxyphenyl-methyl | cyclopentlymethyl | "3,3- |
dimethallyl" | |||
7179 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | "3,3- |
dimethallyl" | |||
7180 | p-aminophenyl-methyl | p-nitrophenylmethyl | "3,3- |
dimethallyl" | |||
7181 | "4-(N,N- | p-aminophenyl-methyl | "3,3- |
dimethylamino)phenyl- | dimethallyl" | ||
methyl" | |||
7182 | benzyl | "4-(N,N- | 3-methallyl |
dimethylamino)-phenyl- | |||
methyl" | |||
7183 | 1-pyrolylmethyl | benzyl | 3-methallyl |
7184 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-methallyl |
7185 | 1-imidazolylmethyl | 1-pyrazoyllmethyl | 3-methallyl |
7186 | 1-indolylmethyl | 1-imidazolylmethyl | 3-methallyl |
7187 | 1-triazolylmethyl | 1-indolylmethyl | 3-methallyl |
7188 | 1-tetrazolylmethyl | 1-triazolylmethyl | 3-methallyl |
7189 | 2-pyridylmethyl | 1-tetrazolylmethyl | 3-methallyl |
7190 | 3-pyridylmethyl | 2-pyridylmethyl | 3-methallyl |
7191 | 4-pyridylmethyl | 3-pyridylmethyl | 3-methallyl |
7192 | cyclohexylmethyl | 4-pyridylmethyl | 3-methallyl |
7193 | 2-naphthylmethyl | cyclohexylmethyl | 3-methallyl |
7194 | 3-naphthylmethyl | 2-naphthylmethyl | 3-methallyl |
7195 | 2-thiophenylmethyl | 3-naphthylmethyl | 3-methallyl |
7196 | 4-(1-methyl)- | 2-thiophenylmethyl | 3-methallyl |
piperidinyl-methyl | |||
7197 | "(3,4- | 4-(1- | 3-methallyl |
methylenedioxyphenyl)- | methyl)piperidinyl- | ||
methyl" | methyl | ||
7918 | 2-thienylmethyl | "(3,4-methylene- | 3-methallyl |
dioxyphenyl)methyl" | |||
7199 | 4-biphenylmethyl | 2-thienylmethyl | 3-methallyl |
7200 | pyrimidinylmethyl | 4-biphenylmethyl | 3-methallyl |
7201 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 3-methallyl |
7202 | 2- | 2-benzothiazolylmethyl | 3-methallyl |
benzothiophenylmethyl | |||
7203 | 2-thiomethylethyl | 2- | 3-methallyl |
benzothiophenylmethyl | |||
7204 | 2-thiomethylmethyl | 2-thiomethylethyl | 3-methallyl |
7205 | 2-methylpropyl | 2-thiomethylmethyl | 3-methallyl |
7206 | 2-methylbutyl | 2-methylpropyl | 3-methallyl |
7207 | 3-methylbutyl | 2-methylbutyl | 3-methallyl |
7208 | cyclopropylmethyl | 3-methylbutyl | 3-methallyl |
7209 | cyclobutylmethyl | cyclopropylmethyl | 3-methallyl |
7210 | cyclopentylmethyl | cyclobutylmethyl | 3-methallyl |
7211 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 3-methallyl |
7212 | p-nitrophenyl-methyl | p-hydroxyphenyl-methyl | 3-methallyl |
7213 | p-aminophenyl-methyl | p-nitrophenylmethyl | 3-methallyl |
7214 | "4-(N,N-dimethyl- | p-aminophenyl-methyl | 3-methallyl |
amino)-phenyl-methyl" | |||
7215 | benzyl | "4-(N,N-dimethyl- | 2-methallyl |
amino)phenylmethyl" | |||
7216 | 1-pyrolylmethyl | benzyl | 2-methallyl |
7217 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 2-methallyl |
7218 | -imidazolylmethyl | 1-pyrazolylmethyl | 2-methallyl |
7219 | 1-indolylmethyl | 1-imidazolylmethyl | 2-methallyl |
7220 | 1-triazolylmethyl | 1-indolylmethyl | 2-methallyl |
7221 | 1-tetrazolylmethyl | 1-triazolylmethyl | 2-methallyl |
7222 | 2-pyridylmethyl | 1-tetrazolylmethyl | 2-methallyl |
7223 | 3-pyridylmethyl | 2-pyridylmethyl | 2-methallyl |
7224 | 4-pyridylmethyl | 3-pyridylmethyl | 2-methallyl |
7225 | cyclohexylmethyl | 4-pyridylmethyl | 2-methallyl |
7226 | 2-naphthylmethyl | cyclohexylmethyl | 2-methallyl |
7227 | 3-naphthylmethyl | 2-naphthylmethyl | 2-methallyl |
7228 | 2-thiophenylmethyl | 3-naphthylmethyl | 2-methallyl |
7229 | 4-(1- | 2-thiophenylmethyl | 2-methallyl |
methyl)piperidinyl- | |||
methyl | |||
7230 | "(3,4-methylene- | 4-(1-methyl)- | 2-methallyl |
dioxyphenyl)methyl" | piperidinyl-methyl | ||
7231 | 2-thienylmethyl | "(3,4-methylene- | 2-methallyl |
dioxyphenyl)methyl" | |||
7232 | 4-biphenylmethyl | 2-thienylmethyl | 2-methallyl |
7233 | pyrimidinylmethyl | 4-biphenylmethyl | 2-methallyl |
7234 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 2-methallyl |
7235 | 2- | 2-benzothiazolylmethyl | 2-methallyl |
benzothiophenylmethyl | |||
7236 | 2-thiomethylethyl | 2- | 2-methallyl |
benzothiophenylmethyl | |||
7237 | 2-thiomethylmethyl | 2-thiomethylmethyl | 2-methallyl |
7238 | 2-methylpropyl | 2-thiomethylmethyl | 2-methallyl |
7239 | 2-methylbutyl | 2-methylpropyl | 2-methallyl |
7240 | 3-methylbutyl | 2-methylbutyl | 2-methallyl |
7241 | cyclopropylmethyl | 2-methylbutyl | 2-methallyl |
7242 | cyclobutylmethyl | cyclopropylmethyl | 2-methallyl |
7243 | cyclopentylmethyl | cyclobutylmethyl | 2-methallyl |
7244 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 2-methallyl |
7245 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 2-methallyl |
7246 | p-aminophenyl-methyl | p-nitrophenylmethyl | 2-methallyl |
7247 | "4-(N,N-dimethyl- | p-aminophenyl-methyl | 2-methallyl |
amino)-phenylmethyl" | |||
7314 | benzyl | "4-(N,N- | cyclopropylmethyl |
dimethylamino)phenyl- | |||
methyl" | |||
7315 | 1-pyrolylmethyl | benzyl | cyclopropylmethyl |
7316 | 1-pyrazolylmethyl | 1-pyrolylmethyl | cyclopropylmethyl |
7317 | 1-imidazolylmethyl | 1-pyrazolylmethyl | cyclopropylmethyl |
7318 | 1-indolylmethyl | 1-imidazolylmethyl | cyclopropylmethyl |
7319 | 1-triazolylmethyl | 1-indolylmethyl | cyclopropylmethyl |
7320 | 1-tetrazolylmethyl | 1-triazolylmethyl | cyclopropylmethyl |
7321 | 2-pyridylmethyl | 1-tetrazolylmethyl | cyclopropylmethyl |
7322 | 3-pyridylmethyl | 2-pyridylmethyl | cyclopropylmethyl |
7323 | 4-pyridylmethyl | 3-pyridylmethyl | cyclopropylmethyl |
7324 | cyclohexylmethyl | 4-pyridylmethyl | cyclopropylmethyl |
7325 | 2-naphthylmethyl | cyclohexylmethyl | cyclopropylmethyl |
7326 | 3-naphthylmethyl | 2-naphthylmethyl | cyclopropylmethyl |
7327 | 2-thiophenylmethyl | 3-naphthylmethyl | cyclopropylmethyl |
7328 | 4-(1- | 2-thiophenylmethyl | cyclopropylmethyl |
methyl)piperidinyl- | |||
methyl | |||
7329 | "(3,4- | 4-(1- | cyclopropylmethyl |
methylenedioxyphenyl)- | methyl)piperdinyl- | ||
methyl" | methyl | ||
7330 | 2-thienylmethyl | "(3,4- | cyclopropylmethyl |
methylenedioxyphenyl)- | |||
methyl" | |||
7331 | 4-biphenylmethyl | 2-thienylmethyl | cyclopropylmethyl |
7332 | pyrimidinylmethyl | 4-biphenylmethyl | cyclopropylmethyl |
7333 | 2-benzothiazolylmethyl | pyrimidinylmethyl | cyclopropylmethyl |
7334 | 2- | 2-benzothiazolylmethyl | cyclopropylmethyl |
benzothiophenylmethyl | |||
7335 | 2-thiomethylethyl | 2- | cyclopropylmethyl |
benzothiophenylmethyl | |||
7336 | 2-thiomethylmethyl | 2-thiomethylethyl | cyclopropylmethyl |
7337 | 2-methylpropyl | 2-thiomethylmethyl | cyclopropylmethyl |
7338 | 2-methylbutyl | 2-methylpropyl | cyclopropylmethyl |
7339 | 2-methylbutyl | 2-methylbutyl | cyclopropylmethyl |
7340 | cyclopropylmethyl | 3-methylbutyl | cyclopropylmethyl |
7341 | cyclobutylmethyl | cyclopropylmethyl | cyclopropylmethyl |
7342 | cyclopentlymethyl | cyclobutylmethyl | cyclopropylmethyl |
7343 | p-hydroxyphenyl-methyl | cyclpentylmethyl | cyclopropylmethyl |
7344 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | cyclopropylmethyl |
7345 | p-aminophenyl-methyl | p-nitrophenyl-methyl | cyclopropylmethyl |
7346 | "4-(N,N- | p-aminophenyl-methyl | cyclopropylmethyl |
dimethylamino)phenylmethyl" | |||
7347 | benzyl | "4-(N,N- | n-pentyl |
dimethylamino)phenylmethyl" | |||
7348 | 1-pyrolylmethyl | benzyl | n-pentyl |
7349 | 1-pyrazolylmethyl | 1-pyrolylmethyl | n-pentyl |
7350 | 1-imidazolylmethyl | 1-pyrazolylmethyl | n-pentyl |
7351 | 1-indolylmethyl | 1-imidazolylmethyl | n-pentyl |
7352 | 1-triazolylmethyl | 1-indolylmethyl | n-pentyl |
7353 | 1-tetrazolylmethyl | 1-triazolylmethyl | n-pentyl |
7354 | 2-pyridylmethyl | 1-tetrazolylmethyl | n-pentyl |
7355 | 3-pyridylmethyl | 2-pyridylmethyl | n-pentyl |
7356 | 4-pyrdiylmethyl | 3-pyridylmethyl | n-pentyl |
7357 | cyclohexylmethyl | 4-pyridylmethyl | n-pentyl |
7358 | 2-naphthylmethyl | cyclohexylmethyl | n-pentyl |
7359 | 3-naphthylmethyl | 2-naphthylmethyl | n-pentyl |
7360 | 2-thiophenylmethyl | 3-naphthylmethyl | n-pentyl |
7361 | 4-(1- | 2-thiophenylmethyl | n-pentyl |
methyl)piperidinyl- | |||
methyl | |||
7362 | "(3,4- | 4-(1- | n-pentyl |
methylenedioxyphenyl)methyl" | methyl)piperdinyl- | ||
methyl | |||
7363 | 2-thienylmethyl | "(3,4- | n-pentyl |
methylenedioxyphenyl)methyl" | |||
7364 | 4-biphenylmethyl | 2-thienylmethyl | n-pentyl |
7365 | pyrimidinylmethyl | 4-biphenylmethyl | n-pentyl |
7366 | 2-benzothiazolylmethyl | pyrimidinylmethyl | n-pentyl |
7367 | 2- | 2-benzothiazolylmethyl | n-pentyl |
benzothiophenylmethyl | |||
7368 | 2-thiomethylethyl | 2- | n-pentyl |
benzothiophenylmethyl | |||
7369 | 2-thiomethylmethyl | 2-thiomethylethyl | n-pentyl |
7370 | 2-methylpropyl | 2-thiomethylmethyl | n-pentyl |
7371 | 2-methylbutyl | 2-methylbutyl | n-pentyl |
7372 | 3-methylbutyl | 2-methylbutyl | n-pentyl |
7373 | cyclopropylmethyl | 3-methylbutyl | n-pentyl |
7374 | cyclobutylmethyl | cyclopropylmethyl | n-pentyl |
7375 | cyclopentlymethyl | cyclobutylmethyl | n-pentyl |
7376 | p-hydroxyphenyl-methyl | cyclopentylmethyl | n-pentyl |
7377 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | n-pentyl |
7378 | p-aminophenyl-methyl | p-nitrophenylmethyl | n-pentyl |
7379 | "4-(N,N- | p-aminophenyl-methyl | n-pentyl |
dimethylamino)phenylmethyl" | |||
7512 | benzyl | "4-(N,N- | propargyl |
dimethylamino)phenylmethyl" | |||
7513 | 1-pyrolylmethyl | benzyl | propargyl |
7514 | 1-pyrazolylmethyl | 1-pyrolylmethyl | propargyl |
7515 | 1-imidazolylmethyl | 1-pyrazolylmethyl | propargyl |
7516 | 1-indolylmethyl | 1-imidazolylmethyl | propargyl |
7517 | 1-triazolylmethyl | 1-indolylmethyl | propargyl |
7518 | 1-tetrazolylmethyl | 1-triazolylmethyl | propargyl |
7519 | 2-pyridylmethyl | 1-tetrazolylmethyl | propargyl |
7520 | 3-pyridylmethyl | 2-pyridylmethyl | propargyl |
7521 | 4-pyridylmethyl | 3-pyridylmethyl | propargyl |
7522 | cyclohexylmethyl | 4-pyridylmethyl | propargyl |
7523 | 2-naphthylmethyl | cyclohexylmethyl | propargyl |
7524 | 3-naphthylmethyl | 2-naphthylmethyl | propargyl |
7525 | 2-thiophenylmethyl | 3-naphthylmethyl | propargyl |
7526 | 4-(1- | 2-thiophenylmethyl | propargyl |
methyl)piperidinyl- | |||
methyl | |||
7527 | "(3,4- | 4-(1- | propargyl |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | ||
methyl | |||
7528 | 2-thienylmethyl | "(3,4- | propargyl |
methylenedioxyphenyl)methyl" | |||
7529 | 4-biphenylmethyl | 2-thienylmethyl | propargyl |
7530 | pyrimidinylmethyl | 4-biphenylmethyl | propargyl |
7531 | 2-benzothiazolylmethyl | 4-biphenylmethyl | propargyl |
7532 | 2- | 2-benzothiazolylmethyl | propargyl |
benzothiophenylmethyl | |||
7533 | 2-thiomethylethyl | 2- | propargyl |
benzothiophenylmethyl | |||
7534 | 2-thiomethylmethyl | 2-thiomethylmethyl | propargyl |
7535 | 2-methylpropyl | 2-thiomethylmethyl | propargyl |
7536 | 2-methylbutyl | 2-methylpropyl | propargyl |
7537 | 3-methylbutyl | 2-methylbutyl | propargyl |
7538 | cyclopropylmethyl | 3-methylbutyl | propargyl |
7539 | cyclobutylmethyl | cyclopropylmethyl | propargyl |
7540 | cyclopentylmethyl | cyclobutylmethyl | propargyl |
7541 | p-hydroxyphenyl-methyl | cyclopentlymethyl | propargyl |
7542 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | propargyl |
7543 | p-aminophenyl-methyl | p-nitrophenylmethyl | propargyl |
7544 | "4-(N,N- | p-aminophenyl-methyl | propargyl |
dimethylamino)phenylmethyl" | |||
7578 | benzyl | "4-(N,N- | cyclobutylmethyl |
dimethylamino)methyl" | |||
7579 | 1-pyrolylmethyl | benzyl | cyclobutylmethyl |
7580 | 1-pyrazolylmethyl | 1-pyrolylmethyl | cyclobutylmethyl |
7581 | 1-imidazolylmethyl | 1-pyrazolylmethyl | cyclobutylmethyl |
7582 | 1-indolylmethyl | 1-imidazolylmethyl | cyclobutylmethyl |
7583 | 1-triazolylmethyl | 1-indolylmethyl | cyclobutylmethyl |
7584 | 1-tetrazolylmethyl | 1-triazolylmethyl | cyclobutylmethyl |
7585 | 2-pyridylmethyl | 1-tetrazolylmethyl | cyclobutylmethyl |
7586 | 2-pyridylmethyl | 2-pyridylmethyl | cyclobutylmethyl |
7587 | 4-pyridylmethyl | 3-pyridylmethyl | cyclobutylmethyl |
7588 | cyclohexylmethyl | 4-pyridylmethyl | cyclobutylmethyl |
7589 | 2-naphthylmethyl | cyclohexylmethyl | cyclobutylmethyl |
7590 | 3-naphthylmethyl | 2-naphthylmethyl | cyclobutylmethyl |
7591 | 2-thiophenylmethyl | 3-naphthylmethyl | cyclobutylmethyl |
7592 | 4-(1- | 2-thiophenylmethyl | cyclobutylmethyl |
methyl)piperidinyl- | |||
methyl | |||
7593 | "(3,4- | 4-(1- | cyclobutylmethyl |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | ||
methyl | |||
7594 | 2-thienylmethyl | "(3,4- | cyclobutylmethyl |
methylenedioxyphenyl)methyl" | |||
7595 | 4-biphenylmethyl | 2-thienylmethyl | cyclobutylmethyl |
7596 | pyrimidinylmethyl | 4-biphenylmethyl | cyclobutylmethyl |
7597 | 2-benzothiazolylmethyl | pyrimidinylmethyl | cyclobutylmethyl |
7598 | 2- | 2-benzothiazolylmethyl | cyclobutylmethyl |
benzothiophenylmethyl | |||
7599 | 2-thiomethylethyl | 2- | cyclobutylmethyl |
benzothiophenylmethyl | |||
7600 | 2-thiomethylmethyl | 2-thiomethylethyl | cyclobutylmethyl |
7601 | 2-methylpropyl | 2-thiomethylmethyl | cyclobutylmethyl |
7602 | 2-methylbutyl | 2-methylpropyl | cyclobutylmethyl |
7603 | 3-methylbutyl | 2-methylbutyl | cyclobutylmethyl |
7604 | cyclopropylmethyl | 3-methylbutyl | cyclobutylmethyl |
7605 | cyclobutylmethyl | cyclopropylmethyl | cyclobutylmethyl |
7606 | cyclopentylmethyl | cyclobutylmethyl | cyclobutylmethyl |
7607 | p-hydroxyphenyl-methyl | cyclopentylmethyl | cyclobutylmethyl |
7608 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | cyclobutylmethyl |
7609 | p-aminophenyl-methyl | p-nitrophenylmethyl | cyclobutylmethyl |
7610 | "4-(N,N- | p-aminophenyl-methyl | cyclobutylmethyl |
dimethylamino)phenylmethyl" | |||
7644 | benzyl | "4-(N,N- | cyclopentylmethyl |
dimethylamino)phenylmethyl" | |||
7645 | 1-pyrolylmethyl | benzyl | cyclopentylmethyl |
7646 | 1-pyrazolylmethyl | 1-pyrolylmethyl | cyclopentylmethyl |
7647 | 1-imidazolylmethyl | 1-pyrazolylmethyl | cyclopentylmethyl |
7648 | 1-indolylmethyl | 1-imidazolylmethyl | cyclopentylmethyl |
7649 | 1-triazolylmethyl | 1-indolylmethyl | cyclopentylmethyl |
7650 | 1-tetrazolylmethyl | 1-triazolylmethyl | cyclopentylmethyl |
7651 | 2-pyridylmethyl | 1-tetrazolylmethyl | cyclopentylmethyl |
7652 | 3-pyridylmethyl | 2-pyridylmethyl | cyclopentylmethyl |
7653 | 4-pyridylmethyl | 3-pyridylmethyl | cyclopentylmethyl |
7654 | cyclohexylmethyl | 4-pyridylmethyl | cyclopentylmethyl |
7655 | 2-naphthylmethyl | cyclohexylmethyl | cyclopentylmethyl |
7656 | 3-naphthylmethyl | 2-naphthylmethyl | cyclopentylmethyl |
7657 | 2-thiophenylmethyl | 3-naphthylmethyl | cyclopentylmethyl |
7658 | 4-(1- | 2-thiophenylmethyl | cyclopentylmethyl |
methyl)piperidinyl- | |||
methyl | |||
7659 | "(3,4- | 4-(1- | cyclopentylmethyl |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | ||
methyl | |||
7660 | 2-thienylmethyl | "(3,4- | cyclopentylmethyl |
methylenedioxyphenyl)methyl" | |||
7661 | 4-biphenylmethyl | 2-thienylmethyl | cyclopentylmethyl |
7662 | pyrimidinylmethyl | 4-biphenylmethyl | cyclopentylmethyl |
7663 | 2-benzothiazolylmethyl | pyrimidinylmethyl | cyclopentylmethyl |
7664 | 2- | 2-benzothiazolylmethyl | cyclopentylmethyl |
benzothiophenylmethyl | |||
7665 | 2-thiomethylethyl | 2- | cyclopentylmethyl |
benzothiophenylmethyl | |||
7666 | 2-thiomethylmethyl | 2-thiomethyethyl | cyclopentylmethyl |
7667 | 2-methylpropyl | 2-thiomethylmethyl | cyclopentylmethyl |
7668 | 2-methylbutyl | 2-methylpropyl | cyclopentylmethyl |
7669 | 3-methylbutyl | 2-methylbutyl | cyclopentylmethyl |
7670 | cyclopropylmethyl | 2-methylbutyl | cyclopentylmethyl |
7671 | cyclobutylmethyl | cyclopropylmethyl | cyclopentylmethyl |
7672 | cyclopentlymethyl | cyclobutylmethyl | cyclopentylmethyl |
7673 | p-hydroxyphenyl-methyl | cyclopentylmethyl | cyclopentylmethyl |
7674 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | cyclopentylmethyl |
7675 | p-aminophenyl-methyl | p-nitrophenylmethyl | cyclopentylmethyl |
7676 | "4-(N,N- | p-aminophenyl-methyl | cyclopentylmethyl |
dimethylamino)phenylmethyl" | |||
7677 | benzyl | "4-(N,N- | 1-hexyl |
dimethylamino)phenylmethyl" | |||
7678 | 1-pyrolylmethyl | benzyl | 1-hexyl |
7679 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 1-hexyl |
7680 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 1-hexyl |
7681 | 1-indolylmethyl | 1-imidazolylmethyl | 1-hexyl |
7682 | 1-triazolylmethyl | 1-indolylmethyl | 1-hexyl |
7683 | 1-tetrazolylmethyl | 1-triazolylmethyl | 1-hexyl |
7684 | 2-pyridylmethyl | 1-tetrazolylmethyl | 1-hexyl |
7685 | 3-pyridylmethyl | 2-pyridylmethyl | 1-hexyl |
7686 | 4-pyridylmethyl | 3-pyridylmethyl | 1-hexyl |
7687 | cyclohexylmethyl | 4-pyridylmethyl | 1-hexyl |
7688 | 2-naphthylmethyl | cyclohexylmethyl | 1-hexyl |
7689 | 3-naphthylmethyl | 2-naphthylmethyl | 1-hexyl |
7690 | 2-thiophenylmethyl | 3-naphthylmethyl | 1-hexyl |
7691 | 4-(1- | 2-thiophenylmethyl | 1-hexyl |
methyl)piperidinyl- | |||
methyl | |||
7692 | "(3,4- | 4-(1- | 1-hexyl |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | ||
methyl | |||
7693 | 2-thienylmethyl | "(3,4- | 1-hexyl |
methylenedioxyphenyl)methyl" | |||
7694 | 4-biphenylmethyl | 2-thienylmethyl | 1-hexyl |
7695 | pyrimidinylmethyl | 4-biphenylmethyl | 1-hexyl |
7696 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 1-hexyl |
7697 | 2- | 2-benzothiazolylmethyl | 1-hexyl |
benzothiophenylmethyl | |||
7698 | 2-thiomethylethyl | 2- | 1-hexyl |
benzothiophenylmethyl | |||
7699 | 2-thiomethylmethyl | 2-thiomethylethyl | 1-hexyl |
7700 | 2-methylpropyl | 2-thiomethylmethyl | 1-hexyl |
7701 | 2-methylbutyl | 2-methylpropyl | 1-hexyl |
7702 | 3-methylbutyl | 2-methylbutyl | 1-hexyl |
7703 | cyclopropylmethyl | 3-methylbutyl | 1-hexyl |
7704 | cyclobutylmethyl | cyclopropylmethyl | 1-hexyl |
7705 | cyclopentlymethyl | cyclobutylmethyl | 1-hexyl |
7706 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 1-hexyl |
7707 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 1-hexyl |
7708 | p-aminophenyl-methyl | p-nitrophenylmethyl | 1-hexyl |
7709 | "4-(N,N- | p-aminophenyl-methyl | 1-hexyl |
dimethylamino)phenylmethyl" | |||
7842 | benzyl | "4-(N,N- | 2-phenylethyl |
dimethylamino)phenylmethyl" | |||
7843 | 1-pyrolylmethyl | benzyl | 2-phenylethyl |
7844 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 2-phenylethyl |
7845 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 2-phenylethyl |
7846 | 1-indolylmethyl | 1-imidazolylmethyl | 2-phenylethyl |
7847 | 1-triazolylmethyl | 1-indolylmethyl | 2-phenylethyl |
7848 | 1-tetrazolylmethyl | 1-triazolylmethyl | 2-phenylethyl |
7849 | 2-pyridylmethyl | 1-tetrazolylmethyl | 2-phenylethyl |
7850 | 3-pyridylmethyl | 2-pyridylmethyl | 2-phenylethyl |
7851 | 4-pyridylmethyl | 3-pyridylmethyl | 2-phenylethyl |
7852 | cyclohexylmethyl | 4-pyridylmethyl | 2-phenylethyl |
7853 | 2-naphthylmethyl | cyclohexylmethyl | 2-phenylethyl |
7854 | 3-naphthylmethyl | 2-naphthylmethyl | 2-phenylethyl |
7855 | 2-thiophenylmethyl | 3-naphthylmethyl | |
7856 | 4-(1- | 2-thiophenylmethyl | 2-phenylethyl |
methyl)piperidinyl)- | |||
methyl | |||
7857 | "(3,4- | 4-(1- | 2-phenylethyl |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | ||
methyl | |||
7858 | 2-thienylmethyl | "(3,4- | 2-phenylethyl |
methylenedioxyphenyl)methyl" | |||
7859 | 4-biphenylmethyl | 2-thienylmethyl | 2-phenylethyl |
7860 | pyrimidinylmethyl | 4-biphenylmethyl | 2-phenylethyl |
7861 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 2-phenylethyl |
7862 | 2- | 2-benzothiazolylmethyl | 2-phenylethyl |
benzothiazolylmethyl | |||
7863 | 2-thiomethylethyl | 2- | 2-phenylethyl |
benzothiophenylmethyl | |||
7864 | 2-thiomethylmethyl | 2-thiomethylethyl | 2-phenylethyl |
7865 | 2-methylpropyl | 2-thiomethylethyl | 2-phenylethyl |
7866 | 2-methylbutyl | 2-methylpropyl | 2-phenylethyl |
7867 | 3-methylbutyl | 2-methylbutyl | 2-phenylethyl |
7868 | cyclopropylmethyl | 3-methylbutyl | 2-phenylethyl |
7869 | cyclobutylmethyl | cyclopropylmethyl | 2-phenylethyl |
7870 | cyclopentylmethyl | cyclobutylmethyl | 2-phenylethyl |
7871 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 2-phenylethyl |
7872 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 2-phenylethyl |
7873 | p-aminophenyl-methyl | p-nitrophenylmethyl | 2-phenylethyl |
7874 | "4-(N,N- | p-aminophenyl-methyl | 2-phenylethyl |
dimethylamino)phenylmethyl" | |||
7875 | benzyl | "4-(N,N- | 3-phenylpropyl |
dimethylamino)phenylmethyl" | |||
7876 | 1-pyrolylmethyl | benzyl | 3-phenylpropyl |
7877 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 3-phenylpropyl |
7878 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 3-phenylpropyl |
7879 | 1-indolylmethyl | 1-imidazolylmethyl | 3-phenylpropyl |
7880 | 1-triazolylmethyl | 1-indolylmethyl | 3-phenylpropyl |
7881 | 1-tetrazolylmethyl | 1-triazolylmethyl | 3-phenylpropyl |
7882 | 2-pyridylmethyl | 1-tetrazolylmethyl | 3-phenylpropyl |
7883 | 3-pyridylmethyl | 2-pyridylmethyl | 3-phenylpropyl |
7884 | 4-pyridylmethyl | 3-pyrdiylmethyl | 3-phenylpropyl |
7885 | cyclohexylmethyl | 4-pyridylmethyl | 3-phenylpropyl |
7886 | 2-naphthylmethyl | cyclohexylmethyl | 3-phenylpropyl |
7887 | 3-naphthylmethyl | 2-naphthylmethyl | 3-phenylpropyl |
7888 | 2-thiophenylmethyl | 3-naphthylmethyl | 3-phenylpropyl |
7889 | 4-(1- | 2-thiophentlmethyl | 3-phenylpropyl |
methyl)piperidinyl- | |||
methyl | |||
7890 | "(3,4- | 4-(1- | 3-phenylpropyl |
methylenedioxyphenyl)methyl" | methylpiperidinyl- | ||
methyl | |||
7891 | 2-thienylmethyl | "(3,4- | 3-phenylpropyl |
methylenedioxyphenyl)methyl" | |||
7892 | 4-biphenylmethyl | 2-thienylmethyl | 3-phenylpropyl |
7893 | pyrimidinylmethyl | 4-biphenylmethyl | 3-phenylpropyl |
7894 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 3-phenylpropyl |
7895 | 2- | 2-benzothiazolylmethyl | 3-phenylpropyl |
benzothiophenylmethyl | |||
7896 | 2-thiomethylethyl | 2- | 3-phenylpropyl |
benzothiophenylmethyl | |||
7897 | 2-thiomethylmethyl | 2-thiomethylethyl | 3-phenylpropyl |
7898 | 2-methylpropyl | 2-thiomethylmethyl | 3-phenylpropyl |
7899 | 2-methylbutyl | 2-methylpropyl | 3-phenylpropyl |
7900 | 3-methylbutyl | 2-methylbutyl | 3-phenylpropyl |
7901 | cyclopropylmethyl | 3-methylbutyl | 3-phenylpropyl |
7902 | cyclobutylmethyl | cyclopropylmethyl | 3-phenylpropyl |
7903 | cyclopentylmethyl | cyclobutylmethyl | 3-phenylpropyl |
7904 | p-hydroxyphenyl-methyl | cyclopentlymethyl | 3-phenylpropyl |
7905 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 3-phenylpropyl |
7906 | p-aminophenyl-methyl | p-nitrophenylmethyl | 3-phenylpropyl |
7907 | "4-(N,N- | p-aminophenyl-methyl | 3-phenylpropyl |
dimethylamino)phenylmethyl" | |||
8073 | benzyl | "4-(N,N- | 2-(1- |
dimethylamino)phenylmethyl" | pyrolyl)ethyl | ||
8074 | 1-pyrolylmethyl | benzyl | 2-(1- |
pyrolyl)ethyl | |||
8075 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8076 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8077 | 1-indolylmethyl | 1-imidazolylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8078 | 1-triazolylmethyl | 1-indolylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8079 | 1-tetrazolylmethyl | 1-triazolylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8080 | 2-pyridylmethyl | 1-tetrazolylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8081 | 3-pyridylmethyl | 2-pyridylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8082 | 4-pyridylmethyl | 3-pyridylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8083 | cyclohexylmethyl | 4-pyridylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8084 | 2-naphthylmethyl | cyclohexylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8085 | 3-naphthylmethyl | 2-naphthylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8086 | 2-thiophenylmethyl | 3-naphthylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8087 | 4-(1- | 2-thiophenylmethyl | 2-(1- |
methyl)piperidinyl- | pyrolyl)ethyl | ||
methyl | |||
8088 | "(3,4- | 4-(1- | 2-(1- |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | pyrolyl)ethyl | |
methyl | |||
8089 | 2-thienylmethyl | "(3,4- | 2-(1- |
methylenedioxyphenyl)methyl" | pyrolyl)ethyl | ||
8090 | 4-biphenylmethyl | 2-thienylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8091 | pyrimidinylmethyl | 4-biphenylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8092 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8093 | 2- | 2-benzothiazolylmethyl | 2-(1- |
benzothiophenylmethyl | pyrolyl)ethyl | ||
8094 | 2-thiomethylethyl | 2- | 2-(1- |
benzothiophenylmethyl | pyrolyl)ethyl | ||
8095 | 2-thiomethylmethyl | 2-thiomethylethyl | 2-(1- |
pyrolyl)ethyl | |||
8096 | 2-methylpropyl | 2-thiomethylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8097 | 2-methylbutyl | 2-methylpropyl | 2-(1- |
pyrolyl)ethyl | |||
8098 | 3-methylbutyl | 2-methylbutyl | 2-(1- |
pyrolyl)ethyl | |||
8099 | cyclopropylmethyl | 3-methylbutyl | 2-(1- |
pyrolyl)ethyl | |||
8100 | cyclobutylmethyl | cyclopropylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8101 | cyclopentylmethyl | cyclobutylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8102 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8103 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 2-(1- |
pyrolyl)ethyl | |||
8104 | p-aminophenyl-methyl | p-nitrophenylmethyl | 2-(1- |
pyrolyl)ethyl | |||
8105 | "4-(N,N- | p-aminophenyl-methyl | 2-(1- |
dimethylamino)phenylmethyl" | pyrolyl)ethyl | ||
8106 | benzyl | "4-(N,N- | 2-(1- |
dimethylamino)phenylmethyl" | imidazolyl)ethyl | ||
8107 | 1-pyrolylmethyl | benzyl | 2-(1- |
imidazolyl)ethyl | |||
8108 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8109 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8110 | 1-indolylmethyl | 1-imidazolylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8111 | 1-triazolylmethyl | 1-indolylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8112 | 1-tetrazolylmethyl | 1-triazolylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8113 | 2-pyridylmethyl | 1-tetrazolylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8114 | 3-pyridylmethyl | 2-pyridylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8115 | 4-pyridylmethyl | 3-pyridylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8116 | cyclohexylmethyl | 4-pyridylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8117 | 2-naphthylmethyl | cyclohexylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8118 | 3-naphthylmethyl | 2-naphthylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8119 | 2-thiophenylmethyl | 3-naphthylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8120 | 4-(1- | 2-thiophenylmethyl | 2-(1- |
methyl)piperidinyl- | imidazolyl)ethyl | ||
methyl | |||
8121 | "(3,4- | 4-(1- | 2-(1- |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | imidazolyl)ethyl | |
methyl | |||
8122 | 2-thienylmethyl | "(3,4- | 2-(1- |
methylenedioxyphenyl)methyl" | imidazolyl)ethyl | ||
8123 | 4-biphenylmethyl | 2-thienylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8124 | pyrimidinylmethyl | 4-biphenylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8125 | 2-benzothioazolylmethyl | pyrimidinylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8126 | 2- | benzothiazolylmethyl | 2-(1- |
benzothiophenylmethyl | imidazolyly)ethyl | ||
8127 | 2-thiomethylmethyl | 2- | 2-(1- |
benzothiophenylmethyl | imidazolyl)ethyl | ||
8128 | 2-thiomehylmethyl | 2-thiomethyl | 2-(1- |
imidazolyl)ethyl | |||
8129 | 2-methylpropyl | 2-thiomethylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8130 | 2-methylbutyl | 2-methylpropyl | 2-(1- |
imidazolyl)ethyl | |||
8131 | 2-methylbutyl | 2-methylbutyl | 2-(1- |
imidazolyl)ethyl | |||
8132 | cyclopropylmethyl | 3-methylbutyl | 2-(1- |
imidazolyl)ethyl | |||
8133 | cyclobutylmethyl | cyclopropylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8134 | cyclopentylmethyl | cyclobutylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8135 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8136 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 2-1- |
imidazolyl)ethyl | |||
8137 | p-aminophenyl-methyl | p-nitrophenylmethyl | 2-(1- |
imidazolyl)ethyl | |||
8138 | "4-(N,N- | p-aminophenyl-methyl | 2-(1- |
dimethylamino)phenylmethyl" | imidazolyl)ethyl | ||
8139 | benzyl | "4-(N,N- | 2-pyridylmethyl |
dimethylamino)phenylmethyl" | |||
8140 | 1-pyrolylmethyl | benzyl | 2-pyridylmethyl |
8141 | 1-pyrazolylmethyl | 1-pyrolylmethyl | 2-pyridylmethyl |
8142 | 1-imidazolylmethyl | 1-pyrazolylmethyl | 2-pyridylmethyl |
8143 | 1-indolylmethyl | 1-imidazolylmethyl | 2-pyridylmethyl |
8144 | 1-triazolylmethyl | 1-indolylmethyl | 2-pyridylmethyl |
8145 | 1-tetrazolylmethyl | 1-triazoylmethyl | 2-pyridylmethyl |
8146 | 2-pyridylmethyl | 1-tetrazolylmethyl | 2-pyridylmethyl |
8147 | 3-pyridylmethyl | 2-pyridylmethyl | 2-pyridylmethyl |
8148 | 4-pyridylmethyl | 3-pyridylmethyl | 2-pyridylmethyl |
8149 | cyclohexylmethyl | 4-pyridylmethyl | 2-pyridylmethyl |
8150 | 2-naphthylmethyl | cyclohexylmethyl | 2-pyridylmethyl |
8151 | 3-naphthylmethyl | 2-naphthylmethyl | 2-pyridylmethyl |
8152 | 2-thiophenylmethyl | 3-naphthylmethyl | 2-pyridylmethyl |
8153 | 4-(1- | 2-thiophenylmethyl | 2-pyridylmethyl |
methyl)piperidinyl- | |||
methyl | |||
8154 | "(3,4- | 4-(1- | 2-pyridylmethyl |
methylenedioxyphenyl)methyl" | methyl)piperidinyl- | ||
methyl | |||
8155 | 2-thienylmethyl | "(3,4- | 2-pyridylmethyl |
methylenedioxyphenyl)methyl" | |||
8156 | 4-biphenylmethyl | 2-thienylmethyl | 2-pyridylmethyl |
8157 | pyrimidinylmethyl | 4-biphenylmethyl | 2-pyridylmethyl |
8158 | 2-benzothiazolylmethyl | pyrimidinylmethyl | 2-pyridylmethyl |
8159 | 2- | 2-benzothiazolylmethyl | 2-pyridylmethyl |
benzothiophenylmethyl | |||
8160 | 2-thiomethylethyl | 2- | 2-pyridylmethyl |
benzothiophenylmethyl | |||
8161 | 2-thiomethylmethyl | 2-thiomethylethyl | 2-pyridylmethyl |
8162 | 2-methylpropyl | 2-thiomethylmethyl | 2-pyridylmethyl |
8163 | 2-methylbutyl | 2-methylpropyl | 2-pyridylmethyl |
8164 | 3-methylbutyl | 2-methylbutyl | 2-pyridylmethyl |
8165 | cyclopropylmethyl | 3-methylbutyl | 2-pyridylmethyl |
8166 | cyclobutylmethyl | cyclopropylmethyl | 2-pyridylmethyl |
8167 | cyclopentylmethyl | cyclobutylmethyl | 2-pyridylmethyl |
8168 | p-hydroxyphenyl-methyl | cyclopentylmethyl | 2-pyridylmethyl |
8169 | p-nitrophenylmethyl | p-hydroxyphenyl-methyl | 2-pyridylmethyl |
8170 | p-aminophenyl-methyl | p-nitrophenylmethyl | 2-pyridylmethyl |
8171 | "4-(N,N- | p-aminophenyl-methyl | 2-pyridylmethyl |
dimethylamino)phenylmethyl" | |||
TABLE 20 | ||||
Ex. | ||||
No. | R4 | R7 | R22 | R23 |
8205 | benzyl | benzyl | 2-methallyl | 2-methallyl |
8206 | 1-pyrolylmethyl | 1-pyrolylmethyl | 4-methylphenyl | 4-methylphenyl |
8207 | 1- | 1- | 3-methallyl | 3-methallyl |
pyrazolylmethyl | pyrazolylmethyl | |||
8208 | 1-imidazolyl | 1-imidazolyl | 3-methylbutyl | 3-methylbutyl |
methyl | methyl | |||
8209 | 1-indolylmethyl | 1-indolylmethyl | 3-methylphenyl | 3-methylphenyl |
8210 | 2-pyridylmethyl | 2-pyridylmethyl | 3-pentyl | 3-pentyl |
8211 | 3-pyridylmethyl | 3-pyridylmethyl | 4-methylphenyl | 4-methylphenyl |
8212 | 4-pyridylmethyl | 4-pyrdiylmethyl | "3,3- | "3,3- |
dimethallyl" | dimethallyl" | |||
8213 | cyclohexyl- | cyclohexylmethyl | "3,3- | "3,3- |
methyl | dimethylbutyl" | dimethylbutyl" | ||
8214 | 2-thiophenyl- | 2- | allyl | allyl |
methyl | thiophenylmethyl | |||
8215 | "(3,4- | "(3,4- | cyclobutyl- | cyclobutyl- |
methylene- | methylene- | methyl | methyl | |
dioxy-phenyl)- | dioxyphenyl)- | |||
methyl" | methyl" | |||
8216 | 2-thienylmethyl | 2-thienylmethyl | cyclopropyl- | cyclopropyl- |
methyl | methyl | |||
8217 | 4- | 4- | isobutyl | isobutyl |
biphenylmethyl | biphenylmethyl | |||
8218 | 2- | 2- | n-butyl | n-butyl |
thiomethylethyl | thiomethylethyl | |||
8219 | p-hydroxy- | p-hydroxy- | n-pentyl | n-pentyl |
phenylmethyl | phenyl-methyl | |||
8220 | p-nitrophenyl- | p-nitrophenyl- | propyl | propyl |
methyl | methyl | |||
8221 | benzyl | benzyl | 2-methallyl | H |
8222 | 1-pyrolylmethyl | 1-pyrolylmethyl | 4-methylphenyl | H |
8223 | 1- | 1- | 3-methallyl | H |
pyrazolylmethyl | pyrazolylmethyl | |||
8224 | 1-imidazolyl- | 1-imidazolyl- | 3-methylbutyl | H |
methyl | methyl | |||
8225 | 1-indolylmethyl | 1-indolylmethyl | 3-methylpentyl | H |
8226 | 2-pyridylmethyl | 2-pyridylmethyl | 3-pentyl | H |
8227 | 3-pyridylmethyl | 3-pyridylmethyl | 4-methylphenyl | H |
8228 | 4-pyridylmethyl | 4-pyridylmethyl | "3,3- | H |
dimethallyl" | ||||
8229 | cyclohexyl- | cyclohexyl- | "3,3- | H |
methyl | methyl | dimethallyl" | ||
8230 | 2-thiophenyl- | 2-thiophenyl- | allyl | H |
methyl | methyl | |||
8231 | "(3,4- | "(3,4- | cyclobutyl- | H |
methylenedioxy- | methylenedioxy- | methyl | ||
phenyl)methyl" | phenyl)methyl" | |||
8232 | 2-thienylmethyl | 2-thienylmethyl | cyclopropyl- | |
methyl | ||||
8233 | 4- | 4- | isobutyl | H |
biphenylmethyl | biphenylmethyl | |||
8234 | 2- | 2- | n-butyl | |
thiomethylethyl | thiomethylethyl | |||
8235 | p- | p- | n-pentyl | H |
hydroxyphenyl- | hydroxyphenyl- | |||
methyl | methyl | |||
8236 | p-nitrophenyl | p-nitrophenyl- | propyl | H |
methyl | methyl | |||
8237 | benzyl | p-nitrophenyl- | 2-methallyl | 2-methallyl |
methyl | ||||
8238 | 1-pyrolylmethyl | benzyl | 4-methylphenyl | 4-methylphenyl |
8239 | 1- | 1-pyrolylmethyl | 3-methallyl | 3-methallyl |
pyrazolylmethyl | ||||
8240 | 1-imidazolyl- | 1- | 3-methylbutyl | 3-methylbutyl |
methyl | pyrazolylmethyl | |||
8241 | 1-indolylmethyl | 1- | 3-methylphenyl | 3-methylphenyl |
imidazolylmethyl | ||||
8242 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl | 3-pentyl |
8243 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylphenyl | 4-methylphenyl |
8244 | 4-pyridylmetyhl | 3-pyrdiylmethyl | "3,3- | "3,3- |
dimethallyl" | dimethallyl" | |||
8245 | cyclohexylmethyl | 4-pyridylmethyl | "3,3- | "3,3- |
dimethylbutyl" | dimethylbutyl" | |||
8246 | 2-thiophenyl- | cyclohexyl- | allyl | allyl |
methyl | methyl | |||
8247 | "(3,4- | 2-thiophenyl- | cyclobutylmethyl | cyclobutylmethyl |
methylenedioxy- | methyl | |||
phenyl)methyl" | ||||
8248 | 2-thienylmethyl | "(3,4- | cyclopropyl- | cyclopropyl- |
methylenedixoy- | methyl | methyl | ||
phenyl)methyl | ||||
8249 | 4- | 2-thienylmethyl | isobutyl | isobutyl |
biphenylmethyl | ||||
8250 | 2- | 4- | n-butyl | n-butyl |
thiomethylmethyl | biphenylmethyl | |||
8251 | p- | 2- | n-pentyl | n-pentyl |
hydroxyphenyl- | thiomethylethyl | |||
methyl | ||||
8252 | p-nitrophenyl- | p- | propyl | propyl |
methyl | hydroxyphenyl- | |||
methyl | ||||
8253 | benzyl | p-nitrophenyl | 2-methallyl | 2-methallyl |
methyl | ||||
8254 | 1-pyrolylmethyl | benzyl | 4-methylpentyl | 4-methylphenyl |
8255 | 1- | 1-pyrolylmethyl | 3-methallyl | 3-methallyl |
pyrazolylmethyl | ||||
8256 | 1-imidazolyl- | 1- | 3-methylbutyl | 2-methylbutyl |
methyl | pyrazolylmethyl | |||
8257 | 1-indolylmethyl | 1-imidazolyl- | 3-methylphenyl | 3-methylphenyl |
methyl | ||||
8258 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl | 3-pentyl |
8259 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylphenyl | 4-methylphenyl |
8260 | 4-pyridylmethyl | 3-pyridylmethyl | "3,3- | "3,3- |
dimethallyl" | dimethyallyl" | |||
8261 | cyclohexylmethyl | 4-pyridylmethyl | "3,3- | "3,3- |
dimethylbutyl" | dimethylbutyl" | |||
8262 | 2-thiophenyl- | cyclohexylmethyl | allyl | allyl |
methyl | ||||
8263 | "(3,4- | 2- | cyclobutylmethyl | cyclobutylmethyl |
methylenedioxy- | thiophenylmethyl | |||
phenyl)methyl" | ||||
8264 | 2-thienylmethyl | "(3,4- | cyclopropyl- | cyclopropyl- |
methylenedioxy- | methyl | methyl | ||
phenyl)methyl" | ||||
8265 | 4- | 2-thienylmethyl | isobutyl | isobutyl |
biphenylmethyl | ||||
8266 | 2- | 4- | n-butyl | n-butyl |
thiomethylphenyl- | biphenylmethyl | |||
methyl | ||||
8267 | p- | 2- | n-pentyl | n-pentyl |
hydroxyphenyl- | thiomethylethyl | |||
methyl | ||||
8268 | p-nitrophenyl- | p- | propyl | propyl |
methyl | hydroxyphenyl- | |||
methyl | ||||
8269 | benzyl | p-nitrophenyl- | 2-methallyl | propyl |
methyl | ||||
8270 | 1-pyrolylmethyl | benzyl | 4-methylphenyl | 2-methallyl |
8271 | 1- | 1-pyrolylmethyl | 3-methallyl | 3-methallyl |
pyrazolylmethyl | ||||
8272 | 1-imidazolyl- | 1- | 3-methylbutyl | 3-methallyl |
methyl | pyrazolylmethyl | |||
8273 | 1-indolylmethyl | 1-imidazoyly- | 3-methylphenyl | 3-methylbutyl |
methyl | ||||
8274 | 2-pyridylmethyl | 1-indolylmethyl | 3-pentyl | 3-methylphenyl |
8275 | 3-pyridylmethyl | 2-pyridylmethyl | 4-methylphenyl | 3-pentyl |
8276 | 4-pyridylmethyl | 3-pyridylmethyl | "3,3- | 4-methylpentyl |
dimethallyl" | ||||
8277 | cyclohexylmethyl | 4-pyridylmethyl | "3,3- | "3,3- |
dimethallyl" | dimethally" | |||
8278 | 2-thiophenyl- | cyclohexyl- | allyl | "3,3- |
methyl | methyl | dimethylbutyl" | ||
8279 | "(3,4- | 2- | cyclobutyl- | allyl |
methylenedioxy- | thiophenylmethyl | methyl | ||
phenyl)methyl" | ||||
8280 | 2-thienylmethyl | "(3,4- | cyclopropyl- | cyclobutylmethyl |
methylenedioxy- | methyl | |||
phenyl)methyl | ||||
8281 | 4- | 2-thienlymethyl | isobutyl | cyclopropyl- |
biphenylmethyl | methyl | |||
8282 | 2- | 4- | n-butyl | isobutyl |
thiomethylethyl | biphenylmethyl | |||
8283 | p- | 2- | n-pentyl | n-butyl |
hydroxyphenyl- | thiomethylethyl | |||
methyl | ||||
8284 | p-nitrophenyl- | p- | propyl | n-pentyl |
methyl | hydroxypehnyl- | |||
methyl | ||||
TABLE 21 | |||
Ex. | |||
No. | R22 | R23 | R4 = R7 |
8285 | (m-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | benzyl |
8286 | (p-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | benzyl |
8287 | (m-hydroxy)benzyl | (m-tetrazolyl)benzyl | benzyl |
8288 | (p-hydroxy)benzyl | (m-tetrazolyl)benzyl | benzyl |
8289 | (m-carboxamido)benzyl | (m-tetrazolyl)benzyl | benzyl |
8290 | (m-(N-methyl | (m-tetrazolyl)benzyl | benzyl |
carboxamido))benzyl | |||
8291 | (m-hydroxymethyl)benzyl | (m-imidaolyl)benzyl | benzyl |
8292 | (p-hydroxymethyl)benzyl | (m-imidaolyl)benzyl | benzyl |
8293 | (m-hydroxy)benzyl | (m-imidaolyl)benzyl | benzyl |
8294 | (p-hydroxy)benzyl | (m-imidaolyl)benzyl | benzyl |
8295 | (m-carboxamido)benzyl | (m-imidaolyl)benzyl | benzyl |
8296 | (m-(N-methyl | (m-imidaolyl)benzyl | benzyl |
carboxamido)benzyl | |||
8297 | (m-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8298 | (p-hydroxymethyl)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8299 | (m-hydroxy)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8300 | (p-hydroxy)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8301 | (m-carboxamido)benzyl | (m-tetrazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8302 | (m-(N-methyl | (m-tetrazolyl)benzyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8303 | (m-hydroxymethyl)benzyl | (m-imidazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8304 | (p-hydroxymethyl)benzyl | (m-imidazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8305 | (m-hydroxy)benzyl | (m-imidazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8306 | (p-hydroxy)benzyl | (m-imidazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8307 | (m-carboxamido)benzyl | (m-imidazolyl)benzyl | (p-fluoro)- |
benzyl | |||
8308 | (m-(N-methyl | (m-imidazolyl)benzyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8309 | (m-carboxy)benzyl | (m-hydroxy)benzyl | benzyl |
8310 | (m-carboxy)benzyl | (p-hydroxy)benzyl | benzyl |
8311 | (m-carboxy)benzyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
8312 | (m-carboxy)benzyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
8313 | (m-carboxy)benzyl | (m-carboxamido) | benzyl |
benzyl | |||
8314 | (m-carboxy)benzyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
8315 | (m-carboxy)benzyl | (m-acetyl)benzyl | benzyl |
8316 | (m-carboxy)benzyl | (m-glycolyl)benzyl | benzyl |
8317 | (m-carboxy)benzyl | (m-sulfonamido) | benzyl |
benzyl | |||
8318 | (m-carboxy)benzyl | (m-(N-methylamino) | benzyl |
benzyl | |||
8319 | (m-carboxamido)benzyl | (m-hydroxy)benzyl | benzyl |
8320 | (m-carboxamido)benzyl | (p-hydroxy)benzyl | benzyl |
8321 | (m-carboxamido)benzyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
8322 | (m-carboxamido)benzyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
8323 | (m-carboxamido)benzyl | (m-carboxamido) | benzyl |
benzyl | |||
8324 | (m-carboxamdio)benzyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
8325 | (m-carboxamido)benzyl | (m-acetyl)benzyl | benzyl |
8326 | (m-carboxamido)benzyl | (m-glycol)benzyl | benzyl |
8327 | (m-carboxamido)benzyl | (m-sulfonamido) | benzyl |
benzyl | |||
8328 | (m-carboxamido)benzyl | (m-(N-methylamino) | benzyl |
benzyl | |||
8329 | (m-(N-methyl | (m-hydroxy)benzyl | benzyl |
carboxamido))benzyl | |||
8330 | (m-(N-methyl | (p-hydroxy)benzyl | benzyl |
carboxamdio))benzyl | |||
8331 | (m-(N-methyl | (m-hydroxymethyl) | benzyl |
carboxamido))benzyl | benzyl | ||
8332 | (m-(N-methyl | (p-hydroxymethyl) | benzyl |
carboxamido))benzyl | benzyl | ||
8333 | (m-(N-methyl | (m-carboxamido) | benzyl |
carboxamido))benzyl | benzyl | ||
8334 | (m-(N-methyl | (m-N-methyl | benzyl |
carboxamido))benzyl | carboxamido))benzyl | ||
8335 | (m-(N-methyl | (m-acetyl)benzyl | benzyl |
carboxamido))benzyl | |||
8336 | (m-(N-methyl | (m-glycol)benzyl | benzyl |
carboxamido))benzyl | |||
8337 | (m-(N-methyl | (m-suldonamido) | benzyl |
carboxamido))benzyl | benzyl | ||
8338 | (m-(N-methyl | (m-(N-methylamino) | benzyl |
carboxamido))benzyl | benzyl | ||
8339 | (m-sulfonamido)benzyl | (m-hydroxy)benzyl | benzyl |
8340 | (m-sulfonamido)benzyl | (m-hydroxybenzyl) | benzyl |
8341 | (m-sulfonamido)benzyl | (m-hydroxymethyl) | benzyl |
benzyl | |||
8342 | (m-sulfonamido)benzyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
8343 | (m-sulfonamido)benzyl | (m-carboxamido) | benzyl |
benzyl | |||
8344 | (m-sulfonamido)benzyl | (m-(N-methyl | benzyl |
carboxamido))benzyl | |||
8345 | (m-sulfonamido)benzyl | (m-acetyl)benzyl | benzyl |
8346 | (m-sulfonamido)benzyl | (m-glycol)benzyl | benzyl |
8347 | (m-sulfonamido)benzyl | (m-sulfonamido) | benzyl |
benzyl | |||
8348 | (m-sulfonamido)benzyl | (m-(N-methylamino) | benzyl |
benzyl | |||
8349 | m-(N-ethylcarboxamido) | (m-hydroxy)benzyl | benzyl |
benzyl | |||
8350 | m-(N-ethylcarboxamido) | (p-hydroxy)benzyl | benzyl |
benzyl | |||
8351 | m-(N-ethylcarboxamido) | (m-hydroxymethyl) | benzyl |
benzyl | benzyl | ||
8352 | m-(N-ethylcarboxamido) | (p-hydroxymethyl) | benzyl |
benzyl | benzyl | ||
8353 | m-(N-ethylcarboxamido) | (m-carboxamdio) | benzyl |
benzyl | benzyl | ||
8354 | m-(N-ethylcarboxamido) | (m-(N-methyl | benzyl |
benzyl | carboxamido)benzyl | ||
8355 | m-(N-ethylcarboxamido) | (m-acetyl)benzyl | benzyl |
benzyl | |||
8356 | m-(N-ethylcarboxamido) | (m-glycolyl)benzyl | benzyl |
benzyl | |||
8357 | m-(N-ethylcarboxamido) | (m-sulfonamido) | benzyl |
benzyl | benzyl | ||
8358 | m-(N-ethylcarboxamido) | (m-methylamino) | benzyl |
benzyl | benzyl | ||
8359 | 3-pyridylmethyl | (m-hydroxy)benzyl | benzyl |
8360 | 3-pyridylmethyl | (p-hydroxy)benzyl | benzyl |
8361 | 3-pyridylmethyl | (m-hydroxymethyl | benzyl |
benzyl | |||
8362 | 3-pyridylmethyl | (p-hydroxymethyl) | benzyl |
benzyl | |||
8363 | 3-pyridylmethyl | (m-cabroxamido) | benzyl |
benzyl | |||
8364 | 3-pyridylmethyl | (m-(N-methyl | benzyl |
carboxmaido)benzyl | |||
8365 | 3-pyridylmethyl | (m-acetyl)benzyl | benzyl |
8366 | 3-pyridylmethyl | (m-glycol)benzyl | benzyl |
8367 | 3-puridylmethyl | (m-sulfonamido) | benzyl |
benzyl | |||
8368 | 3-pyridylmethyl | (m-(N-mtehylamino) | benzyl |
benzyl | |||
8369 | (m-carboxy)benzyl | (m-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8370 | (m-carboxy)benzyl | (p-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8371 | (m-carboxy)benzyl | (m-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8372 | (m-carboxy)benzyl | (p-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8373 | (m-carboxy)benzyl | (m-carboxamido) | (p-fluoro)- |
benzyl | benzyl | ||
8374 | (m-carboxy)benzyl | (m-(N-methyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8375 | (m-carboxy)benzyl | (m-acetyl)benzyl | (p-fluoro)- |
benzyl | |||
8376 | (m-carboxy)benzyl | (m-glycolyl)benzyl | (p-fluoro)- |
benzyl | |||
8377 | (m-carboxy)benzyl | (m-sulfonamido) | (p-fluoro)- |
benzyl | benzyl | ||
8378 | (m-carboxy)benzyl | (m-(M-methylamino) | (p-fluoro)- |
benzyl | benzyl | ||
8379 | (m-carboxamido)benzyl | (m-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8380 | (m-carboxamido)benzyl | (p-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8381 | (m-carboxamido)benzyl | (m-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8382 | (m-carboxamido)benzyl | (p-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8383 | (m-carboxamido)benzyl | (m-carboxamido) | (p-fluoro)- |
benzyl | benzyl | ||
8384 | (m-carboxamido)benzyl | (m-carboxamido) | (p-fluoro)- |
benzyl | benzyl | ||
8385 | (m-carboxamido)benzyl | (m-acetyl)benzyl | (p-fluoro)- |
benzyl | |||
8386 | (m-carboxamido)benzyl | (m-glycolyl)benzyl | (p-fluoro)- |
benzyl | |||
8387 | (m-carboxamido)benzyl | (m-sulfonamido) | (p-fluoro)- |
benzyl | benzyl | ||
8378 | (m-carboxamido)benzyl | (m-(N-methylamino) | (p-fluoro)- |
benzyl | benzyl | ||
8389 | (m-(N-methyl | (m-hydroxy)benzyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8390 | (m-(N-methyl | (p-hydroxy)benzyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8391 | (m-(N-methyl | (m-hydroxymethyl) | (p-fluoro)- |
carboxamido))benzyl | benzyl | benzyl | |
8392 | (m-(N-methyl | (p-hydroxymethyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | benzyl | |
8393 | (m-(N-methyl | (m-carboxamido) | (p-fluoro)- |
carboxamido))benzyl | benzyl | benzyl | |
8394 | (m-(N-methyl | (m-(N-methyl | (p-fluoro)- |
carboxamido))benzyl | carboxamido))benzyl | benzyl | |
8395 | (m-(N-methyl | (m-acetyl)benzyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8396 | (m-(N-methyl | (m-glycolyl)benzyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8397 | (m-(N-methyl | (m-sulfonamido) | (p-fluoro)- |
carboxamido))benzyl | benzyl | benzyl | |
8398 | (m-(N-methyl | (m-(N-methylamino) | (p-fluoro)- |
carboxamido))benzyl | benzyl | benzyl | |
8399 | (m-sulfonamido)benzyl | (m-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8400 | (m-sulfonamido)benzyl | (p-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8401 | (m-sulfonamido)benzyl | (m-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8402 | (m-sulfonamido)benzyl | (p-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8403 | (m-sulfonamido)benzyl | (m-carboxamido) | (p-fluoro)- |
benzyl | benzyl | ||
8404 | (m-sulfonamido)benzyl | (m-(N-methyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8405 | (m-sulfonamido)benzyl | (m-acetyl)benzyl | (p-fluoro)- |
benzyl | |||
8406 | (m-sulfonamido)benzyl | (m-glycolyl)benzyl | (p-fluoro)- |
benzyl | |||
8407 | (m-sulfonamido)benzyl | (m-sulfonamido) | (p-fluoro)- |
benzyl | benzyl | ||
8408 | (m-sulfonamido)benzyl | (m-(N-methylamino) | (p-fluoro)- |
benzyl | benzyl | ||
8409 | (m-(N-ethylcarboxamido) | (m-hydroxy)benzyl | (p-fluoro)- |
benzyl | benzyl | ||
8410 | (m-(N-ethylcarboxamido) | (p-hydroxy)benzyl | (p-fluoro)- |
benzyl | benzyl | ||
8411 | (m-(N-ethylcarboxamido) | (m-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | benzyl | |
8412 | (m-(N-ethylcarboxamido) | (p-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | benzyl | |
8413 | (m-(N-ethylcarboxamido) | (m-carboxamido) | (p-fluoro)- |
benzyl | benzyl | benzyl | |
8414 | (m-(N-ethylcarboxamido) | (m-(N-methyl | (p-fluoro)- |
benzyl | carboxamido)benzyl | benzyl | |
8415 | (m-(N-ethylcarboxamido) | (m-acetyl)benzyl | (p-fluoro)- |
benzyl | benzyl | ||
8416 | (m-(N-ethylcarboxamido) | (m-glycolyl)benzyl | (p-fluoro)- |
benzyl | benzyl | ||
8417 | (m-(N-ethylcarboxamido) | (m-sulfonamido) | (p-fluoro)- |
benzyl | benzyl | benzyl | |
8418 | (m-(N-ethylcarboxamido) | (m-)N-methylamino) | (p-fluoro)- |
benzyl | benzyl | benzyl | |
8419 | 3-pyridylmethyl | (m-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8420 | 3-pyridylmethyl | (p-hydroxy)benzyl | (p-fluoro)- |
benzyl | |||
8421 | 3-pyridylmethyl | (m-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8422 | 3-pyridylmethyl | (p-hydroxymethyl) | (p-fluoro)- |
benzyl | benzyl | ||
8423 | 3-pyridylmethyl | (m-carboxamido) | (p-fluoro)- |
benzyl | benzyl | ||
8424 | 3-pyridylmethyl | (m-(N-methyl | (p-fluoro)- |
carboxamido))benzyl | benzyl | ||
8425 | 3-pyridylmethyl | (m-acetyl)benzyl | (p-fluoro)- |
benzyl | |||
8426 | 3-pyridylmethyl | (m-glycolyl)benzyl | (p-fluoro)- |
benzyl | |||
8427 | 3-pyrdiylmethyl | (m-sulfonamido) | (p-fluoro)- |
benzyl | benzyl | ||
8428 | 3-pyrdiylmethyl | (m-(N-methylamino) | (p-fluoro)- |
benzyl | benzyl | ||
Rodgers, James D., Jadhav, Prabhakar K., De Lucca, George V., Lam, Patrick Y., Eyermann, Charles J., Hodge, Carl N.
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